Urogenital Infections

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Urogenital Infections
Edition 2010

Editors
Kurt G. Naber
Anthony J. Scaeffer
Chris F. Heyns
Tetsuro Matsumoto
Daniel A. Shoskes
Truls E. Bjerklund Johansen
European Association of Urology
Mr. E.N. van Kleffenstraat 5, PO Box 30016, 6803 AA Arnhem, The Netherlands

First edition 2010

Copyright © 2010 European Association of Urology – International Consultation on Urological Diseases.

All rights reserved

No part of this publication may be reproduced, stored in a retrieval system, or transmitted by any means,
electronic, mechanical or photocopying without explicit permission from the copyright holder

No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a
matter of products liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in
particular, independent verification of diagnoses and drug dosages should be made

ISBN: 978-90-79754-41-0

Printed by Grafos, Spain

Cover illustration with thanks to:

Urban Sester, MD, PhD
Department of Internal Medicine IV
for Nephrology and Hypertension
Kirrberger Str., Bld. 6, Room. 1221
University Hospital Saarland
D-66421 Homburg/Saar, Germany
 We would like to thank Ms Jen Tidman

for all of her editorial help and support in

producing this book

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 Contents

Foreword ................................................xiii 2. Aetiology, antimicrobial resistance

Paul Abrams, Christopher Chapple of uropathogens, antibiotic therapy
and policy ................................................ 69
Preface and Introduction ....................... xv
Chair: Gunnar Kahlmeter
Kurt G. Naber, Anthony J. Schaeffer, Chris F.
Heyns, Tetsuro Matsumoto, Daniel A. Shoskes, 2.1 Introduction ............................... 70
Truls E. Bjerklund Johansen Gunnar Kahlmeter
2.2 Uncomplicated and community
acquired urinary tract infections:
1. Pathogenesis of urinary tract aetiology and resistance ............ 72
infections ................................................... 1 Martin Sundquist, Gunnar Kahlmeter
Chair: Anthony J. Schaeffer 2.3 Complicated and healthcare
1.1 Introduction ................................. 2 associated urinary tract infections:
Anthony J. Schaeffer
aetiology and antimicrobial
1.2 Uropathogens and resistance ................................... 82
virulence factors .......................... 4 Martin Sundquist, Gunnar Kahlmeter
Ulrich Dobrindt, Jörg Hacker
2.4 Methicillin-resistant
1.3 Immunity, genetics and Staphylococcus aureus
susceptibility to urinary tract (MRSA) in urology ..................... 92
infection ..................................... 23 Satoshi Takahashi
Björn Wullt, Bryndis Ragnarsdottir,
2.5 ESBL and multi-resistance in
Hans Fischer, Jenny Grönberg-
Hernandez, Nataliya Lutay, urology ..................................... 102
Catharina Svanborg Tetsuro Muratani
1.4 Induction and modulation 2.6 Antimicrobials in urogenital
of host responses by infections .................................. 111
Florian M.E. Wagenlehner, Björn Wullt,
uropathogenic Escherichia Gianpaolo Perletti
coli structures ............................ 32
David J. Klumpp, Anthony J.
2.7 Antibiotic policy ...................... 127
Inge C. Gyssens
Schaeffer
1.5 Immunology of the
3. Urinary tract infections in special groups
urinary tract .............................. 42 of adult patients ................................... 147
Hartwig W. Bauer, Wolfgang G.
Bessler Chair: Kurt G. Naber
1.6 The role of biofilm infection in 3.1 Introduction ............................. 148
Kurt G. Naber
urogenital infections ................. 57
Peter Tenke, Bela Koves, Shinya 3.2 Diagnosis of uncomplicated
Uehara, Hiromi Kumon, Scott J. urinary tract infections ........... 151
Hultgren, Chia Hung Richard Colgan, Samantha Hyner,

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Contents
Stephanie Chu
3.3 The quantitative urine
culture for the diagnosis of
urinary tract infection ............. 160
Lindsay E. Nicolle
3.4 Antibiotic treatment of
uncomplicated urinary tract
infection in premenopausal
women ...................................... 170
Kurt G. Naber, Björn Wullt, Florian
M.E. Wagenlehner
3.5 Urinary tract infections in
pregnancy ................................ 200
Alexander D. Griffin, Richard Grady,
Thomas M. Hooton
3.6 Urinary tract infections in
patients with diabetes
mellitus .................................... 216
Suzanne E. Geerlings
3.7 Urinary tract infections in
postmenopausal women .......... 225
Raul Raz
4. Prevention of recurrent urogenital
tract infections in adult women .......... 235
Chair: Thomas M. Hooton
4.1 Introduction ............................. 236
Thomas M. Hooton
4.2 Antimicrobial prophylaxis in
women with recurrent
urinary tract infections ........... 240
Paola Lichtenberger, Thomas M. Hooton
4.3 Immunoactive prophylaxis of
uncomplicated recurrent
urinary tract infections ........... 252
Kurt G. Naber, Yong-Hyun Cho,
Tetsuro Matsumoto, Anthony J. Schaeffer
4.4 Use of cranberry for prophylaxis
of uncomplicated recurrent
urinary tract infections ........... 269
Henry Botto
4.5 Probiotics for the prophylaxis of
uncomplicated recurrent urinary
tract infections in females....... 278
Peter Cadieux, Gregor Reid
4.6 Prevention of prematurity by
early diagnosis and treatment
of bacterial urogenital
infections – the role of
bacterial vaginosis ................... 288
Udo B. Hoyme
viii
5. Asymptomatic bacteriuria .................... 299
Chair: Lindsay E. Nicolle
5.1 Introduction – The evolution
of asymptomatic bacteriuria .... 300
Lindsay E. Nicolle
5.2 Asymptomatic bacteriuria – to
treat or not to treat ................. 303
Lindsay E. Nicolle
5.3 Asymptomatic bacteriuria with
the model strain Escherichia
coli 83972 protects against
symptomatic urinary tract
infections .................................. 314
Björn Wullt, Fredrik Sundén
6. Urinary tract infections in children ...... 319
Chair: Rien J.M. Nijman
6.1 Introduction ............................. 320
Rien J.M. Nijman
6.2 Classification of urinary tract
infections in children............... 323
Chang-Hee Han, Sang Don Lee
6.3 Diagnostic work-up of urinary
tract infections in children...... 328
Martin Westenfelder, Rolf Beetz
6.4 Antimicrobial therapy of urinary
tract infections in children...... 344
Rolf Beetz, Martin Westenfelder
6.5 Non-operative urological
management of urinary tract
infections in children............... 363
Stephen Shei-Dei Yang, Shang-Jen
Chang
6.6 Medical therapy versus
surgery in vesicoureteral
reflux from the view of the
paediatrician ............................ 374
Rolf Beetz
6.7 Vesico-ureteral reflux: An
American pediatric urologic
perspective ............................... 392
Richard Grady, Martin Koyle
7. Urinary tract infections in
nephropathies, transplant patients
and immunosupression ........................ 401
Chair: Michael C. Bishop
7.1 Introduction ............................. 402
Michael C. Bishop
 Contents

7.2 Emphysematous 9.3 Urinary catheters and drainage

pyelonephritis .......................... 404 systems: prevention and
Kiyohito Ishikawa treatment of urinary
7.3 Renal abscesses ....................... 413 tract infections ....................... 532
Kiyohito Ishikawa Peter Tenke, Bela Koves, Karoly Nagy
7.4 Polycystic renal disease .......... 419 9.4 Evolution of catheter material
Tamara Perepanova, Oleg Apolikhin for prevention of catheter-
7.5 Urinary tract infections associated urinary tract
in renal insufficiency and infections.................................. 541
dialysis ..................................... 426 U-Syn Ha, Yong-Hyun Cho
Reinhard Fünfstück, Kurt G. Naber, 9.5 Infections associated with the
Michael C. Bishop
artificial urinary sphincter ... 549
7.6 Urogenital infections in renal Alexander von Bargen, Margit Fisch
transplant patients – causes 9.6 Infections associated with
and consequences .................... 438 penile prostheses ................... 554
Daniel A. Shoskes, Ismail R. Saad Bela Koves, Peter Tenke, Karoly Nagy

8. Urinary tract infections in patients 10. Healthcare associated urinary tract

with underlying urological infections ............................................... 563
abnormalities ........................................ 449 Chair: Truls E. Bjerklund Johansen
Chair: Chris F. Heyns
10.1 Introduction ........................... 564
8.1 Introduction ............................. 450 Truls E. Bjerklund Johansen
Chris F. Heyns
10.2 Criteria for healthcare associated
8.2 Urinary tract infections in urinary tract infections: an
obstruction of the EAU/ESIU update on current
urinary tract ............................ 452 definitions ............................... 567
Chris F. Heyns Truls Bjerklund Johansen,
8.3 Urinary tract infections in Henry Botto, Mete Cek, Magnus Grabe,
patients with urolithiasis........ 481 Peter Tenke, Florian M.E. Wagenlehner,
Gianpaolo Zanetti, Alberto Trinchieri Kurt G. Naber
8.4 Epidemiology, diagnosis and 10.3 Epidemiology, treatment and
treatment of urinary tract prevention of healthcare-
infections in patients with associated urinary tract
spina bifida .............................. 497 infections ................................ 575
Dan Wood, Christopher Woodhouse Florian M.E. Wagenlehner, Mete Cek,
8.5 Urinary tract infections in Hiroshi Kiyota, Truls E. Bjerklund-
Johansen
patients with neurogenic
bladder ..................................... 507 10.4 Urinary tract infection in
James Salerno, Diana D. Cardenas long term care patients ......... 589
Lindsay E. Nicolle

9. Device associated urinary tract

infections ............................................... 519 11. Urosepsis ............................................... 601
Chair: Peter Tenke Chair: Bernhard Lobel
9.1 Introduction ............................. 520 11.1 Introduction ........................... 602
Peter Tenke Pierre Tattevin, Matthieu Revest,
9.2 Urinary catheters and Bernhard Lobel
drainage systems: definition, 11.2 Pathogenesis of sepsis as
epidemiology and risk factors ... 522 related to novel therapeutic
Paul A. Tambyah, Dariusz P. Olszyna, concepts .................................. 604
Peter Tenke, Bela Koves Evangelos J. Giamarellos-Bourboulis

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Contents
11.3 Urosepsis – from the view
of the intensivist .................... 615
Lifen Li, Bin Ouyang, Weide Zhong,
Xiangdong Guan
11.4 Urosepsis – from the view
of the urologist ....................... 630
Florian M.E. Wagenlehner, Adrian
Platz, Wolfgang Weidner
12. Prevention of infections associated
with urological surgery ........................ 645
Chair: Magnus Grabe
12.1 Introduction ........................... 646
Magnus Grabe
12.2 Hygiene and education .......... 649
Bong-Suk Shim
12.3 Sterilisation and disinfection
of urological instruments
for endoscopy and for
prostate biopsy ....................... 660
Shingo Yamamoto, Ryoichi Hamasuna
12.4 Preoperative assessment
of the patient, risk factors
identification and tentative
classification of surgical field
contamination in urologic
surgery ................................... 667
Magnus Grabe, Henry Botto, Mete
Cek, Peter Tenke, Florian M.E.
Wagenlehner, Kurt G. Naber,
Truls E. Bjerklund Johansen
12.5 Antibiotic prophylaxis
in urological surgery, a
European viewpoint............... 686
Magnus Grabe
12.6 Antibiotic prophylaxis in
urological surgery: a USA
viewpoint of best practice ...... 699
Anthony J. Schaeffer, J. Stuart
Wolf Jr, Carol J. Bennett, Roger R.
Dmochowski, Brent K. Hollenbeck,
Margaret S. Pearle
13. Epididymitis, orchitis, prostatitis
(male adnexitis) .................................... 711
Chair: Wolfgang Weidner
13.1 Introduction ........................... 712
Wolfgang Weidner
13.2 Acute bacterial prostatitis ..... 714
U-Syn Ha, Yong-Hyun Cho
x
13.3 Treatment of chronic
bacterial prostatitis ............... 728
Florian M.E. Wagenlehner, John N.
Krieger
13.4 Epididymitis and orchitis ...... 744
Thorsten Diemer, Florian M.E.
Wagenlehner, Wolfgang Weidner
13.5 Chronic urogenital
infections: alterations of
sperm quality and potential
impact on male fertility ......... 752
Wolfgang Weidner, Thorsten Diemer
14. Sexually transmitted infectious
diseases ................................................. 763
Chair: John N. Krieger
14.1 Introduction ........................... 764
John N. Krieger
14.2 Sexually transmitted infectious
diseases (STDs): updated
synopsis for practicing
urologists ................................ 765
Peter Schneede, Boris Schlenker
14.3 Urethritis ............................... 777
Ryoichi Hamasuna, Hiromasa
Tsukino
14.4 Pelvic infections in women .... 804
Gilbert G.G. Donders, Jasper Verguts
14.5 HIV Infection in urological
practice ................................... 830
Seung-Ju Lee
14.6 Male circumcision and HIV
infection risk .......................... 847
John N. Krieger
15. Special urogenital infections................ 861
Chair: Tetsuro Matsumoto
15.1 Introduction ........................... 862
Tetsuro Matsumoto
15.2 Urinary tuberculosis.............. 864
Severin Lenk, Mitsuru Yasuda
15.3 Male genital tuberculosis ...... 877
Ekaterina Kulchavenya,
Chul-Sung Kim
15.4 Genitourinary tuberculosis
in a developing country
(Vietnam): diagnosis and
treatment ............................... 892
Chuyen Vu Le, Nguyen Phuc
Cam Hoang

15.5 Guidelines for the treatment
of fungal urinary tract
infections .............................. 903
Jack D. Sobel, John Fisher,
Carol A. Kauffman
15.6 Vulvovaginal candidosis ...... 912
Werner Mendling
15.7 Viral genitourinary
infections .............................. 928
Laurent Vaucher, Darius A. Paduch
15.8 Genitourinary
schistosomiasis .................... 943
Ismail Khalaf, Ahmed A. Shokeir
15.9 Brucellosis: genitourinary
involvement ......................... 959
Ziad A. Memish, Georgios Pappas
15.10 Echinococcus/hydatid
disease: genitourinary
involvement ......................... 968
Georgios Pappas, Ziad A. Memish
Contents
16. Classification of urinary tract
infections ............................................... 979
Chair: Truls E. Bjerklund Johansen
16.1 Critical review of current
definitions of urinary
tract infections and
proposal of an EAU/ESIU
classification system ............ 980
Truls E. Bjerklund Johansen,
Henry Botto, Mete Cek, Magnus
Grabe, Peter Tenke, Florian M.E.
Wagenlehner, Kurt G. Naber
References ............................................ 993
xi
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 Foreword

The International Consultation on Urological Diseases (ICUD) was formed as a non-

governmental organization registered with the World Health Organization (WHO).
The ICUD has been responsible, with other professional organizations such as the
EAU and SIU, for more than 30 consultations on urological topics ranging from Penile
Cancer to Urological Trauma. The ICUD has modified the widely accepted Oxford
Centre for Evidence Based Medicine adaptation of the Agency for Health Care Policy
and Research (AHCPR) recommendations, thus allowing direct ‘mapping’ onto the
Oxford system [1]. The ICUD EBM method is now being used for ICUD Consultations.
The ICUD, through its vice-chairman Paul Abrams, with the co-operation of
the European Association of Urology (EAU), represented by Chris Chapple, asked
Kurt G. Naber to chair an International Consultation on Urogenital Infections. This
Consultation was held during the EAU Congress in March 2009 in Stockholm, in
cooperation with the European Section of Infection in Urology (ESIU), represented
by Truls E. Bjerklund Johansen, and other scientific societies, such as the Asian
Association of UTI/STD, represented by Tetsuro Matsumoto, the Society of Infection
and Inflammation in Urology (SIIU), represented by Daniel Shoskes, and the UTI
Commission of the International Society of Chemotherapy for Infection and Cancer
(ISC), represented by Kurt G. Naber.
This book provides the current state of the art knowledge about urogenital infec-
tions provided by international experts in their fields to assist not only urologists, but
also physicians from other medical specialities in their daily practice. All the recom-
mendations provided in the textbook followed the principle of evidence-based medi-
cine and a structured consensus process. We are delighted to recommend this book
as a milestone in recording the progress and research plans in the field of Urogenital
Infections.

Christopher Chapple
Paul Abrams
Adjunct General Secretary of the EAU
Chair of the ICUD

REFERENCE

1. Abrams P, Khoury S, and Grant A, Evidence – based medicine overview of the main steps
for developing and grading guideline recommendations. Prog Urol, 2007. 17(3): 681–4.

xiii
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 Preface and
Introduction

Urinary tract infections (UTIs) are among the most prevalent infectious diseases with
a substantial financial burden on society. Unfortunately, there are no good data con-
cerning the prevalence of various types of UTIs and their impact on the quality of life
of the affected population in Europe.
In the USA, UTIs are responsible for over 7 million physician visits annually,
including more than 2 million visits for cystitis [1]. Approximately 15% of all com-
munity-prescribed antibiotics in the USA are dispensed for UTI, at an estimated
annual cost of over US $1 billion [2]. Furthermore, the direct and indirect costs asso-
ciated with community-acquired UTIs in the USA alone exceed an estimated US $1.6
billion [1].
UTIs account for more than 100,000 hospital admissions annually, most often for
pyelonephritis [1]. They also account for at least 40% of all hospital-acquired infections
and are in the majority of cases catheter-associated [2]. Nosocomial bacteriuria devel-
ops in up to 25% of patients requiring a urinary catheter for > 7 days, with a daily risk
of 5% [3]. It has been estimated that an episode of nosocomial bacteriuria adds US
$500–1,000 to the direct cost of acute-care hospitalization [4]. In addition, the path-
ogens are fully exposed to the nosocomial environment, including selective pressure
by antibiotic or antiseptic substances. Nosocomial UTIs therefore comprise perhaps
the largest institutional reservoir of nosocomial antibiotic-resistant pathogens [3].
Therefore, prevention and best management of nosocomial UTI must have highest
priority worldwide in daily practice and research [5–6].

INTERNATIONAL CONSULTATION ON UROGENITAL INFECTIONS

The International Consultation on Urogenital Infections was initiated by the

International Consultation on Urological Diseases (ICUD), a non-governmental organ-
ization, and the European Association of Urology (EAU) during the EAU Congress on
March 25, 2008 in Milan, Italy, in cooperation with the European Section of Infection
in Urology (ESIU – a full section of the EAU) represented by Truls E. Bjerklund
Johansen, and other scientific societies, such as the Asian Association of UTI/STD,
represented by Tetsuro Matsumoto, the Society of Infection and Inflammation in
Urology (SIIU), represented by Daniel A. Shoskes, and the UTI Commission of the

xv
Preface and Introduction

International Society of Chemotherapy for Infection and Cancer (ISC), represented by

Kurt G. Naber. The aim was to provide the current state of the art knowledge about
urogenital infections in a textbook as a consensus of international experts in their
fields to assist not only urologists, but also physicians from other medical specialities
in their daily practice.

METHODS

The numerous aspects of urogenital infections were structured in 16 sections, cover-

ing the most important issues in this field. Each section was chaired by one expert,
who also assisted to identify other experts for the corresponding section. Each section
was then divided into several chapters, taking care that the experts (reporters) respon-
sible for each chapter came from different parts of the world. As far as appropriate
for each chapter a structured literature search was performed and the criteria used
were presented. The studies cited from the literature were rated according to the level
of evidence and the strength of the recommendations was graded accordingly (Tables
1 and 2). Each chapter was exposed to a vigorous consensus discussion within each
section and updated with the discussion and comments of the group as necessary. After
the consensus process in the sections all manuscripts were placed at the disposal of
all experts involved in this process. Finally, in a consensus conference held on March
17, 2009 in Stockholm, Sweden, to which all experts involved in this process had free
access, the overall concept and (within the sections) the detailed concept and recom-
mendations were again discussed until final consensus was reached. Thereafter all
manuscripts were edited in cooperation with the corresponding chairpersons. In the
last chapter a proposal for an updated classification of urinary tract infections is pre-
sented for further discussion, research and evaluation. All the recommendations

Table 1 Levels of evidence and grades of recommendations, according to [7].

Level Type of evidence

1a Evidence obtained from meta-analysis of randomized trials

1b Evidence obtained from at least one randomized trial

2a Evidence obtained from one well-designed controlled study without randomisation

2b Evidence obtained from at least one other type of well-designed quasi-experimental study

3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies
and case reports

4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities

Grade Nature of recommendation

A Based on clinical studies of good quality and consistency addressing the specific recommendations and including
at least one randomized trial

B Based on well-conducted clinical studies, but without randomized clinical trials

C Made despite the absence of directly applicable clinical studies of good quality

xvi
 Preface and Introduction

provided in the textbook followed the principle of evidence-based medicine and a struc-
tured consensus process.

LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION

For the rating of the level of evidence and the grade of recommendation the follow-
ing system was used according to the Agency for Health Care Policy and Research
(AHCPR) using the ICUD modifications [7–8] as mentioned below.
The following ICUD modifications for grading the recommendations were used [8]:

Grade A recommendation (highly recommended) usually depends on consistent

level 1 evidence and often means that the recommendation is effectively manda-
tory and placed within a clinical care pathway. However, there will be occasions
where excellent evidence (level 1) does not lead to a Grade A recommendation, for
example, if the therapy is prohibitively expensive, dangerous or unethical. Grade A
recommendation can also follow from Level 2 evidence. However, a Grade A recom-
mendation needs a greater body of evidence if based on anything except Level 1
evidence.
Grade B recommendation (recommended) usually depends on consistent level
2 and/or 3 studies, or ‘majority evidence’ from randomized clinical trials.
Grade C recommendation (optional) usually depends on level 4 studies or ‘majority
evidence’ from level 2/3 studies or Delphi processed expert opinion.
Grade D recommendation (no recommendation is possible) could be used where the
evidence is inadequate or conflicting and when expert opinion is delivered without a
formal analytical process, such as by Delphi.

We would like to thank ICUD and EAU for providing this opportunity, all authors
for contributing to this textbook, Silvia de Bruin for organisational assistance and Jen
Tidman for editing the manuscripts.
We hope that by unifying forces we were able to provide the most important knowl-
edge for our colleagues in an easily accessible way to improve their daily practice and
we also hope that we have initiated better international cooperation to improve basic
and clinical research in this very important field for the benefit of our patients.
Stockholm, Sweden, March 2009

Kurt G. Naber (Chair) Anthony J. Schaeffer Chris F. Heyns

Straubing Chicago, Illinois Tygerberg
Germany USA South Africa

Tetsuro Matsumoto Daniel A. Shoskes Truls E. Bjerklund

Johansen
Kitakyushu Cleveland, Ohio Aarhus
Japan USA Denmark

xvii
Preface and Introduction

REFERENCES

1. Foxman B, Epidemiology of urinary tract infections: incidence, morbidity, and economic

costs. Am J Med, 2002. 113 Suppl 1A: 5S–13S.
2. Ruden H, Gastmeier P, Daschner FD, and Schumacher M, Nosocomial and community-
acquired infections in Germany. Summary of the results of the First National Prevalence
Study (NIDEP). Infection, 1997. 25(4): 199–202.
3. Maki DG and Tambyah PA, Engineering out the risk for infection with urinary catheters.
Emerg Infect Dis, 2001. 7(2): 342–7.
4. Patton JP, Nash DB, and Abrutyn E, Urinary tract infection: economic considerations. Med
Clin North Am, 1991. 75(2): 495–513.
5. Johansen TE, Cek M, Naber KG, Stratchounski L, Svendsen MV, and Tenke P, Hospital
acquired urinary tract infections in urology departments: pathogens, susceptibility and use
of antibiotics. Data from the PEP and PEAP-studies. Int J Antimicrob Agents, 2006.
28 Suppl 1: S91–107.
6. Bjerklund Johansen TE, Cek M, Naber K, Stratchounski L, Svendsen MV, and Tenke P,
Prevalence of hospital-acquired urinary tract infections in urology departments. Eur Urol,
2007. 51(4): 1100–11; discussion 1112.
7. U.S. Department of Health and Human Services Public Health Service Agency for Health
Care Policy and Research, 1992: 115–127.
8. Abrams P, Khoury S, and Grant A, Evidence – based medicine overview of the main steps
for developing and grading guideline recommendations. Prog Urol, 2007. 17(3): 681–4.

xviii
 Chapter |1|

Pathogenesis of urinary
tract infections
Chair: Anthony J. Schaeffer

CHAPTER OUTLINE
1.1 Introduction 2
1.2 Uropathogens and virulence factors 4
1.3 Immunity, genetics and susceptibility to urinary
tract infections 23
1.4 Induction and modulation of host responses by
uropathogenic Escherichia coli structures 32
1.5 Immunology of the urinary tract 42
1.6 The role of biofilm infection in urogenital infections 57
|1.1|
Introduction
Anthony J. Schaeffer
Department of Urology, Feinberg School of Medicine, Northwestern University
303 East Chicago Avenue, Chicago, Illinois 60611, USA
Phone: (312) 908-1615, Fax: (312) 908-7275, E-mail: jmz@northwestern.edu
Host pathogen interactions play a pivotal
role in the initiation and development
of urinary tract infections. The con-
stant interplay involves bacterial viru-
lence and host defense factors and the
site and degree of infection is dictated by
which component gains the upper hand.
Dobrindt and Hacker review a variety of
virulence-associated factors that are most
likely spatially and temporally regulated.
Among the initial virulence factors are
adhesins which function not only to pro-
mote adherence but also are involved in
signaling between microorganisms and
epithelial cells. Flagella promote move-
ment of bacteria within the urinary tract.
A variety of other pathogens such as LPS
protect bacterial pathogens against the
host immune system. The host response
to this attack is effective through the
innate immune system.
As outlined by Wullt et al., in resistant
hosts bacteriuria is transient, and com-
plete clearance of infection is achieved
by urine flow, mucosal microbicidal mole-
cules like defensins and recruited inflam-
matory cells. They indicate that persistent
infections engage a more complex host
defense which is controlled by different
receptors and signaling pathways includ-
ing TOLL-like receptors that are criti-
cal for the innate immune response and
to initiate the defense against uropatho-
gens. The response is surprisingly low for
cystitis and asymptomatic bacteriuria,
but for acute pyelonephritis and urosepsis
an exaggerated innate immune response
is effective which can result in renal scar-
ring. Chemokine receptor function is also
critical for the innate response and it is
now apparent that genetic factors influ-
ence the severity and type of response
thus ultimately dictating the site and
severity of infection.
The host response is further elucidated
by Klumpp and Schaeffer who present the
concept that uropathogens can modulate
the urothelial inflammatory response by
suppression of the NFkB dependent path-
way which not only promotes the initial
infection but also subsequent invasion.
UPEC binding to the urothelial surface
induces urothelial PI3 kinase activity
that drives cytoskeletal reorganization

necessary for bacterial invasion, but
recent studies also point to additional sig-
naling events. Modulation of inflamma-
tory responses and UPEC invasion are
coincident with FimH-induced urothelial
apoptosis. Thus, in addition to inflamma-
tion associated with acute infection, com-
plex early interactions between bacteria
and the urothelium drive diverse host
responses critical to UTI pathogenesis.
Bauer and Bessler further develop the
inflammatory response in urinary tract
infection. Macrophages, dendritic and
other antigen-presenting cells orchestrate
the inflammatory and immune defenses
against the invading pathogens. This
defense is complemented by the shedding
of uropathogens with urothelial cells,
trapping of bacteria by mucus, and inter-
mittent washout by urine. Tamm-Horsfall
protein which is capable of both medi-
ating direct antimicrobial activity and
alerting immune cells, as well as secre-
tory IgA, also play a major role.
Lastly, the role of biofilm in urogeni-
tal infections is reviewed by Tenke et al.
Introduction | 1.1 |
They indicate that the formation of bio-
film consists of several steps including
deposition of the conditioning film fol-
lowed by the attachment of microorgan-
isms and the final stage of formation of
a biofilm structure. Resident bacteria
within biofilms are protected from anti-
microbial agents. Biofilm plays a major
role in coating foreign bodies such as
urethral catheters. Emerging data also
indicate that biofilms can form in blad-
der epithelial cells where they are
termed intracellular bacterial commu-
nities. Bacteria in these intracellular
niches can create a chronic quiescent
reservoir in the bladder which can per-
sist undetected for months and lead to
bacterial relapse and then to recurrent
infection.
In summary, these excellent articles
indicate the diversity and constant evo-
lution of the host-bacterial interactions.
Continuing to study and understand
these intricate interplays is pivotal to our
ability to diagnose, treat and prevent uri-
nary tract infections.
3
|1.2|
Uropathogens and virulence factors
Ulrich Dobrindt1, Jörg Hacker2
Julius-Maximilians-Universität Würzburg, Institut für Molekulare Infektionsbiologie, Röntgenring 11, 97070 Würzburg, Germany
1

Robert Koch-Institut, Nordufer 20, 13353 Berlin, Germany

2

ABSTRACT as well as signaling between the patho-

gens and the host. Capsules, smooth
LPS and other extracellular polysac-
Urinary tract infections (UTIs) are among
charides protect bacterial pathogens
the most frequently encountered infec-
against the host immune system. The
tions in developed countries. In contrast
knowledge of biochemical and metabolic
to many commensal bacteria, uropath-
traits of uropathogens associated with
ogens are equipped with a variety of
improved fitness, growth and survival
virulence-associated factors that promote
in the urinary tract is increasing as well
the establishment of infection in different
as that of different extra- and intracellu-
areas of the urinary tract. Expression of
lar bacterial lifestyles that are involved
these virulence factors is most likely spa-
in acute or recurrent UTI. In addition to
tially and temporally regulated. Among
such classical bacterial virulence factors
the first virulence factors required during
directly involved in the successful coloni-
host-pathogen interaction and the estab-
zation of the urinary tract, uropathogens
lishment of an UTI are adhesins which
may also inhibit the mucosal inflam-
function as adhesins or invasins, promote
matory response. It becomes more and
biofilm formation and are involved in sig-
more clear, that not only the presence of
naling between the microorganisms and
virulence-associated genes is required for
epithelial cells. Flagella do not only allow
pathogenesis, but also their functionality
ascension from the urethra to the bladder
and proper expression in the context of
and even further to the kidneys, but can
the urinary tract infection.
also function as adhesins and invasins.
In later stages of an infection, toxins may Key words: uropathogens, virulence
further support infection by destruction factors, siderophores, toxins, adhesins,
of epithelial cells, the release of nutri- flagella, capsule, invasion, urease, auto-
ents, protection against the host response transporter, metabolism

1. INTRODUCTION
Urinary tract infection (UTI) is one of
the most frequently occurring bacterial
infections in industrialized countries
[1] and is an unspecific bacterial infec-
tion which can be caused by a variety of
pathogens. Usually, uropathogenic micro-
organisms derive from the patient’s own
faecal flora which, upon smear infection,
can ascend via the urethra to the urinary
bladder and even further via the ure-
ters to the kidneys. The most frequent
causative agent of UTI is Escherichia
coli (E. coli). Up to 80% of the acute com-
munity acquired uncomplicated UTI are
caused by E. coli. Additionally, 20–40% of
the complicated UTI and approximately
40% of the nosocomial infections in nor-
mal wards are UTI due to catheterization
[2–3]. Uropathogenic E. coli (UPEC) differ
from intestinal pathogenic and many non-
pathogenic faecal E. coli by the expression
of virulence-associated factors. A certain
fraction of the faecal E. coli bacteria (up
to 20%) in healthy individuals represent
strains with uropathogenic potential.
Table 1 Spectrum and prevalence of uropathogenic microorganisms
Uropathogen
Outpatient
Escherichia coli 80%
Proteus mirabilis 6%
Klebsiella, Enterobacter, Serratia, < 5%
Citrobacter spp., Pseudomonas spp.
Staphylococcus saprophyticus 7%
Staphylococcus aureus < 5%
Staphylococcus epidermidis
Enterococcus spp.
Candida spp. < 1%
Uropathogens and virulence factors | 1.2 |
Other Gram-negative uropathogens,
Proteus spp. and Klebsiella spp., are often
associated with the occurrence of bladder
stone formation due to urease expression.
Klebsiella spp. and Pseudomonas spp. are
frequently characterized by multiple anti-
biotic resistances and they are a predomi-
nant cause of nosocomial UTI. Citrobacter
spp., Enterobacter spp. and Serratia spp.
are nosocomial uropathogens as well
([4]; Table 1). Gram-positive bacteria
(Enterococcus spp., Staphylococcus spp.)
play also an important role as uropatho-
gens in nosocomial infections. Due to their
natural resistance against cephalosporins,
they are selected especially under inten-
sive care conditions. Staphylococcus
saprophyticus causes ambulantly acquired
UTI of young women [5]. Many fastidi-
ous anaerobic bacteria that are normally
not detected by the standard culture
conditions have been described in urine
specimens, but their role in UTI remains
to be studied [6].
The number of UTI cases caused by fungi
is increasing. Candida spp. is the most
frequently observed fungal uropathogen.
Remarks
Inpatient
40% Most frequently occurring uropathogen
11% Frequently associated with stone formation and
complicated UTI
25% Frequently associated with complicated and noso-
comial UTI, multiple antibiotic resistances
< 5% Frequently associated with UTI in sexually active
young women
16% Often in immuno-compromized patients
Important catheter-associated uropathogen
Frequently associated with transplantations, up to
8% of the infections develop into urosepsis
5% Frequently associated with antibiotic treatment
and immunosuppression, systemic infection
5
Chapter |1| Pathogenesis of urinary tract infections

Although C. albicans is the most common
species encountered, non-albicans Candida
species are also extremely prevalent [7].
UTI caused by fungi is preferentially
observed in immune-compromised patients
and upon treatment with antibiotics that
are excreted via the kidneys.
2. VIRULENCE-ASSOCIATED FACTORS
OF UROPATHOGENS
Microbial virulence mechanisms are
critical for overcoming the normal host
defences. Uropathogens are facultative
pathogens. The ability to cause disease
cannot alone be attributed to their genus
and species, but rather depends on the
ability to express virulence-associated
factors which crucially contribute to path-
ogenicity and which distinguish uropath-
ogenic from non-pathogenic variants. The
repertoire of virulence genes present in
a certain strain determines the type and
severity of disease (Table 2). Individual
virulence factors are needed only in cer-
tain stages of the infection. Consequently,
their expression is temporally and spa-
tially regulated in response to different
growth conditions (Figure 1).

Table 2 Virulence factors of microbial uropathogens

Organism Virulence factor

E. coli Fimbriae/adhesins (Type 1-, type 3-, P-fimbriae, S-adhesin family, Afa/Dr adhesin family, curli)

Toxins (α-Hemolysin, CNF1)

Autotransporter serine proteases (Sat, Vat)

Autotransporter adhesins (Ag43, UpaG)

Iron acquisition systems (enterobactin, aerobactin, yersiniabactin, salmochelin, Iha, haem

receptors Hma, ChuA)

O antigen

Capsule

Flagella

Extracellular poylsaccharides (cellulose, PGA)

Proteus mirabilis Fimbriae/adhesins (MR/P, PMF, ATF, NAF, UCA, MR/K)

Toxin (HpmA hemolysin)

Autotransporter agglutinin and cytotoxin (Pta)

Capsule

Urease

Flagella

Metalloproteases

Iron acquisition (Amino acid deaminases)

Klebsiella pneumoniae Fimbriae/adhesins (Type 1, Type 3 (MR/K))

Capsule

O-antigen

Iron acquisition systems (enterochelin, aerobactin)

Urease

6
 Uropathogens and virulence factors | 1.2 |

Organism Virulence factor

Pseudomonas aeruginosa Adhesins/fimbriae

Exotoxins (e.g., hemolysin)

Phospholipase C

Protease

Elastase

Pyochelin

Enterococcus spp. Adhesins (aggregation substance, D-mannose and D-glucose-containing carbohydrates)

Toxin (cytolysin)

Staphylococcus saprophyticus Adhesins (Surface associated protein Ssp, lipoteichoic acid, hemagglutinin/fibronectin
binding protein UafA, collagen binding SdrI, lipase Ssp, autolysin Aas)

Surface hydrophobicity

Toxin (Hemolysin)

Extracellular slime

Urease

Staphylococcus aureus Biofilm formation (PIA, Aap)

Toxins

Protease

MrpF

Iron acquisition systems (Isd, staphylobactin)

MSCRAMMs (fibronectin binding protein, laminin binding protein, elastin binding protein,
clumping factor)

Staphylococcus epidermidis Biofilm formation (PIA, Bap/Bhp)

Toxins

Citrobacter spp. Fimbriae/adhesin (Type 1 fimbriae, type 3 fimbriae)

Outer membrane proteins (OmpA)

Capsule (Vi)

Serratia marcescens Lipopolysaccharide

Mannose-resistant (MR) and mannose-sensitive (MS) fimbriae

Chitinase, lipase, chloroperoxidase, extracellular protein HasA

Candida spp. Adhesins (Agglutinin-like sequence genes (ALS), Hwp1)

Dimorphism, hyphae formation

Aspartyl proteinases (SAPs)

Lipases (LIPs), phospholipase B (PLB)

Iron-binding capacity

Metabolic adaptation

Resistance to phagocytosis
Ag43, antigen 43; PGA, poly-β-1,6-N-acetyl-D-glucosamine; PMF, Proteus mirabilis fimbriae; ATF, ambient-temperature fimbriae; NAF, non-
agglutinating fimbriae; MR/P, mannose-resistant Proteus-like hemagglutinin; MR/K, mannose-resistant Klebsiella-like hemagglutinin; UCA,
uroepithelial cell adhesin; MrpF, multiple peptide resistance factor; Pta; Proteus toxic agglutinin, PIA, polysaccharide inter-cellular adhesin.

7
Chapter |1| Pathogenesis of urinary tract infections

Motility Capsules, LPS Adhesins

Adhesins OMVs, Toxins Invasins
Autotransporter adhesins Autotransporter SPATEs Modulins
Siderophores Metabolic traits
Urease Extracellular
Metabolic traits polysaccharides

I II III
Adhesion, Immune evasion Binding to ECM,
colonization, serum resistance plasminogen activation
autoaggregation tissue destruction Invasion
IBC formation

Figure 1 Virulence factors of uropathogenic bacteria required for host-pathogen interaction and different stages of the urinary
tract during infection.
Flagellated and motile bacteria reach the bladder epithelium. This promotes adhesion to the bladder epithelial cells. Together
with metabolic and other enzymatic activities (e.g. urease expression), adhesion enables colonization of the urinary tract. The
secretion of siderophores further supports the establishment of infection (I). LPS and capsules protect the colonizing bacteria
from the host immune response. Toxins that are secreted via specific secretion systems or outer membrane vesicles can be
involved in signaling between the pathogen and the host cells or destroy the superficial epithelial cells to release nutrients
and to gain access to the subjacent tissue (II). Adhesins may also mediate bacterial invasion of the bladder epithelial cells.
Bacteria can exist quiescently in late endosome-like compartments or rapidly multiply within the superficial cells, forming
biofilm-like communities. Release of bacteria from infected host cells before they complete exfoliation likely promotes bacterial
dissemination and persistence within the urinary tract. During efflux, UPEC often become filamentous thus also preventing
phagocytosis (III).
OMVs, outer membrane vesicles; LPS, lipopolysaccharide; SPATEs, serine protease autotransporter toxins of Enterobacteriaceae;
IBCs, intracellular biofilm-like communities; ECM, extracellular matrix.

3. ADHESINS II, and III) that recognize globotria-

UTI usually starts with a specific colo-
nization of uroepithelial cells by micro-
organisms mediated by adhesins which
specifically bind to receptors present
on the surface of uroepithelial cells.
Morphologically, fimbrial adhesins can be
distinguished from non-fimbrial adhesins
(Afa or Nfa). Whereas fimbriae represent
composite fibres which protrude from the
cell surface, non-fimbrial adhesins are
directly located on the outer membrane.
About 80% of all UPEC express P fim-
briae (pyelonephritis-associated fimbriae)
which bind to the globoseries of gly-
cosphingolipids that are anchored in the
cell membrane preferentially of kidney
cells [8–10]. Three types of the PapG
adhesin have been identified (PapG I,
sylceramide variants on the surface of
target cells, particularly in the kidney.
Pyelonephritis isolates frequently express
the PapG II variant that binds the glo-
botetraosylceramide GbO4, a glycolipid
that is abundantly expressed on the sur-
face of human urothelium. Cystitis iso-
lates more commonly express PapG III.
This adhesin binds the globopentaosylce-
ramide GbO5 [11–12].
Type 1 fimbriae are produced by most
E. coli, UPEC and commensal variants,
and are meanwhile considered as one
of the most important virulence factors
involved in the colonization of the urinary
tract [13–15]. FimH recognizes mannose-
containing host glycoprotein receptors
incl. uroplakin 1a and many other host
proteins [16–18]. FimH also mediates

8

bacterial invasion of host cells and con-
tributes to the formation of intracellu-
lar bacterial biofilms [19–20]. Binding of
FimH to α3β1 integrin subunits and most
likely other receptors within lipid rafts
on bladder epithelial cells triggers sign-
aling cascades involving Rho GTPases,
the Src kinase, the PI 3-kinase, and the
focal adhesion kinase (FAK) as well as
transient complex formation between
α-actinin and vinculin. This results in
actin rearrangements and subsequently
bacterial uptake via the zipper mecha-
nism ([16, 19]; see also the chapter “Host
responses to infection” by Klumpp and
Schaeffer). Internalized UPEC can qui-
escently exist in late endosome-like com-
partments and may serve as a reservoir
for recurrent UTI. Bacterial release into
the host cytosol stimulates bacterial
growth and the formation of intracellular
biofilm-like communities [21–23].
Another important fimbrial adhesin,
so-called S/F1C fimbriae, bind to sialic
acid-containing receptors.[24–25] S/F1C
fimbriae can also bind to the Tamm-
Horsfall glycoprotein (THP) which is
exclusively expressed in the kidney and
constitutes the most abundant protein
in human urine. As THP carries high-
mannose as well as sialic acid sequences,
it can function as a ligand for fimbriated
E. coli and thus reduce the number of bac-
teria present in urine.[26–27] According
to complete genome sequence data, indi-
vidual UPEC genomes comprise ten or
more different fimbrial determinants.
[28–30] Except for the already described
type 1-, P- and S/F1C fimbriae, the role
of the other putative adhesins in UTI has
not yet been characterized in detail [31].
Other uropathogens also express fim-
brial and non-fimbrial adhesins (Table 2).
Several types of fimbriae can be
expressed simultaneously by Proteus
mirabilis (reviewed in [32]): The man-
nose-resistant/ Proteus-like (MR/P) fim-
briae, the P. mirabilis fimbriae (PMF),
the uroepithelial cell adhesin (UCA), and
the ambient-temperature fimbriae (ATF).
Uropathogens and virulence factors | 1.2 |
Two different fimbrial adhesins have
been described so far for uropathogenic
Klebsiella pneumoniae isolates including
a type 1 fimbriae-like adhesin which also
recognizes mannose-containing recep-
tors and so-called type 3 fimbriae. Type 3
fimbriae mediate adhesion to several cell
types in vitro [33–34], but their recep-
tor has not been identified yet. Although
the establishment of intracellular niches
during infection is more common in
UPEC, also uropathogenic K. pneumo-
niae have been shown to utilize quiescent
intracellular reservoirs during infec-
tion. Nevertheless, K. pneumoniae forms
less intracellular biofilm-like communi-
ties and has lower titres in bladder than
UPEC. These differences are at least par-
tially due to differences in type 1 fimbriae
expression [35–36].
Afimbrial adhesins mediate adherence
to human epithelial cells and are located
on the bacterial surface in amorphous
outer membrane-associated structures
[37]. The afimbrial Afa and Dr adhesins
are expressed by UPEC. The Dr adhesin
mediates bacterial adherence to poly-
morphonuclear leukocytes (PMNs), thus
decreasing bacterial killing. Members of
the Afa/Dr adhesin family differ in their
ability to specifically bind to the base-
ment membrane protein type IV colla-
gen, the common epithelial cell receptor
decay-accelerating factor (DAF, CD55)
and carcinoembryonic antigen-related
cellular adhesion molecules (CEACAMs).
Recognition of such membrane-bound
receptors including GPI-anchored pro-
teins known to be associated with lipid
rafts promotes eukaryotic cell signaling
and bacterial internalization (reviewed
in [38]).
Whereas adhesins of Gram-negative
uropathogens have been quite well char-
acterized so far, knowledge of adhes-
ins of Gram-positive bacteria involved
in UTI is only slowly accumulating. In
Staphylococcus aureus isolates from UTI
several adhesins, so-called ‘microbial sur-
face components recognising adhesive
9
Chapter |1| Pathogenesis of urinary tract infections
matrix molecules’ (MSCRAMMs) have
been detected including fibronectin bind-
ing proteins, the laminin binding protein,
the clumping factor but also the elastin
binding protein [39]. S. saprophyticus
expresses a cell-wall anchored hemagglu-
tinin, the so-called uro-adherence factor A
(UafA), that is associated with adherence
to eukaryotic cells in the urinary tract
[40]. Additional surface proteins such
as SdrI [41], Ssp [42], and the fibronec-
tin-binding autolysin Aas [43] may also
contribute to adhesion and possibly inter-
nalization of S. saprophyticus into epithe-
lial cells.
Internalization of S. saprophyticus into
a human bladder carcinoma cell line has
been observed and discussed in the light
of recurrent UTI [44]. Adhesive traits
of enterococci are so far supposed to be
mediated by the aggregation substance,
a pheromone-inducible surface protein,
which plays an important role during
the initiation of conjugation but also for
adherence to eukaryotic cell surfaces and
internalisation by enterocytes. In addition
to pheromones, serum can also induce the
expression of aggregation substance [45].
Adhesins of Candida albicans bind to
several extracellular matrix proteins of
mammalian cells, such as fibronectin,
laminin, fibrinogen and collagen type I
and IV (reviewed in [46]).
4. BIOFILM FORMATION
For catheter-associated infections in
general biofilm formation plays a major
role. Recently, the role of biofilm for-
mation during recurrent and chronic
UTI has been intensively investigated
in E. coli (see also chapter “Biofilm” by
Tenke et al.). Many different factors, such
as flagella, various fimbrial adhesins,
curli, antigen 43 as well as cell surface-
associated polysaccharides including
colanic acid and other capsular mate-
rial, poly-β-1,6-N-acetyl-D-glucosamine
(PGA) and cellulose contribute to biofilm
10
formation in E. coli [47–51]. These factors
most likely also promote biofilm forma-
tion in other Gram-negative uropathogens
as well as type 3 fimbriae that have been
recently described to contribute to biofilm
formation by different Gram-negative
uropathogens, i.e. E. coli, Citrobacter
koseri, Citrobacter freundii, Klebsiella
pneumoniae, and Klebsiella oxytoca [52].
Especially nosocomial S. aureus and
S. epidermidis isolates have the ability to
form biofilms on foreign materials. Non-
specific factors such as surface charge and
hydrophobicity are supposed to mediate
initial adherence, but also specific factors
such as cell wall-associated teichoic acids
and proteins which interact with extracel-
lular matrix proteins play an important
role as well as the “polysaccharide inter-
cellular adhesin (PIA) [53–55]. In addition,
other factors such as the surface-associ-
ated protein Aap (accumulation-associated
protein) and Bap/Bhp (biofilm-associated
protein) contribute to biofilm formation by
S. epidermidis and S. aureus [56–57].
5. SIDEROPHORE SYSTEMS
The availability of iron ions is an essen-
tial prerequisite for successful coloniza-
tion of the urinary tract. To overcome iron
limitation in the host, bacteria express
siderophores that scavenge iron from the
environment. In E. coli, different types of
siderophores are expressed. Enterobactin
(or enterochelin) is expressed by pathogenic
and non-pathogenic E. coli. In contrast
to enterobactin, aerobactin is frequently
present in uropathogenic and other extrain-
testinal pathogenic E. coli. Generally,
UPEC encode multiple siderophore sys-
tems in addition to enterobactin, e.g. sal-
mochelin, yersiniabactin, and aerobactin.
[58] UPEC require haem for kidney colo-
nization. Two haem receptors, Hma and
ChuA, have been described so far.[59]
Siderophore receptors may have dual
functions. The adhesin Iha was deter-
mined to be an E. coli urovirulence factor

in a mouse UTI model [60]. In addition,
Iha represents a catecholate siderophore
receptor that exhibits an adherence-en-
hancing phenotype [61]. Interestingly, the
salmochelin siderophore receptor IroN also
functions as an iron uptake receptor as
well as an internalization factor promoting
the invasion of urothelial cells by UPEC in
vitro [62].
These and similar iron uptake sys-
tems have also been described for other
Gram-negative microorganisms such
as Klebsiella spp. Interestingly, Proteus
mirabilis does not express common
siderophores. Alternatively, iron can be
acquired with α-keto acids, phenylpyru-
vate and indolepyruvate [63] and eight
different iron transport mechanisms have
been detected according to the complete
genome sequence of P. mirabilis strain
HI4320 [64]. In Gram-positive bacte-
ria, only little is known about molecular
details of iron acquisition. The isd genes
(iron-regulated surface determinant) of
S. aureus encode factors responsible for
hemoglobin binding and passage of haem-
bound iron from the cell wall to the cyto-
plasm [65]. S. aureus does also express
the siderophore staphylobactin [66].
C. albicans is able to utilize haemin and
haemoglobin as iron sources. A conserved
family of plasma membrane-anchored
haem-binding proteins has been identified
also in other Candida species [67].
6. TOXINS
Colonization by uropathogens frequently
results in inflammatory processes, fever
as well as damage of the urothelium and
the subjacent tissue. Toxins are involved
in these processes. The α-hemolysin
(HlyA), is encoded by about 50% of UPEC
isolates and its expression is associated
with increased clinical severity in UTI
patients [68]. In high concentrations, the
calcium-dependent pore-forming toxin
HlyA leads to cell lysis [69–70]. The func-
tion of HlyA was thus supposed to be
Uropathogens and virulence factors | 1.2 |
primarily the destruction of host cells to
release nutrients and iron, but sublytic
HlyA concentrations seem to be more
physiologically relevant. Sublytic concen-
trations of HlyA stimulate the inactiva-
tion of the serine/threonine kinase Akt,
which plays a central role in host cell
cycle progression, metabolism, vesicular
trafficking, survival, and inflammatory
signaling pathways [71]. These findings
explain that sublytic HlyA concentra-
tions inhibit chemotaxis and bacterial
killing by phagocytes as well as stimula-
tion of host apoptotic and inflammatory
pathways [72–76]. In this context, LPS
is important for targeting of HlyA to the
host cell membrane: HlyA in association
with LPS is presented via the CD14/LPS
binding protein recognition system to the
eukaryotic cell surface, where intracellu-
lar-Ca2+ signaling is initiated via specific
activation of the small GTPase RhoA [73].
Approximately 30% of UPEC strains
code for the cytotoxic necrotizing factor 1
(CNF1) which can constitutively activate
the Rho family GTPases [77]. Activation
of Rho GTPases affects many eukaryotic
cellular functions, e.g. the formation of
actin stress fibers, lamellipodia, filopodia,
the induction of membrane ruffling, and
the modulation of inflammatory signaling
pathways [78]. In murine UTI model sys-
tems CNF1 has been demonstrated to be
a UPEC virulence factor [79]. CNF1 may
facilitate the dissemination and persist-
ence of UPEC within the urinary tract as
it promotes apoptosis of bladder epithelial
cells thus stimulating their exfoliation
and enhancing bacterial access to the sub-
jacent tissue [80]. This toxin also inhibits
the phagocytic activity and chemotaxis of
neutrophils [81]. HlyA and CNF1 can be
associated with outer membrane vesicles
(OMVs) that bleb from the bacterial sur-
face [82]. Both toxins seem to be delivered
to target host cells via OMVs [83–84].
Other uropathogens also express tox-
ins. P. mirabilis expresses the hemo-
lysin HpmA, as well as proteases
[85–86]. Several toxins are expressed in
11
Chapter |1| Pathogenesis of urinary tract infections
Ps. aeruginosa including elastase, pro-
teases, phospholipase C, pyochelin and
hemolysin. Renal colonization of mice
correlated with the expression level of
hemolysin [87]. A well-described toxin
is the hemolysin of Enterococcus faeca-
lis [88]. S. aureus also expresses a broad
variety of toxins, but their impact on UTI
is unclear [89]. C. albicans can secrete
phospholipases and aspartyl proteinases
that promote virulence and invasiveness.
At least nine members of the secreted
aspartyl proteinase (SAP) family have
been detected in Candida species [46].
7. AUTOTRANSPORTERS
The genomes of many Gram-negative
pathogens comprise multiple genes cod-
ing for autotransporter proteins which
may have various virulence-associated
functions, such as adhesins and toxins
[90]. Antigen 43 (Ag43) represents an
entire family of closely related autotrans-
porter proteins in E. coli and contributes
in many ways to the phenotypic vari-
ability of E. coli as this autotransporter
mediates autoaggregation and biofilm for-
mation [91–92]. Ag43 contributes to the
uptake and survival in macrophages and
certain Ag43 variants may be associated
with long-term persistence of uropatho-
genic E. coli in the murine urinary tract.
[93–95] Ag43 also functions as a weak
adhesin capable of binding to proteins
of the extracellular matrix as well as to
T24 bladder epithelial cells [96]. Trimeric
autotransporters have also been recently
described in UPEC to mediate aggrega-
tion, biofilm formation, and adhesion to
various ECM proteins [97].
In addition, UPEC also express different
autotransporter toxins: i.e. the vacuolating
autotransporter toxin (Vat) and secreted
autotransporter toxin (Sat). Vat and Sat
belong to the SPATE (serine protease
autotransporters of Enterobacteriaceae)
protein family [98]. and were initially
characterized by their ability to induce
12
a variety of cytopathic effects in target
host cells. Sat expression has been shown
to induce dramatic kidney damage in a
mouse UTI model system [99–100].
The Proteus toxic agglutinin (Pta) has
been recently discovered in P. mirabilis
and represents a novel autotransporter
cytotoxin that works optimally in the
alkalinized urinary tract during P. mira-
bilis infection [101]. The role(s) of several
other autotransporter encoded by UPEC
and other Gram-negative uropathogens
awaits further investigation.
8. LIPOPOLYSACCHARIDE
The O antigen is a polysaccharide con-
sisting of ~10–25 repeating sugar subu-
nits anchored in the outer core of the
lipopolysaccharide component of the bac-
terial membrane [102]. There is a high
frequency of the antigens O1, O2, O4,
O6, O7, O8, O16, O18, O25, O50 and O75
among UPEC, while specific K and H
antigens have a less defined pattern.[103]
While it is known that certain O and K
antigens provide a survival advantage for
some extraintestinal pathogenic E. coli
(ExPEC) strains, it is unclear how these
antigens specifically affect UPEC viru-
lence. The LPS serotypes mentioned above
seem to specifically interact with other
virulence factors (e.g. LPS-dependent tar-
geting of HlyA to host cell membranes)
and may also play a role in the protection
against the human immune system. Other
Gram-negative uropathogens express
specific LPS structures as well. Gram-
positive microbes are characterized by a
multi-layered peptidoglycan. Fungi dis-
play β-(1,3)-glucans as surface structures
and whether they specifically contribute to
uropathogenesis remains to be elucidated.
9. CAPSULES
Many uropathogens can produce polysac-
charide capsules which play an important

role during pathogenesis because the cap-
sule protects bacteria against the host
complement system and phagocytes thus
contributing to serum resistance. In addi-
tion, certain capsules (e.g. the K1 cap-
sule) can mimic host structures thereby
reducing the immune response against
invading bacteria. E. coli expresses more
than 80 different capsule types. Group II
capsules are found in the vast majority
of UPEC, but there is no clear evidence
for the involvement of specific K anti-
gens in UPEC pathogenesis. The E. coli
K1 capsule is composed of 2,8-linked
sialic acid residues (N-acetylneuraminic
acid) and mimics the neuronal cell adhe-
sion molecule (c-CAM). Also other Gram-
negative and -positive bacteria express
capsules [104].
10. FLAGELLA
The role of flagella in UPEC pathogen-
esis becomes more and more defined. It
has been recently shown that they facili-
tate the ascension of UPEC from the
bladder into the kidneys, dissemination
within the host and invasion into renal
cells [105–109]. It is likely that flagella of
other Gram-negative uropathogens may
have similar functions.
11. UREASE PRODUCTION
One of the major virulence factors of
P. mirabilis is the enzyme urease [110].
Urease hydrolyses urea into carbon
dioxide and ammonia; the liberation of
ammonia creates an alkaline environ-
ment that causes soluble ions to precipi-
tate from urine producing a urinary stone
[111]. Consequently, during P. mirabilis
infection, the urinary tract often becomes
obstructed by urinary stones resulting
from urease production. Urease expres-
sion can also be frequently detected in
K. pneumoniae and S. saprophyticus
isolates [40].
Uropathogens and virulence factors | 1.2 |
12. METABOLIC AND OTHER TRAITS
Uropathogens are able to grow and multi-
ply in urine. Certain aspects of metabolic
properties that may promote growth in
the bladder have been recently character-
ized mainly in E. coli.
D-serine is one of the most prevalent
amino acids excreted in mammalian
urine. D-serine metabolism thus repre-
sents a positive fitness trait during UTI.
High concentrations of D-serine, however,
can also be bacteriostatic. In contrast to
commensal and intestinal pathogenic
E. coli, the majority of UPEC carries at
least one operon for D-serine utilization
[112]. The corresponding E. coli dsd-
CXA locus permits growth on D-serine
as a sole carbon and nitrogen source and
simultaneously represents a competitive
advantage due to detoxification of this
growth inhibitor. It has been hypothe-
sized that D-serine plays role in signaling
and virulence gene regulation [113–116].
Zinc transport has been recently dem-
onstrated to be important for motility and
resistance to hydrogen peroxide of UPEC
strain CFT073. Loss of the zinc transport
systems Znu and ZupT has a cumulative
effect on fitness during UTI, which may
in part be due to a reduced motility and
resistance to oxidative stress [117]. The
ability to resist oxidative stress has been
shown to be required for full urovirulence
of UPEC [118].
C. albicans exhibits marked morpho-
genetic plasticity; it can either grow in a
yeast or in a hyphal form [119]. This vari-
ability and the ability to switch from one
form to the other is linked to pathogenic-
ity of C. albicans, but the importance of
the morphogenetic variability for urovir-
ulence has not yet been studied in detail.
Niche-specific regulation of gene expres-
sion and metabolic adaptation has also
been shown to contribute to urovirulence
of C. albicans [120–121].
Subversion of the innate immune
response is essential for survival during
13
Chapter |1| Pathogenesis of urinary tract infections
the early stages of infection. UPEC can
directly inhibit TLR signaling by secret-
ing a structural homolog of the signaling
domain of human TLRs to prevent proin-
flammatory cytokine secretion. So-called
TIR domain containing–proteins (Tcps)
directly bind to MyD88 and thus impede
TLR signaling through the myeloid dif-
ferentiation factor 88 (MyD88) adap-
tor protein ([122–123]; see also chapter
“Host response induction in UTIs” by
Wullt & Svanborg). The ability of UPEC
to actively suppress the innate immune
response of bladder epithelial cells has
also been reported in other recent publi-
cations [124–125].
13. INSIGHTS INTO THE VIRULENCE-
ASSOCIATED GENE REPERTOIRE
OF UROPATHOGENS DUE TO
GENOMIC ANALYSES
In the era of (patho-)genomics, the global
analysis of gene expression together with
the access to complete genome sequences
of uropathogens enables the definition of
every coding sequence in the uropathogen
and thus opens the door for a more thor-
ough analysis of their virulence traits. The
availability of (multiple) complete genome
sequences of different non-pathogenic
and uropathogenic variants of one spe-
cies allows the global screen and survey
of specific virulence-associated genes of
uropathogens. This also enabled the sys-
tematic analysis of the contribution of
pathogenicity- and genomic islands (PAIs,
GEIs) of UPEC to urovirulence in general
as well as the identification of previously
unknown virulence-associated determi-
nants on these islands [28–30, 126].
Global transcriptome analyses of
UPEC in vivo confirm the importance
of type 1 fimbriae, iron uptake systems,
the capsule and LPS as important viru-
lence factors in the bladder and indi-
cate that genes required for protection
against NO, microaerobic growth under
iron and nitrogen limitation and at high
14
osmolarity are important for intravesical
growth [127–128].
A family of bacterial transcription fac-
tors (MarA, SoxS and Rob), which are
not required for growth in vitro, has been
shown to be necessary for persistence in a
mouse model of UTI. Mutants did not show
any statistically significant differences in
growth rate, cytotoxicity, adherence and
internalization in cell culture, and induc-
tion of cytokine expression [129]. These and
other findings suggest that not only the
presence of functional virulence-associated
genes [130], but also the ability to spatially
and temporarily regulate their expression
is important for the establishment of UTI.
Known virulence factors of P. mirabilis
besides urease, are hemolysin, fimbriae,
metalloproteases, and flagella. Genome
wide screening for urovirulence-related
genes by signature tagged mutagenesis
led to the identification of genes affecting
motility, iron acquisition, transcriptional
regulation, phosphate transport, urease
activity, cell surface structure, and key
metabolic pathways as requirements for
P. mirabilis infection of the urinary tract
[131–132]. Determination of the complete
genome sequence of P. mirabilis isolate
HI4320 confirmed the presence of previ-
ously identified virulence determinants.
Interestingly, genes coding for 17 types
of fimbriae, a potential type III secretion
system were identified as well as four
copies of the zapE metalloprotease gene,
six putative autotransporter-encoding
genes, and genes coding for at least five
iron uptake mechanisms, two potential
type IV secretion systems, and 16 two-
component regulators [64].
Genomic comparison of S. saprophyti-
cus and other staphylococci revealed spe-
cific urovirulence traits including various
transport systems to facilitate adapta-
tion to the varying pH and concentration
of inorganic ions, urea and organic com-
pounds in human urine as well as the
presence of a cell wall-anchored hemag-
glutinin that promotes adhesion to blad-
der epithelial cells [40].

14. CONCLUSIONS
The broad variety of virulence factors
detected in uropathogens together with
considerable overlap between the viru-
lence gene repertoire of uropathogenic
and other pathogenic or even commen-
sal variants of the same species makes
it difficult to define an uropathogen-
specific set of virulence factors. As
uropathogens are facultative pathogens,
it is likely that they can use multiple
strategies to efficiently colonize the uri-
nary tract and establish infection. The
recent developments in (patho-)genom-
ics and cellular microbiology enabled
the comprehensive analysis of patho-
mechanisms of model uropathogens,
especially of UPEC. Nevertheless, so far
unknown virulence-associated traits are
still described even in well-known model
organisms. Furthermore, for many
non-E. coli uropathogens the knowledge
of virulence mechanisms is still incom-
plete and so far unknown causative
agents of UTI are frequently described.
A careful and extensive investigation
of virulence-related traits of uropatho-
gens is required in order to improve
diagnostic, preventive and therapeu-
tic approaches. Increased knowledge of
gene regulation in response to growth
in different niches is also required to
better understand the molecular basis
of urovirulence.
ACKNOWLEDGEMENTS
Our work relating to this topic was sup-
ported by the German Research Founda-
tion (Collaborative Research Centre 479),
the Bavarian Research Foundation, the
European Virtual Institute for Functional
Genomics of Bacterial Pathogens (CEE
LSHB-CT-2005–512061) and the ERA-
NET PathogenoMics project “Deciphering
the intersection of commensal and extrain-
testinal pathogenic E. coli”.
Uropathogens and virulence factors | 1.2 |
REFERENCES
1. Foxman B, Epidemiology of urinary tract
infections: incidence, morbidity, and eco-
nomic costs. Am J Med, 2002. 113 Suppl
1A: 5S-13S.
2. Eggimann P, Sax H, and Pittet D,
Catheter-related infections. Microbes
Infect, 2004. 6(11): 1033–42.
3. Leone M, Garnier F, Avidan M, and
Martin C, Catheter-associated urinary
tract infections in intensive care units.
Microbes Infect, 2004. 6(11): 1026–32.
4. Ronald A, The etiology of urinary tract
infection: traditional and emerging patho-
gens. Dis Mon, 2003. 49(2): 71–82.
5. Raz R, Colodner R, and Kunin CM, Who
are you - Staphylococcus saprophyticus?
Clin Infect Dis, 2005. 40(6): 896–8.
6. Imirzalioglu C, Hain T, Chakraborty T,
and Domann E, Hidden pathogens uncov-
ered: metagenomic analysis of urinary
tract infections. Andrologia, 2008. 40(2):
66–71.
7. Kauffman CA, Vazquez JA, Sobel JD,
Gallis HA, McKinsey DS, Karchmer AW,
Sugar AM, Sharkey PK, Wise GJ, Mangi
R, Mosher A, Lee JY, and Dismukes
WE, Prospective multicenter surveillance
study of funguria in hospitalized patients.
The National Institute for Allergy and
Infectious Diseases (NIAID) Mycoses
Study Group. Clin Infect Dis, 2000. 30(1):
14–8.
8. Kallenius G, Mollby R, Svenson SB,
Winberg J, and Hultberg H, Identification
of a carbohydrate receptor recognized by
uropathogenic Escherichia coli. Infection,
1980. 8 Suppl 3: 288–93.
9. Plos K, Lomberg H, Hull S, Johansson
I, and Svanborg C, Escherichia coli in
patients with renal scarring: genotype
and phenotype of Gal alpha 1–4Gal beta-,
Forssman- and mannose-specific adhesins.
Pediatr Infect Dis J, 1991. 10(1): 15–9.
10. Strömberg N, Nyholm PG, Pascher I, and
Normark S, Saccharide orientation at
the cell surface affects glycolipid receptor
function. Proc Natl Acad Sci U S A, 1991.
88(20): 9340–4.
11. Karr JF, Nowicki BJ, Truong LD, Hull RA,
Moulds JJ, and Hull SI, pap-2-encoded
15
Chapter |1| Pathogenesis of urinary tract infections
fimbriae adhere to the P blood group-
related glycosphingolipid stage-specific
embryonic antigen 4 in the human kidney.
Infect Immun, 1990. 58(12): 4055–62.
12. Strömberg N, Marklund BI, Lund B,
Ilver D, Hamers A, Gaastra W, Karlsson
KA, and Normark S, Host-specificity of
uropathogenic Escherichia coli depends
on differences in binding specificity to Gal
alpha 1–4Gal-containing isoreceptors.
Embo J, 1990. 9(6): 2001–10.
13. Bahrani-Mougeot FK, Buckles EL,
Lockatell CV, Hebel JR, Johnson DE,
Tang CM, and Donnenberg MS, Type 1
fimbriae and extracellular polysac-
charides are preeminent uropathogenic
Escherichia coli virulence determinants in
the murine urinary tract. Mol Microbiol,
2002. 45(4): 1079–93.
14. Connell I, Agace W, Klemm P, Schembri
M, Marild S, and Svanborg C, Type 1 fim-
brial expression enhances Escherichia coli
virulence for the urinary tract. Proc Natl
Acad Sci U S A, 1996. 93(18): 9827–32.
15. Mulvey MA, Lopez-Boado YS, Wilson
CL, Roth R, Parks WC, Heuser J, and
Hultgren SJ, Induction and evasion of
host defenses by type 1-piliated uropatho-
genic Escherichia coli. Science, 1998.
282(5393): 1494–7.
16. Eto DS, Jones TA, Sundsbak JL, and
Mulvey MA, Integrin-mediated host cell
invasion by type 1-piliated uropathogenic
Escherichia coli. PLoS Pathog, 2007. 3(7):
e100.
17. Hung CS, Bouckaert J, Hung D, Pinkner
J, Widberg C, DeFusco A, Auguste CG,
Strouse R, Langermann S, Waksman
G, and Hultgren SJ, Structural basis of
tropism of Escherichia coli to the blad-
der during urinary tract infection. Mol
Microbiol, 2002. 44(4): 903–15.
18. Zhou G, Mo WJ, Sebbel P, Min G, Neubert
TA, Glockshuber R, Wu XR, Sun TT, and
Kong XP, Uroplakin Ia is the urothelial
receptor for uropathogenic Escherichia
coli: evidence from in vitro FimH binding.
J Cell Sci, 2001. 114(Pt 22): 4095–103.
19. Martinez JJ, Mulvey MA, Schilling JD,
Pinkner JS, and Hultgren SJ, Type 1
pilus-mediated bacterial invasion of blad-
der epithelial cells. Embo J, 2000. 19(12):
2803–12.
16
20. Wright KJ, Seed PC, and Hultgren SJ,
Development of intracellular bacterial
communities of uropathogenic Escherichia
coli depends on type 1 pili. Cell Microbiol,
2007. 9(9): 2230–41.
21. Justice SS, Hunstad DA, Seed PC,
and Hultgren SJ, Filamentation by
Escherichia coli subverts innate defenses
during urinary tract infection. Proc Natl
Acad Sci U S A, 2006. 103(52): 19884–9.
22. Mysorekar IU and Hultgren SJ,
Mechanisms of uropathogenic Escherichia
coli persistence and eradication from the
urinary tract. Proc Natl Acad Sci U S A,
2006. 103(38): 14170–5.
23. Rosen DA, Hooton TM, Stamm WE,
Humphrey PA, and Hultgren SJ,
Detection of intracellular bacterial
communities in human urinary tract
infection. PLoS Med, 2007. 4(12):
e329.
24. Ott M, Hacker J, Schmoll T, Jarchau T,
Korhonen TK, and Goebel W, Analysis
of the genetic determinants coding for
the S-fimbrial adhesin (sfa) in different
Escherichia coli strains causing menin-
gitis or urinary tract infections. Infect
Immun, 1986. 54(3): 646–53.
25. Schmoll T, Hoschutzky H, Morschhauser
J, Lottspeich F, Jann K, and Hacker J,
Analysis of genes coding for the sialic
acid-binding adhesin and two other
minor fimbrial subunits of the S-fimbrial
adhesin determinant of Escherichia coli.
Mol Microbiol, 1989. 3(12): 1735–44.
26. Israele V, Darabi A, and McCracken GH,
Jr., The role of bacterial virulence factors
and Tamm-Horsfall protein in the patho-
genesis of Escherichia coli urinary tract
infection in infants. Am J Dis Child, 1987.
141(11): 1230–4.
27. Säemann MD, Weichhart T, Horl WH,
and Zlabinger GJ, Tamm-Horsfall pro-
tein: a multilayered defence molecule
against urinary tract infection. Eur J Clin
Invest, 2005. 35(4): 227–35.
28. Brzuszkiewicz E, Brüggemann H,
Liesegang H, Emmerth M, Ölschläger
T, Nagy G, Albermann K, Wagner C,
Buchrieser C, Emödy L, Gottschalk G,
Hacker J, and Dobrindt U, How to become
a uropathogen: comparative genomic
analysis of extraintestinal pathogenic

Escherichia coli strains. Proc Natl Acad
Sci U S A, 2006. 103(34): 12879–84.
29. Chen SL, Hung CS, Xu J, Reigstad CS,
Magrini V, Sabo A, Blasiar D, Bieri T,
Meyer RR, Ozersky P, Armstrong JR,
Fulton RS, Latreille JP, Spieth J, Hooton
TM, Mardis ER, Hultgren SJ, and Gordon
JI, Identification of genes subject to posi-
tive selection in uropathogenic strains of
Escherichia coli: a comparative genomics
approach. Proc Natl Acad Sci U S A, 2006.
103(15): 5977–82.
30. Welch RA, Burland V, Plunkett G, 3rd,
Redford P, Roesch P, Rasko D, Buckles
EL, Liou SR, Boutin A, Hackett J,
Stroud D, Mayhew GF, Rose DJ, Zhou
S, Schwartz DC, Perna NT, Mobley
HL, Donnenberg MS, and Blattner FR,
Extensive mosaic structure revealed by the
complete genome sequence of uropatho-
genic Escherichia coli. Proc Natl Acad Sci
U S A, 2002. 99(26): 17020–4.
31. Wright KJ and Hultgren SJ, Sticky fibers
and uropathogenesis: bacterial adhesins
in the urinary tract. Future Microbiol,
2006. 1: 75–87.
32. Rocha SP, Pelayo JS, and Elias WP,
Fimbriae of uropathogenic Proteus mira-
bilis. FEMS Immunol Med Microbiol,
2007. 51(1): 1–7.
33. Hornick DB, Allen BL, Horn MA, and
Clegg S, Adherence to respiratory epi-
thelia by recombinant Escherichia coli
expressing Klebsiella pneumoniae type
3 fimbrial gene products. Infect Immun,
1992. 60(4): 1577–88.
34. Tarkkanen AM, Allen BL, Westerlund B,
Holthöfer H, Kuusela P, Risteli L, Clegg
S, and Korhonen TK, Type V collagen as
the target for type-3 fimbriae, enterobacte-
rial adherence organelles. Mol Microbiol,
1990. 4(8): 1353–61.
35. Rosen DA, Pinkner JS, Jones JM, Walker
JN, Clegg S, and Hultgren SJ, Utilization
of an intracellular bacterial community
pathway in Klebsiella pneumoniae uri-
nary tract infection and the effects of
FimK on type 1 pilus expression. Infect
Immun, 2008. 76(7): 3337–45.
36. Rosen DA, Pinkner JS, Walker JN,
Elam JS, Jones JM, and Hultgren SJ,
Molecular variations in Klebsiella pneu-
moniae and Escherichia coli FimH affect
Uropathogens and virulence factors | 1.2 |
function and pathogenesis in the urinary
tract. Infect Immun, 2008. 76(7): 3346–56.
37. Soto GE and Hultgren SJ, Bacterial
adhesins: common themes and variations
in architecture and assembly. J Bacteriol,
1999. 181(4): 1059–71.
38. Servin AL, Pathogenesis of Afa/Dr dif-
fusely adhering Escherichia coli. Clin
Microbiol Rev, 2005. 18(2): 264–92.
39. Baba-Moussa L, Anani L, Scheftel
JM, Couturier M, Riegel P, Haikou N,
Hounsou F, Monteil H, Sanni A, and
Prevost G, Virulence factors produced by
strains of Staphylococcus aureus isolated
from urinary tract infections. J Hosp
Infect, 2008. 68(1): 32–8.
40. Kuroda M, Yamashita A, Hirakawa H,
Kumano M, Morikawa K, Higashide M,
Maruyama A, Inose Y, Matoba K, Toh H,
Kuhara S, Hattori M, and Ohta T, Whole
genome sequence of Staphylococcus sapro-
phyticus reveals the pathogenesis of uncom-
plicated urinary tract infection. Proc Natl
Acad Sci U S A, 2005. 102(37): 13272–7.
41. Sakinc T, Kleine B, and Gatermann SG,
SdrI, a serine-aspartate repeat protein
identified in Staphylococcus saprophyti-
cus strain 7108, is a collagen-binding pro-
tein. Infect Immun, 2006. 74(8): 4615–23.
42. Sakinc T, Kleine B, and Gatermann SG,
Biochemical characterization of the sur-
face-associated lipase of Staphylococcus
saprophyticus. FEMS Microbiol Lett,
2007. 274(2): 335–41.
43. Hell W, Meyer HG, and Gatermann
SG, Cloning of aas, a gene encoding a
Staphylococcus saprophyticus surface pro-
tein with adhesive and autolytic proper-
ties. Mol Microbiol, 1998. 29(3): 871–81.
44. Szabados F, Kleine B, Anders A, Kaase
M, Sakinc T, Schmitz I, and Gatermann
S, Staphylococcus saprophyticus ATCC
15305 is internalized into human urinary
bladder carcinoma cell line 5637. FEMS
Microbiol Lett, 2008. 285(2): 163–9.
45. Shepard BD and Gilmore MS, Differential
expression of virulence-related genes in
Enterococcus faecalis in response to bio-
logical cues in serum and urine. Infect
Immun, 2002. 70(8): 4344–52.
46. Calderone RA and Fonzi WA, Virulence
factors of Candida albicans. Trends
Microbiol, 2001. 9(7): 327–35.
17
Chapter |1| Pathogenesis of urinary tract infections
47. Pratt LA and Kolter R, Genetic analysis
of Escherichia coli biofilm formation:
roles of flagella, motility, chemotaxis and
type I pili. Mol Microbiol, 1998. 30(2):
285–93.
48. Prigent-Combaret C, Prensier G, Le Thi
TT, Vidal O, Lejeune P, and Dorel C,
Developmental pathway for biofilm for-
mation in curli-producing Escherichia
coli strains: role of flagella, curli and col-
anic acid. Environ Microbiol, 2000. 2(4):
450–64.
49. Römling U, Characterization of the rdar
morphotype, a multicellular behaviour
in Enterobacteriaceae. Cell Mol Life Sci,
2005. 62(11): 1234–46.
50. Schembri MA and Klemm P, Coordinate
gene regulation by fimbriae-induced sig-
nal transduction. Embo J, 2001. 20(12):
3074–81.
51. Wang X, Preston JF, 3rd, and Romeo T,
The pgaABCD locus of Escherichia coli
promotes the synthesis of a polysaccharide
adhesin required for biofilm formation.
J Bacteriol, 2004. 186(9): 2724–34.
52. Ong CL, Ulett GC, Mabbett AN, Beatson
SA, Webb RI, Monaghan W, Nimmo GR,
Looke DF, McEwan AG, and Schembri
MA, Identification of type 3 fimbriae in
uropathogenic Escherichia coli reveals
a role in biofilm formation. J Bacteriol,
2008. 190(3): 1054–63.
53. Heilmann C, Niemann S, Sinha B,
Herrmann M, Kehrel BE, and Peters
G, Staphylococcus aureus fibronectin-
binding protein (FnBP)-mediated adher-
ence to platelets, and aggregation of
platelets induced by FnBPA but not by
FnBPB. J Infect Dis, 2004. 190(2): 321–9.
54. Heilmann C, Schweitzer O, Gerke C,
Vanittanakom N, Mack D, and Götz F,
Molecular basis of intercellular adhesion
in the biofilm-forming Staphylococcus
epidermidis. Mol Microbiol, 1996. 20(5):
1083–91.
55. Hussain M, Heilmann C, Peters G, and
Herrmann M, Teichoic acid enhances
adhesion of Staphylococcus epidermidis to
immobilized fibronectin. Microb Pathog,
2001. 31(6): 261–70.
56. Cucarella C, Solano C, Valle J, Amorena
B, Lasa I, and Penades JR, Bap, a
Staphylococcus aureus surface protein
18
involved in biofilm formation. J Bacteriol,
2001. 183(9): 2888–96.
57. Rohde H, Burdelski C, Bartscht K,
Hussain M, Buck F, Horstkotte MA,
Knobloch JK, Heilmann C, Herrmann M,
and Mack D, Induction of Staphylococcus
epidermidis biofilm formation via pro-
teolytic processing of the accumulation-
associated protein by staphylococcal and
host proteases. Mol Microbiol, 2005. 55(6):
1883–95.
58. Alteri CJ and Mobley HL, Quantitative
profile of the uropathogenic Escherichia
coli outer membrane proteome during
growth in human urine. Infect Immun,
2007. 75(6): 2679–88.
59. Hagan EC and Mobley HL, Haem acqui-
sition is facilitated by a novel receptor
Hma and required by uropathogenic
Escherichia coli for kidney infection. Mol
Microbiol, 2009. 71(1): 79–91.
60. Johnson JR, Jelacic S, Schoening LM,
Clabots C, Shaikh N, Mobley HL, and
Tarr PI, The IrgA homologue adhesin Iha
is an Escherichia coli virulence factor
in murine urinary tract infection. Infect
Immun, 2005. 73(2): 965–71.
61. Léveillé S, Caza M, Johnson JR, Clabots
C, Sabri M, and Dozois CM, Iha from
an Escherichia coli urinary tract infec-
tion outbreak clonal group A strain is
expressed in vivo in the mouse urinary
tract and functions as a catecholate
siderophore receptor. Infect Immun, 2006.
74(6): 3427–36.
62. Feldmann F, Sorsa LJ, Hildinger K, and
Schubert S, The salmochelin siderophore
receptor IroN contributes to invasion of
urothelial cells by extraintestinal patho-
genic Escherichia coli in vitro. Infect
Immun, 2007. 75(6): 3183–7.
63. Drechsel H, Thieken A, Reissbrodt R,
Jung G, and Winkelmann G, Alpha-keto
acids are novel siderophores in the genera
Proteus, Providencia, and Morganella
and are produced by amino acid deami-
nases. J Bacteriol, 1993. 175(9): 2727–33.
64. Pearson MM, Sebaihia M, Churcher C,
Quail MA, Seshasayee AS, Luscombe
NM, Abdellah Z, Arrosmith C, Atkin B,
Chillingworth T, Hauser H, Jagels K,
Moule S, Mungall K, Norbertczak H,
Rabbinowitsch E, Walker D, Whithead S,

Thomson NR, Rather PN, Parkhill J,
and Mobley HL, Complete genome
sequence of uropathogenic Proteus mira-
bilis, a master of both adherence and
motility. J Bacteriol, 2008. 190(11):
4027–37.
65. Maresso AW and Schneewind O,
Iron acquisition and transport in
Staphylococcus aureus. Biometals, 2006.
19(2): 193–203.
66. Dale SE, Doherty-Kirby A, Lajoie G, and
Heinrichs DE, Role of siderophore bio-
synthesis in virulence of Staphylococcus
aureus: identification and characteriza-
tion of genes involved in production of a
siderophore. Infect Immun, 2004. 72(1):
29–37.
67. Weissman Z and Kornitzer D, A family of
Candida cell surface haem-binding pro-
teins involved in haemin and haemoglob-
in-iron utilization. Mol Microbiol, 2004.
53(4): 1209–20.
68. Marrs CF, Zhang L, and Foxman B,
Escherichia coli mediated urinary tract
infections: are there distinct uropatho-
genic E. coli (UPEC) pathotypes? FEMS
Microbiol Lett, 2005. 252(2): 183–90.
69. Bhakdi S, Mackman N, Menestrina G,
Gray L, Hugo F, Seeger W, and Holland
IB, The hemolysin of Escherichia coli. Eur
J Epidemiol, 1988. 4(2): 135–43.
70. Ostolaza H, Soloaga A, and Goni FM, The
binding of divalent cations to Escherichia
coli alpha-haemolysin. Eur J Biochem,
1995. 228(1): 39–44.
71. Wiles TJ, Dhakal BK, Eto DS, and
Mulvey MA, Inactivation of host Akt/pro-
tein kinase B signaling by bacterial pore-
forming toxins. Mol Biol Cell, 2008. 19(4):
1427–38.
72. Koschinski A, Repp H, Unver B, Dreyer
F, Brockmeier D, Valeva A, Bhakdi S,
and Walev I, Why Escherichia coli alpha-
hemolysin induces calcium oscillations in
mammalian cells - the pore is on its own.
Faseb J, 2006. 20(7): 973–5.
73. Månsson LE, Kjäll P, Pellett S, Nagy
G, Welch RA, Bäckhed F, Frisan T, and
Richter-Dahlfors A, Role of the lipopoly-
saccharide-CD14 complex for the activ-
ity of hemolysin from uropathogenic
Escherichia coli. Infect Immun, 2007.
75(2): 997–1004.
Uropathogens and virulence factors | 1.2 |
74. TranVan Nhieu G, Clair C, Grompone
G, and Sansonetti P, Calcium signal-
ling during cell interactions with bacte-
rial pathogens. Biol Cell, 2004. 96(1):
93–101.
75. Troeger H, Richter JF, Beutin L,
Gunzel D, Dobrindt U, Epple HJ, Gitter
AH, Zeitz M, Fromm M, and Schulzke
JD, Escherichia coli alpha-haemolysin
induces focal leaks in colonic epithelium:
a novel mechanism of bacterial transloca-
tion. Cell Microbiol, 2007. 9(10): 2530–40.
76. Uhlén P, Laestadius A, Jahnukainen
T, Söderblom T, Bäckhed F, Celsi G,
Brismar H, Normark S, Aperia A, and
Richter-Dahlfors A, Alpha-haemolysin of
uropathogenic E. coli induces Ca2+ oscil-
lations in renal epithelial cells. Nature,
2000. 405(6787): 694–7.
77. Nougayrède JP, Taieb F, De Rycke J,
and Oswald E, Cyclomodulins: bacterial
effectors that modulate the eukaryotic
cell cycle. Trends Microbiol, 2005. 13(3):
103–10.
78. Lemonnier M, Landraud L, and
Lemichez E, Rho GTPase-activating
bacterial toxins: from bacterial viru-
lence regulation to eukaryotic cell biol-
ogy. FEMS Microbiol Rev, 2007. 31(5):
515–34.
79. Rippere-Lampe KE, O’Brien AD,
Conran R, and Lockman HA, Mutation
of the gene encoding cytotoxic necrotizing
factor type 1 (cnf1) attenuates the viru-
lence of uropathogenic Escherichia coli.
Infect Immun, 2001. 69(6): 3954–64.
80. Mills M, Meysick KC, and O’Brien AD,
Cytotoxic necrotizing factor type 1 of
uropathogenic Escherichia coli kills cul-
tured human uroepithelial 5637 cells by
an apoptotic mechanism. Infect Immun,
2000. 68(10): 5869–80.
81. Davis JM, Carvalho HM, Rasmussen SB,
and O’Brien AD, Cytotoxic necrotizing
factor type 1 delivered by outer membrane
vesicles of uropathogenic Escherichia coli
attenuates polymorphonuclear leukocyte
antimicrobial activity and chemotaxis.
Infect Immun, 2006. 74(8): 4401–8.
82. Kuehn MJ and Kesty NC, Bacterial outer
membrane vesicles and the host-pathogen
interaction. Genes Dev, 2005. 19(22):
2645–55.
19
Chapter |1| Pathogenesis of urinary tract infections
83. Balsalobre C, Silvan JM, Berglund S,
Mizunoe Y, Uhlin BE, and Wai SN,
Release of the type I secreted alpha-
haemolysin via outer membrane vesicles
from Escherichia coli. Mol Microbiol,
2006. 59(1): 99–112.
84. Kouokam JC, Wai SN, Fällman M,
Dobrindt U, Hacker J, and Uhlin BE,
Active cytotoxic necrotizing factor 1 associ-
ated with outer membrane vesicles from
uropathogenic Escherichia coli. Infect
Immun, 2006. 74(4): 2022–30.
85. Mobley HL, Chippendale GR, Swihart
KG, and Welch RA, Cytotoxicity of the
HpmA hemolysin and urease of Proteus
mirabilis and Proteus vulgaris against
cultured human renal proximal tubu-
lar epithelial cells. Infect Immun, 1991.
59(6): 2036–42.
86. Walker KE, Moghaddame-Jafari S,
Lockatell CV, Johnson D, and Belas R,
ZapA, the IgA-degrading metalloprotease
of Proteus mirabilis, is a virulence factor
expressed specifically in swarmer cells.
Mol Microbiol, 1999. 32(4): 825–36.
87. Mittal R, Khandwaha RK, Gupta V,
Mittal PK, and Harjai K, Phenotypic
characters of urinary isolates of
Pseudomonas aeruginosa & their associa-
tion with mouse renal colonization. Indian
J Med Res, 2006. 123(1): 67–72.
88. Shankar N, Coburn P, Pillar C, Haas W,
and Gilmore M, Enterococcal cytolysin:
activities and association with other viru-
lence traits in a pathogenicity island. Int
J Med Microbiol, 2004. 293(7–8): 609–18.
89. Ferry T, Perpoint T, Vandenesch F, and
Etienne J, Virulence determinants in
Staphylococcus aureus and their involve-
ment in clinical syndromes. Curr Infect
Dis Rep, 2005. 7(6): 420–8.
90. Henderson IR, Navarro-Garcia F,
Desvaux M, Fernandez RC, and
Ala’Aldeen D, Type V protein secre-
tion pathway: the autotransporter story.
Microbiol Mol Biol Rev, 2004. 68(4):
692–744.
91. Danese PN, Pratt LA, Dove SL, and
Kolter R, The outer membrane protein,
antigen 43, mediates cell-to-cell interac-
tions within Escherichia coli biofilms. Mol
Microbiol, 2000. 37(2): 424–32.
20
92. Henderson IR, Meehan M, and Owen P,
Antigen 43, a phase-variable bipartite
outer membrane protein, determines col-
ony morphology and autoaggregation in
Escherichia coli K-12. FEMS Microbiol
Lett, 1997. 149(1): 115–20.
93. Anderson GG, Palermo JJ, Schilling
JD, Roth R, Heuser J, and Hultgren SJ,
Intracellular bacterial biofilm-like pods
in urinary tract infections. Science, 2003.
301(5629): 105–7.
94. Fexby S, Bjarnsholt T, Jensen PO, Roos
V, Hoiby N, Givskov M, and Klemm
P, Biological Trojan horse: Antigen 43
provides specific bacterial uptake and
survival in human neutrophils. Infect
Immun, 2007. 75(1): 30–4.
95. Ulett GC, Valle J, Beloin C, Sherlock O,
Ghigo JM, and Schembri MA, Functional
analysis of antigen 43 in uropathogenic
Escherichia coli reveals a role in long-
term persistence in the urinary tract.
Infect Immun, 2007. 75(7): 3233–44.
96. Reidl S, Lehmann A, Schiller R, Salam
Khan A, and Dobrindt U, Impact of
O-glycosylation on the molecular and
cellular adhesion properties of the
Escherichia coli autotransporter protein
Ag43. Int J Med Microbiol, 2009.
97. Valle J, Mabbett AN, Ulett GC, Toledo-
Arana A, Wecker K, Totsika M, Schembri
MA, Ghigo JM, and Beloin C, UpaG, a
new member of the trimeric autotrans-
porter family of adhesins in uropatho-
genic Escherichia coli. J Bacteriol, 2008.
190(12): 4147–61.
98. Yen YT, Kostakioti M, Henderson IR,
and Stathopoulos C, Common themes
and variations in serine protease
autotransporters. Trends Microbiol,
2008. 16(8): 370–9.
99. Guyer DM, Radulovic S, Jones FE, and
Mobley HL, Sat, the secreted autotrans-
porter toxin of uropathogenic Escherichia
coli, is a vacuolating cytotoxin for blad-
der and kidney epithelial cells. Infect
Immun, 2002. 70(8): 4539–46.
100. Maroncle NM, Sivick KE, Brady R,
Stokes FE, and Mobley HL, Protease
activity, secretion, cell entry, cytotox-
icity, and cellular targets of secreted
autotransporter toxin of uropathogenic

Escherichia coli. Infect Immun, 2006.
74(11): 6124–34.
101. Alamuri P and Mobley HL, A novel
autotransporter of uropathogenic Proteus
mirabilis is both a cytotoxin and an
agglutinin. Mol Microbiol, 2008. 68(4):
997–1017.
102. Stenutz R, Weintraub A, and Widmalm
G, The structures of Escherichia coli
O-polysaccharide antigens. FEMS
Microbiol Rev, 2006. 30(3): 382–403.
103. Bidet P, Mahjoub-Messai F, Blanco J,
Blanco J, Dehem M, Aujard Y, Bingen
E, and Bonacorsi S, Combined multilo-
cus sequence typing and O serogrouping
distinguishes Escherichia coli subtypes
associated with infant urosepsis and/
or meningitis. J Infect Dis, 2007. 196(2):
297–303.
104. Taylor CM and Roberts IS, Capsular
polysaccharides and their role in viru-
lence. Contrib Microbiol, 2005. 12:
55–66.
105. Lane MC, Alteri CJ, Smith SN, and
Mobley HL, Expression of flagella
is coincident with uropathogenic
Escherichia coli ascension to the upper
urinary tract. Proc Natl Acad Sci U S A,
2007. 104(42): 16669–74.
106. Lane MC, Lockatell V, Monterosso
G, Lamphier D, Weinert J, Hebel JR,
Johnson DE, and Mobley HL, Role of
motility in the colonization of uropatho-
genic Escherichia coli in the urinary
tract. Infect Immun, 2005. 73(11):
7644–56.
107. Lane MC, Simms AN, and Mobley HL,
Complex interplay between type 1 fim-
brial expression and flagellum-mediated
motility of uropathogenic Escherichia
coli. J Bacteriol, 2007. 189(15): 5523–33.
108. Pichon C, Hechard C, du Merle L,
Chaudray C, Bonne I, Guadagnini S,
Vandewalle A, and Le Bouguenec C,
Uropathogenic Escherichia coli AL511
requires flagellum to enter renal col-
lecting duct cells. Cell Microbiol, 2009.
11(4): 616–28.
109. Schwan WR, Flagella allow uropatho-
genic Escherichia coli ascension into
murine kidneys. Int J Med Microbiol,
2008. 298(5–6): 441–7.
Uropathogens and virulence factors | 1.2 |
110. Mobley HL and Belas R, Swarming and
pathogenicity of Proteus mirabilis in the
urinary tract. Trends Microbiol, 1995.
3(7): 280–4.
111. Mobley HL and Hausinger RP, Microbial
ureases: significance, regulation, and
molecular characterization. Microbiol
Rev, 1989. 53(1): 85–108.
112. Roesch PL, Redford P, Batchelet
S, Moritz RL, Pellett S, Haugen
BJ, Blattner FR, and Welch RA,
Uropathogenic Escherichia coli use
D-serine deaminase to modulate infec-
tion of the murine urinary tract. Mol
Microbiol, 2003. 49(1): 55–67.
113. Anfora AT, Halladin DK, Haugen
BJ, and Welch RA, Uropathogenic
Escherichia coli CFT073 is adapted to
acetatogenic growth but does not require
acetate during murine urinary tract
infection. Infect Immun, 2008. 76(12):
5760–7.
114. Anfora AT, Haugen BJ, Roesch P,
Redford P, and Welch RA, Roles of serine
accumulation and catabolism in the colo-
nization of the murine urinary tract by
Escherichia coli CFT073. Infect Immun,
2007. 75(11): 5298–304.
115. Anfora AT and Welch RA, DsdX is the
second D-serine transporter in uropatho-
genic Escherichia coli clinical isolate
CFT073. J Bacteriol, 2006. 188(18):
6622–8.
116. Moritz RL and Welch RA, The
Escherichia coli argW-dsdCXA genetic
island is highly variable, and E. coli K1
strains commonly possess two copies of
dsdCXA. J Clin Microbiol, 2006. 44(11):
4038–48.
117. Sabri M, Houle S, and Dozois CM,
Roles of the extraintestinal pathogenic
Escherichia coli ZnuACB and ZupT
zinc transporters during urinary tract
infection. Infect Immun, 2009. 77(3):
1155–64.
118. Johnson JR, Clabots C, and Rosen H,
Effect of inactivation of the global oxida-
tive stress regulator oxyR on the coloniza-
tion ability of Escherichia coli O1:K1:H7
in a mouse model of ascending urinary
tract infection. Infect Immun, 2006.
74(1): 461–8.
21
Chapter |1| Pathogenesis of urinary tract infections
119. Kumamoto CA and Vinces MD,
Contributions of hyphae and hypha-co-
regulated genes to Candida albicans
virulence. Cell Microbiol, 2005. 7(11):
1546–54.
120. Brown AJ, Odds FC, and Gow NA,
Infection-related gene expression in
Candida albicans. Curr Opin Microbiol,
2007. 10(4): 307–13.
121. Enjalbert B, MacCallum DM, Odds FC,
and Brown AJ, Niche-specific activation
of the oxidative stress response by the
pathogenic fungus Candida albicans.
Infect Immun, 2007. 75(5): 2143–51.
122. Bhushan S, Tchatalbachev S, Klug J,
Fijak M, Pineau C, Chakraborty T, and
Meinhardt A, Uropathogenic Escherichia
coli block MyD88-dependent and activate
MyD88-independent signaling pathways
in rat testicular cells. J Immunol, 2008.
180(8): 5537–47.
123. Cirl C, Wieser A, Yadav M, Duerr
S, Schubert S, Fischer H, Stappert
D, Wantia N, Rodriguez N, Wagner
H, Svanborg C, and Miethke T,
Subversion of Toll-like receptor sign-
aling by a unique family of bacterial
Toll/interleukin-1 receptor domain-con-
taining proteins. Nat Med, 2008. 14(4):
399–406.
124. Billips BK, Schaeffer AJ, and Klumpp
DJ, Molecular basis of uropathogenic
Escherichia coli evasion of the innate
immune response in the bladder. Infect
Immun, 2008. 76(9): 3891–900.
125. Hilbert DW, Pascal KE, Libby EK,
Mordechai E, Adelson ME, and Trama
JP, Uropathogenic Escherichia coli
dominantly suppress the innate immune
response of bladder epithelial cells by a
lipopolysaccharide- and Toll-like receptor
4-independent pathway. Microbes Infect,
2008. 10(2): 114–21.
22
126. Lloyd AL, Henderson TA, Vigil PD,
and Mobley HL, Genomic Islands
of Uropathogenic Escherichia coli
Contribute to Virulence. J Bacteriol, 2009.
127. Roos V and Klemm P, Global gene
expression profiling of the asympto-
matic bacteriuria Escherichia coli strain
83972 in the human urinary tract. Infect
Immun, 2006. 74(6): 3565–75.
128. Snyder JA, Haugen BJ, Buckles EL,
Lockatell CV, Johnson DE, Donnenberg
MS, Welch RA, and Mobley HL,
Transcriptome of uropathogenic
Escherichia coli during urinary tract infec-
tion. Infect Immun, 2004. 72(11): 6373–81.
129. Casaz P, Garrity-Ryan LK, McKenney
D, Jackson C, Levy SB, Tanaka SK,
and Alekshun MN, MarA, SoxS and
Rob function as virulence factors in an
Escherichia coli murine model of ascend-
ing pyelonephritis. Microbiology, 2006.
152(Pt 12): 3643–50.
130. Zdziarski J, Svanborg C, Wullt B,
Hacker J, and Dobrindt U, Molecular
basis of commensalism in the uri-
nary tract: low virulence or virulence
attenuation? Infect Immun, 2008. 76(2):
695–703.
131. Burall LS, Harro JM, Li X, Lockatell CV,
Himpsl SD, Hebel JR, Johnson DE, and
Mobley HL, Proteus mirabilis genes that
contribute to pathogenesis of urinary
tract infection: identification of 25 signa-
ture-tagged mutants attenuated at least
100-fold. Infect Immun, 2004. 72(5):
2922–38.
132. Himpsl SD, Lockatell CV, Hebel
JR, Johnson DE, and Mobley HL,
Identification of virulence deter-
minants in uropathogenic Proteus
mirabilis using signature-tagged muta-
genesis. J Med Microbiol, 2008. 57(Pt 9):
1068–78.
|1.3|

Immunity, genetics and

susceptibility to urinary tract
infection
Björn Wullt1, 2, Bryndis Ragnarsdottir1, Hans Fischer1, Jenny Grönberg-Hernandez, Nataliya Lutay1,
Catharina Svanborg1, 3
1
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine
2
Department of Urology, Lund University, Lund, Sweden.
3
Singapore Immunology Network (SIgN), Biomedical Sciences Institutes, Agency for Science, Technology, and Research
(A*STAR), 8A Biomedical Grove, Immunos, BIOPOLIS, Singapore 138648.
Corresponding author: Björn Wullt, MD, PhD, bjorn.wullt@med.lu.se, Department of Microbiology, Immunology and
Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, 223 62 Lund

ABSTRACT low TLR4 immune response appears to be

The urinary tract is normally kept ster-
ile by the anti-microbial host defense,
through effectors of the innate immune
system. In resistant hosts, bacteriuria is
transient, and complete clearance of infec-
tion is achieved by the urine flow, mucosal
microbicidal molecules like defensins and
recruited inflammatory cells. Persistent
infections engage a more complex host
defense, with a gradual transition from
innate to specific immunity. Immune acti-
vation is controlled by different receptors
and signaling pathways. In experimental
models, TOLL-like receptors (TLRs) are
critical for the innate immune response
and to initiate the defense against viru-
lent E. coli strains, but surprisingly, a
protective, as the host develops asympto-
matic bacteriuria. Acute pyelonephritis
and urosepsis, in contrast, are caused by
an exaggerated innate immune response
to infection, which may cause renal scar-
ring. Chemokine receptor function is criti-
cal to control tissue inflammation through
neutrophil recruitment, and in the mouse,
CXCR2 receptor dysfunctions cause acute
pyelonephritis with bacteremia, as well
as renal scarring. In clinical studies, the
same genetic defects have been found in
patients prone to asymptomatic bacteriu-
ria or acute pyelonephritis, respectively.
TLR4 expression was recently found to
be reduced in children with asympto-
matic bacteriuria, suggesting that low
TLR4 expression might protect against
Chapter |1| Pathogenesis of urinary tract infections
symptomatic UTI. Pyelonephritis-prone
children instead have lower CXCR1
expression levels than controls, and new
genetic polymorphisms have been iden-
tified, in this patient group. These stud-
ies illustrate that genetically controlled
immune mechanisms influence immunity
and UTI susceptibility. It might be useful
to include such variables in future risk
assessment of UTI prone patients.
Key words: Urinary tract infection, Host
susceptibility, TLR4, CXCR1, Inflammation,
Innate immunity
KEY POINTS
In the human urinary tract
1. Innate immunity is responsible for
the defense against acute bacterial
infection
2. Inflammation is triggered by uropath-
ogenic E. coli through virulence fac-
tors, including P and Type 1 fimbriae,
which mediate adherence to the
uroepithelium
3. Activation of the uroepithelial Toll
Receptor 4 (TLR4) signaling initiates
the innate immune response
4. Neutrophils, combating E. coli infec-
tion, are recruited and activated by
the CXCL8 chemokine family and
their receptors, especially CXCR1
5. CXCR1/2 dysfunctions have a major
impact on the individual susceptibil-
ity to UTI. Receptor deficient mice
develop acute pyelonephritis with uro-
sepsis and renal scarring and patients
susceptible to acute pyelonephritis
have low CXCR1 expression and a
high frequency of polymorphisms in
the CXCR1 gene.
6. TLR4 dysfunctions appear to be pro-
tective, as they inhibit the inflamma-
tory response to infection and thus the
symptoms of disease. TLR4 KO mice
develop asymptomatic bacteriuria
24
(ABU) and children with ABU have
reduced TLR4 expression.
7. This evidence of the genetic control
constitutes a rationale for alternative
treatment and research studies.
1. INTRODUCTION
Urinary tract infections (UTI) vary
in severity, depending on the balance
between the infecting bacterial strain
and the antibacterial host defense. The
molecular determinants of bacterial viru-
lence have been extensively studied, and
the pathogenesis of infection is known to
proceed from adherence and initial tissue
contact through many, intricate steps,
ending either in resolution through bac-
terial clearance by the host defense or in
persistence and chronicity [1–5]. Crucial
virulence factors of uropathogenic E. coli
(UPEC) confer resistance to the effects
of the host defense and in addition, viru-
lent bacterial are able to produce mol-
ecules that actively inhibit the immune
response of the host, thereby enhancing
bacterial persistence in the host. This is
exemplified by the TcpC protein, which
acts by reducing TLR4 dependent inflam-
mation and by promoting pyelonephritis
[6–7]. Strains causing asymptomatic bac-
teriuria (ABU), in contrast, often fail to
activate the antibacterial host defense, as
they lack critical virulence factors needed
for host defense activation [5, 8]. They
establish bacteriuria and persist for long
periods of time in asymptomatic hosts
and many ABU strains undergo progres-
sive attenuation, from a more virulent to
an adapted phenotype [9–10].
Innate immune mechanisms control the
antimicrobial defense of the urinary tract.
Studies in cellular systems, animal mod-
els and patients with UTI have identified
critical steps in the activation of innate
immunity by virulent bacteria as well as
critical effector functions that enhance or
disrupt the host defense [2, 11]. This adds
an essential source of molecular variables
 Immunity, genetics and susceptibility to urinary tract infection
to the well-known structural defects
that render the urinary tract susceptible
to infection We have identified genetic
defects that increase the susceptibility
to both symptomatic and asymptomatic
UTI, in patients and animal models and
have shown that genetic variation influ-
ences clinical UTI susceptibility [12–15].
This review concerns two aspects of
the innate immune response to UTI. The
data has been generated in the Svanborg-
Wullt UTI research-group, or by refer-
enced colleagues in the field. The first
aspect is how molecular interactions acti-
vate the innate defense against infection,
including receptors for bacterial virulence
factors and TOLL-Like receptors (TLRs).
The second aspect deals with innate
immune mechanisms needed to elimi-
nate bacteria from the urinary tract. We
review how chemokine receptors deter-
mine the quality of the innate defense
and how tissue pathology may result from
inadequate chemokine receptor function.
We also summarise the results of deliber-
ate establishment of ABU, in the human
inoculation model, and studies of host
immunity and protection by long-term
bacterial carriage in that model.
2. MOLECULAR INTERACTIONS THAT
ACTIVATE THE INNATE DEFENSE
AGAINST INFECTION
Toll like receptors (TLRs) are critical
sensors of infection and control many
aspects of the host immune defense [16].
Different domains of these receptors con-
trol signaling, through a complex cas-
cade of so called adaptor proteins and
through transcription factors that deter-
mine which inflammatory mediators will
be produced by the infected cell [17–18].
TLR-signaling elicits a pro-inflammatory
response, which controls the local activa-
tion of cells at the site of infection, as well
as the recruitment of inflammatory cells
to infected tissues, through the secretion
of cytokines, interferons and chemokines.
| 1.3 |
In this way, these receptors control the
quality of inflammation and the arbitra-
tion of defense versus tissue damage.
The urinary tract mucosa and the
uroepithelial cells respond actively to
infection in a two-step process involving
receptors for bacterial virulence factors
for recognition and the TLRs for signal-
ing [11, 18] (Figure 1). Virulence factors,
expressed by the most pathogenic strains,
function as ligands for epithelial receptors
and biochemical modifications of those
receptors alert the host to the danger of
infection [19–21]. Examples are P and
type 1 fimbriae, which bind to host cells
through different saccharide recognition
mechanisms and trigger TLR4 dependent
signaling [22–23]. For example, the cou-
pling of P fimbriae to glycosphingolipid
receptors releases the membrane domain
of the receptor and this directly acti-
vates TLR4 signaling, the transcription
of specific innate immune response genes
and the production of mediators like
IL-6, IL-8 and TNF [18]. The same cells
respond poorly to asymptomatic carrier
strains and proinflammatory pathways
are not activated but suppressed [24].
This unresponsiveness is probably essen-
tial, to protect the host from constant
innate immune activation and to permit
the symbiotic relationship between bac-
teria and host to develop into the com-
mensal like and protective state of ABU
(Figure 1).
3. INNATE IMMUNE RESPONSE
VARIATION AND GENETICS OF
SUSCEPTIBILITY
Against this background, it is under-
standable that TLR4 defects abrogate
the inflammatory response to UTI. ABU
may result from infection with a strain of
low virulence or from bacterial inhibition
of the host immune response. ABU has
also been shown to result from host sup-
pression of the innate immune response.
Thus, mice lacking the TLR4 receptor or
25
Chapter |1| Pathogenesis of urinary tract infections

Adhesion, signaling Chemokines

and activation

Chemokine
A receptors

Normal TLR4 Dysfunction of TLR 4

A Cytokines A No inflammation signal

Ceramide Ser/Thr PK Ceramide

TLR4

GSL GSL

P fimbriae P fimbriae

Inflammation is Inflammation is not

triggered triggered
Adhesion, signaling Chemokines
Symptoms, pyuria, Asymptomatic
and activation

cleared infection A Bacteriuria Chemokine

receptors

Asymptomatic
Normal TLR4 Dysfunction of TLR 4

Cleared infection
A Cytokines A No inflammation signal
Adhesion, signaling
and activation Bacteriuria
Ceramide
Chemokines
Ser/Thr PK Ceramide
TLR4 Chemokine

Figure 1 Bacterial activation of the inflammatory response.

A receptors

GSL GSL

Bacterial adhesins (P-fimbriae, Type 1 fimbriae) bind to specific receptors on the surface of the uro-epithelial cells, and the
Normal TLR4 Dysfunction of TLR 4
A Cytokines A No inflammation signal

P fimbriae P fimbriae
adhesin-receptor interaction activates different transmembrane signaling Inflammation
pathways.
Ceramide
TLR4
is
Uropathogenic
Ser/Thr PK
E. coli expressing P fimbriae
Ceramide

Inflammation is not
bind to specific glycosphingolipid receptors on the uroepithelial cells, and recruit the TLR4 receptor for signaling. A dysfunc-
GSL
triggered triggered
GSL

tional TLR4 receptor hinders this signaling cascade and prevents inflammation.
Symptoms, pyuria,
cleared infection
P fimbriae
Asymptomatic
Bacteriuria
P fimbriae

Inflammation is Inflammation is not Asymptomatic

In the experimental UTI-model, mice with a dysfunctional TLR4 ( ) have a infection Bacteriuriaresponse to E. coli challenge and
low inflammatory
Cleared triggered triggered

Symptoms, pyuria,

develop asymptomatic bacteriuria (11). Children with ABU ( ) have lower TLR4 expression than children without UTI (15).
Asymptomatic
cleared infection Bacteriuria

Asymptomatic
Cleared infection Bacteriuria

having a dysfunctional signalling domain developed ABU following a prior symp-

show a delayed in inflammation and tomatic infection had intermediate TLR4
bacterial clearance and do not develop expression levels. DNA sequencing did
symptoms or tissue damage [11, 18]. sug- not identify Tir domain mutations in the
gesting that unresponsiveness may be patients and there were no disease asso-
protective at the mucosal level. ciated structural TLR4 gene polymor-
Suppressed TLR4 function was recently phisms. The mechanism of reduced TLR4
detected also in children with primary expression in ABU thus remains unde-
ABU who also had lower RNA levels than fined but should be identified, as this
controls without UTI and children with appears to be highly relevant for human
acute pyelonephritis [15]. Children who disease (Figure 1).

26
 Immunity, genetics and susceptibility to urinary tract infection | 1.3 |

4. CHEMOKINE RECEPTORS CONTROL and activation [25]. Infected uroepithe-

BACTERIAL CLEARANCE AND lial cells produce several chemokines
RENAL SCARRING and recruit inflammatory cells from the
blood to the mucosa within 30 min [26].
Chemokines and their receptors are Neutrophils then cross the epithelial
essential to direct the traffic of different barrier, into the urine and cause pyu-
cell types in the body, and specifically ria, a classical sign of UTI (Figure 2).
to recruit immune cells to sites of tis- This is supported by CXCR1, a recep-
sue damage [6]. CXCL8 (Interleukin-8) tor for CXCL8 on infected uroepithelial
is one of the prototype chemokines and cells and neutrophils, which supports the
is involved in neutrophil recruitment exit of neutrophils from the tissues, thus

Mediator release and

cell recruitment

Normal CXCR1 Dysfunction of CXCR1

B B

Blood Tissue
vessel damage
IL-8
IL-8R

Epithelium

Lumen Lumen

Neutrophils reach the Fewer neutrophils

lumen (pyuria) reach the lumen
Adhesion, signaling Chemokines
and activation

Pyelonephritis heals Pyelonephritis

A
heals Chemokine
receptors
without sequele with scarring
Normal TLR4 Dysfunction of TLR 4

Pyelonephritis heals Pyelonephritis causes

A Cytokines A No inflammation signal
Adhesion, signaling Chemokines
and activation
Ser/Thr PK
without sequele renal destruction
Ceramide Ceramide
TLR4
Chemokine
A receptors

Figure 2 Chemokine release and neutrophil recruitment. Normal TLR4 Dysfunction of TLR 4
GSL GSL

A Cytokines A No inflammation signal

P fimbriae P fimbriae
The activated uroepithelial cells create a chemotactic gradient by secreting members
Ceramide Ser/Thr PK
TLR4
Inflammation is
of the Interleukin
Ceramide
8 (IL-8) family of chem-
Inflammation is not
okines and the IL-8 receptor (CXCR1) is upregulated. Neutrophils are recruitedtriggered
GSL
to the site of infection,
GSL
triggered
migrate through the
tissue and cross the mucosal barrier into the urinary lumen aided by IL-8 and CXCR1.
Symptoms, pyuria,
cleared
P fimbriae
infection DuringAsymptomatic
this process, infection is cleared.
Bacteriuria
P fimbriae

Inflammation is Inflammation is not Asymptomatic

In the experimental UTI-model, mice with a dysfunctional CXCR1 ( ) have
triggered
massive
Cleared infection neutrophils
Bacteriuriaentrapment in the kidney
triggered

Symptoms, pyuria,

tissue leading to renal scarring (28). Children ( ) with recurrent pyelonephritis have lower CXCR1 expression than controls
Asymptomatic
cleared infection Bacteriuria

without UTI (27, 14).

Asymptomatic
Cleared infection Bacteriuria

27
Chapter |1| Pathogenesis of urinary tract infections
creating pyuria in patients with sympto-
matic UTI.
In the mouse UTI model, a chem-
okine receptor defect severely impairs
neutrophil migration into infected kid-
neys and knock out mice develop acute
pyelonephritis with bacteremia [27–28].
Histology showed neutrophil accumulation
under the epithelium and surviving mice
later developed renal scarring [27–28].
This double phenotype reflects the
importance of neutrophils and chemok-
ine receptors for the clearance of kidney
infection (Figure 2).
CXCR1 is also important for human
disease susceptibility. In patients with
symptomatic UTI, there is a strong cor-
relation between urinary CXCL8 levels
and urinary neutrophil numbers [5, 29].
CXCR1 levels vary in the population, and
pyelonephritis prone children have lower
CXCR1 expression levels than controls
without UTI [12]. We have identified five
polymorphisms/mutations in the CXCR1
gene, suggesting a novel, genetically
determined cause of UTI susceptibility.
[14] In a three-generation family study,
we observed that the frequency of APN
was high in family members of pyelone-
phritis prone children. In addition,
CXCR1 expression was lower in the rela-
tives of the APN-prone children than in
paediatric and adult controls. The infec-
tion pattern in some families suggested a
dominant pattern of inheritance, while in
others a recessive pattern was suggested.
The CXCR1 sequence variability and the
family study support the notion that APN
susceptibility and low CXCR1 expression
are inherited [13–14].
5. IMPLICATIONS FOR FUTURE
DIAGNOSTIC/THERAPEUTIC USE
5.1 Diagnostic approach
While current hospital policy in many
countries aims to reduce cost by avoiding
new technology and scientific advance,
28
it is still important to discuss in what
way this new information might be inte-
grated to improve the clinical assessment
of patients with UTI and their risk for
infection and tissue damage. The results
predict that, the assessment of structural
abnormalities and UTI history might be
complemented by genetic profiling. The
aim would be to identify individuals with
a dysregulated inflammatory response,
(CXCR1 low), who may run an increased
risk of recurrent pyelonephritis and renal
scaring. Furthermore, in patients with
ABU, TLR4 might be quantified to dis-
criminate those patients who should be
left without antibiotic therapy, from those
who might run a risk of progression.
Ideally, such analyses should also
include virulence factor typing of the
infecting strain using either single pheno-
typic traits like P fimbriae or gene profil-
ing. With such information, the physician
may assess if the strain is virulent and if
the patient responds adequately to infec-
tion, according to a risk assessment table.
The use of such diagnostic markers needs
to be tested prospectively, in relevant
patient populations, however.
5.2 Treatment by deliberate
establishment of bacteriuria in
UTI prone patients
Several investigators have made the
observation that ABU protects against
recurrent UTI. The presence of one bac-
terial strain in an infected host may
thus protect against superinfection by a
more virulent strain. This has motivated
attempts to deliberately establish pro-
tective bacteriuria with “apathogenic’’
E. coli in patients with therapy-resistant
recurrent UTI [30–33]. We have tested
this approach in several studies, and
have analysed mechanism that control
the establishment of bacteriuria and the
induction of innate immunity during
the first few days after the inoculation.
Our observations suggest that deliber-
ately established bacteriuria may be of
 Immunity, genetics and susceptibility to urinary tract infection
therapeutic value in therapy resistant
patients with recurrent UTI.
The prototype ABU strain E. coli 83972
[30–31] was originally isolated from a girl
with ABU who had carried it for three
years without adverse effects [30, 34]
and has been shown to cause persistent
ABU when deliberately inoculate into the
bladder of patients with recurrent UTI
83972 [30–31]. E. coli 83972 lacks func-
tional fimbriae and defined O and K sur-
face antigens and carries adhesin gene
clusters homologous to fim, pap, uca and
foc, but does not express fimbriae or func-
tional adhesins after in vitro culture or
when recovered from the human urinary
tract [9, 30, 35].
The human inoculation protocol has
also been useful to prove in human
patients that virulence factors influence
the establishment of bacteriuria and the
innate immune response in the urinary
tract. For example, patients were sub-
jected to intravesical inoculation with the
non-fimbriated ABU strain E. coli 83972
or with P fimbriated transformants of
this strain [36–37]. The P-fimbriated
transformants invariably established bac-
teriuria more rapidly and caused higher
immune responses than the ABU strain.
Subsequent studies of PapG adhesin
mutants, attributed the inflammatory
response to the specific binding between
adhesin and receptor [24].
We have also examined the effect of
type 1 fimbriae on bacterial persistence
and innate immunity in the human uri-
nary tract.[38] E.coli 83972 does not
express type 1 fimbriae, due to a fim dele-
tion.[9] Type 1 fimbrial expression was
therefore induced by transformation with
a functional fim gene cluster and used for
human inoculation studies to assess the
effect of type 1 fimbriae in the human uri-
nary tract. In contrast to P fimbriae, type
1 fimbriae failed to improve the establish-
ment of bacteriuria compared to the vec-
tor control. Furthermore, type 1 fimbriae
did not trigger a higher host response
than E. coli 83972 [38].
| 1.3 |
These results suggested that there are
important functional differences between
P fimbriae and type 1 fimbriae in the
human urinary tract. In addition, there
appear to be major differences between
the murine UTI model and the human
urinary tract, in terms of type 1 fimbrial
function.
6. CONCLUSIONS
This chapter presents new data suggest-
ing that the susceptibility to UTI, and
especially of disease prone patients, is
influenced by genetic mechanisms that
control the innate immune response to
infection. Such genetic determinants
include TLR4 and CXCR1; two important
molecules controlling different aspects
of the innate immune defense. It is our
hope, that in the future, it may be possi-
ble to integrate such molecular informa-
tion into the diagnostic and therapeutic
considerations needed to identify the UTI
prone individual and to select a proper
therapeutic approach.
REFERENCES
1. Kunin CM, Urinary Tract Infections.
Detection, Prevention and Management.
5th ed. 1997, Baltimore: Williams and
Wilkins.
2. Ragnarsdottir B, Fischer H, Godaly G,
Gronberg-Hernandez J, Gustafsson M,
Karpman D, Lundstedt AC, Lutay N,
Ramisch S, Svensson ML, Wullt B, Yadav
M, and Svanborg C, TLR- and CXCR1-
dependent innate immunity: insights into
the genetics of urinary tract infections.
Eur J Clin Invest, 2008. 38 Suppl 2:
12–20.
3. Cohn EB and Schaeffer AJ,
Urinary tract infections in adults.
ScientificWorldJournal, 2004. 4 Suppl 1:
76–88.
4. Sedberry-Ross S and Pohl HG, Urinary
tract infections in children. Curr Urol
Rep, 2008. 9(2): 165–71.
29
Chapter |1| Pathogenesis of urinary tract infections
5. Agace WW, Hedges SR, Ceska M, and
Svanborg C, Interleukin-8 and the neu-
trophil response to mucosal gram-negative
infection. J Clin Invest, 1993. 92(2):
780–5.
6. Svanborg C, Bergsten G, Fischer H,
Godaly G, Gustafsson M, Karpman
D, Lundstedt AC, Ragnarsdottir B,
Svensson M, and Wullt B, Uropathogenic
Escherichia coli as a model of host-
parasite interaction. Curr Opin Microbiol,
2006. 9(1): 33–9.
7. Cirl C, Wieser A, Yadav M, Duerr S,
Schubert S, Fischer H, Stappert D,
Wantia N, Rodriguez N, Wagner H,
Svanborg C, and Miethke T, Subversion
of Toll-like receptor signaling by a unique
family of bacterial Toll/interleukin-1
receptor domain-containing proteins. Nat
Med, 2008. 14(4): 399–406.
8. Svanborg-Edén C, Hanson LA, Jodal
U, Lindberg U, and Sohl-Åkerlund A,
Variable adherence to normal urinary
tract epithelial cells of Escherichia coli
strains associated with various forms of
urinary tract infections. Lancet, 1976.
II: 490–492.
9. Klemm P, Roos V, Ulett GC, Svanborg
C, and Schembri MA, Molecular charac-
terization of the Escherichia coli asymp-
tomatic bacteriuria strain 83972: the
taming of a pathogen. Infect Immun,
2006. 74(1): 781–5.
10. Zdziarski J, Svanborg C, Wullt B, Hacker
J, and Dobrindt U, Molecular basis of
commensalism in the urinary tract: low
virulence or virulence attenuation? Infect
Immun, 2008. 76(2): 695–703.
11. Hagberg L, Briles DE, and Eden CS,
Evidence for separate genetic defects in
C3H/HeJ and C3HeB/FeJ mice, that
affect susceptibility to gram-negative
infections. J Immunol, 1985. 134(6):
4118–22.
12. Frendeus B, Godaly G, Hang L, Karpman
D, and Svanborg C, Interleukin-8 receptor
deficiency confers susceptibility to acute
pyelonephritis. J Infect Dis, 2001. 183
Suppl 1: S56–60.
13. Lundstedt AC, Leijonhufvud I,
Ragnarsdottir B, Karpman D,
Andersson B, and Svanborg C, Inherited
30
susceptibility to acute pyelonephritis: a
family study of urinary tract infection. J
Infect Dis, 2007. 195(8): 1227–34.
14. Lundstedt AC, McCarthy S, Gustafsson
MC, Godaly G, Jodal U, Karpman D,
Leijonhufvud I, Linden C, Martinell
J, Ragnarsdottir B, Samuelsson M,
Truedsson L, Andersson B, and Svanborg
C, A genetic basis of susceptibility to
acute pyelonephritis. PLoS ONE, 2007.
2(9): e825.
15. Ragnarsdottir B, Samuelsson M,
Gustafsson MC, Leijonhufvud I, Karpman
D, and Svanborg C, Reduced toll-like
receptor 4 expression in children with
asymptomatic bacteriuria. J Infect Dis,
2007. 196(3): 475–84.
16. Beutler B and Moresco EM, The forward
genetic dissection of afferent innate immu-
nity. Curr Top Microbiol Immunol, 2008.
321: 3–26.
17. Akira S, Toll-like receptor signaling.
J Biol Chem, 2003. 278(40): 38105–8.
18. Fischer H, Yamamoto M, Akira S,
Beutler B, and Svanborg C, Mechanism
of pathogen-specific TLR4 activation in
the mucosa: fimbriae, recognition recep-
tors and adaptor protein selection. Eur J
Immunol, 2006. 36(2): 267–77.
19. Leffler H and Svanborg-Edén C, Chemical
identification of a glycosphingolipid
receptor for Escherichia coli attaching to
human urinary tract epithelial cells and
agglutinating human erythrocytes. FEMS
Microbiol Lett, 1980. 8: 127–134.
20. Hedlund M, Svensson M, Nilsson A,
Duan RD, and Svanborg C, Role of the
ceramide-signaling pathway in cytokine
responses to P-fimbriated Escherichia coli.
J Exp Med, 1996. 183(3): 1037–44.
21. Fischer H, Ellstrom P, Ekstrom K,
Gustafsson L, Gustafsson M, and
Svanborg C, Ceramide as a TLR4 agonist;
a putative signalling intermediate between
sphingolipid receptors for microbial lig-
ands and TLR4. Cell Microbiol, 2007.
22. Frendeus B, Wachtler C, Hedlund M,
Fischer H, Samuelsson P, Svensson M,
and Svanborg C, Escherichia coli P fim-
briae utilize the Toll-like receptor 4 path-
way for cell activation. Mol Microbiol,
2001. 40(1): 37–51.
 Immunity, genetics and susceptibility to urinary tract infection
23. Hedlund M, Frendeus B, Wachtler C,
Hang L, Fischer H, and Svanborg C, Type
1 fimbriae deliver an LPS- and TLR4-
dependent activation signal to CD14-
negative cells. Mol Microbiol, 2001. 39(3):
542–52.
24. Bergsten G, Samuelsson M, Wullt B,
Leijonhufvud I, Fischer H, and Svanborg
C, PapG-dependent adherence breaks
mucosal inertia and triggers the innate
host response. J Infect Dis, 2004. 189(9):
1734–42.
25. Baggiolini M, Dewald B, and Moser B,
Interleukin-8 and related chemotactic
cytokines-CXC and CC chemokines. Adv
in Immunol, 1994. 55: 97–179.
26. Shahin R, Engberg I, Hagberg L, and
Svanborg-Edén C, Neutrophil recruit-
ment and bacterial clearance correlated
with LPS responsiveness in local gram-
negative infection. J Immunol, 1987.
10(10): 3475–3480.
27. Frendeus B, Godaly G, Hang L, Karpman
D, Lundstedt AC, and Svanborg C,
Interleukin 8 receptor deficiency confers
susceptibility to acute experimental pyelone-
phritis and may have a human counter-
part. J Exp Med, 2000. 192(6): 881–90.
28. Hang L, Frendeus B, Godaly G, and
Svanborg C, Interleukin-8 receptor knock-
out mice have subepithelial neutrophil
entrapment and renal scarring following
acute pyelonephritis. J Infect Dis, 2000.
182(6): 1738–48.
29. Benson M, Jodal U, Agace W, Andreasson
A, Mårild S, Stokland E, Wettergren
B, and Svanborg C, Interleukin-6 and
interleukin-8 in children with febrile
urinary tract infection and asymptomatic
bacteriuria. J Infect Dis, 1996. 174:
1080–1084.
30. Andersson P, Engberg I, Lidin-Janson G,
Lincoln K, Hull R, Hull S, and Svanborg
C, Persistence of Escherichia coli bac-
teriuria is not determined by bacterial
adherence. Infect Immun, 1991. 59(9):
2915–21.
| 1.3 |
31. Wullt B, Connell H, Rollano P, Mansson
W, Colleen S, and Svanborg C,
Urodynamic factors influence the duration
of Escherichia coli bacteriuria in deliber-
ately colonized cases. J Urol, 1998. 159(6):
2057–62.
32. Darouiche RO, Donovan WH, Del Terzo
M, Thornby JI, Rudy DC, and Hull RA,
Pilot trial of bacterial interference for pre-
venting urinary tract infection. Urology,
2001. 58(3): 339–44.
33. Darouiche RO, Thornby JI, Cerra-
Stewart C, Donovan WH, and Hull RA,
Bacterial interference for prevention of
urinary tract infection: a prospective, ran-
domized, placebo-controlled, double-blind
pilot trial. Clin Infect Dis, 2005. 41(10):
1531–4.
34. Lindberg U, Hansson LÅ, Jodal U,
Lidin-Janson G, Lincoln K, and Olling S,
Asymptomatic bacteriuria in schoolgirls.
II. Differences in Escherichia coli causing
asymptomatic and symptomatic bacte-
riuria. Acta Paediatr Scand, 1975. 64:
432–436.
35. Hull RA, Rudy DC, Donovan WH, Wieser
IE, Stewart C, and Darouiche RO,
Virulence properties of Escherichia coli
83972, a prototype strain associated with
asymptomatic bacteriuria. Infect Immun,
1999. 67(1): 429–32.
36. Wullt B, Bergsten G, Connell H, Rollano
P, Gebratsedik N, Hang L, and Svanborg
C, P-fimbriae trigger mucosal responses
to Escherichia coli in the human urinary
tract. Cell Microbiol, 2001. 3(4): 255–64.
37. Wullt B, Bergsten G, Connell H, Rollano
P, Gebretsadik N, Hull R, and Svanborg
C, P fimbriae enhance the early establish-
ment of escherichia coli in the human
urinary tract. Mol Microbiol, 2000. 38(3):
456–64.
38. Bergsten G, Wullt B, Schembri MA,
Leijonhufvud I, and Svanborg C, Do type
1 fimbriae promote inflammation in the
human urinary tract? Cell Microbiol,
2007. 9(7): 1766–81.
31
|1.4|
Induction and modulation of
host responses by uropathogenic
Escherichia coli structures
David J. Klumpp*, Anthony J. Schaeffer
Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago,
Illinois 60611
*address all correspondence to: d-klumpp@northwestern.edu
312.908.1996 P, 312.908.7275 F
ABSTRACT
Acute urinary tract infection (UTI) has
been characterized extensively in both
patients and rodent models and is associ-
ated with local cytokine production by the
urothelium, thereby leading to urinary
cytokine accumulation, leukocytic influx,
and pyuria. Recent cellular and molecu-
lar studies that focus on uropathogenic
Escherichia coli (UPEC), however, reveal
strikingly complex host-pathogen interac-
tions. Keys to these interactions are sev-
eral early effects upon urothelial signaling
pathways that are rapidly induced upon
UPEC binding. For example, although
acute UTI is associated with robust
inflammation, UPEC have recently been
shown to modulate urothelial inflamma-
tory responses. This modulation includes
suppression of NFkB-dependent cytokine
secretion and is postulated to transiently
delay the innate immune response and
thus promote establishment of infection.
UPEC have also recently been shown to
invade urothelium in murine UTI and
establish intracellular reservoirs capable
of supporting recurrent infection. UPEC
binding to the urothelial surface induces
urothelial PI3 kinase activity that drives
cytoskeletal reorganization necessary
for bacterial invasion, but recent studies
also point to additional signaling events.
Binding of FimH adhesin to uroplakin
complexes on the urothelial surface trig-
gers signals mediated by uroplakin III
that are required for UPEC invasion.
UPEC binding also triggers elevated
cAMP levels that modulate both bacte-
rial entry and fluxing out of urothelial
cells. Finally, modulation of inflamma-
tory responses and UPEC invasion are
 Induction and modulation of host responses
coincident with FimH-induced urothelial
apoptosis. FimH-dependent urothelial
apoptosis also requires uroplakin III, and
this apoptotic response leads to umbrella
cell exfoliation that is considered a host
defense mechanism, acting in concert with
inflammation to promote pathogen clear-
ance. Numerous gene expression changes
occur as the urothelium is remodeled fol-
lowing UPEC infection and urothelial
apoptosis, where bone morphogenetic pro-
tein 4 signaling is pivotal in this urothelial
renewal. Thus, in addition to inflamma-
tion associated with acute infection, com-
plex early interactions between bacteria
and the urothelium drive diverse host
responses critical to UTI pathogenesis.
Key words: LPS, calcium, uroplakin,
invasion, apoptosis
1. INTRODUCTION
Urinary tract infection (UTI) is among
the most common infectious diseases.
Many clinical aspects of UTI are increas-
ingly well characterized and are described
in detail elsewhere in this text, includ-
ing the causative pathogens, the physi-
ologic and immune responses, effective
therapeutic approaches, and epidemiol-
ogy. But recent data gleaned from ani-
mal and human studies reveal previously
unappreciated complexity in UTI host-
pathogen interactions. These findings
identify multiple aspects of urothelial
cell signaling modulated during infec-
tion, often inducing host responses but
also inhibiting other signaling cascades
in a pathogen-specific manner. Here, we
review the current understanding of host
responses with an emphasis on those
events triggered in the urothelium by
uropathogenic Escherichia coli (UPEC).
We focus on initial signal transduction
events elicited by bacterial binding, the
role of urothelial signaling in bacterial
internalization, and urothelial dynamics
in response to infection.
| 1.4 |
2. UPEC MODULATE UROTHELIAL
INFLAMMATORY RESPONSES
Canonical inflammatory responses to
pathogens are initiated by receptors that
recognize highly-conserved, pathogen-
associated molecular patterns, and
toll-like receptors are the best studied
examples (PAMPs and TLRs, respec-
tively) [1–2]. TLR activation drives sig-
naling cascades that typically result in
nuclear factor kB (NFkB) stimulation
of transcription at promoters of inflam-
matory genes that contain kB binding
sites. IL-6 and IL-8 are two such NFkB-
dependent genes, and UTI is character-
ized by elevated urinary IL-8 and IL-6
due to local secretion of these factors by
the urothelium in response to UPEC
[3–4]. Surprisingly, studies of urothelial
NFkB activity and cytokine secretion
revealed that UPEC modulate inflamma-
tory responses.
The archetypal UPEC isolate, NU14,
was used in an in vitro model of early
events in UTI host-pathogen interac-
tions by assessing NFkB transcriptional
activity [5–6]. Contrary to the robust
inflammation characteristic of acute UTI,
we found that NU14 suppressed NFkB
induction in immortalized human urothe-
lial cell cultures, and this suppression
occurred whether urothelial NFkB activ-
ity was stimulated with LPS or tumor
necrosis factor α (TNF). Since a K12 labo-
ratory strain did not inhibit NFkB, inhi-
bition appeared specific to select strains.
Indeed, quantifying cytokine secretion
in urothelial cultures infected with vari-
ous strains selected from the ECOR ref-
erence panel, modulation of TNF-induced
urothelial IL-8 was observed for 15 of 18
ECOR clinical isolates including cysti-
tis, pyelonephritis, and fecal strains [7].
Some pathogens alter signaling cascades
upstream of NFkB directly by deliver-
ing an inhibitory factor, such as YopJ of
Y. pestis that is injected into host cells via
the type III secretion apparatus where
33
Chapter |1| Pathogenesis of urinary tract infections

it then interacts with multiple kinases to specifically modify PAMPs in a way

[8]. To determine the molecular basis
of inflammatory modulation by UPEC,
we and others employed genetic screens
and targeted studies to identify mutants
defective for inflammatory modula-tion
in NU14 and the closely-related strain
UTI89. Surprisingly, instead of identify-
ing genes for secreted factors, mutations
that abolished inflammatory modulation
mapped to loci encoding biosyn-thetic
activities for bacterial surface struct-ures,
including genes of LPS biosynthesis and
peptidoglycan biosynthesis [9–10]. The
outer membrane protein OmpA was simi-
larly found to be required for NFkB inhi-
bition by the neonatal meningitis E. coli
strain RS218, a strain that is highly
homologous to NU14 [5, 11]. These genes
are found in UPEC and laboratory E. coli
strains alike, suggesting that these gene
products collaborate with other factors
that evades normal host surveillance
mechanisms (Figure 1A). In contrast, the
pyelonephritis isolate CFT073 encodes a
novel toxin, TcpC, a factor that contains a
Toll/Interleukin-1 receptor (TIR) domain
[12]. TcpC inhibits inflammatory signal-
ing directly through TIR-mediated inter-
actions with the critical TLR adaptor
MyD88 (Figure 1A). Although NU14 lacks
a gene with significant homology to TcpC,
it is unclear whether other UPEC encode
a similar toxin. Nonetheless, UPEC uti-
lize multiple mechanisms for modulating
urothelial inflammatory responses.
3. UPEC INDUCE CALCIUM RESPONSES
Calcium is the most pervasive second
messenger in biology, so it is not surpris-
ing that urothelial responses to UPEC

A B

Figure 1 E. coli modulate multiple urothelial signaling cascades. A) TLR4 activation by E. coli LPS increases cytosolic calcium
and activation of adenylate cyclase 3 (AC3). AC3 in turn generates cAMP that activates protein kinase A (PKA), thereby
inducing PKA-mediated phosphorylation of CREB and enhanced transcription of IL-6. Uroplakin III (UPIII) and uroplakin Ia/Ib
act as a complex to also elevate cytosolic calcium. This calcium is induced by the FimH adhesin. B) TLR4 is the classic pattern
recognition receptor that mediates innate responses to gram-negative pathogens by virtue of its capacity to recognize LPS,
and MyD88-mediated signals then result in phosphorylation of IkB by IkB kinases (IKK) and subsequent transcription of NFkB-
dependent inflammatory genes. UPEC modulates TLR4 signaling pathway in at least two ways. UPEC strain CFT073 secretes
the TIR-domain protein TpcC that inhibits MyD88. UPEC strains that do not encode a TpcC-like factor may instead inhibit NFkB
activity at the level of TRL recognition.

34
 Induction and modulation of host responses
include increased levels of cytosolic Ca2+.
Elevated cytosolic Ca2+ was first reported
in association with UPEC-induced
urothelial apoptosis [13]. In that study,
we found that elevated calcium induction
occurred five hours after in vitro infec-
tion of human immortalized urothelial
cultures with NU14, and UPEC-induced
calcium was strictly dependent upon
the expression of FimH, the type 1 pilus
adhesin. Another recent study from the
laboratory of Dr. Soman Abraham iden-
tified elevated urothelial intracellular
resulting from TLR4 activation [14].
Using a K12 laboratory strain encoding
type 1 pili on a plasmid in combination
with urothelial carcinoma cells, TLR4
activation was shown to sequentially
induce Ca2+, cAMP, and CREB-mediated
transcription that accelerates IL-6 secre-
tion (Figure 1B). The transient Ca2+
increase was mimicked in part by puri-
fied LPS, but delayed kinetics relative to
intact bacteria suggest that additional
host-pathogen interactions modulate
Ca2+ responses. Furthermore, given that
many UPEC isolates modulate inflam-
matory responses downstream of TLR4
[7], it would be interesting to determine
whether the same TLR4-dependent Ca2+
responses occur in cultures treated with
UPEC.
A more recent study identified another
mechanism of UPEC-induced Ca2+
response and simultaneously identified
a novel signaling role for uroplakin III
in UPEC pathogenesis. Uroplakin pro-
teins were identified by pioneering stud-
ies in the laboratory of Dr. Tung-Tien Sun
[15–16]. Uroplakins are highly expressed
as complexes in urothelial superficial
umbrella cells and are so abundant that
they constitute the electronic density
characteristic of the asymmetric unit
membrane. While uroplakin Ia (and pos-
sibly uroplakin Ib) was identified by Dr.
Sun’s group as the bladder receptor for
FimH [17–18], a signaling role for uro-
plakins was previously unknown in
the bladder. The absence of uroplakin-
| 1.4 |
mediated signaling studies in the bladder
is surprising given that recent studies in
Xenopus demonstrated a signaling role
for uroplakin III during egg fertiliza-
tion that required tyrosine phosphoryla-
tion [19–21]. We found that application
of purified FimH protein to immortalized
urothelial cells induced a Ca2+ transient
that was dependent upon intracellular
and extracellular Ca2+ stores and decayed
within 150 seconds [22]. But instead of
initiating at TLR4, FimH-induced Ca2+
was strictly dependent upon uroplakin
III, the only uroplakin with an appre-
ciable intracellular domain potentially
capable of transducing intracellular sig-
nals (Figure 1B). Threonine 244 (T244)
within the cytoplasmic tail of uroplakin
III proved essential for FimH-induced
Ca2+, and T244 corresponded to a poten-
tial phosphorylation site for casein
kinase II (CK2). Consistent with this,
FimH treatment resulted in uroplakin
phosphorylation, suggesting that FimH
induces CK2-dependent phosphorylation.
Interestingly, mutation of a highly con-
served tyrosine associated with fertiliza-
tion-induced phosphorylation in Xenopus
had no effect on Ca2+ responses to FimH.
Understanding how uroplakin III phos-
phorylation alters interactions with other
urothelial proteins will be key to under-
standing FimH-induced signaling.
4. UPEC-INDUCED UROTHELIAL
RESPONSES DRIVE BACTERIAL
INVASION
Uropathogen reservoirs have long been
understood to exist within the GI tract
and the vagina, but seminal studies in the
laboratory of Dr. Scott Hultgren demon-
strate that the urothelium represents an
additional potential reservoir for bacteria.
UPEC have been shown to invade urothe-
lial cells and form stable intracellular
populations in vitro and in a murine UTI
model, and these drug-resistant intrac-
ellular populations then drive recurrent
35
Chapter |1| Pathogenesis of urinary tract infections

bacteriuria in mice [23–27]. Similar intra-
cellular UPEC populations have been
observed in exfoliated human urothelial
cells, and K. pneumoniae is also capable
of forming intracellular communities, sug-
gesting that the urothelium is a potential
reservoir that underlies recurrent UTI for
multiple uropathogens [28–29]. A central
question, then, is what events are required
for bacterial invasion of urothelial cells?
Bacterial invasion has been widely
studied in other systems and typi-
cally involves cytoskeletal remodeling.
Similarly, UPEC invasion of urothelial
cells was shown to require actin polym-
erization. Invasion was FimH-dependent
and associated with activation of phos-
phoinositide 3-kinase and focal adhesion
kinase as well as the involvement of the
Rho-GTPases RhoA, Cdc42, and Rac1,
all molecules that are critical media-
tors of cytoskeletal remodeling [30–31].
Interestingly, studies from the Abraham
lab suggest that TLR4 signaling antag-
onizes UPEC invasion (Figure 2). By
stimulating adenylate cyclase 3 and sub-
sequent cAMP accumulation, cAMP-de-
pendent protein kinase A was shown to
inhibit Rac1 and thereby reduce invasion
[32]. Indeed, manipulating cAMP levels
may offer clinical promise, for the ade-
nylate cyclase activator forskolin pro-
moted UPEC exocytosis from urothelial
cells in vitro and in vivo [33].
Despite uroplakin complexes serving
as UPEC receptors via interactions with
FimH (see above), integrins appear to cen-
tral mediators of invasion. Dr. Matthew
Mulvey recently reported that adhesion
of either UTI89 or a piliated laboratory
strain colocalized with integrins β1 and
α3 on carcinoma cells, and antibodies
against these integrins inhibited inva-
sion [34]. Mutation of known β1 integrin
phosphorylation sites resulted in signifi-
cantly reduced invasion in β1-deficient
fibroblasts, and inhibition of Src and focal
adhesion kinases also inhibited invasion.
These data suggest that integrins are
important mediators of UPEC invasion
in vitro, but it is difficult to reconcile the
likely subcellular restriction of integrins
to urothelial umbrella cell baso-lateral
surfaces in urothelium with images that
demonstrate UPEC binding across the
apical surface in the intact bladder [23].
In addition to roles for integrins and
TLR4 signaling in invasion, it now

Figure 2 Multiple factors mediate UPEC invasion of urothelial cells. UPEC entry requires actin remodeling that is dependent
upon phosphoinositde 3-kinase (PI3K) and Rho-like GTPases, such as Rac. TLR4 activation antagonizes this entry through inhi-
bition of Rac by TLR4-induced adenylate cyclase 3 activity (AC3) and subsequent protein kinase A (PKA) activation. PKA also
enhances UPEC exocytosis by promoting fusion of umbrella cell fusiform vesicles, containing UPEC, with the plasma membrane.
UPEC binding to integrins a3 and b1 promotes entry that is dependent upon phosphorylation of the b1 cytosolic tail. The UPEC
adhesin FimH also promotes entry that requires casein kinase 2 (CK2) and uroplakin III (UPIII).

36
 Induction and modulation of host responses
appears that uroplakin III is also an
important mediator of UPEC invasion
(Figure 2). We recently found that expres-
sion of a uroplakin III variant, where T244
was modified to a glutamic acid residue
to mimic constitutive phosphorylation by
CK2, significantly decreased urothelial
invasion by NU14 [35]. Conversely, the
T244-to-alanine mutant that mimics con-
stitutive uroplakin III dephosphoryla-
tion did not affect invasion, suggesting
that T245 phosphorylation plays distinct
roles in UPEC-induced Ca2+ elevation
and UPEC invasion. Nevertheless, CK2
appears important in UPEC invasion
for pharmacologic or genetic CK2 inhi-
bition significantly reduced NU14 inva-
sion in vitro and in a murine UTI model.
Thus, UPEC invasion of urothelial cells
is emerging as a major component of UTI
pathogenesis, and these basic science
studies have identified multiple novel tar-
gets for therapeutic intervention.
5. UROTHELIAL APOPTOSIS IS
A KEY EARLY EVENT IN UTI
PATHOGENESIS
In addition to UPEC invasion, EM analy-
ses in a murine UTI model by the Hultgren
laboratory revealed that NU14 caused
the formation of urothelial lesions devoid
of superficial umbrella cells [23]. Using
TUNEL staining to identify DNA fragmen-
tation characteristic of apoptosis, NU14-
induced urothelial lesions were found to
result from rapid induction of apopto-
sis that was dependent upon FimH and
caused umbrella cell exfoliation. Moreover,
co-instillation of an apoptosis inhibitor
increased NU14 colonization of the blad-
der, suggesting that urothelial apoptosis
is a host defense mechanism so that rapid,
UPEC-induced apoptosis leads to shedding
of the superficial urothelium and pathogen
purging. Urothelial apoptosis likely also
occurs in humans, for UTI patients are
highly sensitive to intravesical instillation
of potassium chloride, a clinical assay used
| 1.4 |
to assess urothelial integrity in interstitial
cystitis patients [36].
A biochemical understanding of UPEC-
induced urothelial apoptosis was facili-
tated by development of in vitro models
of UPEC-pathogen interactions. We found
that immortalized urothelial cell cultures
underwent FimH-dependent apopto-
sis in response to NU14 with the same
kinetics as the murine UTI model, thus
establishing the utility of in vitro models
for studying this key early event in UTI
pathogenesis [36]. This model revealed
that NU14 caused activation of multiple
caspases, proteases pivotal to the ini-
tiation and execution of apoptotic signal-
ing cascades [13]. Indeed, NU14 induced
urothelial caspase 2, 3, and 8 activities
(Figure 3). Specific inhibitors confirmed
the involvement of these caspases and
also implicated caspase 9, an intermedi-
ate caspase that couples mitochondrial
amplification of input apoptotic signals
with executioner caspases. Consistent
Figure 3. UPEC-induced urothelial apoptosis involves intrinsic
and extrinsic cascades. Both the extrinsic apoptotic cascade
(caspase 8) and the intrinsic apoptotic cascade (caspase 2) are
induced by FimH. Bid translocation to mitochondria is associ-
ated with a loss of mitochondrial membrane potential (DYm)
and accumulation of cytochrome C, ultimately resulting in
activation of caspase 3, an executioner caspase. Initiation of
apoptosis requires uroplakin III (UPIII) and casein kinase
II (CK2).
37
Chapter |1| Pathogenesis of urinary tract infections
with this potential role for mitochon-
dria in UPEC-induced apoptosis, over-
expression of Bcl-XL blocked caspase-3
activity, and NU14 induced translocation
of Bid to mitochondria, accumulation of
cytosolic cytochrome c, and loss of mito-
chondrial membrane potential. These
findings together suggest an ordering of
events that includes activation of extrin-
sic (caspase 8) and intrinsic (caspase 2)
apoptotic cascades upstream of mito-
chondrial destabilization and subsequent
activation of executioner caspases (cas-
pase 3). Finally, all of these events were
specifically initiated by NU14 bearing
functional FimH or could be induced by
purified FimC·H. Therefore, in addition
to the long-appreciated role for FimH as
a key UPEC adhesin, FimH also medi-
ates UTI pathogenesis by functioning as
a tethered toxin that promotes apoptosis.
These findings illuminate the role of
apoptosis in UTI, but the membrane-prox-
imal events that initiate urothelial apop-
tosis remained unclear until very recently.
We observed that NU14-induced apoptosis
of immortalized urothelial cells was sig-
nificantly diminished by genetic abroga-
tion of uroplakin III expression [22]. Since
CK2 appears to be a critical mediator of
uroplakin III signaling, we next exam-
ined the role of CK2 in apoptosis. Genetic
knock-down of urothelial CK2 expression
also blocked apoptosis induced by NU14.
Thus, uroplakin III signaling mediates
both UPEC-induced apoptosis and urothe-
lial invasion by UPEC, and future studies
that identify the repertoire of protein-
protein interactions in uroplakin III com-
plexes should define the signaling events
that drive these disparate – indeed mutu-
ally exclusive – cell fates.
6. UPEC INDUCES UROTHELIAL
TURNOVER
Urothelium exhibits the slowest turno-
ver of any epithelium, several months in
mouse and man. The urothelial apoptotic
38
response to UPEC insult naturally
requires epithelial renewal to re-estab-
lish the urothelial permeability barrier
critical to normal bladder function. The
initial EM characterization of urothelial
apoptosis in murine UTI showed compel-
ling evidence for rapid urothelial differ-
entiation [23]. In these images, urothelial
lesions devoid of umbrella cells were
evident within 4 hours of infection, and
lesions were progressively re-populated
with less differentiated urothelial cells
that then reconstituted a mature and
fully differentiated urothelium within
days. In subsequent studies, microarray
analyses were then employed to identify
the changes in gene expression associ-
ated with urothelial renewal in mice
[37]. NU14 infection was associated with
suppression of the bone morphogenetic
protein 4 (BMP-4) signaling pathway,
suppression that was strictly dependent
upon NU14 expressing functional type 1
pili. BMP-4 suppression also correlated
with decreased Wnt5a signaling and a
consequent de-repression of urothelial
markers of proliferation and differentia-
tion. A key promoter of epithelial differ-
entiation, Delta-like 1, was maximally
expressed at 3.5 h following infection,
consistent with the kinetics of apoptosis
in vitro and in vivo [13, 23, 36]. Delta-
like 1 expression subsided entirely by 7
days following expression, by which time
UPEC-induced lesions were repaired.
These events are consistent with rapid
induction of urothelial proliferation
and differentiation that accelerates the
otherwise slow turnover of urothelium
and thus restores normal urothelial
integrity. Indeed, recent studies sug-
gest that UPEC-associated inflamma-
tory responses are critical to activation
of a urothelial stem cell population that
mediates urothelial renewal, and BMP-4
is a key regulator of these processes [38].
Uroplakin III is a marker of termi-
nal differentiation in urothelium. Since
we identified a central role for uroplakin
III in UPEC-induced apoptosis, we also
 Induction and modulation of host responses
examined the effects of uroplakin III on
apoptosis during urothelial apoptosis
in vitro and in murine UTI [39]. Serum-
induced differentiation of immortal-
ized urothelial cultures was associated
with increased expression of urothelial
differentiation markers, including uro-
plakins. Coincident with increased dif-
ferentiation in vitro, urothelial cultures
became increasingly sensitive to NU14-
induced apoptosis. This enhanced apop-
totic response, promoted by urothelial
differentiation, was abrogated in cultures
in which uroplakin III expression was
disrupted. In support of these findings,
selective erosion of superficial urothelial
cells rendered urothelium less sensitive
to NU14-induced apoptosis, relative to
intact murine urothelium. Therefore, the
normal urothelial differentiation program
sensitizes urothelium to UPEC-induced
apoptosis by virtue of uroplakin III
expression, the mediator of the urothelial
apoptotic response during UTI.
7. CONCLUSIONS AND FUTURE
DIRECTIONS
Acute UTI is historically regarded as a
simple inflammatory response to infec-
tion by UPEC. However, recent studies
have identified several early events that
indicate complex host-pathogen interac-
tions and host responses. UPEC modu-
late initial inflammatory responses and
thus extend the window of opportunity
for invading urothelial cells to establish
intracellular reservoirs within the urothe-
lium that are resistant to innate immune
effector cells and antimicrobial therapies.
Novel therapeutic targets will certainly
emerge from precise understanding of
the mechanisms of inflammatory modu-
lation and invasion by UPEC, and these
therapies should reduce recurrent UTI
by inhibiting intracellular UPEC reser-
voirs. Similarly, UPEC induces urothelial
apoptosis by the effects of FimH acting as
a tethered toxin, and understanding this
| 1.4 |
process will foster development of thera-
pies that selectively target urothelial
cells which harbor intracellular UPEC
and may also have utility for treating
carcinoma. Therefore, understanding the
molecular details of the host responses
to UPEC – and how these responses vary
between pathogenic and benign bacte-
ria – will expand our arsenal for treating
bladder disease.
REFERENCES
1. Akira, S., S. Uematsu, and O. Takeuchi,
Pathogen recognition and innate immu-
nity. Cell, 2006. 124(4): p. 783–801.
2. Barton, G.M. and R. Medzhitov, Toll-like
receptor signaling pathways. Science,
2003. 300(5625): p. 1524–5.
3. Hedges, S., et al., Interleukin-6 response
to deliberate colonization of the human
urinary tract with gram-negative bacte-
ria. Infection and Immunity, 1991. 59:
p. 421–427.
4. Agace, W.W., et al., Interleukin-8 and the
neutrophil response to mucosal gram-neg-
ative infection. J Clin Invest, 1993. 92(2):
p. 780–5.
5. Johnson, J.R., et al., Clonal and patho-
typic analysis of archetypal Escherichia
coli cystitis isolate NU14. J Infect Dis,
2001. 184(12): p. 1556–65.
6. Klumpp, D.J., et al., Uropathogenic
Escherichia coli potentiates type 1
pilus-induced apoptosis by suppressing
NF-kappaB. Infect Immun, 2001. 69(11):
p. 6689–95.
7. Billips, B.K., et al., Modulation of host
innate immune response in the bladder
by uropathogenic Escherichia coli. Infect
Immun, 2007. 75(11): p. 5353–60.
8. Orth, K., et al., Inhibition of the mitogen-
activated protein kinase kinase super-
family by a Yersinia effector. Science,
1999. 285(5435): p. 1920–3.
9. Billips, B.K., A.J. Schaeffer, and
D.J. Klumpp, Molecular basis of
uropathogenic Escherichia coli evasion
of the innate immune response in the
bladder. Infect Immun, 2008. 76(9):
p. 3891–900.
39
Chapter |1| Pathogenesis of urinary tract infections
10. Hunstad, D.A., et al., Suppression of
bladder epithelial cytokine responses by
uropathogenic Escherichia coli. Infect
Immun, 2005. 73(7): p. 3999–4006.
11. Selvaraj, S.K. and N.V. Prasadarao,
Escherichia coli K1 inhibits proinflam-
matory cytokine induction in monocytes
by preventing NF-kappaB activation. J
Leukoc Biol, 2005. 78(2): p. 544–54.
12. Cirl, C., et al., Subversion of Toll-like
receptor signaling by a unique family
of bacterial Toll/interleukin-1 receptor
domain-containing proteins. Nat Med,
2008. 14(4): p. 399–406.
13. Klumpp, D.J., et al., Uropathogenic
Escherichia coli induces extrinsic and
intrinsic cascades to initiate urothelial
apoptosis. Infect Immun, 2006. 74(9):
p. 5106–13.
14. Song, J., et al., A novel TLR4-mediated
signaling pathway leading to IL-6
responses in human bladder epithelial
cells. PLoS Pathog, 2007. 3(4): p. e60.
15. Kachar, B., et al., Three-dimensional
analysis of the 16 nm urothelial plaque
particle: luminal surface exposure, pref-
erential head-to-head interaction, and
hinge formation. J Mol Biol, 1999. 285(2):
p. 595–608.
16. Wu, X.R., et al., Mammalian uroplakins.
A group of highly conserved urothelial dif-
ferentiation-related membrane proteins. J
Biol Chem, 1994. 269(18): p. 13716–24.
17. Wu, X.-R., T.-T. Sun, and J. Medina,
In vitro binding of type 1 fimbriated
Esherichia coli to uroplakins Ia and Ib:
relation to urinary tract infections. Proc.
Natl. Acad. Sci., 1996. 93: p. 9630–9635.
18. Zhou, G., et al., Uroplakin Ia is the
urothelial receptor for uropathogenic
Escherichia coli: evidence from in
vitro FimH binding. J Cell Sci, 2001.
114(Pt 22): p. 4095–103.
19. Mahbub Hasan, A.K., et al., Uroplakin
III, a novel Src substrate in Xenopus
egg rafts, is a target for sperm protease
essential for fertilization. Dev Biol, 2005.
286(2): p. 483–92.
20. Sakakibara, K., et al., Molecular identi-
fication and characterization of Xenopus
egg uroplakin III, an egg raft-associated
transmembrane protein that is tyrosine-
40
phosphorylated upon fertilization. J Biol
Chem, 2005. 280(15): p. 15029–37.
21. Mahbub Hasan, A.K., et al.,
Characterization of Xenopus egg
membrane microdomains containing
uroplakin Ib/III complex: roles of
their molecular interactions for
subcellular localization and signal
transduction. Genes Cells, 2007. 12(2):
p. 251–67.
22. Thumbikat, P., et al., Bacteria-induced
uroplakin signaling mediates bladder
response to infection. PLoS Pathog, 2009.
5(5): p. e1000415.
23. Mulvey, M., et al., Induction and eva-
sion of host defenses by type 1-piliated
uropathogenic Escherichia coli. Science,
1998. 282: p. 494–497.
24. Mulvey, M.A., J.D. Schilling, and S.J.
Hultgren, Establishment of a persist-
ent Escherichia coli reservoir during the
acute phase of a bladder infection. Infect
Immun, 2001. 69(7): p. 4572–9.
25. Schilling, J.D., et al., Bacterial invasion
augments epithelial cytokine responses to
Escherichia coli through a lipopolysaccha-
ride-dependent mechanism. J Immunol,
2001. 166(2): p. 1148–55.
26. Anderson, G.G., et al., Intracellular bac-
terial biofilm-like pods in urinary tract
infections. Science, 2003. 301(5629):
p. 105–7.
27. Justice, S.S., et al., Differentiation and
developmental pathways of uropathogenic
Escherichia coli in urinary tract patho-
genesis. Proc Natl Acad Sci U S A, 2004.
101(5): p. 1333–8.
28. Rosen, D.A., et al., Utilization of an intra-
cellular bacterial community pathway
in Klebsiella pneumoniae urinary tract
infection and the effects of FimK on type
1 pilus expression. Infect Immun, 2008.
76(7): p. 3337–45.
29. Rosen, D.A., et al., Detection of intracel-
lular bacterial communities in human
urinary tract infection. PLoS Med, 2007.
4(12): p. e329.
30. Martinez, J.J. and S.J. Hultgren,
Requirement of Rho-family GTPases in
the invasion of Type 1-piliated uropatho-
genic Escherichia coli. Cell Microbiol,
2002. 4(1): p. 19–28.
 Induction and modulation of host responses
31. Martinez, J.J., et al., Type 1 pilus-
mediated bacterial invasion of bladder
epithelial cells. EMBO J, 2000. 19(12):
p. 2803–12.
32. Song, J., et al., TLR4-initiated and cAMP-
mediated abrogation of bacterial invasion
of the bladder. Cell Host Microbe, 2007.
1(4): p. 287–98.
33. Bishop, B.L., et al., Cyclic AMP-regulated
exocytosis of Escherichia coli from infected
bladder epithelial cells. Nat Med, 2007.
13(5): p. 625–30.
34. Eto, D.S., et al., Integrin-mediated host
cell invasion by type 1-piliated uropatho-
genic Escherichia coli. PLoS Pathog,
2007. 3(7): p. e100.
35. Parsons, C.L., Interstitial cystitis
and lower urinary tract symptoms in
males and females-the combined
role of potassium and epithelial
| 1.4 |
dysfunction. Rev Urol, 2002. 4 Suppl 1:
p. S49–55.
36. Klumpp, D.J., et al., Uropathogenic E.
coli potentiate type 1 pili-induced apopto-
sis by suppressing NFkB. Infect Immun,
2001. 69: p. 6689–6695.
37. Mysorekar, I.U., et al., Molecular regu-
lation of urothelial renewal and host
defenses during infection with uropatho-
genic Escherichia coli. J Biol Chem, 2002.
277(9): p. 7412–9.
38. Mysorekar, I.U., et al., Bone morpho-
genetic protein 4 signaling regulates
epithelial renewal in the urinary tract in
response to uropathogenic infection. Cell
Host Microbe, 2009. 5(5): p. 463–75.
39. Thumbikat, P., et al., Differentiation-
induced uroplakin III expression promotes
urothelial cell death in response to uropath-
ogenic E. coli. Microbes Infect, 2008.
41
|1.5|
Immunology of the urinary tract
Hartwig W. Bauer1, Wolfgang G. Bessler2
1
Prof. Dr. med. habil. H. W. Bauer. Facharzt für Urologie und Andrologie, Maximilianstr. 31. D-80539 München, Germany.
2
Institut für Molekulare Medizin und Zellforschung, Universitätsklinikum Freiburg, AK
Tumorimmunologie/Vakzine, Hermann-Herder-Str. 9, 79104 Freiburg, Germany.
ABSTRACT
Infection of the urinary tract is gov-
erned, as elsewhere, by the general
principles of bacterial pathogenesis; the
first encounter of bacteria with their
host involves attachment to a cell sur-
face, which results in colonization of the
host. In such cases, induced antibody
responses at the mucosal surface could
prevent attachment and abrogate coloni-
zation. Recurrent urinary tract infection
represents a case of successful microbial
host evasion and poses a major medi-
cal health problem. In this overview,
after a review of the general character-
istics of the immune system we describe
the peculiarities of the immune system
in the genitourinary tract. The line-
age of macrophages, dendritic and other
antigen-presenting cells orchestrate
the inflammatory and immune defences
against the invader(s). They include the
innate immunity (macrophages, poly-
morphonuclear leukocytes, natural killer
cells, complement system, etc.) and the
adaptative immune system with two
subsystems: 1) the cellular comprising
CD4 T cells (e.g. Th1, Th2) and the CD8
T killer cells, and 2) the humoral where
B cells produce specific IgG, IgA, IgM,
and IgE antibodies. IgA is the secre-
tory immunoglobulin present in body
secretions, including urine. The toll-like
receptor (TLR) family mediates immune
responses; there are ten known human
TLRs. Gram-negative bacterial lipopoly-
saccharide (LPS) activates antigen-pre-
senting cells through TLR-4 whereas
lipopeptides and mycobacterial lipogly-
cans activate cells through TLR-2. TLRs
can influence adaptive immune responses
and exert complex effects on Th1 and
Th2 polarization of CD4+ helper cell
responses.
In the urinary tract there is a well
organised lymphoid tissue, resembling
the mucosa-associated lymphoid tissue,
although in the lower urinary tract it
seems insufficient to generate common
mucosal immune responses. In the uri-
nary tract, the defence mechanism may
be explained by the shedding of uropath-
ogens with urethral cells, trapping of

bacteria by mucus, intermittent wash-
out by urine, local production of immu-
noglobulins, cytokines and defensins and
mobilization of leukocytes in addition to
the Tamm-Horsfall protein which is capa-
ble of both mediating direct antimicro-
bial activity and alerting immune cells.
Locally synthesized sIgA immunoglobu-
lins can be low or normal in the urine of
individuals with recurrent (lower) uri-
nary tract infections (UTIs). The bacte-
rial extract OM-89, which binds to TLR-4,
generally activates the immune system,
and reduces the number of recurrences of
UTIs. A better understanding of the com-
plex immunological factors involved in
fighting UTIs will certainly lead to better
medicines or improved usage of the exist-
ing ones.
Key words: Urinary tract infections,
Innate Immunity, Adaptive Immunity,
TLR, toll like receptors, prevention of
infections, Uro-Vaxom
1. INTRODUCTION
Infection of the urinary tract is governed,
as elsewhere, by the general principles of
bacterial pathogenesis. Proteins produced
by the microbial agent during infection
contribute to (i) colonization of the host,
(ii) evasion of host defence, and (iii) dam-
age of host tissue. The flushing mecha-
nisms and the acidity of urine maintain
the bladder and most of the urethra
almost free of microorganisms most of the
time. For most bacteria and viruses, the
first encounter with their host involves
attachment to a eukaryotic cell surface,
which results in colonization of the host
prior to disease. In such cases, induced
antibody responses at the mucosal sur-
face could prevent attachment and abro-
gate colonization. The ideal target for
such antibodies are bacterial surface
proteins known as adhesins which medi-
ate microbial attachment to host tissue.
To initiate infection, bacterial pathogens
Immunology of the urinary tract | 1.5 |
must first be able to colonize an appropri-
ate target tissue of the host. This tropism
and the ability of the bacterium to breach
mucosal barriers and invade the host,
distinguishes pathogenic from commen-
sal organisms. Colonization begins with
the attachment of the bacterium to recep-
tors expressed by cells forming the lining
of the mucosa. This attachment will give
the opportunity to specialised cells to rec-
ognise this bacterium as “non-self” and
trigger the corresponding chain of events
(see Figure 1). Recurrent urinary tract
infection represents a case of successful
microbial host evasion and poses a major
medical health problem. We shall not dis-
cuss herein other, intimately related, sub-
jects such as basic mechanisms of disease
pathogenesis, host response induction,
and genetic variation in the innate host-
response or the epithelium-derived cathe-
licidin (See chapters 1.3. Host response
induction in urinary tract infections by
Björn Wullt, & Catharina Svanborg, and
1.4. Host reaction by Dave Klumpp &
Anthony Schaeffer) nor the role of bio-
film formation, which has a great impact
on the development or maintenance of
urological infections (See Chapter 1.6.
The role of biofilm infection in urogeni-
tal infections by Peter Tenke & Shinya
Uehara). In the overview presented
herein, we shall review the general char-
acteristics of the immune system and,
thereafter, describe in greater detail the
peculiarities of the immune system in the
genitourinary tract.
2. INNATE IMMUNITY
Innate and adaptive immunity have tra-
ditionally been considered as largely sepa-
rate, though complimentary, mechanisms
of defence against microbial threats.
The adaptive system, being evolution-
ally newer and having the capacity for
selectivity, adaptation, amplification, and
memory, has arguably been regarded as
more sophisticated and potent. However,
43
Chapter |1| Pathogenesis of urinary tract infections

Figure 1 Schematic chain of events In an immune reaction, Involving the Innate and the acquired, T’ and, B’ cell systems.

recent advances in our understand- Some macrophages are concentrated in

ing of the nature and functions of toll-
like receptors (TLRs) has sparked a new
appreciation of the extensive interde-
pendence and cross-talk between innate
and adaptive responses and has led to
renewed interest and higher regard for
the contribution of the innate arm of the
immune network. A phagocyte is a cell
that attracts (by chemotaxis), adheres
to, engulfs, and ingests foreign bodies.
Promonocytes originate in the bone mar-
row, after which they are released into
the blood (circulating monocytes,) and
eventually mature into macrophages.
the lungs, liver (Kupffer cells), lining
of the lymph nodes and spleen, as brain
microglia, kidney mesoangial cells, syno-
vial A cells, and osteoclasts. Once a mac-
rophage phagocytes a cell, it displays
some of its proteins, i.e. “epitopes”, on its
surface. These surface markers serve as
an alarm to other immune cells that then
infer the form of the invader. Dendritic
cells are covered with a maze of mem-
branous processes reminding nerve cell
dendrites. Like the macrophages, most
of them are highly efficient antigen pre-
senting cells (APCs). There are four basic

44

types: Langerhans cells, interstitial den-
dritic cells, interdigitating dendritic
cells, and circulating dendritic cells. The
Langerhans cells are specialized dendritic
cells strategically located in stratified
epithelia, such as those of the skin, oral
cavity, pharynx, oesophagus, upper air-
ways, urethra, and female reproductive
tract, which are exposed to a wide vari-
ety of microbial pathogens. Langerhans
cells play an essential role in the induc-
tion of T-lymphocyte responses against
viruses, bacteria, and parasites that gain
access to those epithelial surfaces, due to
their high antigen capture and processing
potential and their capacity to present
antigen peptides to T cells on migration
to the lymph nodes [1].
Further elements of the innate
immune system are the natural killer
cells which are found in blood and lymph
and are known to lyse cancer cells and
virus-infected body cells. They are large
granular lymphocytes that attach to the
glycoproteins on the surfaces of infected
cells and kill them. To discriminate
between “normal” and virus-infected,
tumour, or allogeneic cells, mammalian
natural killer cells monitor MHC class
I expression on target cells by means of
inhibitory natural killer cell receptors
(NKRs). The receptors transmit an inhib-
itory signal that cancels a program for
cytotoxic action previously triggered by
contact with the target cell. NKRs belong
to two distinct groups of molecules: immu-
noglobulin-like receptors and C-type lec-
tin receptors such as CD94, NKG2, and
NKR-P1 in humans and a group of Ly49
receptors in rodents [2]. Several authors
have shown that dendritic cells can acti-
vate natural killer cells and are prob-
ably responsible for natural killer cell
activation prior to the initiation of adap-
tive immunity. Furthermore, NK cells
activated in this fashion can restrict B
cell transformation, e.g. by Epstein-Barr
virus [3–4].
The polymorphonuclear neutrophil
leukocytes are non-dividing, short-lived
Immunology of the urinary tract | 1.5 |
phagocytes. The neutrophils provide
the major defence against pyogenic bac-
teria and are the first on the scene to
fight infection. Eosinophils are attracted
to cells coated with complement C3b,
where they release major basic protein
(MBP), cationic protein, perforins, and
peroxides, all of which fight infection.
Each of the cells in the innate immune
system binds to antigen using pattern-
recognition receptors. Over the course
of human development these receptors
for pathogen-associated molecular pat-
terns have evolved via natural selection
to be specific to certain characteristics
of broad classes of infectious organ-
isms. There are several hundred of these
receptors and they recognize patterns of
bacterial lipopolysaccharide, peptidogly-
can, bacterial DNA, dsRNA, and other
substances.
The complement system, which con-
sists of some 30 proteins circulating in
blood plasma, is a major enzyme system
which coats microbes with molecules that
make them more susceptible to engulf-
ment by phagocytes. Vascular permeabil-
ity mediators increase the permeability
of the capillaries to allow more plasma
and complement fluid to flow to the site
of infection and induce the neutrophils to
adhere to the walls of capillaries.
3. ADAPTIVE IMMUNITY
Lymphoid stem cells, which originate in
the bone marrow, give rise to the vari-
ous components of the acquired immune
system. Secondary lymphoid tissue is
“peripheral” tissue that provides an
environment for lymphocytes to encoun-
ter antigens and proliferate if neces-
sary. Secondary lymphoid tissue consists
of spleen, lymph nodes, bone marrow
and mucosa-associated lymphoid tis-
sue (MALT) in the tonsils, respiratory
tract, and gut. All of these structures
provide major portals for the entry of
foreign microorganisms into the body.
45
Chapter |1| Pathogenesis of urinary tract infections
Once in secondary lymphoid tissues,
lymphocytes may migrate from one lym-
phoid structure to another by vascular
and lymphatic channel systems. Mucosa
associated lymphoid tissue (MALT) con-
sists of large numbers of lymphocytes,
plasma cells and macrophages in the lam-
ina propria of digestive, respiratory and
nasal-associated lymphoid tissue in the
oropharyngeal cavity. After antigen expo-
sure activated lymphocytes and antigen
presenting cells migrate to regional lymph
nodes where immunologically active cells
are produced. These effector T and B
cells, plasma cell precursors and mem-
ory cells are returned via the circulation
to the mucosa that is threatened. In the
gut-associated lymphoid tissue (GALT)
some of the columnar epithelial cells over
lymph nodules are replaced by cells that
are specialized for antigen processing.
Their surface has short irregular micro-
villous folds and their basal cytoplasmic
folds surround many lymphocytes. These
“M” cells present unprocessed antigens to
the underlying lymphoid tissue [5].
Lymphocytes, the primary defenders of
the acquired immune system, play a cen-
tral role in regulating immune responses
to all antigens; they are the only cells that
have the intrinsic ability to recognize spe-
cific antigens. Lymphocytes are the major
components of lymph nodes; 95% reside
in the lymph nodes and spleen. There are
2 major populations of lymphocytes: T cells
have receptors for class I and class II anti-
gens, and B cells carry immunoglobulins
on their surface. B cells produce antibodies
and mediate what is called the “humoral”
immune response. T cells are involved in
immunologic regulation and mediate what
is called the “cellular” immune response.
During thymic development the recog-
nition of MHC proteins by developing
thymocytes influences their lineage com-
mitment, such that recognition of class
I MHC leads to CD8 T cell development
(killer cells), whereas recognition of class
II MHC leads to CD4 T cell development
(with four known cell types: Th1, Th2,
46
Th17 (IL-17 producing cells) and induced
regulatory T cells (iTreg; also of the CD8 T
cell lineage) [6–7].
When a B cell is stimulated by a par-
ticular antigen, it differentiates into a
lymphoblast which further differentiates
into a plasma cell. Plasma cells release
antibody until the antigen is destroyed.
Following exposure of a B cell to a specific
antigen, the antibody it produces may
combine with a toxic site on the antigen
molecule or cause its removal by phago-
cytes. In addition, memory of the offend-
ing antigen is retained for at least several
months.
Antibodies can be divided into 5 major
classifications: IgM, IgG, IgA, IgD, and
IgE. IgM is the main mediator of the pri-
mary immune response; for IgM “natu-
ral” antibodies there is no known contact
with the antigen that stimulated its pro-
duction [8]. Secreted IgM antibodies play
important roles in the initial phases of
humoral immune responses. Secreted
IgM in combination with complement
promotes antigen trapping and follicular
localization [9]. IgG is the principal medi-
ator of the secondary immune response,
which requires repeated exposure to the
same antigen; it is the major antibody
against bacteria and viruses. IgA is the
secretory immunoglobulin present in
body secretions and offers natural protec-
tion against nonspecific foreign antigens.
Secretory IgA (SIgA) is essential in pro-
tecting mucosal surfaces. It is composed
of at least two monomeric IgA molecules,
covalently linked through the J chain,
and secretory component (SC). The
dimeric/polymeric IgA (IgA(d/p)) is more
efficient when bound to the secretory
component in murine respiratory infec-
tion by anchoring the antibody to mucus
lining the epithelial surface [10]. The
function of IgD is not known and the IgE
antibodies present on basophils and mast
cells play a significant role in inflamma-
tory and allergic reactions. Structurally,
antibodies consist of four polypeptide
chains, two heavy and two light chains.

The light chains have an adaptor compo-
nent (Fab) that binds to antigen, and the
heavy chains have an adaptor component
(Fc) that activates complement.
T cells have molecules on their surfaces
called TcRs, which recognize peptide frag-
ments presented with human leukocyte
antigen (HLA) class I and HLA class II
molecules found on the surface of antigen
presenting cells (APCs). The structure of
the TcR is similar to the structure of an
antibody and also varies in one region
so that each TcR is unique. T cells are
divided into 4 functionally distinct, but
interactive, cell populations or subsets:
cytotoxic (CTL), memory (Tm), (helper)
Th, and suppressor (Ts). Tc and Tm cells
are referred to as effector cells because
they are cytotoxic to antigen-bearing
cells. Th and Ts cells are referred to as
regulatory cells. The cellular immune
response is mediated by T cells which can
recognize antigen only in association with
a class I MHC antigen displayed on the
surfaces of macrophages or antigen pre-
senting cells (APCs). T cells are triggered
by stimulation of antigen receptors on
their cell surfaces. Under the influence of
alloantigen and Th1-derived IL-2, clones
of alloantigen-responsive CTLs prolifer-
ate and seek direct contact with alloanti-
gen-bearing cells. CTLs are programmed
to produce molecules such as perforin and
granzymes which pass from the T-cell
cytoplasm into the donor cell, where they
mediate the killing of the donor cell.
4. TOLL-LIKE RECEPTORS, A BRIDGE
BETWEEN INNATE AND ADAPTIVE
IMMUNITY
Members of the toll-like receptor (TLR)
family mediate dorsoventral pattern-
ing and cellular adhesion in insects as
well as immune responses to microbial
products in both insects and mammals.
TLRs are characterized by extracellular
leucine-rich repeat domains and an intra-
cellular signalling domain that shares
Immunology of the urinary tract | 1.5 |
homology with cytoplasmic sequences of
the mammalian IL-1 receptor and plant
disease resistance genes. Ten human
TLRs have been cloned as well as RP105,
a protein similar to TLR-4 but lacking
the intracellular signalling domain [11].
Recent progress has revealed a require-
ment for accessory molecules in micro-
bial recognition by Toll-like receptors.
Gram-negative bacterial lipopolysaccha-
ride (LPS) activates cells through TLR-4
whereas lipopeptides and mycobacte-
rial lipoglycans activate cells through
TLR-2. Lipopolysaccharide (LPS) rec-
ognition requires LPS binding protein
(LBP), CD14, and MD-2. MD-2 is directly
involved in ligand binding and subse-
quent receptor activation, whereas LBP
and CD14 control ligand presentation
to the receptor complex, Toll-like recep-
tor (TLR-4)/MD-2. CD14 and LBP influ-
ence the amplitude of LPS responses and
LPS-induced type I interferon production.
TLR-2 is also reported to require simi-
lar accessory molecules. Innate immune
responses to microbial products driven
by TLRs are controlled by accessory mol-
ecules working upstream of TLRs [12].
The 11 known TLR receptors in mam-
mals (10 in humans) bind a restricted
repertoire of ligands and recruit com-
mon adaptor molecules to induce cell
signalling. Their description as “pattern
recognition receptors” reflects their abil-
ity to recognize exogenous ligands (lipid,
nucleic acid, or protein) associated with
pathogenic microorganisms—the so-called
pathogen-associated molecular patterns
(PAMPs). Various classes of pathogens can
be recognized by the same pattern PAMPs
[13]; that is, for example,TLR-4, which
recognizes uropathogenic Escherichia
coli, is a critical component of the lipopol-
ysaccharide (LPS) receptor complex,
which forms a detection system for Gram-
negative bacteria [14]. One further exam-
ple is the type VI toxin secretion pathway
which is shared by Pseudomonas aerugi-
nosa, Vibrio cholerae, Salmonella enter-
ica, Yersinia pestis, and Escherichia coli
47
Chapter |1| Pathogenesis of urinary tract infections
[15]. Dendritic cells and macrophages
possess receptors for carbohydrates that
are not normally exposed on the cells of
vertebrates, such as mannose, and there-
fore can discriminate between “foreign”
and “self” molecules. These antigen pre-
senting cells are particularly efficient at
initiating (priming) immune responses
for which immunologic memory has not
been established; that is, they activate
so-called naive T cells. Activation causes
dendritic cells to up-regulate the expres-
sion of B7 co-stimulatory molecules (also
known as CD80 and CD86) on their sur-
face. Co-stimulatory molecules are mol-
ecules that provide the signals necessary
for lymphocyte activation in addition
to those provided through the antigen
receptor. These activated dendritic cells
migrate to the local draining lymph node,
where they present antigen to T cells
[16]. It is apparent now that they also
have the capacity to recognize ligands
from non-pathogenic organisms as well
as various endogenous ligands, including
components of necrotic cells that activate
TLR-2, heat shock proteins, extracellular
matrix components, and Tamm-Horsfall
proteins in urine, which activate TLR-4.
In addition to their ability to augment
innate immune defence mechanisms
(opsonization and phagocytosis of bacteria
and viruses, activation of the complement
and coagulation cascades, and production
of type 1 interferons), TLRs have been
shown to play an important role in initia-
tion and modulation of adaptive immune
responses (via effects on dendritic cells), T
helper subset differentiation, and immune
tolerance [17]. Not present in humans
is TLR-11, that displays a distinct pat-
tern of expression in macrophages and
liver, kidney, and bladder epithelial cells.
Cells expressing TLR-11 fail to respond to
known TLR ligands but instead respond
specifically to uropathogenic bacteria.
Mice lacking TLR-11 are highly suscepti-
ble to infection of the kidneys by uropath-
ogenic bacteria, indicating a potentially
important role for TLR-11 in preventing
48
infection of internal organs of the uro-
genital system [18]. Pathogen recogni-
tion by TLRs promotes the production
of proinflammatory cytokines and acute
inflammation by recruitment of inflam-
matory cells to the site of infection by
activation of local stromal cells and cir-
culating leukocytes. TLR-2 can be found
on professional immune cells, including
neutrophils, macrophages, and dendritic
cells, but also on stromal cells through-
out the body [11]. As epithelial surfaces
provide the first line of defence against
infection, it is not surprising that they
prominently express TLRs. In the kid-
ney, TLRs (mainly TLR-2 and TLR-4) are
constitutively expressed on renal epithe-
lial cells, including the cells of Bowman’s
capsule, proximal and distal tubules, and
the lower urinary tract and bladder. Their
expression is up-regulated in response to
inflammation, and various potential roles
for TLRs have been proposed in renal
inflammation. In inflammation, TLR-4
on renal epithelia is required for protec-
tion against Escherichia coli challenge
from within the urinary tract, although
in response to systemic E. coli lipopoly-
saccharide challenge, TLR-4 on intrinsic
renal cells makes only a minor contribu-
tion to acute renal injury [17]. However,
the TLR-2 ligand Pam3CysSK4 can modu-
late the development of disease in acceler-
ated nephrotoxic nephritis by influencing
the development of adaptive immunity.
This agent can increase profoundly the
severity of disease, and mice that were
given the lipopeptide Pam3CysSK4 at
immunization and had a more severe
disease and also had a greater amount of
antigen-specific IgG1, IgG2b, and IgG3
in the serum and more IgG2b and IgG3
deposited within the glomeruli [19]. TLRs
can influence adaptive immune responses
and exert complex effects on Th1 and
Th2 polarization of CD4+ helper cell
responses [20]. Lipopolysaccharide from
Gram-negative bacteria stimulates TLR-4
to induce IL-12 and IFN-alpha produc-
tion by mouse and human dendritic cells,

which drives Th1 responses [21], although
this effect can be modulated by the level
of LPS exposure or the route of adminis-
tration which can determine the type of
inflammatory response generated [22].
TLRs also may stimulate the production
of humoral antibodies [23].
The TLR-4 signalling may initiate
the symptomatic disease process. In the
absence of TLR-4 signalling the infected
host instead develops an asymptomatic
carrier state. The TLR-4 dependence
has been demonstrated in mice and the
relevance of low TLR-4 function for pro-
tection for human disease was recently
confirmed in children with asymptomatic
bacteriuria, who expressed less TLR-4
than age matched controls [24–25]. The
molecular machinery utilized by bladder
epithelial cells for the recognition of E.
coli is very similar to that described for
traditional innate immune cells, such as
macrophages [26]. It should be reminded
that also the BCG-derived stimulus – a
mainstay for treating superficial bladder
carcinoma – could include TLR agonists;
it has been suggested that TLRs-2 and
-4 and possibly -9, present in immune
cells, mediate BCG-induced immune
responses [27].
5. THE GENITOURINARY TRACT
Human genito-urinary tracts represent
components of the mucosal immune sys-
tem with unique features. One particu-
lar element in the urogenital tract is the
evolutionary conserved Tamm-Horsfall
protein (THP); capable of both mediating
direct antimicrobial activity and alerting
immune cells. Tamm-Horsfall protein is
exclusively produced by the kidney in the
distal loop of Henle; the evidence indi-
cates that beyond a mere direct antimi-
crobial activity, Tamm-Horsfall protein
exerts potent immunoregulatory activ-
ity. In animal experiments, the genetic
ablation of the Tamm-Horsfall protein
gene leads to severe infection and lethal
Immunology of the urinary tract | 1.5 |
pyelonephritis. Recent data show that
Tamm-Horsfall protein links the innate
immune response with specific THP-
directed cell-mediated immunity. It has
been proposed that Tamm-Horsfall pro-
tein acts by two principle non-mutually
exclusive mechanisms involving the cap-
ture of potentially dangerous microbes
and the ability to induce robust pro-
tective immune responses against
uropathogenic bacteria. Tamm-Horsfall
glycoprotein not only binds to fimbri-
ated E. coli and activates complement
and dendritic cells, but also apparently
shows an immunoregulatory function in
UTI via a TLR-4-dependent mechanism
[28–29]. Animal studies have shown an
anatomically well organised lymphoid
tissue in the urinary tract, resembling
the mucosa-associated lymphoid tissue,
which is associated with the epithelium
of the renal pelvis and the ureter, respec-
tively. Immunocytochemistry revealed
S-100-immunoreactive dendritic cells in
both, structurally organised and structur-
ally non-organised lymphoid tissues [30].
Also humans have a well organised lym-
phoid tissue in the urinary tract, particu-
larly in the urinary bladder. The female
urethra has powerful antimicrobial
defence mechanisms, which appears to
differ in women with and without recur-
rent urinary tract infections. The female
urethra is lined by cells identical to those
of the vagina that respond similarly to
estrogens (plus immature basal and
parabasal cells in children) The defence
mechanism may be explained by the
shedding of uropathogens bound to exfo-
liating urethral cells, trapping of bacteria
by mucus secreted by the paraurethral
glands, intermittent washout by urine,
local production of immunoglobulins,
cytokines and defensins and mobiliza-
tion of leukocytes [31]. The human penile
urethra contains numerous IgA and J
chain-positive plasma cells, and the epi-
thelium expresses secretory component,
the transport molecule for polymeric IgA,
indicating that this region is an active
49
Chapter |1| Pathogenesis of urinary tract infections
site of secretory IgA-mediated immune
defence. The mucosa contains intraepi-
thelial dendritic cells while T lym-
phocytes are abundant and ubiquitous in
all regions of the urethra. Both CD8+ and
CD4+ subpopulations of T lymphocytes
are present in lamina propria and epi-
thelium, although CD8+ cells predomi-
nate. The majority of T lymphocytes are
positive for CD45RO (memory marker),
and many are also positive for the alpha
E beta 7 integrin (mucosal-associated
antigen). These data indicate that, in
addition to the bladder, the urethra is a
highly dynamic immunocompetent tissue
possessing all the necessary elements for
antigen presentation and both humoral
and cellular mucosal immune responses.
It is likely that this region plays a domi-
nant role in protecting the urogenital
tract against ascending infections [32].
Although a typical mucosa-associated
lymphoid tissue for generating common
mucosal immune responses is absent,
secretory IgA and IgG are present in tis-
sues and urine secretions of both females
and males. It has been reported that
locally synthesized sIgA immunoglobu-
lins are low or normal in the urine of
individuals with recurrent UTI with or
without bacteriuria at the time of the
study. UTI per se does not interfere with
sIgA secretion as shown by high sIgA in
patients with upper UTI. It has been sug-
gested that low urinary sIgA may repre-
sent one factor predisposing to recurrent
UTI [33–35]. These findings seems con-
troversial; an elevated s-IgA urinary
excretion was found in all patient groups
studied: patients with bladder catheter,
cystotomy and urinary tract infection,
urosepsis, chronic glomerulonephritis,
including IgA-nephritis, in renal allo-
graft recipients, compared to healthy
controls [36]. In a more recent study [37]
all cases of UTI had significantly higher
concentrations of urinary IgG antibody to
mixed coliform antigens. Asymptomatic
UTI cases had higher concentrations
50
of urinary IgG, IgM and IgA antibodies
when compared to controls; sIgA level
was highest in symptomatic UTI. The
discrepancies may be explained by the
fact that an antigen that does not reach
secondary lymphoid tissues in minimum
doses for a sufficiently long period of time
to be appropriately presented by antigen
presenting cells or without sufficient posi-
tive co-stimulatory signalling by dendritic
cells, is immunologically ignored [7].
Studies concerning the origin of pre-
cursors of mucosal IgA plasma cells per-
formed in animal models revealed that
the organized lymphoepithelial struc-
tures found along the gastrointesti-
nal and respiratory tracts are the main
source of such cells. These precursors,
which are committed to IgA synthesis,
mature in mesenteric lymph nodes and
enter the circulation through the thoracic
duct. Subsequently, they lodge in the
lamina propria of the intestinal, respira-
tory, and urogenital tracts, where termi-
nal differentiation into IgA plasma cells
occurs under the influence of locally pro-
duced cytokines [38]. Antibody responses
to genital infections or to locally applied
bacteria or derived vaccines are usually
modest, but alternative strategies for
eliciting genital tract antibodies are being
developed [39]. Animal studies show that
experimental UTIs by P. mirabilis yield
little protection to mice from re-infection
by a homologous strain. Despite produc-
tion of serum immunoglobulin G (IgG)
and IgM, vaccinated (infected and antibi-
otic-cured) mice did not show a decrease
in mortality upon re-challenge; the survi-
vors experienced only modest protection
from infection. There was no correlation
between serum IgG or IgM levels and pro-
tection from mortality or infection [40].
Studies with the FimH protein from
uropathogenic Escherichia coli show that
anti–adhesin antibodies can block micro-
bial attachment and subsequent disease.
Furthermore, the FimH animal studies
demonstrate that immunoglobulin IgG

antibodies alone, which transudate into
secretions after parenteral vaccination
with the FimH adhesin, are sufficient to
block colonization and infection [41]. The
intranasal vaccination with recombinant
modification of the tip adhesin of MR/P
fimbria or recombinant Lactococcus lactis
displaying Proteus mirabilis MrpA fim-
brial protein, were effective in preventing
UTIs with P. mirabilis in mice [42–43].
A small first clinical study was promising;
the response to P fimbria was stronger
among patients with P+ pyelonephritis
than among patients with pyelonephri-
tis caused by non–P-fimbriated E. coli
(P < 0.001) or patients with P+ lower
UTIs (P < 0.001) [44].
OM-89 is an immunomodulator of bac-
terial origin used for the prevention of
recurrent urinary tract infections. The
active principle is prepared from lysates
of 18 E. coli strains obtained by alkaline
lysis, followed by a two-stage tangential
flow filtration and then microfiltration to
remove larger insoluble cellular debris.
The resulting extract is a mixture of mod-
ified bacterial cell components includ-
ing proteins, peptides, free amino acids,
polysaccharides, amphiphilic molecules,
nucleotides and trace amounts of DNA.
Lipopolysaccharide (LPS), a well known
amphiphilic component of the Gram-
negative bacterial cell wall, is also chemi-
cally modified as part of the process. For
the main bacterial components, the modi-
fications are the following:
• Proteins – Partial cleavage of peptide
bonds generating smaller polypeptides,
racemization of amino acids from the
naturally occurring L-amino acids to
D-amino acids, and de-amination of
asparagine and glutamine residues
leading to acidic polypeptides (low pI)
containing aspartic acid and glutamic
acid residues.
• Amphiphilic Molecules – Modification
of E. coli lipopolysaccharide (LPS)
due to the base catalyzed hydrolysis
Immunology of the urinary tract | 1.5 |
of ester-bound fatty acids on the
glucosaminediphosphate which will lead
to partially deacylated LPS structures.
• RNA – Complete hydrolysis of RNA
into individual ribonucleotide and
rearrangement of phosphate groups.
• Other modifications including
partial solubilization of cell wall
polysaccharides.
OM-89 is marketed as an immunos-
timulant for the prevention of recurrent
urinary tract infections. Although there
is a rich body clinical studies (see 4.3.
Immunoprophylaxis by Kurt G. Naber),
only the developments of the latest years
have lead to a better understanding of its
mechanism of action. OM-89 is adminis-
tered per os and therefore its first site of
action will be in the digestive MALT. The
table provides an overview of the main
pharmacodynamic findings:
Thus, OM-89 binds to TLR-4, gener-
ally activates the immune system, and
reduces the number of recurrences of
UTIs. The bacterial extract hereby causes
the expression of CD40 and CD86, a
priming of immune responses, activat-
ing T-cells and the consequent cascade of
cytokine production (enhanced secretion
of TNF-alpha nd IL-12). The “in vitro”
data suggest that OM-89 acts via activa-
tion of antigen presenting cells, mono-
cytes (IL-1, TNF-alpha), T-lymphocytes
(IL-2, IFN-gamma) and natural killer
cells (NK-cells). While the effects on
NK-cells and IL-1 are stronger at the
lower OM-89 concentrations tested, thus
suggesting a bell-shaped dose/response
relation, the remaining effects stud-
ied are clearly concentration-depend-
ent. In human subjects, previously on
short treatment courses, OM-89 stimu-
lated the blastogenic transformation of
T-lymphocytes and the interferon pro-
duction ‘ex vivo’. A duplication of urinary
s-IgA concentrations was observed in girls
after three months of treatment with
OM-89. After three additional months of
51
Chapter |1| Pathogenesis of urinary tract infections

Table: Summary of the effects of OM-89

Non human data Human data

OM-89 is a selective TLR-4-agonist in bone marrow derived “In vitro” OM-89- activated human (monocyte derived)
macrophages (mice); this induced expression of CD40 and dendritic cells displayed a phenotype of mature DCs with
CD86, and an enhanced secretion (via MyD88) of TNF-alpha high levels of MHC molecules and increased levels of
and IL-12 [46]. co-stimulatory molecules (CD80, CD86) [48].
OM-89 stimulated the expression of the costimulatory
molecule CD40 on dendritic cells through TLR-4 but not
through [47].

Oral OM-89 inhibits bladder inflammation caused by instilled
LPS* (mice) [49].
The changes in circulating Immunoglobulin levels (specific
IgAs & IgGs) in pts. with recurrent UTIs did not correlate
significantly with the clinically effective OM-89 treatment
(vs. placebo) although small increases in specific IgAs were
observed [50].

Increases specific IgG & IgA levels against human bacteria in

orally treated mice [51–53].

Different animal models have shown the capacity of OM-89
to protect from both kidneys and bladder infections and
death after experimental infection by Salmonella t., E. coli,
Klebsiella p., Pseudomonas a. or Myxovirus influenza (mice)
[54–56].
In healthy volunteers, there was a non-significant increase
of T & B-lymphocyte counts and no relevant changes in the
IgM, IgG, IgA levels after OM-89 treatment [57].

The Plaque-Forming Cells (PFC) Test** with splenocytes OM-89 increased the levels of secretory IgA in the urine of
of mice has shown a dose-dependent immunostimulating girls with recurrent UTIs [59].
effect of OM-89 after oral administration [56, 58].

Mitogenic properties towards murine spleen cell cultures,

independent of LPS*-response status. In macrophages it
induces the translocation of NF-B into the cell nucleus and
release of RNI *** [60].

Older studies indicated an increased antigen presentation

capacity of the macrophages [61–62].

* LPS binds to TLR-4. TLR-4 activates both MyD88- and TRIF-dependent pathways and, in the bladder, a c-AMP dependent
rapid IL-6 mediated response. Low TLR-4 expression levels have been described in children with asymptomatic bacteriuria.
** The PFC test measures the non-specific immunostimulation of B cells.
*** radical nitrogen intermediates.

follow up, this effect had worn off, thus 7. CONCLUSIONS

indicating a transitory stimulation of uri-
nary s-IgA production. One of the authors
(Bessler) determined the circulating spe-
cific IgGs & IgAs in a sample of patients
with recurrent UTIs [45] and showed in
the OM-89 treated population a transi-
tory increase in the Proteus mirabilis and
OM-89 lyophilisate-specific IgA levels, not
observed in the placebo treated patients.
These transitory increases in specific IgA
levels are probably too small to explain
the therapeutic effect.
Immunology has gone through a tortu-
ous evolution with many theories since
Paul Ehrlich forwarded the first coher-
ent “side chain theory” in 1900, later fol-
lowed by the template model in the 1930s
and the clonal selection model described
by Burnet in 1957. About the same time,
Robert A. Good discovered thymus medi-
ated cellular immunity as assessed by
skin graft rejection, delayed-type hyper-
sensitivity and graft versus host assays,

52

independent of germinal centres, plasma
cells and circulating immunoglobulins.
The discovery in the late 1990s of toll-like
receptors as primary sensors of micro-
bial infection probably was just the latest
major discovery in this field. Hard work
and serendipity will certainly increase
our understanding of immunological phe-
nomena both in general and in the uri-
nary tract in particular. This will also
affect how infections are treated or pre-
vented. For example, it is only in recent
years that it has become evident that
the bacterial OM-89 binds to TLR-4 and
causes a kick-off of the immune system,
hereby reducing the number of recur-
rences of UTIs. Better understanding
of the factors involved in fighting UTIs
will certainly lead to better medicines or
improved usage of the existing ones.
REFERENCES
1. Anjuere F, del Hoyo GM, Martin P, and
Ardavin C, Langerhans cells develop from
a lymphoid-committed precursor. Blood,
2000. 96(5): 1633–7.
2. Khalturin K, Becker M, Rinkevich B, and
Bosch TC, Urochordates and the origin
of natural killer cells: identification of a
CD94/NKR-P1-related receptor in blood
cells of Botryllus. Proc Natl Acad Sci
U S A, 2003. 100(2): 622–7.
3. Brilot F, Strowig T, Roberts SM, Arrey F,
and Munz C, NK cell survival mediated
through the regulatory synapse with
human DCs requires IL-15Ralpha. J Clin
Invest, 2007. 117(11): 3316–29.
4. Strowig T, Brilot F, Arrey F, Bougras G,
Thomas D, Muller WA, and Munz C,
Tonsilar NK cells restrict B cell
transformation by the Epstein-Barr virus
via IFN-gamma. PLoS Pathog, 2008.
4(2): e27.
5. Smith SL, Immunologic Aspects of
Organ Transplantation, in Organ
Transplantation: Concepts, Issues,
Practice And Outcomes, Smith SL,
Editor. 2002, published electronically
on Medscape (www.medscape.com/
viewpublication/704_about).
Immunology of the urinary tract | 1.5 |
6. Paul WE, Th1 fate determination in CD4+
T cells: notice is served of the impor-
tance of IL-12! J Immunol, 2008. 181(7):
4435–6.
7. Adler HS and Steinbrink K, Tolerogenic
dendritic cells in health and disease:
friend and foe! Eur J Dermatol, 2007.
17(6): 476–91.
8. Brändlein S, Tumorimmunity: Specificity,
Genetics and Function of natural IgM
antibodies (http://www.opus-bayern.de/
uni-wuerzburg/volltexte/2003/666/),
in Pathologisches Institut, Fakultät für
Biologie. 2003, Universität Würzburg:
Würzburg.
9. Youd ME, Ferguson AR, and Corley RB,
Synergistic roles of IgM and comple-
ment in antigen trapping and follicular
localization. Eur J Immunol, 2002. 32(8):
2328–37.
10. Phalipon A, Cardona A, Kraehenbuhl
JP, Edelman L, Sansonetti PJ, and
Corthesy B, Secretory component: a new
role in secretory IgA-mediated immune
exclusion in vivo. Immunity, 2002. 17(1):
107–15.
11. Zarember KA and Godowski PJ, Tissue
expression of human Toll-like receptors
and differential regulation of Toll-like
receptor mRNAs in leukocytes in response
to microbes, their products, and cytokines.
J Immunol, 2002. 168(2): 554–61.
12. Miyake K, Roles for accessory molecules
in microbial recognition by Toll-like
receptors. J Endotoxin Res, 2006. 12(4):
195–204.
13. Jerome KR and Corey L, The Danger
Within. N Engl J Med, 2004. 350: 411–2.
14. Anders HJ and Patole PS, Toll-like recep-
tors recognize uropathogenic Escherichia
coli and trigger inflammation in the
urinary tract. Nephrol Dial Transplant,
2005. 20(8): 1529–32.
15. Yahr TL, A critical new pathway for toxin
secretion? N Engl J Med, 2006. 355(11):
1171–2.
16. Delves PJ and Roitt IM, The immune
system. First of two parts. N Engl J Med,
2000. 343(1): 37–49.
17. Tipping PG, Toll-like receptors: the
interface between innate and adaptive
immunity. J Am Soc Nephrol, 2006. 17(7):
1769–71.
53
Chapter |1| Pathogenesis of urinary tract infections
18. Zhang D, Zhang G, Hayden MS,
Greenblatt MB, Bussey C, Flavell RA,
and Ghosh S, A toll-like receptor that pre-
vents infection by uropathogenic bacteria.
Science, 2004. 303(5663): 1522–6.
19. Brown HJ, Sacks SH, and Robson MG,
Toll-like receptor 2 agonists exacerbate
accelerated nephrotoxic nephritis. J Am
Soc Nephrol, 2006. 17(7): 1931–9.
20. Iwasaki A and Medzhitov R, Toll-like recep-
tor control of the adaptive immune responses.
Nat Immunol, 2004. 5(10): 987–95.
21. Liu KJ, Dendritic Cell, Toll-Like Receptor,
and The Immune System. Journal of
Cancer Molecules, 2006. 2(6): 213–5.
22. Eisenbarth SC, Piggott DA, Huleatt JW,
Visintin I, Herrick CA, and Bottomly K,
Lipopolysaccharide-enhanced, toll-like
receptor 4-dependent T helper cell type 2
responses to inhaled antigen. J Exp Med,
2002. 196(12): 1645–51.
23. Meyer-Bahlburg A, Khim S, and
Rawlings DJ, B cell intrinsic TLR signals
amplify but are not required for humoral
immunity. J Exp Med, 2007. 204(13):
3095–101.
24. Ragnarsdottir B, Samuelsson M,
Gustafsson MC, Leijonhufvud I,
Karpman D, and Svanborg C, Reduced
toll-like receptor 4 expression in children
with asymptomatic bacteriuria. J Infect
Dis, 2007. 196(3): 475–84.
25. Ragnarsdottir B, Fischer H, Godaly
G, Gronberg-Hernandez J, Gustafsson
M, Karpman D, Lundstedt AC, Lutay
N, Ramisch S, Svensson ML, Wullt B,
Yadav M, and Svanborg C, TLR- and
CXCR1-dependent innate immunity:
insights into the genetics of urinary tract
infections. Eur J Clin Invest, 2008. 38
Suppl 2: 12–20.
26. Samuelsson P, Hang L, Wullt B, Irjala H,
and Svanborg C, Toll-like receptor 4
expression and cytokine responses in
the human urinary tract mucosa. Infect
Immun, 2004. 72(6): 3179–86.
27. Saban MR, Hellmich HL, Simpson C,
Davis CA, Lang ML, Ihnat MA,
O’Donnell MA, Wu XR, and Saban R,
Repeated BCG treatment of mouse bladder
selectively stimulates small GTPases and
HLA antigens and inhibits single-spanning
uroplakins. BMC Cancer, 2007. 7: 204.
54
28. Saemann MD, Weichhart T, Horl WH,
and Zlabinger GJ, Tamm-Horsfall pro-
tein: a multilayered defence molecule
against urinary tract infection. Eur J Clin
Invest, 2005. 35(4): 227–35.
29. Scherberich JE and Hartinger A, Impact
of Toll-like receptor signalling on urinary
tract infection. Int J Antimicrob Agents,
2008. 31 Suppl 1: S9–14.
30. Kerschbaum HH, Singh SK, and
Hermann A, Lymphoid tissue in the kid-
ney of the musk shrew, Suncus murinus.
Tissue Cell, 1995. 27(4): 421–4.
31. Kunin CM, Evans C, Bartholomew D,
and Bates DG, The antimicrobial defense
mechanism of the female urethra: a reas-
sessment. J Urol, 2002. 168(2): 413–9.
32. Pudney J and Anderson DJ,
Immunobiology of the human penile
urethra. Am J Pathol, 1995. 147(1):
155–65.
33. Riedasch G, Heck P, Rauterberg E, and
Ritz E, Does low urinary sIgA predispose
to urinary tract infection? Kidney Int,
1983. 23(5): 759–63.
34. James-Ellison MY, Roberts R, Verrier-
Jones K, Williams JD, and Topley N,
Mucosal immunity in the urinary tract:
changes in sIgA, FSC and total IgA with
age and in urinary tract infection. Clin
Nephrol, 1997. 48(2): 69–78.
35. Suman E, Gopalkrishna Bhat K, and
Hegde BM, Bacterial adherence and
immune response in recurrent urinary
tract infection. Int J Gynaecol Obstet,
2001. 75(3): 263–8.
36. Marx M, Weber M, Schafranek D,
Wandel E, Meyer zum Buschenfelde KH,
and Kohler H, Secretory immunoglobu-
lin A in urinary tract infection, chronic
glomerulonephritis, and renal transplan-
tation. Clin Immunol Immunopathol,
1989. 53(2 Pt 1): 181–91.
37. Ethel S, Bhat GK, and Hegde BM,
Bacterial adherence and humoral immune
response in women with symptomatic and
asymptomatic urinary tract infection.
Indian J Med Microbiol, 2006. 24(1):
30–3.
38. Mestecky J and Fultz PN, Mucosal
immune system of the human genital
tract. J Infect Dis, 1999. 179 Suppl 3:
S470–4.

39. Russell MW and Mestecky J, Humoral
immune responses to microbial infections
in the genital tract. Microbes Infect, 2002.
4(6): 667–77.
40. Johnson DE, Bahrani FK, Lockatell CV,
Drachenberg CB, Hebel JR, Belas R,
Warren JW, and Mobley HL, Serum
immunoglobulin response and protection
from homologous challenge by Proteus
mirabilis in a mouse model of ascending
urinary tract infection. Infect Immun,
1999. 67(12): 6683–7.
41. Wizemann TM, Adamou JE, and
Langermann S, Adhesins as targets for
vaccine development. Emerg Infect Dis,
1999. 5(3): 395–403.
42. Li X, Lockatell CV, Johnson DE, Lane
MC, Warren JW, and Mobley HL,
Development of an intranasal vaccine to
prevent urinary tract infection by Proteus
mirabilis. Infect Immun, 2004. 72(1):
66–75.
43. Scavone P, Miyoshi A, Rial A,
Chabalgoity A, Langella P, Azevedo V, and
Zunino P, Intranasal immunisation with
recombinant Lactococcus lactis display-
ing either anchored or secreted forms of
Proteus mirabilis MrpA fimbrial protein
confers specific immune response and
induces a significant reduction of kidney
bacterial colonisation in mice. Microbes
Infect, 2007. 9(7): 821–8.
44. Kantele A, Mottonen T, Ala-Kaila K, and
Arvilommi HS, P fimbria-specific B cell
responses in patients with urinary tract
infection. J Infect Dis, 2003. 188(12):
1885–91.
45. Bauer HW, Alloussi S, Egger G,
Blumlein HM, Cozma G, and Schulman
CC, A long-term, multicenter, double-
blind study of an Escherichia coli extract
(OM-89) in female patients with recurrent
urinary tract infections. Eur Urol, 2005.
47(4): 542–8; discussion 548.
46. Ryffel B and Quesniaux V, Draft Report
Study AP001. Comparison of AP-89 ver-
sus OM-89 TLR dependence in macro-
phage activation. Immunology, IEM6218,
CNRS F-45071 2008: Orleans.
47. Ryffel B, Toll-like receptors (TLR) activa-
tion by natural and synthetic TLR lig-
ands. Final report – project TR-2002/02.
2003.
Immunology of the urinary tract | 1.5 |
48. Schmidhammer S, Ramoner R, Holtl
L, Bartsch G, Thurnher M, and Zelle-
Rieser C, An Escherichia coli-based oral
vaccine against urinary tract infections
potently activates human dendritic cells.
Urology, 2002. 60(3): 521–6.
49. Lee SJ, Kim SW, Cho YH, and Yoon MS,
Anti-inflammatory effect of an Escherichia
coli extract in a mouse model of lipopoly-
saccharide-induced cystitis. World J Urol,
2006. 24(1): 33–8.
50. Bessler WG, Antibodies against OM-89,
Proteus mirabilis, and Klebsiella pneu-
moniae in sera of OM-89 treated patients
from the clinical study UV-1996/1
PROJECT UV 1999/03. 2002, Institut für
Molekulare Medizin und Zellforschung,
Arbeitsbereich Tumorimmunologie /
Vakzine. Universitätsklinikum Freiburg:
Freiburg.
51. Sedelmeier EA and Bessler WG,
Biological activity of bacterial cell-
wall components: immunogenic-
ity of the bacterial extract OM-89.
Immunopharmacology, 1995. 29(1):
29–36.
52. Baier W, Sedelmeier EA, and Bessler WG,
Studies on the immunogenicity of an
Escherichia coli extract after oral applica-
tion in mice. Arzneimittelforschung, 1997.
47(8): 980–5.
53. Huber M, Baier W, Serr A, and
Bessler WG, Immunogenicity of an E.
coli extract after oral or intraperitoneal
administration: induction of antibodies
against pathogenic bacterial strains. Int J
Immunopharmacol, 2000. 22(1): 57–68.
54. Elkahwaji JE, Prevention of Recurrent
Lower Urinary Tract Infections by 4
Bacterial Lysates in Female Mice (OM
PHARMA PROJECT: BL 2007/01 FINAL
REPORT «Preclinical». 2007, Department
of Surgery-Division of Urological Surgery,
University of Nebraska Medical Center:
Omaha.
55. Fontanges R, Study in mice of the pro-
tective and immunostimulating capac-
ity of LFC (OM-89) given enterally.
Experimental report. 1979.
56. Bosch A, Benedi VJ, Pares R, and Jofre J,
Enhancement of the humoral immune
response and resistance to bacterial infec-
tion in mice by the oral administration of
55
Chapter |1| Pathogenesis of urinary tract infections
a bacterial immunomodulator (OM-89).
Immunopharmacol Immunotoxicol, 1988.
10(3): 333–43.
57. Rosenthal M, Effect of a bacte-
rial extract on cellular and humoral
immune responses in humans.
J Immunopharmacol, 1986. 8(3): 315–25.
58. Ramsteiner, In vivo study of the immu-
nostimulating activity of OM-89 using the
plaque-forming cells technique in mice.
Experimental report 1990.
59. Riedasch G, Influence of OM-8930
on secretory IgA in urine of children
with frequent urinary tract infections.
56
Experimental Report & Rapport
Biometrix. 1985.
60. Huber M, Ayoub M, Pfannes SD,
Mittenbuhler K, Weis K, Bessler WG, and
Baier W, Immunostimulatory activity of
the bacterial extract OM-8. Eur J Med
Res, 2000. 5(3): 101–9.
61. Clot J, In vitro experiments with
OM-8930. Experimental report 1983.
62. Wybran J, Libin M, and Schandene L,
Enhancement of cytokine production and
natural killer activity by an Escherichia
coli extract. Onkologie, 1989. 12 Suppl 3:
22–5.
|1.6|

The role of biofilm infection in

urogenital infections
Peter Tenkea, Bela Kovesa, Shinya Ueharab, Hiromi Kumonb, Scott J. Hultgrenc, Chia Hungc
a
Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest, Hungary
b
Department of Urology, Okayama University, 2-5-1 Shikata-cho, Okayama city, 700-8558 Japan
c
Department of Molecular Microbiology, Washington University Medical School, St. Louis, MO 63011

ABSTRACT on their inner and outer surfaces once

In medicine biofilm infections have a
major impact on temporary and perma-
nent implants or devices placed in the
human body. The formation of biofilm
consists of several main steps: the depo-
sition of a conditioning film, followed by
the attachment of microorganisms, and
the final stage is the formation of a bio-
film structure. The biofilm is usually built
up from three layers: the linking film, the
base film and the surface film. Even in
the presence of antibiotics bacteria can
adhere, colonize and survive on implanted
medical devices, such as catheters, ure-
teral stents, penile prostheses or artificial
urinary sphincters. Antimicrobial agents
are effective against planktonic bacteria
and appear to clear mucosal surfaces of
adherent bacterial microcolonies but fre-
quently fail to eradicate bacterial biofilms
on urological devices. Urinary catheters
are readily targets of biofilm development
they are inserted. Uropathogenic E. coli
possess mechanisms to overcome host
defenses, and after bacterial binding and
invasion into superficial bladder epithe-
lial cells, they organize into biofilm-like
structures termed intracellular bacterial
communities (IBCs). Bacteria in these
intracellular niches can create a chronic
quiescent reservoir in the bladder, which
can persist undetected for several months
without bacteria shedding in the urine.
These bacteria are completely resistant
to 3- and 10-day courses of antibiotics.
Key words: biofilm, bacterial, urinary
tract, infection, catheter, encrustation,
intracellular, UPEC, IBC
1. INTRODUCTION
Bacterial adherence and the growth of
bacteria on solid surfaces as biofilm are
both naturally occurring phenomena. In
Chapter |1| Pathogenesis of urinary tract infections

medicine, biofilm infections have a major 3. MECHANISM OF BIOFILM

impact on temporary and permanent FORMATION
implants or devices placed in the human
body. In the process of endourological The formation of biofilm generally con-
development, a great variety of foreign sists of several main steps: the first step is
bodies have been invented besides ure- always the deposition of a conditioning film
thral catheters such as ureteral and pro- produced by the host to the foreign body. It
static stents, percutaneous nephrostomy is followed by the attachment of microorgan-
tubes, penile and testicular implants isms. The microbial adhesion and anchor-
and artificial urinary sphincters. Biofilm age to the surface are made by exopolymer
can also build up under natural circum- production. After this process their growth,
stances, for instance on the urothelium multiplication and dissemination can be
or on prostate stones. Biofilms can have observed (LoE 2b) [3–7] (Figure 1).
a positive impact as well, namely lin- Immediately after insertion of the
ing healthy intestine and the female device into the body the material sur-
genitourinary tract. Biofilms have sig- face enters into contact with body fluids
nificant implications for clinical pharma- (such as blood, urine, saliva and mucus)
cology, in particular related to antibiotic around the implant. In the urinary tract
resistance, drug adsorption onto and off Tamm-Horsfall glycoprotein, various
devices, and minimum inhibitory concen- ions, polysaccharides and other compo-
trations of drugs required for effective nents diffuse within minutes toward the
therapy. implant surface from the bulk urine [8].
Macromolecular components from these
body fluids adsorb extremely fast onto the
2. METHODS material surfaces to form a conditioning
film, prior to the arrival of the first organ-
We surveyed the extensive literature isms. Many of the molecules are proteina-
regarding biofilm formation and the ceous, such as serum albumin, fibrinogen,
role of biofilms in urogenital infections. collagen and fibronectin [9]. Thus, the
Studies were identified through a PubMed
search. We systematically searched for
meta-analyses of randomised controlled
trials available in Medline by giving pref-
erence to the Cochrane Central Register
of Controlled Trials and also considered
other relevant publications from the last
25 years until March 2008. The search
was performed by using the following
items in different combinations: biofilm,
infection, catheter, encrustation, urinary.
The identified publications were screened
by title and abstract. After exclusion of
duplicates a total of 53 publication were
included in the analysis, however there
was no prospective comparative study on
this subject within the publications.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [1–2]. Figure 1 Formation of biofilm.

58
 The role of biofilm infection in urogenital infections
creation of a conditioning film alters the
surface characteristics of implants. It is
for this reason that many implants with
altered surface characteristics (includ-
ing hydrophilic gels and antmicrobial
coatings) are ineffective as mechanisms
of preventing microbial attachment.
The role of the conditioning film is vital
as many pathogens do not have mecha-
nisms allowing them to adhere directly or
strongly onto bare implant surfaces [10].
The next step in the development of a
biofilm is the approach and attachment
of microorganisms. The ability of micro-
organisms to adhere to surfaces is influ-
enced by electrostatic and hydrophobic
interactions, ionic strength, osmolality
and urinary pH [11–12]. Several theories
have been put forth to explain the com-
plex interaction that occurs as a microbe
approaches and then attaches to a sur-
face. However, the precise mechanisms
of attachment to biomaterials are still
under investigation.
In order for bacteria to react to a sur-
face or an interface like an air-water
interface, these cells must be able to
‘sense’ their proximity to these surfaces.
The planktonic ‘free-floating’ bacterial
cells release both protons and signaling
molecules as they move through the bulk
fluid. These protons and signaling mol-
ecules must diffuse radially away from
the floating cell if not adjacent to any
surface or interface. But a significantly
higher concentration of either protons or
signaling molecules can develop on the
side of the bacterial cell close to any sur-
face. This allows the cell to sense that it
is near a surface because diffusion is lim-
ited on this side [6]. After the planktonic
bacterial cell has sensed the surface, it
may commit to the active process of adhe-
sion and biofilm formation.
There is no single process or theory
which can completely describe microbial
adhesion. The initial adhesion is reversible
and involves hydrophobic and electrostatic
forces. It is followed by irreversible attach-
ment provided by bacterial polysaccharides
| 1.6 |
which anchor the organisms to the sur-
face. Subsequently, colonization occurs
by species specific factors, such as slow
migration and spreading, rolling, packing
and adhesion of the progress. A developed
biofilm consists of groups of microorgan-
isms, sometimes in mushroom-like forms,
separated by interstitial spaces that are
filled with the surrounding fluid [13]. The
growth rates of organisms on a surface as
well as the strategies used by microorgan-
isms to spread over a surface are impor-
tant for colonization. These strategies are
species specific and can influence the dis-
tribution of a biofilm on a surface [14].
The final stage of microbial coloni-
zation of a surface is the formation of a
biofilm structure. At this point the micro-
organisms have created a microenvi-
ronment which protects against many
antimicrobial agents and host immune
defense mechanisms. Biofilm has been
described as having a heterogeneous
structure with a rough surface [15]. The
microcolony is actually the basic struc-
tural unit of the biofilm, similar to the
tissue which is the basic unit of growth
of more complex organisms. Depending
on the species involved, the microcolony
may be composed of 10–25% cells and
75–90% exopolysaccharide (EPS) matrix.
The biofilm contains ‘water channels’
which allows the transport of essential
nutrients and oxygen for the growth of
the cells [16]. Microorganisms within the
biofilm also secrete chemical signals that
mediate population density-dependent
gene expression, which has an important
role in biofilm development [17]. In sum-
mary, the biofilm is usually built up of
three layers (LoE 2b) (Figure 2) [18]:
1. the linking film which attaches to the
surface of tissue or biomaterials
2. the base film of compact
microorganisms
3. the surface film as an outer layer,
where planktonic organisms can be
released free-floating and spreading
over the surface.
59
Chapter |1| Pathogenesis of urinary tract infections
Figure 2 Composition of biofilm.
4. ANTIMICROBIAL SUSCEPTIBILITY
OF BACTERIA LIVING IN BIOFILM
The use of antibiotics is currently one of
the possibilities for the prevention of bio-
film formation. However, even in the pres-
ence of antibiotics bacteria can adhere,
colonize and survive on implanted medi-
cal devices as has been shown for urinary
catheters and ureteral stent surfaces in
vitro and in vivo [19–21]. In addition,
resistance to antimicrobial agents and
other chemicals is one of the greatest
problems in the age of widely used medi-
cal devices. The problem in conventional
clinical microbiology is how to treat
patients in the best way when choosing
antibiotics, the choice of which is based
on bacterial cultures derived from plank-
tonic bacterial cells which differ very
much from bacteria in the biofilm mode.
This can explain the clinical failure rate
of treating chronic bacterial infection.
The failure of antimicrobial agents to
treat biofilms has been associated with a
variety of mechanisms (LoE 4) [20–26].
One mechanism of biofilm resistance to
antimicrobial agents is the failure of an
agent to penetrate the full depth of the
biofilm (extrinsic resistance). For instance,
the extracellular matrix may block the
penetration at the very beginning.
• The organisms growing at a slower
rate within the biofilm are more
60
resistant to the effects of antimicrobial
agents, which require active growth.
• Bacteria within biofilm are phenotypi-
cally so different from their planktonic
counterparts that antimicrobial agents
developed against the latter often fail
to eradicate organisms in the biofilm.
Bacteria within a biofilm activate many
genes which alter the cell envelope, the
molecular targets and the susceptibil-
ity to antimicrobial agents (intrinsic
resistance). Current opinion is that
phenotypic changes caused by a genetic
switch, when approximately 65–80 pro-
teins change, play a more important
role in the protection from antimicrobial
agents than the external resistance pro-
vided by the exopolysaccharide matrix.
• Bacteria within a biofilm can sense the
external environment, communicate
with each other and transfer genetic
information and plasmids within biofilm.
• Bacteria in a biofilm can usually survive
the presence of antimicrobial agents at
a concentration 1000–1500 times higher
than the concentration that kills plank-
tonic cells of the same species.
5. ANTIBIOTICS AND BIOFILMS
Antimicrobial agents are effective against
planktonic bacteria and appear to clear
mucosal surfaces of adherent bacterial
 The role of biofilm infection in urogenital infections | 1.6 |

microcolonies but frequently fail to a

eradicate bacterial biofilms on urologi-
cal devices (LoE 2b). According to some
in vitro and in vivo studies beta-lactam
antibiotics and aminoglycosides can pre-
vent the formation and the extension of
‘young’ biofilms in growth. On the other
hand, fluoroquinolones, such as ofloxacin,
levofloxacin and ciprofloxacin, are effec-
tive in the case of both ‘young’ and ‘older’
biofilms because of their good penetrative
qualities. Moreover, they are present in
biofilms even one or two weeks after end-
ing antibiotic treatment [27–30].
b
Most researchers believe that antibiot-
ics only slow down the progress of biofilm
formation by eliminating unprotected
planktonic bacteria and stopping or
reducing the metabolic activity of bacte-
ria on the biofilm surface [25, 31–32].

6. BIOFILM ON INDWELLING
URETHRAL CATHETERS

Urinary catheters are ready targets for

biofilm development on their inner and
outer surfaces once they are inserted
(LoE 2b) (Figure 3). The long-term use
of them leads to infection in most cases.
The surface of a catheter (depending on
its material) provides sufficient circum-
stances for bacteria to adhere to and
spread along in two ways.
One route is when organisms ascend the
catheter extraluminally by direct inocula-
tion at the time of the catheter insertion
or migrate in the mucous sheath that sur-
rounds the external aspect of the catheter.
Extraluminal organisms are primarily
endogenous, originating from the gas-
trointestinal tract. These organisms colo-
nize the patient’s perineum and ascend
the urethra after catheter insertion [15,
33–36]. Approximately 70% of bacteriuria
in catheterized women is believed to occur
through extraluminal entry.
Microorganisms may also enter the
catheter by an intraluminal route, which
occurs primarily when organisms gain
Figure 3 a, b Scanning electron microscopic picture of a
developing biofilm.
access to the internal lumen of the cath-
eter via failure of the closed drainage
system or contamination of the collec-
tion bag. These organisms are usually
introduced from exogenous sources,
for instance cross-transmission from
the hands of health care personnel [15,
34–35, 37]. Adhesion of microorganisms
to catheter materials depends on the
hydrophobicity of the organism and cath-
eter surface.
7. THE ROLE OF BIOFILMS IN THE
ENCRUSTATION AND BLOCKAGE
OF CATHETERS
An additional problem relating to the use
of medical biomaterials in the urinary
tract environment is the development of

61
Chapter |1| Pathogenesis of urinary tract infections
encrustation and consecutive obstruction.
When the drained urinary tract becomes
infected by urease-producing bacteria
such as Proteus mirabilis, the bacterial
urease generates ammonia from urea and
elevates the pH of the urine. The urease
derived from Proteus mirabilis hydro-
lyses urea six to ten times faster than
the urease of other species (Morganella
morganii, Providencia stuartii, Klebsiella
pneumoniae, Proteus tettgeri, and Proteus
vulgaris). In the alkaline environment,
crystals of magnesium ammonium phos-
phate (struvite) and calcium phosphate
(hydroxyapatite) are formed and trapped
in the organic matrix surrounding the
cells [22–23, 38–39]. Progression of these
encrustations eventually blocks the cath-
eter lumen (LoE 2b) (Figure 4).
Figure 4 Developed encrustations and biofilms on
stents, different sections and enlargements.
62
8. BIOFILMS ON URETERAL STENTS
Bacterial biofilm can even develop on
ureteral stents that are lying completely
within the urinary tract (LoE 2a-b)
(Figure 4). Reid at al found that 90% of
indwelling silicone double J stents were
colonized by adherent bacteria, however
the incidence of urinary infection detected
clinically was only 27% [40]. Further
remarkable data showed that 45% of
adherent pathogens were present in low
numbers (101–102 per 1 cm3) and 55%
were in small and large microcolony bio-
films (>2 × 102 – 107). The isolated organ-
isms were Gram-positive cocci (77%),
Gram-negative rods (15%) and Candida
sp. (8%) [41]. The difficulty in detecting
biofilm formation by using conventional
laboratory procedures was confirmed in
a large study where 237 ureteral stents
were tested. It was shown that 68% of
stents were actually colonized but only
30% of patients were found to have bac-
teriuria [41]. Therefore, a negative urine
culture does not rule out the possibil-
ity of stent colonization. The study testi-
fied correlation between the length of the
indwelling time and the development of
infection.
9. PENILE PROSTHESES
Prosthesis-associated chronic pain due
to subclinical infection is more common
than clinically apparent infection [5].
Staphylococcus epidermidis accounts for
35–56% of infections and usually becomes
manifest approximately six months after
implantation [42]. S. epidermidis was cul-
tured in 40% of penile prosthesis removed
for malfunction with no clinical evidence
of infection [43]. Staphylococcal species
were also found to enhance biofilm forma-
tion. These cases can be ‘silent’ for many
years before becoming clinically evident
[44] in contrast to Gram-negative bacte-
rial infection (Pseudomonas aeruginosa,
E.coli, Serratia marcescens, and Proteus
 The role of biofilm infection in urogenital infections
mirabilis) which is responsible for 20% of
infections and which usually become man-
ifest in a month after implantation [43].
Antibiotic prophylaxis is desirable for
the above-mentioned facts. Since the most
common pathogen is Staphylococcus epi-
dermidis, first-generation cephalosporins
and broad-spectrum penicillin should be
used [45]. In cases of chronic pain, long-
term administration of quinolones eased
60% of symptoms. Failure involves the
necessity of implant removal.
10. ARTIFICIAL URINARY
SPHINCTERS (AUS)
Around 3% of AUS become infected and
symptoms are mainly associated with
the control pump device. Avoiding risk
factors such as infected urine, prolonged
urinary retention and large bladder
residuals can reduce this high occurrence
[43, 45]. Because parts of the sphincter
device form one continuous surface, the
AUS is suggested to be removed entirely
as the first step to eliminate the infec-
tion. Reimplantation must be preceded by
complete treatment of the infected area.
This is not always achievable as many of
these patients are paraplegic or have a
neurogenic bladder with recurrent UTIs
[43, 45].
11. INFECTED URINARY CALCULI
In the case of urease-producing bacteriu-
ria, infection can be concurrent with the
formation of struvite and calcium phos-
phate calculi as described above. The
infected calculi grow rapidly and pro-
vide a safe environment for the bacteria
adhered to the biofilm (LoE 3) [46]. The
most effective treatment strategy involves
complete removal of all stone frag-
ments during a stone operation (PCNL,
URS, ±combined with ESWL), prolonged
administration of antibiotics (8–10 weeks
for destroying urease-producing bacteria)
and metaphylaxis.
| 1.6 |
12. CHRONIC BACTERIAL
PROSTATITIS
Although the diagnosis and classification
of chronically inflamed prostate glands
have been standardized, great difficul-
ties still exist in differentiating chronic
non-bacterial inflammation from bacte-
rial inflammation. The prostatic ducts
and acini (being out of the sweeping effect
of streaming urine) provide safe circum-
stances for planktonic bacteria to multi-
ply rapidly and induce a host response
with infiltration of acute inflammatory
cells into the ducts. The ducts become
engorged with infiltrate composed of dead
and living bacteria as well as living and
dying acute inflammatory cells, desqua-
mated epithelial cells and cellular debris.
At this point it is relatively easy to eradi-
cate all the offending organisms which
are in a ‘planktonic state’ with appropri-
ate antibiotic therapy. If the bacteria per-
sist from either clinically acute or more
likely, subacute inflammation, they can
form sporadic bacterial microcolonies
or biofilms adherent to the epithelium
of the ductal system (LoE 2b) [47–48].
These bacteria also produce an exopoly-
saccharide slime or glycocalyx that envel-
ops these adherent microcolonies. The
bacteria persisting in the prostate gland
within these focal biofilms can provoke
persistent immunological stimulation and
subsequent chronic inflammation [47].
The diagnosis of chronic bacterial prosta-
titis can be difficult as colonized bacteria
will not get into the prostatic secretion
or urine sample. Antimicrobial therapy
eradicates the planktonic bacteria but
not the adherent bacterial biofilms deep
within the prostate gland. Another cause
of unsuccessful treatment may be the
fact that the bacteria within biofilms dif-
fer significantly from their planktonic
counterparts in metabolic rate, molecular
targets and expression of antimicrobial
binding proteins [5, 21]. The development
of diagnostic tools to recognize small
adherent bacterial biofilms which exist
63
Chapter |1| Pathogenesis of urinary tract infections
deep within the prostate gland in chronic
bacterial prostatitis is needed. New treat-
ment regimens should be carried out in
order to be able to deliver much higher
antibiotic concentrations to the biofilm
within the prostatic duct. Theoretically
this should improve treatment success
rates.
13. INTRACELLULAR BACTERIAL
BIOFILM-LIKE PODS IN THE
RECURRENT CYSTITIS
Entry of E. coli into the urinary tract is
not well understood, although sexual
intercourse is the most clearly defined
predisposing factor. Presumably, a small
number of E. coli from the vaginal or
enteric flora are introduced into the blad-
der during an average incident, and it
seems plausible that in most cases the
innate defenses in the bladder would
be able to prevent infection. However,
sometimes uropathogenic E. coli (UPEC)
clearly possess mechanisms to overcome
these defenses and establish a foothold in
the bladder. UPEC pathogenesis initiates
with bacterial binding of superficial blad-
der epithelial cells via the adhesin FimH
at the tips of bacterially expressed type
1 pili. Initial colonization events activate
inflammatory and apoptotic cascades
in the epithelium, which is normally
inert and only turns over every 6 to 12
months. Bladder epithelial cells respond
to invading bacteria in part by recogniz-
ing bacterial lipopolysaccharide (LPS)
via the Toll-like receptor pathway, which
results in strong neutrophil influx into
the bladder. In addition, FimH-mediated
interactions with the bladder epithelium
stimulate exfoliation of superficial epithe-
lial cells, causing many of the pathogens
to be shed into the urine. Genetic pro-
grams are activated that lead to differen-
tiation and proliferation of the underlying
transitional cells in an effort to renew the
exfoliated superficial epithelium. Despite
the robust inflammatory response and
64
epithelial exfoliation, UPEC are able to
maintain high titers in the bladder for
several days.
A bacterial mechanism of FimH-
mediated invasion into the superficial cells
apparently allows evasion of these innate
defenses. Initially, bacteria replicate rap-
idly inside superficial cells as disorgan-
ized clusters. Subsequently, bacteria in
the clusters divide without much growth
in cell size, resulting in coccoid-shaped
bacteria, presumably due to changes in
genetic programs. Furthermore, the bac-
terial clusters became highly compact
and organized into biofilm-like structures,
termed intracellular bacterial commu-
nities (IBCs), inside bladder superficial
cells [49] (Figure 5). The IBCs push the
bladder superficial cell membranes out-
ward to give a “pod” like appearance by
scanning electron microscopy (Figure 6).
Bacteria in the IBCs are held together
by exopolymeric matrices, reminiscent of
biofilm structures [50] (Figure 7–8). The
IBCs could still grow and expand in size.
At some point during this IBC develop-
mental process, bacteria on the edges of
IBCs become elongated again, become
Figure 5 Confocal laser scanning microscopic image
of an IBC at 16 hrs post-infection. Clinical UPEC isolate
expressing green-fluorescence protein (green) form a compact
and organized intracellular cluster inside a mouse bladder
superficial cell. The membrane of the bladder epithelial cells
are stained with Alexa Fluor 594-conjugated Wheat Germ
Agglutinin (red). A filamentous bacterium is also visible.
 The role of biofilm infection in urogenital infections
Figure 6 Scanning electron microscopic image of a UPEC
infected mouse bladder surface at 16 hrs post-infection.
UPEC infection resulted in formation of IBCs, which pro-
trude bladder superficial cell membrane out into the bladder
lumen.
Figure 7 Scanning electron microscopic image of a
broken UPEC infected mouse bladder cell. IBCs contain
both bacteria and exopolymeric matrices. SEM image of an
infected cell with partial membrane lost reveals the biofilm-
like nature of the IBCs. Bacteria are seen embedded within
fibrous networks.
| 1.6 |
Figure 8 High-resolution freeze-fracture microscopy
image of bacteria inside and IBC. High-resolution
freeze-fracture microcopy shows bacteria embedded within
fibrous networks. Image courtesy of Dr. John Heuser.
motile and start to move away from
IBCs, similar to the detachment event
in abiotic biofilms. Bacteria can exit out
of infected bladder cells, probably due to
compromised membrane integrity. UPEC
undergo such IBC cascade to increase in
numbers, resulting in high bacterial tit-
ers in the bladder. In addition, bacteria
in these intracellular niches can create a
chronic quiescent reservoir in the bladder,
which can persist undetected for several
months without bacteria shedding in the
urine [51–53]. These bacteria are com-
pletely resistant to 3- and 10-day courses
of antibiotics [54].
14. PYELONEPHRITIS AND BIOFILM
Once bacteria reach the kidney either
by ascending infection or vesicoureteral
reflux they are able to adhere to the
urothelium and papillae. Nickel et al
showed that bacteria could adhere in
thin biofilms to the urothelium before
invading the renal tissue with resultant
pyelonephritis (LoE 2b) [46]. These bac-
terial biofilms are more easily eradicated
by antimicrobial agents, in contrast to the
biofilms on catheter surfaces [50], which
may be ascribed to the effective syner-
gistic actions of antimicrobial agents
and host defenses against the biofilms on
urothelium [55].
65
Chapter |1| Pathogenesis of urinary tract infections
15. FUTURE RESEARCH
The future goal is to define easier meth-
ods for diagnosing and quantifying
biofilm infection and to develop antimi-
crobial agents which are effective against
bacteria enclosed in the biofilm.
16. CONCLUSIONS
Antimicrobial agents are effective against
planktonic bacteria and appear to clear
mucosal surfaces of adherent bacte-
rial microcolonies but frequently fail to
eradicate bacterial biofilms on urologi-
cal devices. Urinary catheters are ready
targets for biofilm development on their
inner and outer surfaces once they are
inserted. Use of medical biomaterials
in the urinary tract leads to the devel-
opment of encrustation. Progression of
these encrustations eventually blocks
the catheter lumen. Bacterial biofilm
can even develop on ureteral stents that
are lying completely within the urinary
tract. Infected calculi grow rapidly and
provide a safe environment for the bacte-
ria adhered to the biofilm. Bacteria per-
sisting in the prostate gland can form
focal biofilms and can provoke persist-
ent immunological stimulation and sub-
sequent chronic inflammation. In acute
cystitis bacteria initially replicate rap-
idly inside superficial cells as disorgan-
ized clusters, which finally become highly
compact and organized into biofilm-like
structures. Bacteria reaching the kid-
ney either by ascending infection or vesi-
coureteral reflux are able to adhere in
thin biofilms to the urothelium before
invading the renal tissue with resultant
pyelonephritis.
REFERENCES
1. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
66
2. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
3. Mardis HK and Kroeger RM, Ureteral
stents. Materials. Urol Clin North Am,
1988. 15(3): 471–9.
4. Biering-Sorensen F, Urinary tract infection
in individuals with spinal cord lesion.
Curr Opin Urol, 2002. 12(1): 45–9.
5. Choong S and Whitfield H, Biofilms and
their role in infections in urology. BJU
Int, 2000. 86(8): 935–41.
6. Costerton JW, Introduction to biofilm.
Int J Antimicrob Agents, 1999. 11(3–4):
217–21; discussion 237–9.
7. Habash M and Reid G, Microbial bio-
films: their development and significance
for medical device-related infections.
J Clin Pharmacol, 1999. 39(9): 887–98.
8. Fletcher M, Bacterial adhesion : molecu-
lar and ecological diversity. Wiley series
in ecological and applied microbiology.
1996, New York: Wiley-Liss. xi, 361 p.
9. Busscher HJ, Stokoos I, and Schakenraad
JM, Two-dimensional spatial arrange-
ment of fibronectin adsorbed to bioma-
terials with different wettabilities. Cells
Mater, 1991. 1: 19–57.
10. Busscher HJ and Weerkamp AH, Specific
and non-specific interactions in bacte-
rial adhesion to solid substrata. FEMS
Microbiol Rev, 1987(46): 165–173.
11. van Loosdrecht MC, Lyklema J, Norde
W, Schraa G, and Zehnder AJ, The role of
bacterial cell wall hydrophobicity in adhe-
sion. Appl Environ Microbiol, 1987. 53(8):
1893–7.
12. van Loosdrecht MC, Lyklema J,
Norde W, Schraa G, and Zehnder AJ,
Electrophoretic mobility and hydropho-
bicity as a measured to predict the initial
steps of bacterial adhesion. Appl Environ
Microbiol, 1987. 53(8): 1898–901.
13. Denstedt JD, Wollin TA, and Reid G,
Biomaterials used in urology: current
issues of biocompatibility, infection, and
encrustation. J Endourol, 1998. 12(6):
493–500.
14. Lawrence JR and Caldwell DE,
Behaviour of bacterial stream populations
 The role of biofilm infection in urogenital infections
within the hydrodynamic boundary layers
of surface microenvironments. Microbial
Ecol, 1987. 14: 15–27.
15. Reid G and Habash MB, Urogenital
microflora and urinary tract infections,
in Medical importance of the normal
microflora, Tannock GW, Editor. 1999,
Chapman & Hall: London. p. 423–440.
16. Denstedt JD, Reid G, and Sofer M,
Advances in ureteral stent technology.
World J Urol, 2000. 18(4): 237–42.
17. Costerton JW, Lewandowski Z, Caldwell
DE, Korber DR, and Lappin-Scott HM,
Microbial biofilms. Annu Rev Microbiol,
1995. 49: 711–45.
18. Busscher HJ, Bos R, and van der Mei
HC, Initial microbial adhesion is a deter-
minant for the strength of biofilm adhe-
sion. FEMS Microbiol Lett, 1995. 128(3):
229–34.
19. Caldwell DE, Cultivation and study
of biofilm communities, in Microbial
Biofilms, Lappin-Scott HM and Costerton
JW, Editors, Cambridge University Press:
Cambridge. p. 1195: 4–69.
20. Brown MR, Collier PJ, and Gilbert P,
Influence of growth rate on susceptibility
to antimicrobial agents: modification of
the cell envelope and batch and continu-
ous culture studies. Antimicrob Agents
Chemother, 1990. 34(9): 1623–8.
21. Brown MR, Allison DG, and Gilbert P,
Resistance of bacterial biofilms to anti-
biotics: a growth-rate related effect? J
Antimicrob Chemother, 1988. 22(6):
777–80.
22. Goto T, Nakame Y, Nishida M, and Ohi
Y, Bacterial biofilms and catheters in
experimental urinary tract infection. Int
J Antimicrob Agents, 1999. 11(3–4): 227–
31; discussion 237–9.
23. Choong S, Wood S, Fry C, and Whitfield
H, Catheter associated urinary tract infec-
tion and encrustation. Int J Antimicrob
Agents, 2001. 17(4): 305–10.
24. Nickel JC, Wright JB, Ruseska I, Marrie
TJ, Whitfield C, and Costerton JW,
Antibiotic resistance of Pseudomonas aeru-
ginosa colonizing a urinary catheter in vitro.
Eur J Clin Microbiol, 1985. 4(2): 213–8.
25. Goto T, Nakame Y, Nishida M, and
Ohi Y, In vitro bactericidal activities of
| 1.6 |
beta-lactamases, amikacin, and fluoroqui-
nolones against Pseudomonas aeruginosa
biofilm in artificial urine. Urology, 1999.
53(5): 1058–62.
26. Tsukamoto T, Matsukawa M, Sano M,
Takahashi S, Hotta H, Itoh N, Hirose T,
and Kumamoto Y, Biofilm in complicated
urinary tract infection. Int J Antimicrob
Agents, 1999. 11(3–4): 233–6; discussion
237–9.
27. Kumon H, Pathogenesis and management
of bacterial biofilms in the urinary tract. J
Infect Chemother, 1996. 2: 18–28.
28. Reid G, Habash M, Vachon D, Denstedt
J, Riddell J, and Beheshti M, Oral fluoro-
quinolone therapy results in drug adsorp-
tion on ureteral stents and prevention
of biofilm formation. Int J Antimicrob
Agents, 2001. 17(4): 317–9; discussion
319–20.
29. Reid G, Potter P, Delaney G, Hsieh J,
Nicosia S, and Hayes K, Ofloxacin for
the treatment of urinary tract infections
and biofilms in spinal cord injury. Int J
Antimicrob Agents, 2000. 13(4): 305–7.
30. Shigeta M, Komatsuzawa H, Sugai M,
Suginaka H, and Usui T, Effect of the
growth rate of Pseudomonas aeruginosa
biofilms on the susceptibility to antimicro-
bial agents. Chemotherapy, 1997. 43(2):
137–41.
31. Reid G, Biofilms in infectious dis-
eases and on medical devices. Int.
J. of Antimicrob.l Agents, 1999(11):
223–226.
32. Nickel JC, Downey J, and Costerton JW,
Movement of pseudomonas aeruginosa
along catheter surfaces. A mechanism in
pathogenesis of catheter-associated infec-
tion. Urology, 1992. 39(1): 93–8.
33. Warren J, Bakke A, Desgranchamps
F, Johnson JR, Kumon H, Shah J,
and Tambyah P Catheter-Associated
Bacteriuria and the Role of Biomaterial in
Prevention. Nosocomial and Health Care
Associated Infections In Urology. 2000.
34. Warren JW, Catheter-associated urinary
tract infections. Int J Antimicrob Agents,
2001. 17(4): 299–303.
35. Liedl B, Catheter-associated urinary tract
infections. Curr Opin Urol, 2001. 11(1):
75–9.
67
Chapter |1| Pathogenesis of urinary tract infections
36. Nickel JC, Catheter-associated urinary
tract infection: new perspectives on old
problems. Can J Infect Control, 1991.
6(2): 38–42.
37. Ganderton L, Chawla J, Winters C,
Wimpenny J, and Stickler D, Scanning
electron microscopy of bacterial biofilms
on indwelling bladder catheters. Eur J
Clin Microbiol Infect Dis, 1992. 11(9):
789–96.
38. Stickler DJ, Williams T, Jarman C, Howe
N, and Winters C, The encrustation of
urethral catheters, in The life and death of
biofilm, Wimpenny J, Handley P, Gilbert
P, and Lappin-Scott H, Editors. 1995,
Bioline: Cardiff. p. 119–125.
39. Kunin CM, Chin QF, and Chambers S,
Formation of encrustations on indwell-
ing urinary catheters in the elderly: a
comparison of different types of catheter
materials in “blockers” and “nonblockers”.
J Urol, 1987. 138(4): 899–902.
40. Reid G, Denstedt JD, Kang YS, Lam D,
and Naus C, Microbial adhesion and
biofilm formation on ureteral stents in
vitro and in vivo. J Urol, 1992. 148:
1592–1594.
41. Farsi HM, Mosli HA, Al-Zemaity MF,
Bahnassy AA, and Alvarez M, Bacteriuria
and colonization of double-pigtail ureteral
stents: long-term experience with 237
patients. J Endourol, 1995. 9(6): 469–72.
42. Carson CC, 3rd, Management of prosthe-
sis infections in urologic surgery. Urol
Clin North Am, 1999. 26(4): 829–39, x.
43. Licht MR, Montague DK, Angermeier
KW, and Lakin MM, Cultures from
genitourinary prostheses at reoperation:
questioning the role of Staphylococcus
epidermidis in periprosthetic infection.
J Urol, 1995. 154(2 Pt 1): 387–90.
44. Fishman IJ, Scott FB, and Selam IN,
Rescue procedure: an alternative to com-
plete removal for treatment of infected
penile prosthesis. J Urol, 1987. 137:
202A.
45. Carson CC, Infections in genitourinary
prostheses. Urol Clin North Am, 1989.
16(1): 139–47.
46. Nickel JC, Olson M, McLean RJ, Grant
SK, and Costerton JW, An ecological
68
study of infected urinary stone genesis in
an animal model. Br J Urol, 1987. 59(1):
21–30.
47. Nickel JC, Olson ME, Barabas A,
Benediktsson H, Dasgupta MK, and
Costerton JW, Pathogenesis of chronic
bacterial prostatitis in an animal model.
Br J Urol, 1990. 66(1): 47–54.
48. Nickel JC, Olson ME, and Ceri H
Experimental prostatitis., in Prostatitis.,
Weidner W, Madsen PO, and Schiefer HG,
Editors. 1993, Springer-Verlag: Berlin ;
New York. p. xiii, 276 p.
49. Justice SS, Hung C, Theriot JA, Fletcher
DA, Anderson GG, Footer MJ, and
Hultgren SJ, Differentiation and devel-
opmental pathways of uropathogenic
Escherichia coli in urinary tract patho-
genesis. Proc Natl Acad Sci U S A, 2004.
101(5): 1333–8.
50. Nickel JC, Costerton JW, McLean RJ,
and Olson M, Bacterial biofilms: influ-
ence on the pathogenesis, diagnosis and
treatment of urinary tract infections. J
Antimicrob Chemother, 1994. 33 Suppl
A: 31–41.
51. Mysorekar IU and Hultgren SJ,
Mechanisms of uropathogenic Escherichia
coli persistence and eradication from the
urinary tract. Proc Natl Acad Sci U S A,
2006. 103(38): 14170–5.
52. Mulvey MA, Schilling JD, and Hultgren
SJ, Establishment of a persistent
Escherichia coli reservoir during the
acute phase of a bladder infection. Infect
Immun, 2001. 69(7): 4572–9.
53. Anderson GG, Palermo JJ, Schilling
JD, Roth R, Heuser J, and Hultgren SJ,
Intracellular bacterial biofilm-like pods
in urinary tract infections. Science, 2003.
301(5629): 105–7.
54. Schilling JD, Lorenz RG, and Hultgren
SJ, Effect of trimethoprim-sulfamethoxa-
zole on recurrent bacteriuria and bacterial
persistence in mice infected with uropath-
ogenic Escherichia coli. Infect Immun,
2002. 70(12): 7042–9.
55. Nickel JC, The bottle of the bladder: the
pathogenesis and treatment of uncompli-
cated cystitis Int Urogynecol J, 1990(1):
218–222.
 Chapter |2|

Aetiology,
antimicrobial resistance of
uropathogens, antibiotic
therapy and policy
Chair: Gunnar Kahlmeter

CHAPTER OUTLINE
2.1 Introduction 70
2.2 Uncomplicated and community acquired urinary
tract infections: aetiology and resistance 72
2.3 Complicated and healthcare associated urinary
tract infections: aetiology and antimicrobial resistance 82
2.4 Methicillin-resistant staphylococcus aureus (MRSA)
in urology 92
2.5 ESBL and multi-resistance in urology 102
2.6 Antimicrobials in urogenital infections 111
2.7 Antibiotic policy 127
|2.1|
Introduction
Gunnar Kahlmeter
Corresponding author: Gunnar Kahlmeter, MD
Professor and Head of Clinical Microbiology, Central Hospital, S-35185 Växjö Sweden
Tel 0046-470-587477, Fax 0046-470-587455, E-mail: gunnar.kahlmeter@ltkronoberg.se
Uncomplicated (uUTI) and complicated
urinary tract infections (cUTI) share
Escherichia coli as the most common
etiology. In uUTI, E.coli is without
comparison the dominating pathogen.
S. saprophyticus, is the second most com-
mon pathogen. In temperate climates it
shows a pronounced seasonal variation,
with cases concentrated in late summer
and early autumn. E.coli also dominates
cUTI, but here in competition with many
other Enterobacteriaceae (Klebsiella
spp, Proteus spp, Enterobacter spp) and
Enterococcus species, Staphylococcus
species and Streptococcus agalactiae. In
healthcare associated UTI (HAUTI), the
flora is supplemented with Pseudomonas
aeruginosa, Acinetobacter spp and
Candida spp.
Antimicrobial resistance is a rapidly
increasing problem all over the world.
The problem is less pronounced in uUTI,
although ESBL-producing organisms are
increasingly common in the community.
In cUTI or HAUTI the situation will mir-
ror that of the hospital or institution.
Some Acinetobacter spp, Pseudomonas
and Enterobacteriaceae are occasionally
resistant to almost all therapeutic alter-
natives. Irrespective of species, and also
in uUTI, associated resistance (e.g. an
organism resistant to one antibiotic is
prone to be resistant to any other antibi-
otic) is now very common.
In uUTI, empirical therapy is still
recommended, but in geographic areas
or in age groups where antimicrobial
resistance is high, pre-emptive cultur-
ing (a culture secured prior to instituting
empirical therapy) is recommended. In
cUTI and HAUTI therapy, irrespective of
whether empirical or not, should always
be preceded by a culture. Special atten-
tion should be given to the therapeutic
dilemma caused by methicillin resistant
Staphylococcus aureus (MRSA) and
“ESBL-producing” Enterobacteriaceae in
HAUTI, especially in urology. Due to the
nature of “complicated” and “healthcare
associated” UTI, eradication of causa-
tive organisms is difficult at the best
of times, and even more so when mul-
tiresistant bacteria, not least MRSA or
ESBL-producing organisms, are involved.

Infection control strategies to prevent
dissemination of these organisms are
necessary.
Antibiotics used for the treatment of
uUTI, cUTI and HAUTI are evaluated.
For uUTI antibiotics which are used only
for UTI are recommended for first line
therapy. By doing this, the selection pres-
sure on other classes of antibiotics, with
more general use, is removed or dimin-
ished. For cUTI and HAUTI, antibiot-
ics with broader spectrum and a more
“systemic” set of pharmacokinetic and
pharmacodynamic properties are often
needed.
Introduction | 2.1 |
UTI is a common reason for antimi-
crobial therapy and by addressing issues
related to the treatment and prophylaxis
of UTI, antibiotic consumption can be
reduced. Each institution should develop
an antibiotic policy to further the pru-
dent and economical use of antibiotics.
Antibiotic policies address prescribing
strategies, dosing, route of administra-
tion, duration and timing of antibiotic
therapy to maximize clinical cure or pre-
vention of infection while limiting the
unintended consequences of antibiotic
use, including toxicity and selection of
resistant microorganisms.
71
|2.2|

Uncomplicated and community

acquired urinary tract infections:
aetiology and resistance
Martin Sundqvist1,2, Gunnar Kahlmeter1,3
1
Dept of Clin Microbiology, Central Hospital, Växjö Sweden
2
Dept of Medical Sciences, Div of Infectious diseases, Uppsala University, Uppsala, Sweden
3
Dept of Medical Sciences, Div of Clinical Bacteriology, Uppsala University, Uppsala, Sweden
Corresponding author: Gunnar Kahlmeter, MD, Professor, Dept of Clin Microbiology, Central Hospital
S-35185 Växjö, Sweden
Tel +46-470-588.000, Fax +46-470-587.455, gunnar.kahlmeter@ltkronoberg.se

ABSTRACT low-resistance alternatives: pivmecil-

E. coli and S. saprophyticus are the two
dominating pathogens in uncompli-
cated community acquired urinary tract
infections. In E. coli the level of anti-
biotic resistance is accelerating at an
amazing speed. This is especially true
for trimethoprim (alone and in combi-
nation with sulfamethoxazole) and for
fluoroquinolones with resistance rates
of 15–45% and 10–20% respectively. An
additional problem is that trimethoprim
resistance in fluoroquinolone resistant
E. coli is at least 48% and that fluoroqui-
nolone resistance in trimethoprim resist-
ant E. coli is at least 25%. This means
that in a man presenting with UTI there
is little choice and empirical therapy
may well fail. In women there are three
linam, nitrofurantoin and fosfomycin.
These have not been thoroughly evalu-
ated in men but are thought to be insuf-
ficiently active; something that needs
further investigation.
Key words: resistance development,
Escherichia coli, Staphylococcus sapro-
phyticus
SUMMARY OF RECOMMENDATIONS
A prerequisite for successful antibiotic
therapy is the good understanding of aeti-
ology and antimicrobial resistance. E. coli
dominates the aetiology of both uncom-
plicated urinary tract infections (UTI)
and complicated UTI (cUTI). However, the
 Uncomplicated and community acquired urinary tract infections
latter, and especially healthcare associ-
ated UTI (HAUTI), sprouts a much larger
spectrum of microorganisms than UTI.
Successful empirical therapy rests on the
absolute majority of microorganisms being
susceptible to the drugs chosen. A rapid
worldwide increase in antimicrobial resist-
ance in pathogens causing UTI and espe-
cially cUTI threatens to jeopardize our
empiric traditions. Regional surveillance
studies should be performed regularly to
guide the choice of empiric antimicrobial
therapy (GoR A).
In uncomplicated UTI it is often justifi-
able to initiate antibiotic therapy without
performing a urine culture, provided that
the local epidemiology of antimicrobial
resistance in E. coli is known. A urine
culture should be performed prior to or
in conjunction with treatment in the
following situations:
1. When the patient has received anti-
biotic treatment in the last three
months (GoR B).
2. When planning to give empiric ther-
apy with amoxicillin, sulfamethoxa-
zole, trimethoprim or co-trimoxazole,
to all of which resistance rates are
high and co-resistance to other drugs
common (GoR B).
3. When planning to give empiric
treatment with a fluoroquinolone or
a cephalosporin in areas where local
resistance rates are high (>10%),
i.e. in areas where ESBL-producing
Enterobacteriaceae are increasingly
common (GoR B).
4. When antimicrobial treatment has
recently failed (GoR B).
5. When there are signs of pyelonephritis.
(GoR A)
6. When the patient is a man (GoR B).
7. When the patient is a woman with
complicated and/or recurrent UTI and/or
is over the age of 65 (GoR B).
8. When the patient has a healthcare
associated UTI (GoR A).
| 2.2 |
1. INTRODUCTION
In order to recommend optimal empiric
therapy for each kind of infection we
should be aware of the most common
pathogens and their antibiotic suscepti-
bility in the local area. This review was
undertaken to describe the basics of
resistance development in Escherichia
coli and the worldwide trends in the aeti-
ology and antibiotic resistance of uncom-
plicated UTI. This cannot replace local
epidemiological studies which should be
available.
2. METHODS
The PubMed database was searched for
the terms uncomplicated UTI and cysti-
tis in combination with antibiotic resist-
ance. Articles in English regarding UTI in
adults and judged by the authors of this
review as being of sufficient quality were
included and these formed the basis for
the recommendations in this chapter. In
addition, articles from the last 10 years
describing the antimicrobial resistance
of UTI pathogens were retrieved. Despite
the fact that the rating system is not
optimal for this purpose, the studies were
rated according to the level of evidence
(LoE) and the grade of recommendation
(GoR) using ICUD standards (for details
see Preface) [1–2].
3. AETIOLOGY OF UNCOMPLICATED
UTI
Virtually any bacteria can occasionally
cause a UTI. Although the definition of
uncomplicated UTI is under debate, we
here use: that the bacterium can infect the
(anatomically and physiologically) nor-
mal urinary tract of a woman [3–4] leav-
ing only E. coli and S. saprophyticus [5]
as primary pathogens (Table 1) (LoE 2a).
These two pathogens dominate the picture
73
Chapter |2| Aetiology, antimicrobial resistance of uropathogens

Table 1 Pathogens causing urinary tract infections.

Primary pathogens

E. coli and S. saprophyticus LoE 2a

Secondary pathogens

Bacteria not normally present in the periurethral flora and which only rarely cause uncomplicated UTI eg. K. pneumoniae
(and occasionally other Enterobacteriaceae), E. faecalis and S. agalactiae. LoE 2a

Doubtful pathogens

Bacteria belonging to the normal skin flora/periurethral flora eg. Coagulase Negative Staphylococci (CNS other than
S. saprophyticus), coryneform bacteria and viridans streptococci. LoE 2a

Significant bacteriuria in women with specific UTI symtoms: LoG 2a

Primary pathogens: ≥106 cfu/l

Secondary pathogens in pure culture: ≥107 cfu/l

Doubtful pathogens in pure culture: ≥108 cfu/l

particularly in women under the age of
50 [6–8] (LoE 2a). In older women the eti-
ological spectrum is more complex [9–10]
(LoE 2b). One can argue that infections
in women over 50 are not truly uncompli-
cated, as the number of predisposing fac-
tors (such as incontinence) increase with
age [9–10] (LoE 2b). Secondary pathogens
(Table 1) play an increasing role while the
importance of S. saprophyticus decreases.
Irrespective of age and geography, E. coli
is by far the most common pathogen
[11–14] (LoE 2a). This also holds true
when we broaden the definition to include
all community acquired UTI in men and
women with recurrent infections. The
special features of UTI in children will
not be discussed here, although E. coli
also dominates the aetiology in children
[15] (LoE 2a).
Escherichia coli is held responsible for
at least 80% of all uncomplicated UTI
[11, 13] (LoE 2a) in women under the
age of 65 and at least 50% of community
acquired UTI in other groups [7] (LoE
2a). During the late summer/early fall
in the northern hemisphere [16–17], and
with typical seasonal variation (Fig 1),
as many as 20% of uncomplicated UTI
are caused by S. saprophyticus [18] (LoE
2b). The prevalence of S. saprophyticus is
reported to be 2–10% [19] and 2.3–4.8% in
the ECO-SENS study on uncomplicated
UTI in Europe [11] (LoE 2a). This level
seems to be true not only in Europe and
the USA as, although reported uncom-
mon in Israel [20], a recent study showed
S. saprophyticus to be the third most
common (6.4%) UTI-pathogen in north-
ern Iran [12] (LoE 2b). S. saprophyticus
is more common in younger women [18]
and is reported to colonize the rectum
and, to a lesser extent, the cervix and
urethra in a relatively small proportion
of women [17] (LoE 2b). Other bacteria
occur, including E. faecalis, S. agalactiae,
P. mirabilis and K. pneumoniae, but are
more frequent in men and in the elderly.
Some of these bacteria will be described
more thoroughly in the next chapter and
are therefore only listed here (Table 1).
4. ESCHERICHIA COLI
Escherichia coli is a Gram-negative
rod belonging to the genera of Entero-
bacteriacae. It is a commensal bacte-
rium and is common not only in the
human gut, but also in animals. It is the
most frequent facultative aerobic found
in the intestinal tract [21] (LoE 2a).

74
 Uncomplicated and community acquired urinary tract infections
This, however, corresponds only to a
small proportion of the total flora in
the distal colon, as most of the flora in
this part of the intestine are anaerobic
bacteria (Bacteroides spp and bifidobac-
teria) [21] (LoE 2a). The dominating E.
coli strain in the faecal flora will be the
strain most likely to colonize the periu-
rethral space and to infect the urinary
tract [22] (LoE 2b).
5. ANTIMICROBIAL RESISTANCE
Antimicrobial resistance is increasing
worldwide in almost all pathogenic bac-
teria and fungi. This is certainly true for
E. coli in which resistance to ampicillin,
sulphonamides and trimethoprim, alone
or combined, has gradually increased over
more than 50 years. The recent dramatic
increase in resistance to fluoroquinlones,
cephalosporines (due to the rapid increase
in and spread of extended spectrum beta-
lactamases (ESBLs)) and aminoglycosides
is especially problematic [23] (LoE 3).
Paradoxically, this increase in resist-
ance will cause more therapeutic prob-
lems in complicated and febrile UTI than
in uncomplicated UTI, since three drugs
to which resistance is still uncommon,
fosfomycin, nitrofurantoin and pivmecil-
linam, can be used in the latter but not in
the former. However, on occasion, intrave-
nous carbapenems are the only antibiot-
ics to which the isolate is susceptible. The
magnitude of the problem is best realised
when the following is understood about
resistance development.
5.1 Development of antibiotic
resistance
A prerequisite for antibiotic resistance is
the occurrence of de novo mutations (as
exemplified by point mutations in the gyrA
gene leading to quinolone resistance) and
the ability of bacteria to incorporate new
genetic material into their genome via hor-
izontal gene transfer (exemplified by the
| 2.2 |
modified dfr-genes encoding trimethoprim
resistance). However, this will only be suc-
cessful when the changes encoded for by
the new gene/mutation, are favoured by
the presence of antibiotics in the environ-
ment or if the mutation is combined with
other new traits such as an increased
spreading capacity or ability to survive
[24] (LoE 3). The most important form of
acquisition and spread of resistance in
E. coli and other Enterobacteriacae as well
as in enterococci is horizontal gene trans-
fer (HGT). This way of spreading antibi-
otic resistance genes is very efficient since
many resistance genes can be spread on
the same mobile genetic elements (usually
conjugative plasmids) [25–26] (LoE 3). In
this way the different genetic mechanisms
will hitchhike on one another and thus be
spread as whole packages of resistance,
converting fully susceptible bacteria into
multiresistant organisms in one trans-
fer event [27–28] (LoE 3). The antibiotic
resistance genes can then, at the same
time, be spread vertically in an epidemic
strain [29] and horizontally to other mem-
bers of the same species [26] and to other
species [28] (LoE 3). It is important to
stress the importance of the dissemina-
tion of antibiotic resistance by successful
lineages of bacteria (as exemplified by the
spread of ST 131) containing several resist-
ance genes (including ctxM-15), which are
spreading over the world [30–31] (LoE 3).
In the same way, the E. coli co-trimoxazole
resistant Clonal group A (CgA) causing
UTI in young college women, behaves as
an epidemic strain [29] (LoE 3). It is how-
ever important to point out that these line-
ages or clones are quite heterogeneous and
clonal outbreaks within the clones have
been reported [32] (LoE 3).
There is evidence to suggest that
bacteria already carrying one or more
resistances are better suited to acquire
additional resistance mechanisms than
wild type lineages. Data from Sweden
shows that the rate of E. coli without any
resistance only decreased from 76.4% in
1993 to 76.1% in 2003 while resistance to
75
Chapter |2| Aetiology, antimicrobial resistance of uropathogens

S. saprophyticus, Kronoberg county 1990–2008

60
0–30 years total

50

40

30

20

10

0
jan-90

jan-91

jan-92

jan-93

jan-94

jan-95

jan-96

jan-97

jan-98

jan-99

jan-00

jan-01

jan-02

jan-03

jan-04

jan-05

jan-06

jan-07

jan-08
jul-90

jul-91

jul-92

jul-93

jul-94

jul-95

jul-96

jul-97

jul-98

jul-99

jul-00

jul-01

jul-02

jul-03

jul-04

jul-05

jul-06

jul-07

jul-08
Figure 1 A distinct seasonal variation in the number of S. saprophyticus isolated from urinary specimens, County Kronoberg in
southern Sweden, 1990–2008.

several antibiotics [33–34] (LoE 3), such
as ampicillin (19–26%) and trimethoprim
(8–12 %) increased. The ECO-SENS study
on E. coli causing non-complicated UTI
in 17 European countries in 2000 showed
that the corresponding figure in Spain
was 50% [34] (LoE 3). These figures are
especially important when discussing
empirical treatment.
5.2 Antibiotic resistance in E. coli
The majority of uncomplicated UTIs are
treated with empirical antibiotic ther-
apy and cultures are almost never taken
unless the patient fails to respond. For
empirical therapy to be successful, it
must be based on knowledge of local aeti-
ology, resistance trends and resistance
patterns. The acceptable resistance rate
will be different in uncomplicated UTI
and in septicaemia but in both, resist-
ance will have an impact on the choice
of empirical therapy chosen in order to
avoid failure [35–36] (LoE 2b). A cipro-
floxacin resistance of 10% would be con-
sidered by most to be an acceptable level
for empirical treatment of uncomplicated
UTI, but not for a patient suffering from
septic shock with the same organism.
Antibiotic choice is becoming increasingly
difficult as resistance rates may vary sig-
nificantly between different areas within
the same country. In Sweden resistance
to nalidixic acid (as a sensitive marker
for fluoroquinolone resistance) by E. coli
in urinary tract infections ranged from
9–21% (Swedres 2008, www.strama.se)
and ciprofloxacin resistance by E. coli in
blood stream infections in Europe 2007
varied from 7–30% (www.rivm.nl/earss/)
This is further exemplified in Table 2,
which shows the susceptibility of E. coli
in uncomplicated UTI in different parts
of the world.
5.3 Antibiotic resistance in E. coli –
a global perspective
Studies on antibiotic resistance in unse-
lected uncomplicated UTI are quite
sparse, but some studies have been per-
formed in the past few years. Some of
these studies will be discussed in the fol-
lowing section. The ECO-SENS project
studied antibiotic resistance by E. coli

76
 Table 2 Antimicrobial resistance in Escherichia coli isolated from lower urinary tract infections in women 1998–2008. For some of the antibiotics, resistance rates are heavily influenced
by which breakpoints (BP) were used. In some instances breakpoints artificially divide isolates devoid of any resistance mechanisms into more than one susceptibility category.
NIT: nitrofurantoin, MEC: mecillinam, FOS:fosfomycin, Oral ceph: marker for oral cephalosporines (cefadroxil, cefalexin etc), AMP:ampicillin, AMC: amoxicillin + clavulanic acid,
SUL: sulfamethoxazole, TMP: trimethoprim, SXT: trimethoprim-sulfamethoxazole, NAL: nalidixic acid, CIP: ciprofloxacin, PTZ: piperacillin-tazobactam, 2:nd gen ceph: cefuroxim,
3:rd gen ceph: cefotaxome or ceftriaxone, GEN: gentamicin

Country/ Isolates E.coli Oral 2:nd gen 3:rd gen

Study Region year (n) (n) BP NIT MEC FOS ceph AMP AMC SUL TMP SXT NAL CIP PTZ ceph ceph GEN

Kahlmeter [6] Europe 2001 4734 2478 SRGA 98.8 98.8 99.3 87.9 70.2 96.6 70.9 85.2 85.9 97.7 - - - 99.0

Grude [4] Norway 2001 184 112 NWGA 97 94 - - 72 - 81 88 - - - - - - -

Stratchounski [44] Russia 456 423 CLSI 95.7 - - - 62.9 84.4 - 77.1 79.0 93.1 95.5 - 96.4 - -
1998–2001

Christiaens [45] Belgium 1996 166 138 CLSI 99.3 - - - 73.2 - - - 83.3 - 99.3* - - - -

De Backer [46] Belgium 2006 279 86 CLSI 100 - - - 62.8 - - - 86.0 - 100* - - - -

Naber [13] Europe+Brazil 3980 2315 CLSI 87.0 95.9 96.4 - - - - - 71.5 81.3 90.3 - 82.4 - -
2003

Ho P-I [47] Hong Kong 592 271 CLSI 92.3 - 98.2 36.2 40.6 84.9 - - 69.4 52.8 87.1 - 88.2 81.9 81.9
2006–2008

* fluoroquinolone tested: ofloxacin

Uncomplicated and community acquired urinary tract infections

77
| 2.2 |
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
in uncomplicated UTI in 16 European
countries and Canada in 1999. It pointed
to pronounced variation in antibiotic
resistance with the highest figures being
in the Mediterranean countries and the
lowest in Scandinavia. The proportion
of isolates without resistance to any of
12 antibiotics tested varied from ~50%
(Spain and Portugal) to ~75% (Sweden,
Finland) [6]. The Sentry project is a lon-
gitudinal project but designed differ-
ently as it utilises the specimens that
are sent for culture to the local micro-
biology lab. Thus differences in cultur-
ing practice may influence the result.
However, the Sentry program uses the
same method for susceptibility testing
and the same set of breakpoints every
year. The results from all over the globe
are interesting, indicating high resist-
ance rates in South America and Asia
while levels are more modest in Europe
and North America [37–38]. In the most
recent study, published by Naber and
co-workers, which looked at uncompli-
cated cystitis in females in Europe and
Brazil [13], some countries in Europe
reported almost as high resistance
rates as Brazil. There are some common
traits all over the world in these stud-
ies. Increasing resistance to ampicillin,
trimethoprim, sulfamethoxazole, co-tri-
moxazole, fluoroquinolones and, over the
last few years, to third generation cepha-
losporines and aminoglycosides [6, 13, 38]
(LoE 2a). An additional problem is the
pronounced associated resistance lead-
ing to trimethoprim resistance in fluoro-
quinolone resistant E. coli being at least
48% [34] and fluoroquinolone resistance
in trimethoprim resistant E. coli being at
least 25% (LoE 2b). The resistance rates
to several of these agents are now so high
across the world that empirical treatment
will fail increasingly often. Three anti-
bacterial agents have so far fared better
than the others: resistance to fosfomy-
cin, nitrofurantoin and pivmecillinam is
still very low (1–5%) and this is in spite
of quite intense use in some countries.
78
These agents are all excreted mainly in
urine and the impact on the normal gut
flora is thus limited [39] (LoE 3). A shift
from intense use of fluoroquinolones
and trimethoprim/cotrimoxazole to an
increased use of these agents in uncom-
plicated UTI is thwarted by the fact that
in many countries only one or two of the
drugs are available.
5.4 Antibiotic resistance in
S. Saprophyticus
Acquired antibiotic resistance is uncom-
mon in S. saprophyticus and suscep-
tibility rates of >97% are reported for
nitrofurantoin, sulphonamides, trimetho-
prim, amoxicillin, oral cephalosporines
and ciprofloxacin [16, 19, 40] (LoE 2b).
Methicillin resistance has been reported,
but is still rare, in S. Saprophyticus [41]
(LoE 3). Pivmecillinam is insufficiently
active against Gram-positives in vitro and
susceptibility testing of this antibiotic
is not advocated. However, in a Swedish
study, the clinical cure rate of pivmecil-
linam was acceptable despite the intrin-
sic resistance in vitro [42] (LoE 3). This is
probably due to the high concentrations
of mecillinam reached in the urine [39].
6. FURTHER RESEARCH
The aetiology of uncomplicated UTI has
been amazingly stable over the years
and further studies should now focus
on issues of antibiotic resistance: These
studies must meet some standard criteria
in order to be useful in decision making
regarding empiric antibiotic use:
1. The cohort followed should be
described (i.e. women of the age of so
and so)
2. The number of negative cultures and
the species distribution should always
be reported
3. The algorithms used for when to per-
form a urinary culture and for how
 Uncomplicated and community acquired urinary tract infections
duplicate isolates were excluded [43]
should be stated
4. A description of the methodology for
susceptibility testing and the break-
points for SIR categorization should
be stated
5. When these studies are performed, a
sufficient number of isolates and anti-
biotics should be included
For more information about how to per-
form antibiotic resistance surveillance
please see the reports by G. Cornaglia et al
[44] and R. Jones and R. Masterton [43].
7. CONCLUSIONS
This review highlights the importance
of E. coli as the most important bacteria
causing UTI and that increasing resist-
ance in this species now undermines the
role of several first line agents. However,
nitrofurantoin, pivmecillinam and fosfo-
mycin remain, so far, mostly susceptible.
Well-performed antibiotic resistance sur-
veillance, both locally and internationally,
are needed for a rational choice of empiric
treatment.
REFERENCES
1. Department of Health and Human
Services, Public Health Service, 1992,
Agency for Health Care Policy and
Research. p. 115–127.
2. Abrams P, Khoury S, and Grant A,
Evidence—based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
3. Finer G and Landau D, Pathogenesis
of urinary tract infections with normal
female anatomy. Lancet Infect Dis, 2004.
4(10): 631–5.
4. Grude N, Tveten Y, Jenkins A, and
Kristiansen BE, Uncomplicated urinary
tract infections. Bacterial findings and
efficacy of empirical antibacterial treat-
ment. Scand J Prim Health Care, 2005.
23(2): 115–9.
| 2.2 |
5. Jellheden B, Norrby RS, and Sandberg
T, Symptomatic urinary tract infec-
tion in women in primary health care.
Bacteriological, clinical and diagnostic
aspects in relation to host response to
infection. Scand J Prim Health Care,
1996. 14(2): 122–8.
6. Kahlmeter G, Prevalence and antimicro-
bial susceptibility of pathogens in uncom-
plicated cystitis in Europe. The ECO.
SENS study. Int J Antimicrob Agents,
2003. 22 Suppl 2: 49–52.
7. Ronald A, The etiology of urinary tract
infection: traditional and emerging patho-
gens. Dis Mon, 2003. 49(2): 71–82.
8. Hummers-Pradier E and Kochen MM,
Urinary tract infections in adult general
practice patients. Br J Gen Pract, 2002.
52(482): 752–61.
9. Ruben FL, Dearwater SR, Norden
CW, Kuller LH, Gartner K, Shalley A,
Warshafsky G, Kelsey SF, O’Donnell C,
Means E, and et al., Clinical infections
in the noninstitutionalized geriatric age
group: methods utilized and incidence of
infections. The Pittsburgh Good Health
Study. Am J Epidemiol, 1995. 141(2):
145–57.
10. Molander U, Arvidsson L, Milsom I,
and Sandberg T, A longitudinal cohort
study of elderly women with urinary
tract infections. Maturitas, 2000. 34(2):
127–31.
11. Kahlmeter G, The ECO.SENS Project: a
prospective, multinational, multicentre
epidemiological survey of the prevalence
and antimicrobial susceptibility of uri-
nary tract pathogens—interim report.
J Antimicrob Chemother, 2000. 46 Suppl
1: 15–22; discussion 63–5.
12. Farajnia S, Alikhani MY, Ghotaslou R,
Naghili B, and Nakhlband A, Causative
agents and antimicrobial susceptibilities
of urinary tract infections in the north-
west of Iran. Int J Infect Dis, 2009. 13(2):
140–4.
13. Naber KG, Schito G, Botto H, Palou
J, and Mazzei T, Surveillance study in
Europe and Brazil on clinical aspects and
Antimicrobial Resistance Epidemiology
in Females with Cystitis (ARESC):
implications for empiric therapy. Eur
Urol, 2008. 54(5): 1164–75.
79
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
14. Jombo GT, Egah DZ, Banwat EB, and
Ayeni JA, Nosocomial and commu-
nity acquired urinary tract infections
at a teaching hospital in north central
Nigeria: findings from a study of 12,458
urine samples. Niger J Med, 2006. 15(3):
230–6.
15. Marild S, Jodal U, and Sandberg T,
Ceftibuten versus trimethoprim-sulfame-
thoxazole for oral treatment of febrile
urinary tract infection in children.
Pediatr Nephrol, 2009. 24(3): 521–6.
16. Pead L, Maskell R, and Morris J,
Staphylococcus saprophyticus as a
urinary pathogen: a six year prospective
survey. Br Med J (Clin Res Ed), 1985.
291(6503): 1157–9.
17. Rupp ME, Soper DE, and Archer GL,
Colonization of the female genital tract
with Staphylococcus saprophyticus. J Clin
Microbiol, 1992. 30(11): 2975–9.
18. Hovelius B and Mardh PA,
Staphylococcus saprophyticus as a
common cause of urinary tract infections.
Rev Infect Dis, 1984. 6(3): 328–37.
19. Karlowsky JA, Jones ME, Thornsberry
C, Critchley I, Kelly LJ, and Sahm DF,
Prevalence of antimicrobial resistance
among urinary tract pathogens isolated
from female outpatients across the US
in 1999. Int J Antimicrob Agents, 2001.
18(2): 121–7.
20. Colodner R, Ken-Dror S, Kavenshtock B,
Chazan B, and Raz R, Epidemiology and
clinical characteristics of patients with
Staphylococcus saprophyticus bacteriuria
in Israel. Infection, 2006. 34(5): 278–81.
21. Hill MJ and Drasar BS, The normal
colonic bacterial flora. Gut, 1975. 16(4):
318–23.
22. Mitsumori K, Terai A, Yamamoto S, and
Yoshida O, Virulence characteristics and
DNA fingerprints of Escherichia coli
isolated from women with acute uncom-
plicated pyelonephritis. J Urol, 1997.
158(6): 2329–32.
23. Coque TM, Baquero F, and Canton R,
Increasing prevalence of ESBL-producing
Enterobacteriaceae in Europe. Euro
Surveill, 2008. 13(47).
24. Andersson DI, The biological cost
of mutational antibiotic resistance:
80
any practical conclusions? Curr Opin
Microbiol, 2006. 9(5): 461–5.
25. Dionisio F, Conceicao IC, Marques AC,
Fernandes L, and Gordo I, The evolution
of a conjugative plasmid and its ability to
increase bacterial fitness. Biol Lett, 2005.
1(2): 250–2.
26. Blahna MT, Zalewski CA, Reuer J,
Kahlmeter G, Foxman B, and Marrs CF,
The role of horizontal gene transfer in
the spread of trimethoprim-sulfameth-
oxazole resistance among uropathogenic
Escherichia coli in Europe and Canada.
J Antimicrob Chemother, 2006. 57(4):
666–72.
27. Trobos M, Lester CH, Olsen JE, Frimodt-
Moller N, and Hammerum AM, Natural
transfer of sulphonamide and ampicillin
resistance between Escherichia coli resid-
ing in the human intestine. J Antimicrob
Chemother, 2009. 63(1): 80–6.
28. Schjorring S, Struve C, and Krogfelt
KA, Transfer of antimicrobial resistance
plasmids from Klebsiella pneumoniae to
Escherichia coli in the mouse intestine.
J Antimicrob Chemother, 2008. 62(5):
1086–93.
29. Manges AR, Dietrich PS, and Riley
LW, Multidrug-resistant Escherichia
coli clonal groups causing community-
acquired pyelonephritis. Clin Infect Dis,
2004. 38(3): 329–34.
30. Nicolas-Chanoine MH, Blanco J, Leflon-
Guibout V, Demarty R, Alonso MP, Canica
MM, Park YJ, Lavigne JP, Pitout J, and
Johnson JR, Intercontinental emergence
of Escherichia coli clone O25:H4-ST131
producing CTX-M-15. J Antimicrob
Chemother, 2008. 61(2): 273–81.
31. Canton R, Novais A, Valverde A, Machado
E, Peixe L, Baquero F, and Coque TM,
Prevalence and spread of extended-
spectrum beta-lactamase-producing
Enterobacteriaceae in Europe. Clin
Microbiol Infect, 2008. 14 Suppl 1: 144–53.
32. France AM, Kugeler KM, Freeman A,
Zalewski CA, Blahna M, Zhang L, Marrs
CF, and Foxman B, Clonal groups and
the spread of resistance to trimethoprim-
sulfamethoxazole in uropathogenic
Escherichia coli. Clin Infect Dis, 2005.
40(8): 1101–7.
 Uncomplicated and community acquired urinary tract infections
33. Kahlmeter G and Menday P, Cross-
resistance and associated resistance in
2478 Escherichia coli isolates from the
Pan-European ECO.SENS Project sur-
veying the antimicrobial susceptibility of
pathogens from uncomplicated urinary
tract infections. J Antimicrob Chemother,
2003. 52(1): 128–31.
34. Wimmerstedt A and Kahlmeter G,
Associated antimicrobial resistance
in Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus,
Streptococcus pneumoniae and
Streptococcus pyogenes. Clin Microbiol
Infect, 2008. 14(4): 315–21.
35. Butler CC, Hillier S, Roberts Z, Dunstan
F, Howard A, and Palmer S, Antibiotic-
resistant infections in primary care are
symptomatic for longer and increase
workload: outcomes for patients with
E. coli UTIs. Br J Gen Pract, 2006.
56(530): 686–92.
36. Ortega M, Marco F, Soriano A, Almela
M, Martinez JA, Munoz A, and Mensa J,
Analysis of 4758 Escherichia coli bacter-
aemia episodes: predictive factors for iso-
lation of an antibiotic-resistant strain and
their impact on the outcome. J Antimicrob
Chemother, 2009. 63(3): 568–74.
37. Fluit AC, Jones ME, Schmitz FJ, Acar J,
Gupta R, and Verhoef J, Antimicrobial
resistance among urinary tract infec-
tion (UTI) isolates in Europe: results
from the SENTRY Antimicrobial
Surveillance Program 1997. Antonie Van
Leeuwenhoek, 2000. 77(2): 147–52.
38. Gordon KA and Jones RN, Susceptibility
patterns of orally administered antimi-
crobials among urinary tract infection
pathogens from hospitalized patients
in North America: comparison report to
Europe and Latin America. Results from
the SENTRY Antimicrobial Surveillance
Program (2000). Diagn Microbiol Infect
Dis, 2003. 45(4): 295–301.
39. Mazzei T, Cassetta MI, Fallani
S, Arrigucci S, and Novelli A,
Pharmacokinetic and pharmacodynamic
aspects of antimicrobial agents for the
treatment of uncomplicated urinary tract
infections. Int J Antimicrob Agents, 2006.
28 Suppl 1: S35–41.
| 2.2 |
40. de Allori MC, Jure MA, Romero C, and de
Castillo ME, Antimicrobial resistance and
production of biofilms in clinical isolates
of coagulase-negative Staphylococcus
strains. Biol Pharm Bull, 2006. 29(8):
1592–6.
41. Higashide M, Kuroda M, Ohkawa S,
and Ohta T, Evaluation of a cefoxitin
disk diffusion test for the detection of
mecA-positive methicillin-resistant
Staphylococcus saprophyticus. Int
J Antimicrob Agents, 2006. 27(6): 500–4.
42. Hovelius B, Mardh PA, Nygaard-
Pedersen L, and Wathne B, Nalidixic acid
and pivmecillinam for treatment of acute
lower urinary tract infections. Scand
J Prim Health Care, 1985. 3(4): 227–32.
43. Jones RN and Masterton R, Determining
the value of antimicrobial surveillance
programs. Diagn Microbiol Infect Dis,
2001. 41(4): 171–5.
44. Stratchounski LS and Rafalski VV,
Antimicrobial susceptibility of pathogens
isolated from adult patients with uncom-
plicated community-acquired urinary
tract infections in the Russian Federation:
two multicentre studies, UTIAP-1 and
UTIAP-2. Int J Antimicrob Agents, 2006.
28 Suppl 1: S4–9.
45. Christiaens TH, Heytens S, Verschraegen
G, De Meyere M, and De Maeseneer
J, Which bacteria are found in Belgian
women with uncomplicated urinary tract
infections in primary health care, and
what is their susceptibility pattern anno
95–96? Acta Clin Belg, 1998. 53(3): 184–8.
46. De Backer D, Christiaens T, Heytens
S, De Sutter A, Stobberingh EE, and
Verschraegen G, Evolution of bacterial
susceptibility pattern of Escherichia coli
in uncomplicated urinary tract infections
in a country with high antibiotic con-
sumption: a comparison of two surveys
with a 10 year interval. J Antimicrob
Chemother, 2008. 62(2): 364–8.
47. Ho PL, Yip KS, Chow KH, Lo JY, Que TL,
and Yuen KY, Antimicrobial resistance
among uropathogens that cause acute
uncomplicated cystitis in women in Hong
Kong: a prospective multicenter study in
2006 to 2008. Diagn Microbiol Infect Dis,
2009.
81
|2.3|

Complicated and healthcare

associated urinary tract infections:
aetiology and antimicrobial
resistance
Martin Sundqvist1,2, Gunnar Kahlmeter1,3
1
Dept of Clin Microbiology, Central Hospital, Växjö Sweden
2
Dept of Medical Sciences, Div of Infectious diseases, Uppsala University, Uppsala, Sweden
3
Dept of Medical Sciences, Div of Clinical Bacteriology, Uppsala University, Uppsala, Sweden
Corresponding author: Gunnar Kahlmeter, MD, Professor, Dept of Clin Microbiology, Central Hospital, S-35185 Växjö, Sweden,
Tel +46-470-588 000, Fax +46-470-587 455, gunnar.kahlmeter@ltkronoberg.se

ABSTRACT considered significant should be performed.

Several species are important in compli-
cated (cUTI) and healthcare associated uri-
nary tract infections (HAUTI). Importantly
Escherichia coli still dominates the aetiol-
ogy, however, it is found more often to be
resistant to several antibiotics in cUTI and
HAUTI than in uncomplicated UTI. Other
bacteria like Enterococcus spp, P. aerugi-
nosa and Candida spp. are more common
with the use of urinary catheters and the
high use of broad spectrum antibiotics.
Culture is always advocated in the diagno-
sis of cUTI and HAUTI, and as resistance
rates in these situations are unpredictable
and may be very local within the hospital,
susceptibility testing of all bacterial isolates
The finding of bacteriuria in these patients
should, as always, be related to symptoms
and treated only if necessary.
Key words: Enterobacteriacae, Candida
spp, Pseudomonas spp
SUMMARY OF RECOMMENDATIONS
A prerequisite for successful antibiotic
therapy is the good understanding of aeti-
ology and antimicrobial resistance. E.coli
dominates the aetiology of both uncompli-
cated urinary tract infections (UTI) and
complicated UTI (cUTI). However, the lat-
ter, and especially healthcare associated
 Complicated and healthcare associated urinary tract infections
UTI (HAUTI), sprouts a much larger
spectrum of microorganisms than UTI.
Successful empirical therapy rests on
the absolute majority of microorganisms
being susceptible to the drugs chosen. A
rapid worldwide increase in antimicro-
bial resistance in pathogens causing UTI
and especially cUTI threatens to jeop-
ardize our empiric traditions. Regional
surveillance studies should be performed
regularly to guide the choice of empiric
antimicrobial therapy (GoR A).
In uncomplicated UTI it is often justifi-
able to initiate antibiotic therapy without
performing a urine culture, provided that
the epidemiology of antimicrobial resist-
ance in E. coli is known. A urine culture
should be performed prior to or in con-
junction with treatment in the follow-
ing situations:
1. When the patient has received
antibiotic treatment in the last three
months (GoR B).
2. When planning to give empiric therapy
with amoxicillin, sulfamethoxazole,
trimethoprim or co-trimoxazole, to all
of which resistance rates are high and
co-resistance to other drugs common
(GoR B).
3. When planning to give empiric treat-
ment with a fluoroquinolone or a
cephalosporin in areas where local
resistance rates are high (>10%),
i.e. in areas where ESBL-producing
Enterobacteriaceae are increasingly
common (GoR B).
4. When antimicrobial treatment has
recently failed (GoR B).
5. When there are signs of pyelone-
phritis (GoR A).
6. When the patient is a man (GoR B).
7. When the patient is a woman with
complicated and/or recurrent UTI and/
or is over the age of 65 (GoR B).
8. When the patient has a healthcare
associated UTI (GoR A).
| 2.3 |
1. INTRODUCTION
Patients diagnosed with a complicated
UTI (cUTI) or a health care associated
UTI (HAUTI) are often elderly, have
devices like urinary catheters and/or
have neurological or anatomical disor-
ders resulting in voiding problems and/
or bladder retention [1–3] (LoE 2b).
Although Escherichia coli is the most
common pathogen [1, 4], the above men-
tioned conditions together with the fact
that these patients often are treated with
antibiotics will increase the frequency of
secondary pathogens like Pseudomonas
aeruginosa, Enterococcus faecalis and
Enterococcus faecium, Proteus mirabi-
lis, Staphylococcus spp and Candida spp
(Table 1) [5–6] (LoE 2b).
It is advocated that urine cultures
should be taken in these patients and
that antimicrobial susceptibility testing
should steer therapy (GoR B). The diver-
sity of pathogens and the rapidly increas-
ing levels of antimicrobial resistance
make empirical therapy a lottery with
ever worsening odds. At the same time it
is important to stress that not all bacte-
riuria noticed after 48 hours of hospitali-
zation should be considered as indicative
of complicated UTI or health care associ-
ated UTI (HAUTI) since up to 40% of the
elderly in nursing homes have asympto-
matic bacteriuria (ABU) [7–8] (LoE 2b).
When admitted to hospital, these
patients should not be treated unless
they have symptoms of UTI and if so, cul-
tures should always be obtained. Despite
the location of the onset of the infection,
there is no reason to consider other bacte-
ria or more resistant bacteria than those
outside the hospital environment and
the same antibiotics thus apply (LoE 4).
However, local epidemiology (commonly
occurring pathogens and resistance lev-
els), time after admission, presence of
catheters, recent surgery and recent anti-
biotic use as well as previous cultures
must be taken into consideration when
83
Table 1 Spectrum of nosocomial uropathogens of urological patients (species <2% are not considered).
Adopted from Wagenlehner et al [6]

Pathoaen 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

E. coli 27.9% 26.6% 30.2% 31.7% 28.0% 35.1% 31.3% 31.6% 41.3% 41.4% 38.3% 37.2%

Klebsiella spp. 6.0% 6.7% 9.1% 8.1% 8.7% 7.7% 9.6% 8.0% 5.5% 6.5% 7.6% 7.3%

Proteus spp. 8.0% 5.6% 7.5% 7.9% 5.9% 6.4% 7.5% 8.7% 6.5% 8.8% 7.6% 5.4%

Enterobacter 5.4% 6.0% 4.0% 4.9% 5.4% 4.0% 6.4% 5.5% 4.9% 3.3% 4.0% 3.3%
spp.

Citrobacter spp. 4.0% 3.3% 1.3% 3.7% 2.6% 2.7% 1.3% 3.3% 2.6% 3.3% 3.1% 5.0%

P. aeruginosa 12.7% 13.8% 11.5% 11.5% 12.3% 10.1% 10.8% 6.9% 7.7% 5.6% 6.9% 7.4%

Enterococcus 20.5% 20.8% 22.2% 16.5% 20.1% 19.8% 23.0% 21.8% 18.7% 17.5% 18.0% 17.1%
spp.

CNS 10.9% 14.1% 10.7% 13.3% 13.4% 11.1% 8.0% 10.0% 9.7% 7.7% 9.6% 10.2%

S. aureus 4.5% 3.1% 3.5% 2.5% 3.6% 3.2% 2.1% 4.2% 3.1% 5.9% 4.9% 7.1%

total (n = 100%) 448 448 374 407 389 405 623 550 508 479 447 462
 Complicated and healthcare associated urinary tract infections
choosing empirical therapy for HAUTI.
The importance of urinary catheters as the
main risk factor of HAUTI [9–10] and the
treatment of these infections will be dis-
cussed in more detail in other chapters in
this book.
2. METHODS
The PubMed database was searched for
the terms complicated UTI and Hospital
acquired UTI in combination with anti-
biotic resistance. Articles on cUTI and
HAUTI in adults that were in English
and of appropriate quality were included.
In addition, articles from the last 10 years
describing antimicrobial resistance in
UTI pathogens were retrieved. Despite
the fact that the rating system is not opti-
mal for our purposes, the studies were
rated according to the level of evidence
(LoE) and the grade†of recommendation
(GoR) using ICUD standards (for details
see Preface) [11–12].
3. COMMON PATHOGENS IN
COMPLICATED AND HEALTHCARE
ASSOCIATED UTI
As mentioned in the previous chapter,
almost any bacterium and yeast could
be responsible for, or at least found in,
cultures obtained from patients with
HAUTI. An example of the presence of
different pathogens in urinary samples
from a urology department over time is
reported in Table 1. Most of these organ-
isms have certain features which render
them eminently suitable for colonisa-
tion of the urinary tract of hospitalized
patients and or patients with compli-
cated UTI. Some bacteria are prone to
reside in and promote growth of stones
in the urinary tract (Proteus spp (most
common), Corynebacterium urealyticum,
Staphylococcus spp, Klebsiella spp,
Providencia spp, and Pseudomonas spp).
Their common trait is a prolific production
| 2.3 |
of urease which hydrolyses urea to ammo-
nium and hydroxyl ions. These are not
only involved in the pathogenesis of uro-
lithiasis [13] but also in recurrent UTI
as the treatment given does not penetrate
the biofilm formed around and within the
infectious stone [14] (LoE 3). These bac-
teria are, in many cases, the same that
can be found associated with catheters
but in catheter related infections Gram-
positive bacteria like staphylococci are
more common. Enterococci are mainly a
concern in patients with recurrent UTI,
and often in patients with urinary reten-
tion [15] (LoE 3).
4. ANTIBIOTIC RESISTANCE
In the following section the special fea-
tures regarding antibiotic resistance
in several of the species important in
HAUTI are described. The features of
E. coli, although still the most common
bacteria causing HAUTI, is covered in the
previous chapter. Resistance rates in E.
coli from a number of studies on HAUTI
are presented in Table 2.
Multiresistant bacteria are encountered
increasingly often in the treatment of
cUTI and HAUTI. With exceptions (most
notably rare instances of pan resistant
Acinetobacter spp.and Stenotrophomonas
spp.) one or two antibiotics are still left to
choose between. In some cases multire-
sistant E. coli in UTI may still be suscep-
tible to pivmecillinam, fosfomycin and/
or nitrofurantoin (LoE 4). In all these
cases, one should consult the clinical
microbiologist.
4.1 Enterobacteriacae (not E. coli)
As mentioned and shown in Table 1,
Klebsiella pneumoniae, Klebsiella oxy-
toca, Proteus mirabilis, Citrobacter spp,
Enterobacter spp and Morganella mor-
ganii are the most common aetiology in
complicated infections [5–6]. The resist-
ance rates in these species are in many
85
Table 2 Resistance rates in Escherichia coli isolates from HAUTI and/or routine resistance surveillance utilizing clinical databases. For some of the antibiotics, resistance rates are heavily influenced
by which breakpoints (BP) were used. In some instances breakpoints artificially divide isolates devoid of any resistance mechanisms into more than one susceptibility category. The numbers gives an
impression on the importance of knowing the local epidemiology.
NIT: nitrofurantoin, MEC: mecillinam, FOS: fosfomycin, Oral ceph: marker for oral cephalosporines (cefadroxil, cefalexin etc), AMP: ampicillin, AMC: amoxicillin + clavulanic acid, SUL:
sulfamethoxazole, TMP: trimethoprim, SXT: trimethoprim-sulfamethoxazole, NAL: nalidixic acid, CIP: ciprofloxacin, PTZ: piperacillin-tazobactam, 2:nd gen ceph: cefuroxim, 3:rd gen ceph:
cefotaxime or ceftriaxone, IMI: imipenem, GEN: gentamicin

3:rd
Country/ Isolates E.coli Oral gen
study Region year (n) (n) BP NIT MEC FOS Ceph AMP AMC SUL TMP SXT CIP PTZ ceph IMI GEN

Gales [43] Latin America 1997–1999 1961 801 CLSI 87.0 - - 82.4 41.6 74.2 - - 52.3 81.1 91.0 96.4 100 89.1

Soraya [44] Latin America 2003 403 CLSI 93.1 - - 76.4 43.2 83.6 - - 59.6 77.4 97.3 98.5 100 90.1

Karlowsky USA 1999 5739 3505 CLSI 99.1 - - 71.0 - - - - 83.2 98.3 - - - -
[45]

Johansen [5] Europe 2003/2004 569 175 DIN/CLSI - - - - - 53 - - 48 59 - 77 - -

Akram [46] India 2004–2005 100 61 CLSI 20 - - 31 - - - - 24 31 - 45 100 36

Olson [47] USA 2005–2007 176 176 NS 100 - - - - - - - 70.3 93.2 - - - -

Khameneh Iran 2005–2006 803 631 NS 69.8 - - - - - - - - 83.2 - ?89.5 - 83.9

[48]

Karou [49] Burkina Faso 709 260 NS - - - - 23.4 75.0 - - 25.3 10.0 - - - -

Wagenlehner Germany 1994 448 125 NS 100 71.2 77.6 85.2 95.6 100 100 MIC 96.7
[6] >=16

Wagenlehner Germany 2005 462 172 NS 98.1 65.7 74.4 77.4 84.9 100 100 94.3
[6]

Farajnia [50] Iran 2009 676 504 NS 87.1 76.0 6.9 48.2 94.0 97.0
 Complicated and healthcare associated urinary tract infections
cases a reflection of those found in E. coli
(see Table 2). There are however some
important differences to be pointed out.
Firstly, treatment with cephalosporins
is not advocated in infections caused by
Enterobacter spp, Citrobacter freundii,
Serratia spp and Morganella morganii.
This is due to a chromosomally located
AmpC enzyme that might be derepressed
by the cephalosporin given and resistance
can thus display under ongoing therapy
[16–17] (LoE 3). Secondly, an important
emerging resistance within this group is
the carbapenemases first reported in K.
pneumoniae (KPC) that have now caused
major outbreaks in the USA, Greece and
Israel [18–20]. These multiresistant bac-
teria will be more and more common
and the importance of well-performed
Infection Control Bundles to minimize
their spread cannot be emphasized
enough.
4.2 Enterococcus spp
Enterococcus spp are Gram-positive cocci
normally residing in the gut flora [21].
They frequently colonise the urinary
tract and occasionally cause UTI, in both
cUTI and HAUTI [5, 22]. Antibiotics
active against Gram-negative bacteria
are often poorly active against entero-
cocci. This is true for fluoroquinolones
[23], cephalosporines [24] and enterococci
are considered indeterminant suscepti-
ble to trimethoprim and co-trimoxazole
[25]. Ampicillin is basically always active
against Enterococcus faecalis but only
rarely against Enterococcus faecium (LoE
2b). Cultures taken after some days of
antibiotic treatment will often yield ente-
rococci. It is then important to weigh the
relevance of the finding against the clini-
cal course of the patient. E. faecium is
intrinsically, or by acquisition, resistant
to almost any antibiotic appropriate for
treatment of UTI, except for nitrofuran-
toin. In addition vancomycin resistance
is a major nosocomial problem in many
parts of the world [26–28] (LoE 2a).
| 2.3 |
4.3 Pseudomonas aeruginosa
Pseudomonas aeruginosa is a Gram-
negative rod, easily distinguished in
the microbiology lab from other Gram-
negatives by its production of pigment
and oxidase. P. aeruginosa is intrin-
sically resistant to all oral antibiot-
ics except fluoroquinolones, of which
ciprofloxacin has the highest activity [29]
(LoE 2b). However in many parts of the
world resistance rates to ciprofloxacin
now exceed 20% and in some countries
even higher [30], leaving no oral treat-
ment options in these patients (LoE 3).
In addition an increasing number of P.
aeruginosa have adapted to the constant
selective pressure of antibiotics in hos-
pitals by down-regulating their perme-
ability and up-regulating efflux pumps,
pumping out several antibiotics, among
these β-lactam antibiotics [31] (LoE 3)
resulting in resistance to ceftazidime,
piperacillin/tazobactam and increasingly
also to carbapenems. Isolates produc-
ing metallo-fl-lactamases (MBL) usually
express higher levels of resistance to
carbapenems and other betalactams
[32] (LoE 3). The prevalence of these
fl-lactamases are increasing in most parts
of the world. Such isolates are usually
multi drug resistant and the MBL encod-
ing genes may co-exist with aminoglyco-
side resistance genes [33] leaving only
the “old kids on the block” like colistin as
possible treatment (LoE 3).
4.4 Acinetobacter spp
In this non-fermentative group of Gram-
negative bacteria the Acinetobacter bau-
manii is the most frequently described in
hospital acquired infections [34] (LoE 3).
It is not mainly a UTI pathogen but
rather a colonizer and can be found in the
urine from patients with CAD. In these
cases the resistance pattern is almost
always a depressing sight as resistance to
a large number of antibiotics is manda-
tory and several outbreaks of Extremely
Drug Resistant (XDR) A. baumanii have
87
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
been reported [35] (LoE 3). In some cases
susceptibility testing to colistin and other
not so frequently used antibiotics is advo-
cated to support clinicians in selecting a
treatment option.
4.5 Candida spp
The growth of Candida spp. in urine
is found with increasing frequency in
severely ill patients [1] (LoE 2b) and the
wide use of broad spectrum antibiotics in
ICUs further promotes this. Usually the
finding of Candida spp. reflects a coloni-
zation rather than infection, especially if
the patient has a urinary catheter (LoE
3). Treatment of this condition does not
give any beneficial effects [36] (LoE 3).
However, yeasts in urine might reflect a
concomitant candidemia and candiduria
may be found prior to finding the can-
didemia in blood cultures [37] (LoE 3).
If treatment is initiated, it is important
to decide what species are responsible
for the infection, because C. glabrata, C.
krusei and C. norvegensis are considered
resistant to fluconazole [38–39]. The most
common Candida spp. is C. albicans
which is usually susceptible to azoles and
is not associated with nosocomial spread.
In haematology wards and in intensive
care units azole-resistant Candida spp
are more and more commonly isolated
[40–42].
5. FURTHER RESEARCH
In contrast to the aetiology of uncom-
plicated UTI the aetiology of HAUTI is
very much influenced by the local envi-
ronment. Hospitals with high levels of
Acinetobacter spp. or vancomycin resist-
ant enterococci (VRE) will have to include
the treatment of these microorganisms in
their local guidelines on the treatment of
HAUTI. Local studies are thus needed
to focus both on aetiology and antibiotic
resistance. Further studies regarding
the risk of having an infection with more
88
problematic/antibiotic resistant bacteria
in relation to the time from admission are
also needed, to avoid unnecessary broad
spectrum antibiotic treatments.
6. CONCLUSIONS
In contrast to the aetiology of uncom-
plicated UTI, the aetiology of HAUTI is
very much influenced by local epidemi-
ology. However, E. coli is still the most
important pathogen in these infections
as well as in cUTI. The diverse aetiol-
ogy and increased resistance rates in
these infections call for urinary cul-
tures to be obtained and analysed in all
these patients prior to or in conjunction
with the start of treatment. One should
always keep in mind the possibility of
asymptomatic bacteriuria when inter-
preting the microbiological report in
these patients.
REFERENCES
1. Laupland KB, Zygun DA, Davies HD,
Church DL, Louie TJ, and Doig CJ,
Incidence and risk factors for acquiring
nosocomial urinary tract infection in the
critically ill. J Crit Care, 2002. 17(1):
50–7.
2. Leblebicioglu H and Esen S, Hospital-
acquired urinary tract infections in
Turkey: a nationwide multicenter point
prevalence study. J Hosp Infect, 2003.
53(3): 207–10.
3. Bouza E, San Juan R, Munoz P, Voss A,
and Kluytmans J, A European perspective
on nosocomial urinary tract infections II.
Report on incidence, clinical character-
istics and outcome (ESGNI-004 study).
European Study Group on Nosocomial
Infection. Clin Microbiol Infect, 2001.
7(10): 532–42.
4. Bouza E, San Juan R, Munoz P, Voss A,
and Kluytmans J, A European per-
spective on nosocomial urinary tract
infections I. Report on the microbiol-
ogy workload, etiology and antimicro-
bial susceptibility (ESGNI-003 study).
 Complicated and healthcare associated urinary tract infections
European Study Group on Nosocomial
Infections. Clin Microbiol Infect, 2001.
7(10): 523–31.
5. Johansen TE, Cek M, Naber KG,
Stratchounski L, Svendsen MV, and
Tenke P, Hospital acquired urinary tract
infections in urology departments: patho-
gens, susceptibility and use of antibiotics.
Data from the PEP and PEAP-studies. Int
J Antimicrob Agents, 2006. 28 Suppl 1:
S91–107.
6. Wagenlehner FM, Niemetz AH,
Weidner W, and Naber KG, Spectrum
and antibiotic resistance of uropatho-
gens from hospitalised patients with
urinary tract infections: 1994–2005. Int
J Antimicrob Agents, 2008. 31 Suppl 1:
S25–34.
7. Rodhe N, Lofgren S, Matussek A, Andre
M, Englund L, Kuhn I, and Molstad S,
Asymptomatic bacteriuria in the elderly:
high prevalence and high turnover of
strains. Scand J Infect Dis, 2008. 40(10):
804–10.
8. Rodhe N, Molstad S, Englund L, and
Svardsudd K, Asymptomatic bacteriuria
in a population of elderly residents living
in a community setting: prevalence, char-
acteristics and associated factors. Fam
Pract, 2006. 23(3): 303–7.
9. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008.
31 Suppl 1: S68–78.
10. Nguyen-Van-Tam SE, Nguyen-Van-Tam
JS, Myint S, and Pearson JC, Risk factors
for hospital-acquired urinary tract infec-
tion in a large English teaching hospital:
a case-control study. Infection, 1999.
27(3): 192–7.
11. Department of Health and Human
Services, Public Health Service, 1992,
Agency for Health Care Policy and
Research. p. 115–127.
12. Abrams P, Khoury S, and Grant A,
Evidence—based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
| 2.3 |
13. Miano R, Germani S, and Vespasiani G,
Stones and urinary tract infections. Urol
Int, 2007. 79 Suppl 1: 32–6.
14. Marcus RJ, Post JC, Stoodley P, Hall-
Stoodley L, McGill RL, Sureshkumar KK,
and Gahlot V, Biofilms in nephrology.
Expert Opin Biol Ther, 2008. 8(8):
1159–66.
15. Biering-Sorensen F, Bagi P, and Hoiby N,
Urinary tract infections in patients with
spinal cord lesions: treatment and preven-
tion. Drugs, 2001. 61(9): 1275–87.
16. Chow JW, Fine MJ, Shlaes DM, Quinn
JP, Hooper DC, Johnson MP, Ramphal R,
Wagener MM, Miyashiro DK, and Yu VL,
Enterobacter bacteremia: clinical features
and emergence of antibiotic resistance
during therapy. Ann Intern Med, 1991.
115(8): 585–90.
17. Schwaber MJ, Graham CS, Sands BE,
Gold HS, and Carmeli Y, Treatment with
a broad-spectrum cephalosporin versus
piperacillin-tazobactam and the risk
for isolation of broad-spectrum cepha-
losporin-resistant Enterobacter species.
Antimicrob Agents Chemother, 2003.
47(6): 1882–6.
18. Nadkarni AS, Schliep T, Khan L, and
Zeana CB, Cluster of bloodstream infec-
tions caused by KPC-2 carbapenemase-
producing Klebsiella pneumoniae in
Manhattan. Am J Infect Control, 2009.
37(2): 121–6.
19. Giakoupi P, Maltezou H, Polemis M,
Pappa O, Saroglou G, and Vatopoulos A,
KPC-2-producing Klebsiella pneumoniae
infections in Greek hospitals are mainly
due to a hyperepidemic clone. Euro
Surveill, 2009. 14(21).
20. Samra Z, Ofir O, Lishtzinsky Y, Madar-
Shapiro L, and Bishara J, Outbreak of
carbapenem-resistant Klebsiella pneu-
moniae producing KPC-3 in a tertiary
medical centre in Israel. Int J Antimicrob
Agents, 2007. 30(6): 525–9.
21. Hill MJ and Drasar BS, The normal
colonic bacterial flora. Gut, 1975. 16(4):
318–23.
22. Chan RK, Lye WC, Lee EJ, and
Kumarasinghe G, Nosocomial urinary
tract infection: a microbiological study. Ann
Acad Med Singapore, 1993. 22(6): 873–7.
89
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
23. Arsene S and Leclercq R, Role of a qnr-
like gene in the intrinsic resistance of
Enterococcus faecalis to fluoroquinolones.
Antimicrob Agents Chemother, 2007.
51(9): 3254–8.
24. Dudley MN and Barriere SL, Cefotaxime:
microbiology, pharmacology, and clinical
use. Clin Pharm, 1982. 1(2): 114–24.
25. Wisell KT, Kahlmeter G, and Giske CG,
Trimethoprim and enterococci in urinary
tract infections: new perspectives on an
old issue. J Antimicrob Chemother, 2008.
62(1): 35–40.
26. Werner G, Coque TM, Hammerum AM,
Hope R, Hryniewicz W, Johnson A, Klare
I, Kristinsson KG, Leclercq R, Lester CH,
Lillie M, Novais C, Olsson-Liljequist B,
Peixe LV, Sadowy E, Simonsen GS, Top J,
Vuopio-Varkila J, Willems RJ, Witte W,
and Woodford N, Emergence and spread
of vancomycin resistance among ente-
rococci in Europe. Euro Surveill, 2008.
13(47).
27. Ramsey AM and Zilberberg MD, Secular
trends of hospitalization with vancomy-
cin-resistant enterococcus infection in the
United States, 2000–2006. Infect Control
Hosp Epidemiol, 2009. 30(2): 184–6.
28. Kurup A, Chlebicki MP, Ling ML,
Koh TH, Tan KY, Lee LC, and Howe KB,
Control of a hospital-wide vancomycin-
resistant Enterococci outbreak. Am J
Infect Control, 2008. 36(3): 206–11.
29. Walker RC, The fluoroquinolones. Mayo
Clin Proc, 1999. 74(10): 1030–7.
30. Taneja N, Meharwal SK, Sharma SK, and
Sharma M, Significance and characterisa-
tion of pseudomonads from urinary tract
specimens. J Commun Dis, 2004. 36(1):
27–34.
31. Giske CG, Buaro L, Sundsfjord A, and
Wretlind B, Alterations of porin, pumps,
and penicillin-binding proteins in car-
bapenem resistant clinical isolates of
Pseudomonas aeruginosa. Microb Drug
Resist, 2008. 14(1): 23–30.
32. Walsh TR, Clinically significant carbap-
enemases: an update. Curr Opin Infect
Dis, 2008. 21(4): 367–71.
33. Woodford N, Zhang J, Kaufmann ME,
Yarde S, Tomas Mdel M, Faris C,
Vardhan MS, Dawson S, Cotterill SL, and
90
Livermore DM, Detection of Pseudomonas
aeruginosa isolates producing VEB-
type extended-spectrum beta-lactamases
in the United Kingdom. J Antimicrob
Chemother, 2008. 62(6): 1265–8.
34. Giamarellou H, Antoniadou A, and
Kanellakopoulou K, Acinetobacter bau-
mannii: a universal threat to public
health? Int J Antimicrob Agents, 2008.
32(2): 106–19.
35. Falagas ME, Rafailidis PI, Matthaiou DK,
Virtzili S, Nikita D, and Michalopoulos
A, Pandrug-resistant Klebsiella pneu-
moniae, Pseudomonas aeruginosa and
Acinetobacter baumannii infections: char-
acteristics and outcome in a series of 28
patients. Int J Antimicrob Agents, 2008.
32(5): 450–4.
36. Chen SC, Tong ZS, Lee OC, Halliday C,
Playford EG, Widmer F, Kong FR, Wu
C, and Sorrell TC, Clinician response
to Candida organisms in the urine of
patients attending hospital. Eur J Clin
Microbiol Infect Dis, 2008. 27(3): 201–8.
37. Nassoura Z, Ivatury RR, Simon RJ,
Jabbour N, and Stahl WM, Candiduria as
an early marker of disseminated infection
in critically ill surgical patients: the role
of fluconazole therapy. J Trauma, 1993.
35(2): 290–4; discussion 294–5.
38. Pappas PG, Kauffman CA, Andes D,
Benjamin DK, Jr., Calandra TF, Edwards
JE, Jr., Filler SG, Fisher JF, Kullberg BJ,
Ostrosky-Zeichner L, Reboli AC, Rex JH,
Walsh TJ, and Sobel JD, Clinical practice
guidelines for the management of can-
didiasis: 2009 update by the Infectious
Diseases Society of America. Clin Infect
Dis, 2009. 48(5): 503–35.
39. EUCAST technical note on fluconazole.
Clin Microbiol Infect, 2008. 14(2): 193–5.
40. Slavin MA, The epidemiology of candidae-
mia and mould infections in Australia. J
Antimicrob Chemother, 2002. 49 Suppl
1: 3–6.
41. Viscoli C, Girmenia C, Marinus A,
Collette L, Martino P, Vandercam B,
Doyen C, Lebeau B, Spence D, Krcmery V,
De Pauw B, and Meunier F, Candidemia
in cancer patients: a prospective, multi-
center surveillance study by the Invasive
Fungal Infection Group (IFIG) of the
 Complicated and healthcare associated urinary tract infections
European Organization for Research and
Treatment of Cancer (EORTC). Clin Infect
Dis, 1999. 28(5): 1071–9.
42. Pratikaki M, Platsouka E, Sotiropoulou
C, Douka E, Paramythiotou E, Kaltsas P,
Kotanidou A, Paniara O, Roussos C, and
Routsi C, Epidemiology, risk factors for
and outcome of candidaemia among non-
neutropenic patients in a Greek intensive
care unit. Mycoses, 2009.
43. Gales AC, Sader HS, and Jones RN,
Urinary tract infection trends in Latin
American hospitals: report from the
SENTRY antimicrobial surveillance pro-
gram (1997–2000). Diagn Microbiol Infect
Dis, 2002. 44(3): 289–99.
44. Andrade SS, Sader HS, Jones RN,
Pereira AS, Pignatari AC, and Gales AC,
Increased resistance to first-line agents
among bacterial pathogens isolated from
urinary tract infections in Latin America:
time for local guidelines? Mem Inst
Oswaldo Cruz, 2006. 101(7): 741–8.
45. Karlowsky JA, Jones ME, Thornsberry
C, Critchley I, Kelly LJ, and Sahm DF,
Prevalence of antimicrobial resistance
among urinary tract pathogens isolated
from female outpatients across the US
| 2.3 |
in 1999. Int J Antimicrob Agents, 2001.
18(2): 121–7.
46. Akram M, Shahid M, and Khan AU,
Etiology and antibiotic resistance pat-
terns of community-acquired urinary tract
infections in J N M C Hospital Aligarh,
India. Ann Clin Microbiol Antimicrob,
2007. 6: 4.
47. Olson RP, Harrell LJ, and Kaye KS,
Antibiotic resistance in urinary isolates
of Escherichia coli from college women
with urinary tract infections. Antimicrob
Agents Chemother, 2009. 53(3): 1285–6.
48. Khameneh ZR and Afshar AT,
Antimicrobial susceptibility pattern of
urinary tract pathogens. Saudi J Kidney
Dis Transpl, 2009. 20(2): 251–3.
49. Karou SD, Ilboudo IP, Nadembega WM,
Ameyapoh Y, Ouermi D, Pignatelli S,
Pietra V, Traore AS, de Souza C, and
Simpore J, Antibiotic resistance in uri-
nary tract bacteria in Ouagadougou. Pak
J Biol Sci, 2009. 12(9): 712–6.
50. Farajnia S, Alikhani MY, Ghotaslou R,
Naghili B, and Nakhlband A, Causative
agents and antimicrobial susceptibilities of
urinary tract infections in the northwest of
Iran. Int J Infect Dis, 2009. 13(2): 140–4.
91
|2.4|
Methicillin-resistant Staphylococcus
aureus (MRSA) in urology
Satoshi Takahashi
Corresponding author: Satoshi Takahashi, MD, Department of Urology, Sapporo Medical University, School of Medicine,
S1, W16, Chuo-ku, Sapporo, 060-8543, Japan, stakahas@sapmed.ac.jp
ABSTRACT
Methicillin-resistant Staphylococcus aur-
eus (MRSA) is the main nosocomial patho-
gen worldwide, especially in hospitals and
long-term care facilities. In the field of
urology, there has been a lack of compre-
hensive study of MRSA infection. Indeed,
it is necessary that MRSA infection be
examined comprehensively in clinical tri-
als. We should note that urinary tract
infection caused by MRSA has been an
important origin of healthcare-associated
infection, and surgical site infection
caused by MRSA has been the principal
issue in contaminated operations in uro-
logical surgery. Treatment for MRSA infec-
tion has been uncommonly empirical and
the complicated origin of the urinary tract
makes complete eradication of MRSA dif-
ficult. There have been no randomized
clinical trials of the treatments for various
MRSA infections in urological diseases. In
recent years, community-acquired MRSA
has been noted as an emerging pathogen
causing skin and soft-tissue infections
in the community. Therefore, we should
know how to diagnose and treat such
skin and soft-tissue infections caused by
community-associated MRSA, although
they have been rare in the field of urology.
Key words: methicillin-resistant S.
aureus (MRSA), urology, urinary tract
infection, surgical site infection
SUMMARY OF RECOMMENDATIONS
Epidemology
1. If the rate of MRSA infection is high
or increasing, active surveillance
might be effective for prevention of
outbreaks (GoR B).
Pathogenesis of UTI caused by MRSA
2. In the point of pathogenesis of urinary
MRSA, the multifactorial conditions of
UTI caused by MRSA and especially
the toxins of MRSA involved need fur-
ther research (GoR C).

3. We should have common cognizance
that urinary MRSA could be a poten-
tial reservoir for healthcare-associated
infection (GoR B).
Biofilm
4. Two virulence factors, beta-hemolysin
and fibronectin-binding protein A,
should be recognized as biofilm for-
mation, because they are suggested
to be associated with MRSA coloniza-
tion and infection of the urinary tract
(GoR C).
5. Clarithromycin could be considered for
combination because it has an inhibi-
tory action on the glycocalyx and bio-
film of MRSA (GoR C).
MRSA in surgical site infection
6. The clinical relevance of SSIs caused
by MRSA should be perceived, because
the isolation rate of MRSA from SSIs
was unchanged without regard to the
duration and type of antimicrobial
prophylaxis (GoR B).
7. Preoperative urine culture for the
surveillance of MRSA could be a criti-
cal point in some situations, because
MRSA isolated from wounds tends
to correspond to that in preoperative
infected urine (GoR B).
8. Preoperative urine culture for the
surveillance of MRSA could be a
critical point in some situations,
because MRSA is frequently asso-
ciated with SSI of open urological
surgery and preoperative UTI is the
most important risk factor for SSI
(GoR B).
9. Preoperative urine culture for the
surveillance of MRSA could be a criti-
cal point in some situations, because
preoperative MRSA bacteriuria is
considered to be one of the risk fac-
tors for SSIs in urological surgery
(GoR B).
MRSA in urology | 2.4 |
Treatment
10. In the clinical field, glycopeptides
could be used as treatment for MRSA
urinary tract infection, although
there is a lack of data on the treat-
ment outcomes for glycopeptides for
urinary tract infection caused by
MRSA and not enough data on their
cost, toxicity and the availability of
other agents (GoR C).
11. Daptomycin, a new lipopeptide anti-
microbial agent, could be used as an
alternative treatment option, because
it is considered to be as effective as
linezolid or vancomycin (GoR C).
12. In an in vitro study, treatment with
vancomycin or rifampicin for the
purpose of reducing biofilm growth
was ineffective and combined with
linezolid was also ineffective
(GoR C).
13. Clarithromycin could be an alterna-
tive treatment for MRSA biofilm
infection because it had an inhibitory
action on the glycocalyx and biofilm
of MRSA (GoR C).
14. Combination therapy with vancomy-
cin and clarithromycin might be an
alternative treatment option because
of their efficacy in urinary tract
infection caused by MRSA (GoR C).
Community- versus healthcare-
acquired MRSA (CA- versus HAMRSA)
15. Genetic marker can be an important
diagnostic tool, because use of genetic
markers may make it possible to
discriminate between CAMRSA and
HAMRSA (GoR A).
16. Daptomycin and tigecycline can
be used for skin and soft-tissue
infections by CAMRSA, because
double-blinded clinical trials reveal
that daptomycin and tigecycline
were equally effective for skin and
soft-tissue infections by CAMRSA
(GoR A).
93
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
Prevention
17. For the purpose of prevention of
UTI and SSI caused by MRSA, we
should exploit useful and practi-
cal recommendations because there
are several educational guidelines
for the prevention of UTI and SSI
(GoR A).
1. INTRODUCTION
Staphylococcus aureus (S.aureus) is one
of the normal floras on the human skin
and in the nasal cavity. To date, various
multi drug resistant bacterial pathogens
have been noted and methicillin-resistant
S.aureus (MRSA) is one of the most
important. Multi drug resistant bacterial
organisms have been mostly isolated in
hospitals or long-term care facilities and
that has led to clinical issues, such as
healthcare-associated infections. MRSA
was first isolated in the United Kingdom
in 1961 [1–2] and has become wide-
spread worldwide since then. In Japan,
healthcare-associated MRSA infection,
including urinary tract infection (UTI)
and surgical site infection (SSI), became
an issue of clinical importance especially
during the period 1980 to 1990. At that
time, there were occasional outbreaks
of healthcare-associated MRSA not only
in the intensive care unit but also in the
urology ward. Although frequent out-
breaks of healthcare-associated MRSA in
the urology field in Japan have occurred
rarely in recent years, the isolation rate
of MRSA in the urological field has been
either unchanged or increasing [3–4]
despite the enactment of the standard
precautions advocated by the Centers for
Disease Control and Prevention (CDC) of
the United States. In this chapter, reports
on the mainly healthcare-associated
MRSA isolated from urine or surgical
sites in the urology field are reviewed and
discussed.
94
2. METHODS
A systematic literature search was
performed in PubMed with the follow-
ing keywords: MRSA and urinary tract
infection, MRSA and biofilm, MRSA
and surgical site infection, MRSA and
genital infection, community-associated
MRSA and genital infection, MRSA
and skin and soft tissue infection,
MRSA and balanoposthitis and MRSA
and treatment. Only English publica-
tions with abstracts available were
considered. Publications on infections
irrelevant to the urological field, such
as pneumonia, sepsis and blood stream
infection were excluded from the anal-
ysis. A total of 8227 publications were
found, which were screened by title and
abstract, and finally 30 were included
in the analysis.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[5–6].
3. DEFINITION
MRSA is defined as strains of Staphy-
lococcus aureus resistant to isoxaszoyl
penicillins, such as methicillin and oxa-
cillin. Additionally, at present, the defini-
tion of MRSA should be made according
to clinical background at isolation and
microbiological characteristic findings. In
this chapter, MRSA is defined according
to the clinical background or situation at
isolation because we focused on clinical
MRSA infection. We define both health-
care-associated MRSA (HAMRSA) and
community-associated MRSA (CAMRSA)
mostly according to the guidelines
developed by the British Society for
Antimicrobial Chemotherapy [7] because
of its specific content. We mainly focus on
HAMRSA throughout, except the section
on CAMRSA.

4. HEALTHCARE-ASSOCIATED MRSA
(HAMRSA)
The pattern of transmission is dissemi-
nation within healthcare settings. Most
HAMRSA strains are diagnosed in inpa-
tient settings. In general, the medical
history shows the history of MRSA colo-
nization, infection, recent surgery, anti-
biotic use and admission to a hospital or
nursing home. When infection occurs in
hospitals or healthcare settings, it is hos-
pital or healthcare onset. When it occurs
in the community after hospital dis-
charge, it is community onset [7].
5. COMMUNITY-ASSOCIATED MRSA
(CAMRSA)
The transmission pattern is just commu-
nity-acquired. Diagnosis is done in out-
patient or community settings. Medical
history shows no significant history or
healthcare contact. When infection occurs
in an outpatient or community setting, it
means community onset. When it occurs
within 48 hours of hospital admission,
it means hospital onset. Medical history
shows no history of MRSA and patients
have the absence of indwelling catheters
[7] (LoE 4, GoR A). However, because
S.aureus can persist for a longer duration,
community-onset infections with pos-
sible community-associated MRSA may
indeed be caused by healthcare-associ-
ated MRSA.
6. MRSA IN URINARY TRACT
INFECTION
6.1 Epidemiology
The frequency of S. aureus infections,
mostly MRSA, has been gradually grow-
ing and it is a clinically important issue
for healthcare-associated infection world-
wide [8–9]. In particular, bloodstream
MRSA in urology | 2.4 |
infection and pneumonia due to MRSA
have been frequently observed [10].
In a report on the isolation rate of UTI
bacterial pathogens for urology inpa-
tients in Kobe, Japan [4], the preva-
lence rates of isolated urinary S.aureus
were 1.9% from 1983 to 1987, 4.6% from
1988 to 1992, 5.3% from 1993 to 1997,
and 6.6% from 1998 to 2002. The rate
showed an increasing trend in the past
years. The authors note that the rate of
MRSA showed a similar increasing trend
and accounted for 82.2% of the entire
S. aureus population in 2002 (LoE 3,
GoR B).
In a report examining how to deter-
mine the number of newly diagnosed
cases of MRSA detected in a urology ward
in Portsmouth, UK [11], the ratios of the
number of newly diagnosed MRSA cases
to total urological admissions were 0.82
in 2000, 0.89 in 2001, 1.00 in 2002, 0.67
in 2003, and 0.79 in 2004. The origins of
isolates were urinary indwelling devices
and urine, including three catheters, six
nephrostomy tips, 19 suprapubic cath-
eter tips, six cases of urine from cath-
eter samples, and 11 midstream urine
samples. Other origins were wounds, the
nose, genitalia, groin, blood cultures, leg
ulcers, sputum, and bronchoscopic lavage
fluid. The proportion of MRSA isolates
of urinary origin was 38.8% (45 of 116).
They concluded that the number of new
cases of MRSA remained constant and
low acquisition rates were found (LoE 3,
GoR B).
The isolation rates of urinary MRSA
could be variable and depend on each
hospital and facility. We should track
the isolation rates of urinary MRSA by
surveillance of urinary pathogens and
undertake the prevention of MRSA out-
breaks according to standard precau-
tions. If the rate of MRSA infection is
relatively high or increasing, active sur-
veillance cultures might be effective for
prevention of outbreaks [12] (LoE 1a,
GoR B).
95
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
6.2 Virulence in urinary tract
S.aureus strains, including MRSA (57%),
isolated from patients with UTI were
analyzed, and the prevalence of toxins
and adhesion factors were determined
[13]. Staphylococcal enterotoxin (SE) A
(63%), SE D (20%), toxic shock syndrome
toxin-1 (8.5%) and staphylococcal bicom-
ponent leukotoxin LukE/LukD (60%)
were produced by the isolates. In addi-
tion, S.aureus urinary tract infections
have been associated with implanted
catheters and biomaterials. Adhesin fac-
tors, included clumping factor B (clfb),
elastin-binding protein (ebp) and lam-
inin-binding protein (lbp) are possibly
involved in colonization on urinary cath-
eters. In general, the pathogenesis of
urinary MRSA is multifactorial and tox-
ins causing urinary tract infections have
not been clearly determined yet (LoE 3,
GoR C).
In a cohort study at a long-term care
Veterans Affairs facility [14], 82% of 102
patients had urinary tract catheteriza-
tion. In addition, 33% of the patients had
symptomatic UTI at initial isolation of
S.aureus and 13% were bacteremic. In
this study, 86% of the initial urine cul-
tures were MRSA-positive. Persistent
carriers of urinary MRSA colonization
were determined to be at high risk of
subsequent urinary tract infection and
bacteremia. Therefore, the pathogenesis
of urinary MRSA might be associated
with urinary indwelling catheters and
there was a relatively high prevalence
of asymptomatic patients with urinary
MRSA. In the patients with asympto-
matic urinary MRSA, we should be aware
of urinary MRSA being a potential reser-
voir for healthcare-associated infection
(LoE 2, GoR B).
In a recent review of the pathogenesis
of MRSA [15], selected virulence factors
of S.aureus were presented. Microbial
surface components recognizing adhe-
sive matrix molecules (MSCRAMMs) are
important surface proteins that can bind
96
molecules such as collagen, fibronectin,
and fibrinogen. MSCRAMMs might initi-
ate catheter infections as well as endocar-
ditis, osteomyelitis, septic arthritis and
prosthetic-device infections. One theory
showed that no virulence factors were
suggested for urinary tract infection with-
out any urinary catheter or instrument
(LoE 1a, GoR B). The virulence of MRSA
in the urinary tract depends on urinary
catheters or instruments and it leads to
complicated urinary tract infection. There
are no definite virulence factors of MRSA
reported for uncomplicated urinary tract
infection to date.
6.3 Biofilm
Although there are relatively many
patients with asymptomatic urinary
MRSA, it rarely leads to severe sys-
temic infection or febrile UTI in most.
However, on occasion, it can lead to
serious bacteremia. One of the factors
or background causes of asymptomatic
infection is considered to be biofilm for-
mation in the urinary tract or on a uri-
nary indwelling device. The mechanisms
of biofilm formation in the urinary tract
or on the urinary indwelling device [16]
are as follows: once bacterial adhesion
is completed on the surface of a foreign
body such as a urinary catheter, a gly-
cocalyx consisting of polysaccharides
is produced outside the bacterial cells.
Finally, the condition results in biofilm
formation. The biofilm is considered to
be antimicrobial-resistant, allowing bac-
teria to escape the host defense against
infection and to escape the actions of
antimicrobials. In this condition, two
virulence factors, beta-hemolysin and
fibronectin-binding protein A, were sug-
gested to be associated with MRSA colo-
nization and infection of the urinary
tract [17] (LoE 2b, GoR C). In an experi-
mental study [16], the results suggested
that clarithromycin had an inhibitory
action on the glycocalyx and biofilm of
MRSA (LoE 2b, GoR C).

7. MRSA IN SURGICAL SITE
INFECTIONS
SSIs are strongly associated with morbid-
ity and mortality for inpatients as health-
care-associated infections that occur
despite standard precautions. SSIs caused
by MRSA are common in urology wards
[3, 18]. Two transmission manners are
hypothesized. One is preoperative dis-
semination from MRSA bacteriuria, with
MRSA endogenously transmitted from
the urinary tract to the wound. The other
is exogenous contact transmission from
hand to hand by the medical staff.
In a study [3] on SSIs of open urologi-
cal operations, the results showed that
the most frequently isolated bacterium
was MRSA. The isolation rate of MRSA
from SSIs was unchanged without regard
to the duration and type of antimicrobial
prophylaxis. The frequencies of MRSA iso-
lation from SSI were 73.3% in an uncon-
trolled antimicrobial prophylaxis group
and 93.3% in a controlled antimicrobial
prophylaxis group (LoE 2b, GoR B). In
addition, SSIs for radical cystectomy with
urinary diversion using the small intes-
tine, considered a contaminated opera-
tion by the CDC guideline, were surveyed
and reported [18]. The results showed
that the overall incidence of SSIs was
33% and MRSA was the most frequently
isolated bacterium, accounting for 38%
of the isolated pathogens. This study
showed that MRSA isolated from wounds
tended to correspond to that in preop-
erative infected urine (LoE 3, GoR B).
Another report [19] also showed that
MRSA was frequently associated with
SSI of open urological surgery and preop-
erative UTI was the most important risk
factor for SSI (LoE 3, GoR B).
There have been a few reports about
SSIs of urological surgeries according to
the classification of the CDC guideline;
however, those reports indicated that
MRSA was the organism most frequently
isolated from wound SSIs. Preoperative
MRSA in urology | 2.4 |
MRSA bacteriuria is considered to be one
of the risk factors for SSIs in urological
surgery (LoE 3, GoR B). As we know, the
rate of SSI in clean or clean-contaminated
surgery is much lower than that in con-
taminated surgery [3, 20]. Therefore, SSIs
of urological surgeries caused by MRSA
are mainly related to contaminated sur-
gery such as radical cystectomy with
urinary diversion as described in previ-
ous reports [3, 18–19]. Unfortunately, no
effective antimicrobial prophylaxis regi-
men against SSI caused by MRSA has
been established yet. Because MRSA iso-
lation rates in each medical center are
highly variable, every urologist may not
have trouble about SSI caused by MRSA.
However, MRSA has been the princi-
pal nosocomial pathogen in healthcare-
associated infections and we should
establish an effective regimen as well as
standard precautions.
8. TREATMENT
Surprisingly few studies of antimicrobial
treatment for urinary MRSA have been per-
formed to date. Applicable anti-MRSA drugs
are generally likely to vary in each coun-
try or region. In addition, the frequency of
uncomplicated UTI caused by MRSA is not
high enough to establish a standard treat-
ment regimen. In Japan, there are four
applicable antimicrobial agents for MRSA
infection, including urinary tract infection:
vancomycin, teicoplanin, arbekacin, and
linezolid. Regrettably, there have been no
randomized controlled studies with these
antimicrobial agents [21] although such
studies might lead to favorable treatment
outcomes.
In the guidelines of the United Kingdom
[22], tetracycline is recommended as the
first-line treatment regimen for urinary
tract infection caused by susceptible
MRSA. The guidelines state that there
is a lack of data on the treatment out-
comes for glycopeptides for urinary tract
97
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
infection caused by MRSA and not enough
data on their cost, toxicity and the avail-
ability of other agents. This remark is cat-
egorized as suggestive for implementation
and supported by suggestive clinical and
epidemiological studies as well as a theo-
retical rationale (LoE 4, GoR C). However,
for patients with MRSA bacteremia such
as severe febrile urinary tract infection,
a minimum treatment duration by glyco-
peptides or linezolid of 14 days is recom-
mended in the guidelines. Therefore, it
is possible to apply glycopeptides or lin-
ezolid according to the patients’ condition
or severity.
In an in vitro study of daptomy-
cin, a new lipopeptide antibiotic [23], it
was considered to be as effective as lin-
ezolid or vancomycin (LoE 2b, GoR C).
Unfortunately, there has been no clini-
cal study with daptomycin so it should be
studied in clinical trials in the future.
In the clinical situation, urinary MRSA
is mostly impossible to eradicate per-
fectly from the catheterized urinary tract.
Exchange of the urinary catheter is one
possible procedure to eradicate urinary
MRSA; however, the complicated urinary
tract condition generally makes eradica-
tion of MRSA difficult. It is closely asso-
ciated with biofilm formation on the
urinary catheter. An in vitro study [24]
revealed that treatment with vancomy-
cin or rifampicin to reduce biofilm growth
was ineffective and that with linezolid
was also ineffective [25] (LoE 2b, GoR C).
Another study [16] revealed that clari-
thromycin had an inhibitory action on
the glycocalyx and biofilm of MRSA and
that combination therapy with vancomy-
cin and clarithromycin might be effica-
cious for UTI caused by MRSA (LoE 2b,
GoR C).
To date, there have been no definitive
clinical trials for the treatment of UTI
caused by HAMRSA or for the inhibition
of MRSA biofilm formation on urinary
catheters. Current treatments for these
conditions tend to be highly empirical.
98
9. CAMRSA
CAMRSA has been especially noted as
a pathogen causing skin and soft-tissue
infections in the community. In the field of
urology, a few special genital or perineal
infections might be related to CAMRSA.
However, there has been an epidemic of
CAMRSA in recent years. Therefore, we
should know how to diagnose and treat
the skin and soft-tissue infections caused
by this pathogen.
10. DEFINITION USING BY GENETIC
MARKER
Use of genetic markers may make it pos-
sible to discriminate between commu-
nity- and hospital-acquired MRSA [26]
(LoE 4, GoR A). In the United States,
community-acquired MRSA has the sta-
phylococcal cassette chromosome (SCC)
mec type IV and the gene for Panton-
Valentine leukocidin (PVL) [26] (LoE 4,
GoR A).
11. BALANOPOSTHITIS CAUSED BY
CAMRSA
There has been just 1 case clearly
caused by MRSA to date [27]. The his-
tory of that case revealed that it was
caused by HAMRSA. Indeed, we treated
one case with balanoposthitis caused by
CAMRSA determined by clinical history
with no inpatient or outpatient history,
although SCC mec type IV and the gene
for PVL could not be examined (LoE 3,
GoR C).
To date, skin infections caused by
CAMRSA have not been a critical issue
in the field of urology. However, impetigo,
folliculitis, furuncles and abscesses caused
by CAMRSA are epidemic worldwide.
We should be aware that such infections
could occur in our field in the future.

12. TREATMENT FOR COMMUNITY-
ACQUIRED MRSA SKIN AND
SOFT-TISSUE INFECTIONS
There are four US Food and Drug
Administration (FDA)-approved anti-
MRSA drugs: vancomycin, linezolid, dap-
tomycin, and tigecycline. Vancomycin is
a standard drug for skin and soft-tissue
infections by CAMRSA [26]. Therefore,
clinical trials were carried out by com-
paring the other drugs with vancomycin.
An open-label clinical trial revealed that
the cure rate for CAMRSA infections was
higher in the group treated with linezolid
(88.6%) than in that with vancomycin
(66.9%) [28]. Double-blinded clinical tri-
als revealed that daptomycin and tigecy-
cline were equally effective for skin and
soft-tissue infections by CAMRSA [29–30]
(LoE 1b, GoR A). In addition, oral antimi-
crobial agents such as trimethoprim-sul-
famethoxazole, doxycycline, minocycline,
rifampin, clindamycin, and fusidic acid
are also recommended; however, clinical
trials in the field of urology are lacking.
13. PREVENTION
Prevention of both MRSA UTI and surgi-
cal site infection is the most important
issue especially in the urology ward of
healthcare settings. There are several
educational guidelines for prevention of
UTI and surgical site infection [31–32]
(LoE 1a, GoR A). These guidelines are
commonly available for almost all noso-
comial pathogens including HAMRSA.
Although those are not the guidelines for
the prevention of particular MRSA trans-
mission, the intimate content can cover
the field of urology. I strongly recommend
that urologists peruse these guidelines.
MRSA in urology | 2.4 |
14. FURTHER RESEARCH
There is a lack of comprehensive stud-
ies of MRSA infection in the field of
urology, although UTI caused by MRSA
is an important origin of healthcare-
associated infections and surgical site
infections.
15. CONCLUSIONS
Urinary MRSA is a potential reservoir
for healthcare-associated infection. If
the rate of MRSA infection is high or
increasing, active surveillance might be
effective for prevention of outbreaks. The
pathogenesis of urinary MRSA is mul-
tifactorial and toxins causing urinary
tract infections have not been clearly
determined yet. MRSA is frequently
associated with SSI of open urological
surgery and preoperative MRSA bacte-
riuria is considered to be one of the risk
factors for SSIs in urological surgery.
There is a lack of data on the treat-
ment of UTI caused by MRSA with glyc-
opeptides, e.g. vancomycin, and with
other agents, such as linezolid and dap-
tomycin. In an in vitro study, treatment
with vancomycin or rifampicin to reduce
biofilm growth was ineffective and that
with linezolid was also ineffective.
Clarithromycin had an inhibitory effect
on the glycocalyx and biofilm of MRSA
in contrast to the agents mentioned.
Therefore a combination therapy with
vancomycin and clarithromycin might
be efficacious for the treatment of UTI
caused by MRSA. Daptomycin and tige-
cycline were equally effective for skin
and soft-tissue infections by CAMRSA.
There are several educational guide-
lines for prevention of UTI and SSI.
99
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
REFERENCES
1. Jevons MP, “Celbenin”-resistant staphylo-
cocci. Br Med J, 1961. 1: 124–125.
2. Jevons MP, Coe AW, and Parker MT,
Methicillin resistance in staphylococci.
Lancet, 1963. 1(7287): 904–7.
3. Matsukawa M, Kunishima Y, Takahashi
S, Takeyama K, and Tsukamoto T,
Staphylococcus aureus bacteriuria and
surgical site infections by methicillin-
resistant Staphylococcus aureus. Int J
Antimicrob Agents, 2001. 17(4): 327–9,
discussion 329–30.
4. Shigemura K, Tanaka K, Okada H,
Nakano Y, Kinoshita S, Gotoh A, Arakawa
S, and Fujisawa M, Pathogen occurrence
and antimicrobial susceptibility of uri-
nary tract infection cases during a 20-year
period (1983–2002) at a single institution in
Japan. Jpn J Infect Dis, 2005. 58(5): 303–8.
5. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
6. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
7. Nathwani D, Morgan M, Masterton RG,
Dryden M, Cookson BD, French G, and
Lewis D, Guidelines for UK practice for
the diagnosis and management of methi-
cillin-resistant Staphylococcus aureus
(MRSA) infections presenting in the com-
munity. J Antimicrob Chemother, 2008.
61(5): 976–94.
8. Klevens RM, Edwards JR, Tenover FC,
McDonald LC, Horan T, and Gaynes R,
Changes in the epidemiology of methi-
cillin-resistant Staphylococcus aureus
in intensive care units in US hospitals,
1992–2003. Clin Infect Dis, 2006. 42(3):
389–91.
9. Lescure FX, Biendo M, Douadi Y,
Schmit JL, and Eveillard M, Changing
epidemiology of methicillin-resistant
Staphylococcus aureus and effects on
cross-transmission in a teaching hospital.
Eur J Clin Microbiol Infect Dis, 2006.
25(3): 205–7.
100
10. Kuehnert MJ, Hill HA, Kupronis BA,
Tokars JI, Solomon SL, and Jernigan
DB, Methicillin-resistant-Staphylococcus
aureus hospitalizations, United States.
Emerg Infect Dis, 2005. 11(6): 868–72.
11. Thiruchelvam N, Yeoh SL, and Keoghane
SR, MRSA in urology: a UK hospital expe-
rience. Eur Urol, 2006. 49(5): 896–9.
12. Muto CA, Jernigan JA, Ostrowsky BE,
Richet HM, Jarvis WR, Boyce JM, and
Farr BM, SHEA guideline for preventing
nosocomial transmission of multidrug-
resistant strains of Staphylococcus aureus
and enterococcus. Infect Control Hosp
Epidemiol, 2003. 24(5): 362–86.
13. Baba-Moussa L, Anani L, Scheftel
JM, Couturier M, Riegel P, Haikou N,
Hounsou F, Monteil H, Sanni A, and
Prevost G, Virulence factors produced by
strains of Staphylococcus aureus isolated
from urinary tract infections. J Hosp
Infect, 2008. 68(1): 32–8.
14. Muder RR, Brennen C, Rihs JD,
Wagener MM, Obman A, Stout JE, and
Yu VL, Isolation of Staphylococcus aureus
from the urinary tract: association of
isolation with symptomatic urinary tract
infection and subsequent staphylococcal
bacteremia. Clin Infect Dis, 2006. 42(1):
46–50.
15. Gordon RJ and Lowy FD, Pathogenesis
of methicillin-resistant Staphylococcus
aureus infection. Clin Infect Dis, 2008. 46
Suppl 5: S350–9.
16. Sano M, Hirose T, Nishimura M,
Takahashi S, Matsukawa M, and
Tsukamoto T, Inhibitory action of clari-
thromycin on glycocalyx produced by
MRSA. J Infect Chemother, 1999. 5(1):
10–15.
17. Ando E, Monden K, Mitsuhata R,
Kariyama R, and Kumon H, Biofilm
formation among methicillin-resistant
Staphylococcus aureus isolates from
patients with urinary tract infection. Acta
Med Okayama, 2004. 58(4): 207–14.
18. Takeyama K, Matsukawa M, Kunishima Y,
Takahashi S, Hotta H, Nishiyama N, and
Tsukamoto T, Incidence of and risk factors
for surgical site infection in patients with
radical cystectomy with urinary diversion.
J Infect Chemother, 2005. 11(4): 177–81.

19. Hamasuna R, Betsunoh H, Sueyoshi T,
Yakushiji K, Tsukino H, Nagano M,
Takehara T, and Osada Y, Bacteria of
preoperative urinary tract infections con-
taminate the surgical fields and develop
surgical site infections in urological oper-
ations. Int J Urol, 2004. 11(11): 941–7.
20. Yamamoto S, Kanamaru S, Kunishima Y,
Ichiyama S, and Ogawa O, Perioperative
antimicrobial prophylaxis in urol-
ogy: a multi-center prospective study. J
Chemother, 2005. 17(2): 189–97.
21. Wagenlehner FM and Naber KG, New
drugs for Gram-positive uropathogens. Int
J Antimicrob Agents, 2004. 24 Suppl 1:
S39–43.
22. Gemmell CG, Edwards DI, Fraise AP,
Gould FK, Ridgway GL, and Warren
RE, Guidelines for the prophylaxis
and treatment of methicillin-resistant
Staphylococcus aureus (MRSA) infections
in the UK. J Antimicrob Chemother, 2006.
57(4): 589–608.
23. Wagenlehner FM, Lehn N, Witte W, and
Naber KG, In vitro activity of dapto-
mycin versus linezolid and vancomycin
against gram-positive uropathogens and
ampicillin against enterococci, causing
complicated urinary tract infections.
Chemotherapy, 2005. 51(2–3): 64–9.
24. Jones SM, Morgan M, Humphrey TJ,
and Lappin-Scott H, Effect of vancomycin
and rifampicin on meticillin-resistant
Staphylococcus aureus biofilms. Lancet,
2001. 357(9249): 40–1.
25. Raad I, Hanna H, Jiang Y, Dvorak T,
Reitzel R, Chaiban G, Sherertz R, and
Hachem R, Comparative activities of
daptomycin, linezolid, and tigecycline
against catheter-related methicillin-re-
sistant Staphylococcus bacteremic isolates
embedded in biofilm. Antimicrob Agents
Chemother, 2007. 51(5): 1656–60.
MRSA in urology | 2.4 |
26. Stryjewski ME and Chambers HF, Skin
and soft-tissue infections caused by
community-acquired methicillin-resistant
Staphylococcus aureus. Clin Infect Dis,
2008. 46 Suppl 5: S368–77.
27. Herieka E and Fisk P, Methicillin resist-
ant Staphylococcus aureus (MRSA)
balanoposthitis in an insulin dependent
diabetic male. Sex Transm Infect, 2001.
77(3): 223.
28. Weigelt J, Itani K, Stevens D, Lau W,
Dryden M, and Knirsch C, Linezolid
versus vancomycin in treatment of com-
plicated skin and soft tissue infections.
Antimicrob Agents Chemother, 2005.
49(6): 2260–6.
29. Arbeit RD, Maki D, Tally FP, Campanaro E,
and Eisenstein BI, The safety and efficacy of
daptomycin for the treatment of complicated
skin and skin-structure infections. Clin Infect
Dis, 2004. 38(12): 1673–81.
30. Ellis-Grosse EJ, Babinchak T, Dartois N,
Rose G, and Loh E, The efficacy and
safety of tigecycline in the treatment
of skin and skin-structure infections:
results of 2 double-blind phase 3 com-
parison studies with vancomycin-aztre-
onam. Clin Infect Dis, 2005. 41 Suppl 5:
S341–53.
31. Tenke P, Kovacs B, Bjerklund Johansen TE,
Matsumoto T, Tambyah PA, and Naber KG,
European and Asian guidelines on manage-
ment and prevention of catheter-associated
urinary tract infections. Int J Antimicrob
Agents, 2008. 31 Suppl 1: S68–78.
32. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline
for prevention of surgical site infection,
1999. Hospital Infection Control Practices
Advisory Committee. Infect Control Hosp
Epidemiol, 1999. 20(4): 250–78; quiz
279–80.
101
|2.5|

ESBL and multi-resistance

in urology
Tetsuro Muratani
Corresponding author: Tetsuro Muratani, PhD, The Head of Department, Department of Clinical Laboratory, Kyurin
Corporation and Assistant Professor, Department of Urology, School of Medicine, University of Occupational and
Environmental Health 27-25, Morishita-machi, Yathatanishi-ku, Kitakyushu, 806-0046, Japan
Tel 0081-93-642.3911, Fax 0081-93-642.3967, tetsuro_muratani@ybb.ne.jp

ABSTRACT penicillins, all cephalosporins or mono-

β-lactamases are bacterial enzymes that
are encoded by chromosomal or by plasmid-
mediated genes, the enzymes protecting
the microorganisms against the lethal
effects of β-lactam antibiotics by hydrolyz-
ing the β-lactam ring. The production of
β-lactamases is the most important resist-
ant mechanism to β-lactam antibiotics,
especially for Gram-negative bacteria.
Since the first description of plasmid-
mediated extended-spectrum β-lactamases
(ESBL) in 1983, ESBL-producing Gram-
negative organisms have posed a sig-
nificant threat to hospitalized patients
due to their hydrolyzing activity against
expanded-spectrum cephalosporins, which
are often employed in the treatment of
hospital-acquired infections. Detection of
ESBL producers provides clinicians with
helpful information. Treatment of infec-
tions caused by ESBL-producers with
bactams may result in treatment fail-
ure even when the causative organisms
appear to be susceptible to these anti-
microbial agents by routine susceptibil-
ity testing. Regarding patients colonized
or infected with ESBL-producers, it is
important to pay attention and perform
contact precautions to avoid hospital
transmission. These benefits warrant
the detection of ESBL-producing organ-
isms in clinical laboratories. All ESBL-
detection methods by only phenotype
utilize the characteristics of ESBLs:
conferring a reduced susceptibility to
expanded-spectrum cephalosporins and
inhibition by clavulanic acid. ESBL-
producers showed a significant reduction
in the susceptibility to most antimicro-
bials, such as aminoglycosides, quinolo-
nes and trimethoprim-sulfamethoxazole.
Moreover, community acquired infec-
tions due to ESBL-producing organisms

pose a serious challenge to clinicians in
choosing appropriate empiric therapy.
The incidence of such infections is cur-
rently not so high, but we have to pay
attention to the trend. Furthermore, if
multi-drug resistant Enterobacteriaceae
isolates with carbapenem hydrolyzing
activity such as KPC type β-lactamase
increase, they will pose a serious threat
that will limit choice of antibiotic
treatment.
Key words: Extended-spectrum β-
lactamase (ESBL), urinary tract infection,
antimicrobial therapy, plasmid-mediated
broad spectrum β-lactamase
1. INTRODUCTION
β-lactamases are bacterial enzymes
that are encoded by chromosomal or by
plasmid-mediated genes, and are the
enzymes that protect microorganisms
against the lethal effects of β-lactam anti-
biotics by hydrolyzing the β-lactam ring.
The production of β-lactamases is the
most important resistant mechanism to
β-lactam antibiotics, especially for Gram-
negative bacteria. Based on their struc-
tures, β-lactamases can be classified into
two different groups, serine β-lactamases
and Metallo-β-lactamases (Class B) [1].
Serine β-lactamases can then be classified
Amino acid homology
Basic structure
Serine �-lactamase
�-lactam bond
hydrolyzing enzyme
�-lactamase
ClassB
Metallo-�-lactamase
Figure 1 Classification of β-lactamases based on molecular structure Bellingham Research Institute website (http://homepage
.mac.com/barryghall/BRIHome.html).
Rasmussen and Bush. Carbapenem-hydrolyzing beta-lactamases. Antimicrob. Agents Chemother. 41:223–232, 1997. Hall BG,
Salipante SJ, Barlow M. The metallo-beta-lactamases fall into two distinct phylogenetic groups. J Mol Evol. 2003;57:249–54.
ESBL and multi-resistance in urology | 2.5 |
into three different groups Class A, Class
C [2], and Class D [3]. Class B has been
divided into three subgroups, B1, B2,
and B3, on the basis of sequence similar-
ity [4], but phylogenetic analysis [5] has
shown that subgroup B3 lacks detectable
sequence homology with subgroups B1 &
B2 (Figure 1).
Plasmid-mediated β-lactamases have
become prevalent among Gram-negative
bacteria. The first plasmid-mediated
β-lactamase in Gram-negative bacteria,
TEM-1, was described in the early 1960s
[6]. Carried by transposons on plasmids,
the TEM-1 genes have spread to several
bacterial species and are now distributed
around the world. SHV-1 is another fre-
quently encountered plasmid-mediated
β-lactamase among Gram-negative bac-
teria. Extended-spectrum β-lactamases
(ESBLs) have been increasingly reported
in Europe since their first description in
1983 in Germany [7–8] During the 1990s,
they were described mainly as members
of the TEM- and SHV-β-lactamase fami-
lies in Klebsiella pneumoniae causing
nosocomial outbreaks. Nowadays, they
are mostly found in Escherichia coli that
cause community-acquired infections and
with increasing frequency contain CTX-M
enzymes. The increase in most of the
widespread ESBLs belonging to the
TEM, SHV and CTX-M families across
the world has occurred in community and
Class A
Class C
Class D Sequence homology
Class B1
Class B3 Class B2
(Class E)
103
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
nosocomial settings due to clonal spread.
Multi-resistances, especially to fluoro-
quinolones, aminoglycosides and sulfam-
ethoxazole/trimethoprime, seem to have
contributed to the problem. Moreover, the
emergence of epidemic clones harbour-
ing several β-lactamases simultaneously
(ESBLs, metallo-β-lactamases or Class C
β-lactamases) and of new plasmid-
mediated mechanisms of resistance to
fluoroquinolones (qnr) and aminogly-
cosides (ribosome methylase) warrants
future surveillance studies.
2. DEFINITION OF ESBL
The first plasmid-mediated β-lactamase
capable of hydrolyzing all cepha-
losporins, now known as SHV-2, was
reported in 1983 [7] and a number
of other groups of β-lactamases with
expanded hydrolytic activity were
reported thereafter. The term ‘extended-
spectrum β-lactamases (ESBLs)’ was
applied to denote these enzymes, which
are plasmid-mediated Class A or Class
D β-lactamases, with activity against
penicillin, all cephalosporins including
expanded-spectrum ones (3rd and 4th
generation cephalosporin), and mono-
bactams (aztereonam and carmonam).
ESBLs basically cannot hydrolyze
cephamycins (such as cefoxitin, cefmeta-
zole, moxalactam, etc.), penems (such
as faropenem, ritipenem), and carbap-
enems (such as imipenem, meropenem)
except some groups with a super broad
spectrum (such as GES type, KPC type).
ESBLs are generally inhibited by clavu-
lanic acid. Therefore, ESBLs include not
only TEM-, and SHV-variants but also
CTX-M derivatives. This definition is
practical enough to allow detection in the
hospital laboratory by only phenotype.
Amino acid sequences of TEM, SHV, and
CTX-M enzymes are listed on the Lahey
clinic website [9] which is dedicated to
the nomenclature of β-lactamases and
is hosted by George Jacoby and Karen
104
Bush. It should be considered that some
groups active in hydrolyzing cephamy-
cins and/or carbapenems, such as GES
type or KPC type, are not in the same
ESBL group in terms of method of treat-
ment and method of preventing nosoco-
mial infection.
3. DETECTION OF ESBLS IN CLINICAL
BY CLSI [10]
The Clinical and Laboratory Standards
Institute (CLSI) recommends performing
an ESBL screening test and ESBL confir-
mation test as follows. Strains of Klebsiella
spp., E. coli, and P. mirabilis that produce
ESBLs may be clinically resistant to ther-
apy with penicillins, cephalosporins, or
aztreonam, despite apparent in vitro sus-
ceptibility to some of these agents. Some
of these strains will show MICs above
the normal susceptible population but
below the standard breakpoints for cer-
tain extended-spectrum cephalosporins or
aztreonam; such strains may be screened
for potential ESBL production by using
the screening breakpoints (the screening
positive results of broth microdilution for
E. coli, K. pneumoniae, and K. oxytoca are
MIC ≥ 8 µg/ml for cefpodoxime or MIC ≥ 2
µg/ml cefotaxime, ceftazidime, ceftriaxone,
or aztreonam; and for P. mirabilis MIC ≥ 2
µg/ml for cefpodoxime, ceftazidime, or cefo-
taxime). The screening positive diameters
of the disk diffusion test to screen ESBL
also are defined, as is an initial screen test
according to routine susceptibility results.
Other strains may test intermediate or
resistant by standard breakpoints to one
or more of these agents. In all strains with
ESBLs, the MICs for ceftazidime or cefo-
taxime should decrease in the presence of
clavulanic acid (A ≥ 3 twofold concentra-
tion decrease in an MIC for either antimi-
crobial agent tested in combination with
clavulanic acid vs its MIC when tested
alone. The diameter of disk diffusion test:
A ≥ 5-mm increase in a zone diameter
for either antimicrobial agent tested in

A B
CAZ CAZ
/CVA
CTX CTX
/CVA
E F
Figure 2 The results of ESBL confirmatory test according to CLSI. CAZ: ceftazidime 30µg, CVA: clavulanic acid 10µg, CTX:
cefotaxime 30µg A: Position of disk, B: ESBL non-producing E. coli, C: SHV-12 producing E. coli, D: TEM-6 producing E. coli,
E: ESBL non-producing K. pneumoniae, F: CTX-M-14 producing E. coli, G: CTX-M-2 producing K. pneumoniae, H: CTX-M-2
producing P. mirabilis.
combination with clavulanic acid vs its
zone when tested alone) on a phenotypic
confirmatory test (Figure 2). For all con-
firmed ESBL-producing strains, the test
interpretation should be reported as resist-
ant for all penicillins, cephalosporins, and
aztreonam.
Detection of ESBL producers pro-
vides clinicians with helpful information.
Treatment of infections caused by ESBL-
producers with penicillins, all cepha-
losporins or monobactams may result in
treatment failure even when the causa-
tive organisms appear to be susceptible
to these antimicrobial agents by routine
susceptibility testing [11]. Regarding
patients colonized or infected with ESBL-
producers, it is important to pay attention
and perform contact precautions to avoid
hospital transmission. These benefits
warrant the detection of ESBL-producing
organisms in clinical laboratories. All
ESBL-detection methods by phenotype
only utilize the characteristics of ESBLs:
conferring a reduced susceptibility to
expanded-spectrum cephalosporins and
inhibition by clavulanic acid. Detection
of ESBL production by organisms with
inducible chromosomal and plasmid-
mediated AmpC β-lactamases is difficult
using these methods because not only
ESBL and multi-resistance in urology | 2.5 |
C D
G H
does AmpC β-lactamase resist inhibition
by clavulanic acid but also clavulanic acid
may act as a good inducer of the AmpC
β-lactamases of these organisms.
4. ESBL PRODUCERS IN UROLOGY
It is well known that the prevalence
of ESBL producing microorganisms in
high-risk areas of the hospital, such as
intensive care units, has increased dra-
matically from 3.6% in 1990 to 21.8% in
1993, in U.S. hospitals [12–13]. However,
greater concern has resulted from reports
of the increasing frequency of ESBL-
producing organisms causing infections
in outpatients. Yumuk et al [14] reported
that among the 3108 UTIs diagnosed,
82 (2.6%) were due to community E. coli
isolates and followed the strict inclusion
criteria. Seventeen of them (21%) pro-
duced an ESBL, of which CTX-M-15 was
predominant (53%). These ESBL-positive
isolates, distributed equally into three
phylogenetic groups, displayed 13 PFGE
profiles and three clusters. A Turkish
CTX-M-15-producing isolate as a mem-
ber of the clone ST131 was suggested
by a high similarity of its PFGE profile
to that of the clone representative and
105
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
was confirmed by O serotyping, AmpC
typing and MLST. Ena et al [15] has
reported that ESBL-producing E. coli
significantly increased from two (0.20%)
to 89 (5.52%) isolates per year (P value
for trend = 0.000). ESBL-producing
E. coli showed a significant reduction
in susceptibility to most antimicrobials
(gentamicin, quinolones, trimethoprim-
sulfamethoxazole), although carbapen-
ems and fosfomycin retained significant
activity. Muratani et al [16] also reported
that ESBL-producing E. coli isolates in
Japan showed a significant reduction in
the susceptibility to gentamicin, levo-
floxacin, tetracycline, and trimethoprim-
sulfamethoxazole.
5. TREATMENT OF INFECTIONS
CAUSED BY ESBL-PRODUCERS
CLSI established breakpoints for vari-
ous antibiotics soon after the clinical
release of them. Correlations of MICs of
expanded spectrum cephems to clinical
outcome were excellent; indeed, an MIC
of less than 8 µg/ml correlated with more
than 92% clinical success for all relevant
species [11]. But in treatment of infec-
tions caused by an ESBL producer, cepha-
losporins have been associated with poor
clinical outcome, even with lower MICs
than breakpoint. So CLSI recommends
that organisms revealed as having ESBL
should be reported as resistant for all pen-
icillins, cephalosporins and monobactams.
Non-β-lactam antibiotics, such as fluoro-
quinolones, may be useful for the therapy
for mild infections caused by susceptible
organisms [17]. However, ESBL-producing
isolates tend to show a high rate of resist-
ance to various non-β-lactam antibiotics
such as fluoroquinolones and aminoglyco-
sides. Carbapenems (e.g., imipenem and
meropenem) are regarded as the drug
of choice in treating serious infections
caused by ESBL-producers. Carbapenems
are stable against hydrolytic activity of
ESBLs and treatment with carbapenems
106
showed a significantly better clinical
outcome than that with other antibiot-
ics in a prospective observational study
involving 85 episodes of ESBL-producing
K. pneumoniae bacteremia in 12 hospitals
in seven countries [11]. As noted above,
treatment of infections due to ESBL pro-
ducing organisms with cephalosporins is
not generally recommended irrespective
of the result of MIC. Cephamycins (e.g.,
cefoxitin, cefmetazole, moxalactam, flo-
moxef ) are stable to the hydrolytic activ-
ity of ESBLs. However, a decrease in the
expression of outer membrane protein
[18] and inducible or constitutive produc-
tion of AmpC β-lactamase [19–20] leads
to resistance to cephamycins. β-Lactam/
β-lactamase inhibitor combinations (e.g.,
amoxicillin/clavulanate and piperacillin/
tazobactam) often remain active against
ESBL-producers, but coexistence of other
resistance mechanisms such as decrease
of outer membrane protein or AmpC
production may lead to the resistance
to these drugs. Moreover, the inoculum
effect with piperacillin/tazobactam was
observed among ESBL producing isolates
[21–22]. Due to these reasons, although
cephamycins and piperacillin/tazobactam
have potent activity to most ESBL pro-
ducers, these antibiotics alone are not rec-
ommended as first-line therapy for serious
infections caused by ESBL producers.
Howver, these antibiotics alone or with
the other antibiotics such as aminoglyco-
sides may be effective against moderate
infection caused by ESBL producers [23].
The appropriate use of these antibiotics
is important in avoiding the over use of
carbapenems.
6. PLASMID-MEDIATED CLASS A
β-LACTAMASE CAPABLE OF
CARBAPENEM HYDROLYZING
ACTIVITY
Resistance to carbapenems in Entero-
bacteriaceae can be caused by over-
production of AmpC β-lactamases or

carbapenem hydrolyzing β-lactamases
associated with loss of outer mem-
brane porins and/or overexpression of
efflux pumps [24]. Carbapenemases
can be divided into the metallo-
β-lactamases and serine carbapene-
mases. Carbapenem-hydrolyzing KPC
β-lactamases are a group of recently
identified carbapenemases which belong
to Bush group 2f, molecular class A.
KPCs are capable of hydrolyzing car-
bapenems, penicillins, cephems, and
aztreonam. The initial report on KPC-1
β-lactamase was from carbapenem-
resistant Klebsiella pneumoniae isolates
in the USA in 2001 [25]. KPC-2, the iden-
tical correct sequence of KPC-1 [26], was
then found in isolates of K. pneumoniae,
Salmonella enterica, Klebsiella oxytoca,
Serratia marcescens, and an Enterobacter
sp. [27–31]. KPC-3 was found in K. pneu-
moniae and Enterobacter cloacae iso-
lates in the USA [32–33]. Recently, KPCs
were found in various countries such as
France [34], South America [35], Israel
[36], and China [37]. Furthermore,
KPC-2 was identified for the first time
in Pseudomonas aeruginosa isolates
[38], that is, non-Enterobacteriaceae.
KPC-producing organisms are being
increasingly detected. The host range
of these KPCs is no longer limited to
K. pneumoniae, and the geographical
distribution is no longer limited to the
north-eastern United States. Sporadic
occurrences of KPC-2 were once reported
in China. They are now rapidly spread-
ing in ICUs in our hospital. Effective
measures for early identification and
control should be adopted to prevent
the potential continuous dissemination
of these carbapenem-resistant patho-
gens. Most isolates with carbapnemase
have multi-drug resistance, therefore the
treatment options for infections caused
by carbapenemase producing isolates
are significantly reduced. These multi-
drug resistant isolates with carbapenem
hydrolyzing β-lactamase have created a
serious problem in clinical situations.
ESBL and multi-resistance in urology | 2.5 |
7. CONCLUSIONS
Since the first description of plasmid-
mediated ESBL in 1983, ESBL-producing
Gram-negative organisms have posed
a significant threat to hospitalized
patients due to their hydrolyzing activ-
ity against expanded-spectrum cepha-
losporins, which are often employed in
the treatment of hospital acquired infec-
tions. In the past decade CTX-M-type
ESBLs have become prevalent globally
and their distribution involves not only
healthcare environments but also the
community. Community acquired infec-
tions due to ESBL-producing organisms
pose a serious challenge to clinicians in
choosing appropriate empiric therapy.
The incidence of such infections is cur-
rently not so high, but we have to pay
attention to the trend. Furthermore, if
multi-drug resistant Enterobacteriaceae
isolates with carbapenem hydrolyzing
activity such as KPC type β-lactamase
increase, they will pose a serious threat
which will limit choice of antibiotic
treatment.
REFERENCES
1. Ambler RP, The structure of beta-lactamases.
Philos Trans R Soc Lond B Biol Sci, 1980.
289(1036): 321–31.
2. Jaurin B and Grundstrom T, ampC
cephalosporinase of Escherichia coli K-12
has a different evolutionary origin from
that of beta-lactamases of the penicilli-
nase type. Proc Natl Acad Sci U S A, 1981.
78(8): 4897–901.
3. Huovinen P, Huovinen S, and Jacoby GA,
Sequence of PSE-2 beta-lactamase.
Antimicrob Agents Chemother, 1988.
32(1): 134–6.
4. Rasmussen BA and Bush K, Carbapenem-
hydrolyzing beta-lactamases. Antimicrob
Agents Chemother, 1997. 41(2): 223–32.
5. Hall BG, Salipante SJ, and Barlow M,
The metallo-beta-lactamases fall into two
distinct phylogenetic groups. J Mol Evol,
2003. 57(3): 249–54.
107
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
6. Datta N and Kontomichalou P,
Penicillinase synthesis controlled by infec-
tious R factors in Enterobacteriaceae.
Nature, 1965. 208(5007): 239–41.
7. Knothe H, Shah P, Krcmery V, Antal M,
and Mitsuhashi S, Transferable resistance
to cefotaxime, cefoxitin, cefamandole and
cefuroxime in clinical isolates of Klebsiella
pneumoniae and Serratia marcescens.
Infection, 1983. 11(6): 315–7.
8. Kliebe C, Nies BA, Meyer JF, Tolxdorff-
Neutzling RM, and Wiedemann B,
Evolution of plasmid-coded resistance
to broad-spectrum cephalosporins.
Antimicrob Agents Chemother, 1985.
28(2): 302–7.
9. Jacoby G and Bush K. Amino Acid
Sequences for TEM, SHV and OXA
Extended-Spectrum and Inhibitor
Resistant ß-Lactamases. Available from:
Lahey Clinic website. http://www.lahey
.org/Studies/.
10. Clinical and Laboratory Standards
Institute, Performance standards for
antimicrobial susceptibility testing.
Seventeenth informational supplement
M100-S18, 2008. 27(1): 98–163.
11. Paterson DL, Ko WC, Von Gottberg A,
Casellas JM, Mulazimoglu L, Klugman
KP, Bonomo RA, Rice LB, McCormack
JG, and Yu VL, Outcome of cephalosporin
treatment for serious infections due to
apparently susceptible organisms produc-
ing extended-spectrum beta-lactamases:
implications for the clinical microbiology
laboratory. J Clin Microbiol, 2001. 39(6):
2206–12.
12. Winokur PL, Canton R, Casellas JM,
and Legakis N, Variations in the preva-
lence of strains expressing an extended-
spectrum beta-lactamase phenotype and
characterization of isolates from Europe,
the Americas, and the Western Pacific
region. Clin Infect Dis, 2001. 32 Suppl 2:
S94–103.
13. Itokazu GS, Quinn JP, Bell-Dixon
C, Kahan FM, and Weinstein RA,
Antimicrobial resistance rates among
aerobic gram-negative bacilli recovered
from patients in intensive care units: eval-
uation of a national postmarketing sur-
veillance program. Clin Infect Dis, 1996.
23(4): 779–84.
108
14. Yumuk Z, Afacan G, Nicolas-Chanoine MH,
Sotto A, and Lavigne JP, Turkey: a further
country concerned by community-acquired
Escherichia coli clone O25-ST131 produc-
ing CTX-M-15. J Antimicrob Chemother,
2008. 62(2): 284–8.
15. Ena J, Arjona F, Martinez-Peinado C,
Lopez-Perezagua Mdel M, and Amador
C, Epidemiology of urinary tract infec-
tions caused by extended-spectrum beta-
lactamase-producing Escherichia coli.
Urology, 2006. 68(6): 1169–74.
16. Muratani T and Matsumoto T, Bacterial
resistance to antimicrobials in urinary
isolates. Int J Antimicrob Agents, 2004.
24 Suppl 1: S28–31.
17. Kang CI, Kim SH, Park WB, Lee KD,
Kim HB, Kim EC, Oh MD, and Choe KW,
Bloodstream infections due to extended-
spectrum beta-lactamase-producing
Escherichia coli and Klebsiella pneumo-
niae: risk factors for mortality and treat-
ment outcome, with special emphasis on
antimicrobial therapy. Antimicrob Agents
Chemother, 2004. 48(12): 4574–81.
18. Martinez-Martinez L, Hernandez-Alles
S, Alberti S, Tomas JM, Benedi VJ, and
Jacoby GA, In vivo selection of porin-
deficient mutants of Klebsiella pneumo-
niae with increased resistance to cefoxitin
and expanded-spectrum-cephalosporins.
Antimicrob Agents Chemother, 1996.
40(2): 342–8.
19. Muratani T, Kobayashi T, and Matsumoto T,
Emergence and prevalence of beta-lactamase-
producing Klebsiella pneumoniae resistant to
cephems in Japan. Int J Antimicrob Agents,
2006. 27(6): 491–9.
20. Palasubramaniam S, Subramaniam G,
Muniandy S, and Parasakthi N,
Extended-spectrum beta-lactam resist-
ance due to AmpC hyperproduction and
CMY-2 coupled with the loss of OMPK35
in Malaysian strains of Escherichia coli
and Klebsiella pneumoniae. Microb Drug
Resist, 2007. 13(3): 186–90.
21. Rice LB, Yao JD, Klimm K, Eliopoulos GM,
and Moellering RC, Jr., Efficacy of different
beta-lactams against an extended-spectrum
beta-lactamase-producing Klebsiella pneu-
moniae strain in the rat intra-abdominal
abscess model. Antimicrob Agents
Chemother, 1991. 35(6): 1243–4.

22. Thomson KS and Moland ES, Cefepime,
piperacillin-tazobactam, and the
inoculum effect in tests with extended-
spectrum beta-lactamase-producing
Enterobacteriaceae. Antimicrob Agents
Chemother, 2001. 45(12): 3548–54.
23. Korvick JA, Bryan CS, Farber B,
Beam TR, Jr., Schenfeld L, Muder RR,
Weinbaum D, Lumish R, Gerding DN,
Wagener MM, and et al., Prospective
observational study of Klebsiella bacter-
emia in 230 patients: outcome for antibi-
otic combinations versus monotherapy.
Antimicrob Agents Chemother, 1992.
36(12): 2639–44.
24. Poirel L, Heritier C, Spicq C, and
Nordmann P, In vivo acquisition of
high-level resistance to imipenem in
Escherichia coli. J Clin Microbiol, 2004.
42(8): 3831–3.
25. Yigit H, Queenan AM, Anderson
GJ, Domenech-Sanchez A, Biddle
JW, Steward CD, Alberti S, Bush K,
and Tenover FC, Novel carbapenem-
hydrolyzing beta-lactamase, KPC-1,
from a carbapenem-resistant strain
of Klebsiella pneumoniae. Antimicrob
Agents Chemother, 2001. 45(4):
1151–61.
26. Yigit H, Queenan AM, Anderson GJ,
Domenech-Sanchez A, Biddle JW,
Steward CD, Alberti S, Bush K, and
Tenover FC, Novel Carbapenem-
Hydrolizing β-Lactamase, KPC-1,
from a Carbapenem-Resistant Strain
of Klebsiella Pneumoniae. Antimicrob
Agents Chemother, 2008. 52: 809.
27. Smith Moland E, Hanson ND, Herrera VL,
Black JA, Lockhart TJ, Hossain A, Johnson
JA, Goering RV, and Thomson KS, Plasmid-
mediated, carbapenem-hydrolysing
beta-lactamase, KPC-2, in Klebsiella pneu-
moniae isolates. J Antimicrob Chemother,
2003. 51(3): 711–4.
28. Miriagou V, Tzouvelekis LS, Rossiter S,
Tzelepi E, Angulo FJ, and Whichard JM,
Imipenem resistance in a Salmonella
clinical strain due to plasmid-mediated
class A carbapenemase KPC-2. Antimicrob
Agents Chemother, 2003. 47(4):
1297–300.
29. Yigit H, Queenan AM, Rasheed JK, Biddle
JW, Domenech-Sanchez A, Alberti S, Bush
ESBL and multi-resistance in urology | 2.5 |
K, and Tenover FC, Carbapenem-resistant
strain of Klebsiella oxytoca harboring
carbapenem-hydrolyzing beta-lactamase
KPC-2. Antimicrob Agents Chemother,
2003. 47(12): 3881–9.
30. Zhang R, Zhou HW, Cai JC, and Chen
GX, Plasmid-mediated carbapenem-
hydrolysing beta-lactamase KPC-2 in
carbapenem-resistant Serratia marc-
escens isolates from Hangzhou, China.
J Antimicrob Chemother, 2007. 59(3):
574–6.
31. Hossain A, Ferraro MJ, Pino RM, Dew RB,
3rd, Moland ES, Lockhart TJ, Thomson
KS, Goering RV, and Hanson ND,
Plasmid-mediated carbapenem-
hydrolyzing enzyme KPC-2 in an
Enterobacter sp. Antimicrob Agents
Chemother, 2004. 48(11): 4438–40.
32. Woodford N, Tierno PM, Jr., Young K,
Tysall L, Palepou MF, Ward E, Painter
RE, Suber DF, Shungu D, Silver LL,
Inglima K, Kornblum J, and Livermore
DM, Outbreak of Klebsiella pneumoniae
producing a new carbapenem-hydrolyzing
class A beta-lactamase, KPC-3, in a New
York Medical Center. Antimicrob Agents
Chemother, 2004. 48(12): 4793–9.
33. Bratu S, Landman D, Alam M, Tolentino
E, and Quale J, Detection of KPC
carbapenem-hydrolyzing enzymes in
Enterobacter spp. from Brooklyn, New
York. Antimicrob Agents Chemother,
2005. 49(2): 776–8.
34. Naas T, Nordmann P, Vedel G, and Poyart
C, Plasmid-mediated carbapenem-
hydrolyzing beta-lactamase KPC in
a Klebsiella pneumoniae isolate from
France. Antimicrob Agents Chemother,
2005. 49(10): 4423–4.
35. Villegas MV, Lolans K, Correa A,
Suarez CJ, Lopez JA, Vallejo M, and
Quinn JP, First detection of the plas-
mid-mediated class A carbapenemase
KPC-2 in clinical isolates of Klebsiella
pneumoniae from South America.
Antimicrob Agents Chemother, 2006.
50(8): 2880–2.
36. Navon-Venezia S, Chmelnitsky I,
Leavitt A, Schwaber MJ, Schwartz D, and
Carmeli Y, Plasmid-mediated imipenem-
hydrolyzing enzyme KPC-2 among mul-
tiple carbapenem-resistant Escherichia
109
Chapter |2| Aetiology, antimicrobial resistance of uropathogens

coli clones in Israel. Antimicrob Agents
Chemother, 2006. 50(9): 3098–101.
37. Wei ZQ, Du XX, Yu YS, Shen P, Chen YG,
and Li LJ, Plasmid-mediated KPC-2 in
a Klebsiella pneumoniae isolate from
China. Antimicrob Agents Chemother,
2007. 51(2): 763–5.
38. Villegas MV, Lolans K, Correa A, Kattan
JN, Lopez JA, and Quinn JP, First
identification of Pseudomonas aeru-
ginosa isolates producing a KPC-type
carbapenem-hydrolyzing beta-lactamase.
Antimicrob Agents Chemother, 2007.
51(4): 1553–5.

110
|2.6|

Antimicrobials in urogenital
infections
Florian M.E. Wagenlehner1*, Björn Wullt2, Gianpaolo Perletti3
1
Department of Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany
2
Department of Urology, Skåne University Hospital, Malmö, Sweden
3
Dipartimento di Biologia Strutturale e Funzionale, Laboratorio di Tossicologia e Farmacologia, Universita’ degli Studi
dell’Insubria –Busto Arsizio/Varese, Italy
Corresponding author: Priv.-Doz. Dr. med. Florian Martin Erich Wagenlehner, MD, PhD, Department of Urology, Pediatric
Urology and Andrology, Justus-Liebig-University of Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany,
Phone +49-641-99-44518, Fax +49-641-99-44509, E-mail Wagenlehner@AOL.com

ABSTRACT to be considered. Different antibiotic sub-

Urinary tract infections (UTI) and male
genital infections are amongst the most
prevalent infections. A prudent antibiotic
policy therefore has a large impact on the
society. The clinical classification in uncom-
plicated cystitis, uncomplicated pyelone-
phritis, complicated UTI and genital
infections is useful, also for the right choice
of antibiotic treatment. In this regard
pharmacokinetic and pharmacodynamic
aspects have to be considered. Nowadays
in uncomplicated cystitis antibiotics exclu-
sively reserved for this indication are
preferred, such as fosfomycin trometa-
mol, nitrofuratnoin and pivmecillinam,
in order to reduce antibiotic pressure in
this extremely frequent entity. In compli-
cated UTI a broad bacterial spectrum has
stances should be used for treatment, such
as penicillins, with β-lactamase inhibitors,
cephalosporins or carbapenems, fluoroqui-
nolones, aminoglycosides or cotrimoxazole,
if tested susceptible. For genital infections
the pharmacokinetic properties of the anti-
biotics should especially be considered,
such as in prostatitis, where mainly fluoro-
quinolones and macrolides show sufficient
pharmacokinetic parameters for treatment
of bacterial infections. Furthermore in gen-
ital infections fastidious organisms, such
as chlamydia or mycoplasma spp. have to
be considered with respect to their antimi-
crobial susceptibility.
Key words: Urinary tract infection;
male genital infection; antibiotic treat-
ment; antimicrobial substances
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
1. INTRODUCTION
Urinary tract infections (UTIs) and geni-
tal bacterial infections are among the
most prevalent microbial diseases, and
their financial burden on society is sub-
stantial. A large part of antibacterial
treatment is therefore allotted to these
conditions. The bacterial spectrum, anti-
microbial resistance patterns and the
activity of the antibiotic at the site of
infection are critical for an effective anti-
microbial chemotherapy. When treating
pyelonephritis, different antibiotics have
to be chosen to those for uncomplicated
female UTI and for bacterial prostati-
tis, because the kinetics of the antibiotic
in the various organs will be completely
different. In addition, the increasing
microbial resistance, especially in Gram-
negative uropathogens, require knowl-
edge about the ecological side effects or
“collateral damage” [1] exerted by the dif-
ferent antimicrobial drugs.
2. UNCOMPLICATED UTI
In uncomplicated UTI E. coli is the most
common pathogen, typically being iso-
lated from approximately 80% of outpa-
tients with acute uncomplicated cystitis
across the various regions of the world
[2–5]. In clinical practice, urine culture
is usually not performed in the setting of
community acquired, uncomplicated cysti-
tis. Antibiotic therapy is therefore mostly
empiric and more or less based upon
knowledge of national or international
surveillance studies. The local resist-
ance levels of E. coli therefore determine
the empiric antibiotic treatment. The
range of pathogens associated with acute
uncomplicated pyelonephritis is similar
to that seen in acute uncomplicated cysti-
tis [6]. The most recent surveillance study
in Europe investigating uncomplicated
cystitis is the ARESC (Antimicrobial
Resistance Epidemiology Survey on
Cystitis) project [7]. The results of the
112
ARESC study showed that antibiotic sub-
stances classically used for the treatment
of uncomplicated UTIs, such as co-trimox-
azole (TMP/SMX), fluoroquinolones or
aminopenicillines, lose their effectiveness
due to increasing resistance. Therefore,
ideal substances are those with high sus-
ceptibility rates, exclusively used for this
indication, such as fosfomycin trometh-
amine, nitrofurantoin or pivmecillinam.
2.1 Fosfomycin
Fosfomycin tromethamine is the oral
applicable salt of fosfomycin, an oxirane
antibiotic unrelated to other substances
[8], produced as a secondary metabolite
by Streptomyces and Pseudomonas spp.
Fosfomycin acts as an analogue of phos-
phoenolpyruvate and forms a covalent
bond with the active site cysteine residue
(Cys 115) of UDP-N-acetylglucosamine
enolpyruvyltransferase (MurA), which is a
key enzyme of peptidoglycan synthesis [8].
It thus inhibits cell-wall synthesis with
a different mechanism than β-lactam
antibiotics. Fosfomycin tromethamine
has approximately 40% oral bioavailabil-
ity and is primarily excreted unchanged
in the urine (approximately 90%) [9].
The substance is active against Gram-
positive and Gram-negative bacteria,
but shows decreased activity against
M. morganii, P. vulgaris, P. aerugi-
nosa and E. faecium. Despite many
years of usage, fosfomycin continues to
have a low incidence of E. coli resist-
ant strains (1% to 3%) worldwide [10].
Fosfomycin has retained its activity
against quinolone-resistant strains of
E. coli and cross-resistance with other
classes of antimicrobial agents is pres-
ently not a problem [11]. It is less active
against coagulase-negative staphylococci.
The effect on the intestinal flora after
intake of a single 3g dose of Fosfomycin
has not been well studied. However, due to
the limited exposition, the effect is proba-
bly minor. This statement is supported by
the high rate of E. coli susceptibility also

in regions with frequent use of Fosfomycin
in uncomplicated female UTI [12]. Longer
peroral treatment (5 g twice daily for five
days) affects the intestinal flora signifi-
cantly, mainly with a reduction of entero-
bacteriaceae [13].
2.2 Nitrofurantoin
Nitrofurantoin (NF) belongs to the class
of nitroheterocyclic compounds. The nitro-
group coupled onto the heterocyclic furan
ring represents the specific active site of
the drug and has to be activated by micro-
bial nitroreductases to interfere with
protein and DNA synthesis, energy metab-
olism, cell wall and carbohydrate synthe-
sis [14]. Nitrofurantoin interferes with
the carbohydrate metabolism. The bio-
availability is about 90% and the urinary
excretion is 40% [15]. Activity against
E. coli is excellent. In a recent study, the
susceptibility for E. coli was 99.5%. High
susceptibility of E. coli clinical isolates
to nitrofurantoine (2.3% resistance rate),
compared to TMP/SMX (29%) or cipro-
floxacin (24.2%) was recently confirmed
[16]. However, nitrofurantoin is less sus-
ceptible against Gram-negative patho-
gens other than E. coli, such as Klebsiella
spp. (69.2%) or Enterobacter spp. (63%).
There is no activity against Proteus spp.
or P. aeruginosa [17]. Nitrofurantoin is
mainly used in preventing recurrent UTI
in children and women [18]. Potential
severe side effects with nitrofurantoin
were reported, such as lung- and hepa-
totoxicity, especially in long-term usage
[19]. Due to the effective gastro-intestinal
absorption of nitrofurantoin the effect on
the intestinal flora is minimal [20].
2.3 Pivmecillinam
Pivmecillinam is a β-lactam antimicro-
bial that has been used for the treatment
of acute uncomplicated urinary infections
for more than 20 years. Pivmecillinam
is the pro-drug (ester) of mecillinam and
shows no antibacterial activity until
Antimicrobials in urogenital infections | 2.6 |
hydrolyzed into the active drug after
absorption [21]. Mecillinam is an amidine
derivative of the penicillin group. The
mechanism of action differs slightly from
other β-lactams, because the drug inter-
acts with the penicillin-binding protein 2
[22]. With a bioavailability of 60–75% it
is well absorbed orally; 45% of the drug
is excreted in the urine [21]. Mecillinam
has high activity against Gram-negative
organisms such as E. coli and other
enterobacteriaceae. The level of resistance
has remained low, as approximately less
than 2% of E. coli community isolates are
resistant to mecillinam [23]. The in vitro
MIC for S. saprophyticus is 8–64 mg/L, so
these bacteria are considered resistant.
The favorable situation regarding
E. coli susceptibility is also observed in
the Scandinavian countries, in which
pivmecillinam is one of the most fre-
quently used drugs in female uncompli-
cated UTI. This is thought to be due to the
minor effect of Pivmecillinam on the nor-
mal flora [23], however a moderate reduc-
tion of gram- negative enterobacteriaceae
in the intestinal flora is observed [24].
3. COMPLICATED UTI AND MALE
GENITAL, BACTERIAL INFECTIONS
Gram-negative species account for approx-
imately 60 to 80% of the bacterial spec-
trum of complicated and nosocomially
acquired UTI, and comprise E. coli, fol-
lowed by Klebsiella spp., Pseudomonas
spp., Proteus spp., Enterobacter spp. and
Citrobacter spp. Gram-positive pathogens
account for about 20 to 40% of the spec-
trum and comprise enterococci and sta-
phylococci [25–30]. Male genital bacterial
infections can be caused by the same bac-
terial spectrum as complicated UTI or by
sexually transmitted bacterial pathogens,
such as N. gonorrhoeae, C. trachomatis or
Mycoplasmata.
For treatment of urogenital infections
a suitable pharmacokinetic/pharmaco-
dynamic profile, i.e. high concentration
113
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
and activity in the urogenital tract, is
important. A wide array of different anti-
microbial agents is available. In order to
decrease the antimicrobial pressure the
full spectrum of agents available for these
indications should be used.
3.1 β-lactam-antibiotics
β-lactam antibiotics are chemically charac-
terized by the presence of the β-lactam-ring
in the molecule, i.e. by a cyclic amide form-
ing a four-atom ring. All β-lactam antibiot-
ics inhibit the bacterial cell wall synthesis
by irreversible inhibition of the penicillin
binding proteins known as transpepti-
dases. The β-lactam group includes three
important families of antibiotics, which
differ in the moiety fused to the β-lactam
ring. The penicillins harbour a five-atom
ring, a thiazolidine, the cephalosporins
have a six-atom ring, a dihydrothiazine,
and the carbapenems harbour a five-atom
ring, in which the sulphur atom in position
1 of the structure has been replaced with a
carbon atom [31].
3.1.1 Penicillins
Penicillins are classified mainly according
to the different chemical structures of the
substituents at position 6 of the β-lactam
molecule.
The first penicillin introduced in clini-
cal practice was penicillin G. After intra-
venous injection 95% of the substance is
eliminated by renal excretion. Penicillins
are primarily active against Gram-positive
pathogens, if no resistance mechanisms
have been acquired [31].
The aminopenicillins ampicillin and
amoxicillin feature an amino group,
which confers stability against amidase,
an enzyme produced by some Gram-
negative bacteria that hydrolyzes the
penicillin side chain, and stability against
gastric acid. Oral absorption of ampicillin
is approximately 50%, whereas amoxicil-
lin is absorbed by 90%. Urinary excre-
tion of both antibiotics is about 70%.
114
The aminopenicillins ampicillin and
amoxicillin are active against E. coli and
P. mirabilis, but almost inactive against
other enterobacteria and totally inac-
tive against Pseudomonas spp. However,
Enterocccus faecalis is susceptible. The
aminopenicillins are not stable against
the β-lactamases frequently found in
S. aureus and in many enterobacteria.
Combination with a β-lactamase-inhibitor
such as clavulanic acid or sulbactam
enhances the anti-Gram-negative activ-
ity to a certain extent, but not against
bacteria producing AmpC β-lactamases,
such as Enterobacter spp. or Citrobacter
spp. [32]. N. gonorrhoeae nowadays
exhibits high levels of resistance against
penicillin [33]. The effect of ampicillin
and amoxicillin (including the amoxicil-
lin combination with clavulanic acid)
on the gastro-intestinal flora has been
well characterized; in summary suppres-
sion of Gram-positive aerobic cocci and
an increase of resistant Gram-negative
enterobacteriaceae is demonstrated [34].
The acylamino (ureido)-penicillins,
such as piperacillin, own stronger polar
groups on the amino-group. However,
this compound is not stable against the
β-lactamases of S. aureus and some
strains of Enterobacter spp. and Serratia
spp. Combination of piperacillin with
the β-lactamase inhibitor tazobactam
can counteract the activity of some of
the β-lactamases increasingly produced
by Gram-negative bacteria. Piperacillin/
tazobactam also exhibits activity against
E. faecalis, but not against E. faecium.
Urinary excretion of both piperacillin
and tazobactam is approximately 70%.
Piperacillin exhibits activity against
Pseudomonas spp. and P. vulgaris and
is therefore frequently used for empiric
treatment of complicated nosocomial
UTIs [35].
3.1.2 Cephalosporins
The cephalosporins are classified according
to their primary route of administration

(parenteral vs. oral), and in groups accord-
ing to their antibacterial spectrum. For
structure-activity relationships, com-
parable characteristics can be seen as
with penicillins. Substitutions at the side
chain mainly influence activity, whereas
modifications in position 3 of the nucleus
influence mainly pharmacokinetic and
metabolic properties of these drugs. The
various groups of cephalosporins differ
from one another in the spectrum of activ-
ity and in potency against Gram-negative
bacteria [36]. All cephalosporins are not
active against enterococci. Novel cepha-
losporins are designed to treat multidrug-
resistant pathogens including MRSA,
where current cephalosporins are not
effective.
The first group cephalosporin,
cephalexin, harbours the phenylglycine
side chain that is also encountered in
the aminopenicillins. Cephalexin is pri-
marily active against staphylococci, but
less active against many Gram-negative
bacteria, because it is hydrolyzed by
their β-lactamases. The bioavailability of
cephalexin is about 90%, and the renal
excretion is about 90% as well [37]. First
group cephalosporins should however
not be used for the treatment of UTI, but
only for prophylaxis, because of the over-
all lower activities compared with second
group cephalosporins.
Second group cephalosporins, such as
cefuroxime and cefotiam, show increased
β-lactamase stability. This is mainly due
to the oxime-group in cefuroxime and the
thiazole-amino group in cefotiam. After
intravenous injection the renal excre-
tion is 90% in cefuroxime [38] and 70% in
cefotiam [39]. In contrast to cefuroxime,
the prodrug cefuroxime axetil is absorbed
with a total bioavailability of 40% after
rapid hydrolysis to the active parent
compound, cefuroxime [40]. Against sus-
ceptible Gram-negative bacteria, second
group cephalosporins are four to eight
times more potent than first group com-
pounds. There is no activity against
P. vulgaris, Morganella spp., Serratia
Antimicrobials in urogenital infections | 2.6 |
spp. and P. aeruginosa. Cefotiam is more
active against E. coli, Klebsiella spp. and
P. mirabilis than cefuroxime.
Group 3a cephalosporins, such as cefo-
taxime and ceftriaxone, and the orally
active substances cefpodoxime-proxetil
and ceftibuten, exhibit a further increased
activity against Gram-negative organ-
isms, because the side chain protects the
molecule from cephalosporinases by steric
hindrance [41]. Cefotaxime is metabolized
in about 30% to desacetyl-cefotaxime,
which shows inferior antimicrobiologi-
cal activitiy [42]. Ceftriaxone undergoes
a partial biliary excretion of about 45%
[43]. The bioavailability of cefpodoxime-
proxetil is about 40% [44], while the bio-
availability of ceftibuten is about 90%
[45]. The renal excretion rates are about
80%, 55%, 90% and 90% for cefotaxime,
ceftriaxone, cefpodoxime and ceftibuten,
respectively [42–47]. Group 3 cepha-
losporins are approximately ten times
more active against enterobacteria than
group 2 compounds. Group 3a cepha-
losporins are currently recommended as
empiric treatment of gonorrhoeae by the
Centers for Disease Control of America
(CDC), because of the high resistance lev-
els of other antibiotics [33].
Group 3b comprises the intravenously
administered cephalosporin ceftazidime.
The propylcarboxy moiety at the side
chain is responsible for increased affinity
to penicillin-binding-proteins of Gram-
negative bacilli and for high stability
to β-lactamases. The pyridine group is
responsible for rapid intrabacterial pen-
etration and favourable pharmacokinetic
properties. Ceftazidime undergoes no rel-
evant metabolism and the unchanged uri-
nary excretion averages 90%. Compared
to cefotaxime, ceftazidime exhibits
a 10-fold increased activity against
P. aeruginosa [48].
Group 4 cephalosporins comprise the
intravenously administered cefepime. It
contains a thiazole-amino group and an
oxime group at position 7 and a quater-
nary ammonium substituent at position 3.
115
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
The quaternary nitrogen imparts
β-lactamase stability and improves both
the cell penetration and the pharmacoki-
netic properties. The urinary excretion of
the unchanged drug accounts for about
85%. Cefepime shows excellent activity
against P. aeruginosa and good stability
against β-lactamases [49].
Ceftobiprole is a novel β-lactam. Upon
infusion, the prodrug ceftobiprole medo-
caril is converted rapidly and almost com-
pletely by type A esterases to the active
drug, ceftobiprole. The predominant
mechanism responsible for elimination is
glomerular filtration (90%). Ceftobiprole
exhibits a high activity against methi-
cillin-resistant Staphylococcus aureus
(MRSA) in addition to broad-spectrum
bactericidal activity against other Gram-
positive and Gram-negative pathogens
[50]. Until now, Ceftobiprole has not been
investigated in urinary tract infections,
but seems to be promising for empiric
treatment of UTI due to the coverage
extended to MRSA and P. aeruginosa.
The cephalosporine impact on the
gastro-intestinal flora is significant and
has been well studied [34]. The gen-
eral pattern is a marked reduction of
enterobacteriaceae, an increase of aero-
bic gram-positive cocci and commonly
an overgrowth of Cl. difficile. The recent
emergence of multiresistant E. coli
strains have become a major concern,
which threatens to disarm effective anti-
biotic therapy to common infections such
as UTI [51]. Importantly, cephalasporines
have been suggested to be one of the driv-
ing agents in the selection of multidrug
resistant E. coli [1].
3.1.3 Carbapenems
Most carbapenems are available only
intravenously up to now, because they
are unstable, especially in gastric juice,
but also in more alkaline intestinal pH
conditions [52]. Carbapenems main-
tain antibacterial efficacy against the
vast majority of β-lactamase-producing
116
organisms. This stability against serine-
β-lactamases is due to the trans-1-hy-
droxyethyl substituent and its unique
juxtaposition to the β-lactam carbonyl
group [53]. The stability encompasses
extended spectrum-β-lactamases and
AmpC β-lactamases, but not to metallo-
β-lactamases. The available carbapen-
ems are currently classified by different
criteria. The classification by groups can
follow the bacterial spectrum as in other
antibiotic classes [54].
Ertapenem is the sole representative
of the first group. It contains a 1β-methyl
substituent which reduces hydrolysis
of the β-lactam ring by the renal dihy-
dropeptidase I. It further contains a meta-
substituted benzoic acid substituent,
which increases the molecular weight and
lipophilicity of the substance, and a carbox-
ylic acid moiety resulting in a net negative
charge. This results in a high protein bind-
ing, which leads to a longer serum half-life
[53]. Urinary excretion is 80%. Ertapenem
exhibits a broad-spectrum activity against
Gram-negative and Gram-positive patho-
gens, with only limited activity against
non-fermenting Gram-negative bacteria.
It is also not active against P. aeruginosa,
MRSA and enterococci [53–54].
Imipenem and meropenem are the
representatives of the second group.
Imipenem is hydrolysed by the renal
dihydropeptidase I and is therefore
combined with the specific inhibitor cil-
astatin. Meropenem contains a 1β-methyl-
substituent and is therefore stable against
the renal dihydropeptidase I. Urinary
excretion of imipenem (if combined with
cilastatin) and meropenem is 70%. They
feature an additional broad-spectrum
activity against non-fermenting Gram-
negative bacteria. They are active against
many Gram-positive and Gram-negative
uropathogens excluding MRSA, E. fae-
cium and vancomycin-resistant entero-
cocci (VRE). Compared with imipenem,
meropenem is somewhat more active
against P. aeruginosa, but less active
against Gram-positive uropathogens [55].

Doripenem is a new parenteral car-
bapenem and offers slightly more activ-
ity than meropenem against selected
pathogens including some strains of
P. aeruginosa not susceptible to imipenem
or meropenem. Doripenem is also active
against Gram-positive pathogens except
MRSA, E. faecium and VRE. Urinary
excretion is 75% [56].
The faecal elimination of carbapen-
ems is very small and consequently the
intestinal flora is only slightly changed,
mainly with decreased numbers of entero-
bacteriaceae, increase in gram-positive
cocci, and a decrease in anaerobes [34].
3.2 Aminoglycosides
Aminoglycosides are multifunctional
hydrophilic sugars that possess sev-
eral amino and hydroxy functionalities.
Aminoglycosides act primarily by alter-
ing bacterial protein synthesis through
binding to the 16S ribosomal RNA within
procaryotic ribosomes [57]. There is no
generally agreed clinical classification
of aminoglycosides. Therefore classifica-
tion mainly follows the different chemi-
cal structures. Aminoglycoside antibiotics
can be divided according to the nature
of the core aminocyclitol ring into strep-
tidine, bluensidine, 2-deoxystreptamine
and actinamine antibiotics. Clinically the
2-deoxystreptamine-containing aminogly-
cosides are most important, which are
subdivided into the 4,6-disubstituted, and
the 4,5-disubstituted deoxystreptamines
[57–59]. The 4,6-disubstituted deoxys-
treptamine group comprises the agents
kanamycin, gentamicin, tobramy-
cin, netilmicin and amikacin. The 4,5-
disubstituted deoxystreptamine group
comprises agents such as neomycin,
which are the more potent antibiotics,
but show a high degree of nephrotoxicity
and ototoxicity, which almost exclusively
prevents their systemic use [58–59].
For treatment of UTI therefore only
the 4,6-disubstituted deoxystreptamine
group is indicated. Antibiotic activity in
Antimicrobials in urogenital infections | 2.6 |
this group is related to the number and
location of amino groups in the hexose
moiety linked to the deoxystreptamine
as follows in decreasing order: 2´,6´-
diamino > 6´-amino > 2´-amino > no
amino group. The activity is enhanced if
the same primed sugar is not hydroxy-
lated, thus gentamicins are generally
more potent than kanamycins [57]. In
parallel the more active substances how-
ever are better substrates for inactivating
nucleotidyltransferases. Because of the
aminocyclitol ring the aminoglycosides
are weak bases and have a high degree of
solubility in water and poor solubility in
lipids. They are therefore poorly absorbed
and distributed in the tissues and must
be actively transported across bacterial
cell membranes. Aminoglycosides are
almost exclusively excreted in the urine
by glomerular filtration, but approxi-
mately 5% of the administered doses
are retained in the epithelial cells lining
the S1 and S2 segments of the proximal
tubules [59]. Aminoglycosides thus are
ion-trapped in the lysosomes of the tubu-
lar cells, which eventually causes them to
rupture above a certain cut-off concentra-
tion. The highly concentrated aminogly-
coside together with lysosomal enzymes,
are then released into the cytosol and
eventually lead to cell damage. Single
short-term infusion shows significantly
lower renal drug levels than continuous
infusion of the same dose [60]. This accu-
mulation in renal tubular cells renders
aminoglycosides suitable for treatment of
pyelonephritis.
Ototoxicity has always hampered the
extensive use of aminoglycosides in anti-
bacterial chemotherapy. The extent of
inner ear toxicity can vary, ranging from
mild high-frequency impairment to pro-
found hearing loss, to vestibular dis-
turbances. Vestibular toxicity is more
frequently observed upon administration
of gentamicin and streptomycin, whereas
kanamicin, and amikacin are prevalently
cochleotoxic. Damage caused by reac-
tive oxygen species is believed to be a
117
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
common feature of inner ear hair cell tox-
icity evoked by aminoglycosides [61]. In
genetically predisposed individuals, car-
rying the A1555G and other mutations
targeting the mitochondrial 12S ribos-
omal RNA, profound sensorineural deaf-
ness occurs almost in all cases because
aminoglycosides disrupt mitochondria by
affecting translation in a fashion resem-
bling their bactericidal activity [62].
Spectinomycin is a structural relative of
the aminoglycosides containing the ami-
nocyclitol actinamine. It also binds the
16SrRNA, albeit in a different location
from aminoglycosides. Unlike aminogly-
cosides, spectinomycin does not induce
codon misreading, nor is it bactericidal;
its indication is mainly the treatment of
N. gonorrhoeae and U. urealyticum infec-
tions. Urinary recovery after 2 g i.m. injec-
tion is higher than 80%.
Since aminoglycosides are adminis-
trated systemically and are completely
excreted by glomerular filtration, the effect
on the intestinal flora is insignificant.
3.3 Fluoroqinolones
Fluoroquinolones can be classified accord-
ing to antibacterial spectrum and activ-
ity and the main indications into four
groups [63]. The first group comprises
agents such as norfloxacin, with indica-
tions essentially limited to UTI. The sec-
ond group encompasses agents such as
ofloxacin and ciprofloxacin, with broad
indications for systemic use and pre-
dominant Gram-negative activity. The
third group comprises agents such as
levofloxacin, with good Gram-negative
activity and in addition improved activity
against Gram-positive and atypical path-
ogens. The fourth group comprises agents
with good Gram-negative activity and in
addition further improved activity against
Gram-positive and atypical and anaero-
bic bacteria, such as moxifloxacin and
gatifloxacin. However, gatifloxacin has
been removed from the market because of
severe dysglycemia in some patients [64].
118
Fluoroquinolones form ternary com-
plexes between DNA and the bacterial
topoisomerases II and IV, which play a
critical role in the organisation of the bac-
terial DNA. Quinolones exert their toxic-
ity on the bacterial cell by stabilizing the
double-stranded break in DNA created
by gyrase so that relegation becomes
unfavourable and consequently apopto-
sis of the bacterial cell is induced [65].
The structure-property relationships of
the different substituents corresponding
to the pharmacophore show the follow-
ing aspects [65]: Elements that enhance
activity and reduce resistance selec-
tion include a cyclopropyl at position 1,
a methoxy at position 8, a pyrrolidine
or substituted piperazine at position 7,
and a fluorine substituent at position 6
[65]. Moieties or elements that enhance
the volume of distribution are a cyclopro-
pyl at position 1, and those that enhance
half-life and central nervous system
penetration are a bulky side chain at
position 7 [65]. Fluoroquinolones work
mainly in a concentration dependent
manner and exert a marked post-antibi-
otic effect. The antibacterial activity in
urine however is reduced, because fluor-
oqinolones form antibacterially inactive/
less active complexes with divalent cati-
ons [66].
Most fluoroquinolones show excellent
bioavailability (60–100%) and a high vol-
ume of distribution. Penetration into the
prostate tissue is better than any other
antibiotic substance, with the excep-
tion of macrolides. The serum levels are
usually low [65]. All gyrase inhibitors
undergo tubular secretion as either acids
or bases. Reabsorption then affects tubu-
lar concentrations. The N4’-methylated
derivatives are the most lipophilic, and
addition or removal of the methyl group
can, but does not always, affect reab-
sorption [67]. The urinary excretion of
fluoroquinolones however, differs widely
between substances. A high urinary
excretion (≥ 75%) can be observed with
levofloxacin (84%), lomefloxacin (75%)

and ofloxacin (81%). An intermediate
excretion rate (40–74%) is seen with cip-
rofloxacin (43%), enoxacin (53%), fler-
oxacin (67%), and a low excretion rate
(< 40%) is seen with moxifloxacin (20%)
and norfloxacin (20%) [68]. Whereas
most of the drugs with high or interme-
diate excretion achieved the clinical indi-
cation for the treatment of UTI, of the
drugs with low excretion only the older
substance norfloxacin achieved this indi-
cation, possibly because of the lack of
comparator substances these days.
Fluoroquinolones also play an impor-
tant role in the treatment of bacterial
prostatitis. This is mainly because of
their favourable pharmacokinetic proper-
ties within the prostate fluid.
Drug penetration into prostatic fluid
is considered to consist mainly of pas-
sive diffusion [69–70]. Amongst the drug
characteristics that determine simple dif-
fusion are concentration gradient, lipid
solubility, degree of ionization, degree of
protein binding, and the size of the mol-
ecule. The highest concentrations in pros-
tatic secretion are seen with moxifloxacin,
followed by gatifloxacin, lomefloxacin,
enoxacin, ofloxacin, levofloxacin, fler-
oxacin, ciprofloxacin, norfloxacin [71].
Fluoroquinolones have been excessively
used for the treatment of N. gonorrhoeae
and C. trachomatis induced genital infec-
tions. In many countries, resistance of N.
gonorrhoeae to fluoroquinolones currently
approaches levels to an extent where
empiric usage for treatment seems not
to be advisory any more [33]. Minimal
inhibitory concentrations (MIC) of anti-
biotic substances against C. trachomatis
are generally difficult to assess. In one
attempt using an RT-PCR method, MIC
ranges of moxifloxacin were 0.015 to 0.25
mg/L, and were remarkably lower than
those of ofloxacin 0.25 to 8 mg/L and cip-
rofloxacin 0.5 to 8 mg/L [72].
Fluoroquinolones reach high concen-
trations in the gastro-intestinal tract
and have a significant impact on the
gastro-intestinal flora. There is a strong
Antimicrobials in urogenital infections | 2.6 |
suppression of enterobacteriaceae, includ-
ing emergence of resistant strains. The
colonization of aerobic Gram-positive cocci
is less influenced [34]. Fluoroquinolones
are considered to be driving agents in the
selection of multidrug resistant entero-
bacteriaceae [1].
3.4 Trimethoprim, Cotrimoxazole
Cotrimoxazole is the combination of tri-
methoprim (TMP) and sulfamethoxa-
zole (SMX) in the ratio of 1 to 5. Both
substances inhibit different steps in the
folic acid biosynthetic pathway. SMX is
a structural analogue of p-aminobenzoic
acid, the basic building block used by
bacteria to synthesize dihydrofolic acid,
the first step in the reaction leading to
folic acid. SMX competitively inhibits
this step. TMP competitively prevents
the conversion of dihydrofolic acid to tet-
rahydrofolic acid, the metabolically active
cofactor for synthesis of purines [73].
Of all sulfonamides, SMX was paired
with TMP because of similar absorptive
and pharmacodynamic properties. Each
drug is well absorbed. Approximately
85% of total SMX is recovered in the
urine, 30% as free drug and the rest as
acetylated metabolite. In contrast, most
of TMP is not metabolized and is excreted
unchanged in the urine [73]. For more
than 30 years TMP/SMX has been used
for the treatment of UTIs. Many aerobic
Gram-positive and Gram-negative bac-
teria are inhibited or killed including E.
coli, Proteus mirabilis, Klebsiella spp.
and Enterobacter spp. There is no effect
on Pseudomonas spp. In different sur-
veillance studies in Europe and North-
America, investigating resistance in
uncomplicated UTI, the resistance rates
of the involved uropathogens approached
or exceeded 20% [74–77]. In complicated
UTIs TMP/SMX should only be used
in accordance with sensitivity testing
because of the high resistance rates.
TMP/SMX has been used as first line
agent in the treatment of chronic bacterial
119
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
prostatitis in the past, until the fluoroqui-
nolones emerged. Concentrations of TMP/
SMX in prostatic fluid in patients with
chronic bacterial prostatitis were meas-
ured and achieved approximately one third
of plasma concentrations [78]. The secre-
tory dysfunction of the prostate accompa-
nying bacterial prostatitis results in an
increased alkalinity of solute-poor secre-
tions and adversely affects the accumula-
tion of trimethoprim in the prostatic fluid
[79]. Clinical cure of patients with chronic
bacterial prostatitis treated with TMP/
SMX has been seen in only approximately
40% of patients [80]. TMP/SMX has a role
in the treatment of chronic bacterial pros-
tatitis only in fluoroquinolone-resistant
isolates. Prolonged treatment over three
months is then recommended [81].
TMP/SMX has a significant impact on
the intestinal flora with a strong suppres-
sion of enterobacteriaceae. The aerobic
Gram-positive flora is not affected [20].
3.5 Glycopeptides
The glycopeptides (vancomycin, teico-
planin) inhibit the synthesis of cell walls
in susceptible microbes by inhibiting pep-
tidoglycan synthesis. Vancomycin and
teicoplanin are related but Teicoplanin
is more lipophilic. Both substances are
administered intravenously. Teicoplanin
has a longer half life also due to increased
plasma protein binding, compared to van-
comycin, as well as a better tissue pen-
etration. The urinary excretion of both
substances is 90%. They are active exclu-
sively against Gram-positive uropatho-
gens, such as enterococci and methicillin
susceptible and resistant staphylococci
[82]. Ototoxicity and nephrotoxicity have
been observed upon administration of
glycopeptides, with teicoplanin less likely
to be associated with adverse events [83].
3.6 Linezolid
Linezolid is a member of the oxazolidinone
class, comprising synthetic antibacterial
120
agents that inhibit bacterial protein syn-
thesis through a unique mechanism. In
contrast to other inhibitors of protein syn-
thesis, linezolid acts early in translation
by preventing the formation of a func-
tional initiation complex [84]. Linezolid
is rapidly absorbed after oral dosing with
an absolute bioavailability of about 100%.
Serum half life is about 5.5 hours, and pro-
tein binding approximately 31% [85–86].
Approximately 35% is excreted in urine as
the parent drug and 50% as the two major
metabolites. Linezolid is active exclusively
against Gram-positive uropathogens, such
as enterococci and methicillin susceptible-
and resistant staphylococci. Linezolid can
be used for the treatment of UTI caused
by multi-resistant Gram-positive bacteria
like MRSA or vancomycin resistant ente-
rococci (VRE). However, both MRSA and
VRE isolates resistant to Linezolid have
been reported [87].
Linezolid can induce mitochondrial
toxicity, manifesting as perihperal/optic
neuropathy and lactic acidosis, the latter
being hypothesized to occur in carriers
of specific mutations in the mitochon-
drial DNA [88]. Linezolide adverse effect
appear to be evoked when extended
courses of antimicrobial therapy are pre-
scribed [89].
Linezolid administered perorally
decreases the numbers of aerobe and
anaerobe gram positive cocci in the intes-
tinal flora, but enterobacteriaceae are un-
affected [90].
3.7 Daptomycin
Daptomycin is a semisynthetic lipopeptide
antibiotic with a high specificity for Gram-
positive bacteria [91–92]. Daptomycin
apparently acts via the dissipation of the
bacterial membrane potential and has
a rapid concentration-dependent bacte-
ricidal activity [92]. Daptomycin exhib-
its bactericidal activity against a broad
range of Gram-positive pathogens, includ-
ing organisms resistant to methicillin,
vancomycin or other currently available

agents. Daptomycin is administered intra-
venously, serum half-life averaged 8.5
hours, protein binding is approximately
90%, urinary excretion is 80%, 66% as
active drug. Clinically relevant toxicities
are limited to skeletal muscle effects and
at higher dose levels, peripheral nerve
effects. One study evaluated daptomycin
versus ciprofloxacin in 68 patients with
complicated UTI, concluding equivalent
efficacy in a patient cohort with predomi-
nantly Gram-positive pathogens [93].
3.8 Macrolides
Macrolides are antibiotics containing
aliphatic lactones and are divided in two
classes: antibacterial macrolides and anti-
fungal macrolides (polyene macrolides). The
antibacterial macrolides have generally low
urinary recovery rates, clarithromycin 20%,
roxithromycin 7%, azithromycin 5% and
erythromycin 5%, and are therefore not
indicated for the treatment of UTI. Because
of their efficient distribution into urethral
cells, macrolides are useful for treatment of
non-specific urethritis by very susceptible
C. trachomatis and U. urealyticum.
Whereas N. gonorrhoeae shows increas-
ing acquired resistance to macrolides,
M. hominis displays intrinsic resistance
to these drugs. Thus, macrolides are fre-
quently used for the treatment of genital
infections caused by C. trachomatis and
U. urealyticum.
In a recent report, highlighting the
results of a meeting on prostatitis and
chronic pelvic pain, macrolides have
been recommended as second-line agents
for the treatment of chronic prostatitis,
due to the excellent penetration of these
drugs in the prostate gland, the activity
against Chlamydia, and the penetration
in- and the inhibitory activity against
bacterial biofilms [94].
3.9 Tetracyclines
The tetracyclines can be divided into three
groups based on their pharmacokinetic
Antimicrobials in urogenital infections | 2.6 |
and pharmacodynamic properties. Tetra-
cyclines inhibit cell growth by inhibiting
the translation process via interaction
with the bacterial 30S ribosomal subu-
nit. Group 1 consists of older agents with
reduced GI absorption and less lipophilic-
ity, such as tetracycline.
Group 2 substances are almost com-
pletely absorbed and are more lipophilic
than group 1 substances [95]. Doxycycline
belongs to group 2 and is the best
absorbed tetracycline upon oral adminis-
tration (95%). About 35–60% of the drug
is excreted in urine and the remainder
in faeces [95]. Doxycycline exhibits good
activity against most Gram-positive bac-
teria, variable activity against Gram-
negative pathogens and no activity
against P. aeruginosa and Proteus spp.
Tetracycline is also effective against C.
trachomatis. MIC ranges by a RT-PCR
method were 0.03 to 1 mg/L [72].
Group 3 is composed of the glycylcy-
clines. There is currently one compound
in clinical use named tigecycline. After
intravenous injection the renal elimi-
nation accounts for 33%, while 59% are
excreted with the faeces [95]. The bacte-
rial spectrum of tigecycline shows good
activity against Gram-positive pathogens
including MRSA and VRE, and against
E. coli, Klebsiella spp., Enterobacter spp.
and C. freundii, including ESBL produc-
ing organisms. Tigecycline is less active
against P. aeruginosa, Proteus spp.,
M. morganii and S. marcescens because
of efflux-mechanisms [95]. There are no
data of all three classes on the treatment
of UTI.
4. FURTHER RESEARCH
Antimicrobial treatment will remain
one of the main cornerstones of therapy
in urinary and male genital infections.
Therefore it is of paramount importance
to preserve efficacy of antimicrobial sub-
stances. Several concepts may be followed
to perceive such a goal. Besides infection
121
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
control, implementation strategies for
prudent antibiotic use are most manda-
tory. Novel mechanisms of antibacte-
rial actions are of course most welcome.
However other novel strategies, such as
site directed substances, lacking major
collateral damage, or phage enzymes in
various ways should be exploited further.
5. CONCLUSIONS
The developmental process of new anti-
microbial substances has markedly
slowed down because of a variety of rea-
sons. On the other hand, antimicrobial
resistance is continuously increasing in
uncomplicated as well as complicated
UTI and genital infections. Therefore the
management of infectious diseases must
be highly responsible. The action of cur-
rently available antimicrobial substances
and their structure-property relationships
have to be understood for the prudent
use of antibiotics. Pharmacokinetic and
pharmacodynamic parameters need to be
taken in greater consideration to improve
dosing strategies. Models that are able to
predict efficacy in patients and the degree
of emergence of resistance are needed in
that respect.
REFERENCES
1. Li J, Nation RL, Turnidge JD, Milne RW,
Coulthard K, Rayner CR, and Paterson
DL, Colistin: the re-emerging antibiotic
for multidrug-resistant Gram-negative
bacterial infections. Lancet Infect Dis,
2006. 6(9): 589–601.
2. Gupta K, Hooton TM, and Stamm WE,
Increasing antimicrobial resistance
and the management of uncompli-
cated community-acquired urinary
tract infections. Ann Intern Med, 2001.
135(1): 41–50.
3. Hooton TM, The current management
strategies for community-acquired urinary
tract infection. Infect Dis Clin North Am,
2003. 17(2): 303–32.
122
4. Kahlmeter G, An international survey
of the antimicrobial susceptibility of
pathogens from uncomplicated urinary
tract infections: the ECO.SENS Project.
J Antimicrob Chemother, 2003. 51(1):
69–76.
5. Warren JW, Abrutyn E, Hebel JR,
Johnson JR, Schaeffer AJ, and Stamm
WE, Guidelines for antimicrobial treat-
ment of uncomplicated acute bacterial cys-
titis and acute pyelonephritis in women.
Infectious Diseases Society of America
(IDSA). Clin Infect Dis, 1999. 29(4):
745–58.
6. Talan DA, Stamm WE, Hooton TM,
Moran GJ, Burke T, Iravani A, Reuning-
Scherer J, and Church DA, Comparison of
ciprofloxacin (7 days) and trimethoprim-
sulfamethoxazole (14 days) for acute
uncomplicated pyelonephritis pyelonephri-
tis in women: a randomized trial. Jama,
2000. 283(12): 1583–90.
7. Naber KG, Schito, G.C., Botto, H., Palou,
J., Mazzei, T., Surveillance study in
Europe and Brazil on clinical aspects
and antimicrobial resistance epidemiol-
ogy in females with cystitis (ARESC):
Implications for empiric therapy.
European Urology, 2008. in press.
8. McLuskey K, Cameron S,
Hammerschmidt F, and Hunter WN,
Structure and reactivity of hydroxypropyl-
phosphonic acid epoxidase in fosfomycin
biosynthesis by a cation- and flavin-de-
pendent mechanism. Proc Natl Acad Sci U
S A, 2005. 102(40): 14221–6.
9. Patel SS, Balfour JA, and Bryson HM,
Fosfomycin tromethamine. A review
of its antibacterial activity, pharmacoki-
netic properties and therapeutic
efficacy as a single-dose oral treatment
for acute uncomplicated lower urinary
tract infections. Drugs, 1997. 53(4):
637–56.
10. Schito GC, Why fosfomycin trometamol as
first line therapy for uncomplicated UTI?
Int J Antimicrob Agents, 2003. 22 Suppl 2:
79–83.
11. Ungheri D, Albini E, and Belluco G,
In-vitro susceptibility of quinolone-resist-
ant clinical isolates of Escherichia coli
to fosfomycin trometamol. J Chemother,
2002. 14(3): 237–40.

12. Naber KG, Schito G, Botto H, Palou
J, and Mazzei T, Surveillance study in
Europe and Brazil on clinical aspects and
Antimicrobial Resistance Epidemiology in
Females with Cystitis (ARESC): implica-
tions for empiric therapy. Eur Urol, 2008.
54(5): 1164–75.
13. Knothe H, Schafer V, Sammann A, and
Shah PM, Influence of fosfomycin on the
intestinal and pharyngeal flora of man.
Infection, 1991. 19(1): 18–20.
14. Hof H, [Antimicrobial therapy with nitro-
heterocyclic compounds, for example, met-
ronidazole and nitrofurantoin]. Immun
Infekt, 1988. 16(6): 220–5.
15. Conklin JD, The pharmacokinetics of
nitrofurantoin and its related bioavail-
ability. Antibiot Chemother, 1978. 25:
233–52.
16. Kashanian J, Hakimian P, Blute M, Jr.,
Wong J, Khanna H, Wise G, and Shabsigh
R, Nitrofurantoin: the return of an old
friend in the wake of growing resistance.
BJU Int, 2008. 102(11): 1634–7.
17. Mazzulli T, Skulnick M, Small G,
Marshall W, Hoban DJ, Zhanel GG, Finn
S, and Low DE, Susceptibility of commu-
nity Gram-negative urinary tract isolates
to mecillinam and other oral agents. Can
J Infect Dis, 2001. 12(5): 289–92.
18. Williams GJ, Wei L, Lee A, and Craig
JC, Long-term antibiotics for preventing
recurrent urinary tract infection in chil-
dren. Cochrane Database Syst Rev, 2006.
3: CD001534.
19. Koulaouzidis A, Bhat S, Moschos J, Tan
C, and De Ramon A, Nitrofurantoin-
induced lung- and hepatotoxicity. Ann
Hepatol, 2007. 6(2): 119–21.
20. Mavromanolakis E, Maraki S, Samonis
G, Tselentis Y, and Cranidis A, Effect
of norfloxacin, trimethoprim-
sulfamethoxazole and nitrofurantoin
on fecal flora of women with recurrent
urinary tract infections. J Chemother,
1997. 9(3): 203–7.
21. Sjovall J, Huitfeldt B, Magni L, and Nord
CE, Effect of beta-lactam prodrugs on
human intestinal microflora. Scand J
Infect Dis Suppl, 1986. 49: 73–84.
22. Spratt BG, The mechanism of action of
mecillinam. J Antimicrob Chemother,
1977. 3 Suppl B: 13–9.
Antimicrobials in urogenital infections | 2.6 |
23. Graninger W, Pivmecillinam – therapy of
choice for lower urinary tract infection.
Int J Antimicrob Agents, 2003. 22 Suppl
2: 73–8.
24. Sullivan A, Edlund C, Svenungsson B,
Emtestam L, and Nord CE, Effect of
perorally administered pivmecillinam on
the normal oropharyngeal, intestinal and
skin microflora. J Chemother, 2001. 13(3):
299–308.
25. Jones RN, Kugler KC, Pfaller MA, and
Winokur PL, Characteristics of patho-
gens causing urinary tract infections in
hospitals in North America: results from
the SENTRY Antimicrobial Surveillance
Program, 1997. Diagn Microbiol Infect
Dis, 1999. 35(1): 55–63.
26. Gordon KA and Jones RN, Susceptibility
patterns of orally administered
antimicrobials among urinary tract
infection pathogens from hospitalized
patients in North America: comparison
report to Europe and Latin America.
Results from the SENTRY Antimicrobial
Surveillance Program (2000). Diagn
Microbiol Infect Dis, 2003. 45(4):
295–301.
27. Mathai D, Jones RN, and Pfaller MA,
Epidemiology and frequency of resistance
among pathogens causing urinary tract
infections in 1,510 hospitalized patients:
a report from the SENTRY Antimicrobial
Surveillance Program (North America).
Diagn Microbiol Infect Dis, 2001. 40(3):
129–36.
28. Bouza E, San Juan R, Munoz P,
Voss A, and Kluytmans J, A European
perspective on nosocomial urinary tract
infections I. Report on the microbiology
workload, etiology and antimicrobial
susceptibility (ESGNI-003 study).
European Study Group on Nosocomial
Infections. Clin Microbiol Infect, 2001.
7(10): 523–31.
29. Wagenlehner FM, Niemetz A, Dalhoff A,
and Naber KG, Spectrum and antibiotic
resistance of uropathogens from hospital-
ized patients with urinary tract infections:
1994–2000. Int J Antimicrob Agents,
2002. 19(6): 557–64.
30. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
123
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
31. Donowitz GR and Mandell GL, Beta-
Lactam antibiotics (1). N Engl J Med,
1988. 318(7): 419–26.
32. Nathwani D and Wood MJ, Penicillins. A
current review of their clinical pharma-
cology and therapeutic use. Drugs, 1993.
45(6): 866–94.
33. Surveillance of antibiotic resistance
in Neisseria gonorrhoeae in the WHO
Western Pacific Region, 2005. Commun
Dis Intell, 2006. 30(4): 430–3.
34. Sullivan A, Edlund C, and Nord CE,
Effect of antimicrobial agents on the
ecological balance of human microflora.
Lancet Infect Dis, 2001. 1(2): 101–14.
35. Louie A, Kaw P, Liu W, Jumbe
N, Miller MH, and Drusano GL,
Pharmacodynamics of daptomycin in a
murine thigh model of Staphylococcus
aureus infection. Antimicrob Agents
Chemother, 2001. 45(3): 845–51.
36. Marshall WF and Blair JE, The cepha-
losporins. Mayo Clin Proc, 1999. 74(2):
187–95.
37. Jones RN and Preston DA, The antimicro-
bial activity of cephalexin against old and
new pathogens. Postgrad Med J, 1983. 59
Suppl 5: 9–15.
38. Brumfitt W, Hamilton-Miller JM, Gargan
RA, Cooper J, and Smith GW, Long-
term prophylaxis of urinary infections in
women: comparative trial of trimetho-
prim, methenamine hippurate and topi-
cal povidone-iodine. J Urol, 1983. 130(6):
1110–4.
39. Brogard JM, Jehl F, Willemin B, Lamalle
AM, Blickle JF, and Monteil H, Clinical
pharmacokinetics of cefotiam. Clin
Pharmacokinet, 1989. 17(3): 163–74.
40. Perry CM and Brogden RN, Cefuroxime
axetil. A review of its antibacterial activ-
ity, pharmacokinetic properties and
therapeutic efficacy. Drugs, 1996. 52(1):
125–58.
41. Molavi A, Cephalosporins. Rational for
clinical use-review article. American fam-
ily physician, 1991. March 1991.
42. Dudley MN and Barriere SL, Cefotaxime:
microbiology, pharmacology, and clinical
use. Clin Pharm, 1982. 1(2): 114–24.
124
43. Brogden RN and Ward A, Ceftriaxone.
A reappraisal of its antibacterial activity
and pharmacokinetic properties, and an
update on its therapeutic use with par-
ticular reference to once-daily administra-
tion. Drugs, 1988. 35(6): 604–45.
44. Chocas EC, Paap CM, and Godley PJ,
Cefpodoxime proxetil: a new, broad-
spectrum, oral cephalosporin. Ann
Pharmacother, 1993. 27(11): 1369–77.
45. Owens RC, Jr., Nightingale CH, and
Nicolau DP, Ceftibuten: an overview.
Pharmacotherapy, 1997. 17(4): 707–20.
46. Radwanski E, Teal M, Affrime M,
Cayen M, and Lin CC, Multiple-Dose
Pharmacokinetics of Ceftibuten in
Healthy Adults and Geriatric Volunteers.
Am J Ther, 1994. 1(1): 42–48.
47. Chugh K and Agrawal S, Cefpodoxime:
pharmacokinetics and therapeutic uses.
Indian J Pediatr, 2003. 70(3): 227–31.
48. Bergogne-Berezin E, Structure-activity
relationship of ceftazidime. Consequences
on the bacterial spectrum. Presse Med.,
1988. 17: 1878–1882.
49. Wynd MA and Paladino JA, Cefepime:
a fourth-generation parenteral cepha-
losporin. Ann Pharmacother, 1996.
30(12): 1414–24.
50. Murthy B and Schmitt-Hoffmann
A, Pharmacokinetics and
Pharmacodynamics of Ceftobiprole, an
Anti-MRSA Cephalosporin with Broad-
Spectrum Activity. Clin Pharmacokinet,
2008. 47(1): 21–33.
51. Pitout JD and Laupland KB, Extended-
spectrum beta-lactamase-producing
Enterobacteriaceae: an emerging public-
health concern. Lancet Infect Dis, 2008.
8(3): 159–66.
52. Kumagai T, Tamai, S, Abe, T, Hikida, M,
Current status of oral carbapenem devel-
opment. Current Medicinal Chemistry -
Anti-Infective Agents, 2002. 1: 1–14.
53. Hammond ML, Ertapenem: a Group
1 carbapenem with distinct antibacte-
rial and pharmacological properties. J
Antimicrob Chemother, 2004. 53 Suppl 2:
ii7–9.
54. Shah PM and Isaacs RD, Ertapenem,
the first of a new group of carbapenems.
J Antimicrob Chemother, 2003. 52(4):
538–42.

55. Hellinger WC and Brewer NS,
Carbapenems and monobactams: imi-
penem, meropenem, and aztreonam. Mayo
Clin Proc, 1999. 74(4): 420–34.
56. Jones RN, Sader HS, and Fritsche TR,
Comparative activity of doripenem and
three other carbapenems tested against
Gram-negative bacilli with various beta-
lactamase resistance mechanisms. Diagn
Microbiol Infect Dis, 2005. 52(1): 71–4.
57. Mingeot-Leclercq MP, Glupczynski Y,
and Tulkens PM, Aminoglycosides: activ-
ity and resistance. Antimicrob Agents
Chemother, 1999. 43(4): 727–37.
58. Benveniste R and Davies J, Structure-
activity relationships among the
aminoglycoside antibiotics: role of
hydroxyl and amino groups. Antimicrob
Agents Chemother, 1973. 4(4): 402–9.
59. Mingeot-Leclercq MP and Tulkens PM,
Aminoglycosides: nephrotoxicity. Antimicrob
Agents Chemother, 1999. 43(5): 1003–12.
60. Verpooten GA, Giuliano RA, Verbist L,
Eestermans G, and De Broe ME, Once-
daily dosing decreases renal accumula-
tion of gentamicin and netilmicin. Clin
Pharmacol Ther, 1989. 45(1): 22–7.
61. Sha SH and Schacht J, Stimulation of free
radical formation by aminoglycoside anti-
biotics. Hear Res, 1999. 128(1–2): 112–8.
62. Perletti G, Vral, A., Patrosso, M.C.,
Marras, E., Ceriani, I., Willems, P.,
Magri, V., Prevention and modulation
of aminoglycoside ototoxicity. Molecular
Medicine Reports, 2008. 1: 3–13.
63. Naber KG and Adam D, Classification
of fluoroquinolones. Int J Antimicrob
Agents, 1998. 10(4): 255–7.
64. Park-Wyllie LY, Juurlink DN, Kopp
A, Shah BR, Stukel TA, Stumpo C,
Dresser L, Low DE, and Mamdani MM,
Outpatient gatifloxacin therapy and dys-
glycemia in older adults. N Engl J Med,
2006. 354(13): 1352–61.
65. Van Bambeke F, Michot JM, Van Eldere
J, and Tulkens PM, Quinolones in 2005:
an update. Clin Microbiol Infect, 2005.
11(4): 256–80.
66. Okhamafe AO, Akerele JO, and Chukuka
CS, Pharmacokinetic interactions of
norfloxacin with some metallic medici-
nal agents. International Journal of
Pharmaceutics, 1991. 68(1–3): 11–18.
Antimicrobials in urogenital infections | 2.6 |
67. Sorgel F and Kinzig M, Pharmacokinetics of
gyrase inhibitors, Part 2: Renal and hepatic
elimination pathways and drug interac-
tions. Am J Med, 1993. 94(3A): 56S–69S.
68. Naber KG, Which fluoroquinolones are
suitable for the treatment of urinary tract
infections? Int J Antimicrob Agents, 2001.
17(4): 331–41.
69. Stamey TA, Bushby SR, and Bragonje
J, The concentration of trimethoprim
in prostatic fluid: nonionic diffusion or
active transport? J Infect Dis, 1973. 128:
Suppl:686–92 p.
70. Stamey TA, Meares EM, Jr., and
Winningham DG, Chronic bacterial pros-
tatitis and the diffusion of drugs into pro-
static fluid. J Urol, 1970. 103(2): 187–94.
71. Wagenlehner FM, Kees F, Weidner
W, Wagenlehner C, and Naber KG,
Concentrations of moxifloxacin in plasma
and urine, and penetration into prostatic
fluid and ejaculate, following single oral
administration of 400 mg to healthy vol-
unteers. Int J Antimicrob Agents, 2008.
31(1): 21–6.
72. Cross NA, Kellock DJ, Kinghorn GR,
Taraktchoglou M, Bataki E, Oxley KM,
Hawkey PM, and Eley A, Antimicrobial
susceptibility testing of Chlamydia tra-
chomatis using a reverse transcriptase
PCR-based method. Antimicrob Agents
Chemother, 1999. 43(9): 2311–3.
73. Smilack JD, Trimethoprim-
sulfamethoxazole. Mayo Clin Proc, 1999.
74(7): 730–4.
74. Naber KG, Schito, G.C., Gualco,L. on
behalf of the ARESC working group.
An international survey on etiology
and susceptibility of uropathogens iso-
lated from women with uncomplicated
UTI: the ARESC study. in Interscience
Conference on Antimicrobial Agents and
Chemotherapy (ICAAC). 2007. Chicago,
Ilinois, USA.
75. Kahlmeter G, Prevalence and antimicro-
bial susceptibility of pathogens in uncom-
plicated cystitis in Europe. The ECO.
SENS study. Int J Antimicrob Agents,
2003. 22 Suppl 2: 49–52.
76. Karlowsky JA, Kelly LJ, Thornsberry C,
Jones ME, and Sahm DF, Trends in anti-
microbial resistance among urinary tract
infection isolates of Escherichia coli from
125
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
female outpatients in the United States.
Antimicrob Agents Chemother, 2002.
46(8): 2540–5.
77. Karlowsky JA, Kelly LJ, Thornsberry C,
Jones ME, Evangelista AT, Critchley
IA, and Sahm DF, Susceptibility to fluo-
roquinolones among commonly isolated
Gram-negative bacilli in 2000: TRUST
and TSN data for the United States.
Tracking Resistance in the United States
Today. The Surveillance Network. Int J
Antimicrob Agents, 2002. 19(1): 21–31.
78. Hofstetter A, Friesen A, Bishop-Freudling
GB, and Vergin H, [Co-trimoxazole con-
centration in the prostatic fluid of patients
with subacute and chronic prostatitis].
Fortschr Med, 1984. 102(9): 244–6.
79. Meares EM, Jr., Prostatitis: review of
pharmacokinetics and therapy. Rev Infect
Dis, 1982. 4(2): 475–83.
80. Naber KG, Bartnicki A, Bischoff W,
Hanus M, Milutinovic S, van Belle F,
Schonwald S, Weitz P, and Ankel-Fuchs D,
Gatifloxacin 200 mg or 400 mg once daily
is as effective as ciprofloxacin 500 mg
twice daily for the treatment of patients
with acute pyelonephritis or complicated
urinary tract infections. Int J Antimicrob
Agents, 2004. 23 Suppl 1: S41–53.
81. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H, Lobel
B, Jinenez Cruz F, and Selvaggi FP, EAU
guidelines for the management of urinary
and male genital tract infections. Urinary
Tract Infection (UTI) Working Group
of the Health Care Office (HCO) of the
European Association of Urology (EAU).
Eur Urol, 2001. 40(5): 576–88.
82. Hermans PE and Wilhelm MP, Vancomycin.
Mayo Clin Proc, 1987. 62(10): 901–5.
83. Wood MJ, The comparative efficacy and
safety of teicoplanin and vancomycin. J
Antimicrob Chemother, 1996. 37(2): 209–22.
84. Shinabarger D, Mechanism of action of
the oxazolidinone antibacterial agents.
Expert Opin Investig Drugs, 1999. 8(8):
1195–202.
85. Conte JE, Jr., Golden JA, Kipps J, and
Zurlinden E, Intrapulmonary pharma-
cokinetics of linezolid. Antimicrob Agents
Chemother, 2002. 46(5): 1475–80.
86. MacGowan AP, Pharmacokinetic and
pharmacodynamic profile of linezolid
126
in healthy volunteers and patients with
Gram-positive infections. J Antimicrob
Chemother, 2003. 51 Suppl 2: ii17–25.
87. Tsiodras S, Gold HS, Sakoulas G,
Eliopoulos GM, Wennersten C,
Venkataraman L, Moellering RC, and
Ferraro MJ, Linezolid resistance in a
clinical isolate of Staphylococcus aureus.
Lancet, 2001. 358(9277): 207–8.
88. Carson J, Cerda J, Chae JH, Hirano M, and
Maggiore P, Severe lactic acidosis associ-
ated with linezolid use in a patient with the
mitochondrial DNA A2706G polymorphism.
Pharmacotherapy, 2007. 27(5): 771–4.
89. Beekmann SE, Gilbert DN, and Polgreen
PM, Toxicity of extended courses of lin-
ezolid: results of an Infectious Diseases
Society of America Emerging Infections
Network survey. Diagn Microbiol Infect
Dis, 2008. 62(4): 407–410.
90. Lode H, Von der Hoh N, Ziege S, Borner
K, and Nord CE, Ecological effects of lin-
ezolid versus amoxicillin/clavulanic acid
on the normal intestinal microflora. Scand
J Infect Dis, 2001. 33(12): 899–903.
91. Allen NE, Hobbs JN, and Alborn WE, Jr.,
Inhibition of peptidoglycan biosynthesis
in gram-positive bacteria by LY146032.
Antimicrob Agents Chemother, 1987.
31(7): 1093–9.
92. Snydman DR, Jacobus NV, McDermott
LA, Lonks JR, and Boyce JM,
Comparative In vitro activities of dapto-
mycin and vancomycin against resistant
gram-positive pathogens. Antimicrob
Agents Chemother, 2000. 44(12): 3447–50.
93. Naber KG, Eisenstein, B.I., Tally, F.P.,
Daptomycin versus ciprofloxacin in the
treatment of complicated urinary tract
infection due to Gram-positive bacteria.
Infect Dis Clin Pract, 2004. 12: 322–327.
94. Nickel JC, Patel M, and Cameron M,
Chronic prostatitis/chronic pelvic pain syn-
drome: finding a way forward in the United
kingdom: report from the first United
kingdom symposium on chronic prostatitis,
january 30, 2008, london, United kingdom.
Rev Urol, 2008. 10(2): 160–3.
95. Agwuh KN and MacGowan A,
Pharmacokinetics and pharmacodynam-
ics of the tetracyclines including glycyl-
cyclines. J Antimicrob Chemother, 2006.
58(2): 256–65.
|2.7|

Antibiotic policy
Inge C. Gyssens1,2,3
1
Nijmegen Institute for Infection, Inflammation, and Immunity (N4i) and Department of Medicine, Radboud University
Nijmegen Medical Centre and
2
Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
3
Hasselt University, Diepenbeek, Belgium
Tel secr +31 24 3657514, Fax +32 11 309488, Email i.gyssens@aig.umcn.nl

ABSTRACT The purpose of this chapter is to provide

There is a clear association between
antibiotic use and resistance both on
individual and population levels. In the
European Union, countries with large
antibiotic consumption have higher
resistance rates. Antibiotic resistance
leads to failed treatments, prolonged hos-
pitalizations, increased costs and deaths.
With few new antibiotics in the Research
& Development pipeline, prudent anti-
biotic use is the only option to delay the
development of resistance.
Antibiotic policy consists of prescrib-
ing strategies to optimize the indication,
selection, dosing, route of administration,
duration and timing of antibiotic therapy
to maximize clinical cure or prevention of
infection while limiting the unintended
consequences of antibiotic use, including
toxicity and selection of resistant micro-
organisms. A secondary goal is to reduce
healthcare costs without adversely affect-
ing the quality of care.
the evidence base of prudent antibiotic
policy. Special emphasis is placed on uri-
nary tract infections. The value and sup-
port of antibiotic committees, guidelines,
ID consultants and/or antimicrobial stew-
ardship teams to prolong the efficacy of
available antibiotics will be discussed.
Key words: Antibiotic policy, antimicro-
bial stewardship, antimicrobial resistance,
guidelines, pharmacokinetics, pharmaco-
dynamics, urinary tract infections
SUMMARY OF RECOMMENDATIONS
Indication – therapy
1. Asymptomatic bacteriuria with and
without the presence of urinary cath-
eters should not be treated except
in special circumstances (e.g. preg-
nancy) (GoR A).
2. Perform timely imaging to document
focus, extent of the infection,
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
obstruction and presence of abscesses
(GoR A).
3. Prompt removal of the focus of
infection, relieving obstruction,
and drainage of abscesses improve
the efficacy of antibiotic treatment
(GoR A).
Indication – prophylaxis
4. Use evidence based alternatives
for antibiotics where available
(cranberry – estrogen topical creams)
(GoR B).
5. The benefit of antibiotics should be
balanced against side effects such as
allergy, resistance and costs (GoR A).
The number to treat to avoid a par-
ticular complication is useful for the
decision (GoR B).
6. In the absence of evidence, refrain
from surgical antibiotic prophylaxis
(GoR B).
Collecting the microbiological
samples
7. Because urologists most often treat
complicated UTIs, it is of para-
mount importance to obtain urine
for culture before starting an empiric
antibiotic regimen (GoR A).
8. The determination of a causative
organism and susceptibility is a
prerequisite for targeted therapy,
including streamlining and the
switch to effective oral antibiotic
therapy (GoR A).
Selection of antimicrobial agents
Empirical therapy
9. Build a local hospital or regional
formulary (list) of antibiotics to
treat UTI, according to local suscep-
tibility patterns (GoR A).
10. The formulary should contain one
drug of each major class, previously
determined on the basis of local
128
resistance patterns and local pathol-
ogy (GoR B).
11. The local antibiotic guide should
cite empirical regimens with a
spectrum that is broad enough to
cover the most frequently encoun-
tered pathogens for UTIs in specific
patient groups, in the community
and hospital respectively (GoR A).
12. If local fluoroquinolone resistance of
E. coli exceeds 15%, fluoroquinolo-
nes should not be used for empirical
therapy of UTIs (GoR B).
13. Consider prior use of antibiotics
(within three to six months prior to
presentation) when selecting an anti-
biotic for empiric therapy (GoR B).
Pathogen-directed therapy
14. De-escalate or streamline to a nar-
rower spectrum, less toxic, oral –
this strategy invariably results in
cost containment (GoR A).
15. A switch to oral agents with high
bioavailability can be made after 48h
of clinical improvement and when
the identity and susceptibility of the
causative micro-organism are known
(GoR A).
16. In patients with severe renal failure,
aminoglycosides are probably best
avoided in long term therapy (GoR A).
Dosing regimens
17. Antibiotics should be administered
according to pharmacokinetic/phar-
macodynamic principles (GoR A).
18. Low doses can not only lead to treat-
ment failure, but also to increased
selection of resistance (GoR B).
Timing
19. Starting with intravenous antimi-
crobial therapy within one hour in
patients with severe (uro)sepsis is
recommended (GoR A).

20. Timely start of antibiotics for
patients with UTI is < 4 hours after
admission (GoR A).
21. The optimal administration of iv first
or second generation cephalosporins
for surgical prophylaxis is within 30
min before incision (GoR B).
Antimicrobial stewardship
22. The societies for urology should par-
ticipate in national UTI guideline
development and urology depart-
ments should participate in the
update of their hospital antibiotic
guide (GoR B).
23. Urology ward-specific surveillance
data and inpatient versus outpatient
data should be available to the anti-
biotic committee to select appropri-
ate antibiotics for UTI treatment
guidelines in urological patients
(GoR B).
24. One urologist should have the man-
date on behalf of his department to
support the implementation (GoR B).
25. Implementation of guidelines: use
quality indicators for UTI (GoR B).
26. Good communication with the micro-
biologist will facilitate pathogen -
directed therapy (GoR B).
27. Infectious diseases specialist consul-
tations can optimize the antibiotic
management of individual complex
cases (GoR B).
1. INTRODUCTION
There is a clear association between
antibiotic use and resistance both on
individual and population levels. The
surveillance project EARSS has shown
considerable differences in resistance
of key uropathogens (E. coli) between
European countries (Figure 1). In paral-
lel, the ESAC project has shown remark-
able differences of antibiotic use in the
Antibiotic policy | 2.7 |
same countries. Thus, big consumers have
higher resistance rates. Another major
factor that drives resistance is the spread
of resistant bacteria among individuals in
healthcare institutions by poor infection
control practices. A significant proportion
of heathcare-associated infections (HCAI)
is caused by multiresistant bacteria such
as methicillin-resistant Staphylococcus
aureus (MRSA) and Clostridium dif-
ficile. The health burden associated
with HCAI is considerable and there is
increased awareness of the fact that the
use of antimicrobials in hospitals is a key
determinant of HCAI rates due to these
hospital-acquired pathogens. Numerous
reports in the literature [1–3] provide
evidence that the frequency of infections
caused by multidrug-resistant bacteria
is escalating in many countries. Several
highly resistant gram-negative pathogens
such as Acinetobacter species, multidrug-
resistant (MDR) Pseudomonas aeruginosa,
carbapenem-resistant Klebsiella species
and Escherichia coli are emerging as sig-
nificant pathogens in hospitals. Acquired
resistance to three or more classes of anti-
biotics is commonly reported for some
Gram-negative bacterial species [2, 4].
Antibiotic resistance leads to failed
treatments, prolonged hospitalizations,
increased costs and deaths. Mortality
has since long been known to be higher
in patients with bacteraemia treated
with inappropriate antibiotics (i.e. when
the micro-organism is not susceptible).
Increasingly, limited access to effec-
tive antibiotics is contributing to high
mortality from these resistant bacterial
infections. ESBL producing E. coli and
Klebsiella spp. causing bloodstream infec-
tions are associated with severe adverse
outcomes, including higher overall and
infection-related mortality, length of hos-
pital stay, delay in appropriate therapy
and higher costs [5] (LoE 3).
For approximately 40 years the phar-
maceutical industry has provided a steady
flow of new antibiotics, including several
with new mechanisms of action that were
129
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
Figure 1 Proportion of invasive isolates with resistance to fluoroquinolones in 2007.
effective against bacteria that became
resistant to earlier antibiotics. However,
over the last decade several companies
have abandoned antibacterial research
due partly to scientific challenges of dis-
covery, but also alleged lack of incentives.
Recently, companies have directed their
research to multidrug-resistant Gram-
positive bacteria; three systemically-
administered antibiotics, including only
two from new classes, have been marketed.
However, for Gram-negative bacteria, only
a few antibiotics are in late stage devel-
opment. Already back in 2004, a WHO
report identified antimicrobial resistance
as a public health problem with “a phar-
maceutical gap” , i.e. where existing treat-
ments or preventive measures were likely
to become ineffective in the future [6].
To understand the association of anti-
biotic use with resistance, one should
realise that antibiotic therapy is differ-
ent from other forms of pharmacotherapy.
Antimicrobial therapy is not only based
130
on the characteristics of a patient and a
drug, but also on the characteristics of
the microorganisms causing an infection
and the colonising flora. The complex
interrelationship between man, micro-
organisms and antimicrobial drugs is
best depicted in the pyramid of infectious
diseases (Figure 2).
The pyramid shows multiple interac-
tions between the patient, the drug, the
pathogen(s) and colonising microflora.
Activity of the antimicrobial drug is coun-
teracted by the development of resistance
by the pathogen, but also by exposed col-
onising flora. Resistance to antibiotics,
either by mutation or after acquisition of
foreign genetic information, will continue
to pose problems. Ideally, maximal efficacy
should be combined with minimal toxicity
at the lowest cost. As is illustrated in the
pyramid (Figure 2), appropriate therapy
is dependent on knowledge of many dif-
ferent aspects of infectious diseases. Host
factors, virulence of micro-organisms,
 Antibiotic policy | 2.7 |

The pyramid of infectious diseases

Therapy

ity

Ac
xic

tiv
To

ity
Activity
ics

Re
et

sis
in
ok

ta
ac

nc
m

e
ar
Ph

Resistance
Host Commensals
n
res Host atio
ista l o niz nce
nce Co sista
Vir tion re
ule
nce niza
C olo
Pathogens

Figure 2 The pyramid of infectious diseases.

Table 1 Reasons for misuse of antibiotics.

By providers of health care
•  Lack of education in infectious diseases
•  Uncertainty about the diagnosis
•  Lack of good microbiology laboratory support
•  L  ack of update of syndromic management of infectious diseases
•  Belief that patients expect antibiotics
•  Compensation for failing technique (prophylaxis)
By the public
•  Insufficient knowledge (of viral vs bacterial infection)
•  Former experience of beneficial effect of antibiotics
•  Belief that some conditions require antibiotic treatment
•  Pressure to return to work
•  Fear

pharmacokinetics and dynamics of drugs dissemination of resistance is closely

have to be considered. linked to the magnitude of the selective
Avoiding overuse is an issue that will antimicrobial pressure, a major strategy is
need increasing attention. Overuse of to delay this dissemination. Unnecessary
antibiotics has many causes (Table 1). use of antibiotics as well as irrational use
Antimicrobial drugs have a unique including inadequate dosing and long
feature. Invariably, their use leads to duration are equally important for selec-
antimicrobial resistance, which in turn tion. Therefore, prudent prescribing poli-
leads to loss of their future value. As the cies to preserve the available antibiotics

131
Chapter |2| Aetiology, antimicrobial resistance of uropathogens

are mandatory. Antibiotic policy (recently
renamed antimicrobial stewardship),
includes optimizing the indication, selec-
tion, dosing, route of administration, and
duration of antimicrobial therapy to maxi-
mize clinical cure or prevention of infec-
tion while limiting the collateral damage of
antimicrobial use, including toxicity, selec-
tion of pathogenic organisms (such as C.
difficile), and emergence of resistance [7].
Good microbiology laboratory facilities are
cornerstones of prudent antibiotic policies.
Laboratoriesí multiple tasks consist of sur-
veillance of resistance, determination of the
causative agent and its susceptibility pat-
tern in individual patients and monitoring
of potentially toxic drug concentrations.
Antibiotic resistance is reversible to
some extent. In general, the reversal of
resistance after removal of selection pres-
sure is slower than its increase due to the
same antibiotic pressure. These observa-
tions emphasize the urgency of applying
the principles of prudent antibiotic use in
hospitals. Recent successes of antibiotic
policies in concert with infection control
to reduce resistance have been reported
in European countries e.g. the reduc-
tion of MRSA in high consuming France
[8] (LoE 3), and control of C. difficile in
a US hospital [9] (LoE 2b). On the other
hand, the marketing strategies of antimi-
crobial drug developers are pushing sales
because profit and return to sharehold-
ers are directly linked to volume sales of
their products. This system has created
a paradoxical situation, both for policy
makers and drug developers [10].
In this chapter the evidence base of pru-
dent antibiotic policy is reviewed. A
number of publications provide a thor-
ough understanding of the benefits of
antimicrobial stewardship [7, 11] (LoE 4).
A frequently observed effect of antibiotic
policy programs is a reduction of health-
care costs without adversely affecting the
quality of care [12–13] (LoE 2b). Recently,
antimicrobial stewardship, together with
infection control, has been identified as a
patient safety issue [14], and some suc-
cesses have been obtained by strategies
which are described in this chapter.
2. METHODS
2.1 Definitions
Useful definitions on the field of antibi-
otic policy are listed in table 2.

Table 2 Definitions for understanding prudent policy strategies.

Prophylaxis is used to prevent an infection. When an infection is already present, the antimicrobial drugs are administered
for therapy.
Antibiotic policy, antimicrobial stewardship [11]
Activities to optimize antimicrobial use among patients to
- improve patient outcomes
- ensure cost-effective therapy, and
- reduce adverse sequelae of antimicrobial use (including antimicrobial resistance).
Antibiotic committee
Consists of clinicians, ID physicians, medical microbiologists, hospital epidemiologists, hospital pharmacists.
Formulary
List of drugs. Facilitates restriction policies and stock management by the pharmacy.
Clinical practice (antibiotic) guidelines for infectious diseases
A systematic review of the literature and graded conclusions followed by recommendations based on the conclusions.
Antibiotic guide:
Treatment advice based on the recommendations of the guidelines.

132

2.2 Literature search
A systematic literature search was per-
formed in Medline for the period 1978–
2009 with the following key words:
“Anti-Bacterial Agents” [Mesh] AND
(“Urinary Tract Infections/drug therapy”
[Mesh] OR “Urinary Tract Infections/pre-
vention and control” [Mesh] OR “Urinary
Tract Infections/therapy” [Mesh]) NOT
(“tuberculosis” [MeSH Terms] OR
“Anthelmintics” [Mesh] OR “Case Reports
“[Publication Type]) and the follow-
ing limitations: Humans, Clinical Trial,
Letter, Meta-Analysis, Practice Guideline,
Randomized Controlled Trial, English,
Core clinical journals.
Seventy-nine articles were found and
screened by title and abstract and 32
were finally included into the review sup-
plemented by key publications known to
the author.
The studies were rated according
to the level of evidence (LoE) and the
grade†of recommendation (GoR) using
ICUD standards (for details see Preface)
[15–16]
3. EVIDENCE BASED PRINCIPLES OF
PRUDENT ANTIBIOTIC PRESCRIBING
3.1 Is there an indication? Are
antibiotics necessary?
3.1.1 Antibiotic therapy for UTI
When considering antimicrobial therapy
in a patient with fever whom we suspect
of having a urinary tract infection (UTI),
one should first answer the following
questions:
First, is the fever caused by the UTI?
If so, clinical and laboratory data are
needed to determine the severity of the
infection, the potential site of infection
within the urinary tract, and eventu-
ally a suspected causal microorganism.
Apart from clinical parameters, valu-
able laboratory parameters are quickly
available such as leukocyte count,
Antibiotic policy | 2.7 |
C-reactive protein, or procalcitonin. A
recent prospective study in 202 patients
with pyelonephritis showed a prognostic
value of CRP levels concerning length
of stay, duration of therapy and the
risk of relapse [17] (LoE 3). However,
even when the cause of low grade fever
is infection, one should ask if it wise to
treat it with antimicrobial drugs. A first
principle to avoid overuse is not admin-
istering antibiotics in situations when
they will not work or when there are
alternatives. In terms of efficacy, many
of our indications for antimicrobial use
need re-evaluation. Even when a small
benefit from antimicrobial use is sug-
gested, this should always be weighed
against the disadvantages of adverse
effects, resistance and costs.
Pregnant women are one of the few
patient groups for which it is indicated to
treat asymptomatic bacteriuria [18] (LoE
1); there is no indication to treat asymp-
tomatic bacteriuria in children, diabetics
or patients with indwelling catheters [19]
(LoE 1). Also, four randomised controlled
trials in nursing homes showed no benefit
from treating asymptomatic bacteriuria
in institutionalised elderly people [20–23]
(LoE 1).
If the chance to cure the infection with
antimicrobial drugs alone is small, such
as when an infection is complicated by a
perirenal abscess or in the presence of a
foreign body (stents), a surgical or radio-
logical intervention to drain the focus or
to remove the device should be consid-
ered without delay. Even when antibiot-
ics are administered, removal of foreign
bodies will enhance the effect. Patients
with a long-term indwelling catheter may
carry also enterococci, yeasts and staphy-
lococci, in addition to Enterobacteriaceae,
such as Serratia, Providencia and
Acinetobacter. If the indwelling catheter
is changed at the time of treatment of a
symptomatic UTI, a higher percentage
of patients will exhibit disappearance of
the bacteriuria and a more rapid recov-
ery from the symptoms [24] (LoE 2a).
133
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
3.1.2 Surgical prophylaxis
When antibiotics are considered to pre-
vent an infection, the concept of number
of patients to treat to avoid a specific
infection as patient outcome is a useful
measure to weigh the potential advan-
tages of antimicrobial drugs [25]. The
number to treat is calculated from base-
line risk and odds ratio of the unfavoura-
ble outcome, e.g. a surgical site infection.
For example, in the Scottish prophylaxis
guideline SIGN, antibiotic prophylaxis is
recommended for transrectal biopsies of
the prostate and is highly recommended
for patients undergoing transrectal resec-
tion of the prostate (TURP) [26]. To avoid
bacteriuria after transrectal biopsies the
number of patients to treat (NTT) is 27.
Antibiotic prophylaxis also significantly
reduces bacteriuria in patients undergo-
ing transrectal resection of the prostate
(TURP), but in addition reduces urosep-
sis from 4.4 to 0.7% [27] (LoE 1), and
the NTT is only 8 [26]. The difference
in NTT explains why the recommenda-
tion to use prophylaxis before TURP is
stronger.
3.1.3 Prevention of recurrent UTI
Continuous antibiotic prophylaxis for
six to 12 months reduced the rate of UTI
during prophylaxis when compared to
placebo. However, side effects are vagi-
nal and oral candidiasis and gastrointes-
tinal symptoms [28] (LoE 1). However,
there are a few alternatives to antibi-
otics to prevent recurrent infection in
women. This would help to reduce selec-
tion pressure and allows for the use of
narrower agents in case of unavoidable
prophylaxis failures. There is some evi-
dence that cranberry juice may decrease
the number of symptomatic UTIs over a
12 month period, particularly for women
with recurrent UTIs [29] (LoE 1). Its
effectiveness for other groups (children,
older women) is less certain. For post-
menopausal women, vaginal oestrogens
have proved to be effective, although the
134
evidence is based on only two studies
comparing vaginal oestrogens to placebo
[30] (LoE 1).
3.2 Starting empirical therapy and
prophylaxis timely
Timely administration (<4 hours) in
patients with UTI is associated with a
shorter length of stay [31] (LoE 3).
The recommended period to administer
antibiotics with a relatively short half-
life, such as cephazolin, is determined
at within 1h, from the evidence provided
by correlation studies and interventions.
[32–35] (LoE 2a). Recently, the optimal
period for non-urological procedures has
been defined at 30 min [13, 35] (LoE 2b).
3.3 Collecting microbiological
samples timely
Good communication with the microbiology
laboratory for the entire diagnostic process
from request of the test to interpretation
and application of the results is a major
determinant of quality of prescribing [36]
(LoE 3). Upon suspicion of a complicated
UTI, before the start of empiric therapy,
urine must be collected for culture; the
identification of the microorganism will
direct the selection of an appropriate defin-
itive therapy [19, 37] (LoE 3).
However, waiting time for the urine
sample should not exceed a few hours
as early administration is shown to be
beneficial for the outcome (see 2 a). In
case of an UTI with systemic symptoms
(fever, but also chills and low tempera-
ture) two sets of blood cultures must be
performed. Two sets allow for the differ-
entiation between true bacteremia and
contamination.
3.4 SELECTING THE ANTIBIOTICS
3.4.1 Empirical therapy
If antimicrobial drugs are necessary, one
should determine the choice of the drug

and the dosage regimen. Three possible
situations arise:
– The clinical picture is uniformly
caused by one microorganism, and
the susceptibility in the area is pre-
dictable, e.g. scarlet fever caused by
penicillin-susceptible Streptococcus
pyogenes. This situation does not occur
in urological infections.
– The clinical picture is associated with
a typical microorganism, but the
susceptibility is not predictable, e.g.
urethritis (Ècoulement) caused by
Neisseria gonorrhoeae, posing on-going
problems for individual case manage-
ment and disease control [38].
– The clinical picture can be caused by
different microorganisms, and the sus-
ceptibility is not predictable: all com-
plicated UTIs.
Resistance is variable in time, accord-
ing to geographical region and patient
populations. For some infections encoun-
tered in the community, e.g. uncom-
plicated UTI in women, local/regional/
national resistance surveillance data of
the most likely causing pathogens (E.
coli, K. pneumonae) isolated from unse-
lected urine samples allow recommenda-
tion of first line antibiotics in treatment
guidelines without the need for perform-
ing cultures for the individual patient.
An example is the Dutch practitionerís
UTI guidelines, in which the selection of
antibiotics is based on the annual sur-
veillance report (available on www.swab.
nl) from the national resistance surveil-
lance system conducted by the Working
Party on Antibiotic Policy (SWAB) in the
Netherlands [39].
In complicated UTI, surveillance data
of resistance rates from invasive iso-
lates or pathogens isolated from relevant
patient groups (e.g. urology wards) should
be used to guide the formulation of recom-
mendations for the selection of empirical
antibiotics: the so-called Well informed
bacteriological guess. Epidemiological
Antibiotic policy | 2.7 |
resistance data of invasive E. coli isolates
are available for 30 European countries.
Figure 3 shows the increasing fluoroqui-
nolone resistance rates for E. coli [40].
Compared to general wards and the
community, resistance is uniformly higher
in urology departments. The Netherlandsí
NethMap also provides national suscepti-
bility data for E. coli from urology depart-
ments (mostly outpatients) [39].
More than 15% of E. coli isolated from
patients in urology departments are now
resistant to fluoroquinolones, and in other
hospital departments resistance to these
agents has reached the 5–10% range.
In view of this high degree of resist-
ance among patients admitted to urol-
ogy departments, fluoroquinolones are
not considered as appropriate empirical
antimicrobial therapy in the Netherlands
anymore.
In severely ill or hospitalized patients,
the Gram stain of urine samples can help
to fine tune the broadness of empirical
therapy (Gram-negative bacteria versus
enterococci) in an early stage. Whether
the infection is community-acquired or
nosocomial and whether the patient has
been exposed to previous antimicrobial
therapy should also be taken into account
when selecting an agent for empirical
therapy.
A profile of the optimal antimicrobial
drug is described in Table 3.
Blind empirical therapy often consists
of high-dose, broad spectrum drugs or a
combination of drugs. A rational choice
of antibiotic can only be expected if the
prescriber is aware of the most likely
infective agent, and as explained above,
of the prevailing susceptibility patterns.
Ongoing surveillance of antibiotic resist-
ance must be performed in every institu-
tion [41] (LoE 4). Regularly updated (six
months) local hospital surveillance data
should be available to provide rational
regimens in the local hospital antibi-
otic guide. The national guidelines pro-
vide a framework for these policies [42]
(LoE 4).
135
Chapter |2| Aetiology, antimicrobial resistance of uropathogens

Figure 3 Trends of fluroquinolone resistance by country, 2001–2007. www.rivm.nl/earss

136

Table 3 The ideal antibiotic for therapy or prophylaxis.
•  Is highly active against the (suspected) causative organism
•  Reaches effective concentrations at the site of infection
•  Has a long half-life
•  Has very little toxicity
•  Does not induce allergy
•  Has no interactions with other drugs
•  Does not select for emergence of resistant microorganisms in the patient or the environment
•  Can be administered by the desired route
•  Is not expensive
Prior antimicrobial use is strongly
associated with resistance. Multivariate
analysis demonstrated that isolation of
imipenem-resistant P. aeruginosa was
strongly associated with antibiotic (fluo-
roquinolone) use, and the strength of the
association varied with the duration of
exposure [43] (LoE 3). One study on the
association between antibiotic resistance
and prescribing showed that trimetho-
prim resistance in bacteria isolated from
urine samples was significantly associ-
ated with prior trimethoprim use. The
association was strongest for patients
recently exposed to trimethoprim (within
eight to 15 days prior to the date of the
urine sampling), but lasted up to six
months before the date of urine culture.
There was no association between tri-
methoprim resistance and exposure more
than six months earlier [44] (LoE 3).
3.5 Streamlining empirical therapy
Replacing an empirically chosen agent
by a more narrow-spectrum agent that
is active against the isolated pathogen
is a traditional strategy of infectious dis-
eases consultants, called “streamlining”.
Rationale for this strategy is avoidance of
selection pressure by blindly chosen broad
spectrum agents. Until recently, it was
not prospectively studied. Intensive care
physicians discovered the strategy and
termed it “de-escalation”. For example,
when pathogens are cultured that have
Antibiotic policy | 2.7 |
kept their susceptibility to older, narrow
spectrum drugs e.g. Group B haemolytic
streptococci to penicillin, these infections
can and should still be treated with that
narrow spectrum drug.
In Northern Europe, this ìtailoringî to
narrow spectrum therapy has been con-
sequently taught for many years in medi-
cal schools and this strategy has resulted
in prudent prescribing [45] (LoE 4). In
Denmark, which has one of the lowest
incidences of antibiotic resistance, nar-
row spectrum drugs are most frequently
prescribed [46] (LoE 3).
Prioritization of tested antimicrobials
and selective reporting of susceptibility
profiles (e.g. not routinely reporting sus-
ceptibility of a microorganism to broad
spectrum antibiotics can prevent inad-
vertent overuse of these drugs and sup-
port the prudent use of antimicrobials
and direct appropriate therapy based on
local guidelines) [7] (LoE 4).
3.6 Determining the right dose and
route
In this paragraph, the impact of pharma-
cokinetics and pharmacodynamics on the
optimal selection of dosing schedules is
explained.
3.6.1 Activity of the antibiotic
One of the major characteristics of anti-
biotics that determine the time course
137
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
of their activity is whether their kill-
ing of bacteria is dependent on the drug
concentration or on the duration of expo-
sure [47].
The concentration-time curve of a
drug possesses two major characteristics:
the peak concentration (Cmax) and the
area under the concentration-time curve
(AUC). Both pharmacokinetic parameters
can be related to the minimum inhibi-
tory concentration (MIC) of a microor-
ganism by determining the ratio between
the two to obtain pharmacokinetic/phar-
macodynamic (PK/PD) indices. Thus
the AUC/MIC and Cmax/MIC ratios are
obtained [48].
It is essential to understand the most
important PK/PD principles in order to
justify their recommended dosage regi-
mens. A large number of in vitro and ani-
mal studies have been conducted allowing
the determination of PK/PD properties of
the major antibiotic classes.
Three activity patterns have been
described and are important to con-
sider when defining the optimal
dosage of antibacterial agents in
patients with infections.
The first activity pattern is charac-
terised by concentration-dependent kill-
ing in which the [Cmax]/(MIC) and /or
the (AUC)/MIC ratios are the best PK/
PD indices correlating with efficacy. The
dosing of antibacterial agents exhibiting
this activity pattern is optimised via the
administration of large (once daily) doses.
Several antibiotic classes display this
pattern of activity, e.g. aminoglycosides
and fluoroquinolones. Pharmacokinetic
properties of ‘once a day’ aminoglycoside
regimens are superior to ‘multiple doses
a day’ regimens in that they achieve
higher peak levels while avoiding toxic
trough levels. However, the definition of
concentration-dependent has a maximum
and there is a level beyond which increas-
ing a drugís concentration relative to the
MIC does not improve bacterial killing.
For aminoglycosides, this level appears to
be at a peak/MIC ratio of 10–12. Studies
138
have shown that the most elegant strat-
egy is to administer a initial large dose (6
or 7mg/kg) to all patients, and to adjust
subsequent doses (or intervals) with indi-
vidual pharmacokinetic monitoring as
soon as possible [49] (LoE 3). A once-daily
dosing regimen of 7 mg/kg gentamicin
produced Cmax/MIC ratios > 10 in criti-
cally ill patients [50] (LoE 2b). For fluo-
roquinolones, some authors suggest that
the best PK/PD index associated with effi-
cacy is the Cmax/MIC ratio, which should
be > 10, while others suggest the AUC/
MIC ratio is the best index, which should
be > 30–40 for gram positive and 100–125
for gram negative bacteria [51] (LoE 4).
The second activity pattern is char-
acterised by time-dependent killing and
minimal-moderate persistent effect.
Higher drug concentrations are not asso-
ciated with higher killing rates and opti-
malisation of efficacy is reached through
extending the duration of exposure.
β-lactams (penicillins, cephalosporins)
are characterised by time-dependent kill-
ing. For these drugs, the time serum
levels remain above the MIC (T>MIC) is
the PK/PD index correlating with treat-
ment efficacy. It has been demonstrated
that concentrations of approximately
four times the MIC exert the maximum
effect and that higher concentrations
are not associated with increased bacte-
ricidal activity [52]. In immunocompro-
mised patients and for difficult to reach
infection sites (prostate, abscesses), it is
agreed that multiples of MICs are needed.
T>MIC should be long, from 40 to 70% of
the interval time between doses [47] (LoE
4). As T>MIC is the most important PK/
PD index correlating with the efficacy of
β-lactam antibiotics, continuous infusion
of these agents is an attractive theoretical
concept. Several animal studies showed
improved efficacy of continuous infusion
over intermittent infusion, especially in
neutropenic animals [52]. A meta-analy-
sis of RCTs comparing continuous versus
intermittent infusion of different anti-
biotic classes in patients with various

infections showed a trend towards lower
clinical failure, favouring continuous
infusion, but the differences were not
statistically significant [53] (LoE 1). The
difference was significant in a subset of
RCTs using the same total daily dose in
both arms. No differences in mortality
were found. Larger, well designed trials
are needed to further evaluate the ben-
efits of continuous infusion of β-lactam
agents [51–53]. Prolonged infusion rates
are probably a more feasible alternative
in non ICU wards.
The third activity pattern is character-
ised by time-dependent killing and pro-
longed persistent effects. Although higher
concentrations are not associated with
more efficient killing, higher concentra-
tions do produce prolonged suppression
of growth of the micro-organism. The
AUC/MIC ratio is the index most closely
related to drug efficacy. Azithromycin,
tetracyclines and clindamycin, and the
glycylcyclines (such as tigecycline) exhibit
this pattern of activity.
Reviews of PK/PD have recommended
the AUC/MIC as the pharmacodynamic
parameter that best correlates with a
successful outcome associated with the
use of vancomycin based in part on data
from animal models, in vitro studies, and
limited human studies [47, 54]. There are
very few human studies evaluating the
pharmacodynamics of vancomycin, and
the findings of most of those studies have
not been conclusive in determining which
parameter is most valuable in predicting
patient outcome. The majority of stud-
ies have involved relatively small patient
populations and patients with a variety of
infection types.
However, for most drug/pathogen com-
binations, much less is known on which
PK/PD index correlates with develop-
ment of resistance. Traditionally, PK/
PD parameters have been used to pre-
dict antibiotic efficacy, but there is now
increasing interest in trying to use PK/
PD parameters to minimize develop-
ment of resistance. The AUC/MIC ratio
Antibiotic policy | 2.7 |
has also been used to describe fluoroqui-
nolone drug exposures associated with
either increased or decreased risk of
resistance emergence. Apart from ensur-
ing increased efficacy, high peak concen-
trations, greater than eight to 10 times
the MIC are expected to decrease the
emergence of resistant strains. In addi-
tion, insufficient Cmax/MIC ratios (ie,
<10) have been associated with fluoroqui-
nolone resistance [55–58].
3.6.2 Route
The parenteral route of administration
should be used for empirical therapy in
severely ill patients, in patients with gas-
trointestinal dysfunction and for drugs
with poor oral bio-availability. However,
in practice, cultural factors seem to influ-
ence the choice of route of administra-
tion. Although the site and the severity of
infection in European acute general hos-
pitals were probably comparable, 60% of
in-patients were treated with oral antibi-
otics in the UK, while in Italy over 80%
were injected with over half being intra-
muscular injections [59] (LoE 3).
3.6.3 Step down to oral
Attaining sufficiently high serum and
tissue concentrations is the main cri-
terion for using antimicrobial agents
orally. When limited to oral drugs with
excellent bio-availability, i.e. good gas-
tro-intestinal absorption with minimal
absorption-related drug interactions and
well-documented interactions with food,
sequential therapy is optimal.
3.6.4 Toxicity
For drugs with a narrow therapeutic
index e.g. aminoglycosides, dose adap-
tation in the presence of renal failure
is mandatory. Pharmacokinetic param-
eters are also important in relation to
toxicity. The toxicity of antimicrobial
drugs varies considerably. Most anti-
microbial agents are eliminated by the
139
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
kidney. The therapeutic/toxic index is
much larger for β-lactams, which are rel-
atively nontoxic for humans, compared
to aminoglycosides, which are toxic to
kidneys and the inner ear. Monitoring of
the serum concentrations of aminoglyco-
sides is extensively used in clinical prac-
tice. Moreover, experiments in rats have
shown that the incidence of aminoglyco-
side-induced nephrotoxicity is reduced by
once-daily dosing [60]. Thus, high peaks
of aminoglycosides, e.g. gentamicin, are
associated with optimal efficacy and low
troughs are associated with minimal
toxicity. Therefore, aminoglycosides are
administered in a once daily dosing regi-
men. In patients with severe renal fail-
ure, aminoglycosides are probably best
avoided in long term definitive therapy.
A randomised, double blind study showed
that once-daily dosing had a lower prob-
ability of causing nephrotoxicity in
patients with a normal baseline renal
function [61] (LoE 1). Fear of toxicity can
lead to under-dosing of aminoglycosides
[62] (LoE 2b).
3.7 Limiting the duration of
antibiotic exposure to the
essential
3.7.1 Therapy and duration
There is a lack of evidence-based infor-
mation on the appropriate duration of
treatment for most infectious diseases.
Even the duration of treatment for com-
mon infections is often based on tradition.
There are also cultural differences. In a
1991 European survey, mean duration of
treatment was shortest in the UK (eight
days) and longest in France (12 days)
[59]. For some infections, studies have
addressed the question whether it is safe
to stop treatment after specific infection
parameters are returned to normal val-
ues. For example, in spontaneous bacte-
rial peritonitis antimicrobials can safely
be terminated once ascitic fluid PMN
counts are less than or equal to 250 cells/
mm3 [63].
140
There are some studies and Cochrane
reviews on the duration of treatment of
acute pyelonephritis, lower UTI in chil-
dren, uncomplicated UTIs in elderly
women, cystitis and bacteriuria in preg-
nant women. A retrospective study of the
duration of treatment of pyelonephritis
showed that, independently of the drug
administered, there is a strong risk of
treatment failure whenever the treat-
ment lasts less than 10 days [64] (LoE
3). According to the guidelines of the
Infectious Diseases Society of America
(IDSA) a total duration of treatment for
an acute pyelonephritis of 10–14 days
should be adequate. For women with this
disease seven to 14 days should be suf-
ficient [65]. When ciprofloxacin is pre-
scribed, a course of seven days for women
with pyelonephritis was sufficient [66]
(LoE 1), but when β-lactam antibiot-
ics are prescribed treatment for seven
days would be too short [65]. Antibiotic
therapy for three days is similar to pro-
longed therapy in achieving symptomatic
cure for cystitis, while the prolonged
treatment is more effective in obtaining
bacteriological cure [67] (LoE 1). Short-
course treatment (three to six days) could
be sufficient for treating uncomplicated
UTIs in elderly women, although more
studies on specific commonly prescribed
antibiotics are needed according to a
recent Cochrane review. Conclusions are
hampered by inconsistent study design
[68] (LoE 1). Another meta-analysis of 10
randomized controlled trials showed that
a two to four day course of oral antibiot-
ics is as effective as seven to 14 days in
eradicating lower tract UTI in children
[69] (LoE 1). In pregnant women, a dou-
ble-blind, randomized, placebo controlled
non-inferiority trial on duration treat-
ment of bacteriuria showed that a one
day regimen of nitrofurantoin is signifi-
cantly less effective than a seven day reg-
imen [70] (LoE 1).
It is clear from these studies that, as
for many other types of infections, the
optimal duration for UTIs is defined by

the absence of relapse after an arbitrar-
ily chosen number of days e.g. seven, 10,
14, of treatment. Often, the minimum
duration required is not known. To fur-
ther reduce volume of consumption, and
therefore selection pressure, more studies
on shorter treatments are needed.
3.7.2 Prophylaxis and duration
In surgical prophylaxis, many stud-
ies have shown that a single dose of an
antimicrobial drug is sufficient for most
surgical procedures. Inappropriate use
of prophylaxis is often due to prolonged
administration [71] (LoE 2b), and many
interventions have been successful in
reducing postoperative prophylaxis [72]
[13] (LoE 2b).
4. ANTIBIOTIC STEWARDSHIP
PROGRAMS
Antibiotic stewardship programs include
antibiotic policy structures, tools, and
dedicated personnel.
4.1 Antibiotic committees
Antibiotic committees should be multi-
disciplinary and include at least an infec-
tious diseases physician, a (medical)
microbiologist, a hospital pharmacist
and clinicians from the major disciplines.
The major tasks of an antibiotic commit-
tee are development of evidence-based
practice guidelines that incorporate local
microbiology and resistance patterns,
regular monitoring of the local surveil-
lance of resistance and use, identifying
potential problem areas for audit and
feedback or other interventions including
restriction.
4.2 Antibiotic guidelines
Antibiotic guidelines are intended to
improve the quality of care, to sup-
port public health decisions, to dimin-
ish unwanted diversity of practice and
Antibiotic policy | 2.7 |
to increase transparency (for the health
care worker and the public). As urology
services generally have higher levels of
antimicrobial resistance against Gram-
negative bacteria (E. coli, K. pneumo-
niae, P. aeruginosa) compared to general
wards, urology ward-specific surveillance
data and inpatient versus outpatient data
should be available to the antibiotic com-
mittee to select appropriate antibiotics
for UTI treatment guidelines in urologi-
cal patients.
4.3 Guideline implementation
Guideline implementation can be facili-
tated through provider education and
feedback on antimicrobial use and patient
outcomes [7]. Specific antimicrobial
stewardship teams, mostly consisting
of an ID physician and a hospital phar-
macists have been established in many
countries to fight high resistance levels
by mounting programs adopting similar
techniques as the committees [7, 11, 73].
A Cochrane review on interventions to
improve antibiotic prescribing practices
for hospital inpatients is available [74].
Printed educational materials and edu-
cational conferences alone have had
little effect on changing prescribing prac-
tices for antibiotics or other medications
in the outpatient setting. More inten-
sive and multifaceted interventions are
generally required. Face-to-face educa-
tional sessions provided by physicians
or pharmacists, sometimes known as
academic detailing, have been successful
in improving antibiotic-prescribing prac-
tices. Participative physician feedback
and multidisciplinary interventions have
also been found to be effective methods to
increase the judicious use of antibiotics
and reduce costs [74].
4.4 Quality indicators
In a Dutch study, a systemic evidence-
and consensus-based approach was
used to develop a set of valid quality
141
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
indicators to evaluate antibiotic use for
complicated UTIs. A multidisciplinary
panel reviewed and prioritized recom-
mendations extracted from a recently
developed evidence-based national guide-
line. The content validity, the feasibility,
interobserver reliability, opportunity for
improvement, and case-mix stability of
the potential indicators was assessed for
a data set of 341 inpatients and outpa-
tients with complicated UTIs. The panel
selected and prioritized performance of
urine culture, prescription of treatment
in accordance with guidelines, tailoring of
treatment on the basis of culture results,
and a switch to oral treatment when
possible, selective use of fluoroquinolo-
nes, administration of treatment for at
least 10 days, prescription of treatment
for men in accordance with guidelines,
replacement of catheters in patients with
UTI, and adaptation of the dosage on the
basis of renal function [75] (LoE 3). These
quality indicators can be used to moni-
tor the quality of antibiotic prescribing in
similar settings.
5. FURTHER RESEARCH
More research is needed to optimize the
policies for the diagnosis, therapy and
prevention of urinary tract infections.
For a more specific and faster diagno-
sis, rapid tests that distinguish between
inflammation and infection, identify
the pathogen and its susceptibility (e.g.
resistance genes) are very much awaited.
There is a particular need for new antibi-
otics with a target or a new mechanism
of action against Gram-negative bacteria
to circumvent the problem of resistance
of uropathogens. Other approaches to
combat the infection, such as drugs that
donít kill microorganisms but neutral-
ize their virulence mechanisms or drugs
that stimulate host defences would be
solutions that are less prone to selection
of resistance. Potentiators of available
antibiotics (e.g. efflux pump inhibitors)
142
or novel combinations would be a very
useful alternative while awaiting novel
drugs. PK/PD research should provide the
knowledge for selecting better regimens
of older and new antibiotics. Finally,
more well-conducted clinical studies are
needed on the optimal duration of antibi-
otic therapy.
6. CONCLUSIONS
By applying the strategies for appropri-
ate prescribing described in this chapter,
i.e. optimizing the indication, selection,
dosing, route of administration, duration,
and timing of antibiotic therapy, selec-
tion of resistant microorganisms should
be reduced to the minimum. This goal
should be reached in parallel with maxi-
mizing clinical cure or prevention of infec-
tion and minimal toxicity and costs.
REFERENCES
1. Unal S and Garcia-Rodriguez JA,
Activity of meropenem and compara-
tors against Pseudomonas aeruginosa
and Acinetobacter spp. isolated in the
MYSTIC Program, 2002–2004. Diagn
Microbiol Infect Dis, 2005. 53(4): 265–71.
2. Vatopoulos A, High rates of metallo-beta-
lactamase-producing Klebsiella pneumo-
niae in Greece—a review of the current
evidence. Euro Surveill, 2008. 13(4).
3. Coque TM, Baquero F, and Canton R,
Increasing prevalence of ESBL-producing
Enterobacteriaceae in Europe. Euro
Surveill, 2008. 13(47).
4. Souli M, Galani I, and Giamarellou H,
Emergence of extensively drug-resistant
and pandrug-resistant Gram-negative
bacilli in Europe. Euro Surveill, 2008.
13(47).
5. Schwaber MJ, Navon-Venezia S, Kaye
KS, Ben-Ami R, Schwartz D, and Carmeli
Y, Clinical and economic impact of bac-
teremia with extended- spectrum-beta-
lactamase-producing Enterobacteriaceae.
Antimicrob Agents Chemother, 2006.
50(4): 1257–62.

6. Kaplan W and Laing R, Priority
Medicines for Europe and the World “A
Public Health Approach to Innovation.”
2004, World Health Organisation:
Geneva.
7. Dellit TH, Owens RC, McGowan JE, Jr.,
Gerding DN, Weinstein RA, Burke JP,
Huskins WC, Paterson DL, Fishman
NO, Carpenter CF, Brennan PJ, Billeter
M, and Hooton TM, Infectious Diseases
Society of America and the Society for
Healthcare Epidemiology of America
guidelines for developing an institutional
program to enhance antimicrobial stew-
ardship. Clin Infect Dis, 2007. 44(2):
159–77.
8. Recent trends in antimicrobial resist-
ance among Streptococcus pneumoniae
and Staphylococcus aureus isolates: the
French experience. Euro Surveill, 2008.
13(46).
9. Muto CA, Blank MK, Marsh JW, Vergis
EN, O’Leary MM, Shutt KA, Pasculle
AW, Pokrywka M, Garcia JG, Posey
K, Roberts TL, Potoski BA, Blank GE,
Simmons RL, Veldkamp P, Harrison
LH, and Paterson DL, Control of an out-
break of infection with the hypervirulent
Clostridium difficile BI strain in a uni-
versity hospital using a comprehensive
“bundle” approach. Clin Infect Dis, 2007.
45(10): 1266–73.
10. Gyssens IC, All EU hands to the EU
pumps: the Science Academies of Europe
(EASAC) recommend strong support of
research to tackle antibacterial resistance.
Clin Microbiol Infect, 2008. 14(10): 889–91.
11. MacDougall C and Polk RE,
Antimicrobial stewardship programs in
healthcare systems. Clin Microbiol Rev,
2005. 18: 638–656.
12. Gyssens IC and Kullberg BJ, Improving
the quality of antimicrobial drug use can
result in cost containment. Pharm World
Sci, 1995. 17(5): 163–7.
13. van Kasteren ME, Mannien J, Kullberg
BJ, de Boer AS, Nagelkerke NJ,
Ridderhof M, Wille JC, and Gyssens IC,
Quality improvement of surgical prophy-
laxis in Dutch hospitals: evaluation of
a multi-site intervention by time series
analysis. J Antimicrob Chemother, 2005.
56(6): 1094–102.
Antibiotic policy | 2.7 |
14. Burke JP, Infection control - a problem
for patient safety. N Engl J Med, 2003.
348(7): 651–6.
15. Abrams P, Khoury S, and Grant A,
Evidence-based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17: 681–4.
16. US Department of Health and Human
Services, Public Health Service Agency for
Health Care Policy and Research. 1992.
17. Yang WJ, Cho IR, Seong do H, Song YS,
Lee DH, Song KH, Cho KS, Sung Hong
W, and Kim HS, Clinical implication of
serum C-reactive protein in patients with
uncomplicated acute pyelonephritis as
marker of prolonged hospitalization and
recurrence. Urology, 2009. 73(1): 19–22.
18. Smaill F, Antibiotics for asymptomatic
bacteriuria in pregnancy. Cochrane
Database Syst Rev, 2001(2): CD000490.
19. Hooton TM, The current management
strategies for community-acquired urinary
tract infection. Infect Dis Clin North Am,
2003. 17(2): 303–32.
20. Abrutyn E, Mossey J, Berlin JA, Boscia J,
Levison M, Pitsakis P, and Kaye D, Does
asymptomatic bacteriuria predict mor-
tality and does antimicrobial treatment
reduce mortality in elderly ambulatory
women? Ann Intern Med, 1994. 120(10):
827–33.
21. Ouslander JG, Schapira M, Schnelle JF,
Uman G, Fingold S, Tuico E, and Nigam
JG, Does eradicating bacteriuria affect the
severity of chronic urinary incontinence in
nursing home residents? Ann Intern Med,
1995. 122(10): 749–54.
22. Nicolle LE, Mayhew WJ, and Bryan L,
Prospective randomized comparison of
therapy and no therapy for asymptomatic
bacteriuria in institutionalized elderly
women. Am J Med, 1987. 83(1): 27–33.
23. Nicolle LE, Bjornson J, Harding GK, and
MacDonell JA, Bacteriuria in elderly
institutionalized men. N Engl J Med,
1983. 309(23): 1420–5.
24. Raz R, Schiller D, and Nicolle LE,
Chronic indwelling catheter replacement
before antimicrobial therapy for symp-
tomatic urinary tract infection. J Urol,
2000. 164(4): 1254–8.
143
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
25. Cook RJ and Sackett DL, The number
needed to treat: a clinically useful meas-
ure of treatment effect. BMJ, 1995.
310(6977): 452–4.
26. Scottish Intercollegiate Guidelines
Network S, Antibiotic prophylaxis in
surgery. A national clinical guideline,
Scotland NQI, Editor. 2008: Edinburgh.
27. Berry A and Barratt A, Prophylactic anti-
biotic use in transurethral prostatic resec-
tion: a meta-analysis. J Urol, 2002. 167(2
Pt 1): 571–7.
28. Albert X, Huertas I, Pereiro, II, Sanfelix
J, Gosalbes V, and Perrota C, Antibiotics
for preventing recurrent urinary tract
infection in non-pregnant women.
Cochrane Database Syst Rev, 2004(3):
CD001209.
29. Jepson RG and Craig JC, Cranberries
for preventing urinary tract infections.
Cochrane Database Syst Rev, 2008(1):
CD001321.
30. Perrotta C, Aznar M, Mejia R, Albert X,
and Ng CW, Oestrogens for preventing
recurrent urinary tract infection in post-
menopausal women. Cochrane Database
Syst Rev, 2008(2): CD005131.
31. Hood HM, Allman RM, Burgess PA,
Farmer R, and Xu W, Effects of timely
antibiotic administration and culture
acquisition on the treatment of urinary
tract infection. Am J Med Qual, 1998.
13(4): 195–202.
32. Classen DC, Evans RS, Pestotnik SL,
Horn SD, Menlove RL, and Burke JP, The
timing of prophylactic administration of
antibiotics and the risk of surgical-wound
infection. N Engl J Med, 1992. 326:
281–286.
33. van Kasteren ME, Mannien J, Ott A,
Kullberg BJ, de Boer AS, and Gyssens
IC, Antibiotic prophylaxis and the risk
of surgical site infections following total
hip arthroplasty: timely administration is
the most important factor. Clin Infect Dis,
2007. 44(7): 921–7.
34. Bratzler DW, Houck PM, Richards C,
Steele L, Dellinger EP, Fry DE, Wright
C, Ma A, Carr K, and Red L, Use of
antimicrobial prophylaxis for major sur-
gery: baseline results from the National
Surgical Infection Prevention Project.
Arch Surg, 2005. 140(2): 174–82.
144
35. Steinberg JP, Braun BI, Hellinger
WC, Kusek L, Bozikis MR, Bush AJ,
Dellinger EP, Burke JP, Simmons B, and
Kritchevsky SB, Timing of antimicrobial
prophylaxis and the risk of surgical site
infections: results from the Trial to Reduce
Antimicrobial Prophylaxis Errors. Ann
Surg, 2009. 250(1): 10–6.
36. Gyssens IC, Smits-Caris C, Stolk-
Engelaar MV, Slooff TJ, and Hoogkamp-
Korstanje JA, An audit of microbiology
laboratory utilization: the diagnosis
of infection in orthopedic surgery. Clin
Microbiol Infect, 1997. 3(5): 518–522.
37. Rubenstein JN and Schaeffer AJ,
Managing complicated urinary tract
infections: the urologic view. Infect Dis
Clin North Am, 2003. 17(2): 333–51.
38. Tapsall JW, Neisseria gonorrhoeae and
emerging resistance to extended spectrum
cephalosporins. Curr Opin Infect Dis,
2009. 22(1): 87–91.
39. NethMap, Consumption of antimicro-
bial agents and antimicrobial resistance
among medically important bacteria in
the Netherlands, SWAB Dutch Working
Party on Antibiotic Policy, Editor. 2009:
The Netherlands.
40. EARSS. 2007.
41. Wagenlehner FM, Niemetz AH, Weidner
W, and Naber KG, Spectrum and anti-
biotic resistance of uropathogens from
hospitalised patients with urinary tract
infections: 1994–2005. Int J Antimicrob
Agents, 2008. 31 Suppl 1: S25–34.
42. Gyssens IC, International guidelines for
infectious diseases: a practical guide.
Neth J Med, 2005. 63(8): 291–9.
43. Lautenbach E, Weiner MG, Nachamkin I,
Bilker WB, Sheridan A, and Fishman NO,
Imipenem resistance among pseudomonas
aeruginosa isolates: risk factors for infec-
tion and impact of resistance on clinical
and economic outcomes. Infect Control
Hosp Epidemiol, 2006. 27(9): 893–900.
44. Donnan PT, Wei L, Steinke DT, Phillips
G, Clarke R, Noone A, Sullivan FM,
MacDonald TM, and Davey PG, Presence
of bacteriuria caused by trimethoprim
resistant bacteria in patients prescribed
antibiotics: multilevel model with practice
and individual patient data. BMJ, 2004.
328(7451): 1297.

45. van der Meer JW and Gyssens IC,
Quality of antimicrobial drug prescription
in hospital. Clin Microbiol Infect, 2001. 7
Suppl 6: 12–5.
46. Frimodt-Moller N, Espersen F, Jacobsen
B, Schlundt J, Meyling A, and Wegener
H, Problems with antibiotic resistance
in Spain and their relation to antibiotic
use in humans elsewhere. Clin Infect Dis,
1997. 25: 939–941.
47. Craig WA, Basic pharmacodynamics of
antibacterials with clinical applications to
the use of beta-lactams, glycopeptides, and
linezolid. Infect Dis Clin North Am, 2003.
17(3): 479–501.
48. Mouton JW, Dudley MN, Cars O,
Derendorf H, and Drusano GL,
Standardization of pharmacokinetic/
pharmacodynamic (PK/PD) terminol-
ogy for anti-infective drugs: an update.
J Antimicrob Chemother, 2005. 55(5):
601–7.
49. Kashuba AD, Nafziger AN, Drusano GL,
and Bertino JSJ, Optimizing aminogly-
coside therapy for nosocomial pneumo-
nia caused by gram-negative bacteria.
Antimicrob Agents Chemother, 1999. 43:
623–629.
50. Buijk SE, Mouton JW, Gyssens IC,
Verbrugh HA, and Bruining HA,
Experience with a once-daily dosing pro-
gram of aminoglycosides in critically ill
patients. Intensive Care Med, 2002. 28(7):
936–42.
51. Scaglione F and Paraboni L, Influence of
pharmacokinetics/pharmacodynamics
of antibacterials in their dosing regimen
selection. Expert Rev Anti Infect Ther,
2006. 4(3): 479–90.
52. Mouton JW and Vinks AA, Continuous
infusion of beta-lactams. Curr Opin Crit
Care, 2007. 13(5): 598–606.
53. Kasiakou SK, Lawrence KR, Choulis
N, and Falagas ME, Continuous versus
intermittent intravenous administration
of antibacterials with time-dependent
action: a systematic review of pharmacoki-
netic and pharmacodynamic parameters.
Drugs, 2005. 65(17): 2499–511.
54. Rybak MJ, The pharmacokinetic and
pharmacodynamic properties of vanco-
mycin. Clin Infect Dis, 2006. 42 Suppl 1:
S35–9.
Antibiotic policy | 2.7 |
55. Drusano GL, Johnson DE, Rosen M, and
Standiford HC, Pharmacodynamics of a
fluoroquinolone antimicrobial agent in a
neutropenic rat model of Pseudomonas
sepsis. Antimicrob Agents Chemother,
1993. 37(3): 483–90.
56. Blaser J, Stone BB, Groner MC, and
Zinner SH, Comparative study with
enoxacin and netilmicin in a pharmaco-
dynamic model to determine importance
of ratio of antibiotic peak concentration
to MIC for bactericidal activity and
emergence of resistance. Antimicrob
Agents Chemother, 1987. 31(7):
1054–60.
57. Ambrose PG, Bhavnani SM, and Owens
RC, Jr., Clinical pharmacodynamics of
quinolones. Infect Dis Clin North Am,
2003. 17(3): 529–43.
58. Zelenitsky S, Ariano R, Harding G, and
Forrest A, Evaluating ciprofloxacin dos-
ing for Pseudomonas aeruginosa infection
by using clinical outcome-based Monte
Carlo simulations. Antimicrob Agents
Chemother, 2005. 49(10): 4009–14.
59. Halls GA, The management of infections
and antibiotic therapy: a European sur-
vey. J Antimicrob Chemother, 1993. 31:
985–1000.
60. Bennett WM, Plamp CE, Gilbert DN,
Parker RA, and Porter GA, The influ-
ence of dosage regimen on experimental
gentamicin nephrotoxicity: dissociation
of peak serum levels from renal failure. J
Infect Dis, 1979. 140(4): 576–80.
61. Rybak MJ, Abate BJ, Kang SL, Ruffing
M, J., Lerner SA, and Drusano GL,
Prospective evaluation of the effect of an
aminoglycoside dosing regimen on rates
of observed nephrotoxicity and ototoxicity.
Antimicrob Agents Chemother, 1999. 43:
1549–1555.
62. Gyssens IC, Blok WL, van den Broek
PJ, Hekster YA, and van der Meer JW,
Implementation of an educational pro-
gram and an antibiotic order form to
optimize quality of antimicrobial drug use
in a department of internal medicine. Eur
J Clin Microbiol Infect Dis, 1997. 16(12):
904–12.
63. Fong T, Akriviadis EA, Runyon BA, and
Reynolds TB, Polymorphonuclear cell
count response and duration of antibiotic
145
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
therapy in spontaneous bacterial peritoni-
tis. Hepatology, 1989. 9: 423–426.
64. Carrie AG, Metge CJ, Collins DM,
Harding GK, and Zhanel GG, Use of
administrative healthcare claims to
examine the effectiveness of trimethoprim-
sulfamethoxazole versus fluoroquinolones
in the treatment of community-acquired
acute pyelonephritis in women. J
Antimicrob Chemother, 2004. 53(3):
512–7.
65. Warren JW, Abrutyn E, Hebel JR,
Johnson JR, Schaeffer AJ, and Stamm
WE, Guidelines for antimicrobial treat-
ment of uncomplicated acute bacterial cys-
titis and acute pyelonephritis in women.
Infectious Diseases Society of America
(IDSA). Clin Infect Dis, 1999. 29(4):
745–58.
66. Talan DA, Stamm WE, Hooton TM,
Moran GJ, Burke T, Iravani A, Reuning-
Scherer J, and Church DA, Comparison of
ciprofloxacin (7 days) and trimethoprim-
sulfamethoxazole (14 days) for acute
uncomplicated pyelonephritis pyelonephri-
tis in women: a randomized trial. JAMA,
2000. 283(12): 1583–90.
67. Katchman EA, Milo G, Paul M,
Christiaens T, Baerheim A, and Leibovici
L, Three-day vs longer duration of anti-
biotic treatment for cystitis in women:
systematic review and meta-analysis. Am
J Med, 2005. 118(11): 1196–207.
68. Lutters M and Vogt-Ferrier NB,
Antibiotic duration for treating uncom-
plicated, symptomatic lower urinary tract
infections in elderly women. Cochrane
Database Syst Rev, 2008(3): CD001535.
69. Michael M, Hodson EM, Craig JC, Martin
S, and Moyer VA, Short compared with
standard duration of antibiotic treatment
for urinary tract infection: a systematic
review of randomised controlled trials.
Arch Dis Child, 2002. 87(2): 118–23.
146
70. Lumbiganon P, Villar J, Laopaiboon
M, Widmer M, Thinkhamrop J, Carroli
G, Duc Vy N, Mignini L, Festin M,
Prasertcharoensuk W, Limpongsanurak
S, Liabsuetrakul T, and Sirivatanapa
P, One-day compared with 7-day nitro-
furantoin for asymptomatic bacteriuria
in pregnancy: a randomized controlled
trial. Obstet Gynecol, 2009. 113(2 Pt 1):
339–45.
71. Gyssens IC, Geerligs IE, Dony JM, van
der Vliet JA, van Kampen A, van den
Broek PJ, Hekster YA, and van der
Meer JW, Optimising antimicrobial
drug use in surgery: an intervention
study in a Dutch university hospital.
J Antimicrob Chemother, 1996. 38(6):
1001–12.
72. Evans RS, Pestotnik SL, Classen DC,
Clemmer TP, Weaver LK, Orme JF, Lloyd
JF, and Burke JP, A computer-assisted
management program for antibiotics and
other anti-infective agents. N Engl J Med,
1998. 338: 232–238.
73. Goossens H, Coenen S, Costers M, De
Corte S, De Sutter A, Gordts B, Laurier
L, and Struelens M, Achievements of the
Belgian Antibiotic Policy Coordination
Committee (BAPCOC). Euro Surveill,
2008. 13(46).
74. Davey P, Brown E, Fenelon L, Finch R,
Gould I, Hartman G, Holmes A, Ramsay
C, Taylor E, Wilcox M, and Wiffen P,
Interventions to improve antibiotic pre-
scribing practices for hospital inpatients.
Cochrane Database Syst Rev, 2005(4):
CD003543.
75. Hermanides HS, Hulscher ME, Schouten
JA, Prins JM, and Geerlings SE,
Development of quality indicators for the
antibiotic treatment of complicated uri-
nary tract infections: a first step to meas-
ure and improve care. Clin Infect Dis,
2008. 46(5): 703–11.
 Chapter |3|

Urinary tract infections

in special groups of
adult patients
Chair: Kurt G. Naber

CHAPTER OUTLINE
3.1 Introduction 148
3.2 Diagnosis of uncomplicated urinary tract infections 151
3.3 The quantitative urine culture for the diagnosis of
urinary tract infection 160
3.4 Antibiotic treatment of uncomplicated urinary tract
infection in premenopausal women 170
3.5 Urinary tract infections in pregnancy 200
3.6 Urinary tract infections in patients with diabetes mellitus 216
3.7 Urinary tract infections in postmenopausal women 225
|3.1|
Introduction
Kurt G. Naber
Technical University of Munich, Munich, Germany
Address of corresponding author: Prof. Kurt G. Naber, MD, PhD, Karl-Bickleder-Str. 44c, D-94315 Straubing, Germany
Tel +49-9421-33369, kurt@nabers.de
Uncomplicated urinary tract infections
(UTIs) are extremely common infec-
tions in the community. About 50% of
adult women report a UTI some point
during their lifetime [1]. Approximately
2,500,000 women in the United Kingdom
experience an attack of dysuria and
frequency each year and 100,000 suf-
fer recurrent infections [2]. In the USA
5,740,000 office visits to physicians were
reported in 1990 for one of the follow-
ing primary complaints: painful urina-
tion, frequency and urgency, or UTI [3].
Most of the visits (75.8%) were made by
females to general physicians.
In this section the diagnostic and ther-
apeutic considerations of UTI are pre-
sented in special groups of adult patients,
such as premenopausal, pregnant and
postmenopausal women, and diabetic
patients. Each group has some peculiar
problems to be considered, but they also
have much in common.
Richard Colgan, Samantha Hyner from
Baltimore, MD, and Stephanie Chu from
Boston, MA, USA, discuss the evidence for
specific diagnostic steps, because experts
agree in general that the full diagnostic
program including urine culture is not
always necessary in otherwise healthy
women with uncomplicated cystitis and
typical symptoms. On the other hand the
final diagnosis of UTI requires microbio-
logical confirmation according to Lindsay
Nicolle from Winnipeg, MB, Canada.
However, urine specimens should be col-
lected minimizing contamination and also
considering quantitative criteria. A group
comprising of Kurt G. Naber (Straubing,
Germany), Björn Wullt (Malmö, Sweden),
and Florian ME Wagenlehner (Giessen,
Germany) discuss the antibiotic treatment
of uncomplicated cystitis and pyelonephri-
tis in otherwise healthy premenopausal
women. Most studies have been performed
in this group of patients in whom short
term therapy of uncomplicated cystitis can
be considered today as standard. However,
the choice of antimicrobials depends very
much on the susceptibility pattern of E.
coli, the most frequent uropathogen, which
may differ considerably between countries.

UTIs in pregnant women play an impor-
tant role. Even asymptomatic bacteriuria
(ASB) may have a negative impact on the
pregnancy. Therefore careful screening
and management of any UTI including
ASB – and other urogenital infections as
presented in chapter 4.6 – is necessary
as outlined by Alexander D. Griffin and
Thomas Hooton from Miami, FL, and
Richard Grady from Seattle, WA, USA.
Because of the physical changes during
pregnancy especially any obstruction of
the upper urinary tract has to be looked
for by ultrasonography and in case of
pyelonephritis early hospitalisation may
be considered.
Patients with diabetes mellitus
(Suzanne Geerlings, Amsterdam, The
Netherlands) and postmenopausal women
(Raul Raz, Afula, Israel) have in common
an increased rate of UTI episodes. The
bacterial spectrum of these two groups
of patients is usually similar to that of
premenopausal women; if no additional
risk factors are present [4]. However,
short term therapy of cystitis is not so
well established and is probably less
effective than in premenopausal women.
More studies are needed to establish the
best management in these two groups of
patients.
If no additional risk factors are present,
treatment of cystitis and pyelonephri-
tis usually results in high cure rates.
There is, however, no agreement between
experts, whether a UTI without any addi-
tional risk factors in all these groups of
patients can uniformly be considered as
“uncomplicated”.
The usual definition of uncomplicated
UTI comprises UTI in a patient without
abnormalities in the urinary tract (uropa-
thies); without kidney diseases (neph-
ropathies), and without comorbidities
favouring UTI and leading to a more seri-
ous outcome requiring additional diagnos-
tic and therapeutic care. Uncomplicated
UTI (cystitis and pyelonephritis) are
mostly seen in premenopausal women
without any risk factor known to increase
Introduction | 3.1 |
the risk of complications or treatment
failure. This classification can also be
applied to women with recurrent UTI if
such risk factors can be excluded. Each
acute infection episode can be handled
similarly, but additional care is necessary
to prevent recurrences (see chapter 4).
Most researchers would also agree that
UTI in otherwise healthy postmenopau-
sal and diabetic women with stable met-
abolic conditions still can be considered
as “uncomplicated”, although UTI may
occur more frequently in these groups of
patients and standard short term ther-
apy is not as well established or even
not so effective as in otherwise premeno-
pausal women. In contrast, UTI in preg-
nant women and in otherwise healthy
young men (discussed elsewhere [5–6])
are often classified as “complicated” per
se, even if no additional risk factors can
be recognized. This classification is usu-
ally argued for in terms of the normal
physical changes in pregnancy and the
frequent involvement of the prostate in
men as documented by a transient rise of
serum PSA. If this is generally accepted,
then how should we classify a UTI in
these groups of patients if additional
risk factors are present? “More compli-
cated”? Other differences have also to
be considered, for example in pregnant
women asymptomatic bacteriuria must
be treated, but this is not indicated in the
other groups of patients.
In each group of patients it is very
important to differentiate whether a UTI
occurs in a patient without (otherwise
healthy) or with additional risk factors,
such as renal insufficiency, obstruction
of the urinary tract, neurogenic bladder
disturbances or indwelling urinary cath-
eter. These considerations already dem-
onstrate that a classification with only
two categories, complicated and uncom-
plicated, is difficult to use, because every
time one category is defined very strictly
the other category becomes more heterog-
enous. This inherent problem can only be
solved by better differentiation of patients’
149
Chapter |3| Urinary tract infections in special groups of adult patients
characteristics (groups of patients) and
the additional risk factors, e.g. urological/
nephrological pathologies, and/or relevant
comorbidities, e.g. immunosuppressive
therapy in transplant patients.
In the last section of the textbook a
group of experts has made an attempt
to introduce a more differentiated clas-
sification system. Whether it can replace
the traditional classification system [7–8]
remains to be seen.
REFERENCES
1. Kunin CM, Detection, prevention and
management of UTIs. 5th ed. 1997,
Philadephia, PA, USA: Lea & Febiger.
2. Brumfitt W and Hamilton-Miller JM,
Prophylactic antibiotics for recurrent
urinary tract infections. J Antimicrob
Chemother, 1990. 25(4): 505–12.
3. Schappert SM, National ambulatory
medical survey: 1990 summary. Advance
data from vital and health statistics: no.
213. 1992, Hyattsville, Maryland, USA:
National Center for Health Statistics.
150
4. Naber KG, Schito G, Botto H, Palou J,
and Mazzei T, Surveillance study in
Europe and Brazil on clinical aspects and
Antimicrobial Resistance Epidemiology in
Females with Cystitis (ARESC): implica-
tions for empiric therapy. Eur Urol, 2008.
54(5): 1164–75.
5. Stamm WE, Urinary tract infections in
young men, in Urinary tract infections,
Bergan T, Editor. 1997, Karger: Basel;
London. p. vii, 142 p.
6. Krieger JN, Ross SO, and Simonsen JM,
Urinary tract infections in healthy
university men. J Urol, 1993. 149(5):
1046–8.
7. Rubin RH, Beam TR, Jr., and Stamm
WE, An approach to evaluating antibac-
terial agents in the treatment of urinary
tract infection. Clin Infect Dis, 1992.
14 Suppl 2: S246–51; discussion S253–4.
8. Rubin RH, Shapiro ED, Andriole VT,
Davies RJ, Stamm WE, and with modi-
fications by a European Working Party
(Norrby SR), General guidelines for the
evaluation of new anti-infective drugs for
the treatment of UTI. 1993, Taufkirchen,
Germany: The European Society of Clinical
Microbiology and Infectious Diseases.
|3.2|

Diagnosis of uncomplicated
urinary tract infections
Richard Colgan1*, Samantha Hyner1, Stephanie Chu2
1
University of Maryland School of Medicine, Baltimore, Maryland, USA
2
Boston University School of Medicine, Boston, Massachutes
Corresponding author: Richard Colgan, M.D., Associate Professor, Director Undergraduate Education,
Department of Family and Community Medicine, University of Maryland School of Medicine,
29 S. Paca Street, Lower Level, Baltimore, Maryland 21201, USA
Phone: +1 (410) 328-3525, Fax: +1 (410) 328-8726, rcolgan@som.umaryland.edu

ABSTRACT and acute uncomplicated pyelonephri-

The most common bacterial infections in
women are urinary tract infections, the
majority of which are uncomplicated,
yet there have been few recent studies
investigating the diagnosis of uncompli-
cated urinary tract infection (uUTI). This
chapter uses information from the most
recent studies, reviews, and guidelines
found by searching Medline, Pubmed,
and the Cochrane database to give an
overview on the diagnosis of uUTIs. An
important step in diagnosing an uUTI is
ruling out the presence of a more seri-
ous complicated urinary tract infection
(cUTI), thus we first discuss some of
the most agreed upon criteria and risk
factors for cUTI. The remainder of the
chapter focuses on the history, physical
exam, and laboratory findings of patients
with acute uncomplicated cystitis (AUC)
tis (AUP), which involve infection of the
lower and upper urinary tracts, respec-
tively. Throughout the chapter we high-
light differences upon evaluation that,
if present, can be helpful in differentiat-
ing between AUC and AUP. The history
is the most important tool for diagno-
sis. The presence and absence of certain
symptoms and risk factors can have a
positive predictive value of infection as
high as 90%. The physical exam is often
normal in patients with AUC, but can be
particularly important for distinguishing
patients with AUP. Urine dipstick test-
ing, which interestingly does not appear
to depend on preparatory cleansing for
accuracy, is also an important tool for
diagnosis. Authors vary in opinion as to
the necessity of urine culture in AUC,
but it is indicated when AUP or a resist-
ant uropathogen is suspected. Further
Chapter |3| Urinary tract infections in special groups of adult patients
studies beyond urinalysis and urine cul-
tures are rarely indicated for uUTIs.
Finally, we discuss how women who have
had recurrent uUTIs are usually accu-
rate in self-diagnosing when they have
an infection, and present evidence that
cases diagnosed by phone have similar
outcomes as compared to cases diagnosed
by the clinician in his/her office.
Key words: Diagnosis, Uncomplicated
Urinary Tract Infections, Acute Uncom-
plicated Cystitis
SUMMARY OF RECOMMENDATIONS
1. Clinical Diagnosis: The diagnosis of
acute uncomplicated cystitis can be
made with a high probability based on
a focused history of urinary irritative
symptomatology (dysuria, frequency
and urgency) and the absence of vagi-
nal discharge or irritation, in those
women who have no other risk factors
for complicated urinary tract infec-
tions [1] (LoE 2, GoR B)
2. Laboratory Diagnosis:
2.1 Urine dipstick testing, as
opposed to urinary microscopy,
is a reasonable alternative to
urinalysis in diagnosing acute
uncomplicated cystitis [2–3]
(LoE 3, GoR B)
2.2 Urine cultures are recommended
for those with: i) suspected acute
pyelonephritis; ii) symptoms that
do not resolve or recur within
2–4 weeks after the completion of
treatment and iii) those women
who present with atypical symp-
toms at presentation [4–5] (LoE 4,
GoR B)
2.3 A colony count of greater than > or
equal to 103 CFU/ml of a uropatho-
gen is microbiologically diagnostic
in women presenting with symp-
toms of acute uncomplicated cysti-
tis [6] (LoE 3, GoR B)
152
3. Additional diagnostic studies: Women
who present with atypical symptoms
of either acute uncomplicated cystitis
or acute uncomplicated pyelonephritis,
as well as those who fail to respond
to appropriate antimicrobial therapy
should be considered for additional
diagnostic studies (LoE 4, GoR B)
1. INTRODUCTION
Infections of the urinary tract are the
most common bacterial infections in
women. The term urinary tract infec-
tion (UTI) encompasses several differ-
ent manifestations of bacterial infections
of one or more structures in the urinary
tract. UTIs can be classified using vari-
ous different criteria, such as community
acquired versus nosocomial, acute versus
recurrent, or asymptomatic versus symp-
tomatic, for examples. In this chapter we
discuss the division of UTIs according to
whether they are uncomplicated (uUTI)
or complicated (cUTI). It is important to
make this distinction when diagnosing a
UTI, because cUTIs are more often asso-
ciated with multiple pathogens, or mul-
tiple drug resistances, and thus carry a
higher risk for treatment failures than
uUTIs [7–8]. This chapter will focus on
the diagnosis of uUTIs, but given that a
main objective of diagnosing an uUTI is
ruling out a cUTI, complicated infections
will be discussed briefly.
2. METHODS
Here we provide information from a litera-
ture search done over the past three years,
including published studies, reviews, and
guidelines found by searching Medline,
PubMed, and the Cochrane database
using keywords urinary tract infection
and cystitis. Because of the sparse amount
of new research in this area important
older studies have been included as well
if new research in these areas is lacking.
 Diagnosis of uncomplicated urinary tract infections
In PubMed the MeSH term “urinary tract
infection” with the subheading of diagno-
sis was used. Only publications in English
addressing uUTIs in adult women were
ultimately included. We found over 100
publications in this search and included
38 in our analysis.
The studies were rated according to
the level of evidence (LoE) and the grade
of recommendation (GoR) using ICUD
standards (for details see Preface) [9–10].
3. DIAGNOSIS OF UNCOMPLICATED
URINARY TRACT INFECTIONS
The classification of UTI’s is based on fac-
tors in the history, physical exam, and lab-
oratory testing. We will be discussing two
types of uUTI, acute uncomplicated cystitis
(AUC) and acute uncomplicated pyelone-
phritis (AUP). AUC is the most common
type of UTI and involves sudden-onset
infection of the lower urinary tract (blad-
der, urethra), while AUP is a sudden-onset
infection that has spread to the upper uri-
nary tract (kidney involvement).
3.1 Historical diagnosis
3.1.1 Acute uncomplicated cystitis
The focus of this chapter is on the diag-
nosis of uncomplicated urinary tract
infections, and we begin with the single
greatest tool in diagnosing woman with
an uUTI : the history. Before diagnosing
a woman with an uUTI it important to
be sure that she does not have a compli-
cated UTI (cUTI) as the evaluation and
treatment may be different. Qualifiers
which denote a cUTI are male gender,
preadolescents, or pregnant women and
those with metabolic, functional, or ana-
tomic abnormalities of the genitourinary
tract [1, 11–12]. A UTI can also qualify as
complicated based on many items in the
past medical history, such as a history of
childhood UTIs, polycystic renal disease,
immunosupression, indwelling catheteri-
zation, or neurogenic bladder (as may
| 3.2 |
be seen following a stroke or spinal cord
injury). Additional qualifiers include labo-
ratory findings of a resistant pathogen in
the urine or recent antibiotic use [10–11].
The typical patient with AUC is a female
of reproductive age who notes urinary irri-
tative symptomatology. Postmenopausal
women and women with diabetes without
underlying functional or structural abnor-
malities of the urinary tract may also be
considered as included with the acute
uncomplicated UTIs, as the management
for these two groups does not differ. The
classic symptoms of AUC include dysu-
ria, frequent voiding of small volumes,
and urgency, though sometimes hematu-
ria and less often suprapubic discomfort
can also occur. According to Bent and col-
leagues, the pretest probability of UTI in
women is 5%, but when a woman presents
to her physician with the acute onset of
even just one of the classic symptoms of
AUC, the probability of infection rises
tenfold to 50% [13]. Thus presenting to a
clinician with one or more symptoms of
an AUC is cited in and of itself as a valu-
able “diagnostic test.” The probability of
infection further increases in the absence
of certain symptoms. Patients who also
report a vaginal discharge or irritation are
less likely to suffer from AUC and more
likely to have vaginitis or cervicitis. These
authors report that the new onset of fre-
quency and dysuria, together with the
absence of vaginal discharge or irritation,
has a positive predictive value of 90% for
UTI, effectively ruling in the diagnosis
based on history alone. Furthermore, the
authors note that while the pretest prob-
ability of UTI in the average patient who
presents with one or more symptoms is
approximately 50%, the actual probabil-
ity varies considerably depending on the
patient‘s risk profile. One cohort study of
796 sexually active young women found a
strong dose-response relationship between
risk of infection and both recent sexual
intercourse as well as use of diaphragms
with spermicide [14]. There was also an
association between the incidence of AUC
153
Chapter |3| Urinary tract infections in special groups of adult patients
and history of recurrent infection. In addi-
tion to these three well-established risk
factors, genetics have also been shown to
play a role in an individual’s susceptibility
to AUC [4].
3.1.2 Acute uncomplicated
pyelonephritis
Women with AUP often present with
the same symptoms discussed for AUC
(dysuria, frequency, urgency, haematu-
ria, suprapubic pain), and commonly also
present with flank or back pain, which are
classical symptoms of upper urinary tract
infection. Additionally, these women can
sometimes present with systemic symp-
toms, such as nausea, vomiting, fever,
chills, and abdominal pain. Risk fac-
tors for AUP include all those mentioned
for AUC; however diabetes and inconti-
nence have been shown to independently
increase the risk for pyelonephritis in
otherwise healthy women [15–16].
3.1.3 Using history to predict antibiotic
resistance
According to one study, the history can
also guide the choice of an antibiotic for
treatment. Several studies have attempted
to elucidate individual risks that predict
trimethoprim-sulfamethoxazole resist-
ance in those with uUTIs [17–22]. In a
retrospective study of women with acute
uncomplicated cystitis seen at a univer-
sity health center and at primary care
clinics in southeastern Michigan from
1992–1999 women who had recently
taken TMP-TMX were more than 16
times as likely as women who had not
taken antibiotics recently to be infected
with an isolate resistant to this agent.
Those who had taken any other antibi-
otic were more than twice as likely to
be infected with a resistant isolate [17].
In another study at an emergency depart-
ment in a tertiary care university hospital
enrolling 448 patients 14 years or older
with any urinary tract infection, not just
AUC, investigators found that TMP-SMX
154
resistance was common. Factors identified
as independent risk factors for TMP-SMX
resistance in this population were diabe-
tes, recent hospitalization, and the use of
antibiotics, particularly TMP-SMX [22].
A study of women with AUC done at
an urban primary care clinic was able
to show that Asian ethnicity and travel
outside the state or country were predic-
tive of resistance of E. coli to TMP-SMX.
It was demonstrated that if the clinician
asked the patient if she was of Asian eth-
nicity and if she had travelled outside the
state or country in the past three months,
the correct antibiotic could be chosen for
this group of patients more than 95% of
the time [23]. Further studies specifi-
cally enrolling women with AUC from a
broader demographic area are needed to
confirm these findings.
A recent study looking at risk factors
for E coli resistance by Trimethoprim-
Sulfamethoxazole among emergency
department patients with pyelonephri-
tis showed that only Trimethoprim-
Sulfamethoxazole exposure within two
days before presentation and Hispanic eth-
nicity were associated with E coli resist-
ance to Trimethoprim-sulfamethoxazole,
compared with resistance rates of approx-
imately 20% among women lacking these
risk factors [24].
3.1.4 Self-diagnosis and diagnosis
by phone
Given the increased difficulty that many
women face in gaining access to a clinician
when suffering from uUTI, researchers
have investigated the effectiveness of self-
diagnosis and self-treatment of these infec-
tions. Women who have had uUTIs before
are usually accurate in determining when
they are suffering from another uUTI. In
one study of 172 women with a history of
recurrent UTI, 88 women self-diagnosed
UTI on the basis of symptoms, and self-
treated with ofloxacin or levofloxacin [25].
According to laboratory evaluation, 84% of
cases showed a uropathogen, 11% showed
 Diagnosis of uncomplicated urinary tract infections
sterile pyuria, and only 5% of cases were
negative for pyuria and bacteriuria.
Laboratory-confirmed cases showed clini-
cal and microbiological cure rates of 92%
and 96%, respectively [25].
Again, because of increased difficulties
when suffering from uUTI, women often
seek help and obtain care by consult-
ing with their physician over the phone.
A small randomized controlled trial com-
pared the outcomes of uUTIs in healthy
women managed over the phone with
those managed in the office. No difference
in symptom scores or satisfaction was
noted. The authors conclude that short-
term outcomes of managing suspected
UTIs by telephone appear to be compara-
ble with usual office care [26].
3.2 Physical examination
3.2.1 Acute uncomplicated cystitis
The physical exam of those suffering from
AUC is usually normal, except in the
10–20% of women who have suprapubic
tenderness [26]. The presence of vaginal
discharge on exam decreases the like-
lihood of UTI, although this finding is
less powerful than when the symptom of
vaginal discharge reported by the patient
[13]. The authors further suggest that one
may consider not proceeding with a urine
dipstick test if the patient presents to the
clinician with frequency and dysuria and
without vaginal discharge, as the positive
predictive value of UTI is already 90%.
3.2.2 Acute uncomplicated
pyelonephritis
More often than women with AUC,
women with AUP will appear uncomfort-
able or ill. They may or may not have
objective findings of fever, tachycardia, or
costovertebral angle (CVA) tenderness. If
present, the tenderness is most commonly
unilateral over the involved kidney,
though discomfort can occur bilaterally.
The discomfort is usually not subtle and
may be elicited with mild or moderately
firm palpation [16].
| 3.2 |
3.3 Laboratory studies
3.3.1 Urine sample collection
So as to avoid contamination, convention
has called for a mid-stream, clean-caught
urine specimen for those presenting with
a potential UTI; however, at least two
studies have shown that there is no sig-
nificant difference in numbers of con-
taminated or unreliable results between
specimens collected with and without
preparatory cleansing [2–3]. In one of
these studies, patients using the clean-
ing method were instructed to wash their
hands and then use three provided cotton
wool swabs to cleanse the genital area
with soap and water [26]. They were told
to part the labia and wipe from front to
back three times using a clean swab each
time. Participants not using the cleaning
method were instructed simply to pass
some urine in to the toilet, stop, and then
catch the next urine in a sterile boric acid
container. An infection was classified as
one with greater than 108 organisms per
liter of urine in the presence of signifi-
cant numbers of white cells (greater than
104 cells per liter) with or without the
presence of red blood cells. Again, there
was no significant difference in numbers
of contaminated or unreliable results
between the two groups.
3.3.2 Urine dipstick testing
Urine dipstick testing is widely used in
clinical practice and has largely replaced
microscopic analysis and urine cultures
in the evaluation of uUTI because of its
low cost, speed, and convenience. Two
high quality systematic reviews looking
at the accuracy of dipstick analysis both
show the nitrite positive and leukocyte
esterase positive combination to be the
most accurate in predicting the existence
of a UTI [27–28]. The dipstick alone is a
useful test in aiding clinicians when diag-
nosing UTI. According to the review by
Hurlbut and Littenberg, this combination
has a sensitivity of 75% and a specificity
of 82%. If the dipstick alone is used, the
155
Chapter |3| Urinary tract infections in special groups of adult patients
posttest probabilities for women with
symptoms of a UTI are 81% (positive test)
and 23% (negative test) [2].
Several reviews recommend that a
diagnosis of uUTI can be made in women
with typical urinary irritative symptoma-
tology who are found to have a positive
urine dipstick test or urinalysis, with-
out obtaining a urine culture [7, 29–31].
McIsaac et al [32] found three decision
variables (burning or discomfort with uri-
nation, the presence of leukocytes greater
than a trace amount, and the presence of
any nitrites) in a cohort of 331 females
with suspected cystitis demonstrat-
ing significant association with a posi-
tive urine culture result (>102 CFU/ml).
There was, however, a graded relation-
ship between the number of decision aid
criteria and the outcome of a positive
urine culture result (p<0.001). The rate
of positive urine culture result was 23.1%
with 0 criteria, 43.2% with 1 criterion,
68.8% with 2 criteria, and 89.1% with 3
criteria. Incorporating the 3 significant
variables (empirical antibiotics without
culture if >2 variables present: otherwise
obtain a culture and wait for results) had
a sensitivity of 80.3% and a specificity of
53.7%.
Nitrite tests may be negative if the
UTI is caused by a non-nitrate reducing
pathogen (e.g. enterococci, S. saprophyti-
cus, Acinetobacter) or if the urine is too
dilute [33]. The sensitivity of the nitrite
test alone ranges from 35% to 85%, yet
with a higher specificity of 95% [30].
According to one large meta-analysis, the
urine dipstick test was found to be use-
ful in all populations to exclude the pres-
ence of infection if the results for nitrites
or leukocyte esterase are negative [34].
Sensitivities of the combination of both
tests vary between 68–88% in different
patient groups, but according to Deville
et al. positive test results must be con-
firmed. While the combination of positive
test results is very sensitive in family
practice, with high pre-test probabili-
ties, what is not clear is whether urine
156
culture testing is needed to confirm these
cases.
Pyuria is almost always present in
women with AUC. While its presence is
supportive of this diagnosis, the absence
of pyuria does not exclude a urinary tract
infection in those with symptoms sugges-
tive of AUC [5], The presence of blood in
the urine of those with AUC is common
and non-specific. Microscopic hematuria
is found in 40–60% of patients with UTI
[33]. Almost all patients with AUP have
significant pyuria, however gross hema-
turia occurs infrequently with pyelone-
phritis and is more common with lower
UTI [16].
3.3.3 Urine cultures
Opinions differ as to the necessity of
doing a urine culture in diagnosing
AUC. One school of thought is that a
urine culture is not necessary to diag-
nose AUC, and adds substantially to the
cost of therapy [35]. A more aggressive
approach would advocate for a microbio-
logic diagnosis of all UTIs, and require
that a quantitative isolation of a uropath-
ogenic organism from an appropriately
collected urine specimen be done. Urine
cultures are indicated in women with a
suspected AUP [16], and should be done
for women with any variety of UTI whose
symptoms do not resolve or recur within
two to four weeks after the completion
of treatment and for those women who
present with atypical symptoms at pres-
entation. In the emergency room set-
ting, urine cultures are recommend in
patients at high risk for pyelonephritis or
bacteremia/urosepsis, as well as in those
expected to have uncommon or resistant
organisms [36].
Previously, a quantitative count of
greater than or equal to 105 colony forming
units (CFU) per milliliter was the accepted
standard for diagnosing AUC [36], but
30–50% of women presenting with symp-
toms suggestive of AUC have lower col-
ony counts in the 103 to 105 range [5, 37].
 Diagnosis of uncomplicated urinary tract infections
Therefore, a colony count of greater than
or equal to 103 CFU/ml of a uropathogen is
now the commonly accepted microbiologic
diagnostic criteria for AUC [38]. Of inter-
est is the fact that as many as 10–20% of
symptomatic women have negative urine
cultures, and yet the clinical response to
treatment of these women is similar to that
of women with positive urine cultures [39].
Up to 95% of episodes of AUP are associ-
ated with greater than or equal to 105
CFU/mL of a uropathogen, though as with
AUC, some patients with AUP have lower
colony counts. It is proposed that a quanti-
tative count of greater than or equal to 104
CFU/mL defines significant bacteriuria in
AUP [38].
3.4 Additional diagnostic studies
Further studies beyond urinalysis and
urine cultures are rarely indicated in
diagnosing an uncomplicated urinary
tract infection. Patients presenting with
atypical symptoms of either AUC or AUP,
as well as those who fail to respond to
appropriate antimicrobial therapy, may
need imaging studies such at computed
tomography (CT) scans or ultrasound to
rule out complicated disorders. The pres-
ence of a renal abscess or an obstructing
calculus in the genitourinary tract of a
patient with clinical pyelonephritis would
support the diagnosis of a complicated
pyelonephritis, for example. Bladder
scans are helpful in identifying post void
residual volumes, which if high may be
indicative of urinary tract obstruction,
but scans are not necessary in the typical
patient with an uUTI.
4. FURTHER RESEARCH
Further research is needed to determine
the role of urine dipstick testing, and
subsequent management of the results of
these findings in primary care. Additional
research is recommended to elucidate
risk factors for E. coli resistance based
| 3.2 |
on epidemiological data obtainable by the
primary care physician.
5. CONCLUSIONS
The clinician should identify all suspected
cases of UTIs as being either uncom-
plicated or complicated based upon a
focused history, physical exam, and basic
laboratory studies, including a urinalysis
and possibly a urine culture. The history
is the greatest tool in diagnosing uUTIs,
and it can be used to asses a patient’s
risk of having an antibiotic resistant
uropathogen. A history of back or flank
pain, along with certain physical exam
and laboratory findings can sometimes
help distinguish AUC from AUP. Women
who have previously had an uUTI are
usually accurate in identifying when they
are suffering from an uUTI, and phone
triaging has been shown to have similar
beneficial outcomes when compared to
care rendered by the clinician in his/her
office.
Acknowledgements
The authors thank Drs. John W. Warren
and Kalpana Gupta for their thoughtful
review of this chapter.
REFERENCES
1. Stamm WE and Hooton TM, Management
of urinary tract infections in adults.
N Engl J Med, 1993. 329(18): 1328–34.
2. Bradbury SM, Collection of urine speci-
mens in general practice: to clean or not to
clean? J R Coll Gen Pract, 1988. 38(313):
363–5.
3. Lifshitz E and Kramer L, Outpatient
urine culture: does collection technique
matter? Arch Intern Med, 2000. 160(16):
2537–40.
4. Foxman B and Brown P, Epidemiology
of urinary tract infections: transmission
and risk factors, incidence, and costs.
Infect Dis Clin North Am, 2003. 17(2):
227–41.
157
Chapter |3| Urinary tract infections in special groups of adult patients
5. Fihn SD, Clinical practice. Acute uncom-
plicated urinary tract infection in women.
N Engl J Med, 2003. 349(3): 259–66.
6. Kunin CM, Urinary tract infections:
detection, prevention, and management.
5th ed. 1997, Baltimore: Williams &
Wilkins. ix, 419 p.
7. Hooton TM and Stam WE, Management
of acute uncomplicated urinary tract
infection in adults. Med Clin North Am,
1991. 75(2): 339–57.
8. Wright SW, Wrenn KD, Haynes M, and
Haas DW, Prevalence and risk factors
for multidrug resistant uropathogens in
ED patients. Am J Emerg Med, 2000.
18(2): 143–6.
9. Abrams P, Khoury S, and Grant A,
Evidence—based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. U.S. Department of Health and Human
Services Public Health Service Agency
for Health Care Policy and Research,
1992: 115–127.
11. Nicolle LE, A practical guide to the man-
agement of complicated urinary tract
infection. Drugs, 1997. 53(4): 583–92.
12. Sobel J and Kaye D, Urinary tract infec-
tions, in Mandell, Douglas, and Bennett’s
principles and practice of infectious dis-
eases, Mandell GL, Douglas RG, Bennett
JE, and Dolin R, Editors. 1995, Churchill
Livingstone: New York. p. 662–90.
13. Bent S, Nallamothu BK, Simel DL, Fihn
SD, and Saint S, Does this woman have
an acute uncomplicated urinary tract
infection? JAMA, 2002. 287(20): 2701–10.
14. Hooton TM, Scholes D, Hughes JP,
Winter C, Roberts PL, Stapleton AE,
Stergachis A, and Stamm WE, A prospec-
tive study of risk factors for symptomatic
urinary tract infection in young women.
N Engl J Med, 1996. 335(7): 468–74.
15. Scholes D, Hooton TM, Roberts PL, Gupta
K, Stapleton AE, and Stamm WE, Risk
factors associated with acute pyelonephri-
tis in healthy women. Ann Intern Med,
2005. 142(1): 20–7.
16. Shoff W. Pyelonephritis, Acute. 2008;
Available from: http://www.emedicine
.com/Med/topic2843.htm.
158
17. Brown PD, Freeman A, and Foxman
B, Prevalence and predictors of
trimethoprim-sulfamethoxazole resistance
among uropathogenic Escherichia coli iso-
lates in Michigan. Clin Infect Dis, 2002.
34(8): 1061–6.
18. Burman WJ, Breese PE, Murray BE,
Singh KV, Batal HA, MacKenzie TD,
Ogle JW, Wilson ML, Reves RR, and
Mehler PS, Conventional and molecu-
lar epidemiology of trimethoprim-
sulfamethoxazole resistance among
urinary Escherichia coli isolates. Am J
Med, 2003. 115(5): 358–64.
19. Mentler PA, Kuhn BR, and Gandhi G,
Risk stratification for trimethoprim-
sulfamethoxazole resistance in
community-acquired, uncomplicated uri-
nary tract infections. Am J Health Syst
Pharm, 2006. 63(17): 1588, 1590.
20. Metlay JP, Strom BL, and Asch DA, Prior
antimicrobial drug exposure: a risk fac-
tor for trimethoprim-sulfamethoxazole-
resistant urinary tract infections. J
Antimicrob Chemother, 2003. 51(4):
963–70.
21. Steinke DT, Seaton RA, Phillips G,
MacDonald TM, and Davey PG, Prior
trimethoprim use and trimethoprim-
resistant urinary tract infection: a
nested case-control study with multi-
variate analysis for other risk factors.
J Antimicrob Chemother, 2001. 47(6):
781–7.
22. Wright SW, Wrenn KD, and Haynes ML,
Trimethoprim-sulfamethoxazole resistance
among urinary coliform isolates. J Gen
Intern Med, 1999. 14(10): 606–9.
23. Colgan R, Johnson JR, Kuskowski
M, and Gupta K, Risk factors for
trimethoprim-sulfamethoxazole resistance
in patients with acute uncomplicated cys-
titis. Antimicrob Agents Chemother, 2008.
52(3): 846–51.
24. Talan DA, Moran GJ, Mower WR,
Newdow M, Ong S, Slutsker L,
Jarvis WR, Conn LA, and Pinner RW,
EMERGEncy ID NET: an emergency
department-based emerging infections
sentinel network. The EMERGEncy ID
NET Study Group. Ann Emerg Med,
1998. 32(6): 703–11.
 Diagnosis of uncomplicated urinary tract infections
25. Gupta K, Hooton TM, Roberts PL, and
Stamm WE, Patient-initiated treatment
of uncomplicated recurrent urinary tract
infections in young women. Ann Intern
Med, 2001. 135(1): 9–16.
26. Barry HC, Hickner J, Ebell MH, and
Ettenhofer T, A randomized control-
led trial of telephone management
of suspected urinary tract infections
in women. J Fam Pract, 2001. 50(7):
589–94.
27. Hurlbut TA, 3rd and Littenberg B, The
diagnostic accuracy of rapid dipstick tests
to predict urinary tract infection. Am J
Clin Pathol, 1991. 96(5): 582–8.
28. St John A, Boyd JC, Lowes AJ, and Price
CP, The use of urinary dipstick tests to
exclude urinary tract infection: a system-
atic review of the literature. Am J Clin
Pathol, 2006. 126(3): 428–36.
29. Bacheller CD and Bernstein JM, Urinary
tract infections. Med Clin North Am,
1997. 81(3): 719–30.
30. Orenstein R and Wong ES, Urinary tract
infections in adults. Am Fam Physician,
1999. 59(5): 1225–34, 1237.
31. Hooton TM, Practice guidelines for uri-
nary tract infection in the era of man-
aged care. Int J Antimicrob Agents, 1999.
11(3–4): 241–5; discussion 261–4.
32. McIsaac WJ, Moineddin R, and Ross S,
Validation of a decision aid to assist phy-
sicians in reducing unnecessary antibiotic
drug use for acute cystitis. Arch Intern
Med, 2007. 167(20): 2201–6.
| 3.2 |
33. Faro S and Fenner DE, Urinary tract
infections. Clin Obstet Gynecol, 1998.
41(3): 744–54.
34. Deville WL, Yzermans JC, van Duijn NP,
Bezemer PD, van der Windt DA, and
Bouter LM, The urine dipstick test useful
to rule out infections. A meta-analysis of
the accuracy. BMC Urol, 2004. 4: 4.
35. Powers RD, New directions in the diagno-
sis and therapy of urinary tract infections.
Am J Obstet Gynecol, 1991. 164(5 Pt 2):
1387–9.
36. Werman HA and Brown CG, Utility of
urine cultures in the emergency depart-
ment. Ann Emerg Med, 1986. 15(3): 302–7.
37. Raz R, Gennesin Y, Wasser J, Stoler Z,
Rosenfeld S, Rottensterich E, and Stamm
WE, Recurrent urinary tract infections in
postmenopausal women. Clin Infect Dis,
2000. 30(1): 152–6.
38. Rubin RH, Shapiro ED, Andriole VT,
Davis RJ, and Stamm WE, Evaluation
of new anti-infective drugs for the treat-
ment of urinary tract infection. Infectious
Diseases Society of America and the Food
and Drug Administration. Clin Infect Dis,
1992. 15 Suppl 1: S216–27.
39. Nicolle LE, Madsen KS, Debeeck GO,
Blochlinger E, Borrild N, Bru JP,
McKinnon C, O’Doherty B, Spiegel W,
Van Balen FA, and Menday P, Three days
of pivmecillinam or norfloxacin for treat-
ment of acute uncomplicated urinary
infection in women. Scand J Infect Dis,
2002. 34(7): 487–92.
159
|3.3|
The quantitative urine culture
for the diagnosis of urinary
tract infection
Lindsay E. Nicolle
Professor, Department of Medical Microbiology and Internal Medicine, University of Manitoba Health Sciences Centre,
Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9
Tel: (204) 787-7029, Fax: (204) 787-4826, e-mail: lnicolle@hsc.mb.ca
ABSTRACT
A diagnosis of urinary tract infection
requires microbiological confirmation. The
only exception is the clinical presentation
of acute uncomplicated urinary tract infec-
tion in women. A urine specimen for cul-
ture must be obtained prior to initiation
of antimicrobial therapy, use a collection
method which minimizes contamination,
be forwarded promptly to the laboratory,
and processed in the laboratory using
appropriate standard procedures. The
quantitative diagnostic criterion for uri-
nary tract infection for a voided urine
specimen is ≥ 105 cfu/ml of a single organ-
ism. Lower quantitative counts, gram pos-
itive organisms, and multiple organisms
usually represent contaminants. This
quantitative criterion is generally relevant
for all patients with asymptomatic bacte-
riuria, complicated urinary tract infection,
and all patients with pyelonephritis. It is
likely also appropriate for specimens col-
lected through an indwelling urethral
catheter, as these are subject to contami-
nation from organisms growing in bio-
film on the catheter. Further studies are
needed to determine what proportion of
selected symptomatic populations, includ-
ing men and patients with short term ind-
welling catheters, meet this quantitative
criterion. When lower quantitative counts
or multiple organisms are isolated from
voided specimens in patients in whom the
clinical diagnosis of urinary tract infection
is considered, careful assessment of the
clinical presentation and the number and
types of organisms isolated is necessary to
avoid overinterpretation of contaminated
urine specimens. Specimens obtained by
in and out catheter, including intermittent
catheterization, or by suprapubic aspira-
tion, are less subject to contamination,
 The quantitative urine culture for the diagnosis of urinary tract infection
and lower quantitative counts are consist-
ent with urinary infection with these col-
lection methods.
Key words: urinary tract infection,
bacteriuria, urine culture, complicated
urinary infection, uncomplicated urinary
infection
SUMMARY OF RECOMMENDATIONS
1. A urine specimen for culture should
be collected prior to the initiation of
antimicrobial therapy using a collec-
tion method which minimizes contam-
ination, be forwarded promptly to the
laboratory, and processed following
standard laboratory procedures
(GoR B).
2. The usual diagnostic criterion for
urinary tract infection with a voided
specimen is ≥ 105 cfu/ml of a single
gram negative organism (GoR B).
2.1 For specimens collected by in and
out catheter, a quantitative count
≥ 102 cfu/ml of any number or type
of organisms is considered diag-
nostic (GoR B).
2.2 For specimens collected by
suprapubic aspiration, any quanti-
tative count of any number or type
of organisms is considered diag-
nostic (GoR B).
3. For asymptomatic women, a single
voided urine culture with ≥ 105 cfu/ml
of a gram negative organism identifies
bacteriuria (GoR B).
3.1 A second urine specimen with the
same organism isolated identifies
women with persistent asympto-
matic bacteriuria (GoR B).
4. For asymptomatic men, a single
voided urine culture with ≥ 105 cfu/ml
of a gram negative organism is con-
sistent with bacteriuria (GoR B).
4.1 No recommendation can be
made for quantitative criteria for
| 3.3 |
Gram-positive organisms to identify
asymptomatic bacteriuria in men.
4.2 For specimens collected using a
freshly applied external condom
catheter, a quantitative count
of ≥ 105 cfu/ml of any number of
organisms identifies bacteriuria
(GoR B).
5. For voided specimens from women
with acute uncomplicated urinary
tract infection:
5.1 Isolation of a single predomi-
nant gram negative organism
or Staphylococcus saprophyti-
cus at any quantitative count is
consistent with urinary infection
(GoR B).
5.2 Isolation of gram positive organ-
isms other than S. saprophyticus
in any quantitative count, or
multiple organisms without a pre-
dominant Gram-negative isolate,
should be interpreted as contami-
nation (GoR B).
6. For women or men presenting with
acute uncomplicated pyelonephritis,
the quantitative criterion for infection
is ≥ 105 cfu/ml (GoR B).
6.1 In 5% of episodes, urine cultures
may have quantitative counts
between 104–105 cfu/ml (GoR B).
7. For symptomatic men, isolation of
a single gram negative organism in
quantitative counts ≥ 103 cfu/ml is
consistent with urinary infection.
7.1 Further evaluation is needed to
define the appropriate quantita-
tive count for symptomatic infec-
tion for specimens collected with
an external catheter.
8. For patients with indwelling
catheters:
8.1 Further evaluation is necessary to
define the appropriate quantita-
tive count for diagnosis of symp-
tomatic infection in patients with
short term indwelling catheters.
161
Chapter |3| Urinary tract infections in special groups of adult patients
8.2 For patients with chronic ind-
welling catheters, a quantitative
count of ≥ 105 cfu/ml in bladder
urine collected following catheter
replacement is consistent with
symptomatic or asymptomatic
urinary tract infection (GoR B).
9. For patients with spinal cord injury
and a urine specimen collected by
intermittent catheter, a quantitative
count of ≥ 102 cfu/ml is consistent with
symptomatic or asymptomatic infec-
tion (GoR B).
1. INTRODUCTION
It has been 50 years since the descrip-
tion of the quantitative criterion of ≥ 105
cfu/ml of organisms isolated in a urine
culture for the microbiologic diagnosis of
urinary tract infection [1–4]. The defini-
tive studies of Kass et al in the late 1950s
were instrumental in validating this
criterion and promoting the rapid and
widespread implementation into practice
[3, 5]. In these investigations, Kass con-
cluded that “bacilluria is the most sig-
nificant finding, and significant bacilluria
occurs when more than 105 bacteria/ml
are found in the urine” [5]. However,
Kass also recognized that “certain defined
circumstances which inhibit bacterial
multiplication in urine may lead to lower
bacterial counts in urine in the presence
of infection” [5]. These variables include
inoculum size, intrinsic microorganism
growth in urine, urine pH, urine constit-
uents, urine flow rate, frequency of void-
ing, residual urine volume, and urinary
antiseptics [6].
The introduction of the quantitative
urine culture facilitated a rapid advance
in the understanding and management
of many clinical aspects of urinary tract
infection. An important early success was
the reliable ascertainment of asympto-
matic bacteriuria in pregnant women,
leading to recognition that treatment
162
of asymptomatic bacteriuria in these
women is beneficial [7]. However, in the
early 1980s several reports revisited
limitations of the uniform application
of a quantitative count of ≥ 105 cfu/ml
for a diagnosis of urinary infection. In
particular, the relatively high propor-
tion of women with acute uncomplicated
urinary tract infection from whom lower
quantitative counts of uropathogens are
isolated was recognized [8]. Subsequent
guidelines for identification of urinary
infection proposed variable quantita-
tive criteria for bacterial growth depend-
ing upon the clinical presentation, from
≥ 103 to ≥ 105 cfu/ml [9]. These varying
diagnostic recommendations led to confu-
sion in clinical practice and, in particu-
lar, overinterpretation of contaminated
urine cultures leading to inappropriate
antimicrobial treatment. This document
reviews evidence addressing the question
of the appropriate quantitative count of
organisms isolated from urine specimens
for the microbiologic diagnosis of urinary
infection, and provides recommendations
for the interpretation of this important
diagnostic parameter.
2. METHODS
This document was developed using
available reviews and guidelines, includ-
ing the 2005 Infectious Diseases Society
of America Guideline for the Management
of Asymptomatic Bacteriuria [7] and the
IDSA/FDA recommendations [9]. These
were updated using a systematic lit-
erature search performed in Medline,
Cochrane and Embase. Key words
included urine culture, quantitative urine
culture, symptomatic urinary infection,
and asymptomatic urinary tract infection.
Limitations included adult, clinical stud-
ies, English, and peer reviewed. The infor-
mation identified through the literature
review was supplemented by other papers
identified by the author. The studies were
rated according to the level of evidence
 The quantitative urine culture for the diagnosis of urinary tract infection
(LoE) and the grade of recommendation
(GoR) using ICUD standards (for details
see Preface) [10–11].
3. DEFINITIONS
Asymptomatic urinary infection, also
called asymptomatic bacteriuria, occurs
when organisms are isolated from a urine
culture in quantitative counts meeting
microbiological criteria for infection, but
without acute symptoms or signs refera-
ble to the urinary tract [7]. Symptomatic
infection occurs when there are symptoms
referable to the urinary tract, including
the bladder, kidneys or, in men, the pros-
tate. Uncomplicated urinary tract infec-
tion is symptomatic lower tract (bladder)
infection occurring in women with a nor-
mal genitourinary tract. Complicated uri-
nary tract infection occurs in individuals
with functional or structural abnormali-
ties of the urinary tract.
4. URINE COLLECTION METHOD
These recommendations assume the
urine specimen for culture is collected
prior to antimicrobial therapy being ini-
tiated, using a method which minimizes
contamination, and forwarded promptly
to the laboratory where appropriate lab-
oratory methods are followed for isola-
tion, identification, and quantification of
organisms [12].
A voided urine specimen collected from
a woman will be contaminated with one
or more organisms from the periurethral
and vaginal flora, usually in quantitative
counts of ≥ 102 cfu/ml [13]. These organ-
isms are predominantly gram positive bac-
teria which are normal flora of the skin or
mucous membranes. In a comprehensive
study, Kunin reported that 77% of asymp-
tomatic women had a Staphylococcal spe-
cies other than S. saprophyticus grown
in quantitative counts of ≥ 102 cfu/ml
from voided urine specimens, and 51.8%
| 3.3 |
of symptomatic women; none of these
organisms were isolated in quantitative
counts ≥ 105 cfu/ml. Diphtheroids ≥ 102
cfu/ml were isolated from 42% of asymp-
tomatic women (including 1.8% with ≥ 105
cfu/ml) and 27% of symptomatic women.
Other Gram-positive organisms isolated
at ≥ 102 cfu/ml included Corynebacterium
spp (64% of asymptomatic and 46% of
symptomatic), Lactobacillus spp (55%
and 35%), Gardnerella spp (15% and
1.2%), and Streptococcus spp (37.4% and
22%). Quantitative counts ≥ 105 cfu/ml
were isolated for Corynebacterium spp
(3.9% asymptomatic and 2.4% symp-
tomatic), Lactobacillus spp (13% and
1.2%), Gardnerella spp (5.4% and 1.2%)
and Streptococcus spp (1% and 1.2%)
[14]. A more recent study of 120 young
women presenting with acute uncompli-
cated cystitis compared paired voided
and in and out catheter urine speci-
mens. Organisms isolated in any quan-
titative count from the voided specimen
but not present in the catheter speci-
men included 14 of 15 Enterococcus spp,
16 of 17 group B streptococci, and 123 of
132 mixed Gram-positive organisms [15].
Thus Gram-positive bacteria other than
S. saprophyticus isolated from otherwise
healthy symptomatic or asymptomatic
women should be interpreted as contam-
inants (LoE 2a). For men, contamina-
tion of voided specimens is less frequent,
reported to be only 1–4% with ≤ 105 cfu/ml
organisms isolated [16].
Urine specimens collected by catheter
puncture or from the collecting port of an
indwelling urethral catheter are subject
to contamination by organisms present
in biofilm which has formed along the
catheter. A urine specimen obtained by
in and out bladder catheterization is less
subject to contamination, although small
numbers of organisms, usually present at
< 102 cfu/ml, are attributable to contami-
nation as the catheter passes through the
urethra [13]. Urine obtained by suprapu-
bic aspiration is presumed to be sterile,
and any quantitative count is interpreted
163
Chapter |3| Urinary tract infections in special groups of adult patients
as positive [13]. Particularly for women,
use of collection methods which are less
susceptible to contamination may be con-
sidered to confirm urinary infection when
a voided specimen is not diagnostic but
the clinical presentation is suggestive.
5. ASYMPTOMATIC BACTERIURIA
For women who are asymptomatic, two
consecutive urine specimens with the
same gram negative organism isolated
at ≥ 105 cfu/ml is recommended to iden-
tify asymptomatic bacteriuria [7] (LoE
2a). Transient asymptomatic bacteriuria
appears to be frequent, particularly in
young women. A second specimen con-
firmed an initial isolate of E. coli ≥ 105
cfu/ml in only 42% of women aged 23–29
years when the repeat urine was obtained
weekly or monthly [17], but for 90% of
40–64 year old women in Finland with an
initial positive repeated within two weeks
[18]. For diabetic women of mean age 56
years, a repeat urine specimen within
two weeks confirmed bacteriuria in 69%
[19], and 56% of diabetic women aged
18–75 years with a repeat urine speci-
men obtained at two to four months [20].
A single positive specimen with a Gram-
negative organism ≥ 105 cfu/ml is likely
true bacteriuria in most women cases,
but a second specimen obtained within a
few days or weeks will identify persist-
ent bacteriuria, which may be more clini-
cally relevant. Lower quantitative counts
of any organism, or ≥ 105 cfu/ml of more
than one organism, including mixed gram
negative and gram positive cultures,
should be interpreted as contamination
[13–14, 17]. If it is essential to confirm
the presence of asymptomatic bacteriuria
and repeated specimens, including first
morning voids, continue to grow < 105 of a
single gram negative organism, obtaining
a specimen by in and out catheter to doc-
ument bacteriuria should be considered.
Katz and Hodder reported 7.0% of
pregnant women had an initial specimen
164
with ≥ 105 cfu/ml of a gram negative
organism isolated, but only 4.4% had two
consecutive specimens [21]. However,
in another study a second specimen
remained positive with a single gram
negative organism ≥ 105 cfu/ml in over
90% of pregnant women, and a third
specimen remained positive in 87% [22].
In this study, pyelonephritis in later preg-
nancy occurred with similar frequency for
untreated women with mixed gram posi-
tive and gram negative organisms iso-
lated from urine cultures at ≥ 105 cfu/ml
and women with specimens with quan-
titative counts of < 103 cfu/ml isolated,
consistent with the mixed cultures repre-
senting contamination [22].
Asymptomatic bacteriuria may be
more likely to persist in older women. In
Swedish women resident in the commu-
nity of mean age 83 years, 85% with an
initial urine specimen from which a sin-
gle Gram-negative organism ≥ 105 cfu/ml
was isolated had a second positive urine
specimen obtained within two weeks [23].
Residents of a Canadian long term care
facility of mean age 83.4 years had bac-
teriuria confirmed by a repeat specimen
within two weeks in 90% of women [24].
However, a repeat positive specimen was
reported from only 55–68% of institution-
alized Swedish women of mean age 85
years [25].
An initial voided urine specimen with
≥ 105 cfu/ml of a Gram-negative organ-
ism isolated was confirmed on a follow-
up specimen at one week in 58 (98%) of
59 men [26]. The interpretation of lower
quantitative counts of Gram-negative
organisms or any Gram-positive organ-
isms isolated in asymptomatic men has
not been reported. When urine specimens
are collected from elderly men using
freshly applied clean condom catheters,
the positive predictive value is 85–100%
for ≥ 105 cfu/ml in the voided culture
being confirmed with the catheter speci-
men, and a negative predictive value of
86–94% [27–28]. For asymptomatic men
with spinal cord injury using external
 The quantitative urine culture for the diagnosis of urinary tract infection
urine collecting devices, 81% of organ-
isms isolated from a suprapubic aspirate
were isolated in counts ≥ 105 cfu/ml from
the voided specimen [29]. However, 79%
of these subjects were receiving prophy-
lactic antimicrobials or antiseptics. Thus,
for collection by voided external catheter
collected specimens, ≥ 105 cfu/ml is the
appropriate quantitative count (LoE 2a).
6. ACUTE UNCOMPLICATED URINARY
TRACT INFECTION
6.1 Cystitis
25–30% of young women who present
with acute uncomplicated urinary tract
infection will have < 105 cfu/ml of a gram
negative organism or S. saprophyticus
isolated [8, 30–32]. Lower quantitative
counts of other gram positive organisms
or of yeast should be interpreted as con-
tamination [13–14]. The explanation for
this high proportion of specimens with
lower quantitative counts of uropatho-
gens isolated is unclear. Frequent void-
ing leading to limited bladder dwell time
together with dilution attributable to
increased fluid intake likely explains part
of this observation. Infection initially
localized to the urethra (i.e. urethritis)
has also been suggested [14]. It should
be recognized, however, that the major-
ity of these women will have ≥ 105 cfu/ml
isolated.
For post-menopausal women with
acute cystitis, lower quantitative counts
may be less common, being reported in
10% of episodes in healthy women aged
55–75 years in the community [33], and
15% of women from a long term care
and community population of mean age
80 years [34]. For women of mean age
81 years with genitourinary or atypical
symptoms, 88% of voided specimens with
≥ 105 cfu/ml of a single organism isolated
had the same organism isolated from a
paired suprapubic aspirate [35]. In con-
trast, individuals with a negative or
| 3.3 |
contaminated (< 105 of any organism or
≥ 105 cfu/ml of multiple organisms) voided
specimen had consistently negative cul-
tures from the suprapubic aspirate. Thus,
older women who present with acute cys-
titis are less likely to have < 105 cfu/ml of
organisms isolated from the urine culture
compared with younger women (LoE 3a).
6.2 Acute uncomplicated
(nonobstructive)
pyelonephritis
Over 95% of individuals presenting with
acute uncomplicated pyelonephritis will
have ≥ 105 cfu/ml of a single gram nega-
tive organism isolated from the urine cul-
ture [3, 34, 36–37]. The small proportion
of individuals with pyelonephritis from
whom lower quantitative counts are iso-
lated will usually have 104–105 cfu/ml of
organisms.
7. COMPLICATED URINARY TRACT
INFECTION
7.1 Symptomatic urinary infection
in men
A study comparing urine specimens col-
lected from men by suprapubic aspirate,
voided specimen without cleaning of the
meatus, voided specimen with clean-
ing of the meatus, or in and out catheter
reported the optimal sensitivity for bacte-
riuria of voided compared to suprapubic
or catheter specimens was ≥ 103 cfu/ml
[38]. This study, however, enrolled men
with irritative genitourinary symptoms
or scheduled for a urologic procedure (i.e.
both symptomatic and asymptomatic), did
not distinguish between Gram-positive
and Gram-negative organisms, and
included subjects receiving antimicro-
bial therapy. For the uncommon, in men,
syndrome of acute uncomplicated cystitis
the quantitative counts of gram negative
organisms isolated from young men was
of < 105 cfu/ml in 35% [39] and < 104 in
19% [40] of patients. Thus, the frequency
165
Chapter |3| Urinary tract infections in special groups of adult patients
of lower quantitative counts isolated
from these men may be similar to young
women with acute uncomplicated urinary
infection (LoE 3a).
7.2 Indwelling urethral catheter
When daily urine cultures are monitored
following insertion of a short term cathe-
ter, a quantitative count of ≥ 102 cfu/ml of
any organism isolated after an initial neg-
ative culture progresses to ≥ 105 cfu/ml
of the same organism within 48–72 hours
if antimicrobial therapy is not initiated
and the catheter remains in situ [41].
This was observed, however, for only 20%
of all patients with short term catheters
inserted in the study facility, bacteriu-
ric patients were all asymptomatic, and
over one-half of organisms isolated were
coagulase negative staphylococci or yeast.
While this study has been interpreted as
supporting a recommendation for a quan-
titative count of ≥ 102 cfu/ml for the diag-
nosis of bacteriuria in individuals with a
short term indwelling catheter, the lower
quantitative counts likely reflect contami-
nation by bacteria present on the biofilm,
rather than bladder bacteriuria. A quanti-
tative count of ≥ 105 cfu/ml likely remains
appropriate to identify asymptomatic
bacteriuria for patients with a short term
indwelling catheter [4]. Further study
is necessary to identify the appropri-
ate quantitative count for patients with
a short term indwelling catheter and
symptomatic urinary infection, given the
potential for biofilm contamination of
specimens collected through the catheter.
An established biofilm incorporating
multiple organisms is present on a long
term indwelling catheter. Specimens col-
lected from the catheter have substantial
contamination with organisms present
in the biofilm, and a larger number of
organisms at higher quantitative counts
are present when compared with bladder
urine [42]. If a urine specimen for culture
is indicated in these patients contamina-
tion from biofilm is avoided by replacing
166
the indwelling catheter with a new cath-
eter, with bladder urine for culture sam-
pled through the new catheter. Of note,
organisms isolated from the bladder
urine at quantitative counts < 105 fol-
lowing catheter replacement tend not to
persist [43]. When suprapubic aspirates
are compared with specimens obtained
by needle puncture of the catheter in pre-
sumably asymptomatic men, isolation of
organisms in quantitative counts ≥ 105
cfu/ml was similar when the catheter had
been in place for over one month [44]. In
these individuals, growth of ≥ 105 cfu/ml
from the catheter urine was confirmed
in the suprapubic urine in 25 of 32 speci-
mens (81%). When the organism was not
present in the suprapubic aspirate, five
out of six patients had had the catheter
in situ less than one month, and four of
these for less than two weeks. Pending
further studies in symptomatic subjects,
≥ 105 cfu/ml is likely the appropriate diag-
nostic criteria for bladder urine in symp-
tomatic or asymptomatic subjects with a
chronic indwelling catheter (LoE 3a).
7.3 Patients with spinal cord
injury using intermittent
catheterization
A specimen obtained by intermittent
catheterization is, conceptually, an in
and out catheter specimen. Gribble et al
compared intermittent catheter speci-
mens with suprapubic aspirates and con-
cluded ≥ 102 cfu/ml for gram negative or
gram positive organisms was the opti-
mal quantitative count from an inter-
mittent catheter specimen [45]. In this
study, however, four of five subjects with
definite symptomatic urinary infection
had ≥ 105 cfu/ml of organisms isolated.
Thus, defining the appropriate quantita-
tive criteria for symptomatic infection
warrants further study. Currently, how-
ever, the National Institute on Disability
and Rehabilitation Research Consensus
Statement (NIDRRCS) recommends ≥ 102
cfu/ml as criteria [46].
 The quantitative urine culture for the diagnosis of urinary tract infection
8. GUIDELINES
Several guidelines addressing urinary
tract infection provide statements rel-
evant to the appropriate quantitative
count of organisms from urine culture,
although this topic is not the primary
objective of the guidelines. These include
the IDSA Guidelines for asymptomatic
bacteriuria [7] and catheter acquired uri-
nary tract infection [47], the European
Union (EU) Guidelines [48], and
NIDRRCS [46]. In addition, the Clinical
Laboratory Standards Institute (CLSI)
provides recommendations for interpre-
tation of the quantitative urine culture,
although these are not developed as evi-
dence based guidelines [12].
9. FURTHER RESEARCH
Further research is necessary to clarify
the appropriate interpretation and appli-
cation of the quantitative urine culture in
selected symptomatic populations. These
include individuals with short term and
long term indwelling catheters, men with
external collecting devices, and some pres-
entations of complicated urinary infection.
10. CONCLUSIONS
The observations of Kass in the 1950s
remain valid today. Specifically, “for sur-
vey purposes, a count of 105 bacteria or
more per ml of urine has been designated
arbitrarily as the defining line between
true bacilluria and contamination.
Obviously, for individual clinical purposes
a reinvestigation of counts higher than
100 may at times be useful, but only occa-
sionally” [3].
The quantitative count of ≥ 105 cfu/ml
remains an important diagnostic crite-
rion, and is present for the large majority
of patients with urinary tract infection.
It should also be appreciated that Gram-
positive organisms and mixed cultures
| 3.3 |
isolated from voided specimens should
usually be interpreted as contamination.
When lower quantitative counts are iso-
lated from urine specimens, a careful
evaluation of the urine culture results
considering the method of specimen col-
lection, handling in transportation to the
laboratory, and the number and types of
organisms isolated, together with the
clinical presentation, is necessary.
REFERENCES
1. Marple CD, The frequency and character
of urinary tract infections in an unselected
group of women. Ann Intern Med 1941.
14: 2220–39.
2. Sanford JP, Favour CB, Mao FH, and
Harrison JH, Evaluation of the positive
urine culture; an approach to the differ-
entiation of significant bacteria from con-
taminants. Am J Med, 1956. 20(1): 88–93.
3. Kass EH, Asymptomatic infections of the
urinary tract. Trans Assoc Am Physicians,
1956. 69: 56–64.
4. Hoeprich PD, Culture of the urine. J Lab
Clin Med, 1960. 56: 899–907.
5. Kass EH, Chemotherapeutic and antibi-
otic drugs in the management of infections
of the urinary tract. Am J Med, 1955.
18(5): 764–81.
6. Kunin CM, Bacteriuria, pyuria, pro-
teinuria, hematuria, and pneumaturia,
in Urinary tract infections : detection,
prevention, and management, Kunin
CM, Editor. 1997, Williams & Wilkins:
Baltimore; London. p. ix, 419p.
7. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
8. Stamm WE, Counts GW, Running KR,
Fihn S, Turck M, and Holmes KK,
Diagnosis of coliform infection in acutely
dysuric women. N Engl J Med, 1982.
307(8): 463–8.
9. Rubin RH, Shapiro ED, Andriole VT,
Davis RJ, and Stamm WE, Evaluation of
new anti-infective drugs for the treatment
167
Chapter |3| Urinary tract infections in special groups of adult patients
of urinary tract infection. Infectious
Diseases Society of America and the Food
and Drug Administration. Clin Infect Dis,
1992. 15 Suppl 1: S216–27.
10. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
11. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
12. McCarter YS and Sharp SE, Laboratory
diagnosis of urinary tract infections.
2009, Washington, D.C.: ASM Press. 25 p.
13. Platt R, Quantitative definition of bacte-
riuria. Am J Med, 1983. 75(1B): 44–52.
14. Kunin CM, White LV, and Hua TH, A
reassessment of the importance of “low-
count” bacteriuria in young women with
acute urinary symptoms. Ann Intern Med,
1993. 119(6): 454–60.
15. Hooton TM, Stapleton AE, Roberts PL,
and Stamm WE, Comparison of micro-
biologic findings in paired midstream
and catheter urine specimens from
women with acute uncomplicated cysti-
tis. Abstract L-609 48th Annual ICAAC
Washington DC, 2008.
16. Lipsky BA, Urinary tract infections in
men. Epidemiology, pathophysiology,
diagnosis, and treatment. Ann Intern
Med, 1989. 110(2): 138–50.
17. Hooton TM, Scholes D, Stapleton AE,
Roberts PL, Winter C, Gupta K,
Samadpour M, and Stamm WE, A pro-
spective study of asymptomatic bac-
teriuria in sexually active young women.
N Engl J Med, 2000. 343(14): 992–7.
18. Takala J, Jousimies H, and Sievers K,
Screening for and treatment of bacte-
riuria in a middle-aged female popula-
tion. I. The prevalence of bacteriuria,
urinary tract infections under treatment
and symptoms of urinary tract infections
in the Sakyla-Koylio project. Acta Med
Scand, 1977. 202(1–2): 69–73.
19. Harding GK, Zhanel GG, Nicolle LE, and
Cheang M, Antimicrobial treatment in
diabetic women with asymptomatic bac-
teriuria. N Engl J Med, 2002. 347(20):
1576–83.
168
20. Geerlings SE, Brouwer EC, Gaastra W,
and Hoepelman AI, Is a second urine
specimen necessary for the diagnosis of
asymptomatic bacteriuria? Clin Infect
Dis, 2000. 31(3): E3–4.
21. Kaitz AL and Hodder EW, Bacteriuria
and pyelonephritis of pregnancy. A pro-
spective study of 616 pregnant women.
N Engl J Med, 1961. 265: 667–72.
22. Savage WE, Hajj SN, and Kass EH,
Demographic and prognostic characteris-
tics of bacteriuria in pregnancy. Medicine
(Baltimore), 1967. 46(5): 385–407.
23. Rodhe N, Lofgren S, Matussek A, Andre
M, Englund L, Kuhn I, and Molstad S,
Asymptomatic bacteriuria in the elderly:
high prevalence and high turnover of
strains. Scand J Infect Dis, 2008. 40(10):
804–10.
24. Nicolle LE, Mayhew WJ, and Bryan L,
Prospective randomized comparison of
therapy and no therapy for asymptomatic
bacteriuria in institutionalized elderly
women. Am J Med, 1987. 83(1): 27–33.
25. Hedin K, Petersson C, Wideback K,
Kahlmeter G, and Molstad S,
Asymptomatic bacteriuria in a population
of elderly in municipal institutional care.
Scand J Prim Health Care, 2002. 20(3):
166–8.
26. Gleckman R, Esposito A, Crowley M,
and Natsios GA, Reliability of a single
urine culture in establishing diagnosis of
asymptomatic bacteriuria in adult males.
J Clin Microbiol, 1979. 9(5): 596–7.
27. Ouslander JG, Greengold BA, Silverblatt
FJ, and Garcia JP, An accurate method
to obtain urine for culture in men with
external catheters. Arch Intern Med, 1987.
147(2): 286–8.
28. Nicolle LE, Harding GK, Kennedy J,
McIntyre M, Aoki F, and Murray D, Urine
specimen collection with external devices
for diagnosis of bacteriuria in elderly
incontinent men. J Clin Microbiol, 1988.
26(6): 1115–9.
29. Deresinski SC and Perkash I, Urinary
tract infections in male spinal cord
injured patients. Part one: Bacteriologic
diagnosis. J Am Paraplegia Soc, 1985.
8(1): 4–6.
30. Saginur R and Nicolle LE, Single-dose
compared with 3-day norfloxacin treatment
 The quantitative urine culture for the diagnosis of urinary tract infection
of uncomplicated urinary tract infection
in women. Canadian Infectious Diseases
Society Clinical Trials Study Group. Arch
Intern Med, 1992. 152(6): 1233–7.
31. Nicolle LE, DuBois J, Martel AY,
Harding GK, Shafran SD, and Conly JM,
Treatment of acute uncomplicated uri-
nary tract infections with 3 days of lom-
efloxacin compared with treatment with
3 days of norfloxacin. Antimicrob Agents
Chemother, 1993. 37(3): 574–9.
32. Nicolle LE, Hoepelman AI, Floor M,
Verhoef J, and Norgard K, Comparison of
three days’ therapy with cefcanel or amox-
icillin for the treatment of acute uncom-
plicated urinary tract infection. Scand J
Infect Dis, 1993. 25(5): 631–7.
33. Jackson SL, Boyko EJ, Scholes D,
Abraham L, Gupta K, and Fihn SD,
Predictors of urinary tract infection after
menopause: a prospective study. Am J
Med, 2004. 117(12): 903–11.
34. Gomolin IH, Siami PF, Reuning-Scherer
J, Haverstock DC, and Heyd A, Efficacy
and safety of ciprofloxacin oral suspension
versus trimethoprim-sulfamethoxazole
oral suspension for treatment of older
women with acute urinary tract infection.
J Am Geriatr Soc, 2001. 49(12): 1606–13.
35. Michielsen WJ, Geurs FJ, Verschraegen
GL, Claeys GW, and Afschrift MB,
A simple and efficient urine sampling
method for bacteriological examination
in elderly women. Age Ageing, 1997.
26(6): 493–5.
36. Pinson AG, Philbrick JT, Lindbeck GH,
and Schorling JB, ED management of
acute pyelonephritis in women: a cohort
study. Am J Emerg Med, 1994. 12(3):
271–8.
37. Johnson JR, Lyons MF, 2nd, Pearce W,
Gorman P, Roberts PL, White N, Brust P,
Olsen R, Gnann JW, Jr., and Stamm
WE, Therapy for women hospitalized
with acute pyelonephritis: a randomized
trial of ampicillin versus trimethoprim-
sulfamethoxazole for 14 days. J Infect Dis,
1991. 163(2): 325–30.
38. Lipsky BA, Ireton RC, Fihn SD,
Hackett R, and Berger RE, Diagnosis of
bacteriuria in men: specimen collection
and culture interpretation. J Infect Dis,
1987. 155(5): 847–54.
| 3.3 |
39. Krieger JN, Ross SO, and Simonsen
JM, Urinary tract infections in healthy
university men. J Urol, 1993. 149(5):
1046–8.
40. Spach DH, Stapleton AE, and Stamm WE,
Lack of circumcision increases the risk
of urinary tract infection in young men.
JAMA, 1992. 267(5): 679–81.
41. Stark RP and Maki DG, Bacteriuria in
the catheterized patient. What quantita-
tive level of bacteriuria is relevant? N
Engl J Med, 1984. 311(9): 560–4.
42. Tenney JH and Warren JW, Bacteriuria
in women with long-term catheters: paired
comparison of indwelling and replace-
ment catheters. J Infect Dis, 1988.
157(1): 199–202.
43. Tenney JH and Warren JW, Long-term
catheter-associated bacteriuria: species at
low concentration. Urology, 1987. 30(5):
444–6.
44. Bergqvist D, Bronnestam R, Hedelin H,
and Stahl A, The relevance of urinary
sampling methods in patients with ind-
welling Foley catheters. Br J Urol, 1980.
52(2): 92–5.
45. Gribble MJ, McCallum NM, and
Schechter MT, Evaluation of diagnos-
tic criteria for bacteriuria in acutely
spinal cord injured patients undergoing
intermittent catheterization. Diagn
Microbiol Infect Dis, 1988. 9(4): 197–206.
46. The prevention and management of uri-
nary tract infections among people with
spinal cord injuries. National Institute on
Disability and Rehabilitation Research
Consensus Statement. January 27–29,
1992. J Am Paraplegia Soc, 1992. 15(3):
194–204.
47. Hooton TM, Bradley SF, Cardenas DD,
Colgan R, Geerling SE, Rice JC, Saint S,
Schaeffer AJ, Tam byah PA, Tenke P,
and LE N, International clinical practice
guidelines for the diagnosis, prevention
and treatment of catheter-associated uri-
nary tract infection in adults. 2010 (in
press).
48. Naber KG, Bishop MC, Bjerklund-
Johansen TE, Botto H, Cek M, Grabe M,
Lobel B, Palou J, and PT, Guidelines on
the Management of Urinary and Male
Genital Tract Infections. EU Guidelines,
2006.
169
|3.4|

Antibiotic treatment of
uncomplicated urinary tract
infection in premenopausal
women
Kurt G. Naber1, Björn Wullt2, Florian M.E. Wagenlehner3
1
Technical University of Munich, Munich, Germany
2
Department of Urology, Skåne University Hospital, Malmö,
3
Department of Urology, University of Giessen-Marburg, Giessen, Germany
Corresponding Author: Kurt G. Naber, MD, PhD, Karl-Bicklederstr. 44c, D-94315 Straubing, Germany
Tel +49-9421-33369, E-mail: kurt@nabers.de

ABSTRACT recommendations for empiric treatment

Uncomplicated urinary tract infections
(UTI) in otherwise healthy premenopau-
sal women are one of the most frequent
infections in the community. Therefore
any improvement in management will
have a high impact not only on the qual-
ity of life of the individual patient but
also on the health system. In placebo-
controlled studies antimicrobial treat-
ment was significantly more effective
than placebo, but on the other hand
showed more adverse events. The choice
of antibiotic depends on the spectrum and
susceptibility patterns of the uropatho-
gens, its effectiveness for this indication,
its tolerability, its collateral effects and
cost. After a systematic literature search,
of acute uncomplicated cystitis and acute
uncomplicated pyelonephritis and for fol-
low-up strategies were developed.
Key words: uncomplicated urinary
tract infection, cystitis, pyelonephritis,
premenopausal women, empiric therapy,
aminoglycosides, ampicillin, amoxicil-
lin, cephalosporines, cefpodoxime, cipro-
floxacin, cotrimoxazole, fluoroquinolones,
fosfomycin, levofloxacin, nitrofurantoin,
ofloxacin, pivmecillinam, trimethoprim
SUMMARY OF RECOMMENDATIONS
1. Principles for choosing an antibiotic
for empiric therapy: the choice of an
 Antibiotic treatment of uncomplicated urinary tract infection
antibiotic for empiric therapy should
be guided by i) spectrum and suscep-
tibility patterns of the uropathogens;
ii) efficacy for this indication; iii) toler-
ability; iv) collateral effects; v) cost;
and vi) availability (GoR A).
2. Uncomplicated cystitis
2.1 Antibiotic therapy is recom-
mended because clinical success
is significantly more likely in
women treated with antibiotics
versus those treated with placebo
(GoR A).
2.2 According to available susceptibil-
ity patterns fosfomycin trometamol
3 g as a single dose, pivmecillinam
400 mg for 3 days and nitrofuran-
toin macrocrystal 100 mg bid for
5 days, can be considered the first
drugs of choice in many countries,
where available (GoR A).
2.3 Cotrimoxazole 160/800 mg bid for
3 days or trimethoprim 200 mg for
5 days should only be considered
as the first drug of choice in areas
with known resistance rates of
E. coli below 20% (GoR A).
2.4 Alternative antibiotics are cipro-
floxacin 250 mg bid, ciprofloxacin
ER 500 mg qd, levofloxacin
250 mg qd, norfloxacin 400 mg bid
and ofloxacin 200 mg bid, each as
a 3-day course (GoR B). However,
collateral effects have to be con-
sidered (GoR B).
2.5 Symptomatology may be sufficient
for routine follow-up (GoR C).
2.6 In treated patients where
symptoms do not resolve and
in patients with early relapse
(<2 weeks) urine culture and anti-
microbial susceptibility testing
should be performed for guidance
of therapy (GoR B).
3. Acute uncomplicated pyelonephritis
3.1 Because of lacking suitable sur-
veillance studies the spectrum
| 3.4 |
and susceptibility patterns of
uropathogens causing uncom-
plicated cystitis can be used as
guide for empiric therapy (GoR B).
However, S. saprophyticus is to be
less considered in acute pyelone-
phritis as compared to acute cysti-
tis (GoR B).
3.2 In mild and moderate cases of
acute uncomplicated pyelonephri-
tis an oral therapy of 10–14 days
is usually sufficient.
3.2.1 A fluoroquinolone for 7–10
days can be recommended
as first-line therapy if the
resistance rate of E. coli
is still below 10% (GoR
A). If the fluoroquinolone
dosage is increased, the
treatment can probably be
reduced to 5 days (GoR B).
However, increasing rates
of fluoroquinolone resist-
ant E. coli also in the com-
munity are already found
in some parts of the world
restricting the empiric use
of fluoroquinolones.
3.2.2 A 3rd generation oral cepha-
losporin, e.g. cefpodoxime
proxetil or ceftibuten, may
be an alternative (GoR B).
However, available studies
demonstrated only equiva-
lent clinical, but not micro-
biological, efficacy compared
with ciprofloxacin.
3.2.3 Because of increasing E. coli
resistance rates above 10%,
cotrimoxazole is not suitable
for empiric therapy in most
areas, but can be used
as test conform therapy
when susceptibility of the
pathogen is already known
(GoR B).
3.2.4 Amoxiclav is not recom-
mended as a drug of first
171
Chapter |3| Urinary tract infections in special groups of adult patients
choice for empiric oral ther-
apy of acute pyelonephritis
(GoR B). It is recommended
when susceptibility testing
shows a susceptible Gram-
positive organism (GoR C).
3.2.5 In communities with high
rates of fluoroquinolone
resistant and ESBL produc-
ing E. coli (>10%) an initial
empiric therapy with an
aminoglycoside or a carbap-
enem has to be considered
until susceptibility test-
ing demonstrates that oral
drugs can also be used
(GoR B).
3.3 Patients with severe pyelonephri-
tis who cannot take oral medica-
tion because of systemic symptoms
like nausea and vomiting, have to
be treated initially with one of the
following parenteral antibiotics
3.3.1 a parenteral fluoroqui-
nolone, in communities with
resistance rates of E. coli
to fluoroquinolones <10%
(GoR B)
3.3.2 a 3rd generation cepha-
losporin, in communities
with resistance rates of
ESBL producing E. coli
<10% (GoR B)
3.3.3 an aminopenicillin plus a
beta-lactamase-inhibitor in
case of a known susceptible
Gram-positive pathogen
(GoR B)
3.3.4 an aminoglycoside or a
carbapenem in communities
with resistance rates to fluo-
roquinolones and/or ESBL
producing E. coli >10%
(GoR B).
3.4 Hospital admission should be
considered if complicating factors
cannot be ruled out by available
172
diagnostics and/or the patient has
clinical signs and symptoms of
sepsis (GoR B)
3.5 After improvement, the patient
can be switched to an oral
regimen using one of the above-
mentioned antibacterials, if active
against the infecting organism, to
complete the 1–2 week course of
therapy (GoR B).
3.6 In women whose pyelonephritis
symptoms do not improve within
3 days, or that resolve and then
recur within 2 weeks, a repeat
urine culture, antimicrobial sus-
ceptibility testing and an appro-
priate investigation, such as renal
ultrasound, computertomography
or scan, should be performed
(GoR B). In the patient with no
urological abnormality, it should
be assumed that the infecting
organism is not susceptible to the
agent originally used and an alter-
native tailored therapy should
be considered based on culture
results (GoR B).
3.7 For those patients who have a
symptomatic relapse with the
same pathogen as the initial
infecting strain, diagnosis of
uncomplicated pyelonephritis
should be reconsidered and fur-
ther diagnostic steps are neces-
sary (GoR C).
3.8 Routine post-treatment urinalysis
and urine cultures in an asymp-
tomatic patient may not be indi-
cated (GoR C).
4. Follow up
4.1 Uncomplicated Cystitis
4.1.1 Routine post-treatment uri-
nalysis or urine cultures in
asymptomatic patients are
not indicated (GoR B).
4.1.2 In women whose symptoms
do not resolve by the end
 Antibiotic treatment of uncomplicated urinary tract infection
of treatment and in those
whose symptoms resolve but
recur within 2 weeks, urine
culture and antimicrobial
susceptibility tests should
be performed (GoR B).
4.1.3 For therapy in this situa-
tion, one should assume that
the infecting organism is
not susceptible to the agent
originally used. Retreatment
with a 7-day regimen using
another agent should be
considered (GoR C).
4.2 Uncomplicated Pyelonephritis
4.2.1 Routine post-treatment
urinalysis and urine cultures
in an asymptomatic patient
may not be indicated (GoR C).
4.2.2 In women whose pyelone-
phritis symptoms do not
improve within 3 days,
or resolve and then recur
within 2 weeks, repeated
urine culture and antimi-
crobial susceptibility tests
and an appropriate investi-
gation, such as renal ultra-
sound or scan, should be
performed (GoR B).
4.2.3 In the patient with no uro-
logical abnormality, it should
be assumed that the infect-
ing organism is not suscep-
tible to the agent originally
used and tailored treatment
with a 2-week regimen using
another agent should be
considered (GoR B).
4.2.4 For those patients who
relapse with the same
pathogen, the diagnosis of
uncomplicated pyelonephri-
tis should be reconsidered.
Appropriate diagnostic steps
are necessary to rule out
any complicating factors
(GoR C).
| 3.4 |
1. INTRODUCTION AND DEFINITION
Uncomplicated urinary tract infections
(UTI) in otherwise healthy premenopau-
sal women comprise uncomplicated cys-
titis and uncomplicated pyelonephritis.
Uncomplicated UTI is classified as UTI
without relevant structural and func-
tional abnormalities within the urinary
tract (uropathies), without relevant kid-
ney diseases (nephropathies), and with-
out relevant comorbidities which can
lead to more serious outcomes and there-
fore require additional care (see chapter
Introduction).
Since uncomplicated cystitis in females
is one of the most frequent infections in
the community, each improvement of
management will have a high impact not
only on the quality of life of the individ-
ual patient but also on the health system
and thus on health economics. The rec-
ommended diagnostic steps are discussed
elsewhere (see chapter Colgan et al).
Before antimicrobial therapy is consid-
ered, the natural history of this infection
should be known and also the evidence
based indication for antimicrobial ther-
apy. The choice of an antibiotic agent
depends on the spectrum of uropatho-
gens, their antimicrobial susceptibility
and whether a drug is suitable for this
indication. This again depends on the
dosage regimen, which form of admin-
istration is available, efficacy, tolerance
and collateral effects in comparison with
other drugs. Some of these aspects have
already been discussed in more details in
section 4, but will briefly be summarized
in their context as far as necessary.
2. METHODS
Up until 1997 the meta-analysis of
Warren et al [1], the basis for the guide-
lines of the Infectious Diseases Society
of America (IDSA) for the treatment of
uncomplicated UTI, was used also for this
article. The most relevant studies from
173
Chapter |3| Urinary tract infections in special groups of adult patients
this meta-analysis are included in Tables
1 and 3. For the following period up until
30 April 2008 two different searches were
performed in MEDLINE: one for the
therapy of acute uncomplicated cystitis
and one for the therapy of uncomplicated
pyelonephritis of adult non pregnant
women.
The following key words were used:
cystitis, urinary tract infection, pyelone-
phritis, kidney infection; with the follow-
ing limitations: included and published
in PubMed 1 January 1998 until 30 April
2008, human, female, adults 19 years
and older, clinical studies, randomised
controlled trials (RCT) or studies, meta-
analysis, English, German, only publica-
tions with abstracts.
From the MEDLINE search 1219 pub-
lications were identified. After elimination
of duplicates according to title and abstract
27 prospective, randomised, controlled
studies for the treatment of acute uncom-
plicated cystitis were found (Table 1).
Two of them [2]–[3] were not considered,
because in the first study not only women
with uncomplicated UTI were included
and in the second study only Japanese cri-
teria were used which are quite different.
Seven studies on oral treatment of
uncomplicated pyelonephritis were found,
in an additional six studies (seven publi-
cations) oral therapy followed after initial
parenteral therapy, and in four studies
parenteral therapy only was performed
(Table 3). In some of these studies acute
uncomplicated pyelonephritis in female
patients was studied with the same pro-
tocol as complicated UTI/pyelonephritis.
Unfortunately substratification of the
patients was not always available. For
parenteral use, two earlier uncontrolled
studies were added (cefepime, mero-
penem). These publications were supple-
mented by studies known by the authors
and considered relevant for this topic.
In addition, three meta-analyses on
general aspects of antibiotic therapy for
acute uncomplicated cystitis [4–6] and
one recently published meta-analysis on
174
antibiotic versus placebo treatment of
women with uncomplicated cystitis [7]
were also considered. The studies were
rated according to the level of evidence
(LoE) and the grade of recommendation
(GoR) using ICUD standards (for details
see Preface) [8–9].
3. UNCOMPLICATED CYSTITIS
3.1 Natural history and
placebo-controlled studies
There seems to be no long-term adverse
effects with respect to renal function
or increased mortality associated with
acute uncomplicated cystitis in the non-
pregnant population, even in women
who experience frequent recurrences.
Untreated cystitis rarely progresses to
symptomatic upper tract infection. The
significance of lower tract infection in
non-pregnant women seems to be limited
to the morbidity of symptoms caused by
the infection, which can lead to substan-
tial disruption of the lives of affected indi-
viduals. In fact, most lower UTIs clear
spontaneously if untreated, although
symptoms may persist for several months.
In a prospective, placebo-controlled study
(LoE 1b) [10], 288 of a total of 1143
women consulting for symptoms sugges-
tive of UTI were treated with placebo for
seven days. Interestingly, the associations
between all symptoms and bacteriuria or
bacterial counts were unpredictable.
The spontaneous cure rate of symp-
toms was 28% after the first week, and
after five to seven weeks 37% had neither
symptoms nor bacteriuria. Considering
the high dropout rate after the first fol-
low-up visit, the spontaneous cure rate of
symptoms and bacteriuria was calculated
to be 24% at the end of the study.
In a recently published meta-analysis
on antibiotic versus placebo treatment
of women with uncomplicated cystitis by
Falagas and coworkers [7] among system-
atic literature searches in the PubMed
 Table 1 Relevant clinical trials on antimicrobial therapy of acute uncomplicated cystitis in adult non-pregnant females.

Test Dosage Dosage First author,

Antibiotic (mg) Duration Comparison (mg) Duration LoE year Ref Remarks
Amoxicillin/ 500/125 bid 3 days Ciprofloxacin 250 bid 3 days 2b Hooton 2005 [33] Amoxiclav was significantly inferior to
Clavulanic Acid ciprofloxacin

Cefdinir* 100 bid 5 days Cefaclor 250 tid 5 days 1b Leigh 2000 [37] Cefdinir as effective as cefaclor 250 mg
tid for 5 days, but more adverse events

Cefpodoxime 100 bid 3 days TMP-SMX 800/160 bid 3 days 1b Kavatha 2003 [38] Cefpodoxime as effective and as tolerable
proxetil as TMP-SMX for 3 days

Cefuroxime 125 bid 3 days Ofloxacin 100 bid 3 days 1b Naber 1993° [35] Cefuroxime similar effective and as toler-
axetil able as TMP-SMX. Study underpowered
to show equivalence

Ciprofloxacin 500 SD 1 day Norfloxacin 400 bid 3 days 1b Auquer 2002 [61] Ciprofloxacin as effective and as tolerable
as norfloxacin 400 mg bid for 3 days.

Ciprofloxacin 100 bid 3 days Ofloxacin 200 bid 3 days 1b McCarty 1999 [62] Ciprofloxacin as effective as ofloxacin
and TMP-SMX, but significantly better
TMP-SMX 800/160 bid
tolerable

Ciprofloxacin 100 bid 3 days Nitrofurantoin 100 bid 7 days 1b Iravani 1999 [63] Ciprofloxacin as effective as cotrimoxa-
zole and nitrofurantoin
TMP-SMX 800/160 bid 7 days

Ciprofloxacin 500 SD 1 day Norfloxacin 400 bid 7 days 1b Iravani 1995 [64] Ciprofloxacin 3 days as effective as 5–7
days and 7 days norfloxacin, respectively,
100–500 bid 3–7 days
but more effective as 500 mg SD

Ciprofloxacin 250 bid 3 days Ciprofloxacin 250 bid 7 days 1b Vogel 2004 [65] For treatment of postmenopausal, not in
long-term facilities, and otherwise healthy
women 3 days as effective as 7 days

Ciprofloxacin 250 bid 3 days Norfloxacin 400 bid 7 days 1b Arredondo- [66] Ciprofloxacin similarly effective as nor-
Garcia 2004 floxacin and TMP-SMX. Study underpow-
TMP-SMX 800/160 bid 7 days
ered for equivalence. Highest drug-related
adverse events in the TMP-SMX group.
Antibiotic treatment of uncomplicated urinary tract infection

continued

175
| 3.4 |
 Table 1 Relevant clinical trials on antimicrobial therapy of acute uncomplicated cystitis in adult non-pregnant females – cont’d

176
Chapter

Test Dosage Dosage First author,

Antibiotic (mg) Duration Comparison (mg) Duration LoE year Ref Remarks
Ciprofloxacin 500 qd 3 days Ciprofloxacin 250 bid 3 days 1b Henry 2002 [67] Ciprofloxacin XR 500 mg qd as effective
|3|

XR* and as tolerable as ciprofloxacin 250 mg

bid for 3 days

Ciprofloxacin 500 qd 3 days Ciprofloxacin 250 bid 3 days 1b Fourcroy 2005 [68] Ciprofloxacin XR 500 mg qdas effective as
XR* ciprofloxacin 250 mg bid for 3 days, but
better tolerable

Enoxacin 200 bid 3 days Enoxacin 600 SD 1 day 1b Backhouse [69] Enoxacin 3 days better than SD, but
1989° statistically underpowered

Fleroxacin* 400 SD 1 day Fleroxacin 200 qd 7 days 1b Iravani 1993 [70] Fleroxacin comparable clinical success,
but decreased microbiological eradication
Ciprofloxacin 250 bid 7 days
than 7 days

Fleroxacin* 200 SD 3 days Fleroxacin 200 qd 7 days 1b Iravani 1995° [71] Fleroxacin as effective and as tolerable
as 7 days fleroxacin 200 mg qd or
Ciprofloxacin 250 bid 7 days
ciprofloxacin 250 mg bid (abstract)

Fosfomycin 3000 SD 1 day Pipemidic acid 400 bid 5 days 1b Jardin 1990 [72] Fosfomycin as effective as pipemidic acid
trometamol and better tolerable

Fosfomycin 3000 SD 1 day Norfloxacin 400 bid 7 days 1b Boerema 1990 [73] Fosfomycin as effective as norfloxacin,
trometamo l but more (not significant) adverse events.
Study underpowered to show equivalence

Fosfomycin 3000 SD 1 day Norfloxacin 400 bid 5 days 1b De Jong 1991 [74] Fosfomycin as effective as norfloxacin but
trometamol significantly less adverse events. Study
underpowered to show equivalence

Fosfomycin 3000 SD 1 day Nitrofurantoin 50 q6h 7 days 1b Van Pienbroek [75] Fosfomycin as effective as nitrofurantoin,
Urinary tract infections in special groups of adult patients

trometamol but more gastrointestinal sideeffects with

fosfomycin

Fosfomycin 3000 SD 1 day Not applicable - - 1a Lecomte 1996 [76] Meta analysis of 15 comparative studies:
trometamol TA in general as effective and as toler-
Lecomte 1997° [22]
able as the comparators if compared to
SD as well as to longer duration therapy;
TA long term results even better than
comparators
 Fosfomycin 3000 SD 1 day Trimethoprim 200 bid 5 days 1b Minassian 1998 [23] Fosfomycin as effective and as tolerable
trometamol as trimethoprim

Fosfomycin 3000 SD 1 day Nitrofurantoin 100 bid 7 days 1b Stein 1999 [24] Fosfomycin as effective and as tolerable
trometamol macrocrystal as nitrofurantoin

Fosfomycin 3000 SD 1 day no comparator - - 1b Bonfiglio 2004 [77] Open, not comparative study by GPs, 387
trometamol female patients,18–65y, after 8–10 d
94.5% microbiological eradication and
88.9% clinical success (cure + improve-
ment), GI adverse events 4.3%

Gatifloxacin* 400 SD 1 day Gatifloxacin 200 qd 3 days 1b Richard 2002 [78] Gatifloxacin as effective and as tolerable
as gatifloxacin and ciprofloxacin for 3
Ciprofloxacin 250 bid 3 days
days each

Gatifloxacin* 400 SD 1 day Gatifloxacin 200 qd 3 days 1b Naber 2004 [79] Gatifloxacin as effective and as tolerable
as gatifloxacin and ciprofloxacin for 3
Ciprofloxacin 250 bid 3 days
days each

Levofloxacin 250 qd 3 days Ofloxacin 200 bid 3 days 1b Richard 1998° [32] Levofloxacin as effective and as tolerable
as ofloxacin, but better tolerable
[80]

Lomefloxacin* 400 qd 3 days Lomefloxacin 400 qd 7 days 1b Neringer 1992 [81] Lomefloxacin as effective and as tolerable
as norfloxacin, but less tolerable
Norfloxacin 400 bid 7days

Lomefloxacin* 400 qd 3 days Lomefloxacin 400 qd 7 days 1b Nicolle 1993 [82] Lomefloxacin as effective and as tolerable
as norfloxacin
Norfloxacin 400 bid 7days

Nitrofurantoin 50–100 q6h 3 days Nitrofurantoin 50–100 q6h 5–7 days 2b Goettsch 2004° [29] Nitrofurantoin 3 days less effective than
than 5–7 days
MC 100 bid 100 bid (MC)

Nitrofurantoin 100 bid 5 days TMP-SMX 800/160 bid 3 days 1b Gupta 2007 [31] Nitrofurantoin 5 days equivalent to 3 days
MC TMP-SMX

Nitrofurantoin 100 bid 7 days Trimethoprim 200 bid 7 days 1b Spencer 1994 [30] Bacterial elimination rate was low
MC (77%–83%) for all three comparators
TMP-SMX 800/160 bid 7 days
(nitrofurantoin, trimethoprim, TMP-SMX)
Antibiotic treatment of uncomplicated urinary tract infection

Norfloxacin 400 bid 3 days Norfloxacin 400 bid 7 days 1b Inter-Nordic [83] Norfloxacin 3 days as effective and as
1988 tolerable as 7 days, but recurrence rate
higher with 3 days than with 7 days

177
| 3.4 |

continued
 Table 1 Relevant clinical trials on antimicrobial therapy of acute uncomplicated cystitis in adult non-pregnant females – cont’d

178
Chapter

Test Dosage Dosage First author,

Antibiotic (mg) Duration Comparison (mg) Duration LoE year Ref Remarks
|3|

Norfloxacin 400 bid 3 days Norfloxacin 400 bid 7 days 1b Piipo 1990 [84] Norfloxacin 3 days as effective and as
tolerable as 7 days

Norfloxacin 800 qd 3 days Norfloxacin 400 bid 3 days 1b Pimentel 1998 [85] Norfloxacin 3 days as effective and as
tolerable as 800 mg qd

Ofloxacin 100 bid 3 days TMP-SMX 800/160 bid 3 days 1b Block 1987 [86] Ofloxacin as effective and as tolerable as
3 days TMP-SMX

Ofloxacin 200 bid 3 days TMP-SMX 800/160 bid 7 days 1b Hooton 1989 [87] Ofloxacin as effective and as tolerable as
7 days TMP-SMX

Ofloxacin 200 bid 3 days Ofloxacin 400 SD 1 day 1b Hooton 1991 [88] Ofloxacin as effective and as tolerable
as 7 days TMP-SMX ; ofloxacin SD less
TMP-SMX 800/160 bid 7 days
effective

Pefloxacin* 800 SD 1 day Norfloxacin 400 bid 5 days 1a Naber 1994° [89] Pefloxacin as effective and as tolerable
as norfloxacin and TMP-SMX, but less
TMP-SMX 800/160 bid 3–7 days
tolerable. Pefloxacin should be taken with
meals to reduce gastrointestinal adverse
events

Pefloxacin* 400 bid 5 days Ofloxacin 200 bid 5 days 1b Kadiri 1999 [90] Pefloxacin as effective as ofloxacin, but
study underpowered to show equivalence

Pivmecillinam* 200 bid 7days Cephalexin 250 q6h 7 days 1b Menday 2000 [91] Pivmecillinam as effective and as tolerable
as cephalexin

Pivmecillinam* 200 bid 3 days Pivmecillinam 200 bid 7 days 1a Nicolle 2000° [25] 3 days TA less effective than 7 days
Urinary tract infections in special groups of adult patients

(review)

Pivmecillinam* 400 bid 3 days Norfloxacin 400 bid 3 days 1b Nicolle 2002 [26] Pivmecillinam clinically as effective as nor-
floxacin, but bacteriological less effective,
Menday 2002 [27]
however significantly less Candida vagini-
tis with pivmecillinam
 Pivmecillinam* 200 bid-tid 7 days Placebo - 7 days 1b Ferry 2007 [11] Pivmecillinam 7 days more effective as
3 days, and both significantly more effec-
400 bid 3 days
tive than placebo

Rufloxacin* 400 SD 1 day Pefloxacin 800 SD 1 day 1b Jardin 1995 [92] Rufloxacin as effective as pefloxacin and
norfloxacin but less tolerable (more CNS
adverse events)
Sparfloxacin* 400, 200, 200 3 days Ofloxacin 200 bid 3 days 1b Henry 1998 [93] Sparfloxacin as effective as ofloxacin
qd 200 mg bid for 3 days, but higher rate
of phototoxicity. ofloxacin higher rate of
sleeplessness
Sparfloxacin* 400, 200, 200 3 days Ciprofloxacin 250 bid 7 days 1b Henry 1999 [94] Sparfloxacin as effective as ciprofloxacin
qd 250 mg bid for 7 days, and better than SD,
but higher rate of phototoxicity
Trimethoprim 200 bid 5–7 days (metaanalysis) - - 1a Warren 1999 [1] Trimethoprim recommended as standard,
if E. coli resistance is below 20%

Trimethoprim 200 bid 3 days Trimethoprim 200 bid 5–7 days 2b Goettsch 2004° [29] 3 days less effective than 5–7 days

Trimethoprim 200 bid 3 days Trimethoprim 200 bid 10 days 1b Gossius 1985° [95] Trimethoprim 3 days less adverse events
than 10 days

Trimethoprim 200 bid 3 days Trimethoprim 200 bid 5 days 1b Van Merode [96] Trimethoprim 3 days not different to 5 days,
2005 but follow up too short. In the abstract
number of patients and dosage are missing.
TMP-SMX 320/1600 SD 1 day TMP-SMX 160/800 bid 3 days 1b Gossius 1984 [97] TMP-SMX single dose as effective as 3–10
days, but less side effects
10 days
TMP-SMX 160/800 bid 3 days (metaanalysis) - - 1a Warren 1999 [1] TMP-SMX recommended as standard if
the E. coli resistance is below 20%; 3-day
course trend to higher recurrence rate,
but better tolerable than longer treatment
TMP-SMX 160/800 bid 3 days TMP-SMX 160/800 bid 3 days 2a Raz 2002 [40] Clinical and microbiological success in
E. coli S E. coli R female patients due to suceptible as com-
pared to resistant E. coli about twice as high
Antibiotic treatment of uncomplicated urinary tract infection

LoE-level of evidence; SD-single dose; qd-once daily; bid-twice daily; tid-three times daily; q6h-four times daily; TMP-SMX-cotrimoxazole; MC-macrocrystal.
*not available in all countries; ° not found in Warren 1999 and MEDLINE search 1998 until 2008.

179
| 3.4 |
Chapter |3| Urinary tract infections in special groups of adult patients
database, Cochrane Central Register of
Controlled Trials (both up to 7 November
2008), and Scopus (up to 12 November
2008) as well as by hand-searching the
bibliographies of relevant articles, five
individual RCTs were considered as eli-
gible for inclusion in their meta-analysis
[11–15]. All five RCTs enrolled adult
women with clinical symptoms suggestive
of a lower UTI. In all five included stud-
ies, the enrolled patients had documented
bacteriuria. In the five studies different
antibiotics (pivmecillinam, nitrofuran-
toin, cefixime, amoxicillin, cotrimoxazole,
and sulphadimidine) with different dos-
age regimens (single dose, three-day or
seven-day courses) were compared with
placebo. In all five RCTs, the patients
allocated in the placebo treatment arms
were treated with placebo for the same
durations as the patients allocated in
the respective antibiotic treatment arms.
The duration of follow up varied between
three days after treatment initiation and
three months after the end of treatment.
Clinical success (cure and improvement)
was significantly more likely in women
treated with antibiotics than in those
treated with placebo. Antibiotics were
also superior to placebo regarding cure
(complete disappearance of all clinical
symptoms), microbiological eradication at
the end of treatment and microbiological
reinfection and relapse. However, adverse
events were more likely to occur in anti-
biotic-treated patients than in placebo-
treated women (four RCTs, 1068 patients,
REM, OR=1.64, 95%CI=1.10–2.44). No dif-
ference was found between the compared
treatment arms regarding study with-
drawals from adverse events, the develop-
ment of pyelonephritis and emergence of
resistance.
3.2 Bacterial spectrum and
antimicrobial susceptibility
Knowledge of the antimicrobial susceptibil-
ity profile of uropathogens causing uncom-
plicated UTIs in the community should
180
guide therapeutic decisions (GoR A),
although the trend away from routinely
culturing patients with uncomplicated cys-
titis may unfortunately lead to the lack of
such data. The resistance pattern of E. coli
strains causing an uncomplicated UTI,
however, may vary considerably between
European regions and countries, so that
no general recommendations are suitable
throughout Europe. In an international
survey of the antimicrobial susceptibility
of uropathogens from uncomplicated UTI,
the overall resistance rate was lowest in
the Nordic countries and Austria, and
highest in Portugal and Spain (LoE 2b)
[16–17].
A recently published international sur-
veillance study on women with uncom-
plicated cystitis was performed in nine
European countries and in Brazil [18]
and determined the susceptibility of
the uropathogens for nine oral anti-
biotics according to CLSI breakpoints
[19]. Escherichia coli was most fre-
quent causative pathogen (74.6%), fol-
lowed by Enterococcus faecalis (4.0%),
Staphylococcus saprophyticus (3.6%),
Klebsiella pneumoniae (3.5%), and Proteus
mirabilis (3.5%). E. coli showed the high-
est rate of susceptibility to fosfomycin
(98.1%), followed by mecillinam (95.8%),
nitrofurantoin (95.2%), and ciprofloxacin
(91.8%). The lowest rates were found for
ampicillin (45.1%), cotrimoxazole (70.5%).
Amoxicillin combined with clavulanic acid
(amoxiclav) (82.1%), cefuroxime (82.5%),
and nalidixic acid (82.5%) showed mod-
erate susceptibility rates. For the total
spectrum the order was for fosfomycin
(96.4%), mecillinam (95.9%), ciprofloxacin
(90.3%), and nitrofurantoin (87.0%). In all
countries a susceptibility rate to E. coli
above 90% was found only for fosfomy-
cin, mecillinam, and nitrofurantoin; and
to the total spectrum only for fosfomycin
(96.4%), and mecillinam (95.9%), but not
for nitrofurantoin (87.0%). The suscep-
tibility rates varied significantly from
country to country, except for fosfomycin,
mecillinam, and nitrofurantoin.
 Antibiotic treatment of uncomplicated urinary tract infection
3.3 Treatment modalities
Short courses (1–3–5 days) of antimicro-
bials are highly effective in the treatment
of acute uncomplicated cystitis in pre-
menopausal women (LoE 1a) [1, 20].
Short-course regimens are desirable
because of the improved compliance that
they promote, their lower cost, lower fre-
quency of adverse reactions in the indi-
vidual patient and less collateral effects
on the environmental flora (see Chapter
2.6). However, in assessing the potential
advantages of short-course regimens,
it is necessary to consider the potential
added expense associated with treat-
ment failures or recurrences arising from
short-course therapy. It is also important
to consider the potential psychological
aspects of single-dose therapy; as symp-
toms may not subside for two or three
days, the patient may have misgivings
during this time about the “insufficient”
treatment provided to her. Such a sce-
nario may result in unnecessary visits or
calls to the physician.
A wide variety of antimicrobial regimens
comprising different drugs, doses, sched-
ules and durations have been used to treat
these common bacterial infections. Only a
few of these regimens have been compared
directly in adequately designed studies. To
develop evidence-based guidelines for the
antimicrobial therapy of uncomplicated
acute bacterial cystitis and pyelonephritis
in women, a committee of the IDSA sys-
tematically reviewed the English medical
literature up to 1997 and developed guide-
lines for the antimicrobial treatment of
acute uncomplicated bacterial cystitis and
pyelonephritis in women [1]. Using this
database and more recent publications
(up until April 2008) the following anti-
microbials were considered: trimethoprim
(TMP), trimethoprim-sulfamethoxazole
(TMP-SMX), fluoroquinolones (cipro-
floxacin, enoxacin, fleroxacin, gatifloxacin,
levofloxacin, lomefloxacin, norfloxacin,
ofloxacin, pefloxacin, rufloxacin), ß-lactams
(amoxycillin, ampicillin-like compounds,
| 3.4 |
cefadroxil, cefuroxime axetil, cefpodoxime
proxetil, ceftibuten, pivmecillinam, riti-
penem axetil), fosfomycin trometamol, and
nitrofurantoin (Table 1).
The following conclusions regarding
antimicrobial therapy can be made con-
sidering epidemiology especially in the
light of the recent results of the ARESC
study [18], efficacy, tolerance and collat-
eral effects (see also Chapter 2.6).
3.3.1 Fosfomycin
The findings on susceptibility/resistance
of E. coli to fosfomycin closely resemble
those from other surveys [16–17, 21].
Fosfomycin’s low level of resistance does
not seem to be jeopardized by its high
consumption in some areas [17]. A meta-
analysis of 15 comparative studies and
two additional large comparative stud-
ies published later showed an equivalent
clinical and bacteriologic efficacy and tol-
erance between fosfomycin trometanol
(FT) 3 g as single dose and comparative
drugs [22–24]. Therefore FT can be rec-
ommended as a drug of choice in coun-
tries where it is available for the empiric
therapy of uncomplicated cystitis in
women.
3.3.2 Mecillinam
After fosfomycin, mecillinam showed the
lowest resistance rates in all countries.
In two studies pivmecillinam was either
used as 200 mg for seven days or as 400
mg bid for three days [25–26]. Three
day pivmecillinam was compared with
norfloxacin 400 mg bid for three days.
Norfloxacin was superior in terms of bac-
teriologic outcome, although differences
in clinical outcome were less marked. On
the other hand adverse events, especially
candida vaginitis, occurred less frequent
in patients treated with pivmecillinam
than in those treated with norfloxacin
[27]. Although not available in all coun-
tries, pivmecillinam 400 mg twice daily
for three days can also be considered as
181
Chapter |3| Urinary tract infections in special groups of adult patients
one drug of choice in countries where it
is available for the treatment of uncom-
plicated cystitis in women. Because
pivmecillinam short term therapy was
not equivalent with norfloxacin in bac-
teriological outcome, the recent Swedish
guidelines recommended a dosage of
200 mg tid for five days as a compromise,
although no studies have been performed
using this dosage regimen [28].
3.3.3 Nitrofurantoin
In all countries, susceptibility rates of
E. coli were above 90%, which did not
apply to the total spectrum. However
the resistance rates of the total spectrum
stayed, below 10%. Thus, nitrofuran-
toin could also be an alternative drug for
empiric therapy but is not suitable for
short term therapy [29–30]. A 5-d therapy
with nitrofurantoin was equivalent to
a three day therapy with cotrimoxazole
[31]. In this study the resistance rate of
E. coli for cotrimoxazole was not as high
(12%). In some countries the usage of
nitrofurantoin is limited. In Germany, for
example, nitrofurantoin can only be pre-
scribed if no other effective or tolerable
drugs are available. Under these precau-
tions nitrofurantoin macrocrystal 100 mg
bid for 5 days can be considered a good
alternative for the treatment of uncom-
plicated cystitis in women.
3.3.4 Fluoroquinolones
Comparable dosages considered, the sus-
ceptibility/resistance rates of ciprofloxacin
can be extrapolated to other fluorquinolo-
nes recommended for the treatment of
UTI. In the ARESC study [18] on average
91.8% of E. coli were susceptible and 8.1%
resistant to ciprofloxacin, with significant
variations between different countries. In
Brazil, Hungary, Italy, Russia, and Spain
the rate of resistance was already over
10% (up to 12.9% in Russia). The vary-
ing resistance of E. coli to nalidixic acid
(on average 18.5%), from 6.3% in the
Netherlands to 32.6% in Hungary, shows
182
that the high proportion of E. coli strains
causing community-acquired UTI has
already acquired at least a first-step qui-
nolone resistance.
In several studies ciprofloxacin has
been very effective in the treatment of
uncomplicated cystitis. It was used in
various dosage regimens, mainly 100 mg
bid, 250 mg bid, or in the slow release
form 500 mg qd, each dosage for three
days. The same applies to other fluoroqui-
nolones. According to a Cochrane analysis
[4] all fluoroquinolones suitable for the
treatment of UTI showed the same effec-
tiveness for this indication, but the toler-
ability differed. Levofloxacin, for example,
is used as 250 mg qd for three days and
is as effective as ofloxacin 200 mg bid for
three days, but has better tolerance [32].
However, due to the already consider-
ably increased rate of resistance to E. coli
in some countries, fluoroquinolones should
not be recommended as first-line drug
for the empiric therapy of uncomplicated
lower UTI. However, if they are used (for
any reason) they should not be used in low
dosages (ciprofloxacin or ofloxacin 100 mg
bid), as low doses may promote the emer-
gence of resistance according to expert
opinion. These drugs should be reserved
for pyelonephritis and more complicated
infections in higher suitable dosages and
when susceptibility testing is available.
3.3.5 Aminopenicillins
In the ARESC study [18] ampicillin
showed the highest resistance rates in all
countries and can therefore not be recom-
mended for empiric therapy. Amoxiclav
showed a wide range of susceptible E. coli
strains between 51.9% and 93.5% (mean
82.1%). Similar susceptibility rates were
found for the total spectrum. Amoxiclav
is not suitable for short term therapy,
because a 3-d therapy was inferior to
a three day therapy of ciprofloxacin
[33]. Therefore amoxiclav could only be
regarded second choice for empiric ther-
apy of uncomplicated cystitis.
 Antibiotic treatment of uncomplicated urinary tract infection
3.3.6 Oral cephalosporines
The oral cephalosporines of group 2,
e.g. cefuroxime, have improved activ-
ity against E. coli compared with those
of group 1, e.g. cephalexin, cefaclor,
cefadroxil, but lower activity compared
with those of group 3, e.g. cefpodoxime,
cefixime, ceftibutin [34]. In the ARESC
study [18] the overall susceptibility pat-
tern of E. coli and of the total bacterial
spectrum for cefuroxime was very simi-
lar to that of amoxiclav. There are, how-
ever, country specific differences. Three
day therapy with cefuroxime axetil is
not well established because studies
have been underpowered to demonstrate
its equivalence to cotrimoxazole [35].
It is also debatable whether the same
breakpoints can be applied for the oral
form as for the parenteral form, because
the absolute bioavailability of the
parenteral form is about six to 12 times
higher when the usual intravenous dose
of 750 mg is compared with the usual
oral dose of 250 mg (or 125 mg), assum-
ing an enteral reabsorption of about
50%. Therefore much lower breakpoints
are suggested in other systems for the
oral form than for the parenteral form,
e.g. ≤1 mg/l as susceptible and >4 mg/l
as resistant according to DIN 58940
[36], which means less susceptible/more
resistant strains. In this case the resist-
ance rate would increase from 2.3% to
17.5%, because 15.2% were intermediate
according to CLSI breakpoints, which
then become resistant if the DIN break-
points are used.
A treatment course with cefdinir 100
mg bid for five days was as effective as
cefaclor 250 mg tid for 5 days, but had
more adverse events [37]. The clinical
cure rates by patient at test of cure (5–9
days post-treatment) were 91.3% and
93.0%, respectively, and the microbiologi-
cal response rates by patient were 84.7%
and 79.7%, respectively, while the resist-
ance rate of admission pathogens was
higher for cefaclor than for cefdinir.
| 3.4 |
One sound study with cefpodoxime
proxetil (100 mg bd for three days) showed
equivalent results to co-trimoxazole 960
mg bid for three days in the treatment of
uncomplicated cystitis [38].
3.3.7 Cotrimoxazole
A 3-d therapy with cotrimoxazole was
considered standard in the past [30–31].
According to the ARESC study [18] the
resistance rates to co-trimoxazole var-
ied significantly between countries.
The resistance rates of E. coli are above
20% in most countries tested (range:
20.0–45.4%), except in France (12.2%)
as well as for the total spectrum (range:
26.0–39.2%), except for France (13.4%),
the Netherlands (17.1%), and Poland
(19.2%). For other studies see also chap-
ter 2.2. Therefore, recommendations for
cotrimoxazole (trimethoprim) have to
be country specific. For most European
countries and in Brazil cotrimoxazole
can no longer be recommended as first
choice drug for empiric therapy of uncom-
plicated cystitis. A resistance rate above
20% is recommended as threshold [1, 39],
because patients infected with resistant
E. coli strains showed significantly infe-
rior microbiologic and clinical outcomes
as compared with those infected with sus-
ceptible strains [40]. This applies also for
trimethoprim as monotherapy, which has
the advantage of a lower rate of adverse
events than cotrimoxazole due to the sul-
phonamide part.
3.4 Conclusion for the treatment of
uncomplicated cystitis (Table 2)
Despite wide cross-country variability of
bacterial susceptibility/resistance rates
to the other antimicrobials tested, fosfo-
mycin, mecillinam, and nitrofurantoin
have preserved their in vitro activity in
all countries investigated. They represent
effective options for the empiric therapy
of patients with uncomplicated lower
UTI (cystitis) (GoR A). Other antibiotics,
such as cotrimoxazole, fluoroquinolones,
183
Chapter |3| Urinary tract infections in special groups of adult patients

Table 2 Recommended empiric antimicrobial therapy in acute uncomplicated cystitis in otherwise healthy premenopausal
women.

Substance Daily dosage Duration

Fosfomycin trometamol° 3000 mg SD 1 day

Nitrofurantoin 50–100 mg q6h 5–7 days

Nitrofurantoin MC 100 mg bid 5–7 days

Pivmecillinam* 400 mg bid 3 days

Pivmecillinam* 200 mg bid 7 days

Alternatives:
Ciprofloxacin 250 mg bid 3 days

Levofloxacin 250 mg qd 3 days

Norfloxacin 400 mg bid 3 days

Ofloxacin 200 mg bid 3 days

Cefpodoxime proxetil 100 mg bid 3 days

If local resistance pattern is known (E. coli resistance <20%):

TMP-SMZ 160/800 mg bid 3 days

Trimethoprim 200 mg bid 5 days

MC= macrocrystal; °not in all countries available.

*not in all countries available.

cephalosporins and amoxiclav, should
be considered as second choice taking
account of the local susceptibility pat-
terns of the uropathogens, tolerability,
and collateral effects (GoR B).
3.5 Follow up
Symptomatology may be sufficient for
routine follow-up (LoE 4, GoR C). Routine
post-treatment urinalysis or urine cul-
tures in asymptomatic patients are not
indicated (LoE 4, GoR B) because the
benefit of detecting and treating asymp-
tomatic bacteriuria in healthy women
has been demonstrated only in preg-
nancy and prior to urological instrumen-
tation or surgery [41]. In women whose
symptoms do not resolve by the end of
treatment and in those whose symptoms
resolve but recur within two weeks, urine
culture and antimicrobial susceptibil-
ity testing should be performed (GoR B).
For therapy in this situation, one should
assume that the infecting organism is
not susceptible to the agent originally
used. Retreatment with a 7-day regimen
using another agent should be considered
(LoE 4, GoR C).
4. ACUTE UNCOMPLICATED
PYELONEPHRITIS
The appearance of uncomplicated
pyelonephritis can be mild, moderate, but
in some cases severe and septic.
4.1 Diagnosis
Acute pyelonephritis is suggested by
flank pain, nausea and vomiting, fever
(>38°C), or costovertebral angle tender-
ness, and may occur with or without
cystitis symptoms. The presentation of
an acute uncomplicated pyelonephritis

184
 Antibiotic treatment of uncomplicated urinary tract infection
usually varies from mild to moderate ill-
ness. A life-threatening condition with
multi-organ system dysfunction, includ-
ing sepsis syndrome with or without
shock and renal failure, must be consid-
ered a complicated case. The diagnostic
procedure is discussed in more details in
chapter 3.2.
Unfortunately, no systematic surveil-
lance studies for uncomplicated pyelone-
phritis have been published. From the
published clinical trials, however, it can
be seen that the bacterial spectrum and
the susceptibility pattern is similar for
uncomplicated pyelonephritis and cysti-
tis. However, S. saprophyticus seems to
be less frequent in acute pyelonephritis
as compared to acute cystitis.
4.2 Treatment of uncomplicated
pyelonephritis
There are no placebo-controlled studies
available because, according to clinical
experience, early and effective antimi-
crobial therapy is considered to be the
treatment of choice to prevent prolonga-
tion of the infection and more serious
outcome.
Of several hundred articles screened
by the IDSA group [1], only five were pro-
spective, randomized, controlled trials
[42–46]. One study [42] used a variety
of antimicrobial regimens and therefore
was not suitable for further evaluation.
Eleven randomized studies [47–58] were
published thereafter. In some of these
studies acute uncomplicated pyelone-
phritis was treated with the same pro-
tocol as complicated UTI/pyelonephritis.
Unfortunately substratification was
not always available. For parenteral,
two earlier uncontrolled studies were
added (cefepime,meropenem) [48, 50].
Inclusion of such studies seems to be jus-
tified, because in general the therapeutic
outcome in female patients with acute
uncomplicated pyelonephritis is usually
more favourable than in patients with
complicated UTI.
| 3.4 |
Assuming the susceptibility pat-
tern found in the ARESC study [18] for
uncomplicated cystitis is similar to that
of uncomplicated pyelonephritis (for
which no systematic surveillance studies
are available), the following conclusions
can be drawn for initial therapy from
their analysis.
In Table 3, the antimicrobial treatment
options of acute uncomplicated pyelone-
phritis in adult pre-menopausal non-
pregnant women according to LoE and
GoR as defined in chapter Preface are
summarized. However, in some studies
acute uncomplicated pyelonephritis was
treated with the same protocol as compli-
cated UTI/pyelonephritis and substratifi-
cation was not always available.
4.2.1 Trimethoprim-sulphamethoxazole
(TMP-SMX)
4.2.1.1 TMP-SMX can only be consid-
ered as empiric therapy in communities
in which the resistance rate of E. coli to
TMP is known to be <10%. In this case,
two weeks of therapy with TMP-SMX
for acute uncomplicated pyelonephritis
appears to be adequate for the majority
of women [43](LoE Ib).
4.2.1.2 In communities in which the
resistance rate of E. coli to TMP is >10%,
TMP-SMX should only be considered if
the pathogen is known to be suscepti-
ble, e.g. for a step down therapy from
parenteral to oral therapy.
4.2.2 Fluoroquinolones
A fluoroquinolone can be recommended
as drug of choice for empirical therapy
if the resistance rate of E. coli is below
10%. A 7-day regimen of ciprofloxacin,
500 mg twice daily, showed a signifi-
cantly higher rate of bacterial eradica-
tion and a lower rate of adverse effects
when compared with a 14-day ther-
apy using TMP-SMX, 960 mg twice
daily (LoE 1b) [58]. The higher efficacy
with ciprofloxacin was mainly due to
185
 Table 3 Relevant clinical trials on therapy of acute uncomplicated pyelonephritis. In some trials patients with acute uncomplicated pyelonephritis were treated with the same protocol as

186
patients with complicated pyelonephritis or urinary tract infections, but substratification was not possible.

IV/
Test antibiotic Dosage Duration Comparison Dosage Duration LoE Author, year Ref oral Remarks

Ampicillin 30 g per day for 7 days Ampicillin moderate 1 month 1b Ode 1980 [44] IV Ampicillin in excessive high
3 days, then 20 dosages dosage was inferior to nor-
g per day for 4 (abstract) mal dosage, conventional
days therapy relatively bad results
(Cure 9/21), low number

Cefepime 1 g bid 8.5 days no comparator - - 4 Giamarellou [48] IV Cefepime 1g bid is safe and
(mean) 1993 effective as other parenteral
cephalosporins for the treat-
ment of acute bacterial UTI
and serious bacterial infec-
tions (historical comparison)

Cefixime 400 mg qd 10 days Ceftriaxone 1 g qd 10 days 1b Sanchez 2002 [55] IV/ After initial ceftriaxone i.v.
Initial Ceftriaxone 1g oral oral cefixime as effective as
IV ceftriaxone 1g qd i.v. for
10 days in women with acute
uncomplicated pyelonephritis

Ciprofloxacin oral 500 mg bd 7 days TMP-SMZ 800/160 mg 14 days 1b Talan 2000 [58] IV/ Ciprofloxacin significantly
+ Ciprofloxacin IV + 400 mg IV bd + Cetriaxone IV bid + 1 g IV qd oral more effective than ceftri-
axone/cotrimoxazole for 10
days, also with trend of bet-
ter tolerance

Ciprofloxacin XR* 1000 mg qd 7–14 days Ciprofloxacin 500 mg bid 7–14 days 1b Talan 2004 [56– oral Cefpodoxime as effective
57] and as tolerable as 7–10 days
ciprofloxacin 500 mg bid

Cefpodoxime 200 mg bid 10 days Ciprofloxacin 500 mg bid 10 days 1b Naber 2001 [52] oral Clinically, but not micro-
proxetil biologically as effective as
ciprofloxacin 500 mg bid
 Ceftibuten 200 mg bid 10 days Norfloxacin 400 mg bid 10 days 1b Cronberg 2001 [47] IV/ Clinically, but not micro-
+ initial + 750 mg bid + initial + 750 mg bid oral biologically as effective as
Cefuroxime Cefuroxime norfloxacin 400 mg bid for
10 days. Both treatment
regimens after initial cefuro-
xime i.v.

Doripenem IV 0.5 g tid 10 days Levofloxacin IV 250 mg qd 10 days 1b Naber 2009 [98] IV/ Doripenem 0.5 g tid is as
+ followed by oral + 250 mg qd + followed by oral effective as levofloxacin
(optional) oral 250 mg qd for the treatment
(optional) of uncomplicated pyelone-
Levofloxacin
Levofloxacin phritis and complicated UTI

Ertapenem 1.0 g qd 4 ( 2–14) Ceftriaxone (after 1 g qd 4( 2–14) 1b Wells 2004 [99] IV/ Ertapenem 1 g qd is as ef-
(after >3 days days >3 days possible days oral fective as ceftriaxone 1 g qd
possible oral oral therapy, usu- for the treatment of uncom-
therapy, usually ally ciprofloxacin) plicated pyelonephritis and
ciprofloxacin) complicated UTI followed by
appropriate oral therapy

Gatifloxacin* 400 mg qd vs 10 ( 5–14) Ciprofloxacin 500 mg bid 10 ( 5–14) 1b Naber 2004 [51] oral Levofloxacin as effective and
200 mg qd days days as tolerable as ciprofloxacin
500 mg bid

Levofloxacin 250 mg qd 10 days Ciprofloxacin 500 mg bid 10 days 1b Richard 1998 [54] oral Levofloxacin as effective and
as tolerable as ciprofloxacin
500 mg bid (underpowered)

Levofloxacin 250 mg qd 10 days Lomefloxacin 400 mg qd 10 days 1b Richard 1998 [54] oral Levofloxacin as effective and
as tolerable as lomefloxacin
400 mg qd (underpowered)

Levofloxacin IV/oral 750 mg qd 5 days Ciprofloxacin IV/ 400/500 mg 10 days 1b Klausner 2007 [49] IV/ Levofloxacin as effective and
(IV-optional) oral (IV optional) bid Peterson 2008 oral as tolerable as ciprofloxacin
[53]
IV/ 400/500 mg bid for 10 days.
oral Both treatment regimens
after initial i.v. therapy. Both
studies refer to the same
cohort.

187
continued
 Table 3 Relevant clinical trials on therapy of acute uncomplicated pyelonephritis. In some trials patients with acute uncomplicated pyelonephritis were treated with the same protocol as

188
patients with complicated pyelonephritis or urinary tract infections, but substratification was not possible – cont’d

IV/
Test Antibiotic Dosage Duration Comparison Dosage Duration LoE Author, year Ref oral Remarks

Meropenem 1 g tid ? Ceftazidime + 2 g tid ? 4 Mouton 1995 [50] IV Meropenem is as well toler-
Amikacin 15 mg/kg per ated and as effective as the
day combination of ceftazidime
plus amikacin in the treat-
ment of serious infections
(including pyelonephritis)

Piperacillin/ 2/0.5 g tid 5–14 days Imipenem/ 0.5/0.5 g tid 5–14 days 1b Naber 2002 [100] IV Piperacillin/Tazobactam
Tazobactam Cilastatin 2/0.5 g tid is as effective as
imipenem/cilastatin 05/05 g
tid for the treatment of un-
complicated pyelonephritis
and complicated UTI

Pivampicillin(PA)/ 0.5 gPA/0.4 1 week Pivampicillin(PA)/ 0.5 gPA/0.4 3 weeks 1b Jernelius 1988 [45] oral 1-week treatment is too
Pivmecillinam(PM) gPM tid Pivmecillinam(PM) gPM tid short. Side-effects more com-
mon with 3-week treatment
(0.5 gPA/0.4 gPM tid 1 week
+ 0.25 gPA/0.2 gPM tid 2
week) and bacteriological
success still low (69%)

TMP-SMX 160/800 mg bid 14 days TMP-SMX 160/800 mg 6 weeks 1b Stamm 1987 [43] oral As effective as TMP-SMX for
bid 6 weeks, but better tolerable

TMP-SMX + 160/800 mg bid 14 days Ampicillin + IV 1 g q6h for 14 days 1b Johnson 1991 [46] oral Cotrimoxazole more effec-
initially Gentamicin IV for 3 days, initially 3 days, then tive than ampicillin due to
then oral Gentamicin oral 500 mg 1) more resistant strains and
+ GM tid q6h 2) increased recurrence even
+ GM tid with susceptible strains

*not available in all countries; TMP = trimethoprim; SMX = sulphamethoxazole.

 Antibiotic treatment of uncomplicated urinary tract infection
TMP-resistant E. coli strains. In clinical
trials, the following fluoroquinolones were
comparable to conventional ciprofloxacin
500 mg twice daily, ciprofloxacin extended
release formulation (1000 mg once daily),
gatifloxacin (400 mg once daily), levo-
floxacin (250 mg twice daily), and lom-
efloxacin (400 mg once daily) (LoE 1b)
[51, 54, 56]. An interesting concept with
fluoroquinolones is the use of higher dos-
age and shorter treatment duration. In a
double-blind, randomized study [49, 53]
levofloxacin 750 mg once-daily for five
days was as effective and tolerable as cip-
rofloxacin 400/500 mg twice-daily for 10
days in the treatment of complicated UTI
and acute pyelonephritis. In this study
most of the patients were females with
uncomplicated pyelonephritis.
4.2.3 Aminopenicillins
Aminopenicillins (mono without beta-
lactamase inhibitors), e.g. ampicillin,
amoxicillin, are not longer suitable for
the empiric therapy of acute uncompli-
cated pyelonephritis (GoR A), because
resistance rates are generally too high
and TMP-SMX is preferred to ampicillin
(LoE 1b) [46]. No controlled study used
TMP alone.
4.2.4 Aminopenicillins plus BLI and oral
cephalosporins
For an aminopenicillin plus a BLI, e.g.
amoxiclav, as well as for most group two
and group three oral cephalosporins,
there are no sufficiently powered com-
parative studies versus a fluoroquinolone
or TMP-SMX. In one prospectively rand-
omized study, cefpodoxime proxetil 200
mg twice daily compared to ciprofloxacin
500 mg twice daily (LoE 1b) [52] and in
another prospectively randomized study
with ceftibuten 200 mg once daily com-
pared with norfloxacin 400 mg twice
daily [47], each treatment for 10 days, the
cephalosporins showed equivalent clinical
but not microbiological outcome as the
fluoroquinolones.
| 3.4 |
In areas with a rate of E. coli resistance
to fluoroquinolones >10% and in situations
in which fluoroquinolones are contrain-
dicated (e.g. pregnancy, lactating women,
adolescence), group three oral cepha-
losporin, such as cefpodoxime proxetil or
ceftibutin, or an aminopenicillin plus a
BLI, e.g. amoxiclav, sultamicillin (ampicil-
lin + sulbactam), for a pyelonephritis due to
a Gram-positive pathogen is recommended,
either for initial use, or if a patient has to
be switched to an oral regimen (LoE 3).
4.3 Conclusion of treatment
An algorithm of the clinical manage-
ment of acute pyelonephritis is shown
in Figure 1. (modified according to EAU
guidelines 2008 [59]
4.3.1 Mild and moderate cases of
uncomplicated pyelonephritis
(Table 4)
In mild and moderate cases of acute uncom-
plicated pyelonephritis an oral fluoroqui-
nolone for seven days can be recommended
as first-line therapy (GoR A). In situations
where a fluoroquinolone is not indicated (see
above), a group three oral cephalosporin,
e.g. cefpodoxime proxetil, ceftibuten, may
be an alternative for empirical therapy
(GoR B). Cotrimoxazole or an aminopeni-
cillin plus a BLI should only be used if the
pathogen is known to be susceptible, e.g. for
step down therapy after initial parenteral
therapy (GoR B). In communities with a
high rate of ESBL in E. coli (>10%) an ini-
tial therapy with an aminoglykoside or a
carbapenem has to be considered until sus-
ceptibility testing is available demonstrat-
ing that other, preferably oral, drugs (see
above) can also be used.
4.3.2 More severe cases of acute
uncomplicated pyelonephritis
(Table 4)
Patients with severe pyelonephritis who
cannot take oral medication because of
the severity of the infection with nausea
189
Chapter |3| Urinary tract infections in special groups of adult patients

Symptoms/signs of
pyelonephritis
fever, flank pain
pyuria, leucozytosis

Nausea
vomiting
instability

NO YES

Urinalysis und urine

Urinalysis und urine
culture sonography
culture sonography
(in all patients)
(if anomaly suspected)
Consider hospitalisation
outpatient therapy
and initial parenteral
initial oral therapy
therapy for 1-3 days

Ciprofloxacin or levofloxacin
Aminopenicillin plus BLI Ciprofloxacin or
Cephalosporin Gr. 3 e.g.
levofloxacin
cefpodoxime proxetil Aminopenicillin-or
TMP-SMX, only if piperacillin plus BLI
susceptibility of Cephalosporin (Gr.3)
pathogen is known Aminoglycosid
(not for empiric therapy)

Clinical improvement No clinical improvement Clinical improvement No clinical improvement

within 72 hrs or even detoriation within 72 hrs or even detoriation
Switch to oral therapy
Oral therapy continued Switch to parenteral Parenteral therapy
(test conform)
(test conform) Therapy (test conform) continued (test conform)
Outpatient therapy
Total duration of therapy Total duration of therapy
1-2 Weeks Hospitalisation 1-2 Weeks Hospitalisation continued

Urine culture at day 4
of therapy (optional)
Urine culture at 5-10 days
after end of therapy
Urological investigation if
atypical course or
complicating factors suspected
Additional urine and blood
cultures urological investigation
for complicating factors
drainage, in case of
obstruction or abscess
Total duration of therapy
2-3 Weeks
Urine culture at day 4
of therapy (optional)
Urine culture at 5-10 days
after end of therapy
Urological investigation if
atypical course or complicating
factors suspected
Additional urine and blood
cultures urological
investigation for complicating
factors drainage, in case
of obstruction or abscess
Total duration of therapy
2-3 Weeks

BLI = beta-Lactamase inhibitor; TMP = Trimethoprim; SMX = Sulfamethoxazole

Figure 1. Clinical management of acute pyelonephritis (modified according [59].

190
 Antibiotic treatment of uncomplicated urinary tract infection | 3.4 |

Table 4 Recommended initial empiric antimicrobial therapy in acute uncomplicated pyelonephritis (AUP) in otherwise healthy
premenopausal women. Limitations for each antimicrobial substance see text.

I. Oral therapy in mild and moderate cases

Substance Daily dosage Duration Reference

Ciprofloxacin1 500–750 mg bid 7–10 days [58]

Levofloxacin1 250–500 mg qd 7–10 days [54]

Levofloxacin 750 mg qd 5 days [49, 53]

Alternatives (only clinical but not microbiological equivalent efficacy as compared with
fluoroquinolones):

Cefpodoxime proxetil 200 mg bid 10 days [52]

Ceftibuten 400 mg qd 10 days [47]

Only if the pathogen is known to be susceptible (not for initial empiric therapy):
TMP-SMZ 160/800 mg bid 14 days

Amoxiclav 2,3
0.5/0.125 g tid 14 days

II. Initial parenteral therapy in severe cases

After improvement, the patient can be switched to an oral regimen using one of the above-mentioned antibacterials (if
active against the infecting organism) to complete the 1–2 weeks’ course of therapy. Therefore only daily dosage and no
duration is indicated:

Substance Daily dosage Reference

Ciprofloxacin 400 mg bid [58]

Levofloxacin 1
250–500 mg qd [54]

Levofloxacin 750 mg qd [49]

[58]

Alternatives:

Cefotaxime2 2 g tid

Ceftriaxone 1,4
1–2 g qd [99]

Ceftazidime2 1–2 g tid [50]

Cefepime1,4 1–2 g bid [48]

AmoxiClav2,3 1.5 g tid

Piperacillin/ Tazobactam1,4 2. 5–4.5 g tid [100]

Gentamicin 2
5 mg/kg qd

Amikacin2 15 mg/kg qd

Ertapenem4 1 g qd [99]

Imipenem/Cilastatin 4
0.5/0.5 g tid [100]

continued

191
Chapter |3| Urinary tract infections in special groups of adult patients

Table 4 Recommended initial empiric antimicrobial therapy in acute uncomplicated pyelonephritis (AUP) in otherwise healthy
premenopausal women. Limitations for each antimicrobial substance see text – cont’d

Substance Daily dosage Reference

Alternatives:
Meropenem4 1 g tid [50]

Doripenem4 0.5 g tid [98]

1
lower dose studied, but higher dose recommended by experts.
2
not studied as monosubstance in AUP.
3
mainly for Gram positive pathogens.
4
same protocol for AUP and complicated UTI (stratification not always possible).

and vomiting, have to be treated initially 4.4. Follow up

with suitable parenteral antibiotics, such
as a fluoroquinolone (in communities with
resistance rates of E. coli to fluoroquinolo-
nes <10%), an aminopenicillin plus a BLI
(in case of a susceptible Gram-positive
pathogen), a group three cephalosporin
(in communities with resistance rates of
ESBL <10% of E. coli), an aminoglycoside
and a carbapenem in communities with
a rate of ESBL >10% of E. coli. (GoR B).
Hospital admission should be considered,
especially when complicating factors can-
not be ruled out by available diagnos-
tics and/or the patient has clinical signs
and symptoms of sepsis (GoR B). In gen-
eral, also severe cases of uncomplicated
pyelonephritis can be treated with antibi-
otics alone.
After improvement, the patient can be
switched to an oral regimen using one of
the above-mentioned antibacterials (if
active against the infecting organism) to
complete the 1–2 week course of therapy
(GoR B).
Although approximately 12% of patients
hospitalized with acute uncomplicated
pyelonephritis have bacteraemia [60], it is
common practice to obtain blood cultures
only if the patient appears ill enough to
warrant hospitalization. There is no evi-
dence that bacteraemia has prognostic
significance or warrants longer therapy
in an otherwise healthy individual with
pyelonephritis.
Routine post-treatment urinalysis and
urine cultures in an asymptomatic patient
may not be indicated (GoR C). In women
whose pyelonephritis symptoms do not
improve within three days, or resolve and
then recur within two weeks, repeated
urine culture, antimicrobial susceptibility
testing and an appropriate investigation,
such as renal ultrasound or scan, should
be performed (GoR B). In the patient
with no urological abnormality, it should
be assumed that the infecting organism
is not susceptible to the agent originally
used and tailored treatment with a two-
week regimen using another agent should
be considered (GoR B). For those patients
who relapse with the same pathogen the
diagnosis of uncomplicated pyelonephritis
should be reconsidered. Appropriate diag-
nostic steps are necessary to rule out any
complicating factors (GoR C).
5. FURTHER RESEARCH
Since the recommendations for empiric
therapy depend very much on the epide-
miology and bacterial susceptibility pat-
terns, valid and timely updated local or
regional results need to be available for a
rational decision. It is not clear how this
can be managed, if on the other hand no
routine urine culture is recommended

192
 Antibiotic treatment of uncomplicated urinary tract infection
as a standard. Further studies on acute
uncomplicated cystitis should better
investigate the social and economic
impact of treatment failure. Studies on
uncomplicated pyelonephritis are often
mixed with studies on complicated UTI.
Although the treatment regime may
be the same, it is of utmost importance
to substratify the results accordingly.
Otherwise, no valid results are avail-
able for the specific therapy of uncom-
plicated pyelonephritis. Most studies on
UTI were performed in premenopausal
women without risk factors. Further
studies should investigate, which regi-
mens could be applied to patients with
so called risk factors without compro-
mising the clinical and microbiological
outcome.
6. CONCLUSIONS
Epidemiological studies show a stead-
ily increase of resistance for many anti-
microbials recommended as first line
antibiotics in the past for the empiric
treatment of uncomplicated UTI. For
most of the countries, however, the resist-
ance of E. coli against fosfomycin, mecil-
linam and nitrofurantoin is still low. The
oral forms of these substances can there-
fore be considered first line drugs for the
treatment of uncomplicated cystitis, but
they are not suitable for the therapy of
uncomplicated pyelonephritis. In most
countries the resistance of E. coli for tri-
methoprim has already exceeded the
threshold for empiric therapy of 20% and
resistance for fluoroquinolones are also
rising, which compromises their use as
first line drugs.
To select first line antimicrobials for
the empiric therapy of uncomplicated
pyelonephritis is more difficult, because
treatment failure is more serious than
in cystitis and all antimicrobials recom-
mended as first line drugs in the past suf-
fer from increasing resistance rates very
much dependent on the area.
| 3.4 |
REFERENCES
1. Warren JW, Abrutyn E, Hebel JR, Johnson
JR, Schaeffer AJ, and Stamm WE,
Guidelines for antimicrobial treatment of
uncomplicated acute bacterial cystitis and
acute pyelonephritis in women. Infectious
Diseases Society of America (IDSA). Clin
Infect Dis, 1999. 29(4): 745–58.
2. Gomolin IH, Siami PF, Reuning-Scherer J,
Haverstock DC, and Heyd A, Efficacy and
safety of ciprofloxacin oral suspension ver-
sus trimethoprim-sulfamethoxazole oral
suspension for treatment of older women
with acute urinary tract infection. J Am
Geriatr Soc, 2001. 49(12): 1606–13.
3. Goto T, Kitagawa T, Kawahara M,
Hayami H, and Ohi Y, Comparative study
of single-dose and three-day therapy for
acute uncomplicated cystitis. Hinyokika
Kiyo, 1999. 45(2): 85–9.
4. Rafalsky V, Andreeva I, and Rjabkova E,
Quinolones for uncomplicated acute cys-
titis in women. Cochrane Database Syst
Rev, 2006. 3: CD003597.
5. Katchman EA, Milo G, Paul M, Christiaens
T, Baerheim A, and Leibovici L, Three-day
vs longer duration of antibiotic treatment
for cystitis in women: systematic review
and meta-analysis. Am J Med, 2005.
118(11): 1196–207.
6. Lutters M and Vogt N, Antibiotic dura-
tion for treating uncomplicated, symp-
tomatic lower urinary tract infections in
elderly women. Cochrane Database Syst
Rev, 2002(3): CD001535.
7. Falagas ME, Kotsantis IK, Vouloumanou
EK, and Rafailidis PI, Antibiotics versus
placebo in the treatment of women with
uncomplicated cystitis: a meta-analysis
of randomized controlled trials. J Infect,
2009. 58(2): 91–102.
8. US Department of Health and Human
Services, Public Health Service, Agency
for Health Care Policy and Research.
1992: 115–127.
9. Abrams P, Khoury S, and Grant A,
Evidence–based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. Ferry SA, Holm SE, Stenlund H,
Lundholm R, and Monsen TJ,
193
Chapter |3| Urinary tract infections in special groups of adult patients
The natural course of uncomplicated
lower urinary tract infection in women
illustrated by a randomized placebo con-
trolled study. Scand J Infect Dis, 2004.
36(4): 296–301.
11. Ferry SA, Holm SE, Stenlund H,
Lundholm R, and Monsen TJ, Clinical
and bacteriological outcome of differ-
ent doses and duration of pivmecillinam
compared with placebo therapy of uncom-
plicated lower urinary tract infection in
women: the LUTIW project. Scand J Prim
Health Care, 2007. 25(1): 49–57.
12. Christiaens TC, De Meyere M,
Verschraegen G, Peersman W, Heytens S,
and De Maeseneer JM, Randomised
controlled trial of nitrofurantoin versus
placebo in the treatment of uncomplicated
urinary tract infection in adult women.
Br J Gen Pract, 2002. 52(482): 729–34.
13. Asbach HW, Single dose oral administra-
tion of cefixime 400mg in the treatment of
acute uncomplicated cystitis and gonor-
rhoea. Drugs, 1991. 42 Suppl 4: 10–3.
14. Brooks D, Garrett G, and Hollihead R,
Sulphadimidine, co-trimoxazole, and
a placebo in the management of symp-
tomatic urinary tract infection in gen-
eral practice. J R Coll Gen Pract, 1972.
22(123): 695–703.
15. Dubi J, Chappuis P, and Darioli R,
[Treatment of urinary infection with a
single dose of co-trimoxazole compared
with a single dose of amoxicillin and a
placebo]. Schweiz Med Wochenschr, 1982.
112(3): 90–2.
16. Kahlmeter G, An international survey
of the antimicrobial susceptibility of
pathogens from uncomplicated urinary
tract infections: the ECO.SENS Project. J
Antimicrob Chemother, 2003. 51(1): 69–76.
17. Kahlmeter G, Prevalence and antimicro-
bial susceptibility of pathogens in uncom-
plicated cystitis in Europe. The ECO.
SENS study. Int J Antimicrob Agents,
2003. 22 Suppl 2: 49–52.
18. Naber KG, Schito G, Botto H, Palou J,
and Mazzei T, Surveillance study in
Europe and Brazil on clinical aspects and
Antimicrobial Resistance Epidemiology in
Females with Cystitis (ARESC): implica-
tions for empiric therapy. Eur Urol, 2008.
54(5): 1164–75.
194
19. Institute. CaLS, Methods for dilution
antimicrobial susceptibility testing.,
in 17th Informational supplement,
Institute. CaLS, Editor. 2007, Clinical and
Laboratory Standards Institute.: PA, USA.
20. Naber KG, Short-term therapy of acute
uncomplicated cystitis. Curr Opin Urol,
1999. 9(1): 57–64.
21. Fadda G, Nicoletti G, Schito GC, and
Tempera G, Antimicrobial susceptibil-
ity patterns of contemporary pathogens
from uncomplicated urinary tract infec-
tions isolated in a multicenter Italian
survey: possible impact on guidelines. J
Chemother, 2005. 17(3): 251–7.
22. Lecomte F, Allaert, FA, Single-dose treat-
ment of cystitis with fosfomycin trometa-
mol (Monuril): Analysis of 15 comparative
trials on 2.048 patients. Giorn. It. Ost.
Gin., 1997. 19: 399–404.
23. Minassian MA, Lewis DA,
Chattopadhyay D, Bovill B, Duckworth
GJ, and Williams JD, A comparison
between single-dose fosfomycin trometamol
(Monuril) and a 5-day course of trimetho-
prim in the treatment of uncomplicated
lower urinary tract infection in women. Int
J Antimicrob Agents, 1998. 10(1): 39–47.
24. Stein GE, Comparison of single-dose
fosfomycin and a 7-day course of nitro-
furantoin in female patients with uncom-
plicated urinary tract infection. Clin Ther,
1999. 21(11): 1864–72.
25. Nicolle LE, Pivmecillinam in the
treatment of urinary tract infections.
J Antimicrob Chemother, 2000. 46 Suppl
1: 35–9; discussion 63–5.
26. Nicolle LE, Madsen KS, Debeeck GO,
Blochlinger E, Borrild N, Bru JP,
McKinnon C, O’Doherty B, Spiegel W,
Van Balen FA, and Menday P, Three days
of pivmecillinam or norfloxacin for treat-
ment of acute uncomplicated urinary
infection in women. Scand J Infect Dis,
2002. 34(7): 487–92.
27. Menday AP, Symptomatic vaginal
candidiasis after pivmecillinam and
norfloxacin treatment of acute uncompli-
cated lower urinary tract infection. Int J
Antimicrob Agents, 2002. 20(4): 297–300.
28. (Läkemedelsverket) SMPA,
Guidelines for treatment of uncom-
plicated female UTI (Swedish title:
 Antibiotic treatment of uncomplicated urinary tract infection
Behandlingsrekommendationer vid nedre
okomplicerad UVI). Läkemedelsverket
2007. 18(2): 8–15.
29. Goettsch WG, Janknegt R, and
Herings RM, Increased treatment failure
after 3-days’ courses of nitrofurantoin and
trimethoprim for urinary tract infections
in women: a population-based retrospec-
tive cohort study using the PHARMO
database. Br J Clin Pharmacol, 2004.
58(2): 184–9.
30. Spencer RC, Moseley DJ, and Greensmith
MJ, Nitrofurantoin modified release ver-
sus trimethoprim or co-trimoxazole in the
treatment of uncomplicated urinary tract
infection in general practice. J Antimicrob
Chemother, 1994. 33 Suppl A: 121–9.
31. Gupta K, Hooton TM, Roberts PL, and
Stamm WE, Short-course nitrofurantoin
for the treatment of acute uncomplicated
cystitis in women. Arch Intern Med, 2007.
167(20): 2207–12.
32. Richard GA, DeAbate, C.A.,
Ruoff, G.E.,Corrado, M., Fowler, C.L.,
Morgan, N., A double-blind, randomised
trial of the efficacy and safety of short-
course, once-daily levofloxacin versus
ofloxacin twice daily in uncomplicated uri-
nary tract infection. Infectious Diseases in
Clinical Practice, 1998. 9: 323–329.
33. Hooton TM, Scholes D, Gupta K,
Stapleton AE, Roberts PL, and
Stamm WE, Amoxicillin-clavulanate vs
ciprofloxacin for the treatment of uncom-
plicated cystitis in women: a randomized
trial. Jama, 2005. 293(8): 949–55.
34. Scholz H NKaaEGotP-E-SfCP,
Classification of the oral cephalosporins.
Arzneimitteltherapie 2000. 18: 17–19.
35. Naber KG and Koch EM, Cefuroxime axe-
til versus ofloxacin for short-term therapy
of acute uncomplicated lower urinary
tract infections in women. Infection, 1993.
21(1): 34–9.
36. e.V. DIfN, Medizinische Mikrobiologie -
Empfindlichkeitsprüfung von
mikrobiellen Krankheitserregern
gegen Chemotherapeutika - Teil 4:
Bewertungsstufen für die minimalen
Hemmkonzentrationen - MHK-Grenzwerte -
von antibakteriellen Wirkstoffen., in
Beiblatt zu DIN 58940–1., e.V. DIfN,
Editor. August 2005: Beuth, Berlin.
| 3.4 |
37. Leigh AP, Nemeth MA, Keyserling CH,
Hotary LH, and Tack KJ, Cefdinir versus
cefaclor in the treatment of uncomplicated
urinary tract infection. Clin Ther, 2000.
22(7): 818–25.
38. Kavatha D, Giamarellou H, Alexiou Z,
Vlachogiannis N, Pentea S, Gozadinos T,
Poulakou G, Hatzipapas A, and
Koratzanis G, Cefpodoxime-proxetil
versus trimethoprim-sulfamethoxazole for
short-term therapy of uncomplicated acute
cystitis in women. Antimicrob Agents
Chemother, 2003. 47(3): 897–900.
39. Gupta K and Stamm WE, Outcomes
associated with trimethoprim/sulpham-
ethoxazole (TMP/SMX) therapy in TMP/
SMX resistant community-acquired
UTI. Int J Antimicrob Agents, 2002.
19(6): 554–6.
40. Raz R, Chazan B, Kennes Y, Colodner R,
Rottensterich E, Dan M, Lavi I, and
Stamm W, Empiric use of trimethoprim-
sulfamethoxazole (TMP-SMX) in the
treatment of women with uncomplicated
urinary tract infections, in a geographical
area with a high prevalence of TMP-SMX-
resistant uropathogens. Clin Infect Dis,
2002. 34(9): 1165–9.
41. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
42. Gleckman R, Bradley P, Roth R, Hibert D,
and Pelletier C, Therapy of symptomatic
pyelonephritis in women. J Urol, 1985.
133(2): 176–8.
43. Stamm WE, McKevitt M, and Counts GW,
Acute renal infection in women: treatment
with trimethoprim-sulfamethoxazole or
ampicillin for two or six weeks. A ran-
domized trial. Ann Intern Med, 1987.
106(3): 341–5.
44. Ode B, Broms M, Walder M, and
Cronberg S, Failure of excessive doses of
ampicillin to prevent bacterial relapse in
the treatment of acute pyelonephritis. Acta
Med Scand, 1980. 207(4): 305–7.
45. Jernelius H, Zbornik J, and Bauer CA,
One or three weeks’ treatment of acute
pyelonephritis? A double-blind com-
parison, using a fixed combination of
195
Chapter |3| Urinary tract infections in special groups of adult patients
pivampicillin plus pivmecillinam. Acta
Med Scand, 1988. 223(5): 469–77.
46. Johnson JR, Lyons MF, 2nd, Pearce
W, Gorman P, Roberts PL, White N,
Brust P, Olsen R, Gnann JW, Jr., and
Stamm WE, Therapy for women hos-
pitalized with acute pyelonephritis: a
randomized trial of ampicillin versus
trimethoprim-sulfamethoxazole for 14
days. J Infect Dis, 1991. 163(2): 325–30.
47. Cronberg S, Banke S, Bergman B,
Boman H, Eilard T, Elbel E, Hugo-
Persson M, Johansson E, Kuylenstierna
N, Lanbeck P, Lindblom A, Paulsen O,
Schonbeck C, Walder M, and Wieslander
P, Fewer bacterial relapses after oral
treatment with norfloxacin than with cef-
tibuten in acute pyelonephritis initially
treated with intravenous cefuroxime.
Scand J Infect Dis, 2001. 33(5): 339–43.
48. Giamarellou H, Low-dosage cefepime as
treatment for serious bacterial infections.
J Antimicrob Chemother, 1993. 32 Suppl
B: 123–32.
49. Klausner HA, Brown P, Peterson J, Kaul
S, Khashab M, Fisher AC, and Kahn JB,
A trial of levofloxacin 750 mg once daily
for 5 days versus ciprofloxacin 400 mg
and/or 500 mg twice daily for 10 days in
the treatment of acute pyelonephritis. Curr
Med Res Opin, 2007. 23(11): 2637–45.
50. Mouton YJ and Beuscart C, Empirical
monotherapy with meropenem in serious
bacterial infections. Meropenem Study
Group. J Antimicrob Chemother, 1995.
36 Suppl A: 145–56.
51. Naber KG, Bartnicki A, Bischoff W,
Hanus M, Milutinovic S, van Belle
F, Schonwald S, Weitz P, and Ankel-
Fuchs D, Gatifloxacin 200 mg or 400 mg
once daily is as effective as ciprofloxacin
500 mg twice daily for the treatment of
patients with acute pyelonephritis or
complicated urinary tract infections. Int
J Antimicrob Agents, 2004. 23 Suppl 1:
S41–53.
52. Naber KG SS, Hauke W, Cefpodoxime
proxetil in patients with acute uncompli-
cated pyelonephritis. International, pro-
spective, randomized comparative study
versus ciprofloxacin in general practice.
Chemotherapie Journal, 2001. 10: 29–34.
196
53. Peterson J, Kaul S, Khashab M, Fisher
AC, and Kahn JB, A double-blind, rand-
omized comparison of levofloxacin 750 mg
once-daily for five days with ciprofloxacin
400/500 mg twice-daily for 10 days for
the treatment of complicated urinary
tract infections and acute pyelonephritis.
Urology, 2008. 71(1): 17–22.
54. Richard GA, Klimberg IN, Fowler
CL, Callery-D’Amico S, and Kim SS,
Levofloxacin versus ciprofloxacin versus
lomefloxacin in acute pyelonephritis.
Urology, 1998. 52(1): 51–5.
55. Sanchez M, Collvinent B, Miro O,
Horcajada JP, Moreno A, Marco F,
Mensa J, and Milla J, Short-term effec-
tiveness of ceftriaxone single dose in the
initial treatment of acute uncomplicated
pyelonephritis in women. A randomised
controlled trial. Emerg Med J, 2002.
19(1): 19–22.
56. Talan DA, Klimberg IW, Nicolle LE,
Song J, Kowalsky SF, and Church DA,
Once daily, extended release ciprofloxacin
for complicated urinary tract infections
and acute uncomplicated pyelonephritis.
J Urol, 2004. 171(2 Pt 1): 734–9.
57. Talan DA, Naber KG, Palou J, and
Elkharrat D, Extended-release cipro-
floxacin (Cipro XR) for treatment of uri-
nary tract infections. Int J Antimicrob
Agents, 2004. 23 Suppl 1: S54–66.
58. Talan DA, Stamm WE, Hooton TM,
Moran GJ, Burke T, Iravani A, Reuning-
Scherer J, and Church DA, Comparison of
ciprofloxacin (7 days) and trimethoprim-
sulfamethoxazole (14 days) for acute
uncomplicated pyelonephritis pyelonephri-
tis in women: a randomized trial. Jama,
2000. 283(12): 1583–90.
59. Grabe M (chairman) BM, Bjerklund-
Johansen TE, Botto H, Cek M, Lobel B,
Naber KG, Palou J, Tenke P., Guidelines
on the management of urinary and male
genital tract infections., in European
Association of Urology Guidelines,
Urology EAo, Editor. 2008, European
Association of Urology Arnhem, The
Netherlands. p. 1–116.
60. Finkelstein R, Kassis E, Reinhertz G,
Gorenstein S, and Herman P,
Community-acquired urinary tract
 Antibiotic treatment of uncomplicated urinary tract infection
infection in adults: a hospital viewpoint.
J Hosp Infect, 1998. 38(3): 193–202.
61. Auquer F, Cordon F, Gorina E, Caballero
JC, Adalid C, and Batlle J, Single-dose
ciprofloxacin versus 3 days of norfloxacin
in uncomplicated urinary tract infections
in women. Clin Microbiol Infect, 2002.
8(1): 50–4.
62. McCarty JM, Richard G, Huck W, Tucker
RM, Tosiello RL, Shan M, Heyd A, and
Echols RM, A randomized trial of short-
course ciprofloxacin, ofloxacin, or trimeth-
oprim/sulfamethoxazole for the treatment
of acute urinary tract infection in women.
Ciprofloxacin Urinary Tract Infection
Group. Am J Med, 1999. 106(3): 292–9.
63. Iravani A, Klimberg I, Briefer C,
Munera C, Kowalsky SF, and Echols RM,
A trial comparing low-dose, short-course
ciprofloxacin and standard 7 day therapy
with co-trimoxazole or nitrofurantoin in
the treatment of uncomplicated urinary
tract infection. J Antimicrob Chemother,
1999. 43 Suppl A: 67–75.
64. Iravani A, Tice AD, McCarty J, Sikes DH,
Nolen T, Gallis HA, Whalen EP, Tosiello
RL, Heyd A, Kowalsky SF, and et al.,
Short-course ciprofloxacin treatment of
acute uncomplicated urinary tract infec-
tion in women. The minimum effective
dose. The Urinary Tract Infection Study
Group [corrected]. Arch Intern Med, 1995.
155(5): 485–94.
65. Vogel T, Verreault R, Gourdeau M, Morin
M, Grenier-Gosselin L, and Rochette L,
Optimal duration of antibiotic therapy for
uncomplicated urinary tract infection in
older women: a double-blind randomized
controlled trial. Cmaj, 2004. 170(4):
469–73.
66. Arredondo-Garcia JL, Figueroa-Damian
R, Rosas A, Jauregui A, Corral M, Costa A,
Merlos RM, Rios-Fabra A, Amabile-Cuevas
CF, Hernandez-Oliva GM, Olguin J, and
Cardenosa-Guerra O, Comparison of short-
term treatment regimen of ciprofloxacin
versus long-term treatment regimens of
trimethoprim/sulfamethoxazole or nor-
floxacin for uncomplicated lower urinary
tract infections: a randomized, multicentre,
open-label, prospective study. J Antimicrob
Chemother, 2004. 54(4): 840–3.
| 3.4 |
67. Henry DC, Jr., Bettis RB, Riffer E,
Haverstock DC, Kowalsky SF, Manning
K, Hamed KA, and Church DA,
Comparison of once-daily extended-release
ciprofloxacin and conventional twice-daily
ciprofloxacin for the treatment of uncom-
plicated urinary tract infection in women.
Clin Ther, 2002. 24(12): 2088–104.
68. Fourcroy JL, Berner B, Chiang YK,
Cramer M, Rowe L, and Shore N, Efficacy
and safety of a novel once-daily extended-
release ciprofloxacin tablet formulation for
treatment of uncomplicated urinary tract
infection in women. Antimicrob Agents
Chemother, 2005. 49(10): 4137–43.
69. Backhouse CI and Matthews JA, Single-
dose enoxacin compared with 3-day
treatment for urinary tract infection.
Antimicrob Agents Chemother, 1989.
33(6): 877–80.
70. Iravani A, Multicenter study of single-dose
and multiple-dose fleroxacin versus cipro-
floxacin in the treatment of uncomplicated
urinary tract infections. Am J Med, 1993.
94(3A): 89S-96S.
71. Iravani A CP, Maladorno D. Fleroxacin
in the treatment of uncomplicated
urinary tract infections in women. in
7th European Congress of Clinical
Microbiology and Infectious Diseases
(ECCMID). 1995. Vienna, Austria.
72. Jardin A, A general practitioner mul-
ticenter study: fosfomycin trometamol
single dose versus pipemidic acid mul-
tiple dose. Infection, 1990. 18 Suppl 2:
S89–93.
73. Boerema JB and Willems FT, Fosfomycin
trometamol in a single dose versus nor-
floxacin for seven days in the treatment of
uncomplicated urinary infections in gen-
eral practice. Infection, 1990. 18 Suppl 2:
S80–8.
74. de Jong Z, Pontonnier F, and Plante P,
Single-dose fosfomycin trometamol
(Monuril) versus multiple-dose norfloxacin:
results of a multicenter study in females
with uncomplicated lower urinary tract
infections. Urol Int, 1991. 46(4): 344–8.
75. Van Pienbroek E, Hermans J, Kaptein AA,
and Mulder JD, Fosfomycin trometamol in
a single dose versus seven days nitrofuran-
toin in the treatment of acute uncomplicated
197
Chapter |3| Urinary tract infections in special groups of adult patients
urinary tract infections in women. Pharm
World Sci, 1993. 15(6): 257–62.
76. Lecomte F, Allaert, FA., Le traitement
monodose de la cystite par fosfomycin
trometamol. Analyse de 15 essais com-
paratifs portant sur 2048 malades.
Médecine et Maladies infectieuses, 1996.
26: 338–343.
77. Bonfiglio G, Mattina R, Lanzafame
A, Cammarata E, and Tempera G,
Fosfomycin tromethamine in uncompli-
cated urinary tract infections: a clinical
study. Chemotherapy, 2005. 51( 2–3):
162–6.
78. Richard GA, Mathew CP, Kirstein JM,
Orchard D, and Yang JY, Single-dose
fluoroquinolone therapy of acute uncom-
plicated urinary tract infection in women:
results from a randomized, double-blind,
multicenter trial comparing single-dose to
3-day fluoroquinolone regimens. Urology,
2002. 59(3): 334–9.
79. Naber KG, Allin DM, Clarysse L,
Haworth DA, James IG, Raini C,
Schneider H, Wall A, Weitz P, Hopkins G,
and Ankel-Fuchs D, Gatifloxacin 400
mg as a single shot or 200 mg once daily
for 3 days is as effective as ciprofloxacin
250 mg twice daily for the treatment of
patients with uncomplicated urinary tract
infections. Int J Antimicrob Agents, 2004.
23(6): 596–605.
80. Richard G dC, Ruoff G, Corrado M,
Fowler C. Short-course levofloxacin
(250 mg qid) vs ofloxacin (200 mg bid)
in uncomplicated UTI: a double-blind,
randomized trial. Abstract. in 6th Int
Symp New Quinolones. Nov 15–17, 1998.
Denver, Colorado, USA.
81. Neringer R, Forsgren A, Hansson C, and
Ode B, Lomefloxacin versus norfloxacin
in the treatment of uncomplicated urinary
tract infections: three-day versus seven-
day treatment. The South Swedish Lolex
Study Group. Scand J Infect Dis, 1992.
24(6): 773–80.
82. Nicolle LE, DuBois J, Martel AY,
Harding GK, Shafran SD, and Conly JM,
Treatment of acute uncomplicated uri-
nary tract infections with 3 days of lom-
efloxacin compared with treatment with
3 days of norfloxacin. Antimicrob Agents
Chemother, 1993. 37(3): 574–9.
198
83. Double-blind comparison of 3-day ver-
sus 7-day treatment with norfloxacin in
symptomatic urinary tract infections.
The Inter-Nordic Urinary Tract Infection
Study Group. Scand J Infect Dis, 1988.
20(6): 619–24.
84. Piipo T PT, Salo SA, Three-day versus
seven-day treatment with norfloxacin in
acute cystitis. Curr Ther Res, 1990. 47:
644–653.
85. Pimentel FL, Dolgner A, Guimaraes J,
Quintas M, and Mario-Reis J, Efficacy
and safety of norfloxacin 800 mg once-
daily versus norfloxacin 400 mg twice-
daily in the treatment of uncomplicated
urinary tract infections in women: a
double-blind, randomized clinical trial. J
Chemother, 1998. 10(2): 122–7.
86. Block JM, Walstad RA, Bjertnaes A,
Hafstad PE, Holte M, Ottemo I, Svarva
PL, Rolstad T, and Peterson LE, Ofloxacin
versus trimethoprim-sulphamethoxazole
in acute cystitis. Drugs, 1987. 34 Suppl 1:
100–6.
87. Hooton TM, Latham RH, Wong ES,
Johnson C, Roberts PL, and Stamm WE,
Ofloxacin versus trimethoprim-sulfame-
thoxazole for treatment of acute cystitis.
Antimicrob Agents Chemother, 1989.
33(8): 1308–12.
88. Hooton TM, Johnson C, Winter C,
Kuwamura L, Rogers ME, Roberts PL,
and Stamm WE, Single-dose and three-
day regimens of ofloxacin versus trimeth-
oprim-sulfamethoxazole for acute cystitis
in women. Antimicrob Agents Chemother,
1991. 35(7): 1479–83.
89. Naber KG BW, Fischer M, Kresken M,
Pefloxacin single-dose in the treatment of
acute uncomplicated lower urinary tract
infections in women: a meta-analysis of
seven clinical trials. Int J Antimicrob
Agents, 1994. 4: 197–202.
90. Kadiri S, Ajayi SO, and Toki RA,
Quinolones for short-term treatment of
uncomplicated urinary tract infection.
East Afr Med J, 1999. 76(10): 587–9.
91. Menday AP, Comparison of pivmecillinam
and cephalexin in acute uncomplicated
urinary tract infection. Int J Antimicrob
Agents, 2000. 13(3): 183–7.
92. Jardin A and Cesana M, Randomized,
double-blind comparison of single-dose
 Antibiotic treatment of uncomplicated urinary tract infection
regimens of rufloxacin and pefloxacin for
acute uncomplicated cystitis in women.
French Multicenter Urinary Tract
Infection-Rufloxacin Group. Antimicrob
Agents Chemother, 1995. 39(1): 215–20.
93. Henry D, Ellison W, Sullivan J, Mansfield
DL, Magner DJ, Dorr MB, and Talbot
GH, Treatment of community-acquired
acute uncomplicated urinary tract
infection with sparfloxacin versus
ofloxacin. The Sparfloxacin Multi Center
UUTI Study Group. Antimicrob Agents
Chemother, 1998. 42(9): 2262–6.
94. Henry DC, Nenad RC, Iravani A, Tice AD,
Mansfield DL, Magner DJ, Dorr MB, and
Talbot GH, Comparison of sparfloxacin
and ciprofloxacin in the treatment of
community-acquired acute uncompli-
cated urinary tract infection in women.
Sparfloxacin Multicenter Uncomplicated
Urinary Tract Infection Study Group.
Clin Ther, 1999. 21(6): 966–81.
95. Gossius G VL, The treatment of acute dys-
uria-frequency syndrome in adult women:
double-blind, randomized comparison of
three-day vs ten-day trimethoprim ther-
apy. Curr Ther Res, 1985. 37: 34–42.
96. van Merode T, Nys S, Raets I, and
Stobberingh E, Acute uncomplicated
lower urinary tract infections in general
practice: clinical and microbiological
cure rates after three- versus five-day
| 3.4 |
treatmenth trimethoprim. Eur J Gen
Pract, 2005. 11(2): 55–8.
97. Gossius G and Vorland L, A randomised
comparison of single-dose vs. three-day
and ten-day therapy with trimethoprim-
sulfamethoxazole for acute cystitis in
women. Scand J Infect Dis, 1984. 16(4):
373–9.
98. Naber KG, Llorens, L., Kaniga, K.,
Kotey, P., Redman, R., Intravenous ther-
apy with doripenem versus levofloxacin
with an option to switch to oral therapy
for the treatment of complicated lower
urinary tract infection and pyelonephri-
tis. Antimicr Agents Chemotherapy,
submitted.
99. Wells WG, Woods GL, Jiang Q, and
Gesser RM, Treatment of compli-
cated urinary tract infection in adults:
combined analysis of two randomized,
double-blind, multicentre trials com-
paring ertapenem and ceftriaxone
followed by appropriate oral therapy.
J Antimicrob Chemother, 2004.
53 Suppl 2: ii67–74.
100. Naber KG, Savov O, and Salmen HC,
Piperacillin 2 g/tazobactam 0.5 g is as
effective as imipenem 0.5 g/cilastatin
0.5 g for the treatment of acute uncom-
plicated pyelonephritis and complicated
urinary tract infections. Int J Antimicrob
Agents, 2002. 19(2): 95–103.
199
|3.5|
Urinary tract infections
in pregnancy
Alexander D. Griffin1, Richard Grady2, Thomas M. Hooton1*
1
University of Miami Miller School of Medicine, Miami, FL
2
University of Washington School of Medicine, Seattle, WA
*Corresponding author: Thomas M. Hooton, M.D., Professor of Medicine, University of Miami Miller School of Medicine
1120 NW 14th Street, Suite 1144, Miami, FL 33136, USA,
Tel +1 (305) 243 2576, Fax +1(305) 243 4037, THooton@med.miami.edu
ABSTRACT
Urinary tract infection (UTI) in pregnant
women is common and has a spectrum
that ranges from lower tract infection
(asymptomatic bacteriuria and acute cys-
titis) to upper tract infection (pyelone-
phritis). The epidemiology of UTI is
similar to that in non-pregnant women,
although the anatomic and physiologic
changes of the urinary tract in pregnancy
result in an increased susceptibility to
progress from asymptomatic bacteriuria
to pyelonephritis [1]. Asymptomatic bac-
teriuria is associated with an increased
risk of pyelonephritis and adverse out-
comes of pregnancy [1–2]. Such outcomes
are significantly reduced by appropriate
antimicrobial treatment of asymptomatic
bacteriuria early in pregnancy [1–2].
Thus, antepartum screening is recom-
mended to detect asymptomatic bacteriu-
ria in pregnancy. The cost effectiveness
of screening is governed by the cost of
screening and the prevalence of asymp-
tomatic bacteriuria, which varies among
different socioeconomic groups [3].
Antimicrobial selection is dictated by
drug safety concerns and urine culture
susceptibility data in the face of emerging
resistance.
Acute pyelonephritis during pregnancy
is associated with preterm delivery, yet
there are conflicting data on fetal out-
comes [4]. Although pregnant women with
acute pyelonephritis have traditionally
been hospitalized for parenteral therapy,
outpatient antimicrobial therapy has been
shown to be safe and effective for selected
women prior to the third trimester [5].
A minority of UTI in pregnancy is com-
plicated by factors which warrant drain-
age or longer courses of treatment. Such
factors include obstruction of urinary
drainage or compromised immunity. Such
patients may require drainage and/or

longer durations of antibiotics than is
normally recommended.
In summary, urinary tract infections
are common in pregnancy and contrib-
ute to morbidity in the mother and pos-
sibly the fetus. Appropriate diagnosis and
treatment modalities are an important
aspect of optimal maternal health care.
Key words: bacteriuria, asymptom-
atic bacteriuria, cystitis, pyelonephritis,
pregnancy
SUMMARY OF RECOMMENDATIONS
Definition of significant bacteriuria
1. In an asymptomatic pregnant
woman, bacteriuria is considered
significant if two consecutive voided
urine specimens grow ≥105 cfu/ml of
the same bacterial species on quan-
titative culture; or a single catheter-
ized specimen grows ≥105 cfu/ml of a
uropathogen (GoR A).
2. In a pregnant woman with symptoms
compatible with UTI, bacteriuria is
considered significant if a voided or
catheterized urine specimen grows
≥103 cfu/ml of a uropathogen (GoR B).
Screening
3. Pregnant women should be screened
for bacteriuria during the first trimes-
ter (GoR A).
Treatment of asymptomatic
bacteriuria
4. Asymptomatic bacteriuria detected in
pregnancy should be eradicated with
antimicrobial therapy (GoR A).
Duration of therapy
5. Short courses of antimicrobial therapy
(3 days) should be considered for the
treatment of asymptomatic bacteriuria
and cystitis in pregnancy (GoR A).
Urinary tract infections in pregnancy | 3.5 |
Follow-up
6. Urine cultures should be obtained
soon after completion of therapy for
asymptomatic bacteriuria and sympto-
matic UTI in pregnancy (GoR A).
Prophylaxis
7. Post-coital prophylaxis should be
considered in pregnant women with a
history of frequent urinary tract infec-
tions prior to the onset of pregnancy
to reduce their risk of UTI (GoR B).
Treatment of pyelonephritis
8. Outpatient management with
appropriate antibiotics should be
considered in women with pyelone-
phritis in pregnancy provided symp-
toms are mild and close follow-up is
feasible (GoR A).
Complicated UTI
9. Prolonged courses of antibiotic ther-
apy (7–10 days) should be considered
in this patient population (GoR B).
When indicated, ultrasonography or
magnetic resonance imaging should
be used preferentially in this patient
population to decrease risk to the
fetus (GoR B).
1. INTRODUCTION
Urinary tract infection in pregnancy
encompasses asymptomatic bacteriuria,
lower tract infection (acute cystitis), and
upper tract infection (acute pyelonephri-
tis). Each of these entities is reviewed
here. In addition, the concept of compli-
cated urinary tract infection in pregnancy
and resultant special considerations are
discussed. The overall object of this chap-
ter is to provide a broad review of aspects
of urinary tract infection in pregnancy
with a focus on evidence-based recom-
mendations for diagnosis and treatment.
201
Chapter |3| Urinary tract infections in special groups of adult patients
2. METHODS
A systematic literature search was per-
formed in PubMed over the last 60 years
using the following key words: “asympto-
matic bacteriuria in pregnancy”, “urinary
tract infection in pregnancy”, “pyelone-
phritis in pregnancy”, and “complicated
urinary tract infection”. Search results
were limited to studies of pregnant
women written in the English language.
A total of 1,462 publications were found
and subsequently screened by title and,
when appropriate, abstract. Eighty-four
publications that the authors felt were
applicable to the subject matter were
included for analysis. These publications
were supplemented by an additional 31
publications obtained from their bibliog-
raphies. For complicated UTI, an addi-
tional 114 publications were found and
screened by title and abstract. Of these,
10 publications were included in this
review and were supplemented by pub-
lications mentioned in the selected pub-
lications or known by the authors. The
studies were rated according to the level
of evidence (LoE) and the grade of recom-
mendation (GoR) using ICUD standards
(for details see Preface) [6–7].
3. EPIDEMIOLOGY
The prevalence and microbiology of bac-
teriuria are similar in pregnant and
non-pregnant women. Asymptomatic
bacteriuria occurs in 4–7% of pregnant
women [1, 8], though in certain popu-
lations rates as high as 10% have been
reported [1]. Detection and eradication of
asymptomatic bacteriuria in pregnancy
have been shown to reduce the risk of
subsequent pyelonephritis and fetal com-
plications [2]. Risk factors for asympto-
matic bacteriuria in pregnancy include
underlying genitourinary anatomic or
functional defects, diabetes, sickle cell
disease, and history of recurrent uri-
nary tract infections [9]. Multiparity
202
and disadvantaged socioeconomic sta-
tus are also significant risk factors [1,
3]. Bladder catheterization should be
avoided in pregnancy due to an associa-
tion with the development of bacteriuria
[1]. Enterobacteriaceae comprise approxi-
mately 95% of urine isolates, of which
E. coli is the most common pathogen [10].
Gram positive organisms including Group
B Streptococci and Staphylococcus sapro-
phyticus are isolated in a small propor-
tion of women with bacteriuria [1].
Acute cystitis has been shown to com-
plicate 1%–2% of pregnancies, with a
microbial spectrum similar to that of
asymptomatic bacteriuria in pregnancy
and uncomplicated UTI in non-pregnant
women [9, 11]. In contrast to the impact
on pyelonephritis, screening and treat-
ment programs to eradicate asymptomatic
bacteriuria in pregnancy do not seem to
reduce the incidence of cystitis. In 9,734
pregnant women in a US Air Force base
hospital over six years, 126 (1.3%) devel-
oped acute cystitis, mostly in the second
trimester [11]. The majority had negative
initial screening cultures (64%), while
31% had acute cystitis on initial presen-
tation. This was in contrast to those who
developed pyelonephritis, in whom only
20% had a negative initial screening cul-
ture [11]. No correlation has been estab-
lished between acute cystitis of pregnancy
and increased risk of low birth weight,
preterm delivery or pyelonephritis [10].
The incidence of pyelonephritis in
pregnant women in the era of routine
prenatal screening for asymptomatic
bacteriuria is approximately 14 per 1000
deliveries [4]. In a study of 440 episodes
in 32,282 pregnant women, the majority
of cases occurred in the second trimester
of pregnancy (53%), but 20% occurred in
the first trimester. Enterobacteriaceae
caused approximately 75% of episodes
and Gram-positive organisms comprised
most of the other episodes [4]. In another
prospective study of 24,000 pregnant
women, 656 of whom developed pyelone-
phritis, the incidence was similar in both

the second and third trimesters [12].
Previous upper urinary tract infection,
urinary tract malformations, renal calculi
and sickle cell disease or trait are risk
factors for the development of pyelone-
phritis during pregnancy [10, 13].
Septic shock syndrome or its variants
has been reported in up to 20% of pregnant
women with severe pyelonephritis [14].
Acute renal failure with suppuration has
been reported independent of sepsis [15].
Anemia, which may be caused by endo-
toxin-induced hemolysis [16], has been
reported in 23% - 66% of cases [4, 17].
4. PATHOGENESIS
Pregnancy-related changes in the urinary
tract predispose to progression of asymp-
tomatic bacteriuria to pyelonephritis. The
renal pelvis and ureters dilate by the sev-
enth week of gestation. By term, the ure-
ters may contain over 200 ml of urine [1].
This dilation is secondary to mechani-
cal obstruction by the expanding uterus
and is exacerbated by the smooth muscle
relaxation and decreased ureteral peri-
stalsis caused by progesterone. The result
of these anatomic and physiologic changes
of pregnancy is the facilitation of ascent of
bacteria from bladder to kidney and the
greater propensity for development of
pyelonephritis. Gestational glucosuria,
aminoaciduria and decreased concentra-
tion capacity of the urine are physiological
co-factors that contribute to a reduction in
the natural antibacterial capacity of urine
and increased bacterial proliferation [1].
Immunosuppression of pregnancy may
also play a role in the pathogenesis of
pyelonephritis in that the serum antibody
response to E. coli and serum and urine
interleukin-6 levels appear to be lower in
pregnant women with pyelonephritis com-
pared with non-pregnant women [18].
As with non-pregnant healthy women,
bacteria from the fecal reservoir colonize
the urinary tract via ascension through
the urethra. Bacterial virulence factors
Urinary tract infections in pregnancy | 3.5 |
play an important role in adherence to
urinary epithelium and pathogenesis of
infection. Differences in expression of viru-
lence factors may explain why some preg-
nant hosts with asymptomatic bacteriuria
progress to pyelonephritis, whereas others
do not [10]. One study examined virulence
traits in E. coli strains from 24 pregnant
women with pyelonephritis and compared
them with E. coli strains from 37 preg-
nant women with asymptomatic bacteriu-
ria detected in pre-natal screening [19].
E. coli strains from the pyelonephritis
group, compared with E. coli strains from
the asymptomatic bacteriuria group, dis-
played significantly increased human
serum resistance (83% vs. 51%, p < 0.05)
and uroepithelial binding capacity (mean
adherence 47 bacteria/cell vs. 18 bacte-
ria/cell). This binding capacity is partly
mediated by bacterial surface molecules
called adhesins, also referred to as pili or
fimbriae. It has previously been demon-
strated that P fimbriae are expressed in
approximately 80% of E. coli strains caus-
ing pyelonephritis, compared with 20% of
strains causing asymptomatic bacteriuria
or cystitis [10]. The E. coli strains from
pregnant women with pyelonephritis did
not significantly differ from those from
non-pregnant women [19]. Thus, preg-
nancy was shown not to abolish the differ-
ence in virulence between E. coli causing
acute pyelonephritis and asymptomatic
bacteriuria, as has been demonstrated in
other types of complicated UTIs.
5. DEFINITION OF SIGNIFICANT
BACTERIURIA
Significant bacteriuria is the level of bacte-
riuria that suggests true bladder bacteriu-
ria as opposed to contamination. It is based
on urine specimens obtained by using
careful handling and processing protocols
in order to minimize contamination and
false positive results. The level of bacteriu-
ria considered significant in asymptomatic
pregnant women is derived from studies in
203
Chapter |3| Urinary tract infections in special groups of adult patients
which colony counts in voided urine speci-
mens were compared with paired catheter
specimens [20]. In these studies, a bacte-
rial count of ≥105 cfu/ml in a catheterized
specimen was confirmed by a repeat cath-
eterized specimen in >95% of cases, and
two consecutive voided specimens with
≥105 cfu/ml predicted bladder bacteriuria
with the same degree of accuracy as a sin-
gle specimen obtained through a catheter.
Therefore, two consecutive voided urine
specimens with growth of the same bacte-
rial strain in counts ≥105 cfu/ml are highly
suggestive of bladder bacteriuria [21] (LoE
2a). In clinical practice, however, only one
voided urine specimen is typically obtained
due to cost and patient convenience, and
treatment is usually instigated in women
with ≥105 cfu/ml without obtaining a con-
firmatory repeat culture. Routine cath-
eterization to screen for bacteriuria is not
recommended due to the slightly increased
risk of causing infection.
Although studies to define colony count
thresholds representing significant bac-
teriuria in pregnant women with urinary
symptoms have not been performed, lower
colony counts have been shown to be sig-
nificant in symptomatic non-pregnant
women. For example, in women with
uncomplicated cystitis, coliform colony
counts in voided urine as low as 102 cfu/ml
have been shown to reflect bladder infec-
tion [22]. However, most clinical labo-
ratories do not routinely quantify urine
isolates to 102 cfu/ml, so it is reasonable to
use a quantitative count ≥103 cfu/ml in a
symptomatic person, whether catheterized
or not, as an indicator of symptomatic UTI
(LoE 4). It should be noted, however, that
95% of women with pyelonephritis will
have ≥105 cfu/ml on quantitative culture.
6. PRINCIPLES OF ANTIMICROBIAL
TREATMENT IN PREGNANCY
6.1 Safety
Much of the data addressing antibiotic
safety in the pregnant population was
204
obtained decades ago prior to the exclu-
sion of pregnant women from most clini-
cal trials. As a result, the safety of some
newer antibiotics in pregnant women has
not been well defined. The pharmacoki-
netic properties of antibiotics are affected
by physiological changes during preg-
nancy since there is an increased volume
of distribution [23], and glomerular fil-
tration rate increases by up to 50% [24].
Despite this, usual doses of antimicrobi-
als are typically sufficient for treatment
of UTIs during pregnancy.
Aminopenicillins are commonly used in
pregnancy and are not considered tera-
togenic [24]. Amoxicillin is well absorbed
orally and has been a mainstay of treat-
ment. Cephalosporins have generally
been considered as safe options. The high
serum protein binding capacity of ceftri-
axone raises concern about potential dis-
placement of bilirubin and development
of kernicterus. Therefore, it should be
used with caution shortly before child-
birth. Possible teratogenicity of cefaclor,
cephalexin and cephradine was noted
in a surveillance study of over 4,000
Michigan Medicaid recipients exposed to
these agents [25]. Amongst those exposed
to these agents in the first trimester of
pregnancy, the incidence of major birth
defects (including cardiovascular and oral
cleft defects) was higher than expected.
However, other factors such as maternal
health and concurrent use of other phar-
maceuticals may have obfuscated the
results. In addition, these findings were
not corroborated in a cohort of 308 women
also exposed to cephalosporins during
the first trimester [26]. Cephalosporins
are widely used in pregnancy; however,
the potential teratogenic associations
seen in the Michigan Medicaid cohort
may warrant further investigation.
Nitrofurantoin remains a viable first
choice agent or alternative in the setting of
penicillin allergy for asymptomatic bacte-
riuria in pregnancy or cystitis [27]. A meta-
analysis of the use of nitrofurantoin
during pregnancy failed to demonstrate

any link to the development of congenital
malformations [28]. However, it has been
reported to cause hemolytic anemia in the
mother with G-6PD deficiency and this can
potentially occur in the fetus. Therefore, it
is not recommended for use near term by
some authors [27]. An acute immune-me-
diated pulmonary reaction characterized
by fever, cough, dyspnea and diffuse pul-
monary infiltrates occurs at an incidence
of 0.00018% [29]. A case was described in
a 16-week pregnant woman that resulted
in severe respiratory insufficiency six days
into a treatment course of nitrofurantoin
for an E. coli UTI. Cessation of nitro-
furantoin and use of steroids resulted in
convalescence [30]. A chronic pulmonary
reaction, characterized by diffuse intersti-
tial pneumonitis and fibrosis has also been
reported [31]. Although such complications
occur very rarely, clinicians utilizing pro-
longed courses of nitrofurantoin for proph-
ylaxis of UTI should be aware of them.
Despite infrequent use in the US, fosfo-
mycin appears to be safe in pregnancy and
may play a role in targeting drug resist-
ant isolates [32]. Trimethoprim should
be avoided in the first trimester due to
potential teratogenicity associated with
antagonism of folate metabolism [33].
Sulfonamides have been reported to cause
kernicterus and should be avoided late in
pregnancy [34]. Clindamycin is an alter-
native for the treatment of group B strep-
tococcus in the penicillin-allergic host.
Teratogenicity has not been reported [35].
Aminoglycosides are ototoxic but no other
teratogenic effects have been described [23].
Tetracyclines are contraindicated during
pregnancy due to discoloration of deciduous
teeth and reports of maternal acute fatty
liver degeneration [36].
Animal studies have demonstrated
an association between fluoroquinolone
use and fetal arthropathy [37]. However,
no developmental abnormalities have
been described in children exposed in
utero. Specifically, no significant mus-
culoskeletal deficits in infants have been
noted [37–38]. Despite this, the use of
Urinary tract infections in pregnancy | 3.5 |
fluoroquinolones is contraindicated dur-
ing pregnancy.
6.2 Resistance
Sulfonamides, cephalosporins, nitrofuran-
toin and aminopenicillins have demon-
strated equivalent efficacy in eradicating
asymptomatic bacteriuria in pregnancy
[39–40] (LoE 1b). However, the increasing
incidence of resistance to aminopenicillins
and sulfonamides highlights the impor-
tance of susceptibility testing to guide
treatment choice. Caution should be used
when choosing amoxicillin, ampicillin or
sulfonamides as treatment options when
antibiotic susceptibility has not yet been
confirmed. A review of 1,142 outpatient
E. coli strains causing UTIs in patients
from the USA and Canada between
2003 and 2004 was carried out by the
North American Urinary Tract Infection
Collaborative Alliance (NAUTICA) [41].
The overall resistance to ampicillin was
37.7% and to trimethoprim-sulfameth-
oxazole 23.3%, whereas only 1.1% of the
isolates were resistant to nitrofurantoin.
Of note, no distinction was made between
symptomatic UTI and asymptomatic bac-
teriuria, and approximately 20% of the
isolates were obtained from males. Similar
results, however, were seen in a study
of 4,734 adult women presenting with
acute uncomplicated cystitis in Europe
and Canada. Of the 2,478 E. coli isolates
tested from this group, the prevalence of
resistance to ampicillin was 30% and to
trimethoprim-sulfamethoxazole 14%, but
only 1.2% were resistant to nitrofurantoin
and 0.7% to fosfomycin [42].
Nitrofurantoin and fosfomycin also
appear to be active in vitro against
ESBL-producing E. coli strains from the
urinary tract [43]. Moreover, in a recent
case-control study including 113 patients
with ESBL E. coli UTIs, no resistance to
fosfomycin was detected and clinical cure
rates were high (93%) [44].
Despite the necessity for caution with
the use of aminopenicillins or sulfonamides,
205
Chapter |3| Urinary tract infections in special groups of adult patients
in most cases of asymptomatic bacteriuria
in pregnancy there is no urgency to treat
until susceptibility data are available.
7. ASYMPTOMATIC BACTERIURIA
7.1 Diagnosis
Asymptomatic bacteriuria is defined as
the presence of significant bacteriuria in
women without symptoms or signs ref-
erable to the urinary tract, regardless of
the presence or absence of pyuria.
7.2 Screening
Up to 40% of pregnant women with
asymptomatic bacteriuria will proceed
to develop pyelonephritis and potential
adverse effects in the fetus if not treated
[45–46]. A fall in the incidence of pyelone-
phritis in pregnancy from 4.0% to 0.8%
subsequent to the introduction of routine
screening and treatment of asymptomatic
bacteriuria was reported in one study [47].
A recent Cochrane meta-analysis of 14
randomized trials compared outcomes in
pregnant women with asymptomatic bac-
teriuria who were treated with antibiotics
against those who received no treatment
or placebo. The risk of complications was
shown to be reduced significantly by the
eradication of asymptomatic bacteriu-
ria [2] (LoE 1a). Thus, antibiotic therapy
results in significantly greater clearance
of asymptomatic bacteriuria (risk ratio
[RR] 0.25, 95% C.I. 0.14 – 0.48), signifi-
cantly lower incidence of pyelonephritis
(RR 0.23, 95% C.I. 0.13 – 0.41), and signif-
icantly lower incidence of low birth weight
infants (RR 0.66, 95% C.I. 0.49 – 0.89),
but not preterm delivery [2].
Given these potential benefits from
screening and treating asymptomatic
bacteriuria in pregnancy, the current rec-
ommendation from the American College
of Obstetricians and Gynecologists is to
screen for bacteriuria at the initial pre-
natal visit by performing a midstream
clean-catch urine culture (LoE 2b). If the
206
initial culture is negative, routine repeat
screening is not warranted given that the
majority of cases of asymptomatic bacte-
riuria are detected on the initial screen,
with only 1.0%–2.0% developing bacte-
riuria subsequent to the initial screen
[1, 48]. In a study of 216 pregnant women
in Sweden, only 1.1% of women developed
asymptomatic bacteriuria between the 12th
week of pregnancy and term. The authors
concluded that the 16th week of pregnancy
is the optimum time to screen for bacte-
riuria [49]. A subset of pregnant women
is at higher risk for the acquisition of
bacteriuria, including those with urinary
tract anomalies and history of recurrent
urinary tract infections. Consideration
should be given to perform surveillance
cultures in such individuals at regular
intervals throughout pregnancy.
Newer methodologies, including dipstick
enzymatic assays, have been advocated
as potential rapid screening modalities
to obviate the costs of routine urine cul-
ture [50–51]. In a study of 528 pregnant
women who underwent urine culture, the
efficacy of nitrite and leukocyte esterase
reagent strips and Gram stain for detect-
ing significant bacteriuria was determined
[50]. Using ≥105 cfu/ml as the gold stand-
ard for significant bacteriuria, the sensi-
tivity and specificity of the reagent strip
for detecting significant bacteriuria was
47.2% and 80.3%, respectively, and the
Gram stain was 100% and 7.7%, respec-
tively. None of these techniques provide
sufficient sensitivity and specificity to
replace urine culture as the gold stand-
ard to detect asymptomatic bacteriuria in
pregnancy. Furthermore, urine cultures
provide microbiologic information that
assists with selection of an appropriate
antimicrobial agent.
Ultimately, the cost effectiveness of a
screening/treatment approach to asympto-
matic bacteriuria in pregnancy is contin-
gent on the cost of the screening test, the
prevalence of asymptomatic bacteriuria
in the local population, and the propor-
tion of those that progress to symptomatic

urinary tract infection. Despite uniform
national guidelines, the level of adher-
ence to screening is unknown.
7.3 Treatment choice and duration
Choice of antimicrobial agent is gov-
erned by safety, as described above, and
uropathogen resistance data obtained
from the urine culture. Short-course
regimens (e.g., 3 to 5 days) are usually
effective in eradicating asymptomatic bac-
teriuria of pregnancy [52–53] (Table 1). In
this regard, a single dose of fosfomycin
has also been successfully used to treat
asymptomatic bacteriuria in pregnancy
with eradication rates comparable to
those with longer courses of other antimi-
crobials [54]. A meta-analysis of 10 studies
comparing single-dose versus longer regi-
mens showed no clear difference in the
cure or recurrence rates for asymptomatic
bacteriuria, or in the risk of preterm
births or pyelonephritis [55] (LoE 1a).
Likewise, duration of antibiotic treat-
ment was not associated with any of the
outcome measures in a more recent meta-
analysis of treatment of asymptomatic
bacteriuria in pregnancy [2]. Short course
regimens are desirable as the host is
asymptomatic and can be closely followed
and retreated if bacteriuria persists, and
fetal drug exposure is minimized.
7.4 Follow-up
Up to 30% of women will fail to clear
asymptomatic bacteriuria following short-
Table 1 Treatment Regimens for Asymptomatic Bacteriuria in Pregnancy.
Antibiotic Duration of therapy
Nitrofurantoin (Macrobid®) 100mg q12 hours 5–7 days
Amoxicillin 500mg Q12 hours 3–7 days
Amoxicillin/Clavulanate 500mg q12 hours 3–7 days
Cephalexin (Keflex®) 500mg Q12 hours 3–7 days
Fosfomycin 3gm Single dose
Urinary tract infections in pregnancy | 3.5 |
course therapy [1]. Thus, a urine cul-
ture should be repeated approximately
one week after completion of therapy as
a test of cure, then monthly until com-
pletion of the pregnancy (LoE 4). If the
urine culture remains positive a week
after treatment with an appropriate
antibiotic, a further course of therapy of
longer duration [10] or with another anti-
biotic is warranted. Failure to respond
to two or more courses of antibiotics or
further recurrences of asymptomatic
bacteriuria during pregnancy warrants
consideration of suppressive therapy or
prophylaxis, respectively, for the duration
of pregnancy. Uropathogen susceptibility
must be taken into account when select-
ing an agent for suppression or prophy-
laxis. Daily nitrofurantoin 50–100mg or
cephalexin 250mg are each reasonable
choices for prophylaxis [56].
8. ACUTE CYSTITIS
8.1 Diagnosis
Urinary symptoms are common in preg-
nant women, and therefore, symptoms
of acute cystitis in pregnancy are less
specific than in non-pregnant women.
The constellation of typical lower uri-
nary tract symptoms (dysuria, frequency,
urgency, suprapubic discomfort) along
with pyuria and significant bacteriuria
(≥103 CFU/ml) establishes the diagno-
sis of acute cystitis. Urine culture helps
separate those who have true infection
Comments
Avoid in G6PD deficiency
Increasing resistance
Increasing resistance
207
Chapter |3| Urinary tract infections in special groups of adult patients

from the 10%–15% that have pyuria in pregnancy. Recurrent cystitis can be man-
the absence of infection [10]. Symptoms aged with another short-course regimen
and signs of pyelonephritis such as flank based on susceptibility data from previous
pain, costovertebral angle tenderness or cultures, and continuous or post-coital anti-
fever (> 38 centigrade) must be absent. microbial prophylaxis may be indicated.
A subset of women has co-existing medical
8.2 Treatment choice and duration conditions that may exacerbate the risk of
complications from UTI (such as diabetes or
The choice and duration of antibiotic
sickle cell anemia). Prophylaxis should be
treatment are similar to that of asymp-
considered after the first episode of cystitis
tomatic bacteriuria (Table 1). A Cochrane
in this setting. Acute cystitis is frequently
review of acute cystitis in pregnancy
related to sexual activity, and postcoital
failed to identify any particular regimen
prophylaxis is a reasonable prophylac-
as superior in rates of cure, rates of recur-
tic strategy in women who are sexually
rence or rates of preterm delivery [57].
active. The antibiotic of choice is governed
All antibiotics studied were effective and
by susceptibility of the urine culture iso-
complications were rare. Thus, there
late. Either nitrofurantoin 50–100 mg or
appears to be no difference in outcome for
cephalexin 250–500 mg postcoitally or daily
short (one to three days) or long (five or
are reasonable choices, providing they are
more days) courses of therapy. Three-day
active against the uropathogen(s) causing
regimens are effective and should be con-
recent infections.
sidered in pregnant women, as has been
Women with a history of recurrent UTI
recommended for uncomplicated UTI [58].
prior to the onset of pregnancy are also at
Of note, short regimens of nitrofuran-
increased risk of developing symptomatic
toin have not performed as well as other
UTI during pregnancy. Such cases of recur-
antibiotics in non-pregnant women with
rent UTI in women of childbearing age are
uncomplicated UTIs in some studies, and
often related to sexual intercourse. The
such regimens have generally not been
potential role of postcoital antibiotics to
recommended. However, a recent pro-
prevent UTIs during pregnancy in this pop-
spective open-label trial comparing three
ulation has been examined. Thirty-three
days of trimethoprim-sulfamethoxazole
women with a history of recurrent UTI
to five days of nitrofurantoin in 338 cases
who had 39 pregnancies were observed.
of uncomplicated cystitis found that clini-
During a mean observation period of seven
cal and microbiological cure rates were
months, 130 symptomatic UTIs were iden-
equivalent [59]. Although no such studies
tified. Following the institution of postcoi-
have been performed in pregnant women,
tal prophylaxis with 250 mg of cephalexin
a 5-day course of nitrofurantoin is likely
or 50 mg of nitrofurantoin, only one UTI
to be similarly effective in acute cystitis
during pregnancy was observed [56].
in pregnancy. Fosfomycin is approved in
Therefore, post-coital prophylaxis should
a single-dose regimen for treatment of
be considered in pregnant women with a
cystitis in pregnancy [32], and it is a rea-
history of frequent urinary tract infections
sonable first-line choice in pregnancy.
prior to the onset of pregnancy (LoE 2b).
8.3 Follow-up
A surveillance culture should be performed 9. ACUTE PYELONEPHRITIS
approximately one week after completion
of therapy for acute cystitis to ensure erad-
ication of significant bacteriuria. Persistent 9.1 Diagnosis
bacteriuria should be managed as described The clinical spectrum of pyelonephri-
above for asymptomatic bacteriuria in tis in pregnancy is equivalent to that in

208

non-pregnant women, except that preg-
nant women are more likely to have
involvement of other organ systems, such
as respiratory insufficiency, renal insuffi-
ciency or anemia [4, 14]. The constellation
of typical upper urinary tract symptoms
or signs (fever, chills/rigors, nausea,
vomiting and costovertebral angle pain
and tenderness) along with pyuria and
significant bacteriuria establishes the
diagnosis of acute pyelonephritis. Lower
urinary tract symptoms may or may not
be present.
9.2 Treatment choice and duration
Traditionally, hospitalization has been
recommended for pregnant women with
pyelonephritis, and parenteral beta
lactams or aminoglycosides have been
used for treatment. See Table 2 for rec-
ommended treatment regimens. The ini-
tial choice of empiric antimicrobial agent
should be tailored to local microbiology
data. In a randomized trial of 179 women
with acute pyelonephritis prior to the 24th
week of pregnancy, the efficacy of intra-
venous ampicillin and gentamicin was
equivalent to that of intravenous cefazo-
lin or intramuscular ceftriaxone [60]. Of
note, only 5.2% of the pathogens were
resistant to cefazolin, which is lower
than that observed in other reports [5].
Thus, monotherapy with first generation
cephalosporins is not recommended due
Table 2 Treatment Regimens for Pyelonephritis.
Antibiotic Dosing
Ceftriaxone 1–2gm IV or IM q24 hours
Aztreonam 1gm IV q8-12 hours
Piperacillin-tazobactam 3.375–4.5gm IV
q6 hours
Cefepime 1gm IV q12 hours
Imipenem-cilastatin 500mg IV q6 hours
Ampicillin + 2gm IV q6 hours
Gentamicin 3–5mg/kg/day IV in 3
divided doses
Urinary tract infections in pregnancy | 3.5 |
to concerns about microbial resistance.
In addition, aminoglycosides have been
associated with ototoxicity following pro-
longed fetal exposure [27], and therefore
should be avoided unless intolerance or
resistance prohibits the use of less toxic
agents.
Improvement in clinical parameters
should be observed by 24–48 hours. The
absence of improvement within this time
frame warrants investigation for urinary
obstruction or complication such as renal
abscess. Once the patient is afebrile for
48 hours it is reasonable to switch to an
oral agent as appropriate based on sus-
ceptibility data. There are no studies that
address the optimal duration of treat-
ment for pyelonephritis in pregnancy,
but most practitioners use a 14-day
course [10]. However, it is likely that
shorter courses of treatment, such as a
seven-day regimen, are as effective. This
has been demonstrated for pyelonephritis
in non-pregnant women [61].
Some studies have addressed the fea-
sibility of outpatient management of
pyelonephritis in pregnancy. In one such
study, 120 women under 24 weeks gesta-
tion were randomized to receive either
outpatient intramuscular ceftriaxone
for two days followed by oral cephalexin,
or inpatient intravenous cefazolin fol-
lowed by oral cephalexin at discharge
[5]. Clinical response and birth outcomes
were similar in both arms, although six
patients in the ceftriaxone group required
eventual admission. One of these devel-
oped septic shock during the emergency
department observation period and
two developed recurrent pyelonephri-
tis after completion of oral antibiotics.
Nevertheless, we recommend empiric
use of ceftriaxone IM or IV once daily for
outpatient treatment of pregnant women
with mild symptoms provided daily fol-
low-up or contact with the patient is fea-
sible (LoE 1b). We do not recommend the
use of first generation cephalosporins for
empiric treatment of pyelonephritis for
the reasons expressed above.
209
Chapter |3| Urinary tract infections in special groups of adult patients
9.3 Prophylaxis
The risk of recurrent pyelonephritis dur-
ing pregnancy following the first episode
is 6%–8% [60, 62]. In a randomized pro-
spective study, 200 subjects were followed
after an episode of acute pyelonephritis
in pregnancy. One group received antimi-
crobial prophylaxis and the other group
underwent surveillance cultures. Despite
the lower incidence of recurrent or per-
sistent bacteriuria in the prophylaxis
arm, the incidence of recurrent pyelone-
phritis was similar in both groups- 7% in
the prophylaxis group versus 8% in the
surveillance group [62]. Although this
study did not demonstrate a reduction in
the incidence of recurrent pyelonephri-
tis, antimicrobial prophylaxis and urine
surveillance is recommended by some for
the remainder of the pregnancy following
the first episode of pyelonephritis [63],
using the same prophylaxis strategies
mentioned above for lower urinary tract
infection.
10. COMPLICATED UTI IN
PREGNANCY
Although UTI during pregnancy is by def-
inition considered complicated, compared
with UTI in the non-pregnant healthy
woman, a minority of pregnant women
will experience a more complicated UTI,
such as a UTI occurring in a person with
compromised urinary drainage or immu-
nity. Host factors that increase the risk
for complicated UTI during pregnancy
include congenital anomalies such as
bladder exstrophy, cloacal anomalies,
and versicoureteral reflux [64–65]. Other
risk factors include obstructive phe-
nomena such as renal or ureteral calculi
[66]; neurogenic bladder conditions that
impair bladder emptying such as diabetic
cystopathy, multiple sclerosis, spina bif-
ida, and spinal cord injury [67] (includes
patients who have undergone augmenta-
tion cystoplasty to treat a neurogenic or
210
exstrophic bladder [68]); and conditions
that decrease the immunological response
to infection including sickle cell disease or
trait, gestational and nongestational dia-
betes mellitus, and immunosuppression
secondary to solid organ or bone marrow
transplantation [69–71]. Patients with
any of these conditions are at increased
risk for the development of complicated
cystitis and pyelonephritis during preg-
nancy [71–72].
Pathogenic bacteria that produce ure-
ase increase the risk of struvite stone for-
mation. These calculi increase the risk
of a UTI complicated by acute or chronic
urinary tract obstruction and increase the
risk for xanthogranulomatous pyelone-
phritis. Some pathogens can also cause
emphysematous pyelonephritis during
pregnancy. E. coli is the most common
bacteria to cause emphysematous pyelone-
phritis, but other Enterobacteriaceae may
also be responsible [73].
A complicated UTI during pregnancy
should be suspected clinically when a
patient fails to respond to a standard
course of antibiotic therapy or presents
with urosepsis or acute renal failure.
Imaging studies, such as ultrasonographic
or magnetic resonance imaging, should be
performed in these situations [72, 74–75]
(LoE 4). Both of these imaging techniques
are believed to present minimal risk to the
developing fetus since no ionizing radia-
tion is used for either imaging modality.
Ultrasonographic imaging, in particular,
is advantageous when intervention such
as percutaneous nephrostomy or retro-
grade ureteral stent placement is required
to relieve obstruction since it offers excel-
lent visualization while avoiding fetal
exposure to ionizing radiation.
The body of knowledge surrounding
the management of pregnant women
with complicated UTI is largely experi-
mental, principally because complicated
UTIs in pregnancy are uncommon. The
optimal duration of antimicrobial treat-
ment is not known. Recommended treat-
ment durations for complicated UTI in

non-pregnant persons have ranged from
7 to 21 days, depending on the severity
of the infection, but 7 to 10 days should
be adequate in the vast majority of indi-
viduals (LoE 4). In addition, drainage in
either a retrograde or antegrade fash-
ion must be performed in the setting
of obstruction. The second trimester of
pregnancy is the safest time to intervene;
rates of fetal loss and premature delivery
are lower during the second trimester fol-
lowing a surgical intervention.
11. FURTHER RESEARCH
Many aspects of urinary tract infection
in pregnancy warrant further investiga-
tion in adequately constructed clinical
trials. Such areas include: acquiring a
better understanding of the mechanism
by which bacteriuria results in adverse
pregnancy outcomes; further characteri-
zation of the virulence factors of bacterial
strains causing asymptomatic bacteriuria
and pyelonephritis in pregnancy; evalu-
ation of adherence to prenatal screening
guidelines and cost effectiveness of the
screening/treatment approach of asympto-
matic bacteriuria of pregnancy; the utility
of repeat urine culture or other screening
tests to confirm the presence of asymp-
tomatic bacteriuria following a positive
initial prenatal screening culture; char-
acterization of the optimum duration of
antimicrobial therapy for asymptomatic
bacteriuria of pregnancy; identification
of optimal treatment strategies of multi-
drug resistant isolates; and the fetal
safety of antimicrobial agents. With
regard to the latter, a recent case-control
study of women in the United States
who had pregnancies affected by selected
major birth defects reported that women
who used sulfonamides or nitrofurantoins
in the month before pregnancy through
the first trimester had babies with more
birth defects than controls [76]. Clearly
this needs to be sorted out quickly since
Urinary tract infections in pregnancy | 3.5 |
nitrofurantoin is widely considered a safe
antibiotic for use in pregnancy. Pregnancy
is a common and complicated condition,
and more resources should be allocated to
address these infection-related issues.
12. CONCLUSION
Urinary tract infection is a common com-
plication of pregnancy. Physiological
changes of pregnancy predispose to the
progression of asymptomatic bacteriuria
to pyelonephritis with ensuing maternal
morbidity and suboptimal fetal outcomes.
Urine culture remains the gold standard
to detect asymptomatic bacteriuria in
pregnancy, and screening is an important
element of routine prenatal care during
early pregnancy. Antimicrobial treatment
should be selected on the basis of uropath-
ogen susceptibility data and fetal safety.
Short courses of therapy are effective in
eradicating bacteriuria and significantly
reducing the incidence of pyelonephritis.
Close follow-up is warranted following
therapy for asymptomatic bacteriuria or
symptomatic urinary tract infection, as
some women may benefit from antimi-
crobial suppression or prophylaxis for
the remainder of pregnancy. Complicated
UTI in pregnancy may require drainage
and/or longer durations of treatment for
optimal results.
REFERENCES
1. Patterson TF and Andriole VT, Detection,
significance, and therapy of bacteriuria in
pregnancy. Update in the managed health
care era. Infect Dis Clin North Am, 1997.
11(3): 593–608.
2. Smaill F and Vazquez JC, Antibiotics for
asymptomatic bacteriuria in pregnancy.
Cochrane Database Syst Rev, 2007(2):
CD000490.
3. Turck M, Goffe BS, and Petersdorf RG,
Bacteriuria of pregnancy. Relation to
211
Chapter |3| Urinary tract infections in special groups of adult patients
socioeconomic factors. N Engl J Med,
1962. 266: 857–60.
4. Hill JB, Sheffield JS, McIntire DD, and
Wendel GD, Jr., Acute pyelonephritis in
pregnancy. Obstet Gynecol, 2005.
105(1): 18–23.
5. Millar LK, Wing DA, Paul RH, and
Grimes DA, Outpatient treatment of
pyelonephritis in pregnancy: a rand-
omized controlled trial. Obstet Gynecol,
1995. 86(4 Pt 1): 560–4.
6. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
7. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
8. Stamey T, Pathogenesis and Treatment of
Urinary Tract Infections. 1980, Baltimore:
Williams and Wilkins.
9. Gilstrap LC, 3rd and Ramin SM, Urinary
tract infections during pregnancy. Obstet
Gynecol Clin North Am, 2001. 28(3):
581–91.
10. Millar LK and Cox SM, Urinary tract
infections complicating pregnancy. Infect
Dis Clin North Am, 1997. 11(1): 13–26.
11. Harris RE and Gilstrap LC, 3rd, Cystitis
during pregnancy: a distinct clinical entity.
Obstet Gynecol, 1981. 57(5): 578–80.
12. Gilstrap LC, 3rd, Cunningham FG, and
Whalley PJ, Acute pyelonephritis in preg-
nancy: an anterospective study. Obstet
Gynecol, 1981. 57(4): 409–13.
13. Thurman AR, Steed LL, Hulsey T, and
Soper DE, Bacteriuria in pregnant
women with sickle cell trait. Am J Obstet
Gynecol, 2006. 194(5): 1366–70.
14. Cunningham FG, Lucas MJ, and Hankins
GD, Pulmonary injury complicating
antepartum pyelonephritis. Am J Obstet
Gynecol, 1987. 156(4): 797–807.
15. Thompson C, Verani R, Evanoff G, and
Weinman E, Suppurative bacterial
pyelonephritis as a cause of acute renal
failure. Am J Kidney Dis, 1986. 8(4):
271–3.
16. Cox SM, Shelburne P, Mason R, Guss S,
and Cunningham FG, Mechanisms of
212
hemolysis and anemia associated with
acute antepartum pyelonephritis. Am J
Obstet Gynecol, 1991. 164(2): 587–90.
17. Gilstrap LG, 3rd, Hankins GD,
Snyder RR, and Greenberg RT, Acute
pyelonephritis in pregnancy. Compr Ther,
1986. 12(12): 38–42.
18. Petersson C, Hedges S, Stenqvist K,
Sandberg T, Connell H, and Svanborg C,
Suppressed antibody and interleukin-6
responses to acute pyelonephritis in preg-
nancy. Kidney Int, 1994. 45(2): 571–7.
19. Stenqvist K, Sandberg T, Lidin-Janson G,
Orskov F, Orskov I, and Svanborg-Eden C,
Virulence factors of Escherichia coli in
urinary isolates from pregnant women.
J Infect Dis, 1987. 156(6): 870–7.
20. Norden CW and Kass EH, Bacteriuria of
pregnancy – a critical appraisal. Annu
Rev Med, 1968. 19: 431–70.
21. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
22. Stamm WE, Counts GW, Running KR,
Fihn S, Turck M, and Holmes KK,
Diagnosis of coliform infection in acutely
dysuric women. N Engl J Med, 1982.
307(8): 463–8.
23. Niebyl JR, Antibiotics and other
anti-infective agents in pregnancy and
lactation. Am J Perinatol, 2003. 20(8):
405–14.
24. Christensen B, Which antibiotics are
appropriate for treating bacteriuria in
pregnancy? J Antimicrob Chemother,
2000. 46 Suppl A: 29–34.
25. Briggs GG, Freeman RK, and Yaffe SJ,
Drugs in lactation. 2nd ed. 2002,
Baltimore: Williams & Wilkins.
26. Czeizel AE, Rockenbauer M, Sorensen
HT, and Olsen J, Use of cephalosporins
during pregnancy and in the presence of
congenital abnormalities: a population-
based, case-control study. Am J Obstet
Gynecol, 2001. 184(6): 1289–96.
27. Le J, Briggs GG, McKeown A, and
Bustillo G, Urinary tract infections dur-
ing pregnancy. Ann Pharmacother, 2004.
38(10): 1692–701.

28. Ben David S, Einarson T, Ben David Y,
Nulman I, Pastuszak A, and Koren G,
The safety of nitrofurantoin during
the first trimester of pregnancy: meta-
analysis. Fundam Clin Pharmacol, 1995.
9(5): 503–7.
29. Jick SS, Jick H, Walker AM, and
Hunter JR, Hospitalizations for pulmo-
nary reactions following nitrofurantoin
use. Chest, 1989. 96(3): 512–5.
30. Boggess KA, Benedetti TJ, and Raghu G,
Nitrofurantoin-induced pulmonary
toxicity during pregnancy: a report of a
case and review of the literature. Obstet
Gynecol Surv, 1996. 51(6): 367–70.
31. Cunha BA, Nitrofurantoin – current con-
cepts. Urology, 1988. 32(1): 67–71.
32. Stein GE, Single-dose treatment of acute
cystitis with fosfomycin tromethamine.
Ann Pharmacother, 1998. 32(2): 215–9.
33. Hernandez-Diaz S, Werler MM, Walker AM,
and Mitchell AA, Folic acid antagonists
during pregnancy and the risk of birth
defects. N Engl J Med, 2000. 343(22):
1608–14.
34. Dashe JS and Gilstrap LC, 3rd, Antibiotic
use in pregnancy. Obstet Gynecol Clin
North Am, 1997. 24(3): 617–29.
35. Keenan C, Prevention of neonatal group
B streptococcal infection. Am Fam
Physician, 1998. 57(11): 2713–20, 2725.
36. Whalley PJ, Adams RH, and Combes B,
Tetracycline Toxicity in Pregnancy. Liver
and Pancreatic Dysfunction. JAMA, 1964.
189: 357–62.
37. Shrim A, Garcia-Bournissen F, and
Koren G, Pharmaceutical agents and
pregnancy in urology practice. Urol Clin
North Am, 2007. 34(1): 27–33.
38. Loebstein R, Addis A, Ho E, Andreou R,
Sage S, Donnenfeld AE, Schick B,
Bonati M, Moretti M, Lalkin A,
Pastuszak A, and Koren G, Pregnancy
outcome following gestational exposure to
fluoroquinolones: a multicenter prospec-
tive controlled study. Antimicrob Agents
Chemother, 1998. 42(6): 1336–9.
39. Harris RE, Gilstrap LC, 3rd, and Pretty A,
Single-dose antimicrobial therapy for
asymptomatic bacteriuria during preg-
nancy. Obstet Gynecol, 1982.
59(5): 546–9.
Urinary tract infections in pregnancy | 3.5 |
40. Pedler SJ and Bint AJ, Comparative
study of amoxicillin-clavulanic acid
and cephalexin in the treatment
of bacteriuria during pregnancy.
Antimicrob Agents Chemother, 1985.
27(4): 508–10.
41. Zhanel GG, Visanaga TL, Laing NM,
DeCorby MR, Nichol KA, Weshnoweski B,
Johnson J, Noreddin A, Low DE,
Karlowsky JA, and Hoban DJ,
Antibiotic resistance in Escherichia
coli outpatient urinary isolates: final
results from the North American Urinary
Tract Infection Collaborative Alliance
(NAUTICA). Int J Antimicrob Agents,
2006. 27(6): 468–75.
42. Kahlmeter G, Prevalence and antimicro-
bial susceptibility of pathogens in uncom-
plicated cystitis in Europe. The ECO.
SENS study. Int J Antimicrob Agents,
2003. 22 Suppl 2: 49–52.
43. Akyar I, [Antibiotic resistance rates of
extended spectrum beta-lactamase produc-
ing Escherichia coli and Klebsiella spp.
strains isolated from urinary tract infec-
tions in a private hospital]. Mikrobiyol
Bul, 2008. 42(4): 713–5.
44. Rodriguez-Bano J, Alcala JC, Cisneros JM,
Grill F, Oliver A, Horcajada JP, Tortola T,
Mirelis B, Navarro G, Cuenca M, Esteve M,
Pena C, Llanos AC, Canton R, and
Pascual A, Community infections caused
by extended-spectrum beta-lactamase-
producing Escherichia coli. Arch Intern
Med, 2008. 168(17): 1897–902.
45. Sweet RL, Bacteriuria and pyelonephritis
during pregnancy. Semin Perinatol, 1977.
1(1): 25–40.
46. Kass EH, Bacteriuria and pyelonephritis
of pregnancy. Arch Intern Med, 1960.
105: 194–8.
47. Harris RE, The significance of eradication
of bacteriuria during pregnancy. Obstet
Gynecol, 1979. 53(1): 71–3.
48. Whalley P, Bacteriuria of pregnancy. Am
J Obstet Gynecol, 1967. 97(5): 723–38.
49. Stenqvist K, Dahlen-Nilsson I, Lidin-
Janson G, Lincoln K, Oden A, Rignell S,
and Svanborg-Eden C, Bacteriuria in
pregnancy. Frequency and risk of acquisi-
tion. Am J Epidemiol, 1989.
129(2): 372–9.
213
Chapter |3| Urinary tract infections in special groups of adult patients
50. McNair RD, MacDonald SR, Dooley SL,
and Peterson LR, Evaluation of the cen-
trifuged and Gram-stained smear, uri-
nalysis, and reagent strip testing to detect
asymptomatic bacteriuria in obstetric
patients. Am J Obstet Gynecol, 2000.
182(5): 1076–9.
51. Millar L, DeBuque L, Leialoha C,
Grandinetti A, and Killeen J, Rapid
enzymatic urine screening test to detect
bacteriuria in pregnancy. Obstet Gynecol,
2000. 95(4): 601–4.
52. Tan JS and File TM, Jr., Treatment of
bacteriuria in pregnancy. Drugs, 1992.
44(6): 972–80.
53. Vercaigne LM and Zhanel GG,
Recommended treatment for urinary
tract infection in pregnancy. Ann
Pharmacother, 1994. 28(2): 248–51.
54. Reeves DS, Treatment of bacteriuria in
pregnancy with single dose fosfomycin
trometamol: a review. Infection, 1992.
20 Suppl 4: S313–6.
55. Villar J, Lydon-Rochelle MT,
Gulmezoglu AM, and Roganti A, Duration
of treatment for asymptomatic bacteriuria
during pregnancy. Cochrane Database
Syst Rev, 2000(2): CD000491.
56. Pfau A and Sacks TG, Effective prophy-
laxis for recurrent urinary tract infections
during pregnancy. Clin Infect Dis, 1992.
14(4): 810–4.
57. Vazquez JC and Villar J, Treatments for
symptomatic urinary tract infections dur-
ing pregnancy. Cochrane Database Syst
Rev, 2000(3): CD002256.
58. Warren JW, Abrutyn E, Hebel JR,
Johnson JR, Schaeffer AJ, and Stamm
WE, Guidelines for antimicrobial treat-
ment of uncomplicated acute bacterial cys-
titis and acute pyelonephritis in women.
Infectious Diseases Society of America
(IDSA). Clin Infect Dis, 1999. 29(4):
745–58.
59. Gupta K, Hooton TM, Roberts PL, and
Stamm WE, Short-course nitrofurantoin
for the treatment of acute uncomplicated
cystitis in women. Arch Intern Med, 2007.
167(20): 2207–12.
60. Wing DA, Hendershott CM, Debuque
L, and Millar LK, A randomized trial of
three antibiotic regimens for the treatment
214
of pyelonephritis in pregnancy. Obstet
Gynecol, 1998. 92(2): 249–53.
61. Talan DA, Stamm WE, Hooton TM,
Moran GJ, Burke T, Iravani A, Reuning-
Scherer J, and Church DA, Comparison of
ciprofloxacin (7 days) and trimethoprim-
sulfamethoxazole (14 days) for acute
uncomplicated pyelonephritis pyelonephri-
tis in women: a randomized trial. JAMA,
2000. 283(12): 1583–90.
62. Lenke RR, VanDorsten JP, and
Schifrin BS, Pyelonephritis in pregnancy:
a prospective randomized trial to prevent
recurrent disease evaluating suppressive
therapy with nitrofurantoin and close
surveillance. Am J Obstet Gynecol, 1983.
146(8): 953–7.
63. ACOG educational bulletin. Antimicrobial
therapy for obstetric patients. Number
245, March 1998 (replaces no. 117, June
1988). American College of Obstetricians
and Gynecologists. Int J Gynaecol Obstet,
1998. 61(3): 299–308.
64. Mansfield JT, Snow BW, Cartwright PC,
and Wadsworth K, Complications of
pregnancy in women after childhood reim-
plantation for vesicoureteral reflux: an
update with 25 years of followup. J Urol,
1995. 154(2 Pt 2): 787–90.
65. Weaver E and Craswell P, Pregnancy
outcome in women with reflux nephropa-
thy – a review of experience at the Royal
Women’s Hospital Brisbane, 1977–1986.
Aust N Z J Obstet Gynaecol, 1987. 27(2):
106–11.
66. Cheriachan D, Arianayagam M, and
Rashid P, Symptomatic urinary stone
disease in pregnancy. Aust N Z J Obstet
Gynaecol, 2008. 48(1): 34–9.
67. Richmond D, Zaharievski I, and Bond A,
Management of pregnancy in mothers
with spina bifida. Eur J Obstet Gynecol
Reprod Biol, 1987. 25(4): 341–5.
68. Hill DE and Kramer SA, Management of
pregnancy after augmentation cystoplasty.
J Urol, 1990. 144(2 Pt 2): 457–9; discus-
sion 460.
69. Tan PK, Tan AS, Tan HK, Vathsala A, and
Tay SK, Pregnancy after renal transplan-
tation: experience in Singapore General
Hospital. Ann Acad Med Singapore, 2002.
31(3): 285–9.

70. McMahon MJ, Ananth CV, and Liston RM,
Gestational diabetes mellitus. Risk fac-
tors, obstetric complications and infant
outcomes. J Reprod Med, 1998. 43(4):
372–8.
71. Klebe JG, Espersen T, and Allen J,
Diabetes mellitus and pregnancy.
A seven-year material of pregnant diabet-
ics, where control during pregnancy was
based on a centralized ambulant regime.
Acta Obstet Gynecol Scand, 1986.
65(3): 235–40.
72. Gontero P, Masood S, Sogni F, Fontana F,
Mufti G, and Frea B, Upper urinary tract
complications in pregnant women with an
ileal conduit. Lessons learned from two
cases. Scand J Urol Nephrol, 2004.
38(6): 523–4.
Urinary tract infections in pregnancy | 3.5 |
73. Gaither K, Ardite A, and Mason TC,
Pregnancy complicated by emphysema-
tous pyonephrosis. J Natl Med Assoc,
2005. 97(10): 1411–3.
74. Ushioda N, Matsuo K, Nagamatsu M,
Kimura T, and Shimoya K, Maternal
urinoma during pregnancy. J Obstet
Gynaecol Res, 2008. 34(1): 88–91.
75. McAleer SJ and Loughlin KR,
Nephrolithiasis and pregnancy. Curr
Opin Urol, 2004. 14(2): 123–7.
76. Crider KS, Cleves MA, Reefhuis J,
Berry RJ, Hobbs CA, and Hu DJ,
Antibacterial medication use during preg-
nancy and risk of birth defects: National
Birth Defects Prevention Study. Arch
Pediatr Adolesc Med, 2009. 163(11):
978–85.
215
|3.6|
Urinary tract infections in
patients with diabetes mellitus
Suzanne E. Geerlings
Corresponding author: Suzanne E. Geerlings, MD PhD, Academic Medical Center, F4-217, Center for Infection and
Immunity Amsterdam (CINIMA), Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Phone: 31(0)205664380, Fax: 31(0)206972286, e-mail: s.e.geerlings@amc.nl
ABSTRACT
Epidemiology: Patients with diabetes
mellitus (DM) have a higher prevalence
of asymptomatic bacteriuria (ASB) and
incidence of urinary tract and other infec-
tions compared to patients without DM.
Pathogenesis: It seems that the
increased prevalence of ASB in diabetic
women is not the result of a difference in
bacteria, but due to an increased adher-
ence of E. coli expressing type 1 fimbriae
to uroepithelial cells in women with DM.
The bacterial growth in urine after the
addition of glucose is increased in vitro,
however glucosuria is not a risk factor for
ASB or the development of urinary tract
infections (UTIs) in vivo.
Diagnosis: The diagnosis of a UTI is
primarily based on typical patient symp-
tomatology and urinary evaluation for
the presence of bacteria and white blood
cells. Easy obtainable parameters can
predict whether a (complicated course of)
UTI is present in older patients with
DM type 2. Imaging should be reserved
for those patients who do not respond
to therapy after 48–72 hours especially
with conditions, such as DM, predispos-
ing to (complications of an) infection.
Computerised tomography (CT) has now
become accepted as a sensitive modality
for diagnosis and follow-up of a compli-
cated UTI.
Clinical symptoms: Diabetes patients
with a UTI have the same symptoms of
lower and upper UTIs as patients with-
out diabetes, but they more often develop
severe and rare complications.
Treatment: ASB in patients with DM
does not lead to complications and there-
fore screening and treatment is not war-
ranted. No randomized prospective trials
are present answering the question of
what the optimal duration of treatment of
UTIs in diabetic patients is. The analysis
of a large retrospective database demon-
strated that women with diabetes receive
 Urinary tract infections in patients with diabetes mellitus
longer and more potent antimicrobial
treatment but have more recurrences of
their UTIs. However, the results about
treatment failure in women with DM in
other studies are not consistent.
Key words: diabetes mellitus; uri-
nary tract infections; asymptomatic
bacteriuria
SUMMARY OF RECOMMENDATIONS
Diagnosis
1. Predictors for recurrent UTIs in women
and lower UTIs in men, with DM type
2 older than 45 years are: age, number
of GP visits, urinary incontinence, cere-
brovascular disease or dementia in
men and women and also renal disease
in only women (GoR B).
2. Predictors for a complicated course
(pyelonephritis, prostatitis, recurrent
cystitis) of a UTI in patients with DM
type 2 older than 45 years are: age
above 60 years, chronic use of antibiot-
ics, more than 6 physician contacts in
the previous year, hospitalization in the
previous year, the presence of renal dis-
ease and incontinence of urine (GoR B).
3. Because of the frequency and severity
of UTI and the development of rare
and severe complications in diabetes
patients, prompt diagnosis and early
therapy is warranted (GoR C).
4. Discontinuate metformin from the day
of contrast injection, if the Glomerular
Filtration Rate (GFR) is < 60 ml/
min/1.73 m2, and restart it 2 days fol-
lowing contrast infusion providing the
GFR has not significantly deteriorated
(GoR C).
Treatment
5. Asymptomatic bacteriuria in patients
with diabetes does not lead to compli-
cations, therefore screening and treat-
ment is not warranted (GoR A).
| 3.6 |
6. The agent of choice can be the same
in diabetic and non-diabetic patients
and depends on the local resistance
patterns of commonly found uropatho-
gens (GoR B).
7. Besides the high resistance percent-
age of most uropathogens to trimetho-
prim/sulfamethoxazole (TMP/SMX),
this agent can lead to hypoglycaemia
and therefore also is not a good first
choice in diabetes patients (GoR C).
8. Women with diabetes with a lower
urinary tract infection need a longer
treatment duration compared to
women without diabetes, but it is
not clear what the optimal treatment
duration is (GoR B).
1. INTRODUCTION
Diabetes Mellitus (DM) is an increasingly
important endocrine disease; the preva-
lence worldwide in 2000 was 2.8% and is
estimated to be 4.4% in 2030 [1] (LoE 3).
The incidence of infections is increased in
diabetes (type 1 and type 2) patients com-
pared to controls [2] (LoE 2a); [3] (LoE 2a)
and the urinary tract is the most preva-
lent site of these infections [4] (LoE 2a).
It has been suggested that the presence
of glucosuria can explain this increased
incidence, but this has never been scien-
tifically confirmed. Furthermore, some
experts consider UTIs in diabetic patients
generally as complicated UTIs and there-
fore recommend treating them longer
than non-diabetic patients. In this chap-
ter the epidemiology, pathogenesis, diag-
nosis, clinical symptoms and treatment
of UTIs in diabetes patients will be dis-
cussed and recommendations for diagno-
sis and treatment will be made.
2. METHODOLOGY
A systematic literature search was per-
formed for the last 10 years in PubMed
217
Chapter |3| Urinary tract infections in special groups of adult patients
with the following key words: diabetes
mellitus and urinary tract infections or
diabetes mellitus and bacteriuria and the
following limitations: humans, adults,
English. A total of 216 (DM and UTI) and
40 (DM and ASB) publications were iden-
tified, which were screened by title and
abstract (when available). After exclusion
of duplicates a total of 27 were included
into the review (analysis), supplemented
by 10 citations known by the author.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [5–6].
3. DEFINITION OF THE DISEASE
3.1 Epidemiology
Patients with DM have a higher preva-
lence of asymptomatic bacteriuria (ASB)
(26% in women with compared to 6% to
those without DM) [7] (LoE 2a) and inci-
dence of urinary tract and other infections
compared to patients without DM [2] (LoE
2a). Compared to patients without DM
the relative risk (RR) of a symptomatic
UTI ranged between 1.39 and 1.43 for all
diabetic patients in a large retrospective
Canadian study [2] (LoE 2a) and Odds
Ratios (ORs) were 1.56 for DM type 1
and 1.21 for DM type 2 Dutch patients [3]
(LoE 2a), and 2.2 for American postmeno-
pausal diabetic women [8] (LoE 2a).
3.2 Classifications
Diabetes mellitus (DM) is defined follow-
ing the criteria of the American Diabetes
Association as a fasting plasma glucose
≥ 7,0 mmol/l. DM type 1 is defined as the
absolute deficiency of insulin secretion
and the absence of C-peptide, and DM
type 2 as the combination of resistance to
insulin action and an inadequate compen-
satory insulin secretory response [9].
Asymptomatic bacteriuria is defined
as the presence of bacteriuria, at least
10e5 cfu/ml of one or two microorganisms
218
in a clean voided midstream urine, iso-
lated from a patient without symptoms of
a UTI.
Symptomatic urinary tract infection
(UTI) is defined as the presence of bac-
teriuria in a patient with symptoms of
a UTI.
3.3 Pathogenesis
3.3.1 Pathogens
The increased prevalence of ASB and UTI
in diabetic patients can be the result of
differences in the host responses between
diabetic and non-diabetic patients, or a
difference in the infecting bacterium itself.
It seems that the increased prevalence of
ASB in diabetic women is not the result of
a difference in bacteria, because the same
number of virulence factors were found in
the infecting Escherichia coli (most com-
mon causative microorganism of ASB) in
diabetic women with ASB, as listed in the
literature for non-diabetic patients with
ASB [10] (LoE 3). Also no differences were
found in the resistance percentages to
the most commonly used antimicrobials
in these isolates from diabetic patients
compared to other uropathogens iso-
lated from the general population in the
Netherlands [11] (LoE 2a).
It has been suggested that the pres-
ence of glucosuria and impairment in
granulocyte functions are the patho-
genetic mechanisms which explain the
increased prevalence of ASB and UTI.
The bacterial growth in vitro is increased
after the addition of glucose in concen-
trations found in urine of poorly control-
led patients [12] (LoE 3), but in a large
cohort of 636 diabetic women it could not
be confirmed that glucosuria is a risk fac-
tor for ASB [7] (LoE 2a) or the develop-
ment of UTIs in vivo [13] (LoE 2a).
3.3.2 Host response
Concerning the host response, it seems
that glucosuria or impaired granulocyte
dysfunctions cannot explain the increased
incidence of bacteriuria, but more that a
 Urinary tract infections in patients with diabetes mellitus
quantitative decrease of leukocytes plays
a role in the pathogenesis of ASB and
UTI in patients with DM [14] (LoE 2a).
Furthermore, considering the microor-
ganism-host interaction it has been dem-
onstrated that E. coli expressing type 1
fimbriae (the virulence factor that plays
an important role in the pathogenesis
of UTIs) adhere better to uroepithelial
cells isolated from the urine of women
with DM compared to those isolated from
women without DM [15] (LoE 2a).
4. CLINICAL EVALUATION / RISK
ASSESSMENT
4.1 Diagnosis
The diagnosis of a UTI is primarily based
on typical patient symptomatology and
urinary evaluation for the presence of
bacteria and white blood cells. Because of
the frequency and severity of UTI and the
development of rare and severe complica-
tions in diabetics, prompt diagnosis and
early therapy is warranted [16] (LoE 4).
Imaging should, in general, be reserved
for all patients who do not respond to
therapy after 48–72 hours especially
with conditions, such as DM, predispos-
ing to (a complication of) an infection [17]
(LoE 4). For example, emphysematous
cystitis has a highly variable presentation
and course, with a considerable potential
for complications. Knowledge of this rare
entity may lead to early diagnosis and
appropriate management [18] (LoE 3).
For the diagnosis of emphysematous cys-
titis a plain abdominal X-ray is highly
sensitive (97.4%), but CT is the most
sensitive and specific diagnostic tool [18]
(LoE 3).
To recognize a UTI and a possible
complicated course of it in patients with
DM, a prediction rule was developed
in DM type 2 patients aged 45 years
or older. Predictors for recurrent UTIs
in women and lower UTIs in men were
age, number of general practitioner (GP)
| 3.6 |
visits, urinary incontinence, cerebrov-
ascular disease or dementia. In women,
the presence of renal disease was an
additional predictor [19] (LoE 2a). The
combined outcome measure for a com-
plicated course was a defined episode of
acute pyelonephritis, prostatitis or recur-
rent cystitis. Independent predictors for
a complicated course were age above 60
years, chronic use of antibiotics, more
than six physician contacts in the previ-
ous year, hospitalization in the previous
year, the presence of renal disease and
incontinence of urine [20] (LoE 2a).
Considering additional diagnostic
imaging for the assessment of all patients
with a UTI, intravenous urogram and
ultrasound have traditionally been used,
allowing detection of calculi, obstruc-
tion and incomplete bladder emptying.
However, these imaging techniques have
limitations and computerised tomogra-
phy (CT) has now become accepted as a
more sensitive modality for diagnosis and
follow-up of a complicated UTI. Contrast-
enhanced CT allows different phases of
excretion to be studied and can define
extent of disease and identify significant
complications or obstruction. However,
ultrasound is harmless, cheaper and eas-
ier to perform and for that reason still can
be diagnostic for possible complications in
patients, who are very ill at the moment
of presentation or remain ill after 48–72
hours. Furthermore, DM and the pres-
ence of renal diseases are important risk
factors for the development of contrast-
induced nephropathy, which is associated
with an increased mortality. Therefore
it has been recommended to discontinue
metformin from the day of contrast injec-
tion, if the Glomerular Filtration Rate
(GFR) is < 60 ml/min/1.73 m2, and to
restart it two days after contrast infusion,
providing the GFR has not significantly
deteriorated [21] (LoE 4). Nuclear medi-
cine has a limited role in the evaluation
of UTIs in adults. Its main role is in the
assessment of renal function, often prior
to surgery. Magnetic resonance imaging
219
Chapter |3| Urinary tract infections in special groups of adult patients
(MRI) has a limited but increasing role.
It is particularly useful in those with
iodinated contrast allergies [17] (LoE 4).
See also Chapter, Diagnostics of uncom-
plicated UTI.
4.2 Clinical presentation
Diabetes patients with a UTI have the
same symptoms of lower and upper UTIs
as patients without diabetes, but they
more often develop severe and rare com-
plications such as emphysematous cys-
titis and papillary necrosis [22] (LoE 4);
[23] (LoE 3). Patients with DM also are
at higher risk for intrarenal abscess, with
a spectrum of disease ranging from acute
focal bacterial pyelonephritis to renal cor-
ticomedullary abscess or carbuncle [16]
(LoE 4). Some infections, for example
emphysematous cystitis [18] (LoE 3) or
pyelonephritis [24] (LoE 4) are mainly
present in patients with DM, and clas-
sic symptoms of a UTI can be absent in
these diseases. The results of a prospec-
tive study with bacteraemic patients
showed that patients with DM compared
with those without DM more often had
bacteraemia and that the urinary tract
was the most prevalent focus for these
infections [4] (LoE 2a). Concerning the
mortality due to these infections it was
demonstrated that diabetic patients have
a higher mortality outside (RR 1,38, 99%
CI 1,23-1,55) [2] (LoE 2a), but not inside
the hospital [4] (LoE 2a).
5. TREATMENT
5.1 Asymptomatic bacteriuria
No differences in the renal function dete-
rioration between diabetic women (not
very well regulated, mean HbA1c 8.5%)
with and without ASB were demonstrated
after the follow-up of a cohort with 644
diabetic women for a mean period of six
years [25] (LoE 2a). This is in concordance
with an earlier study in which women
with DM and ASB were randomized to
220
be treated with antimicrobial therapy or
placebo to keep them nonbacteriuric [26]
(LoE 1b). The investigators did show that
the incidence of symptomatic UTIs (pri-
mary endpoint) and the serum creati-
nine increase (secondary endpoint) were
not different between the two groups.
In conclusion, ASB in patients with DM
does not lead to complications and there-
fore screening and treatment is not war-
ranted [27] (LoE 1a).
5.2 Choice antimicrobial agent
The causative microorganisms of UTIs in
patients with DM are comparable to those
found in other UTIs. Microorganisms
other than E. coli are more often cul-
tured than in women without DM [28]
(LoE 2a), In the ARESC study [29] (LoE 3)
the proportion of E. coli in premenopau-
sal women with uncomplicated cystitis
and without any risk factors was 81%
and thus significantly (multivariate
analysis; p<0.001) higher than in female
patients with DM with clinical symptoms
of an acute episode of uncomplicated cys-
titis since 67% of them had E. coli. This
proportion is, however, still much higher
than in patients with complicating fac-
tors within the urinary tract with about
50% of E. coli [30] (LoE 1b) and above
all much higher than in patients with
mainly nosocomial UTI [31] (LoE 3).
Despite the lower proportion of E. coli
found in patients with DM the percent-
ages of resistance to the most commonly
prescribed antimicrobials: amoxicillin,
nitrofurantoin, trimethoprim/sulfameth-
oxazol (TMP/SMX) seem comparable [11]
(LoE 2a). Amoxicillin, nitrofurantoin,
trimethoprim/sulfamethoxazol (TMP/
SMX) seem comparable [11] (LoE 2a).
Therefore, the choice of treatment can
be the same in diabetic and non-diabetic
patients and depends on the local resist-
ance patterns of the commonly found
uropathogens. Besides the high resistance
percentage of most uropathogens to TMP/
SMX, this agent can lead to hypoglycemia
 Urinary tract infections in patients with diabetes mellitus
and therefore is not a good first choice in
this patient group [32] (LoE 4).
5.3 Duration
It has been suggested that diabetes
patients more often have upper tract
involvement when they have a UTI [33]
(LoE 4). However, in a prospective study
only 0.5% of the diabetes patients with
a UTI had clinical symptoms of pyelone-
phritis [34] (LoE 2a) compared to 0.2% in
controls [35] (LoE 4). Others have dem-
onstrated that the risk ratio for pyelone-
phritis in diabetic patients compared to
those without diabetes ranges from 1.86
to 4.4 [36] (LoE 4); [37] (LoE 2a).
No randomised trials are present
answering the question as to what the
optimal duration of treatment of UTIs in
diabetic patients is. Some experts sug-
gest considering these patients as having
a complicated UTI and therefore treating
them during a period of 7–14 days [38]
(LoE 4); [33] (LoE 4). However, in a
(national) guideline it has been recom-
mended not to consider all UTIs in dia-
betic women as complicated UTIs, but to
differentiate between a lower and upper
UTI and consequently treating the lower
UTI with the same agents and only a lit-
tle bit longer (seven instead of five days)
as in women without DM [35] (LoE 4).
However, the results relating to treat-
ment failure in women with DM are not
consistent: in two studies more recur-
rences were seen after UTI treatment in
diabetic patients compared to those with-
out DM [39] (LoE 2a); [3] (LoE 2a). In
contrast, a subanalysis of two large retro-
spective studies in women in a lower [40]
(LoE 2a) and upper UTI [41] (LoE 2b)
could not confirm this finding.
The analysis of a large retrospective
database with pharmacy dispensing data
demonstrated that both pre- and post-
menopausal women with diabetes receive
longer and more potent antimicrobial
treatment for lower UTI’s (cystitis) com-
pared to pre- and postmenopausal women
| 3.6 |
without diabetes. However, despite this
more aggressive treatment, both pre-
and postmenopausal women with diabe-
tes had more recurrences of their UTIs.
Besides that, hospitalisation for compli-
cations of the UTI was seen significantly
more often in postmenopausal women
with diabetes [42] (LoE 2a). Therefore,
it seems that women with diabetes need
a longer treatment duration for a lower
UTI compared to women without diabe-
tes, but it is not clear what the optimal
treatment duration is.
6. FURTHER RESEARCH
Considering the pathogenesis, the micro-
organism-host interaction especially
must be further elucidated, because
it has been demonstrated that E. coli
expressing type 1 fimbriae adhere better
to uroepithelial cells of patients with DM
compared to controls. The study ques-
tion is whether this is due to a higher
number of receptors which are present
on the uroepithelial cell or to a difference
in the uroepithelial cell receptor itself,
for example in the glycosylation of this
glycoprotein in diabetes patients. Clinical
research should be done to define better
risk factors for UTI in DM patients as
predictors of more severe complications.
Furthermore, randomised trials must
be performed, to answer the question
as to what the optimal agent choice and
treatment duration of UTIs in diabetic
patients is.
7. CONCLUSIONS
Patients with DM have a higher preva-
lence of ASB. ASB, however, does not lead
to complications and therefore screening
and treatment of ASB in diabetic patients
is not warranted. There is also a higher
incidence of symptomatic UTIs, which
lead more often to complications com-
pared to those without DM. Therefore
221
Chapter |3| Urinary tract infections in special groups of adult patients
these UTIs have to be diagnosed and
treated as early as possible and followed
more carefully not to overlook a compli-
cated course. No prospective clinical trials
are present, which answer the question
as to what the optimal antimicrobial
treatment strategy (especially duration
of treatment) in diabetic patients with
a UTI is, but it seems that despite more
aggressive treatment, women with diabe-
tes have more recurrences of their UTIs.
REFERENCES
1. Wild S, Roglic G, Green A, Sicree R, and
King H, Global prevalence of diabetes:
estimates for the year 2000 and projec-
tions for 2030. Diabetes Care, 2004. 27(5):
1047–53.
2. Shah BR and Hux JE, Quantifying the
risk of infectious diseases for people with
diabetes. Diabetes Care, 2003. 26(2):
510–3.
3. Muller LM, Gorter KJ, Hak E,
Goudzwaard WL, Schellevis FG,
Hoepelman AI, and Rutten GE, Increased
risk of common infections in patients with
type 1 and type 2 diabetes mellitus. Clin
Infect Dis, 2005. 41(3): 281–8.
4. Carton JA, Maradona JA, Nuno FJ,
Fernandez-Alvarez R, Perez-Gonzalez
F, and Asensi V, Diabetes mellitus and
bacteraemia: a comparative study between
diabetic and non-diabetic patients. Eur J
Med, 1992. 1(5): 281–7.
5. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
6. P. Abrams SK, A. Grant, Evidence-based
medicine overview of the main steps for
developing and grading guideline recom-
mendations. Progress in Urology, 2007.
17(3): 681–4.
7. Geerlings SE, Stolk RP, Camps MJ,
Netten PM, Hoekstra JB, Bouter KP,
Bravenboer B, Collet JT, Jansz AR, and
Hoepelman AI, Asymptomatic bacteriu-
ria may be considered a complication in
women with diabetes. Diabetes Mellitus
Women Asymptomatic Bacteriuria Utrecht
222
Study Group. Diabetes Care, 2000. 23(6):
744–9.
8. Boyko EJ, Fihn SD, Scholes D, Chen CL,
Normand EH, and Yarbro P, Diabetes and
the risk of acute urinary tract infection
among postmenopausal women. Diabetes
Care, 2002. 25(10): 1778–83.
9. Report of the Expert Committee on the
Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care, 1997. 20(7):
1183–97.
10. Geerlings SE, Brouwer EC, Gaastra W,
Stolk R, Diepersloot RJ, and Hoepelman
AI, Virulence factors of Escherichia coli
isolated from urine of diabetic women
with asymptomatic bacteriuria: correla-
tion with clinical characteristics. Antonie
Van Leeuwenhoek, 2001. 80(2): 119–27.
11. Meiland R, Geerlings SE, De Neeling
AJ, and Hoepelman AI, Diabetes mellitus
in itself is not a risk factor for antibiotic
resistance in Escherichia coli isolated
from patients with bacteriuria. Diabet
Med, 2004. 21(9): 1032–4.
12. Geerlings SE, Brouwer EC, Gaastra W,
Verhoef J, and Hoepelman AI, Effect
of glucose and pH on uropathogenic
and non-uropathogenic Escherichia
coli: studies with urine from diabetic
and non-diabetic individuals. J Med
Microbiol, 1999. 48(6): 535–9.
13. Geerlings SE, Stolk RP, Camps MJ,
Netten PM, Collet TJ, and Hoepelman
AI, Risk factors for symptomatic uri-
nary tract infection in women with
diabetes. Diabetes Care, 2000. 23(12):
1737–41.
14. Geerlings SE, Brouwer EC, Van Kessel
KC, Gaastra W, Stolk RP, and Hoepelman
AI, Cytokine secretion is impaired in
women with diabetes mellitus. Eur J Clin
Invest, 2000. 30(11): 995–1001.
15. Geerlings SE, Meiland R, van Lith EC,
Brouwer EC, Gaastra W, and Hoepelman
AI, Adherence of type 1-fimbriated
Escherichia coli to uroepithelial cells:
more in diabetic women than in control
subjects. Diabetes Care, 2002. 25(8):
1405–9.
16. Patterson JE and Andriole VT, Bacterial
urinary tract infections in diabetes. Infect
Dis Clin North Am, 1997. 11(3): 735–50.
 Urinary tract infections in patients with diabetes mellitus
17. Browne RF, Zwirewich C, and Torreggiani
WC, Imaging of urinary tract infection in
the adult. Eur Radiol, 2004. 14 Suppl 3:
E168–83.
18. Grupper M, Kravtsov A, and Potasman
I, Emphysematous cystitis: illustrative
case report and review of the literature.
Medicine (Baltimore), 2007. 86(1): 47–53.
19. Venmans LM, Gorter KJ, Rutten GE,
Schellevis FG, Hoepelman AI, and Hak E,
A clinical prediction rule for urinary tract
infections in patients with type 2 diabe-
tes mellitus in primary care. Epidemiol
Infect, 2009. 137(2): 166–72.
20. Venmans LM, Sloof M, Hak E, Gorter KJ,
and Rutten GE, Prediction of complicated
urinary tract infections in patients with
type 2 diabetes: a questionnaire study
in primary care. Eur J Epidemiol, 2007.
22(1): 49–54.
21. van Dijk Azn R, Wetzels JF, ten Dam MA,
Aarts NJ, Schimmelpenninck-Scheiffers
ML, Freericks MP, Said SA, Geenen RW,
Stuurman A, and van Everdingen JJ,
[Guideline ‘Precautionary measures for
contrast media containing iodine’]. Ned
Tijdschr Geneeskd, 2008. 152(13): 742–6.
22. Nicolle LE, Asymptomatic bacteriuria
in diabetic women. Diabetes Care, 2000.
23(6): 722–3.
23. Griffin MD, Bergstralhn EJ, and Larson
TS, Renal papillary necrosis--a sixteen-
year clinical experience. J Am Soc
Nephrol, 1995. 6(2): 248–56.
24. Joshi N, Caputo GM, Weitekamp MR,
and Karchmer AW, Infections in patients
with diabetes mellitus. N Engl J Med,
1999. 341(25): 1906–12.
25. Meiland R, Geerlings SE, Stolk RP,
Netten PM, Schneeberger PM, and
Hoepelman AI, Asymptomatic bacteriuria
in women with diabetes mellitus: effect on
renal function after 6 years of follow-up.
Arch Intern Med, 2006. 166(20): 2222–7.
26. Harding GK, Zhanel GG, Nicolle LE, and
Cheang M, Antimicrobial treatment in
diabetic women with asymptomatic bac-
teriuria. N Engl J Med, 2002. 347(20):
1576–83.
27. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
| 3.6 |
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
28. Horcajada JP, Moreno I, Velasco M,
Martinez JA, Moreno-Martinez A,
Barranco M, Vila J, and Mensa J,
Community-acquired febrile urinary
tract infection in diabetics could deserve
a different management: a case-control
study. J Intern Med, 2003. 254(3): 280–6.
29. Naber KG, Schito G, Botto H, Palou
J, and Mazzei T, Surveillance study in
Europe and Brazil on clinical aspects and
Antimicrobial Resistance Epidemiology in
Females with Cystitis (ARESC): implica-
tions for empiric therapy. Eur Urol, 2008.
54(5): 1164–75.
30. Naber KG, Bartnicki A, Bischoff W,
Hanus M, Milutinovic S, van Belle F,
Schonwald S, Weitz P, and Ankel-Fuchs D,
Gatifloxacin 200 mg or 400 mg once
daily is as effective as ciprofloxacin
500 mg twice daily for the treatment of
patients with acute pyelonephritis or
complicated urinary tract infections.
Int J Antimicrob Agents, 2004.
23 Suppl 1: S41–53.
31. Wagenlehner FM, Niemetz AH, Weidner W,
and Naber KG, Spectrum and antibiotic
resistance of uropathogens from hospital-
ised patients with urinary tract infections:
1994–2005. Int J Antimicrob Agents,
2008. 31 Suppl 1: S25–34.
32. Poretsky L and Moses AC, Hypoglycemia
associated with trimethoprim/sulfam-
ethoxazole therapy. Diabetes Care, 1984.
7(5): 508–9.
33. Stapleton A, Urinary tract infections in
patients with diabetes. Am J Med, 2002.
113 Suppl 1A: 80S-84S.
34. Geerlings SE, Stolk RP, Camps MJ,
Netten PM, Collet JT, Schneeberger
PM, and Hoepelman AI, Consequences of
asymptomatic bacteriuria in women with
diabetes mellitus. Arch Intern Med, 2001.
161(11): 1421–7.
35. Haaren van K.Visser HS, Vliet van S,
Timmermans AE, Yadava R, Geerlings
SE, Rietter G, and B Pv, NHG-Standaard
Urineweginfecties (tweede herziening).
Huisarts & Wetenschap, 2005. 48:
341–352.
223
Chapter |3| Urinary tract infections in special groups of adult patients
36. Nicolle LE, Urinary tract infection in dia-
betes. Curr Opin Infect Dis, 2005. 18(1):
49–53.
37. Scholes D, Hooton TM, Roberts PL,
Gupta K, Stapleton AE, and Stamm
WE, Risk factors associated with acute
pyelonephritis in healthy women. Ann
Intern Med, 2005. 142(1): 20–7.
38. Meiland R, Geerlings SE, and Hoepelman
AI, Management of bacterial urinary tract
infections in adult patients with diabetes
mellitus. Drugs, 2002. 62(13): 1859–68.
39. Lawrenson RA and Logie JW, Antibiotic
failure in the treatment of urinary tract
infections in young women. J Antimicrob
Chemother, 2001. 48(6): 895–901.
40. Goettsch WG, Janknegt R, and Herings
RM, Increased treatment failure after
3-days’ courses of nitrofurantoin and tri-
methoprim for urinary tract infections in
224
women: a population-based retrospective
cohort study using the PHARMO data-
base. Br J Clin Pharmacol, 2004. 58(2):
184–9.
41. Carrie AG, Metge CJ, Collins DM,
Harding GK, and Zhanel GG, Use of
administrative healthcare claims to exam-
ine the effectiveness of trimethoprim-sul-
famethoxazole versus fluoroquinolones in
the treatment of community-acquired acute
pyelonephritis in women. J Antimicrob
Chemother, 2004. 53(3): 512–7.
42. Schneeberger C, Stolk RP, Devries JH,
Schneeberger PM, Herings RM, and
Geerlings SE, Differences in the pat-
tern of antibiotic prescription profile and
recurrence rate for possible urinary tract
infections in women with and without
diabetes. Diabetes Care, 2008. 31(7):
1380–5.
|3.7|
Urinary tract infections in
postmenopausal women
Raul Raz
Infectious Diseases Unit, Ha‘Emek Medical Center, Afula, Rappaport Faculty of Medicine, Technion, Haifa, Israel
Corresponding Author: Prof. Raul Raz, Infectious Diseases Unit, Ha’Emek Medical Center, Afula, Rappaport Faculty of
Medicine, Technion, Haifa, ISRAEL
Tel 00972-4-649.4259, Fax 00972-4-649.4470, raz_r@clalit.org.il, hana_e@clalit.org.il
ABSTRACT
UTI is the most common bacterial infec-
tion in women in general and in post-
menopausal women in particular. There
are two groups of elderly women with
recurrent UTI that should be differenti-
ated regarding age and general status:
healthy young postmenopausal women
aged ~50–70 years, who are neither insti-
tutionalized nor catheterized, and elderly
institutionalized women with or without
catheter.
Bacteriuria occurs more often in eld-
erly functionally impaired women but
in general it is asymptomatic. However,
the risk factors associated with recurrent
UTI in elderly women has not previously
been widely described. In a multivari-
ate analysis it was found that urinary
incontinence, a history of UTI before
menopause and non-secretor status were
strongly associated with recurrent UTI in
young postmenopausal women.
Another study described the incidence
and risk factors of acute cystitis among
nondiabetic and diabetic postmeno-
pausal women. Independent predictors
of infection included insulin treated
patients and a lifetime history of uri-
nary infection. Borderline associations
included a history of vaginal estrogen
cream use in the last months, kidney
stones and asymptomatic bacteriuria at
baseline.
Another important factor in postmeno-
pausal women is the potential role that
estrogen deficiency plays in the develop-
ment of bacteriuria. There are at least
two studies showing a beneficial effect
of estrogen in the management of recur-
rent bacteriuria in elderly women. One
of these studies showed that vaginal
estrogen cream reduced vaginal pH from
5.5 ± 0.7 to 3.6 ± 1.0, restore lactobacil-
lus and decreased new episodes of UTI.
Another study reported similar results
using an estriol vaginal ring. However,
Chapter |3| Urinary tract infections in special groups of adult patients
contradictory results are found in the lit-
erature. For example, additional studies
found that the use of an estriol containing
vaginal pessaries was less effective than
macrocristals oral nitrofurantoin in pre-
venting UTI in postmenopausal women
and two other also did not find any ben-
efit in the reduction of UTI by oral estro-
gen therapy. Unfortunately the use of
estrogen in preventing UTI in postmeno-
pausal women remains questionable.
New strategies were searched for
reducing the use of antibiotics in the pre-
vention and treatment of UTI. Two of
them are probiotics and cranberry juice
or capsules. Although there are several
studies regarding probiotics and cran-
berry reporting reduction of episodes of
UTI, there is not any conclusive evidence
that they are useful in the prevention of
UTI in postmenopausal women. As for
the optimal drug, dosage and length of
treatment for UTI in the elderly, there
are no studies comparing these data with
the treatment for young women.
Key words: Bacteriuria in elderly
women, urinary tract infection, post-
menopausal women.
SUMMARY OF RECOMMENDATIONS
Risk factors in postmenopausal
women
1. In older institutionalized women,
urine catheterization and functional
status deterioration appeared to be
the most important risk factors associ-
ated with UTI (GoR A).
2. Atrophic vaginitis is a risk factor to be
considered (GoR B).
3. Incontinence, cystocelle and post-
voiding residual volume (GoR A).
4. UTI before menopause (GoR A).
5. Non-secretor status (GoR A).
6. Bacteriuria per-se did not appear to be
a risk factor for mortality (GoR A).
226
Diagnosis in postmenopausal
women
7. History, physical examination and
urinalysis, including culture (GoR B).
8. Treatment according to physician
clinical judgment (GoR C).
9. Genitourinary symptoms are not nec-
essarily related to UTI and are not
necessarily an indication for antimi-
crobial treatment (GoR B).
Treatment
10. Treatment of acute cystitis in post-
menopausal women is similar as in
premenopausal women however short
term therapy is not so well estab-
lished as in premenopausal women
(see chapter 3.4).
11. Treatment of pyelonephritis in
postmenopausal women is similar
as in premenopausal women (see
chapter 3.4).
12. Asymptomatic bacteriuria in elderly
women should not be treated with
antibiotics. (GoR A) (see chapter 5.2).
13. The optimal antimicrobials, dosages
and duration of treatment in elderly
women appeared to be similar to
those recommended for younger post-
menopausal women (GoR C).
Prevention
14. Estrogen (especially vaginal) could be
administered for prevention of UTI
yet results are contradictive (GoR C).
15. Alternative methods, like cranberry
and probiotic lactobacilli, can con-
tribute but they are not sufficient to
prevent recurrent UTI (GoRC).
16. Once complicating factors, like uri-
nary obstruction, neurogenic bladder
disturbances etc, could be ruled out,
an antimicrobial prophylaxis should
be carried out as recommended for
premenopausal women (see chapter
4.2) (GoR C).
 Urinary tract infections in postmenopausal women
1. INTRODUCTION
UTI is the most common bacterial infec-
tion in young and elderly women. Despite
the higher incidence of bacteriuria in eld-
erly women, most UTI research has been
conducted in young women. This chap-
ter will discuss epidemiological studies
regarding risk factors associated with
bacteriuria in elderly women. Bacteriuria
in the elderly is associated with high mor-
tality rates, however in most of the cases
bacteriuria is asymptomatic and not a
causal factor of death.
Estrogen deficiency plays an impor-
tant role in the development of bacteriu-
ria. Several studies have been conducted
showing the efficacy of estrogen (orally
and vaginally) in the prevention of UTI.
Yet, the literature is divided on this sub-
ject and other studies have not shown
any advantage in using estrogen.
This chapter will focus on the updated
known data regarding the use of estro-
gen in the prevention of bacteriuria in
elderly women. The alarming increase of
multidrug resistant uropathogens makes
it imperative that alternative strategies
are found. One strategy is the restora-
tion of flora with lactobacilli using probi-
otics and another is the use of cranberry,
a competitive compound that inhibits the
attachment of bacteria to the uroepithe-
lial mucosa and thereby reduces the fre-
quency of UTI.
2. METHODOLOGY
A systematic literature search was
performed covering the last 15 years.
Recently, few recent studies have inves-
tigated the management of UTI in post-
menopausal women. The data was
collected from the most up-to-date pub-
lished studies and guidelines found by
searching Medline, PubMed and the
Cochrane database using the following
keywords: bacteriuria in elderly women
and postmenopausal women and UTI.
| 3.7 |
A total of 190 papers were screened by
title and abstract: 111 for the first key-
word and 79 for the second. Only English
publications addressing the keywords
were screened.
The 25 references used in the text were
assessed according to the level of scien-
tific evidence involved. The studies were
rated according to the level of evidence
(LoE) and the grade of recommendation
(GoR) using ICUD standards (for details
see Preface) [1–2].
3. DEMOGRAPHY
Urinary Tract Infection (UTI) is the most
common bacterial infection in women.
There are three groups of women with
recurrent UTI that should be distinguished
on the basis of age: pre-menopausal
women, healthy post-menopausal women
between the ages ~50–70 years who are
neither institutionalized nor catheterized,
and elderly institutionalized women, who
are in many cases catheterized.
Bacteriuria occurs more often in func-
tionally impaired women than in those
not impaired, persistent bacteriuria is
seen more often in nursing home resi-
dents, and transient bacteriuria more
often in young healthy postmenopausal
women. The majority of elderly women
with bacteriuria are asymptomatic [3–4]
and should not be treated with antibi-
otics (LoE 1b). In young to middle-age
women, the prevalence of UTI is <5%,
rising considerably with advancing age.
Epidemiologic studies have shown that
~15%–20% of 65–70 year old women have
bacteriuria, compared with ~20%–50% of
women >80 years old.
Despite the high incidence of bacteriu-
ria in postmenopausal women (young and
institutionalized), most UTI researches
were conducted in younger women.
Hence, the most common UTI risk factors
among healthy younger women such as
frequent vaginal intercourse, spermicide,
diaphragm, condom use, a previous UTI
227
Chapter |3| Urinary tract infections in special groups of adult patients
history, a recent antibiotic use and non-
secretor status were not widely investi-
gated in middle-aged and elderly women
(LoE 2a) [5].
4. BACTERIURIA IN YOUNG VERSUS
ELDERLY WOMEN
Foxman et al. conducted a case-control
study investigating the role of health
behavior and sexual and medical history
in UTI risk among otherwise healthy
women aged 40–65 years. They showed
that sexual activity was not associated
with acquiring UTI in this age group,
but a history of UTI during the past year,
urine loss, antibiotic use during the pre-
vious 2 weeks and exposure to cold dur-
ing the previous 2 weeks were positively
associated with UTI. In addition, drink-
ing cranberry juice and taking vitamin C
were moderately protective (LoE 2b) [4].
5. RISK FACTORS
A case control study compared 149 post-
menopausal women with a history of
recurrent UTI with 53 age-matched
women with no history of UTI. They
looked for risk factors in healthy non-
institutionalized and non-catheterized
women. Three urological factors, namely
incontinence (41% of case patients vs. 9%
control patients; p<0.001), presence of a
cystocele (19% vs. 0%; p<0.001) and post
voiding residual volume (28% vs. 2%;
p<0.000008), were strongly associated
with recurrent UTI. Multivariate analy-
sis showed that urinary incontinence
(OR 5.79; 95% CI’ 2.05 – 16.42; p=0.0009)
a history of UTI before menopause (OR,
4.85; 95% C.I; 1.7 – 13.84; p<0.003) and
non secretor status (OR, 2.9; 95% C.I.;
1.28 – 6.25; p=0.005) were most strongly
associated with recurrent UTI in post
menopausal women (LoE 2a) [5].
Jackson et al. (LoE 2a) [6] described
the incidence and risk factors for acute
228
cystitis among non-diabetic and diabetic
postmenopausal women and the possi-
ble effect of estrogens on those women.
During 1773 person-years of follow-up,
138 symptomatic UTIs occurred (inci-
dence 0.07 person-year). Independent
prediction of infection included insulin
dependent diabetes (Hazard Ratio 95%
C.I, 1.7-7.0) and a lifetime history of UTI
(Hazard Ratio for six or more infections =
6.9, 95% C.I, 3.5 – 13.6). However, a bor-
derline association included a history
of vaginal estrogen cream use in recent
months (Hazard Ratio = 1.8; 95% C.I,
1.0 – 3.4) and a history of kidney stones
(Hazard Ratio = 1.95, 95% C.I, 0.9-3.5).
However, sexual activity, urinary incon-
tinence, parity, post-coital urination,
vaginal dryness, use of cranberry juice,
vaginal bacterial flora and post void
residual bladder volume were not associ-
ated with the incidence of acute cystitis
after multivariable adjustment.
A study by Moore et al. found that
recent sexual intercourse, as described
for younger women, was also strongly
associated with the incidence of UTI in
other healthy post-menopausal women
(LoE 2b) [7]. In the older, institutional-
ized women, urine catheterization and
functional status deterioration appeared
to be the most important risk factors
Table 1 Major factors predisposing adult women to
urinary tract infection (UTI) as related to age. [9]
Age group Predisposing factor
15 – 50 y Sexual intercourse; Diaphragm/
spermicide; Spermicide;
Antimicrobials; Prior UTI; Maternal
history of UTI; Childhood history
of UTI; Nonsecretor status
50 – 70 y Lack of estrogen; Urogenital
surgery; Incontinence; Cystocele;
Postvoid residual urine;
Nonsecretor status; Prior UTI
> 70 y Catheterization; Incontinence;
Urogenital surgery; Diminished
mental status; Antimicrobials
 Urinary tract infections in postmenopausal women
associated with UTI (LoE 2a) [8]. The
risk of UTI increases dramatically with
catheterization. Table 1 describes the
major factors predisposing adult women
to urinary tract infection (UTI) as related
to age [9].
6. BACTERIURIA AND MORTALITY
Bacteriuria has been discovered as a
cause of increased mortality in elderly
individuals. Studies of Greek, Finnish
and American patients showed decreased
longevity associated with UTI (LoE 1b)
[10–12]. The elderly patients with UTI
were suffering from a variety of diseases
other than UTI that might have increased
their susceptibility to infections as well
as their mortality.
Nordestam et al. studied a popula-
tion of elderly patients and compared
their longevity in relation to bacteriuria
(LoE 1b) [13]. There was no increase in
mortality related to bacteriuria for oth-
erwise healthy individuals. Bacteriuria
per-se did not appear to be a risk factor
for mortality. In patients with concomi-
tant disease, bacteriuria was associated
with increased mortality, but was not the
cause.
7. THE ROLE OF ESTROGEN
Another important factor in post-
menopausal women is the potential role
that estrogen deficiency plays in the devel-
opment of bacteriuria. Postmenopausal
women frequently present with genitouri-
nary symptoms, half have genitourinary
disorders and 29% urinary incontinence
(LoE 1b) [14]. Postmenopause is charac-
terized by a significant reduction of ovary
estrogen secretion, which is often associ-
ated with vaginal atrophy. Clinically, it
manifests as a syndrome characterized by
vaginal dryness, itching, dyspareunia and
urinary incontinence. This may some-
times imitate UTI (LoE 2a) [15–16].
| 3.7 |
Estrogen stimulates the prolifera-
tion of lactobacillus in the vaginal epi-
thelium, reduces pH and avoids vaginal
colonization of Enterobacteriaceae, which
are the main pathogens of the urinary
tract. Figure 1 describes the relation-
ship between estrogen and the vaginal
flora and the pathophysiology of urinary
tract infections in elderly women (LoE
1a) [17]. In addition, the absence of estro-
gen decreases the volume of the vaginal
muscles, resulting in slackness of the
ligaments holding the uteric pelvic floor
and the bladder, resulting in the develop-
ment of prolapse of the internal genitalia.
Kicovic et al. (LoE1b) [18] showed that
vaginal cream decreased urogenital com-
plaints associated with atrophic vaginitis.
A previous randomized, double-
blind, placebo-controlled study, demon-
strated that vaginal estriol treatment
had a dramatic effect on recurrent UTI
in postmenopausal women. The results
showed that the incidence of UTI in
women who received vaginal estriol was
reduced to 0.5 episodes/year compared to
5.9 episodes/year in women who received
placebo. In addition, after one month of
treatment, lactobacillus appeared in 60%
of the estrogen-treated group but in none
of the placebo group and the vaginal pH
decreased from 5.5 ± 0.7 before treatment
to 3.6 + 1.0 after treatment (LoE 1b) [19].
Several years later, similar results were
obtained by Eriksen, using an estradiol-
vaginal ring (LoE1b) [20]. In that study,
the women in the estradiol group had a
↓ Estrogen
↓ Vaginal lactobacilli
↑ Vaginal pH
↑ Colonization of the vaginal with Enterobacteraceae from
the rectum
Figure 1 Relationship between estrogen and the vaginal
flora and pathophysiology of urinary tract infections in elderly
women. [17]
229
Chapter |3| Urinary tract infections in special groups of adult patients

significant reduction in the frequency of
urogenital symptoms, such as vaginal
dryness, dyspareunia and urge and stress
incontinence, and after 36 weeks of study
45% of the women receiving estradiol were
still free from UTI, in contrast to only 20%
of the women treated with placebo.
However, contradicting results are
found in the literature. For example,
another study showed that the use of
estriol-containing vaginal pessaries was
less effective than the use of oral nitro-
furantoin macrocrystals in the prevention
of bacteriuria in postmenopausal women.
This study also showed the failure of the
estriol-containing vaginal pessaries to
restore vaginal lactobacilli and to reduce
vaginal pH in those women (LoE 1a) [21].
Brown et al. (LoE 3) [22] assessed the
effects of hormonal therapy on UTI fre-
quency and examined potential risk fac-
tors. They used data from the Health
and Estrogen/Progesterone Replacement
Study, a randomized, blinded trial of the
effect of hormone therapy on coronary
heart disease events among 2763 post-
menopausal women aged 44–79 with
coronary diseases. UTI frequency was
higher in the group receiving hormone
treatment (0.625 mg conjugated estrogen
plus 2.5 mg medroxy progesterone ace-
tate or placebo followed for a mean of 4.1
years), although the difference was not
statistically significant. Statistical signif-
icant risk factors for UTI in multivariate
analysis included: women with diabetes

Indications

Oral Therapy Advantages

– Young postmenopausal women – Avoid menopausal symptoms

– Prevent osteoporosis

– Prevent ischemic heart disease

– Prevent UTI

Vaginal Therapy Advantages

– Women > 60 years old – Improve symptoms related to atrophic vaginitis

– Improve urge incontinence

– Prevent UTI

Contraindications

Absolute Relative

– Endometrial carcinoma – High blood pressure?

– Breast carcinoma – Diabetes mellitus?

– Thromboembolic disorders – Gall stones?

– Liver disease

Difficulties in vaginal therapy

Physical limitations

Tremor; Obesity; Status after cerebrovascular accident; Dementia;

Psychological problems; Education/cultural behavior

Figure 2 Indications and contraindications for estrogen therapy in UTI. [3]

230
 Urinary tract infections in postmenopausal women
on treatment (insulin OR 1.81, 95% C.I,
1.4 – 2.34); oral medication (OR 1.44, 95%
C.I, 1.09 – 1.9); poor health (OR 1.34;
95% C.I, 1.14 – 1.57); vaginal itching (OR
1.63, 95% C.I, 1.07 – 2.5); and urge incon-
tinence (OR 1.51, 95% C.I, 1.30 – 1.75).
UTIs in previous years were strongly
associated with a simple UTI (OR 7.00,
95% C.I, 5.91 – 8.92) as well as multiple
UTIs (OR 18.51, 95% C.I, 14.27 – 24.02).
In addition, data from the Hearth
and Estrogen/Progesterone Replacement
Study compared women aged 44–79
years, randomized in two groups, receiv-
ing 0.625 mg conjugated estrogens plus
2.5mg of medroxyprogesterone acetate
or placebo, and followed up for a mean of
4.1 years. In this study no effect was seen
in reducing UTI episodes in the women
treated with oral hormone therapy in
comparison to the placebo group. Jackson
et al. did not see that the use of oral or
vaginal estrogen was a protective factor in
order to avoid recurrent UTI (LoE 2a) [6].
In conclusion, the efficacy of estrogen
in the prevention of UTI in postmeno-
pausal women with recurrence remains
questionable. From a clinical perspec-
tive, the current recommended use of
estrogen (probably vaginal and not oral)
is in postmenopausal women, especially
those infected with multi-drug resistant
uropathogens which limit the options
and effectiveness of antimicrobial proph-
ylaxis, and in women where the symp-
toms were related to atrophic vaginitis.
Figure 2 summarises the indications
and contraindications for estrogen ther-
apy in UTI [3].
8. TREATMENT
Treatment of acute cystitis and pyelone-
phritis in otherwise healthy post-
menopausal women is similar as in
premenopausal women (see chapter
Naber et al.), however, short-term therapy
in post-menopausal women is not as well
documented by controlled studies as in
| 3.7 |
younger women. Raz et al. [23] (LoE 1b)
published a study in post-menopausal
women (mean age 65 years) with an
uncomplicated UTI in which ofloxacin,
200 mg once daily for 3 days, was signifi-
cantly more effective in both short- and
long-term follow-up than a 7-day course of
cephalexin, 500 mg four times daily, even
though all the uropathogens were suscep-
tible to the two agents. In another double-
blind study [24] (LoE 1b), including a total
of 183 post-menopausal women of at least
65 years of age with acute uncomplicated
UTI, similar results were obtained with
either a 3-day or a 7-day oral course of
ciprofloxacin 250 mg two times daily (bac-
terial eradication 2 days after treatment
98% vs 93%, p=0.16), but the shorter
course was better tolerated. The rate of
bacterial eradication in this study was
generally high and the rate of bacterial
resistance to ciprofloxacin low. (GoR A).
Asymptomatic bacteriuria in elderly
women should not be treated with antibi-
otics (GoR A).
The optimal antimicrobials, dosages
and duration of treatment in elderly
women appeared to be similar to those
recommended for young postmenopausal
women (GoR C). however, these results
should not be extended to the frail of an
elderly geriatric population with sig-
nificant comorbidities, who frequently
present with UTI caused by more resist-
ant Gram-negative organisms and in
whom treatment duration should better
be prolonged as in complicated UTI.
Estrogen (especially vaginal) could be
administered for prevention of UTI yet
results are contradictive. (GoR C). There
are at least two clinical studies showing
that vaginal estriol and estradiol-releas-
ing vaginal ring restore vaginal flora,
reduce pH and the number of sympto-
matic and asymptomatic bacteriuria (19,
20). However, it appears that oral estro-
gen does not reduce the incidence of UTI
in PMN. (See chapter Hooton et al.)
Alternative methods, like cranberry
and probiotic lactobacilli, can contribute
231
Chapter |3| Urinary tract infections in special groups of adult patients
to prevent recurrent UTI in PMN but
more well conducted studies are required
to define their exact role and efficiency.
(GoRC).
Once complicating factors, like urinary
obstruction, neurogenic bladder distur-
bances etc, could be ruled out, an anti-
microbial prophylaxis should be carried
out as recommended for premenopausal
women (see chapter Hooton et al.) (GoRC).
9. NEW STRATEGIES
The alarming increase of multidrug
resistant uropathogens makes it imper-
ative that alternative strategies are
found. One strategy is the restoration of
the normal flora with lactobacilli using
probiotics. Another option is the use of
a competitive compound that inhibits
attachment of bacteria to the uroepi-
thelium. Unfortunately both methods
have been evaluated without conclusive
results, although there is some evidence
that probiotics and cranberry are useful
in preventing UTI.
Reid et al. [25] demonstrated the pos-
sibility of preventing uropathogen infec-
tion by using lactobacillus in vitro.
Several clinical studies have shown that
L. rhamnosus Gr-1 and L. fermentum-RC
are able to colonize the vagina, a first
step in the management to prevent bac-
teriuria (LoE 2a). However, more studies,
especially clinical studies, should be car-
ried out in order to determine the role of
probiotics in the prevention of UTI.
Another possibility is the use of cran-
berry. Cranberries contain a proanthocy-
anidin that can prevent the colonization
of the E.coli uropathogen in the vaginal
mucosa and reduce the frequency of bac-
teriuria (GoR C) [26]. McMurdo et al.
(GoR C) [27] carried out a randomized
controlled trial in elderly women to com-
pare the efficacy in preventing UTI of
cranberry capsules with trimethoprim.
The time to first recurrence of UTI was
not significantly different between both
232
groups. In addition, trimethoprim had a
very limited advantage over cranberry in
the prevention of recurrent UTI in older
women but had more adverse effects and
withdrawals.
However, few clinical studies have
been conducted and in small and hetero-
genic populations an advantage in the
use of cranberry juice or other oral prep-
arations in the prevention of bacteriuria
has been shown. In the elderly popula-
tion there is only one clinical quasi-ran-
domized study (GoR C) [28] in elderly
women with asymptomatic bacteriuria,
which showed that bacteriuria and pyu-
ria were significantly reduced in women
taking cranberry juice in comparison with
women who received placebo. However,
since asymptomatic bacteriuria in the
elderly is not treated, the clinical signifi-
cance of this study remains inconclusive.
10. FURTHER RESEARCH
Further wide randomized studies are
essential to define and establish the
exact role of estrogen therapy, probiot-
ics, lactobacilli and other possible and
available methods to reduce the use of
antibiotics.
11. CONCLUSIONS
Bacteriuria, particularly asymptomatic
bacteriuria, is a very frequent finding in
both healthy postmenopausal and insti-
tutionalized women. Urological factors,
such as urinary incontinence, presence
of any grade of cystocele and a post-void-
ing residual volume, together with pre-
vious UTI and non-secretor status, are
associated with recurrent UTI in this
population. Some studies showed a rela-
tionship between bacteriuria and dia-
betes or sexual intercourse. The role of
vaginal/oral estrogen, together with the
use of probiotics and lactobacilli remains
questionable.
 Urinary tract infections in postmenopausal women
REFERENCES
1. Abrams, P., S. Khoury, and A. Grant,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): p. 681–4.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
p. 115–127.
3. Raz, R., Hormone replacement therapy or
prophylaxis in postmenopausal women
with recurrent urinary tract infection. J
Infect Dis, 2001. 183 Suppl 1: p. S74–6.
4. Foxman, B., et al., Urinary tract infection
among women aged 40 to 65: behavioral
and sexual risk factors. J Clin Epidemiol,
2001. 54(7): p. 710–8.
5. Raz, R., et al., Recurrent urinary tract
infections in postmenopausal women. Clin
Infect Dis, 2000. 30(1): p. 152–6.
6. Jackson, S.L., et al., Predictors of urinary
tract infection after menopause: a pro-
spective study. Am J Med, 2004. 117(12):
p. 903–11.
7. Moore, E.E., et al., Sexual intercourse and
risk of symptomatic urinary tract infec-
tion in post-menopausal women. J Gen
Intern Med, 2008. 23(5): p. 595–9.
8. Nicolle, L.E., Asymptomatic bacteriuria
in the elderly. Infect Dis Clin North Am,
1997. 11(3): p. 647–62.
9. Stamm, W.E. and R. Raz, Factors con-
tributing to susceptibility of postmeno-
pausal women to recurrent urinary tract
infections. Clin Infect Dis, 1999. 28(4):
p. 723–5.
10. Dontas, A.S., et al., Bacteriuria and sur-
vival in old age. N Engl J Med, 1981.
304(16): p. 939–43.
11. Nordenstam, G.R., et al., Bacteriuria and
mortality in an elderly population. N Engl
J Med, 1986. 314(18): p. 1152–6.
12. Platt, R., et al., Mortality associated
with nosocomial urinary-tract infection.
N Engl J Med, 1982. 307(11): p. 637–42.
13. Nordenstam, G., et al., Bacteriuria in rep-
resentative population samples of persons
aged 72–79 years. Am J Epidemiol, 1989.
130(6): p. 1176–86.
| 3.7 |
14. Iosif, C.S. and Z. Bekassy, Prevalence of
genito-urinary symptoms in the late meno-
pause. Acta Obstet Gynecol Scand, 1984.
63(3): p. 257–60.
15. Haspels, A.A., H.J. Bennink, and W.H.
Schreurs, Disturbance of tryptophan
metabolism and its correction during
oestrogen treatment in postmenopausal
women. Maturitas, 1978. 1(1): p. 15–20.
16. Thomas, T.M., et al., Prevalence of uri-
nary incontinence. Br Med J, 1980.
281(6250): p. 1243–5.
17. Raz, R., Intravaginal estriol and the blad-
der., in The Millennium Review 2000. The
Management of the Menopause., JAMA,
Editor. 1999. p. 1–3.
18. Kicovic, P.M., et al., The treatment of post-
menopausal vaginal atrophy with Ovestin
vaginal cream or suppositories: clini-
cal, endocrinological and safety aspects.
Maturitas, 1980. 2(4): p. 275–82.
19. Raz, R. and W.E. Stamm, A controlled
trial of intravaginal estriol in postmeno-
pausal women with recurrent urinary
tract infections. N Engl J Med, 1993.
329(11): p. 753–6.
20. Eriksen, B., A randomized, open, parallel-
group study on the preventive effect of an
estradiol-releasing vaginal ring (Estring)
on recurrent urinary tract infections in
postmenopausal women. Am J Obstet
Gynecol, 1999. 180(5): p. 1072–9.
21. Raz, R., et al., Effectiveness of estriol-
containing vaginal pessaries and nitro-
furantoin macrocrystal therapy in the
prevention of recurrent urinary tract
infection in postmenopausal women. Clin
Infect Dis, 2003. 36(11): p. 1362–8.
22. Brown, J.S., et al., Urinary tract infec-
tions in postmenopausal women: effect of
hormone therapy and risk factors. Obstet
Gynecol, 2001. 98(6): p. 1045–52.
23. Raz, R. and S. Rozenfeld, 3-day course
of ofloxacin versus cefalexin in the treat-
ment of urinary tract infections in post-
menopausal women. Antimicrob Agents
Chemother, 1996. 40(9): p. 2200–1.
24. Vogel, T., et al., Optimal duration of anti-
biotic therapy for uncomplicated urinary
tract infection in older women: a double-
blind randomized controlled trial. CMAJ,
2004. 170(4): p. 469–73.
233
Chapter |3| Urinary tract infections in special groups of adult patients
25. Reid, G. and J. Burton, Use of
Lactobacillus to prevent infection by path-
ogenic bacteria. Microbes Infect, 2002.
4(3): p. 319–24.
26. Raz, P., Urinary tract infection in elderly
women. Int J Antimicrob Agents, 1998.
10(3): p. 177–9.
27. McMurdo, M.E., et al., Cranberry or
trimethoprim for the prevention of
234
recurrent urinary tract infections? A ran-
domized controlled trial in older women.
J Antimicrob Chemother, 2009. 63(2):
p. 389–95.
28. Avorn, J., et al., Reduction of bacteriuria
and pyuria after ingestion of cranberry
juice. JAMA, 1994. 271(10): p. 751–4.
 Chapter |4|

Prevention of recurrent
urogenital tract infections
in adult women
Chair: Thomas M Hooton

CHAPTER OUTLINE
4.1 Introduction 236
4.2 Antibiotic prophylaxis in women with recurrent
urinary tract infections 240
4.3 Immunoactive prophylaxis of uncomplicated recurrent
urinary tract infections 252
4.4 Use of cranberry for prophylaxis of uncomplicated
recurrent urinary tract infections 269
4.5 Probiotics for the prophylaxis of uncomplicated recurrent
urinary tract infections in females 278
4.6 Prevention of prematurity by early diagnosis and
treatment of bacterial urogenital infections – the role
of bacterial vaginosis 288
|4.1|
Introduction
Thomas M. Hooton
University of Miami Miller School of Medicine, Miami, FL, USA
Corresponding author: Thomas M. Hooton, M.D., Professor of Clinical Medicine, University of Miami Miller School of
Medicine, 1120 NW 14th Street, Suite 1144, Miami, FL 33136, USA
Tel: +1 (305) 243 2576, THooton@med.miami.edu
Recurrent UTIs are common in women,
including healthy young women, and are
associated with considerable morbidity
and expense. Moreover, their manage-
ment can be problematic for clinicians in
this era of increasing antimicrobial resist-
ance. In contrast, recurrent UTIs are
rare in healthy men. Non-antimicrobial
prevention strategies are desirable given
the adverse effects associated with anti-
microbials and the increasing problem
with antimicrobial resistance. This sec-
tion reviews different approaches to the
prevention of recurrent UTIs. Of note,
most recurrent UTIs in young women
are reinfections, rather than relapses, in
which retreatment can be accomplished
with short-course antimicrobial regimens
and urologic evaluation is not indicated
generally.
In young healthy women, sexual inter-
course is the risk factor most highly asso-
ciated with recurrent UTI [1]. Other risk
factors in young women include spermi-
cide use, having a new sexual partner,
having a mother with a history of UTI,
and having a UTI during childhood. There
are several behaviors that are thought to
increase the risk of recurrent UTI, but
their association with UTI has not been
clearly demonstrated in trials. These
include reduced fluid intake, habitually
delaying urination, delaying post-coital
urination, wiping from back to front after
defecation, douching, and wearing occlu-
sive underwear. In older women, risk fac-
tors include urinary incontinence, history
of UTI before menopause, blood group
antigen nonsecretor status, and having a
cystocele and an increased post-void resid-
ual. Not surprisingly, intercourse has also
been shown to be a risk factor for recur-
rent UTI in post-menopausal women [2].
In addition, there is a growing body of
evidence that UTIs in children and adults
are associated with genetic mutations that
affect the innate immune system [3–4].
Given the frequency of recurrent UTI
and associated morbidity even in healthy
young women, different prevention

strategies have been investigated. Although
there are no well-designed studies address-
ing the impact of behavioral changes in
reducing recurrent UTIs, there are some
strategies that are highly likely to be effec-
tive. Reducing sexual activity is one such
strategy, even if it is not always feasible.
Reducing use of spermicides that include
nonoxynol-9 is also likely to be highly
effective, although the number of women
who use these products is relatively small.
Women with recurrent UTI should be
counseled about the pathogenesis of UTI
and how behavior modification might be
useful in reducing one’s risk. For example,
women should understand the rationale for
proper wiping habits and how early post-
coital micturition might reduce one’s risk
of infection.
Antimicrobial prophylaxis, as reviewed
in this section by Drs. Lichtenberger and
Hooton, is highly effective in reducing the
risk of recurrent UTI, and is occasion-
ally warranted to prevent bothersome
recurrent UTIs. These authors review
the antimicrobial prevention strategies
that have been shown to be effective in
preventing UTIs: continuous prophylaxis,
post-coital prophylaxis and intermittent
self-treatment. The decision as to which
approach to use depends upon the fre-
quency and pattern of recurrences and
willingness of the patient to commit to a
specific regimen. Adverse events, patient’s
lifestyle and compliance and plans for
a pregnancy should be considered. The
choice of antibiotic should be based upon
the identification and susceptibility pat-
tern of the organism causing the patient’s
UTIs and history of drug allergies.
Before considering antimicrobial
prophylaxis to prevent UTI, however, one
should try non-antimicrobial approaches
to avoid antimicrobial side effects.
Common side effects include rash, nau-
sea, diarrhoea, vaginal candidiasis, and
antibiotic-associated diarrhea. A major
concern with any antimicrobial use is
the selection of microbial flora resistant
to the drug being used as well as other
Introduction | 4.1 |
drugs. Non-antimicrobial approaches to
prevent recurrent UTIs include behav-
ioral modification as mentioned above,
and the use of topical estrogen (in post-
menopausal women) (not reviewed in this
section), cranberry products, probiotics
and immunoprophylaxis.
Estrogen alleviates atrophy of vaginal
and urethral epithelium in older women.
Although oral estrogens appear not to
reduce the incidence of UTI in postmeno-
pausal women, topical vaginal estrogens
do appear to have a beneficial effect [5].
One randomized placebo-controlled study
showed a dramatic benefit of vaginal
estriol in reducing UTI risk and reconsti-
tution of vaginal flora [6]. In this 8-month
study, the rate of recurrent UTI went
from 5.9 to 0.5 UTI per year, and reconsti-
tution of the vaginal flora with lactobacilli
was demonstrated in the estriol group.
Similar beneficial results were shown in
a study with an estradiol-releasing vagi-
nal ring [7].
Cranberry products, reviewed by
Dr. Botto, are widely used by women
for UTI prevention. Cranberry products
block attachment of E. coli to uroepithe-
lial cells via a non-dialyzable condensed
tannin, the proanthocyanidin type A. The
evidence for their clinical effectiveness
remains inconclusive, although recent
small studies suggest a beneficial effect.
A recent Cochrane review of clinical stud-
ies concluded that there is some evidence
for use of cranberry in young women, but
it is not clear what is the optimum dosage
or method of administration (e.g., juice
or tablets), and that further properly
designed trials with relevant outcomes
are needed. Such studies are ongoing.
Until such data are available, it is rea-
sonable to support the use of cranberry
as a preventive strategy in women with
recurrent UTI.
Probiotics, reviewed by Drs. Cadieux
and Reid, offer a natural approach to
health maintenance with the potential
for reduced cost. Probiotics are living
microorganisms administered to promote
237
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
the health of the host by treating or pre-
venting disease. The correlation between
depletion of vaginal lactobacilli and risk
of UTI has led to efforts to replenish the
lactobacilli organisms as a means to pre-
vent recurrent UTI. Clinical studies pro-
vide limited evidence that Lactobacillus
rhamnosus GR-1 with L. reuteri RC-14
and L. crispatus CTV05 can populate the
vagina and displace urogenital patho-
gens leading to reduced risk of infection.
However, studies with larger sample sizes
and well characterized and reliably pro-
duced products are needed to strengthen
the level of evidence. Although many
products are touted as probiotics, the con-
tent and viability of most are unreliable.
Further study of probiotics and their role
in reconstituting vaginal lactobacilli and
reducing the risk of recurrent UTI are
clearly indicated.
Naber et al. performed a meta-analysis
to assess the therapeutic efficacy and
safety of bacterial lysates in the prevention
of recurrent UTIs. Such trials are based on
the presence in the urinary tract of immu-
nological and cellular machinery necessary
for an efficient antibacterial defence and
the development of approaches to activate
it. Several placebo-controlled trials have
been performed with an oral immunos-
timulant (OM-89 capsules, heat killed
uropathogenic Escherichia coli), and these
trials have shown a mean reduction of
36% in the number of UTIs (some trials
define UTI as the presence of significant
bacteriuria) in OM-89 treated patients as
well as a reduction in the use of antibac-
terials. Smaller placebo-controlled stud-
ies using a vaginal vaccine (heat killed
uropathogenic E. coli, Proteus vulgaris,
Klebsiella pneumoniae, Morganella mor-
ganii and Enterococcus faecalis) suggest
that this vaccine is also effective in reduc-
ing UTI when administered with a booster
cycle. Other promising vaccine approaches
are mentioned in the review. Vaccine
approaches offer an exciting alternative
to antimicrobial prophylaxis for prevent-
ing UTI, but larger more definitive trials
238
are warranted to determine their effective-
ness, optimal regimens, and appropriate
target populations.
Hoyme discusses a novel strategy
to prevent premature birth, a common
syndrome with very costly complica-
tions. Bacterial vaginosis, a syndrome in
which vaginal microflora is altered due
to unknown causes, is commonly found
in pregnancy. Bacterial vaginosis is asso-
ciated with an increased risk for prema-
turity, and treatment has been shown
to reduce this risk. Hoyme describes the
results of a trial to determine whether
self-screening of vaginal pH with gynae-
cologic consultation for elevated vaginal
pH results in reduced rates of prema-
turity. Women participating in the trial
were observed to have a reduced rate of
prematurity compared with those who
had routine care during pregnancy. This
simple approach needs to be confirmed in
randomized trials, but it could possibly
reduce the incidence of the common and
extremely costly complications associated
with prematurity at minimal cost.
In summary, effective and safe strate-
gies to prevent recurrent UTIs that avoid
the use of antimicrobials are highly desir-
able. Education and counselling with the
aim of behavioural modification should
be offered to all persons with recurrent
UTI. Topical estrogen should be consid-
ered in post-menopausal women with
recurrent UTI. Although cranberry prod-
ucts have not definitively been proven
effective, there is no reason to discour-
age their use as we await more defini-
tive trials. Although vaginal colonization
and clinical effectiveness data on pro-
biotics are sparse, preliminary data
with some lactobacilli preparations are
promising; however, there are no widely
available products with these lactoba-
cilli species commercially available for
persons who would like to try them.
Immunoprophylaxis with OM-89 appears
to be significantly superior to placebo
in reducing UTI recurrences, but is not
available in many countries, including

the United States. Cranberry, probiotics,
and immunoprophylaxis are promising
antimicrobial-sparing approaches that
warrant further study. For those women
with frequent recurrent UTIs not respond-
ing to the measures discussed above, one
should consider antimicrobial approaches,
especially the intermittent self-treatment
strategy to reduce antimicrobial exposure.
REFERENCES
1. Hooton TM, Recurrent urinary tract infec-
tion in women. Int J Antimicrob Agents,
2001. 17(4): 259–68.
2. Moore EE, Hawes SE, Scholes D, Boyko
EJ, Hughes JP, and Fihn SD, Sexual inter-
course and risk of symptomatic urinary
tract infection in post-menopausal women.
J Gen Intern Med, 2008. 23(5): 595–9.
3. Finer G and Landau D, Pathogenesis
of urinary tract infections with normal
Introduction | 4.1 |
female anatomy. Lancet Infect Dis, 2004.
4(10): 631–5.
4. Lundstedt AC, Leijonhufvud I,
Ragnarsdottir B, Karpman D, Andersson
B, and Svanborg C, Inherited susceptibil-
ity to acute pyelonephritis: a family study
of urinary tract infection. J Infect Dis,
2007. 195(8): 1227–34.
5. Perrotta C, Aznar M, Mejia R, Albert X,
and Ng CW, Oestrogens for preventing
recurrent urinary tract infection in post-
menopausal women. Cochrane Database
Syst Rev, 2008(2): CD005131.
6. Raz R and Stamm WE, A controlled trial
of intravaginal estriol in postmenopau-
sal women with recurrent urinary tract
infections. N Engl J Med, 1993. 329(11):
753–6.
7. Eriksen B, A randomized, open, parallel-
group study on the preventive effect of an
estradiol-releasing vaginal ring (Estring)
on recurrent urinary tract infections in
postmenopausal women. Am J Obstet
Gynecol, 1999. 180(5): 1072–9.
239
|4.2|

Antimicrobial prophylaxis in
women with recurrent urinary tract
infections
Paola Lichtenberger, Thomas M. Hooton
Division of Infectious Disease, Department of Medicine, University of Miami Miller School of Medicine,
Miami, FL, United States
*Corresponding author: Thomas M. Hooton, M.D., Professor of Clinical Medicine,
University of Miami Miller School of Medicine
1120 NW 14th Street, Suite 1144, Miami, FL 33136, USA, Tel +1 (305) 243 2576, THooton@med.miami.edu

ABSTRACT compliance and plans for a pregnancy also

Recurrent urinary tract infections (UTIs) in
women are common, result in considerable
morbidity and expense, and can be a man-
agement problem for clinicians. Behavioral
changes can be useful antimicrobial-sparing
measures in the prevention of recurrent
UTIs, but antimicrobial prophylaxis may
be necessary in those who continue to
have recurrences. Continuous prophylaxis,
post-coital prophylaxis and intermittent
self-treatment with antimicrobials have
all been demonstrated to be effective in
the prevention of recurrent uncomplicated
UTIs. The decision as to which approach to
use depends upon the frequency and pat-
tern of recurrences and willingness of the
patient to commit to a specific regimen.
The risk of adverse events, including anti-
microbial resistance, patient’s lifestyle and
need to be considered. The choice of anti-
microbial should be based upon the suscep-
tibility pattern of the organisms causing
the patient’s previous UTIs and history of
drug allergies.
Key words: Recurrent UTI, antimicrobial
prophylaxis, prophylactic antimicrobials,
and suppressive treatment
SUMMARY OF RECOMMENDATIONS
1. Antimicrobial prophylaxis for
prevention of recurrent UTI should
be considered only after counseling
and behavioral modification have been
attempted (GoR A).
2. Continuous or post-coital antimicro-
bial prophylaxis should be considered
 Antimicrobial prophylaxis in women with recurrent urinary tract infections
to prevent recurrent uncomplicated
cystitis in women in whom non-
antimicrobial measures have been
unsuccessful (GoR A). For drug regi-
mens see Tables 1 and 2.
Table 1 Continuous antimicrobial prophylaxis regimens
for women with recurrent urinary tract infection.
Adapted from [60].
Regimens
TMP-SMX* 40mg/200mg once daily
TMP-SMX 40mg/200mg thrice weekly
Trimethoprim 100mg once daily
Nitrofurantoin 50mg once daily
Nitrofurantoin 100mg once daily
Cefaclor 250mg once daily
Cephalexin 125mg once daily
Cephalexin 250mg once daily
Norfloxacin 200mg once daily
Ciprofloxacin 125mg once daily
Fosfomycin 3gm every 10 days
*Trimethoprim-sulfamethoxazole.
**High recurrence rates observed with trimethoprim use associ-
ated with trimethoprim-resistance.
Table 2 Post-coital antimicrobial prophylaxis regimens
for women with recurrent urinary tract infection.
Adapted from [60].
Regimens
TMP-SMX* 40mg/200mg
TMP-SMX 80mg/400mg
Nitrofurantoin 50mg or 100mg
Cephalexin 250mg
Ciprofloxacin 125mg
Norfloxacin 200mg
Ofloxacin 100mg
*Trimethoprim-sulfamethoxazole.
| 4.2 |
3. In appropriate women with recurrent
uncomplicated cystitis, self-diagnosis
and self-treatment with a short-course
regimen of an antimicrobial should be
considered for management (GoR A).
1. INTRODUCTION
Recurrent urinary tract infections (UTIs)
are common in women, result in consid-
Expected erable morbidity and expense, and can
UTIs per year be a vexing management problem for
0 to 0.2 clinicians. In a study of college women
with their first UTI, 27% experienced at
0.1
least one culture-confirmed recurrence
0 to 1.5** within the six months following the ini-
0 to 0.6 tial infection and 2.7% had a second
recurrence during this same time period
0 to 0.7
[1]. When the first infection is caused
0.0 by Escherichia coli, women appear to
0.1
be more likely to develop a second UTI
within six months than those with a
0.2
first UTI due to another organism [2]. In
0.0 a Finnish study of women ages 17 to 82
0.0
who had E. coli cystitis, 44 percent had a
recurrence within one year [3].
0.14 Most recurrences in young healthy
women are thought to represent episodes
of exogenous reinfection, typically months
apart [4]. In the normal host, most
uropathogens originate in the rectal flora,
colonize the periurethra, and ascend to
the bladder. Increasing evidence suggests
that alteration of the normal vaginal
flora, especially loss of hydrogen peroxide-
producing lactobacilli, may predispose
Expected to introital colonization with E. coli and
UTIs per year to UTI [5]. Only rarely do young women
0.30 with recurrent UTI have anatomical or
functional abnormalities of the urinary
0.00
tract, and excretory urography, cystogra-
0.10 phy and cystoscopy are therefore of little
0.03
use in the evaluation of such women [6].
Of note, recent studies in mice have
0.00
shown that E. coli may invade and repli-
0.00 cate within bladder epithelial cells and
0.06
reemerge later to cause infection [7].
There is new evidence that this pathway
may occur in women with cystitis in whom
241
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
evidence of intracellular bacterial commu-
nities has been found in exfoliated cells in
urine [8]. Further studies are needed to
determine whether this pathway occurs in
women and causes same-strain recurrent
UTI and, if it does, how it might influence
prophylactic strategies.
In a large case-control study of women
with and without a history of recurrent
UTIs, the frequency of sexual intercourse
was the strongest risk factor for recurrent
UTI in a multivariate analysis [9]. Other
risk factors identified were spermicide
use during the past year, having a new
sex partner during the past year, having a
first UTI at or before 15 years of age and
having a mother with a history of UTIs.
In a recent population-based case-control
study of 1,278 women ages 18–49, the risk
of both recurrent cystitis and pyelonephri-
tis was significantly increased for women
reporting female relatives with a history
of UTI, with associations similar in magni-
tude to those for behavioral exposures such
as new or multiple sex partners, inter-
course frequency, and spermicide exposure
[10]. These data strongly suggest a possi-
ble genetic role for increased susceptibility
to these infections in community-dwelling
women.
Postmenopausal women may also have
frequent recurrences of UTI. Risk factors
for UTI in postmenopausal women are
similar to those in younger women, but
other factors also appear to play a role.
In a case-control study of 149 healthy
postmenopausal women with a history of
recurrent UTI and 53 controls without a
history of UTI, mechanical and/or physi-
ologic factors that affect bladder empty-
ing were found to be strongly associated
with recurrent UTIs [11]. Multivariate
analysis showed that urinary inconti-
nence (odds ratio (OR) 5.79), a history
of UTI before menopause (OR 4.85) and
non-secretor status (OR 2.9) were the
factors most strongly associated with
recurrent UTI (presence of a cystocele or
a postvoid residual urine were excluded
because of low frequency in the controls).
242
In addition, the lack of estrogen causes
marked changes in the vaginal microflora
including loss of lactobacilli and increased
colonization by E. coli. Topically applied
intravaginal estriol cream is an effective
preventive measure in such women [12].
The risk of recurrent UTI in women
has been demonstrated to be reduced by
the use of prophylactic antimicrobials
[13–14]. Prophylactic antimicrobials have
been advocated for women who have expe-
rienced two or more symptomatic UTIs
over a six-month period (13) or three or
more over a 12-month period [15] after
an existing infection has been eradicated
as demonstrated by a negative urine cul-
ture one to two weeks after treatment.
However, the discomfort or inconvenience
experienced by the woman as a result of
her recurrent infections should be consid-
ered when deciding whether antimicro-
bial prophylaxis should be tried.
2. METHODS
A systematic search in the English litera-
ture was performed in PubMed for the last
20 years using the following key words:
recurrent UTI, antimicrobial prophylaxis,
recurrent UTI in women, prophylactic
antimicrobials, and suppressive treatment
for recurrent UTI. We reviewed published
randomized controlled trials as well as
case-control studies, cochrane reviews
and meta-analyses. Publications were
screened by title and, when appropri-
ate, abstracted. These publications were
supplemented by additional publications
obtained from their bibliographies. The
studies were rated according to the level
of evidence (LoE) and the grade of recom-
mendation (GoR) using ICUD standards
(for details see Preface) [16–17].
3. PREVENTION STRATEGIES
Several strategies have been used in an
attempt to prevent recurrent UTIs. These
preventive approaches are reviewed in
 Antimicrobial prophylaxis in women with recurrent urinary tract infections
this section of the book. Although many
such strategies have not been adequately
tested in well-designed studies, patients
and providers often hold very strong
biases about their effectiveness. Non-
antimicrobial approaches to prevent UTI
should first be tried as a way of minimiz-
ing antimicrobial exposure. Thus, women
with recurrent UTI who are sexually
active or who use spermicides should be
counseled about the possible associa-
tion between their infections and sexual
intercourse and use of spermicides and
advised, when appropriate, to decrease
or eliminate the usage of spermicide-
containing products. It is reasonable to
counsel women about the use of cranberry
to prevent UTI (see Botto), although
there is no definitive study showing that
cranberry products are effective in pre-
venting UTI. Probiotics (see Cadieux et
al.) and vaccines (see Naber et al.) for the
prevention of recurrent UTI hold promise
but are not widely available and warrant
further trials to determine efficacy.
4. ANTIMICROBIAL PROPHYLAXIS
There are several approaches to choose
from when using antimicrobial prophy-
laxis. Continuous prophylaxis, post-
coital prophylaxis and intermittent
self-treatment (which is not really a
prophylactic method) have all been
demonstrated to be effective in the man-
agement of recurrent uncomplicated
UTIs. The decision as to which approach
to use depends upon the frequency and
pattern of recurrences and willingness of
the patient to commit to a specific regi-
men. The choice of antimicrobial should
be based upon the identification and sus-
ceptibility pattern of the organism caus-
ing the patient’s UTIs and the patient’s
history of drug allergies. Before any
prophylaxis regimen is initiated, eradica-
tion of a previous UTI should be assured
by a negative urine culture one to two
weeks after treatment.
| 4.2 |
4.1 Continuous prophylaxis
Continuous prophylaxis has been dem-
onstrated to decrease the number of
recurrent episodes of UTI by up to 95%
in several studies in different popula-
tions (LoE 1b) [13, 18–20]. A Cochrane
meta-analysis evaluated 19 trials involv-
ing 1120 healthy non-pregnant women
with two or more UTIs during the previ-
ous 12-month period. Ten of those nine-
teen trials compared antimicrobials with
other antimicrobialss or placebo [20].
Antimicrobial agents reviewed in the
meta-analysis included norfloxacin, cip-
rofloxacin, nitrofurantoin, trimethoprim-
sulfamethoxazole, cephalexin, cefaclor
and perfloxacin. During active prophy-
laxis, the range of microbiological recur-
rences was 0 to 0.9 per person-year in the
antimicrobial group compared with 0.8 to
3.6 in the placebo group. The relative risk
(RR) of having one microbiological recur-
rence was 0.21 (95% CI: 0.13 to 0.33) in
favor of antimicrobial prophylaxis. For
clinical recurrences, the RR was 0.15 (95%
CI: 0.08 to 0.28) in favor of antimicrobial
prophylaxis. Side effects included vaginal
and oral candidiasis and gastrointestinal
symptoms. No conclusions could be made
regarding the best antimicrobial or the
optimal duration of prophylaxis (the max-
imal duration tested was one year).
There are few data available evaluating
fosfomycin for prophylaxis. In a double-
blind randomized placebo-controlled
study, the efficacy and safety of fosfo-
mycin for prophylaxis was assessed in
317 non-pregnant women with a his-
tory of recurrent UTIs for a period of 12
months [21]. Fosfomycin was adminis-
tered in 3-gram sachets every 10 days
for six months. The number of UTIs per
patient-year in the fosfomycin group was
0.14 compared with 2.97 in the placebo
group (P<0.001). The time to first infec-
tion recurrence was significantly longer
in the fosfomycin group (38 days) than
in the placebo group (6 days) (P<0.01).
Fosfomycin was well tolerated.
243
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
Some authorities recommend that anti-
microbial prophylaxis be administered for
a six-month period followed by an obser-
vation period based upon observations
that UTIs seem to cluster in some women
[22–23]. However, some trials suggest that
prophylaxis does not appear to modify the
natural history of recurrent UTI and that
most women revert back to their previous
patterns of recurrent UTI once prophy-
laxis is stopped [20]. In those patients
who continue to have symptomatic infec-
tions after antimicrobial prophylaxis is
stopped, prophylaxis may be restarted and
extended to two or more years [13, 24–25].
The use of trimethoprim-sulfamethoxazole
for as long as five years has been reported
to be effective and well-tolerated [25].
Nitrofurantoin has also been shown to be
safe and well-tolerated in long-term (12
months) prophylaxis regimens, although
16% of women did not benefit in one study
[26]. In addition, there are concerns about
toxicity with long term nitrofurantoin use
as discussed below.
The regimens used for continuous
prophylaxis are shown in Table 1.
4.2 Post-coital prophylaxis
A single postcoital dose of antimicrobials
may be a more efficient and acceptable
method of prevention than continuous
prophylaxis in women whose symptoms
appear related to sexual intercourse (LoE
1b). Depending upon the frequency of sex-
ual activity, postcoital prophylaxis usu-
ally results in receipt of smaller amounts
of antimicrobials than continuous proph-
ylaxis. Uncontrolled studies suggest a
comparable reduction in infection rates
with postcoital trimethoprim-sulfameth-
oxazole, nitrofurantoin, cephalexin and
the fluoroquinolones [19, 27–30]. The
only published placebo-controlled trial
of postcoital prophylaxis for recurrent
uncomplicated UTI showed a decrease
in cystitis recurrence rates with postcoi-
tal trimethoprim-sulfamethoxazole at a
dose of 40/200mg (0.3 per patient-year)
244
compared with placebo (3.6 per patient-
year), and the regimen was effective for
patients with both low and high inter-
course frequencies [31]. In another rand-
omized trial, postcoital ciprofloxacin was
as effective in reducing recurrent cystitis
as daily ciprofloxacin in sexually active
young women [32].
The regimens used for postcoital proph-
ylaxis are shown in Table 2.
4.3 Self-diagnosis and
self-treatment
Many women do not want to take antimi-
crobials over an extended period of time
and prefer to minimize their intake of anti-
microbials. If such women are reliable, they
may be candidates for self-diagnosis and
self-treatment with a short-course regimen
of an antimicrobial such as trimethoprim-
sulfamethoxazole or a fluoroquinolone
(LoE 1b). In a randomized, crossover trial,
38 women with recurrent cystitis were
assigned to use either continuous prophy-
laxis with trimethoprim-sulfamethoxazole
or intermittent self-administered ther-
apy with trimethoprim-sulfamethoxazole
(single-dose of 320/1600mg) at the onset
of urinary symptoms [33]. The infection
rate for those on prophylaxis was 0.2 epi-
sodes per patient-year compared with 2.2
episodes per patient-year for patients on
intermittent self-therapy (P<0.001). In the
self-treatment group, UTI was correctly
diagnosed in 35 (92%) of 38 symptomatic
episodes and self-treatment was effective
in 30 (86%) of the 35 infections. In another
study, 34 women with recurrent cystitis
were similarly evaluated for the self-treat-
ment of UTIs with norfloxacin [34]. The
incidence of microbiologically confirmed
UTIs was 2.3 per patient-year (range 0 to
9). There was a total of 84 symptomatic
episodes, in which 78 (92%) responded
clinically to self-treatment. Similar results
were found in a third study of 172 women
with recurrent UTI, 88 of whom self-
diagnosed 172 UTI and then started self-
treatment with ofloxacin or levofloxacin.
 Antimicrobial prophylaxis in women with recurrent urinary tract infections
Clinical and microbiological cure occurred
in 92% and 96%, respectively, of culture-
confirmed episodes, and there were no
serious adverse events [35].
Use of this strategy should be restricted
to those women who have clearly docu-
mented recurrent infections and who
are motivated, compliant with medical
instructions and have a good relation-
ship with a medical provider. The trials
have been performed with trimethoprim-
sulfamethoxazole or a fluoroquinolone,
but any of the first-line agents discussed
below should be adequate to use with this
strategy. Women should be reminded to
call their provider if they have symptoms
suggestive of pyelonephritis or if their
symptoms are not completely resolved by
48 hours on treatment.
5. ANTIMICROBIALS USED FOR UTI
PROPHYLAXIS
5.1 Trimethoprim-sulfamethoxazole
Trimethoprim-sulfamethozaxole has been
employed for more than 30 years as a
first-line therapy for UTI [36]. It is also a
first-line choice for prophylaxis for recur-
rent cystitis. However, antimicrobial resist-
ance to this agent has been increasing over
the years, approaching 18–22% in some
areas of the United States and Europe,
raising questions about its role in the treat-
ment of cystitis [37–38]. A more recent
surveillance study of antimicrobial resist-
ance in women with cystitis from nine
countries of Europe and Brazil (ARESC
study) reported high rates of resistance
among E. coli to several commonly used
antimicrobials used for UTI, including
trimethoprim-sulfamethoxazole (29%) and
fluoroquinolones (8%) [39]. In the US, but
perhaps not in Europe and some other
parts of the world, the use of trimethoprim-
sulfamethoxazole for prophylaxis to prevent
recurrent UTI is reasonable if previous
causative isolates are susceptible to this
agent. It is well-tolerated and inexpensive.
| 4.2 |
5.2 Nitrofurantoin
Nitrofurantoin, a synthetic nitrofurane
derivative, has maintained excellent
in vitro activity against E. coli and
Enterococcus faecalis even though it has
been on the market for over 50 years. It
is one of the most commonly used antimi-
crobials for prophylaxis. Nitrofurantoin,
unlike trimethoprim or the fluoroquinolo-
nes, appears not to select for drug-resistant
bowel flora or to eradicate coliforms from
the bowel flora [26]. Thus, during long-
term prophylaxis with nitrofurantoin in 92
women, nitrofurantoin-sensitive coliforms
were present in the fecal flora of almost
all patients during antimicrobial prophy-
laxis; no resistant organisms were found
in 80 women [26]. In the 12 women who
had nitrofurantoin-resistant organisms in
their fecal flora, none had breakthrough
infections with these organisms.
A review of 1,142 outpatient E. coli
strains causing UTIs in patients from the
USA and Canada between 2003 and 2004
was carried out by the North American
Urinary Tract Infection Collaborative
Alliance (NAUTICA) [40]. The overall
resistance to ampicillin was 37.7% and
to trimethoprim-sulfamethoxazole 23.3%,
whereas only 1.1% of the isolates were
resistant to nitrofurantoin. Similar results
were seen in a study of 4,734 adult women
presenting with acute uncomplicated cysti-
tis in Europe and Canada [41]. Of the 2,478
E. coli isolates tested from this group, the
prevalence of resistance to ampicillin was
30% and to trimethoprim-sulfamethoxazole
14%, but only 1.2% were resistant to nitro-
furantoin and 0.7% to fosfomycin. However,
in a recent survey performed in Italy, more
than 20% of E. coli strains were resistant
to nitrofurantoin [42].
Nitrofurantoin is well tolerated, but
with long-term exposure, as with proph-
ylaxis, acute, subacute and chronic pul-
monary reactions, chronic hepatitis and
neuropathy have been reported. These
toxicities are exceedingly rare, but the
patient should be warned about them.
245
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
5.3 Fluoroquinolones
Ciprofloxacin and levofloxacin are the
most commonly used fluoroquinolones for
the treatment of UTI. The other agents in
this class do not offer any advantages over
these two. Of concern, fluoroquinolones
are increasingly used for treatment and
prophylaxis of UTI and, as noted above,
resistance among UTI strains is increas-
ing. They are generally well tolerated,
although they can cause gastrointesti-
nal, neurological and cardiovascular side
effects, including a prolonged QTc interval
and, infrequently, Torsade de pointe [43].
Fluoroquinolones are not recommended
in patients with a history of prolonged
QTc interval, in patients with uncorrected
hypokalemia or hypomagnesemia, or with
concomitant use of medications that can
increase the QTc interval.
The use of fluoroquinolones has also
been associated with tendon, mainly the
Achilles, rupture. A recent Danish study
suggested that the risk of Achilles tendon
rupture within 90 days of fluoroquinolone
use was 17.7 per 100,000 person-years
(95% CI: 5.7–41.3) which was three times
higher than that calculated for the back-
ground population [44]. This corresponds
to only one excess Achilles tendon rupture
per 8300 treatments. Another study of
46,776 patients treated with fluoroquinolo-
nes found 704 cases of Achilles tendinitis
and 38 cases of Achilles tendon rupture
accounting for an overall excess risk of 3.2
cases of tendon problems for every 1000
person-years of exposure [45]. However,
the risk of having Achilles tendon disease
after 30 days of exposure to fluoroquinolo-
nes was the same compared with the non-
exposed population [45]. Achilles tendon
rupture is mainly related to physical activ-
ity, although rheumatoid arthritis, the use
of corticosteroids, age and male sex are
additional risk factors [43, 45–46]. The
mechanism behind the fluoroquinolones
effect is unknown, but it is probably due to
direct toxicity and degenerative changes on
collagen fibers [44]. Patients undergoing
246
long-term prophylaxis with fluoroquinolo-
nes, especially those undergoing strenuous
physical activity and those with chronic
use of steroids, should be counseled about
the risk of tendon rupture.
Fluoroquinolones are classified by the
manufacturer as pregnancy category
C. They cross the placenta and produce
measurable concentrations in the amni-
otic fluid and cord serum [47]. Although
an increased risk of teratogenic effects has
not been observed in animals or humans,
fluoroquinolones should not be used dur-
ing pregnancy because of concerns of car-
tilage damage in immature animals [48].
Contraception and pregnancy plans should
be discussed before prescribing fluoroqui-
nolones to females of child-bearing age.
Fluoroquinolones should not be consid-
ered as first- line agents for prophylaxis
for recurrent uncomplicated cystitis given
concerns about selection for resistance.
However, if other measures have failed
in women with frequent bothersome
recurrences, it is reasonable to consider
their use.
5.4 Cephalosporins
Cephalosporins have been studied as an
alternative to nitrofurantoin or placebo
for the prophylaxis of recurrent UTIs in
women with good clinical and microbio-
logic outcomes [49–50]. In the ECO.SENS
project that determined antimicrobial
susceptibility of bacterial pathogens caus-
ing community acquired UTIs in 16 coun-
tries of Europe and Canada, resistance to
cefadroxil was seen in only 53/2478 E. coli
strains tested [41]. In one study of 49
patients taking long-term cephalosporins
as prophylaxis for recurrent UTI, only 13
bacteriuric episodes were detected and
among those, only 50% were resistant to
cephalosporins – findings were similar in
the comparator nitrofurantoin group [49].
5.5 Fosfomycin tromethamine
Fosfomycin tromethamine is a phosphonic
acid derivative, bactericidal cell-wall
 Antimicrobial prophylaxis in women with recurrent urinary tract infections
active antimicrobial agent effective with
a broad spectrum of antibacterial activity
[51]. This antimicrobial has good in vitro
activity against most of the bacterial spe-
cies responsible for uncomplicated cysti-
tis and is approved for the treatment of
uncomplicated cystitis caused by E. coli
and E. faecalis [52]. The rate of resist-
ance to fosfomycin among uropathogens
is quite low, even in countries such as
Japan, Spain, Germany, France, Brazil
and South Africa, where it has been used
extensively for more than 20 years [39,
53]. Clinical studies have shown that,
in countries where fosfomycin has been
used for many years, about 3% of bacte-
rial pathogens are resistant to fosfomy-
cin and this percentage has been stable
for several years [54–55]. The emergence
of fosfomycin-resistance is mainly due to
mutation of genes controlling the alpha
glycerolphosphate transport [55].
There appears to be little cross-
resistance between fosfomycin and other
antibacterial agents [56], possibly because
it differs from other agents in its general
chemical structure and site of action. Loss
of fitness due to resistance mutations
may explain the stably low incidence of
fosfomycin resistance.
6. PRECAUTIONS WHEN USING
ANTIMICROBIAL PROPHYLAXIS
FOR RECURRENT UTI
6.1 Antimicrobial resistance
Antimicrobial resistance is a concern in
persons on antimicrobial prophylaxis,
especially with those antimicrobials that
have other important uses in medicine,
such as fluoroquinolones. However, the
contribution that antimicrobial prophy-
laxis has on overall resistance has not
been determined. This concern warrants
further study.
The prophylactic efficacy of any anti-
microbial agent depends upon compliance
with taking the drug and the continued
| 4.2 |
susceptibility to the drug of potential
uropathogens colonizing the patient’s
perineal flora [18, 23]. In one study of
long-term prophylaxis with cefaclor or
nitrofurantoin, patients reported lack
of compliance shortly before the onset
of an episode of bacteriuria with cul-
tures reporting susceptible strains [49].
Monitoring rectal or vaginal flora for the
presence of resistant organisms has not
been proven to be helpful in anticipating
breakthrough infections in patients on
antimicrobial prophylaxis [18]. Moreover,
the emergence of uropathogens resist-
ant to the agents being used for UTI
prophylaxis is not frequently seen [18,
23, 26], but has been reported in some
studies. For example, in one study com-
paring post-intercourse versus daily cip-
rofloxacin prophylaxis for UTIs, 5 of 62
patients receiving daily prophylaxis for
three months had breakthrough UTIs,
two with organisms resistant to cipro-
floxacin [32]. Likewise, in a long-term
trimethoprim-sulfamethoxazole proph-
ylaxis study, breakthrough infecting
organisms were generally resistant to tri-
methoprim-sulfamethoxazole, and organ-
isms colonizing the periurethral and rectal
regions also tended to be resistant to the
trimethoprim-sulfamethoxazole [25].
Cross resistance was evaluated in 2478
E. coli isolates from the Pan-European
ECO.SENS Project [56]. Ampicillin/ sul-
famethoxazole resistance, seen in 8.7%
of strains, was the most common pattern
of multiple resistance. This was followed
by ampicillin/sulfamethoxazole/trimetho-
prim/trimethoprim- sulfamethoxazole
resistance, observed in 6.4% of all strains.
With the exception of fosfomycin, resist-
ance to any agent was associated with
increased resistance to the other agents
tested. This study showed that a multiple-
resistant phenotype involving fluoro-
quinolone resistance is present in most
countries in Europe, and that this phe-
notype is selected for not only by the
use of quinolones, but also by the use
247
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
of ampicillin, sulfamethoxazole and
trimethoprim-sulfamethoxazole.
6.2 Contraceptives
Some antimicrobials interfere with the
effectiveness of oral contraceptives by
interrupting the enterohepatic recycling
of estrogen by altering the gut flora that
participate in the process or by inducing
hepatic estrogen metabolism. As a result,
estrogen concentrations may be reduced.
Examples of such drugs include rifampin,
some macrolides, tetracyclines, metroni-
dazole and penicillins [57]. Women who
use an oral contraceptive and who are
placed on such an antimicrobial should
be warned to use a second contraceptive
alternative such as a barrier contracep-
tive while on the antimicrobial.
6.3 Antimicrobial-associated
diarrhea
Almost all antimicrobials used for UTIs
have been associated with an increased risk
of Clostridium difficile diarrhea (CDAD).
Clostridium difficile is responsible for
20% of all cases of antimicrobial-associated
diarrhea and has been increasingly rec-
ognized as a major nosocomial pathogen
[58]. Moreover, there have been alarming
increases in both the incidence and sever-
ity of CDAD reported over the past decade
[59]. The risk of acquiring CDAD should be
discussed with patients when using anti-
microbials for the prophylaxis of recurrent
UTIs, and strong consideration should
be given to non-antimicrobial preventive
approaches for patients with a history of
recurrent CDAD.
7. FURTHER RESEARCH
The optimal duration of long-term prophy-
lactic antimicrobials remains unknown,
although most authors advocate the use
of approximately six months, or longer in
women who continue to have recurrent
248
UTI. More research is warranted to deter-
mine the impact of long-term antimicro-
bial use as a contributing factor for the
emergence of multi-drug resistant bac-
teria in gut and vaginal flora. More data
are needed on side effects associated with
long-term use of low-dose antimicrobials
used for prophylaxis.
8. CONCLUSIONS
Antimicrobial prophylaxis should be con-
sidered in women with frequent recurrent
UTIs when non-antimicrobial measures
are not working. Antimicrobial prophy-
laxis is highly effective, but is usually used
for long periods of time and, thus, likely
contributes to the widespread problem of
antimicrobial resistance. Post-coital proph-
ylaxis and self-diagnosis/self-treatment
result in less antimicrobial use and should
be used in appropriate settings.
REFERENCES
1. Foxman, B., Recurring urinary tract
infection: incidence and risk factors. Am
J Public Health, 1990. 80(3): p. 331–3.
2. Foxman, B., et al., Risk factors for sec-
ond urinary tract infection among college
women. Am J Epidemiol, 2000. 151(12):
p. 1194–205.
3. Ikaheimo, R., et al., Recurrence of uri-
nary tract infection in a primary care
setting: analysis of a 1-year follow-up of
179 women. Clin Infect Dis, 1996. 22(1):
p. 91–9.
4. Pfau, A., T. Sacks, and D. Engelstein,
Recurrent urinary tract infections in pre-
menopausal women: prophylaxis based
on an understanding of the pathogenesis.
J Urol, 1983. 129(6): p. 1153–7.
5. Gupta, K. and W.E. Stamm, Pathogenesis
and management of recurrent urinary
tract infections in women. World J Urol,
1999. 17(6): p. 415–20.
6. Fowler, J.E., Jr. and E.T. Pulaski,
Excretory urography, cystography, and
 Antimicrobial prophylaxis in women with recurrent urinary tract infections
cystoscopy in the evaluation of women with
urinary-tract infection: a prospective study.
N Engl J Med, 1981. 304(8): p. 462–5.
7. Mulvey, M.A., et al., Bad bugs and
beleaguered bladders: interplay between
uropathogenic Escherichia coli and innate
host defenses. Proc Natl Acad Sci U S A,
2000. 97(16): p. 8829–35.
8. Rosen, D.A., et al., Detection of intracel-
lular bacterial communities in human
urinary tract infection. PLoS Med, 2007.
4(12): p. e329.
9. Scholes, D., et al., Risk factors for recur-
rent urinary tract infection in young
women. J Infect Dis, 2000. 182(4):
p. 1177–82.
10. Scholes, D., et al., Family UTI history
and increased risk of recurrent UTI
and pyelonephritis, in 48th Annual
Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC) and
the Infectious Diseases Society of America
(IDSA) 46th Annual Meeting. October
25–28, 2008: Washington, DC, . p. a.
L-604, p. 583.
11. Raz, R., et al., Recurrent urinary tract
infections in postmenopausal women. Clin
Infect Dis, 2000. 30(1): p. 152–6.
12. Stamm, W.E., Estrogens and urinary-
tract infection. J Infect Dis, 2007. 195(5):
p. 623–4.
13. Nicolle, L.E. and A.R. Ronald, Recurrent
urinary tract infection in adult women:
diagnosis and treatment. Infect Dis Clin
North Am, 1987. 1(4): p. 793–806.
14. Stamm, W.E. and T.M. Hooton,
Management of urinary tract infections
in adults. N Engl J Med, 1993. 329(18):
p. 1328–34.
15. Ronald, A.R. and B. Conway, An approach
to urinary tract infections in ambulatory
women. Curr Clin Top Infect Dis, 1988. 9:
p. 76–125.
16. Abrams, P., S. Khoury, and A. Grant,
Evidence–based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): p. 681–4.
17. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
p. 115–127.
| 4.2 |
18. Nicolle, L.E., Prophylaxis: recurrent uri-
nary tract infection in women. Infection,
1992. 20 Suppl 3: p. S203–5; discussion
S206–10.
19. Chew, L.D. and S.D. Fihn, Recurrent cys-
titis in nonpregnant women. West J Med,
1999. 170(5): p. 274–7.
20. Albert, X., et al., Antibiotics for prevent-
ing recurrent urinary tract infection in
non-pregnant women. Cochrane Database
Syst Rev, 2004(3): p. CD001209.
21. Rudenko, N. and A. Dorofeyev, Prevention
of recurrent lower urinary tract infections
by long-term administration of fosfomycin
trometamol. Double blind, randomized,
parallel group, placebo controlled study.
Arzneimittelforschung, 2005. 55(7):
p. 420–7.
22. Kraft, J.K. and T.A. Stamey, The natural
history of symptomatic recurrent bacteriu-
ria in women. Medicine (Baltimore), 1977.
56(1): p. 55–60.
23. Stamm, W.E., et al., Natural history of
recurrent urinary tract infections in women.
Rev Infect Dis, 1991. 13(1): p. 77–84.
24. Harding, G.K., et al., Long-term antimi-
crobial prophylaxis for recurrent urinary
tract infection in women. Rev Infect Dis,
1982. 4(2): p. 438–43.
25. Nicolle, L.E., et al., Efficacy of five years
of continuous, low-dose trimethoprim-
sulfamethoxazole prophylaxis for urinary
tract infection. J Infect Dis, 1988. 157(6):
p. 1239–42.
26. Brumfitt, W. and J.M. Hamilton-Miller,
Efficacy and safety profile of long-term
nitrofurantoin in urinary infections:
18 years’ experience. J Antimicrob
Chemother, 1998. 42(3): p. 363–71.
27. Pfau, A. and T.G. Sacks, Effective prophy-
laxis of recurrent urinary tract infections
in premenopausal women by postcoital
administration of cephalexin. J Urol,
1989. 142(5): p. 1276–8.
28. Pfau, A. and T.G. Sacks, Effective post-
coital quinolone prophylaxis of recurrent
urinary tract infections in women. J Urol,
1994. 152(1): p. 136–8.
29. Pfau, A. and T.G. Sacks, Effective prophy-
laxis for recurrent urinary tract infections
during pregnancy. Clin Infect Dis, 1992.
14(4): p. 810–4.
249
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
30. Nicolle, L.E., et al., Prospective, ran-
domized, placebo-controlled trial of
norfloxacin for the prophylaxis of recur-
rent urinary tract infection in women.
Antimicrob Agents Chemother, 1989.
33(7): p. 1032–5.
31. Stapleton, A., et al., Postcoital antimi-
crobial prophylaxis for recurrent urinary
tract infection. A randomized, double-
blind, placebo-controlled trial. JAMA,
1990. 264(6): p. 703–6.
32. Melekos, M.D., et al., Post-intercourse
versus daily ciprofloxacin prophylaxis for
recurrent urinary tract infections in pre-
menopausal women. J Urol, 1997. 157(3):
p. 935–9.
33. Wong, E.S., et al., Management of recur-
rent urinary tract infections with patient-
administered single-dose therapy. Ann
Intern Med, 1985. 102(3): p. 302–7.
34. Schaeffer, A.J. and B.A. Stuppy, Efficacy
and safety of self-start therapy in women
with recurrent urinary tract infections.
J Urol, 1999. 161(1): p. 207–11.
35. Gupta, K., et al., Patient-initiated treat-
ment of uncomplicated recurrent urinary
tract infections in young women. Ann
Intern Med, 2001. 135(1): p. 9–16.
36. Mazzei, T., et al., Pharmacokinetic and
pharmacodynamic aspects of antimicro-
bial agents for the treatment of uncom-
plicated urinary tract infections. Int J
Antimicrob Agents, 2006. 28 Suppl 1:
p. S35–41.
37. Gupta, K., et al., Antimicrobial resistance
among uropathogens that cause commu-
nity-acquired urinary tract infections in
women: a nationwide analysis. Clin Infect
Dis, 2001. 33(1): p. 89–94.
38. Sahm, D.F., et al., Multidrug-resistant
urinary tract isolates of Escherichia coli:
prevalence and patient demographics in
the United States in 2000. Antimicrob
Agents Chemother, 2001. 45(5):
p. 1402–6.
39. Schito, G.C., et al., The ARESC study: an
international survey on the antimicrobial
resistance of pathogens involved in uncom-
plicated urinary tract infections. Int J
Antimicrob Agents, 2009. 34(5): p. 407–13.
40. Zhanel, G.G., et al., Antibiotic resist-
ance in Escherichia coli outpatient
250
urinary isolates: final results from the
North American Urinary Tract Infection
Collaborative Alliance (NAUTICA). Int J
Antimicrob Agents, 2006. 27(6): p. 468–75.
41. Kahlmeter, G., Prevalence and antimicro-
bial susceptibility of pathogens in uncom-
plicated cystitis in Europe. The ECO.
SENS study. Int J Antimicrob Agents,
2003. 22 Suppl 2: p. 49–52.
42. Fadda, G., et al., Antimicrobial suscepti-
bility patterns of contemporary pathogens
from uncomplicated urinary tract infec-
tions isolated in a multicenter Italian
survey: possible impact on guidelines.
J Chemother, 2005. 17(3): p. 251–7.
43. Owens, R.C., Jr. and P.G. Ambrose,
Torsades de pointes associated with fluo-
roquinolones. Pharmacotherapy, 2002.
22(5): p. 663–8; discussion 668–72.
44. Sode, J., et al., Use of fluroquinolone
and risk of Achilles tendon rupture: a
population-based cohort study. Eur J Clin
Pharmacol, 2007. 63(5): p. 499–503.
45. van der Linden, P.D., et al.,
Fluoroquinolones and risk of Achilles ten-
don disorders: case-control study. BMJ,
2002. 324(7349): p. 1306–7.
46. Corrao, G., et al., Evidence of tendinitis
provoked by fluoroquinolone treatment: a
case-control study. Drug Saf, 2006. 29(10):
p. 889–96.
47. Giamarellou, H., et al., Pharmacokinetics
of three newer quinolones in pregnant
and lactating women. Am J Med, 1989.
87(5A): p. 49S-51S.
48. Food and Drug Administration (FDA).
CIPRO (ciprofloxacin) use by pregnant
and lactating Women. Available from:
www.fda.gov/cder/drug/infopage/cipro/
ciprogreg.htm.
49. Brumfitt, W. and J.M. Hamilton-Miller, A
comparative trial of low dose cefaclor and
macrocrystalline nitrofurantoin in the
prevention of recurrent urinary tract infec-
tion. Infection, 1995. 23(2): p. 98–102.
50. Gower, P.E., The use of small doses of
cephalexin (125 mg) in the management
of recurrent urinary tract infection in
women. J Antimicrob Chemother, 1975.
1(3 Suppl): p. 93–8.
51. Falagas, M.E., et al., Fosfomycin: use
beyond urinary tract and gastrointestinal
 Antimicrobial prophylaxis in women with recurrent urinary tract infections
infections. Clin Infect Dis, 2008. 46(7):
p. 1069–77.
52. Patel, S.S., J.A. Balfour, and H.M.
Bryson, Fosfomycin tromethamine. A
review of its antibacterial activity, phar-
macokinetic properties and therapeutic
efficacy as a single-dose oral treatment for
acute uncomplicated lower urinary tract
infections. Drugs, 1997. 53(4): p. 637–56.
53. Hayashi, K., Other antibiotics. Clin
Orthop Relat Res, 1984(190): p. 109–13.
54. Arca, P., G. Reguera, and C. Hardisson,
Plasmid-encoded fosfomycin resistance in
bacteria isolated from the urinary tract
in a multicentre survey. J Antimicrob
Chemother, 1997. 40(3): p. 393–9.
55. Alos, J.I., P. Garcia-Pena, and J. Tamayo,
[Biological cost associated with fosfomy-
cin resistance in Escherichia coli isolates
from urinary tract infections]. Rev Esp
Quimioter, 2007. 20(2): p. 211–5.
| 4.2 |
56. Kahlmeter, G. and P. Menday, Cross-
resistance and associated resistance in
2478 Escherichia coli isolates from the
Pan-European ECO.SENS Project sur-
veying the antimicrobial susceptibility of
pathogens from uncomplicated urinary
tract infections. J Antimicrob Chemother,
2003. 52(1): p. 128–31.
57. The Medical Letter Handbook of adverse
Drug Interaction. 2000.
58. Barbut, F., et al., Epidemiology of recur-
rences or reinfections of Clostridium diffi-
cile-associated diarrhea. J Clin Microbiol,
2000. 38(6): p. 2386–8.
59. Blossom, D.B. and L.C. McDonald,
The challenges posed by reemerging
Clostridium difficile infection. Clin Infect
Dis, 2007. 45(2): p. 222–7.
60. Hooton, T.M., Recurrent urinary tract
infection in women. Int J Antimicrob
Agents, 2001. 17(4): p. 259–68.
251
|4.3|

Immunoactive prophylaxis of
uncomplicated recurrent urinary
tract infections
Kurt G. Naber1, Yong-Hyun Cho2, Tetsuro Matsumoto3, Anthony J. Schaeffer4
1
Technical University Munich, Munich, Germany
2
St. Marys Hospital, The Catholic University of Korea, Seoul, South Korea
3
Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
4
Department of Urology, Northwestern University Medical School, Chicago, Illinois, USA
Corresponding Author: Prof. Dr. Dr. h.c. Kurt G. Naber, Karl-Bickleder-Str. 44c, D-94315 Straubing, Germany
Tel +49-9421-33369, E-mail: kurt@nabers.de

ABSTRACT immunostimulant (OM-89 capsules, heat

Background: Recurrent urinary tract
infections (UTIs) are the most common
medical complaint, particularly among
women in their reproductive years. There
is an increasing need for alternatives to
antibacterial prophylaxis, particularly
measures to increase defences. Various
bacterial lysates have been proposed with
this indication.
Methods: The objective of this review and
meta-analysis is to assess the therapeutic
efficacy and safety of bacterial lysates in
the management of recurrent UTIs.
Results: Electronic databases identified 11
studies with the descriptors UTI, immu-
notherapy or vaccines and double blind.
Seven of these studies dealt with an oral
killed uropathogenic Escherichia coli) of
which 5 (1000 adult patients) could be
retained for analysis with an observation
period of 6–12 months. The mean number
of UTIs was significantly lower, by an
average of 36%, in the OM-89 treated
patients in all the trials analysed; also
the use of antibacterials was lower.
Four of these studies dealt with a
vaginal vaccine (heat killed uropatho-
genic E. coli, P. vulgaris, K. pneumonia,
M. morganii & E. faecalis), of which three
small studies could be retained for anal-
ysis with a total of 220 adult patients.
The results suggest that this vaginal vac-
cine is effective when administered with
a booster cycle (no recurrence of UTI
in 50% vs. 14% with placebo). No blind
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections
controlled studies could be identified with
other bacterial lysates claiming the same
indication.
Conclusions: Among the various immu-
notherapeutic products offered on the
market only one (OM-89) has published
studies which are in accordance with cur-
rent standards. This product was shown
to be effective under conditions of daily
practice. The second product, also seems
effective but adequate phase III studies
are necessary.
Key words: Urinary tract infections,
bacterial lysates, clinical review, meta-
analysis, OM-89, Uro-Vaxom, Solco-Urovac
SUMMARY OF RECOMMENDATIONS
1. OM-89 (Uro-Vaxom®) is sufficiently
well documented and has shown to be
more effective than placebo in several
randomised trials. Therefore, it can
be recommended for immunoprophy-
laxis in female patients with recur-
rent uncomplicated UTI (GoR B). Its
efficacy in other patients’ groups and
its relative efficacy to antimicrobial
prophylaxis should be established.
2. For other immunotherapeutic prod-
ucts offered on the market larger
phase III studies are still missing. In
smaller phase II studies StroVac® and
Solco-Urovac® have been shown to be
effective when administered with a
booster cycle (GoR C).
3. For other immunotherapeutic prod-
ucts, e.g. Urostim®, Urvakol®, no
controlled studies are available.
Therefore no recommendations are
possible (GoR D).
1. INTRODUCTION
Urinary tract infections (UTIs) are the
most common medical complaint among
women in their reproductive years.
Women are 30 times more likely to have
UTIs than men are. Every year, 15% of
| 4.3 |
sexually active women have at least one
such infection, and up to 60% of all women
will develop a UTI at some time in their
lives. At least one in four of these women
will have a recurrence within a year [1].
Urinary tract infections (UTIs) fre-
quently present with acute onset of dysu-
ria, frequency or urgency and suprapubic
pain. The UTIs are confirmed by urine
analysis > 10 WBC/mm3 and urine cul-
ture with > 103 colony forming units/mL
of uropathogen in mid-stream sample of
urine. UTIs were defined as recurrent
if there were at least three episodes of
uncomplicated infection documented by
culture within a 12 month period. On
average, each episode of acute UTI in
pre-menopausal women was shown to be
associated with 6.1 days of symptoms,
2.4 days of restricted activity, 1.2 days
in which they were not able to attend
classes or work and 0.4 days in bed [2].
In women there are several well defined
risk-factors for recurrent UTIs such as a
maternal history of cystitis or history of
previous episodes of cystitis and the use
of spermicidal agents [3]. In postmeno-
pausal women the incidence of recurrent
UTIs is increased in diabetic patients [4];
in nonsecretor patients, patients with
urinary incontinence or with a history of
UTI before menopause [5–6].
The idea of employing bacterial
immune stimulants in order to reduce
recurrent UTIs was born some 40 years
ago and they have been used, rather
empirically, to prevent recurrent infec-
tions in the non-immunocompromised
host. These early attempts were ham-
pered at the time by a lack of knowledge
regarding the potential mechanisms
involved. Only in recent years has bet-
ter understanding of the innate immune
system provided a solid rationale for such
immune stimulants. The requirements
for a bacterial extract to be effective are
that it stimulates infection-combating,
circulating elements within the lymphoid
tissue and that the target organ envi-
sioned is immunocompetent in order to
253
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
adequately translate such a stimulus in
an efficient response. Bacterial extracts
can act as immune stimulants through
the activation of monocyte-derived den-
dritic cells, as was shown for OM-89
[7]. Human monocyte-derived dendritic
cells (moDCs) and circulating conven-
tional DCs coexpress activating (CD32a)
and inhibitory (CD32b) isoforms of IgG
Fcγ receptor. The balance between these
divergent receptors establishes a thresh-
old of dendritic cell activation and enables
immune complexes to mediate oppos-
ing effects on dendritic cell maturation
and function. The activating and inhibi-
tory FcγRs on DCs offer rational targets
for immunotherapy based on the unique
capacity of DCs to play critical roles in
both immunity and tolerance [8].
Some bacterial extracts are admin-
istered orally with the goal of increas-
ing the immune defences of organs with
a mucous lining, although parenteral,
intravaginal and intranasal applications
have also been described. In animal mod-
els and in normal humans, gut-associated
lymphoid tissue stimulation is able to
induce a generalised response by the
whole mucosal-associated lymphoid tis-
sue. Mucosa-associated lymphoid tissue
(MALT) is found in the digestive tract, the
respiratory tract and the genitourinary
tract. Migration and adherence of lamina
propria lymphocytes are in part dictated
by integrins and selectins. Lymphocyte
circulation leads to the distribution of
effector cells to particular parts of the
body where homing of the lymphocytes
is controlled by the expression of various
receptors on the cell surface and counter
receptors on the vascular endothelium [9].
In addition to the bladder, the urethra
is a highly dynamic immunocompetent
tissue possessing all the necessary ele-
ments for antigen presentation and both
humoral and cellular mucosal immune
responses. It is likely that this region
plays a dominant role in protecting the
urogenital tract against ascending infec-
tions [10]. The objective of the review
254
and meta-analysis presented herein is to
assess the therapeutic efficacy and safety
of the bacterial lysates currently availa-
ble in the management of recurrent UTIs.
2. METHODS
The primary objective of this review is to
assess the efficacy and safety of immu-
nostimulants based on bacterial lysates
from a clinical point of view and taking
into account clinically relevant endpoints.
Meta-analysis may produce a stronger
conclusion than can be provided by any
individual study. The purpose of meta-
analysis is to increase the statistical
power for primary end points, increase the
general applicability (external validity)
of findings, resolve uncertainty when
reports disagree, provide quantita-
tive estimates of effects, call attention
to strengths and weaknesses of a body
of research in a particular area and to
identify needs for new primary data
collection.
2.1 Search strategy and material
scrutinized
Among the data sources consulted in the
identification of trials were bibliographic
databases (TOXLINE, PaperChase brows-
ing the databases of the National Library
of Medicine and the National Cancer
Institute i.e. MEDLINE, HealthSTAR,
AIDSLINE and CANCERLIT, Embase,
AMED, Cochrane Col., PubMed (/www
.ncbi.nlm.nih.gov), TOXLINE Special,
DART Special, HSDB, IRIS, ITER,
GENETOX, CHEMIDplus, Haz-Map), ref-
erence lists from pertinent review articles
and books, and personal contacts with and
experts active in the area, up to January
2009. All papers were screened and any
dealing with prospective clinical trials
were retained for classification according
to the selection criteria described below.
In the case of double publications, the
authors retained those which were most
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections
recent and/or had appeared in a peer-
reviewed journal.
Selection criteria and description of
studies: The search criteria were urinary
tract infection double or single blind, and
bacterial vaccines or immunization or
immunotherapy or vaccination or vac-
cines. To be retained, a study had to be
a randomized placebo-controlled clinical
trial with the primary aim of reducing
the number of UTIs over a period of 6–12
months.
All trials rendered eligible were clas-
sified by indication and summarized in
a tabulated format by one reviewer. The
standard table included a full reference,
a quality rating, the type of pathology,
demographic data and treatments, end-
points and adverse events. The trials
were grouped by indication and by treat-
ment. These tables were verified and dis-
cussed by the authors until consensus
was reached. No formal validation proc-
ess was employed.
The electronic databases identified 1°)
urinary tract infection in 25757 references
and 2°) double or single blind in 88121 +
10220 references and 3°) bacterial vac-
cines or immunization or immunotherapy
or vaccination or vaccines in 155209 ref-
erences, but only 10 complied with the
three descriptors. One additional clinical
study was identified through other chan-
nels and duly scrutinized. The search also
yielded one meta-analysis [11] concerning
OM-89 (Product ‘A’; Uro-Vaxom®). As will
be described under results, three studies
were eliminated because of duplication of
data, particular patient selection or inad-
equate reporting (one study each).
Furthermore, the electronic databases
were searched for trials conducted with
specific products identified1; that is,
OM-89 capsules (Product ‘A’; five differ-
ent serotypes of heat killed uropathogenic
Escherichia coli), Product ‘B’ for intramus-
cular or vaginal administration (StroVac®
and Solco-Urovac® respectively; contain
1 http://focosi.altervista.org/preventionprimaryimmunovaccine.html
| 4.3 |
10 heat killed uropathogenic bacteria,
including six different serotypes of
uropathogenic Escherichia coli, Proteus
vulgaris, Klebsiella pneumoniae, Mor-
ganella morganii and Enterococcus
faecalis), Urostim® (‘Other products’;
killed bacterial cells and their lysates
of four microbial species: uropathogenic
Escherichia coli expressing type 1 pili,
Rc mutant of E. coli, Klebsiella pneumo-
niae, Proteus mirabilis and Enterococcus
faecalis) and Urvakol® (‘Other prod-
ucts’; uropathogenic Escherichia coli,
Klebsiella pneumoniae, Proteus mirabilis,
Pseudomonas aeruginosa and Enterococcus
faecalis; adjuvant activity is provided by
Propionibacterium acnes). However, this
search did not identify additional trials
complying with the predefined criteria.
The resulting selection of trials was:
• Product ‘A’: Identified 7 trials;
excluded 2 trials, retained for analysis
5 trials.
• Product ‘B’: Identified 4 trials;
excluded 1 trial, retained for analysis
3 trials
• ‘Other products’: Identified 1 trial;
excluded 1 trial.
2.2 Analysis of data
The guidelines provided by the Cochrane
Collaboration Handbook for Reviews
[12] and the corresponding software
have been used in the analysis of the
clinical data (Review Manager 4.2.7).
Ordinal data were compared using the
Mantel-Haenszel-Peto Method [13].
Significances were calculated using two
sided tests, the threshold of significance
being p ≤ 0.05 and for non-significance
p > 0.1; values between p > 0.05 and
p ≤ 0.1 were reported as trends. Means
and standard deviations (SDs) cor-
respond to those reported for the ITT
analysis, where available, N patients
correspond therefore to the number
of patients admitted to the trial and
exposed to the treatment.
255
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
3. RESULTS
3.1 Product ‘A’: OM-89
(Uro-Vaxom®)
Of the original seven studies identified,
only five could be retained for further
analysis. One study [14] was excluded
because, although double blind, it dealt
with a special group of patients: in a six-
month, double-blind, placebo-controlled
clinical trial with cross-over, the authors
administered the bacterial extract OM-89
in 70 spinal cord injured patients with
chronic lower urinary tract infections. In
the treated patients, compared to those
given placebo, there was a statistically
significant decrease in the degree of bac-
teriuria, a considerably decreased inci-
dence of infectious episodes and a lesser
requirement for antibiotics. One further
trial [15] with 64 out-patients suffer-
ing from an acute recurrent UTI was
excluded because there was insufficient
reporting of demographics and the pub-
lication did not account for drop-outs or
missing data. In this trial, dysuria, bac-
teriuria, leukocyturia and consumption
of antibacterials were reported to show
a significant reduction under OM-89 in
comparison with the placebo after six
months.
• The five studies [16–20] retained
for further analysis present a large
amount of commonalities, although
they differ in some aspects. A sum-
mary of treatment schedules, various
definitions of urinary tract infections,
admission and exclusion criteria, and
the patients’ flow is given in Table 1.
In four studies [17–20] men were
also included, but always comprised
less than 20% of the total patients.
Unfortunately, the results could not
be stratified by gender. In the larg-
est study [16], however, only female
patients with recurrent uncompli-
cated urinary tract infection (UTI)
were included, thus the proportion
of men decreased to less than 7%
256
in the total population. In all these
studies, recruited patients were suf-
fering from UTI, had a history of
recurrent UTIs, were treated with an
antibacterial agent until cure, while
at the same time starting treatment
with OM-89, one capsule daily for
three months. Thereafter, there was
a follow-up period of an additional
three months. In the largest study
(Bauer) [16] the patients received
thereafter a booster treatment at
months seven to nine (one capsule
daily during 10 days per month),
again with an additional follow up
of three months, thus completing a
study period of 12 months. However,
the study design does not allow for a
distinction between effects due to the
booster treatment and the possible
‘carry-over’ effects of the initial treat-
ment cycle. In all the studies exam-
ined the patients were comparable
at baseline concerning demographic
and clinical data. In addition to the
planned visits, the patients could
return for consultation if they were
symptomatic; these UTIs were assim-
ilated to the following planned visit.
Only two trials (Bauer and Pisani)
[16–17] reported the type of bacte-
ria identified at baseline, which was
Escherichia coli in about 70% of the
cases in both trials.
3.1.1 Mean Number of Urinary Tract
Infections
In all the studies examined, the authors
reported the mean number of UTIs dur-
ing the trial or described the actual
number of UTIs, which could be trans-
formed in the corresponding means. The
data were calculated in two ways: ‘as
reported’ in the studies (that is data after
6 and 12 months) or employing a cut-off
at six months.
For the mean number of UTIs, the
weighted mean difference (inverse of
the variance) has been used, because
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections | 4.3 |

Table 1 Summary of demographic data, definitions of urinary tract infections, admission and exclusion criteria, quality
standards, reporting and patients flow.

1st Author, Bauer, Pisani, Magasi, Schulman, Tammen,

year 2005 [16] 2000 [17] 1994 [18] 1993 [19] 1990 [20]

Quality GCP (ITT / per GCP (ITT / per Not stated (per GCP (per Not stated (per
(Reported as ) Protocol) Protocol) Protocol) Protocol) Protocol)

UTI, variables
rated

Bacteriuria ≥ 103 * > 105 * > 105 > 105 § > 105 §
(bacteria/mL)

Dysuria +++ [++] ** +++ +++ +++

Miction pain +++ [++] ** --- --- ---

Pollakisuria +++ [++] ** --- --- ---

Excluded pyelonephritis, Antibiotic resist- pyelonephritis, anatomical post-coital UTI,

catheter, neuro- ant UTI, pyelone- catheter, obstruc- abnormalities, pyelonephritis,
genic bladder, phritis, catheter, tion, etc. etc. catheter, obstruc-
etc. obstruction, etc. tion, etc.

Definition of Bacteriuria + 2 Bacteriuria Bacteriuria Bacteriuria not defined

UTI symptoms

Age mean(sd)

OM-89 41.7 (15.3) 46.9 (15.9) Range 16–82 45.3 (18.4) 51.2 (20.9)

Placebo 39.8 (15.1) 45 (16.1) 50.4 (19.8)

Gender

Males/ Females 0 / 453 9 / 128 26 / 140 17 / 95 17 / 133

N patients
(OM-89/Placebo)

Admitted 231 / 222 81 / 79 63 / 59 85 / 81 76 / 74

Completed 195 / 191 66 / 71 58 / 54 72 / 68 61 / 59

(184 / 186) §§

*midstream urine sample. Glossary:

**Rated Sum Score fever, dysuria, pollakisuria, stranguria, burning, GCP: Good Clinical Practice.
flank suprapubic and perineal pain, fullness, haematuria, odorous ITT: Intent to treat analysis.
and cloudy urine, other.
Per protocol: analysis excluding protocol violators.
§
105 cfu/ml midstream urine or 104 cfu/ml catheter urine
(cfu – colony forming units).
§§
Between (): Completed 12 months.

outcomes are measured in a standard
way across studies. In view of the het-
erogeneity between trials, both the fixed
and the random effect models have been
calculated. Treatment yields significantly
fewer UTIs than placebo in the fixed
effect model with a weighted mean dif-
ference of -0.36 [95% CI: -0.48, -0.24] for
the data after six or 12 months (test for
heterogeneity: P = 0.002; test for overall
effect: P < 0.00001). The weighted mean
difference for the data after six months
was -0.26 [95% CI: -0.36, -0.16] (test for
heterogeneity: P = 0.0004; test for overall
effect: P < 0.00001). In the random effect
model, the weighted mean differences

257
Chapter |4| Prevention of recurrent urogenital tract infections in adult women

were -0.516 [95% CI: -0.80, -0.22] for the 3.1.2 Proportion of Patients without
data after six or 12 months and -0.42 recurrent Urinary Tract Infection
[95% CI: -0.69, -0.16] for the data after There were significantly more patients
six months with significances similar without any UTI among the OM-89
to those reported with the fixed model. treated patients at the end of the studies,
Even after allowing for differences in the regardless of study duration. Regarding
rating method employed for diagnosing the percentages of patients with UTIs,
UTIs, the standardised mean difference shown as difference between OM-89
continues to show a highly significant dif- (41.7% of the patients) and placebo
ference in favour of the active treatment. (62.4% of the patients) in Table 3, the dif-
Examining the mean number of UTIs ference was: -20.7% patients with UTIs
with OM-89, as a function of N UTIs with OM-89 (P<0,001, Odds ratio = 0.43
with placebo, the studies with the largest [95% CI 0.34 - 0.55]). Taking the cut-off as
number of UTIs with placebo were those the end of the sixth month, available for
showing the largest reduction with the all studies, the difference in patients with
active medication (Figure 1). recurrence of UTI between OM-89 (35.1%

Table 2 Mean number of recurrent UTIs, by trial and pooled mean.

OM-89 UV Placebo Difference

Study
N Mean (95% CI) N Mean (95% CI) Mean (95% CI)

Bauer 6 mo. 195 0.47 (0.36, 0.58) 215 0.6 (0.47, 0.73) 0.13 (0.25, 0.01)

Pisani 66 0.23 (0.14, 0.32) 71 0.41 (0.26, 0.56) 0.18 (0.3, 0.06)

Schulman 72 1.22 (0.81, 1.63) 68 1.96 (1.6, 2.32) 0.74 (1.12, 0.36)

Magasi 58 0.47 (0.26, 0.68) 54 1.35 (1.07, 1.63) 0.88 (1.12, 0.64)

Tammen 61 0.82 (0.63, 1.01) 59 1.26 (0.8, 1.72) 0.44 (0.76, 0.12)

Mean 452 0.60 (0.51, 0.69) 467 0.94 (0.82, 1.06) -0.34 (-0.23, -0.45)

Reduction of mean N UTIs as a function of N-UTIs with placebo

1.20
Reduction of mean N UTIs & 2 SEM

1.00
R2 � 0.7142
0.80

OM-89 UV
0.60 Linear (OM-89 UV)

0.40

0.20

0.00
0.00 0.50 1.00 1.50 2.00 2.50
Mean N UTIs placebo

Figure 1 Reduction of the mean number of episodes of UTIs (± 2 SEM) with OM-89, as a function of the mean N UTIs with
placebo (± SEM) in the studies examined.

258
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections | 4.3 |

Table 3 Percent patients with recurrence(s) of UTIs, difference between OM-89 and placebo at the end of the studies.

OM-89 Placebo Significance Relative Risk

Bauer et al., 2005 6 mo. 29.90% 39.20% P<0,05 76.20%

Pisani, 2000; 18.50% 36.70% P<0,01 50.40%

Magasi, 1994 35.00% 80.00% P<0,001 43.80%

Schulman 1993 (Re-Anal.). 52.40% 83.30% P<0,001 62.90%

Tammen, 1990; 50.00% 66.20% P<0,05 75.50%

TOTAL 35.10% 54.20% P<0,001 64.80%

Difference -19.10%

Bauer et al., 2005 12 mo. 45.00% 58.10% P<0,01 77.50%

TOTAL 41.70% 62.40% P<0,001 66.80%

Difference -20.70%

of the patients) and placebo (54.2% of the
patients) was -19.1% patients [95% CI
-0.25, -0.13] (P<0,001, Odds ratio = 0.46
[95% CI 0.36 - 0.59]). Both outcomes were
thus significantly in favour of the active
treatment in all the trials, although there
is a significant heterogeneity between tri-
als (P= 0.001).
In conclusion, Three out of five patients
will have no further UTI in the six
months following OM-89 treatment. Of
the remaining OM-89 treated patients
still having acute episodes, 35% will have
fewer UTIs than with placebo, on average.
3.1.3 Consumption of antibacterials for
Urinary Tract Infections
This variable was examined using the
Standardised mean difference2 method,
indicated when an outcome is measured
in a variety of ways across studies (using
different scales), as is the case here. One
study (Magasi) [18] did not provide data
concerning the use of antibacterials dur-
ing the trial; the remaining four did so
(representing 88.4% of the population),
2 Difference between two means divided by an estimate of the
within-group standard deviation.
but employed different ways of present-
ing the data. As shown in Table 4, the
Standardised mean difference shows a
significant difference in favour of the
active treatment.
In conclusion: Although it is difficult to
assign a specific value to this assertion
due to differences in the presentation of
data, it may be concluded that there was
a significant reduction of the use of anti-
bacterials with OM-89, in line with the
reduction of UTIs described above.
3.1.4 Findings at the end of the trials
3.1.4.1 Dysuria
Four of the five trials examined reported
on this variable (representing 84.8% of
the study population, Table 5). Examining
the outcome at 6 months, only a minority
of the patients reported dysuria, signifi-
cantly less so among the OM-89 treated
patients: -9.4% of the patients (P<0,001,
Odds ratio = 0.43 [95% CI 0.28–0.66].
Examining the outcome as reported at
the end of the studies (that is, the Bauer
trial at 12 months) the results are simi-
lar; that is with OM-89 -6.6% of the
patients has dysuria (P<0,01, Odds ratio
= 0.49 [95% CI 0.3 - 0.77]).

259
Chapter |4| Prevention of recurrent urogenital tract infections in adult women

Table 4 Consumption of antibacterials and Standardised mean difference.

Study Bauer Pisani Schulman Tammen Total

(95% CI)
Variable: Prescriptions Patients with days with/3 mo. Prescriptions

OM-89 N 195 66 85 76 422

UV Mean (SD) 2.44(1.75) 0.16(0.36) 2.90(18.00) 0.85(1.65)

N 215 71 81 74 441
Placebo
Mean (SD) 2.79(2.03) 0.35(0.48) 6.90(19.00) 2.78(5.40)

Weight 43.28 17.26 20.81 18.65 100

SMD (random) & -0.18 -0.44 -0.22 -0.48 -0.29

95% CI [-0.38, 0.01] [-0.78, -0.10] [-0.52, 0.09] [-0.81, -0.16] [-0.44, -0.14]

Test for heterogeneity: P = 0.32.

Test for overall effect: P = 0.0001.

Table 5 Incidence of dysuria at final visit.

OM-89 Placebo Significance Relative Risk

Bauer, 2005 (6 mo.) 10.8% 18.8% P<0,05 57.1%

Magasi, 1994 3.3% 16.7% P<0,05 20.0%

Schulman 1993 9.8% 16.7% N.S. 58.5%

Tammen, 1990; 6.6% 18.9% P<0,05 34.8%

TOTAL 8.7% 18.1%

P<0,001 48.1%
Difference -9.4%

No data: Pisani, 2000.

In conclusion: the incidence of dysuria
at final visit was significantly lower with
OM-89 at final visit.
3.1.4.2 Leukocyturia
Only three of the five trials examined
reported on this variable (representing
42.6% of the population studied, Table 6).
Examining the outcome at six months,
only a minority of the patients reported
leukocyturia >5/field, significantly less
so among the OM-89 treated patients:
-13.3% of the patients (P<0,001, Odds
ratio = 0.45 [95% CI 0.28 – 0.72].
In conclusion: the incidence of leuko-
cyturia at final visit was significantly
lower with OM-89 but the findings were
derived from only three out of five trials,
representing less than half the popula-
tion studied.
3.1.4.3 Bacteriuria
Four of the five trials examined reported
on this variable (representing 85.7% of the
population studied, Table 7). Examining
the outcome at six months, only a minor-
ity of the patients reported bacteriuria,
significantly less so among the OM-89
treated patients: -6.2% of the patients
(P<0,05, Odds ratio = 0.62 [95% CI 0.42 –
0.91]. However, this outcome was driven
mainly by one study (Magasi) as shown in
sensitivity analysis. There was significant
heterogeneity between studies. In one trial
(Schulman) the data were provided for
both 105 bacteria/mL and 104 bacteria/mL

260
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections | 4.3 |

Table 6 Incidence of leukocyturia at final visit.

OM-89 Placebo Significance Relative Risk

Pisani, 2000; 14.8% 19.0% N.S. 78.0%

Magasi, 1994 15.0% 33.3% P<0,05 45.0%

Schulman 1993 15.9% 34.6% P<0,01 45.8%

TOTAL 15.2% 28.6%

P<0,001 53.4%
Differences -13.3%

No data: Bauer, 2005 & Tammen, 1990.

Table 7 Incidence of bacteriuria at final visit.

OM-89 Placebo Chi-square Relative Risk

Bauer, 2005 (6 mo.) 19.5% 20.9% N.S. 93.1%

Pisani, 2000; 3.7% 11.4% (P<0,1) 32.5%

Magasi, 1994 3.3% 21.7% P<0,01 15.4%

Schulman 1993; 11.0% 17.9% N.S. 61.1%

TOTAL 12.4% 18.6%

P<0,05 66.8%
Differences -6.2%

No data: Tammen, 1990.

as cut-off; taking this lower level the dif-
ferences become significant in this trial
too (OM-89: 19.5% of the patients; pla-
cebo 35.9% of the patients). Examining
the outcome as reported at the end of the
studies (that is, the Bauer trial [14] at 12
months) the results are similar; that is
with OM-89: -5.4% patients with bacte-
riuria (P<0,05, Odds ratio = 0.65 [95% CI
0.44 – 0.96]).
In conclusion: the incidence of bacteriu-
ria at final visit was lower with OM-89
but the findings are inconsistent between
trials. However, the incidence of bacteriu-
ria among the OM-89 treated patients is
not much higher than the one reported in
the general female population, which has
been reported to lie between 2.8% (women
aged 50–59 years) and 17% (women aged
> 75 years) [21].
3.1.5 Safety of OM-89 in Placebo
controlled clinical trials
The differences of incidences of adverse
events in comparative trials showed that
they were slightly more frequent during
OM-89 therapy than with placebo (+0.8%)
and somewhat more patients withdrew
from the trials due to side-effects (+0.6%).
No serious adverse events were attrib-
uted to OM-89 in these clinical studies;
no disease- or age-related mortality was
recorded in the studied population. The
most frequent adverse events reported
are detailed in Figure 2.
4. PRODUCT ‘B’
There were no blind trials identified
for the parenteral formulation of this

261
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
„Flu“; Bronchitis
4.5%
4.0%
Back-pain
3.5%
3.0%
2.5%
2.0%
Pollakisuria
1.5%
1.0%
0.5%
0.0%
Renal pain
Allergic rash
Vaginitis, Leucorrhoea
Figure 2 Adverse events reported in controlled clinical trials by 0.7% of the patients or more.
product. This formulation causes signifi-
cant undesirable side-effects at the injec-
tion site [22] and systemic reactions [23].
The published studies in recent years
deal only with the intravaginal formula-
tion, which is discussed herein.
Because of the similarity of the data,
design and outcomes, it was concluded
that the study by Uehling et al. [24]
published in 2001 was a preliminary
presentation of the data published two
years later and therefore excluded from
analysis.
In a first study with this product [25],
a total of 91 women with recurrent uri-
nary infections were entered into the
double-blind randomized study. Subjects
received three vaginal suppositories at
weekly intervals. Depending on the treat-
ment group each suppository contained
one or two vaccine doses or suppository
material only. Each patient was followed
for five months to record infection epi-
sodes and obtain urine, vaginal irrigates
and serum to measure immunological
responses. The Verum treated women
who were off antibiotic prophylaxis
262
Cephalea
Sleep disorders
OM-89
Placebo
Gastric intolerance
Diarrhoea
Nausea / Vomiting
(prevention discontinued in about half
the patients) had a significant delay in
interval to reinfection during the first
eight weeks and the mean interval until
reinfection was delayed from 8.7 weeks
for placebo treated to 13 weeks for vac-
cine treated women (no significances pro-
vided). However, the overall incidence of
urinary infections was similar, regardless
of the treatment received (on average, 1.4
UTIs per patient).
In the second and the third study by
the same group [26–27], a total of 54 and
75 women respectively were entered into
the double-blind, placebo controlled trials
using the vaginal suppositories. Patients
were withdrawn from prophylactic anti-
biotics and randomly assigned to one of
three treatment groups, namely placebo
only, primary immunization (given on
weeks 0, 1, and 2) or primary plus booster
immunizations (booster given on weeks 6,
10 and 14). All women were followed for
six months to determine the time until
first recurrence, number of infections.
In the second study, the women receiv-
ing “primary + booster” remained free
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections
of infections for a significantly longer
period than those receiving placebo
or “primary” immunization only. The
patients receiving “primary + booster”
immunizations had significantly fewer
infections (average = 1.1 UTIs/patient)
than the placebo treated women (aver-
age = 1.5 UTIs/patient) or those receiv-
ing “primary” only (average = 1.7 UTIs/
patients). The interest of this study is
limited by the small number of patients
treated and the fact that placebo treated
patients were on average 13 years older
than the Verum treated patients. Five
of the 36 Verum treated patients expe-
rienced vaginal irritation within one
day of immunization or had transient
diarrhoea.
In the third study, the results were
similar; that is placebo was equivalent
to “primary” immunization, both inferior
to “primary + booster” vaccine (Kaplan-
Meier; p < 0.1). Thirty per cent of the
patients in the placebo group, 57% of
the “Primary” only group and 72.5% of
the patients in the “primary + booster”
group remained free of E. coli infection.
Furthermore, the results suggested that
the vaccine may provide the most benefit
Table 8 Percent patients with UTIs, difference between Verum and placebo. Product ‘B’ vaginal suppositories “primary“ on
weeks 0, 1, 2, and “primary + booster“ additionally on weeks 6, 10, and 14.
Product ‚B’
Hopkins, 2007 (27): 53.8%
Primary + Booster
Hopkins, 2007 (27): 75.0%
Primary
Uehling, 2003 (26): 44.4%
Primary + Booster
Uehling, 2003 (26): 88.9%
Primary
Uehling, 1997 (25): 98.4%
Primary
TOTAL 78.9%
Difference -10.7%
| 4.3 |
to women in the 20 to 50-year-old age
group. The interest of this study is again
limited by the small number of patients
treated and the fact that placebo treated
patients were on average nine years older
than the Verum treated patients. Twelve
percent of the women reported episodes
of a burning sensation shortly after treat-
ment both with the active product and
with placebo. There were single occur-
rences of mild-moderate adverse events
(four with the active product and four
with placebo).
A quantitative analysis of anti E. coli
IgA and IgG antibodies in the urine and
vaginal fluid samples collected during the
course of these two studies did not reveal
any significant differences between the
three groups. The findings concerning the
difference between Verum and placebo,
as percent patients with UTIs, are illus-
trated below (Table 8).
In conclusion, with ‘Product B’, whilst
the shorter “primary” immunization
was not effective, the longer “primary +
booster” treatment was probably effec-
tive. Confirmation by larger phase III
studies by independent investigators is
absolutely necessary.
Placebo Significance Relative Risk
84.0% P<0,05 64.1%
84.0% N.S. 89.3%
88.9% P<0,01 50.0%
88.9% N.S. 100.0%
100.0% N.S. 98.4%
89.7%
P<0,05 88.0%
263
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
5. DISCUSSION
The management of recurrent urinary
tract infections is complex due to the var-
ious factors predisposing to such bacterial
invasions. It is further complicated by the
increasing prevalence of antibiotic-resist-
ant strains of E. coli. These facts stress
the need for therapies directed to dimin-
ish susceptibility and enhance the host’s
defences against urinary tract infection
rather than administering antibacterials
on a broad base. The urinary tract pos-
sesses the immunological and cellular
machinery for an efficient antibacterial
defence and it seems a sensible approach
to activate it.
Among the various immunotherapeu-
tic products offered on the market only
two have published studies which are in
accordance with current standards. Of
these, ‘Product A’ (OM-89) is fairly well
documented and has shown to be more
effective than placebo in several ran-
domised trials. In three small phase II
trials ‘Product B’ has been shown to be
effective only when administered with
a booster cycle; larger studies by inde-
pendent investigators are awaited with
interest.
Concentrating on OM-89, the data
show that the product reduces the
number of recurrences of uncomplicated
UTIs by about 36% and one out of five
patients will be entirely free of UTIs for
at least six months, with corresponding
reduction of antibacterial treatments. It
has to be noted, however, that only in one
study [16] was a UTI defined as sympto-
matic uncomplicated UTI (symptomatic
bacteriuria), whereas in three studies
[17–19] the definition of UTI was based
on bacteriuria alone, and in one study
[20] there was no precise definition of
UTI. At the end of the six month observa-
tion period, fewer OM-89 treated patients
had dysuria (RR= 48%) and possibly leu-
kocyturia (RR= 53%) or bacteriuria (RR=
67%). A further aspect worth examining
264
is the potential reduction of vulvo-vaginal
infections with OM-89 (Odds Ratio = 0.42
(95% CI 0.18 – 0.98) vs. placebo in women
with recurrent UTIs.
The studies with OM-89 appear to
have good internal and external validity;
that is, the investigations were conducted
on out-patients with a relatively broad
admission / exclusion criteria and thus
can be generalized to the circumstances
of daily practice. It seems quite probable
that a particular sub-population might
benefit more than others.
From the reported results in the lit-
erature, it seems that the efficacy of anti-
microbial prophylaxis is superior to the
immunization regimens presently avail-
able [2]. However, since 1990, there has
been a steadily increasing rate of resist-
ance to trimethoprim/sulphametoxazol,
reaching >30% in some areas; in the USA
the average resistance rate for E. coli is
18%. Also resistance rates to fluoroqui-
nolones have been increasing worldwide
at alarming rates, reaching >20% in
Spain [28–31]. Another potential down-
side of antibacterial prophylaxis is the
side effects, such as rash, nausea, diar-
rhoea, vaginitis and oral candidiasis
[32–33]. Treatments with antibacterials
have to be monitored closely since they
also can cause major adverse reactions;
for example, phototoxicity and rare but
serious hepatotoxicity has been reported
with fluoroquinolones [34], while nitro-
furantoin is known to infrequently
cause both acute and chronic pulmo-
nary reactions (interstitial lung disease
and pulmonary fibrosis may develop
with long-term use) [35], as well as
rare cases of blood dyscrasia, Erythema
exsudativum multiforme (Stevens-
Johnson-Syndrom) and Epidermolysis
acuta toxica (Lyell-Syndrom) with
trimethoprim+sulfamethoxazol or with
nitrofurantoin, to mention a few [36].
Additionally, oral administration of
antibiotics for treatment of urinary
tract infections can cause ecological
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections
disturbances in the normal urethral [37]
and intestinal microflora [38]. Increasing
the mucosal defences through immunoac-
tive prophylaxis looks like a compelling
alternative which merits further studies
and improvements.
6. FURTHER RESEARCH
The studies examined do not provide any
information on how to optimize treat-
ment. Since only about one third of UTIs
are avoided with immunoprophylaxis
with OM-89, it would be important to
know whether gender, type of infection,
secretor status, hormonal status, con-
centration of Tamm–Horsfall protein or
other variables are predictors of response
to the product. Unfortunately, there are
also no studies directly comparing anti-
microbial prophylaxis with immunoactive
prophylaxis; head to head studies should
be performed.
The future may bring new and possibly
more effective immunostimulants like the
vaccine derived from purified E.coli FimH
adhesion [39], P. mirabilis fimbriae (PMF
and purified recombinant structural fim-
brial proteins of these fimbriae) [39–41]
and others, currently tested on animals.
7. CONCLUSIONS
Many females are suffering from recur-
rent urinary tract infections, which has a
high impact on the quality of life. Since
there is a steadily increase of resistance
of E. coli observed against antibiotic
agents commonly used for the treatment
of UTI, alternative methods should be
favoured to prevent recurrent UTI (see
chapter 4.2). Among the various immu-
notherapeutic products offered on the
market only OM-89 (Uro-Vaxom®) is suf-
ficiently well documented and has shown
to be more effective than placebo in sev-
eral randomised trials. Therefore, it can
be recommended for immunoprophylaxis
| 4.3 |
in female patients with recurrent
uncomplicated UTI. Its efficacy in other
patients’ groups and its relative efficacy
to antimicrobial prophylaxis should be
established.
REFERENCES
1. Nicolle LE, Managing recurrent uri-
nary tract infections in women. Womens
Health (Lond Engl), 2005. 1(1): 39–50.
2. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H, Lobel
B, Jinenez Cruz F, and Selvaggi FP,
EAU guidelines for the management of
urinary and male genital tract infec-
tions. Urinary Tract Infection (UTI)
Working Group of the Health Care Office
(HCO) of the European Association of
Urology (EAU). Eur Urol, 2001. 40(5):
576–88.
3. Fihn SD, Clinical practice. Acute uncom-
plicated urinary tract infection in women.
N Engl J Med, 2003. 349(3): 259–66.
4. Boyko EJ, Fihn SD, Scholes D, Abraham
L, and Monsey B, Risk of urinary tract
infection and asymptomatic bacteriuria
among diabetic and nondiabetic postmen-
opausal women. Am J Epidemiol, 2005.
161(6): 557–64.
5. Raz R, Gennesin Y, Wasser J, Stoler Z,
Rosenfeld S, Rottensterich E, and Stamm
WE, Recurrent urinary tract infections in
postmenopausal women. Clin Infect Dis,
2000. 30(1): 152–6.
6. Ishitoya S, Yamamoto S, Mitsumori K,
Ogawa O, and Terai A, Non-secretor sta-
tus is associated with female acute uncom-
plicated pyelonephritis. BJU Int, 2002.
89(9): 851–4.
7. Schmidhammer S, Ramoner R, Holtl L,
Bartsch G, Thurnher M, and Zelle-Rieser
C, An Escherichia coli-based oral vaccine
against urinary tract infections potently
activates human dendritic cells. Urology,
2002. 60(3): 521–6.
8. Boruchov AM, Heller G, Veri MC, Bonvini
E, Ravetch JV, and Young JW, Activating
and inhibitory IgG Fc receptors on human
DCs mediate opposing functions. J Clin
Invest, 2005. 115(10): 2914–23.
265
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
9. David J and Terhorst C, Organs and
cells of the immune system, in Scientific
American Medicine; Ch. 6. Immunology.
1999, WebMD Corp.
10. Pudney J and Anderson DJ,
Immunobiology of the human penile ure-
thra. Am J Pathol, 1995. 147(1): 155–65.
11. Bauer HW, Rahlfs VW, Lauener PA, and
Blessmann GS, Prevention of recurrent
urinary tract infections with immuno-
active E. coli fractions: a meta-analysis of
five placebo-controlled double-blind stud-
ies. Int J Antimicrob Agents, 2002. 19(6):
451–6.
12. Alderson P, Green S, and Higgins JPT,
eds. Cochrane Reviewers’ Handbook 4.2.2.
[updated March 2004]. 2004, John Wiley
& Sons, Ltd. The Cochrane Library, Issue
1, 2004: Chichester, UK.
13. Bax L, Yu LM, Ikeda N, Tsuruta H, and
Moons KG, Development and validation
of MIX: comprehensive free software for
meta-analysis of causal research data.
BMC Med Res Methodol, 2006. 6: 50.
14. Hachen HJ, Oral immunotherapy in par-
aplegic patients with chronic urinary tract
infections: a double-blind, placebo-con-
trolled trial. J Urol, 1990. 143(4): 759–62;
discussion 762–3.
15. Frey C, Obolensky W, and Wyss H,
Treatment of recurrent urinary tract infec-
tions: efficacy of an orally administered
biological response modifier. Urol Int,
1986. 41(6): 444–6.
16. Bauer HW, Alloussi S, Egger G, Blumlein
HM, Cozma G, and Schulman CC, A long-
term, multicenter, double-blind study of
an Escherichia coli extract (OM-89) in
female patients with recurrent urinary
tract infections. Eur Urol, 2005. 47(4):
542–8; discussion 548.
17. Pisani E, Palla R , and Bono AV, Double-
blind randomised clinical study of OM-8930
vs placebo in patients suffering from recur-
rent urinary tract infections. 1992. Quoted
in Chiavaroli C Moore A. An Hypothesis to
Link the Opposing Immunological Effects
Induced by the Bacterial Lysate OM-89 in
Urinary Tract Infection and Rheumatoid
Arthritis. Biodrugs 2006; 20: 141–149:
Geneva: OM Pharma.
18. Magasi P, Panovics J, Illes A, and Nagy
M, Uro-Vaxom and the management
266
of recurrent urinary tract infection in
adults: a randomized multicenter dou-
ble-blind trial. Eur Urol, 1994. 26(2):
137–40.
19. Schulman CC, Corbusier A, Michiels H,
and Taenzer HJ, Oral immunotherapy of
recurrent urinary tract infections: a dou-
ble-blind placebo-controlled multicenter
study. J Urol, 1993. 150(3): 917–21.
20. Tammen H, Immunobiotherapy with
Uro-Vaxom in recurrent urinary tract
infection. The German Urinary Tract
Infection Study Group. Br J Urol, 1990.
65(1): 6–9.
21. Scottish Intercollegiate Guidelines
Network, Management of suspected bacte-
rial urinary tract infection in adults. A
national clinical guideline. . July 2006.
22. Das P, Vaginal vaccine for recurrent uri-
nary-tract infections. Lancet Infect Dis,
2002. 2(2): 68.
23. Überempfindlichkeitsreaktionen auf
“Impfstoff” STROVAC (Hypersensitivity
reactions to “vaccine“ STROVAC). Arznei-
Telegram 2007. 38(2): 31.
24. Uehling DT, Hopkins WJ, Beierle LM,
Kryger JV, and Heisey DM, Vaginal
mucosal immunization for recurrent
urinary tract infection: extended phase
II clinical trial. J Infect Dis, 2001. 183
Suppl 1: S81–3.
25. Uehling DT, Hopkins WJ, Balish E, Xing
Y, and Heisey DM, Vaginal mucosal
immunization for recurrent urinary tract
infection: phase II clinical trial. J Urol,
1997. 157(6): 2049–52.
26. Uehling DT, Hopkins WJ, Elkahwaji JE,
Schmidt DM, and Leverson GE, Phase 2
clinical trial of a vaginal mucosal vaccine
for urinary tract infections. J Urol, 2003.
170(3): 867–9.
27. Hopkins WJ, Elkahwaji J, Beierle LM,
Leverson GE, and Uehling DT, Vaginal
mucosal vaccine for recurrent urinary
tract infections in women: results of
a phase 2 clinical trial. J Urol, 2007.
177(4): 1349–53; quiz 1591.
28. Hooton TM and Stamm WE, Diagnosis
and treatment of uncomplicated urinary
tract infection. Infect Dis Clin North Am,
1997. 11(3): 551–81.
29. Kahlmeter G, The ECO*SENS Project:
a prospective, multinational, multicentre
 Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections
epidemiological survey of the prevalence
and antimicrobial susceptibility of uri-
nary tract pathogens-interim report.
J Antimicrob Chemother, 2000. 46 Suppl
A: 15–22.
30. Gupta K, Sahm DF, Mayfield D, and
Stamm WE, Antimicrobial resistance
among uropathogens that cause commu-
nity-acquired urinary tract infections in
women: a nationwide analysis. Clin Infect
Dis, 2001. 33(1): 89–94.
31. Manges AR, Johnson JR, Foxman B,
O’Bryan TT, Fullerton KE, and Riley LW,
Widespread distribution of urinary tract
infections caused by a multidrug-resistant
Escherichia coli clonal group. N Engl J
Med, 2001. 345(14): 1007–13.
32. Albert X, Huertas I, Pereiro, II, Sanfelix
J, Gosalbes V, and Perrota C, Antibiotics
for preventing recurrent urinary tract
infection in non-pregnant women.
Cochrane Database Syst Rev, 2004(3):
CD001209.
33. Gradwohl SE (Team Leader) and
University of Michigan Health System
(Agency for Healthcare Research and
Quality (AHRQ)), Urinary tract infection.
May 2005, Ann Arbor (MI): University of
Michigan Health System.
34. Ball P, Mandell L, Niki Y, and Tillotson
G, Comparative tolerability of the newer
fluoroquinolone antibacterials. Drug Saf,
1999. 21(5): 407–21.
35. Sheehan RE, Wells AU, Milne DG, and
Hansell DM, Nitrofurantoin-induced lung
disease: two cases demonstrating resolu-
tion of apparently irreversible CT abnor-
malities. J Comput Assist Tomogr, 2000.
24(2): 259–61.
36. Howe RA and Spencer RC, Cotrimoxazole.
Rationale for re-examining its indications
for use. Drug Saf, 1996. 14(4): 213–8.
37. Norinder BS, Norrby R, Palmgren AC,
Hollenberg S, Eriksson U, and Nord CE,
Microflora changes with norfloxacin and
pivmecillinam in women with recurrent
urinary tract infection. Antimicrob Agents
Chemother, 2006. 50(4): 1528–30.
38. Edlund C and Nord CE, Effect on the
human normal microflora of oral antibi-
otics for treatment of urinary tract infec-
tions. J Antimicrob Chemother, 2000. 46
Suppl A: 41–48.
| 4.3 |
39. Langermann S, Mollby R, Burlein JE,
Palaszynski SR, Auguste CG, DeFusco
A, Strouse R, Schenerman MA, Hultgren
SJ, Pinkner JS, Winberg J, Guldevall L,
Soderhall M, Ishikawa K, Normark S,
and Koenig S, Vaccination with FimH
adhesin protects cynomolgus monkeys
from colonization and infection by
uropathogenic Escherichia coli. J Infect
Dis, 2000. 181(2): 774–8.
40. Pellegrino R, Galvalisi U, Scavone P, Sosa
V, and Zunino P, Evaluation of Proteus
mirabilis structural fimbrial proteins as
antigens against urinary tract infections.
FEMS Immunol Med Microbiol, 2003.
36(1–2): 103–10.
41. Li X, Lockatell CV, Johnson DE, Lane MC,
Warren JW, and Mobley HL, Development
of an intranasal vaccine to prevent urinary
tract infection by Proteus mirabilis. Infect
Immun, 2004. 72(1): 66–75.
ACKNOWLEDGEMENT
The study was supported in part by a
research grant from OM-Pharma, Geneva,
Switzerland.
The authors are thankful to Dr. Reto
G. Brignoli in assistance to prepare the
statistical analysis and the manuscript
FINANCIAL DISCLOSURE
Kurt G. Naber: Bayer: Investigator,
speaker at scientific meetings. Combi-
nature/MerLion: Investigator, consultant.
Daiichi: Speaker at scientific meetings.
Mucos Pharma: Consultant, speaker
at scientific meetings. OM Pharma:
Investigator, scientific publication.
Ocean Spray cranberries: Investigator.
Peninsula/Johnson & Johnson/Janssen-
Cilag: Investigator, speaker at scien-
tific meetings, scientific publication.
Zambon: Investigator, speaker at scien-
tific meetings.
Yong-Hyun Cho: Asia Pharm: Con-
sultant, speaker at scientific meetings.
267
Chapter |4| Prevention of recurrent urogenital tract infections in adult women

Handok Pharmaceuticals: Consultant, scientific meetings. Combinature/

speaker at scientific meetings. Pacific
Pharma: Consultant, speaker at scientific
meetings.
Tetsuro Matsumoto: Daiichi Sankyo;
Consultant, Investigator, Speaker at sci-
entific meetings. Asteras; Consultant,
Investigator. Kyorin; Investigator,
Speaker at scientific meetings. Meiji;
Consultant, Investigator. Nisshin sci-
ence; Consultant, Investigator. Takeda;
Speaker at scientific meetings. Taisho-
Toyama; Investigator, Speaker at
MerLion; Consultant.
Anthony J Schaeffer: American
Urological Association – editorial fees
and faculty honorarium; IMS Health –
consultant; Alita Pharmaceuticals, Inc. –
consultant; NovaBay Pharmaceuticals,
Inc. – consultant; cme2 – speaker at scien-
tific meeting; Blackwell Publishing – book
royalty; Advanstar Communications Inc. –
consultant; Elsevier Science USA – book
royalty; Regeneron Pharmaceuticals, Inc. –
consultant.

268
|4.4|
Use of cranberry for prophylaxis
of uncomplicated recurrent urinary
tract infections
Henry Botto
Address of Corresponding Author: Prof. Henry Botto, Prof. Assoc. des Universites, France, Service d’Urologie,
Hôpital Foch 40, rue Worth - B.P.36, F-92150 Suresnes Cedex, France
Tel 0033-1-4625.2465, Fax 0033-1-4625.2026, h.botto@hopital-foch.org
ABSTRACT
Over the last few years, an increase in
the use of cranberry (C) has been noted
for the following two reasons: i) the high
number of UTIs has lead to increased
antibiotic use and thus increased antibi-
otic resistance; and ii) the main mecha-
nisms of action in reducing UTIs have
been identified. C inhibits the adherence
of E.coli to uro-epithelial cells, the first
and necessary step for UTI. This competi-
tive inhibition is due to a non-dialyzable
compound, a condensed tannin, the
proanthocyanidin (PAC) type A. Among
the three species of C vaccinium macro-
carpon is only one to have PAC-A.
The first dosage used was 36 mg served
as 300 ml of juice presentation (Avorn). In
2006, a double-blind randomised placebo-
controlled cross-over trial comparing
two dosages of C. juice presentation (250
and 750 ml) found a significant reduc-
tion of E. coli adherence (p > 0,001) dose
dependent.
In 2008 a double-blind randomised
placebo-controlled cross-over trial tested
a commercially available capsule of vac-
cinium macrocarpon containing 36 mg of
PAC. A statistically significant reduction
of bacterial adherence of E. coli was found
(p < 0,001), dose-dependent. For the first
time this study established clearly the
bio-activity of a C. capsule.
Two methods of PAC dosage are avail-
able : the reference DMAC and NP-HPLC
with a conversion factor of one to two
(36 mg PAC by DMAC = 72 mg PAC by
NP-HPLC).
Quantification of bio-activity in urine:
Given that 36 mg of PAC per day is nec-
essary to obtain a preventive clinical
effect on UTIs (Avorn Study); and given
that we lack a method to evaluate active
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
metabolites in urine, surrogates are
needed to quantify bio-activity in urine.
There are two surrogates: i) the red
blood cell hemagglutination test (Howell)
and ii) the direct cellular adhesion test
(Lavigne).
Jepson and Craig have recently
reviewed the clinical studies for the
Cochrane database. Juice presentation is
too unwieldy to be recommended for long
periods of time as a prophylactic treat-
ment for recurrent UTI, thus the neces-
sity to develop capsules/tablets. However,
there is no standardisation for these; not
in C species, in method of PAC measure-
ment, nor in dosage of PAC per day. Apart
from one capsule, there is no data about
the bio-activity of the commercially avail-
able products, no dose-ranging and no
direct correlation between in vitro and
clinical effects.
SUMMARY OF RECOMMENDATIONS
1. Despite the lack of pharmacological
data and the few, and weak clinical
studies, there is evidence to consider
C vaccinium macrocarpon to be useful
in reducing the rate of lower urinary
tract infections in women.
2. For everyday practice one could
recommend (GoR C; LoE 2) the
daily consumption of C products,
giving a minimum of 36 mg of PAC
(proanthocyanindin A, the active
compound) per day, providing this
amount is proven. The best approach
would be to use those compounds that
have demonstrated clear bio-activity
in urine.
1. INTRODUCTION
The traditonal use of cranberry (C) to
prevent UTIs has been found mainly
in North America with limited spread
to other countries, notably European
Countries.
270
However, steadily over the last few years,
increased C use outside North America
has been noted. It can be seen that this is
for the following reasons:
The high number of UTIs has lead
to increased antibiotic use and thus
increased antibiotic resistance. From the
ARESC [1] study we have learnt that
only three of the antibiotic families are
possible for empiric prescription. Thus
it is mandatory to reduce antibiotic use
and therefore to find some other products
to replace antibiotics in certain circum-
stances, for example in prophylaxis.
The main mechanisms of action in
reducing UTIs have been identified by
Foo [2] and Howell [3]. In the past it
was thought that C acted through acidi-
fication of urine like other fruits. In fact,
the acidification linked to fructose con-
tained in C (as well as in other fruits)
only excretes low and transient acidifica-
tion [4] and only inhibits pili type 1 [5].
The inhibition of pili type P is not con-
cerned with fructose. Cranberry inhibits
the adherence of E.coli to uro-epithelial
cells, the first and necessary step for UTI.
This competitive inhibition is due to a
none-dialyzable compound; a condensed
tannin, the proanthocyanidin (PAC) type
A. Cranberry contains a high proportion
of PAC A, unlike other fruit. Only the
PAC-(A) is able to inhibit E. coli adhesion
through inactivation of pili type P. The
other PAC (B) found in most fruits does
not have this capacity. There are three
species of C: vaccinium macrocarpon is
the only one to have PAC (A). The two
others (vaccinium vitis idaea and oxy-
coccus) may contain some quantities of
A-type PAC to inhibit E.coli adhesion but
their efficacy has not been validated.
Despite the low number of clinical
studies published, it is a trend to support
the role of C products in preventing UTIs.
But some limitations remain and have to
be clarified.
The Cochrane Library [6] review pub-
lished in 2008 is clear: “There is some evi-
dence that cranberry juice may decrease
 Use of cranberry for prophylaxis of uncomplicated recurrent urinary tract infections | 4.4 |

the number of symptomatic UTIs over a 3. PHARMACOKINETICS

12 month period, particulary for women
with recurrent UTIs. Its effectiveness
for other groups is less certain over long
periods of time. It is not clear what is the
optimum dosage or method of administra-
tion (e.g. juice, tablets or capsules)”.
Taking into account all these data the
French food and drug agency (AFFSSA)
delivered a clear allegation in 2004 [7]:
“The daily consumption of cranberry
vaccinium macrocarpon juice/powder
containing 36 mg of proanthocyanidins/
day contributes to decrease the fixation
of certain bacteria E. coli on the walls of
the urinary tract”. The 36 mg PAC were
measured by DMAC method.
“It is the first-ever health claim for
cranberries and it is believed to be the first
time that any fruit anywhere has been per-
mitted to make a specific health claim” [8].
Despite the traditional American use
of juice presentation and the conclusions
of the Cochrane review, more data are
needed to confirm the role of C in the pre-
vention of UTIs. Specifically, the pharma-
co-kinetics and the correlations between
the in vitro studies and clinical effects
have to be developed.
2. METHODS
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [9–10].
We know that PAC is one of the active
compounds of C but the other active
compounds (metabolites) are not
yet clearly identified. It is generally
accepted that active dimers and trimers
are absorbed in the gut. These small
oligomers are unstable and they have
a tendency to polymerize naturally
under the influence of temperature and
oxygen [11].
3.1 Dosage of PAC
The first dosage used was 36 mg served
as 300 ml of juice presentation [12]. In
the vast majority of the other studies the
amount of PAC was not clearly stated and
only a certain amount of C was declared.
In 2006 a double-blind randomised pla-
cebo-controlled cross-over trial in twenty
healthy volunteers compared two dosages
of C juice presentation: 750 and 250 ml
using six E.coli strains and a direct
anti-adhesion test [13]. There was a sig-
nificant reduction of E. coli adherence
(p > 0,001), dose dependent. Thus 300 ml
of juice presentation may not be the right
dosage per day. In this study it was also
shown that the anti-adhesion effect was
independent from antibiotic susceptibility
and type P pili present.
Gupta [14] recently confirmed the dose
dependent anti-adhesion effect of E.coli to
uro-epithelial cells.

Table 1 Index of Adhesion of E. coli (IA) after 2 regimens of Urell® and placebo control.

Strains Placebo Urell Capsule 1 Urell Capsule 3

FimH+ IA = 22,43 IA = 14,35 IA = 5,18 p. < 0,001

Pap GII+ ± 3,73 ± 3,45 ± 4,32

FimH- IA = 4,80 IA = 3,37 IA = 1,74 p. < 0,001

papGII- ± 0,70 ± 0,97 ± 0,75

FimH+ IA = 7,50 IA = 4,73 IA = 2,78 p. < 0,001

papGII- ± 1,60 ± 0,87 ± 1,12

One or three capsules of Urell® caused a highly significant reduction in bacterial adherence to T24 cells as compared with placebo (p< 0,001).
The adherence index obtained with bacteria grown in urine samples collected after intake of three cranberry capsules was lower than that
observed with one Cranberry capsule (p<0,001), even though a reduction in adherence was also noted with one Urell® capsule.

271
 Chapter |4| Prevention of recurrent urogenital tract infections in adult women
In 2008, a double-blind randomised
placebo-controlled cross-over trial tested
a commercially available capsule of vac-
cinium macrocarpon containing 36 mg of
PAC (Urell®/Ellura) using T24 human epi-
thelial cell line and three regimens intake
in the morning : (placebo ; one capsule
of Urell® = 36 mg of PAC ; 3 capsules =
108 mg of PAC) (13). A statistically signif-
icant reduction of bacterial adherence of
E. coli was found (p< 0,001), dose-depend-
ent and independent from antibiotic sus-
ceptibiliity and the type of P pili present.
For the first time this study established
clearly the bio-activity of a C capsule.
In our last study, currently under
revision, we correlated the bio-activity
in urine after six and 24 hours with the
same capsule of Urell® and using three
regimens with intake in the morning :
(half capsule = 18 mg PAC ; one capsule =
36 mg of PAC and two capsules = 72 mg
of PAC). As shown in Table 2 anti-adhe-
sion activity is significantly higher with
36 and 72 mg of PAC than with 18 at
six hours. At 24 hours the anti-adhesion
activity is significantly higher with 72 mg
of PAC compared to 36 and there is no
real activity with urine samples collected
after intake of 18 mg of PAC.
3.2 Methods of PAC dosage
The DMAC/PAC003, a proprietary
colorimetric method (4-diméthylamino-
cinnimaldéhyde), was the first described
Table 2 Anti-adhesion activity in urine measured by Lavigne
Test with three regimens of Urell® and placebo control.
1
Placebo
0,9 18 mg
Anti-adhesion activity
0,8 36 mg
72 mg
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0 well is evaluated microscopically for the
0H 6H
PAC (proanthocyanidin)
272
and is reliable with great precision
(95 %) [15].
Meanwhile, the DMAC method has
been simplified and shortened and is now
validated by the USDA and four inde-
pendent laboratories. The publication of
the revised method yielding 36 mg for 300
g of Cranberry juice drink is currently
under revision.
There are other methods but the
results they produce are quite different
from the DMAC method :
DMAC : 36 mg
NP-HPLC : 72 mg
(USA)
Pharmacopeia Europe : 89 mg
Vannilin : 174 mg
Bate Smith : 187 mg
Therefore it is important to refer to the
DMAC method which corresponds to the
36 mg PAC in 300 ml C juice drink.
4. QUANTIFICATION OF BIO-ACTIVITY
IN URINE
Given that 36 mg of PAC per day is nec-
essary to obtain a preventive clinical
effect on UTIs (Avorn study [12]) and
given that we lack a method to evaluate
active metabolites in urine we therefore
need surrogates to quantify bio-activity
in urine. There are two surrogates :
The first is the red blood cell hemag-
glutination test, described by Howell [3].
Each E. coli strain is incubated for 20
minutes in the volunteer’s urine at a con-
centration of 105 CFU/ml, to correspond
to the bacterial concentration indicative
of a clinical UTI. Hemagglutination is
carried out on microplates (96 wells) in
the presence of group A+ or O+ human
red blood cells (HRBCs) newly drawn
in citrated tubes. A 3% suspension of
HRBCs is added to each well containing
the bacteria/urine suspensions and the
microplate agitated for 15 minutes. Each
24H
presence or absence of hemagglutination.
 Use of cranberry for prophylaxis of uncomplicated recurrent urinary tract infections
If the HRBCs in a well are not aggluti-
nated, the urine in that particular well
is considered to have C metabolites with
antiadhesion activity. The results of this
rapid and indirect test are given using 3
thresholds (0 ; 50% ; 100%). It is indeed
a very good test for screening and to
compare different available commercial
products.
The second surrogate is a direct cel-
lular adhesion test described by Lavigne
[16], adapted from Di Martino [13]. This
study consists of testing the capacity of
the E. coli strains to adhere in vitro to
urothelial T24 cell lines. Each strain is
cultured in the volunteer’s urine for 12
hours. These bacteria are then placed
in contact with the urothelial cells for
three hours. After fixing, the bacteria are
stained with 20% Giemsa and examined
under a microscope. An adherence index
(AI) corresponding to the mean number of
adherent bacteria per cell for 100 cells is
then calculated. The morphologies of the
different E. coli strains (morphology of
rod, lengthening, thickening…) are evalu-
ated using an electronic microscope after
fixing the slides containing the bacteria
in contact with the cells. Three independ-
ent experiments are carried out for each
test. An anti-adhesion control test is car-
ried out.
5. FORMULATION OF CRANBERRY
Besides the problem of measurement of
bio-activity, there is another great con-
cern about the chemical composition of
commercialy available C products. Their
composition is not standardized and thus
bio-equivalence between all of them is not
clear.
The first dosage proposed was 36 mg of
PAC extracted from the Avorn study [12].
This 36 mg was given by 300 ml of juice
presentation. But juice presentation is not
convenient for long-duration leading to a
withdrawal rate of up to 55% [17] . Thus
capsules and tablets have been developed
| 4.4 |
but there is no strict standarization for
these products. Moreover their labels are
very often unscientific, even dishonest,
because there is little regulation (if any)
in the field of food-supplements.
In addition a lot of capsules or tablets
contain a mixture of C species: the vali-
dated form (vaccinium macrocarpon) and
the non-validated forms (vaccinium vitis
idaea (lingonberry) and vaccinium oxy-
coccus (European Cranberry)). Thus, it is
impossible to compare by using the dos-
age of PAC written on the label. The only
way to compare is by one or two of the
surrogate bioactivity methods described,
however if any surrogate is used for a pre-
cise product, it is still impossible to take
into consideration the results present in
the leaflet.
The final concern regarding the compo-
sition of capsules or tablets is their activ-
ity in connection with products other than
PAC. Up to now, no compound of C other
than PAC has been shown to be active in
the prevention of UTIs.
6. CLINICAL STUDIES
The existing clinical studies have been
recently reviewed by Jepson and Craig for
the Cochrane database [6, 18]. For this
reason we did not perform a systematic
literature search, but used the results of
the Cochrane database. Only ten stud-
ies met their criteria and two were rap-
idly excluded [17, 19] because they were
published only in letter form and no addi-
tional data were available.
6.1 Neurologic patients
For neurologic patients needing cath-
eterisation (intermittent or indwelling)
there was no statistical difference in the
number of symptomatic UTIs between C
(juice) and placebo [20–21]. Nevertheless
in a recent study (randomised, double-
blind, placebo-controlled with a cross-over
design in a 12 month period) involving
273
Chapter |4| Prevention of recurrent urogenital tract infections in adult women

47 patients with spinal cord injury, Hess study in this field needs to be longer than
[22] found a reduction of UTI to 0.3 per six months.
year during the C period. compared to
1.0 UTI per year while receiving pla-
6.3 Sexually active women
cebo. Interestingly he also reported that
patients with a high glomerular filtration In sexually active women with recur-
rate may receive the most benefit. rent cystitis there were only two studies.
Kontiokari [25] and Stothers [26] each
6.2 Elderly patients recruited 150 women for one year of treat-
ment. In the Kontiokari study patients
In elderly patients three studies were
had one previous UTI, compred to two
available. The first one was conducted by
in the Stothers trial. The absolute risk
Avorn [12] in asymptomatic bacteriuric
reduction of UTI was respectively 20%
patients. However, the group receiving
and 14%. Nevertheless the Kontiokari
placebo were significantly more bacte-
study was stopped prematurely (at six
riuric before their inclusion in the trial.
months) because the C juice supplier
Nevertheless, he concluded that the
stopped producing the juice.
subjects receiving C juice were 58% less
likely than the control group to have bac-
teriuria. Here 300 ml of C juice was used 6.4 Side-effects
containing 36 mg of PAC.
Side effects were very uncommon, mainly
In the second study conducted by
related to juice presentation and limited
McMurdo [23] 376 hospitalised sympto-
to the gastro-intestinal area.
matic patients were recruited. There was
no statistical difference between either
group (C juice and placebo). Because the 6.5 Withdrawals
infection rate observed was lower than
Withdrawals are common with juice pres-
anticipated it made this study under-
entation (up to 55%); the compliance is
powered.
much better with capsule.
The final study was also conducted
by McMurdo [24] in 137 women (mean
age : 63 years) with two or more antibi- 6.6 Conclusions and
otic-treated UTI’s in the previous twelve recommendations
months. They were randomised to either
receive 500 mg of C extract (the amount Juice presentation is too unwieldy to be
of PAC is not stated) or 100 mg of tri- recommended for a long period of time
methoprim for six months. The amount of as a prophylactic treatment for recurrent
UTIs treated by the G.P. were 36% in the UTI. Thus the necessity to develop cap-
C group versus 20% in the trimethoprim sules or tablets.
group, and the microbiologically con- For these there is no standardisation :
firmed UTIs were respectively 16% and - In C species
12%. The authors concluded “trimetho- - In method of PAC measurment
prim had a very limited advantage over C - In dosage of PAC per day
extract in the prevention of UTIs”. In fact
- Apart from one capsule, there is no
the actual infection rate with trimetho-
data about the bio-activity of the
prim was much higher than expected (1%)
commercially available products
and this made the study inconclusive.
Furthermore UTIs often occur in clus- - No dose-ranging
ters, with patients often being symptom - No direct correlation between in-
free for several months. A preventive vitro and clinical effects.

274
 Use of cranberry for prophylaxis of uncomplicated recurrent urinary tract infections
At the least, as for active drugs, we need
a minimum standardisation:
- the precise amont of PAC
- measured by DMAC method
- allowing clinical studies with
stronger methodology
if we want to confirm the hopes regarding
the efficacy of C in reducing UTIs.
Despite the lack of pharmacological
data and the few and weak clinical stud-
ies, there is evidence to consider C vaccin-
ium macrocarpon to be useful in reducing
the rate of lower urinary tract infections
in women.
Despite the GoR C (LoE 2) referring to
the scientific data, it is logical in every-
day practice to recommend the consump-
tion of C products giving a minimum of
36 mg of PAC (vaccinium macrocarpon)
per day providing this amount is proven.
The best approach would be to use those
compounds that have demonstrated their
clear bio-activity in urine.
7. SUMMARY
Over the last few years, we have noted a
spread of cranberry (C) use for the follow-
ing two reasons: the high number of UTIs
has lead to an increased use of antibiotics
and thus increased antibiotic resistance;
the main mechanisms of action in reduc-
ing UTIs have been indentified. C inhibits
the adherence of E.coli to uro-epithelial
cells, the first and necessary step for UTI.
This competitive inhibition is due to a
non-dialyzable compound; a condensed
tannin, the proanthocyanidin (PAC) type
A. Among the three species of C vaccinium
macrocarpon is only one to have PAC-A.
The first dosage used was 36 mg served
as 300 ml of juice presentation[12]. In
2006, a double-blind randomised placebo-
controlled cross-over trial comparing
two dosages of C juice presentation (250
and 750 ml) found a significant reduc-
tion of E. coli adherence (p > 0,001) dose
dependent.
| 4.4 |
In 2008 a double-blind randomised
placebo-controlled cross-over trial tested
a commercially available capsule of vac-
cinium macrocarpon containing 36 mg of
PAC. A statistically significant reduction
of bacterial adherence of E. coli was found
(p < 0,001), dose-dependent. For the first
time this study established clearly the
bio-activity of a C capsule.
The method of measure of PAC is the
DMAC method which yields a result of
36 mg PAC for 300 ml C juice drink.
7.1 Quantification of bio-activity
in urine
Given that 36 mg of PAC per day is nec-
essary to obtain a preventive clinical
effect on UTIs (Avorn Study [12]) and
given that we lack a method to evaluate
active metabolites in urine we therefore
need surrogates to quantify bio-activity
in urine. There are two surrogates :
The first is the red blood cell hemagglu-
tination test (Howell [3]) ; the second is the
direct cellular adhesion test (Lavigne [16]).
7.2 Clinical studies
These have been recently reviewed by
Jepson and Craig [6, 18] for the Cochrane
database. Juice presentation is too
unwieldy to be recommended for a long
period of time as a prophylactic treatment
for recurrent UTI. Thus the necessity to
develop capsules or tablets. However, there
is no standardisation for these: in C spe-
cies, in method of PAC measurement, in
dosage of PAC per day, apart from one cap-
sule there is no data about the bio-activity
of the commercially available products,
no dose-ranging and no direct correlation
between in-vitro and clinical effets.
8. CONCLUSIONS
Despite the lack of pharmacological data
and the few and weak clinical studies
there is evidence to consider C vaccinium
275
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
macrocarpon to be useful in reducing the
rate of lower urinary tract infections in
women (GoR C ; LoE 2).
Despite the GoR C (LoE 2) referring to
the scientific data, it is logical in every-
day practice to recommend the consump-
tion of C products giving a minimum of
36 mg of PAC (vaccinium macrocarpon)
per day providing this amount is proven.
The best approach would be to use those
compounds that have demonstrated their
clear bio-activity in urine.
REFERENCES
1. Naber K, Schito G, Botto H, Palou J, and
Mazzei T, Surveillance Study in Europe
and Brazil on Clinical Aspects and
Antimicrobial Resistance Epidemiology
in Females with Cystitits (ARESC):
Implications for Empiric Therapy. Eur
Urol, 2008. 54(5): 1164–78.
2. Foo L, Lu Y, Howell A, and Vorsa N, The
structure of Cranberry proanthocyanidins
which inhibit adherence of uropathogenic
P-fimbriated Escherichia coli in vitro.
Phytochemistry, 2000. 54(2): 173–81
3. Howell A, Vorsa N, Marderosian AD,
and Foo L, Inhibition of adherence of
P-fimbriated Eschericha coli to uroepi-
thelial-cell surfaces by proanthocyanidin
extracts from Cranberries. N Engl J Med
1998. 339(19): 1085–6.
4. Bodel P, Cotran R, and Kass E, Cranberry
juice and the antibacterial action of
hippuric acid. J Lab Clin Med, 1959.
54(Dec): 881–8.
5. Zafriri D, Ofek I, Adar R, Pocino M, and
Sharon N, Inhibitory activity of Cranberry
juice on adherence of type 1 and type P
fimbriated Escherichia coli to eucaryo-
tic cells. Antimicrob Agents Chemother,
1989. 33(1): 92–8.
6. Jepson R and Craig J, Cranberries for
preventing urinary tract infections.
Cochrane Database Syst Rev, 2008:
CD001321.
7. Hirsch M: AFSSA – Saisine n° 2003-SA-
0352.
8. New Nutrition Business, 2004. 9(8).
276
9. Abrams P, Khoury S, and Grant A,
Evidence–based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
11. Howell A, Bioactive compounds in cran-
berries and their role in prevention of uri-
nary tract infections. Mol. Nutr. Food Res,
2007. 51(6): 732–7.
12. Avorn J, Monane M, Gurwitz J, Glynn R,
Choodnovskiy I, and Lipsitz L, Reduction
of bacteriuria and pyuria after ingestion
of Cranberry juice. JAMA, 1994. 271(10):
751–4.
13. DiMartino P, Agniel R, David K,
Templer C, Botto H, and al e, Reduction
of Escherichia coli adherence to uroepi-
thelial bladder cells after consumption
of cranberry juice: a double-blind rand-
omized placebo-controlled cross-over trial.
World J Urol, 2006. 24(1): 21–7.
14. Gupta K, Chou M, Howell A, Wobbe C,
Grady R, and Stapteton A, Cranberry
products inhibit adherence of P-fimbriated
Escherichia coli to primary cultured blad-
der and vaginal epithelial cells. J Urol,
2007. 177(6): 2357–60.
15. Cunningham D, Analysis and standardi-
zation of Cranberry products. American
Chemical Society 2002(803): 151–6.
16. Lavigne J, Bourg G, Combescure C,
Botto H, and Sotto A, In-vitro and in-
vivo evidence of dose-dependent decrease
of uropathogenic Escherichia coli viru-
lence after consumption of commercial
Vaccinium macrocarpon (Cranberry) cap-
sules. Clin Microbiol Infect, 2008. 14(4):
350–5.
17. Haverkorn M and Mandigers J,
Reduction of bacteriuria and pyuria using
Cranberry juice (letter). JAMA, 1994.
272(8): 590.
18. Jepson R, Mihaljevic L, and Craig J,
Cranberries for preventing urinary tract
infections. Cochrane Database Syst Rev,
2004. 23(1): CD001321.
19. Walker E, Barney D, Michelsen J,
Walton R, and Mickelsen R, Cranberry
 Use of cranberry for prophylaxis of uncomplicated recurrent urinary tract infections
concentrate: UTI prophylaxis
(letter). J Fam Pract, 1997. 45(2):
167–8.
20. Linsenmeyer T, Harrison B, Oakley A,
Kirshblum S, Stock J, and Millis S,
Evaluation of cranberry supplement for
reduction of urinary tract infections in
individuals with neurogenic bladders
secondary to spinal cord injury. A prospec-
tive, double-blinded, placebo-controlled,
crossover study. J Spinal Cord Med, 2004.
27(1): 29–34.
21. Waites K, Canupp K, Armstrong S, and
DeVivo M, Effect of cranberry extract on
bacteriuria and pyuria in persons with
neurogenic bladder secondary to spinal
cord injury. J Spinal Cord Med, 2004.
27(1): 35–40.
22. Hess M, Hess P, Sullivan M, Nee M, and
Yalla S, Evaluation of cranberry tablets
for the presentation of urinary tract infec-
tions in spinal cord injured patients with
neurogenic bladder. Spinal Cord, 2008.
46: 622–6.
| 4.4 |
23. McMurdo M, Bissett L, Price R, Phillips
G, and Crombie I, Does ingestion of cran-
berry juice reduce symptomatic urinary
tract infections in older people in hospi-
tal? A double-blind, placebo-controlled
trial. Age Ageing 2005. 34(3): 256–61.
24. Marion E, McMurdo M, Argo I, Phillips G,
Daly F, and Davey P, Cranberry or tri-
methoprim for the prevention of recurrent
urinary tract infections? A randomised con-
trolled trial in older women. J Antimicrob
Chemother, 2008. 63(2): 1000–8.
25. Kontiokari T, Sundqvist K, Nuutinen
M, Pokla T, Koskela M, and Uhari
M, Randomised trial of Cranberry-
lingonberry juice and Lactobacillus
GG drink for the prevention of urinary
tract infection in women. BMJ, 2001.
322(7302): 1751–3.
26. Stothers L, A randomised trial to evalu-
ate effectiveness and cost effectiveness of
naturopathic cranberry products as proph-
ylaxis against urinary tract infection in
women. Can J Urol, 2002. 9(3): 1558–62.
277
|4.5|

Probiotics for the prophylaxis of

uncomplicated recurrent urinary
tract infections in females
Peter Cadieux, Gregor Reid
Canadian Research and Development Centre for Probiotics, Lawson Health Research Institute, (1) and Departments of
Microbiology and Immunology,) and Surgery (2), The University of Western Ontario, London, Ontario, Canada
*Corresponding author: Prof. Gregor Reid, Canadian Research and Development Centre for Probiotics, F2-116 Lawson
Health Research Institute, 268 Grosvenor Street, London, Ontario, N6A 4V2 Canada.
Tel: 519-646-6100 x65256; Fax: 519-646-6031; gregor@uwo.ca.
Running title: Probiotics to prevent UTI

ABSTRACT that has not yet been given a desig-

Recurrent urinary tract infections (UTI)
in women remain a common occurrence
despite management with antibiot-
ics and health foods such as cranberry
juice. With growing drug resistance, side
effects of such therapy, and few new anti-
biotic classes in the pipeline, alternative
approaches are needed. The correlation
between depletion of vaginal lactoba-
cilli and risk of UTI has led to efforts to
replenish the lactobacilli organisms as
a means to prevent infection. This con-
cept, termed probiotics, has some sound
scientific basis, but to date very few
Lactobacillus strains have been clini-
cally tested for vaginal benefits. Clinical
studies provide Level 1 and 2 evidence
that Lactobacillus acidophilus (a strain
nated number), L. rhamnosus GR-1 with
L. reuteri RC-14, and possibly L. crispatus
CTV05 can populate the vagina and dis-
place urogenital pathogens leading to
reduced risk of infection. In addition, a
recent 2009 study provides Level 1 evi-
dence supporting the use of orally admin-
istered L. rhamnosus GR-1 and L. reuteri
RC-14 for the prevention of rUTI in post-
menopausal women. Importantly, while
the long-term use of prophylactic antibi-
otics in that study strongly promoted bac-
terial drug resistance, the application of
GR-1 and RC-14 capsules did not. Thus,
certain probiotics have strong support
for prophylaxis against recurrent UTI.
In order to increase the level of evidence,
further randomized controlled stud-
ies are needed with larger sample sizes,
 Probiotics for the prophylaxis of uncomplicated recurrent urinary tract infections
and manufacturers have to make oral
and vaginal products more accessible to
patients for this approach to truly make a
dent in the large number of patients suf-
fering each year from UTI.
Key words: probiotics, urinary tract
infection, lactobacilli, vagina, microbiota,
prophylaxis
SUMMARY OF RECOMMENDATIONS
Availability of Probiotics: Accessibility
of clinically proven probiotics for UTI
prophylaxis is currently not universal.
The L. acidophilus strain used in the
Lee et al. [1] study is not available, nor
is L. crispatus CTV05. The L. rhamnosus
GR-1 and L. reuteri RC-14 product is
available as an orally administered cap-
sule which has been used vaginally to
treat bacterial vaginosis (BV) [2] but not
for UTI prophylaxis. These capsules have
also been used orally to prevent UTI [3].
1. Where commercially available, twice
daily application of the oral probiotic
containing strains GR-1 and RC-14
for the prevention of recurrent UTI is
suggested (GoR C).
2. It is also reasonable to consider the
intravaginal use of this probiotic for
recurrent UTI prevention, as it has
been shown to prevent and treat BV,
a condition that increases UTI risk.
Based upon clinical studies, once or
twice weekly application could be
recommended for prophylaxis (GoR C).
1. INTRODUCTION
The purpose of this guideline is to discuss
the rationale and level of evidence for pro-
biotics to prevent urinary tract infections
(UTI). There are few if any true prophy-
lactic measures to prevent UTI. In most
cases, patients are prescribed low dose
antibiotics designed to kill pathogens
| 4.5 |
entering the bladder and thereby prevent
infection. However, with increasing drug
resistance, side effects of treatment, and
failure to prevent recurrences in many
instances, there is a need for alternative
approaches.
The scope of this review will include
the scientific basis for why and how pro-
biotic bacteria might prevent UTI, and
recommendations will be made for clini-
cal practice.
2. METHODS
The literature search was performed
using PubMed, with various search
words including urinary tract infection,
lactobacillus, probiotics, clinical trials,
prevention, prophylaxis, antibiotics, and
vaginal microbiota. Only clinical stud-
ies using properly documented probiotic
products and strains were included in
this review, as only they fit the criteria of
a probiotic (“live microorganisms which
when administered in adequate amounts
confer a health benefit on the host”). Due
to the limited number of human studies
performed in this area, it was not pos-
sible to restrict the citation to the past
three years. However, special mention is
given to three studies within that recent
timeframe, and overall almost half of the
citations are from 2006 onwards. Of the
earlier references, many are included to
put the topic and mechanisms of action
into context and to understand why and
how probiotics might be useful to pre-
vent UTI. The studies were rated accord-
ing to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[4–5].
3. THE RATIONALE FOR PROBIOTICS
Microorganisms have dominated this
planet for billions of years and humans
have evolved from these simple species.
279
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
Humans would not be alive but for these
microbes, which outnumber our own cell
count by over ten to one. In our intesti-
nal tract, there are organisms capable of
killing us. The fact that they don’t do so
under normal circumstances is in large
part due to the epithelial barrier and
the development of a highly sensitive,
integrated and potent immune system,
as well as our own non-pathogenic (and
largely commensal) microbiota. There are
over 1500 species of microbes inside our
gut, and many of these have access to the
female urinary bladder through ascension
from the rectal skin to the perineum and
vagina. Yet, relatively few of these sur-
vive this ascension and infect the urinary
tract.
One of the main reasons that organ-
isms residing on the skin or shed from
the gastrointestinal tract fail to illicit a
UTI is the host’s own indigenous micro-
biota which contains a number of mecha-
nisms for interfering with pathogenesis.
Lactobacillus species are the principal
non-pathogens in the healthy vagina of
most females, and studies have shown
that they possess several anti-microbial
components capable of killing or inhib-
iting the growth of uropathogens [6–9],
others that can interfere with uropatho-
gen adhesion and spread [10–11], and fac-
tors which modulate host anti-infective
immunity [12–13]. The severe depletion
of these lactobacilli has been shown to
correlate with onset of localized infection,
namely bacterial vaginosis (BV), and
with UTI [14–16]. The factors responsi-
ble for this depletion are not fully known,
but appear to include the use of spermi-
cides [17], douching [18], menstrual hor-
mones levels [19], and antibiotics [20], as
well as potentially low levels of lactoba-
cilli replenishment from the rectal sur-
face [21].
Given the association between low
lactobacilli counts and increased risk of
UTI, it was proposed by our group that
replenishment of lactobacilli into the
vagina, either through oral ingestion or
280
direct vaginal application, could enhance
the host’s ability to defend against infec-
tion [22]. This application of beneficial
bacteria to the host is termed probiotics,
defined by the World Health Organization
and United Nations Food and Agriculture
Organization above. This is an extremely
important definition as it means that
unless a product is suitably prepared
with properly speciated strains, appropri-
ate viable count at end of shelf-life, and
clinical evidence that the host benefits
from the use in a tangible, proven way,
then the product is not a probiotic, even
if it says so on the label or in the manu-
script. In many cases, so-called probiotics
do not meet these guidelines.
The concept of using probiotic lactoba-
cilli to prevent UTI was long ignored by
the urological community, in part because
it was too simple and the antibiotic option
was better known and clinically quite
effective, but also because it was viewed
as impossible for lactobacilli to compete
against pathogens that had a wide array
of virulence factors for host cell attach-
ment and invasion, biofilm formation,
host-cell cytotoxicity, iron-acquisition,
evasion or disruption of host defences and
increased antibiotic resistance [23–28].
These virulence properties are invariably
encoded as single genes or entire oper-
ons, and their expression is important
for the development and maintenance of
both primary and recurrent UTI [29]. In
addition, pathogen reservoirs have been
shown to be key in the establishment of
recurrent UTI, with studies identifying
the gastrointestinal tract, bladder epithe-
lium and vagina all as major sites of their
development [30–31].
4. CLINICAL EVIDENCE OF
PROBIOTIC USE TO PREVENT
RECURRENCE OF UTI
The following evidence will be for studies
that examine the ability of probiotics to
reduce recurrences of UTI.
 Probiotics for the prophylaxis of uncomplicated recurrent urinary tract infections
4.1 Populating the vagina
In order for any probiotic to prevent
UTI, the organisms must be shown to
populate the vaginal area after oral or
vaginal administration. Several stud-
ies have provided this level of evidence
(LoE 2b).
i. Following vaginal instillation of 1011
Lactobacillus rhamnosus GR-1 in
saline twice weekly until a repeat
episode of infection occurred, lacto-
bacilli levels in the vagina increased
in four of five subjects, including a
13 year old girl [32]. Three of the
patients remained infection free for
more than three months, compared
to their pre-treatment situation of
an episode every month.
ii. In a study of 10 women with a
history of recurrent symptomatic
UTI, a gelatin suppository con-
taining 109 L. rhamnosus GR-1
and L. fermentum (now known as
reuteri) B-54 was administered
vaginally once per week for 12–16
months [33]. Two subjects were
non-compliant, but of the others
there was a 66% reduction in UTI
episodes compared to the previ-
ous year’s history. The lactobacilli
were recovered from the vagina
and noted adherent to epithelial
cells.
iii. The development of molecular meth-
ods to indentify lactobacilli provided
a new tool to examine their ability
to survive in the vagina. The first
report of this was published in 1994
[34]. A 33 year old woman with a
history of recurrent UTI inserted a
single pessary of >109 L. rhamnosus
GR-1. Subsequent swabs showed
that the organism persisted for at
least six weeks.
iv. Ten healthy women inserted vagi-
nally a capsule containing >109
L. rhamnosus GR-1 and L. reuteri
RC-14 and the organisms were
| 4.5 |
recovered up to 19 days after instil-
lation [35].
v. An independent study in ten sub-
jects further confirmed that >109
L. rhamnosus GR-1 and L. reuteri
RC-14 administered orally in dried
capsule form could lead to vaginal
colonization [36].
vi. Using an in vitro bacterial adherence
assay, candidate probiotic L. crispatus
CTV-05 was shown to adhere well to
vaginal epithelial cells collected from
51 women with a history of recurrent
UTI and 51 controls [37].
4.2 Clinical evidence that probiotics
can prevent UTI
The ultimate proof-of-concept is for probi-
otics to actually impact the recurrent rate
of UTI. The following studies provide dif-
fering degrees of evidence.
vii. Forty-one premenopausal women
were treated with three days
norfloxacin or trimethoprim-
sulfamethoxazole plus randomized
to receive intravaginal probiotic
L. rhamnosus GR-1 and L. reuteri
B-54 (>109 viable count) or placebo
twice weekly for two weeks and then
at the end of each of the next two
months [38]. UTI recurrence rate
was lower in the probiotic treated
group (21% versus 47%). This is a
good study but with small numbers
of patients in each group. Still, it
indicates that probiotics can restore
the vaginal lactobacilli in patients
treated for UTI with trimethoprim-
sulfamethoxazole. (LoE 2a)
viii. Intravaginal probio tic L.
rhamnosus GR-1 and L. reuteri B-54
(>109 viable count) capsules admin-
istered weekly for one year resulted
in a UTI recurrent rate of 1.6 per
25 patients, compared to six per
patient the previous year [39]. This
supports the concept but has been
criticized because it uses historical
281
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
comparison of UTI rates from the
previous year. (LoE 2b)
ix. A study of 150 women with a
history of UTI caused by E. coli
were randomly allocated into
three groups: 50 ml of cranberry-
lingonberry juice daily for six
months or 100 ml of L. rhamnosus
GG drink five days a week for
one year, or no intervention. At
six months, eight (16%) women in
the cranberry group, 19 (39%) in
the L. rhamnosus GG group, and
18 (36%) in the control group had
at least one recurrence [40]. This
showed that probiotic L. rhamno-
sus GG given orally did not prevent
UTI recurrence. (LoE 2a)
x. Another negative outcome with
L. rhamnosus GG was reported in
a double-blind study of newborns
[41]. Five hundred and eighty-
five infants with a gestational age
<33 weeks or birth weight <1,500
g were randomized to receive
standard milk feed supplemented
with Lactobacillus GG (Dicoflor,
Dicofarm, Rome, Italy) in a dose of
6 × 109 CFU once a day until dis-
charge (47 days on average), start-
ing with the first feed or placebo.
Although UTIs (3.4 vs. 5.8%) were
found less frequently in the probi-
otic group compared to the control
group, these differences were not
significant. (LoE 2a)
In the past three years, three studies
have provided further evidence to suggest
that probiotics can help to reduce recur-
rence of UTI.
xi. Vaginal suppositories containing
L. crispatus GAI 98332, 1.0 × 108
CFU (colony-forming units) per one
suppository were administered to
nine subjects every two days for
one year [42]. Two of nine patients
performed clean intermittent cath-
eterization when necessary and
282
seven patients had uncomplicated
UTI. The participants’ mean age
was 57.2 ± 17.2 years, and they had
suffered from recurrent UTI for
7.1 ± 5.2 years. A significant reduc-
tion was observed in the number of
recurrences during treatment (from
an average of 5.0 ± 1.6 episodes per
year to 1.3 ± 1.2, P = 0.0007). This
study supports the concept but is
a pilot study in complicated UTI
patients. (LoE 2b)
xii. Czaja et al. [43] performed a phase
I randomized, placebo-controlled
trial with L. crispatus CTV05
(5 × 108 CFU) vaginal supposi-
tory in 30 women for five days. No
severe adverse events occurred.
Mild to moderate vaginal dis-
charge and genital irritation were
reported by women in both study
arms. Seven women randomized
to L. crispatus CTV-05 developed
pyuria without associated symp-
toms. Most women had high concen-
trations of vaginal H202-producing
lactobacilli before randomization,
therefore it is difficult to verify that
replenishment of lactobacilli per se
occurred. (LoE 2b).
xiii. Lee et al. [1] showed in a study
of 120 children who had persist-
ent primary vesico-ureteral reflux
that Lactobacillus acidophilus
(108 CFU/g 1 g b.i.d., n = 60) was
as effective at preventing recurrent
UTI as trimethoprim/sulfamethoxa-
zole (2/10 mg/kg h.s., n = 60) over
a year. The incidence of recurrent
UTI was 18.3% (11/60) in the probi-
otics group, which was not different
from 21.6% (13/60) in the antibiotic
group (P = 0.926). The causative
organisms of recurrent UTI were
not significantly different between
the two groups (P = 0.938). Even
after stratification by VUR grade,
age, gender, phimosis, voiding
 Probiotics for the prophylaxis of uncomplicated recurrent urinary tract infections
dysfunction and renal scar, the
incidence of recurrent UTI did not
differ significantly between the two
groups (P > 0.05). This is an excel-
lent study that provides supporting
evidence that probiotic use is as
effective as antibiotic prophylaxis
in patients who commonly receive
long term, low-dose antimicrobial
prophylaxis. The one criticism is
that the strain of L. acidophilus
needs to be designated. (LoE 1b)
xiv. In arguably the most important
study to date regarding the use
of probiotics for the prevention
of rUTI, Beerepoot et al. [3] ran-
domized 252 postmenopausal
women with rUTI to receive 12
months prophylaxis with either
trimethoprim/sulfamethoxazole
(TMP/SMX) (480mg 4 times daily)
or twice daily oral capsules con-
taining 109 CFU L. rhamnosus
GR-1 and L. reuteri RC-14. Both
groups demonstrated a greater
than 50% reduction in the mean
number of reported symptomatic
UTIs (TMP/SMX – 2.8 vs. 7.0
pretrial, GR-1/RC-14 – 3.1 vs.
6.8 pretrial) and median times
to first UTI were 6 and 3 months
for the antibiotic and probiotic
arms, respectively. Importantly,
while resistance following the
first month of prophylaxis in the
TMP/SMX group increased from
~20–40% up to ~80–95% for TMP/
SMX, TMP and amoxicillin in
faecal and bacteriuria isolates of
E. coli, no such increase in resist-
ance occurred in the probiotic
group. This double dummy double-
blind randomized non-inferiority
trial clearly showed that the pro-
phylactic use of certain urogenital
probiotics can greatly reduce rUTI
development without increasing
the risk of antibiotic resistance.
(LoE 1b)
| 4.5 |
5. CONCLUSIONS AND FUTURE
RESEARCH
There is good evidence to support the
concept that females colonized with lacto-
bacilli are at lower risk of UTI. Further
studies, now possible with molecular
bacterial identification methods being
available, are needed to determine if par-
ticular species of Lactobacillus are bet-
ter able to compete with uropathogens.
Studies on BV have suggested that H202-
producing lactobacilli are more protec-
tive and thus the same could be true for
UTI. At the same time, one might argue
the fact that these strains are displaced
during the infection process, imply-
ing that those with better colonization
and persistence may be more important.
For example, while the low level H2O2-
producing L. rhamnosus GR-1 has been
shown to induce membrane stress and
downregulate virulence in uropathogenic
E. coli (UPEC) [44], L. iners strains are
potent colonizers and not as easily dis-
placed by pathogens [45]. In addition,
future research should investigate the
effects of lactobacilli strains on viru-
lence factor expression in uropathogens.
It has already been shown that lactoba-
cilli can down-regulate toxin release in
S. aureus and E. coli [46–47] as well as
expression of both type 1 and P fimbriae
in UPEC [43], thus providing potential
mechanisms whereby they counter the
uropathogenesis process. Additional stud-
ies could further this knowledge and help
us determine why and how some persist-
ent pathogens only cause symptomatic
infections when commensals like lactoba-
cilli are at low levels.
Lactic acid produced by lactobacilli as
a by-product of metabolism is also protec-
tive for the host. This weak acid has been
shown to exhibit potent antibacterial
effects on numerous pathogens includ-
ing uropathogenic strains [48], especially
under nutrient limiting conditions such
as those observed in the vagina. A recent
283
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
study showed no uropathogen growth
in concentrations above 30mM and an
almost 70% growth reduction in as lit-
tle as 10mM. Much of these effects are
thought to be due to both increased cel-
lular and membrane stress, indicated by
the upregulated expression of outer mem-
brane proteins (Omps) and porins impor-
tant in maintaining osmotic balance and
membrane stability [44]. For example,
30mM lactic acid increased OmpA and
OmpX expression in UPEC C1212 by 13.8
and 12.2 fold (both p<0.001), respectively.
Since L. rhamnosus GR-1 and L. reuteri
RC-14 cultures can produce approxi-
mately 45 and 35mM lactic acid within
24 hours, respectively [43], their protec-
tive potential is further supported. Since
the normal vaginal lactic acid content
typically measures between 10–50 mM, if
patients have low vaginal counts of lacto-
bacilli, such as post-menopausal women
not using estrogen replacement, they
would be particularly good candidates for
probiotic use.
Given the increasing antibiotic resist-
ance amongst uropathogens [49], their
use is becoming more and more lim-
ited, and alternatives are needed. There
is growing evidence, presently at LoE
1b-2b, that probiotic lactobacilli can help
prevent recurrent UTI. More placebo-
controlled, randomized studies with
larger sample sizes and well charac-
terized and reliably produced products
are needed to strengthen the level of
evidence.
Acknowledgements: Supported
by a grant from the Natural Sciences
and Engineering Research Council of
Canada.
Conflicts of interest: Dr. Reid devel-
oped the use of Lactobacillus rham-
nosus GR-1 and Lactobacillus reuteri
RC-14 for urogenital health. These
strains are now owned by Chr Hansen,
Denmark.
284
REFERENCES
1. Lee SJ, Shim YH, Cho SJ, and Lee JW,
Probiotics prophylaxis in children with
persistent primary vesicoureteral reflux.
Pediatr Nephrol, 2007. 22(9): 1315–20.
2. Anukam KC, Osazuwa E, Osemene
GI, Ehigiagbe F, Bruce AW, and Reid
G, Clinical study comparing probiotic
Lactobacillus GR-1 and RC-14 with met-
ronidazole vaginal gel to treat sympto-
matic bacterial vaginosis. Microbes Infect,
2006. 8(12–13): 2772–6.
3. Beerepoot MAJ and et al, Lactobacillus
rhamnosus GR-1 and L. reuteri RC-14
versus trimethoprim-sulfamethoxazole
(TMP/SMX) in the prevention of recur-
rent urinary tract infections (rUTIs) in
postmenopausal women: a randomized
double-blind non-inferiority trial. ICAAC,
2009: Abstract L1-1656a.
4. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
5. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
6. McGroarty JA and Reid G, Detection of
a Lactobacillus substance that inhibits
Escherichia coli. Can J Microbiol, 1988.
34(8): 974–8.
7. McGroarty JA and Reid G, Inhibition of
enterococci by Lactobacillus species in
vitro. Microbial Ecol. Health Dis, 1988. 1:
215–219.
8. Hutt P, Shchepetova J, Loivukene
K, Kullisaar T, and Mikelsaar M,
Antagonistic activity of probiotic lacto-
bacilli and bifidobacteria against entero-
and uropathogens. J Appl Microbiol, 2006.
100(6): 1324–32.
9. Tomas MS, Claudia Otero M, Ocana V,
and Elena Nader-Macias M, Production
of antimicrobial substances by lactic acid
bacteria I: determination of hydrogen
peroxide. Methods Mol Biol, 2004. 268:
337–46.
10. Chan RC, Reid G, Irvin RT, Bruce AW,
and Costerton JW, Competitive exclusion
 Probiotics for the prophylaxis of uncomplicated recurrent urinary tract infections
of uropathogens from human uroepithe-
lial cells by Lactobacillus whole cells and
cell wall fragments. Infect Immun, 1985.
47(1): 84–9.
11. Velraeds MM, van der Mei HC, Reid
G, and Busscher HJ, Inhibition of
initial adhesion of uropathogenic
Enterococcus faecalis by biosurfactants
from Lactobacillus isolates. Appl Environ
Microbiol, 1996. 62(6): 1958–63.
12. Corr SC, Li Y, Riedel CU, O’Toole PW, Hill
C, and Gahan CG, Bacteriocin production
as a mechanism for the antiinfective activ-
ity of Lactobacillus salivarius UCC118.
Proc Natl Acad Sci U S A, 2007. 104(18):
7617–21.
13. Kirjavainen PK, Laine RM, Carter D,
Hammond J-A, and Reid G, Expression
of anti-microbial defense factors in
vaginal mucosa following exposure to
Lactobacillus rhamnosus GR-1. Int J
Probiotics, 2008. 3: 99–106.
14.Hillebrand L, Harmanli OH, Whiteman V,
and Khandelwal M, Urinary tract infec-
tions in pregnant women with bacterial
vaginosis. Am J Obstet Gynecol, 2002.
186(5): 916–7.
15. Sharami SH, Afrakhteh M, and Shakiba
M, Urinary tract infections in pregnant
women with bacterial vaginosis. J Obstet
Gynaecol, 2007. 27(3): 252–4.
16. Cherpes TL, Hillier SL, Meyn LA, Busch
JL, and Krohn MA, A delicate balance:
risk factors for acquisition of bacterial
vaginosis include sexual activity, absence
of hydrogen peroxide-producing lacto-
bacilli, black race, and positive herpes
simplex virus type 2 serology. Sex Transm
Dis, 2008. 35(1): 78–83.
17. McGroarty JA, Faguy D, Bruce AW, and
Reid G, Influence of the spermicidal com-
pound nonoxynol-9 on adhesion of E. coli.
Int. Urogynecol. J, 1993. 4(4): 194–198.
18. Ness RB, Hillier SL, Richter HE, Soper
DE, Stamm C, McGregor J, Bass DC,
Sweet RL, and Rice P, Douching in rela-
tion to bacterial vaginosis, lactobacilli,
and facultative bacteria in the vagina.
Obstet Gynecol, 2002. 100(4): 765.
19. Chan RC, Bruce AW, and Reid G,
Adherence of cervical, vaginal and distal
urethral normal microbial flora to human
uroepithelial cells and the inhibition of
| 4.5 |
adherence of gram-negative uropathogens
by competitive exclusion. J Urol, 1984.
131(3): 596–601.
20. Reid G, Bruce AW, Cook RL, and Llano
M, Effect on urogenital flora of antibiotic
therapy for urinary tract infection. Scand
J Infect Dis, 1990. 22(1): 43–7.
21. Reid G, Charbonneau D, Erb J,
Kochanowski B, Beuerman D, Poehner R,
and Bruce AW, Oral use of Lactobacillus
rhamnosus GR-1 and L. fermentum
RC-14 significantly alters vaginal flora:
randomized, placebo-controlled trial in
64 healthy women. FEMS Immunol Med
Microbiol, 2003. 35(2): 131–4.
22. Reid G, Chan RC, Bruce AW, and
Costerton JW, Prevention of urinary
tract infection in rats with an indigenous
Lactobacillus casei strain. Infect Immun,
1985. 49(2): 320–4.
23. Mulvey MA, Adhesion and entry of
uropathogenic Escherichia coli. Cell
Microbiol, 2002. 4(5): 257–71.
24. Burmolle M, Bahl MI, Jensen LB,
Sorensen SJ, and Hansen LH, Type 3 fim-
briae, encoded by the conjugative plasmid
pOLA52, enhance biofilm formation and
transfer frequencies in Enterobacteriaceae
strains. Microbiology, 2008. 154(Pt 1):
187–95.
25. Hancock V, Ferrieres L, and Klemm
P, The ferric yersiniabactin uptake
receptor FyuA is required for efficient
biofilm formation by urinary tract infec-
tious Escherichia coli in human urine.
Microbiology, 2008. 154(Pt 1): 167–75.
26. Hagan EC and Mobley HL, Haem acqui-
sition is facilitated by a novel receptor
Hma and required by uropathogenic
Escherichia coli for kidney infection. Mol
Microbiol, 2009. 71(1): 79–91.
27. Alamuri P, Eaton KA, Himpsl SD, Smith
SN, and Mobley HL, Vaccination with
proteus toxic agglutinin, a hemolysin-
independent cytotoxin in vivo, protects
against Proteus mirabilis urinary tract
infection. Infect Immun, 2009. 77(2):
632–41.
28. Gesu GP and Marchetti F, Increasing
resistance according to patient’s age and
sex in Escherichia coli isolated from
urine in Italy. J Chemother, 2007. 19(2):
161–5.
285
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
29. Johnson JR, O’Bryan TT, Delavari P,
Kuskowski M, Stapleton A, Carlino U,
and Russo TA, Clonal relationships and
extended virulence genotypes among
Escherichia coli isolates from women with
a first or recurrent episode of cystitis. J
Infect Dis, 2001. 183(10): 1508–17.
30. Rosen DA, Hooton TM, Stamm WE,
Humphrey PA, and Hultgren SJ,
Detection of intracellular bacterial com-
munities in human urinary tract infec-
tion. PLoS Med, 2007. 4(12): e329.
31. González Pedraza Avilés A, Sánchez
Hernández G, and Ponce Rosas RE,
Frequency, risk factors and vaginal colo-
nization due to Escherichia coli. Ginecol
Obstet Mex, 2004(72): 68–75.
32. Bruce AW and Reid G, Intravaginal instil-
lation of lactobacilli for prevention of
recurrent urinary tract infections. Can J
Microbiol, 1988. 34(3): 339–43.
33. Bruce AW, Reid G, McGroarty JA, Taylor
M, and Preston C, Preliminary study on
the prevention of recurrent urinary tract
infections in ten adult women using intra-
vaginal lactobacilli. Int. Urogynecol. J,
1992. 3: 22–25.
34. Reid G, Millsap K, and Bruce AW,
Implantation of Lactobacillus casei var
rhamnosus into vagina. Lancet, 1994.
344(8931): 1229.
35. Gardiner GE, Heinemann C, Bruce AW,
Beuerman D, and Reid G, Persistence
of Lactobacillus fermentum RC-14 and
Lactobacillus rhamnosus GR-1 but not L.
rhamnosus GG in the human vagina as
demonstrated by randomly amplified pol-
ymorphic DNA. Clin Diagn Lab Immunol,
2002. 9(1): 92–6.
36. Morelli L, Zonenenschain D, Del Piano M,
and Cognein P, Utilization of the intesti-
nal tract as a delivery system for urogeni-
tal probiotics. J Clin Gastroenterol, 2004.
38(6 Suppl): S107–10.
37. Kwok L, Stapleton AE, Stamm WE,
Hillier SL, Wobbe CL, and Gupta K,
Adherence of Lactobacillus crispatus to
vaginal epithelial cells from women with
or without a history of recurrent urinary
tract infection. J Urol, 2006. 176(5):
2050–4; discussion 2054.
38. Reid G, Bruce AW, and Taylor M,
Influence of three-day antimicrobial
286
therapy and lactobacillus vaginal sup-
positories on recurrence of urinary tract
infections. Clin Ther, 1992. 14(1): 11–6.
39. Reid G, Bruce AW, and Taylor M,
Instillation of Lactobacillus and stimula-
tion of indigenous organisms to prevent
recurrence of urinary tract infections.
Microecol. Ther., 1995(23): 32–45.
40. Kontiokari T, Sundqvist K, Nuutinen
M, Pokka T, Koskela M, and Uhari
M, Randomised trial of cranberry-
lingonberry juice and Lactobacillus
GG drink for the prevention of urinary
tract infections in women. BMJ, 2001.
322(7302): 1571.
41. Dani C, Biadaioli R, Bertini G, Martelli
E, and Rubaltelli FF, Probiotics feeding in
prevention of urinary tract infection, bac-
terial sepsis and necrotizing enterocolitis
in preterm infants. A prospective double-
blind study. Biol Neonate, 2002. 82(2):
103–8.
42. Uehara S, Monden K, Nomoto K, Seno Y,
Kariyama R, and Kumon H, A pilot study
evaluating the safety and effectiveness
of Lactobacillus vaginal suppositories
in patients with recurrent urinary tract
infection. Int J Antimicrob Agents, 2006.
28 Suppl 1: S30–4.
43. Czaja CA, Stapleton AE, Yarova-Yarovaya
Y, and Stamm WE, Phase I trial of a
Lactobacillus crispatus vaginal supposi-
tory for prevention of recurrent urinary
tract infection in women. Infect Dis
Obstet Gynecol, 2007. 2007: 35387.
44. Cadieux PA, Burton J, Devillard E, and
Reid G, Lactobacillus by-products inhibit
the growth and virulence of uropatho-
genic Escherichia coli. Pharmacol, 2009.
Accepted.
45. Dahn A, Saunders S, Hammond JA,
Carter D, Kirjavainen P, Anukam K,
and Reid G, Effect of bacterial vaginosis,
Lactobacillus and Premarin estrogen
replacement therapy on vaginal gene
expression changes. Microbes Infect, 2008.
10(6): 620–7.
46. Laughton JM, Devillard E, Heinrichs DE,
Reid G, and McCormick JK, Inhibition of
expression of a staphylococcal superantigen-
like protein by a soluble factor from
Lactobacillus reuteri. Microbiology, 2006.
152(Pt 4): 1155–67.
 Probiotics for the prophylaxis of uncomplicated recurrent urinary tract infections | 4.5 |

47. Medellin-Pena MJ, Wang H, Johnson R,
Anand S, and Griffiths MW, Probiotics
affect virulence-related gene expression in
Escherichia coli O157:H7. Appl Environ
Microbiol, 2007. 73(13): 4259–67.
48. Alakomi HL, Skytta E, Saarela M,
Mattila-Sandholm T, Latva-Kala K, and
Helander IM, Lactic acid permeabilizes
gram-negative bacteria by disrupting the
outer membrane. Appl Environ Microbiol,
2000. 66(5): 2001–5.
49. Gupta V, Yadav A, and Joshi RM, Antibiotic
resistance pattern in uropathogens. Indian
J Med Microbiol, 2002. 20(2): 96–8.

287
|4.6|
Prevention of prematurity by
early diagnosis and treatment of
bacterial urogenital infections – The
role of bacterial vaginosis
Udo B. Hoyme
Professor and Head of the Department of Gyecology and Obstetrics, HELIOS Hospital Erfurt Ltd.
Nordhäuser Strasse 74, D-99084 Erfurt, Germany
Tel +49-361-781.4001, Fax +49-61-781.4002, E-mail: udo.hoyme@helios-kliniken.de; hoymej@aol.com
ABSTRACT
Bacterial vaginosis has a significant rela-
tive risk for miscarriage or prematurity
of 1.4–6.9%. In the initial Erfurt trial
0.3% of the neonates with gestational age
< 32 + 0 weeks were seen in an interven-
tion group vs. 3.3% (p < .01) in the con-
trol group; in the Thuringia campaign
the figures were 0.94% vs. 1.36% (p < .01)
for the entire state. The rate of newborns
< 1000 g was reduced to 0.38%, the lowest
incidence ever seen in any of the German
states in the past.
The Erfurt and Thuringia programmes
represent a preventional prospective,
controlled study. This should count even
more, as there was no success in reducing
the rate of underweight children either
on federal state or national levels in the
decades preceding the study. However,
following discontinuation of the cam-
paign the prematurity rates in Thuringia
(monitored until 2005) returned to rates
as high as prior to our state-wide pro-
gramme in general, as well as for our hos-
pital in particular.
Now, following correction, detailed
analysis and extensive discussion of the
data, a model trial of four health insur-
ance providers in five German states
was initiated, aimed at scientific evalu-
ation as well as cost-benefit analysis.
The preliminary new data and calcula-
tions also signal substantial savings as
well as implementation of new simpli-
fied pH-measurement techniques and
tools.
 Prevention of prematurity by early diagnosis
Prevention of prematurity by screen-
ing, diagnosis and therapy of genital
infections is without any doubt a step for
optimising and rationalising the health
care system. Also the extraordinary non-
commensurable strain on all parties
involved could be reduced in a most ben-
eficial way. Similar developments take
place abroad: the described innovative pH
measurement regime has been introduced
in more than 20 countries so far.
Key words: bacterial vaginosis, pre-
vention of prematurity, intravaginal
pH-screening
SUMMARY OF RECOMMENDATIONS
1. Routine screening for N. gonorrhoeae,
C. trachomatis and bacterial vagino-
sis is indicated in defined populations
because of infection associated mis-
carriage and preterm birth as well as
postpartum complications (GoR B).
2. The intravaginal pH self-measure-
ment as a screening procedure fol-
lowed by antimicrobial therapy in the
case of bacterial vaginosis is a signifi-
cant step in reduction of prematurity
(GoR B).
1. INTRODUCTION
Ectopic pregnancy, spontaneous abortion
and stillbirth, prematurity, congenital and
perinatal infections as well as puerperal
maternal infections represent outcomes
of pregnancy in which bacterial (sexu-
ally transmitted) infectious agents play
an important etiologic role, especially in
pregnant adolescents and young adults
compared to older pregnant women, who
are more likely to be involved in a stable
monogamous relationship [1]. The preva-
lence of bacterial sexually transmitted
infections (STI), such as with Chlamydia
trachomatis and Neisseria gonorrhoeae is
in general highest among women younger
| 4.6 |
than 25 years; Mycoplasma genitalium,
leptotrichia, and other still uncultivable
organisms may prove to be important in
the future.
The anatomy and physiology of the
urogenital tract change dramatically
during pregnancy: the glycogen content
of the urethral and vaginal epithelium
increases, the intravaginal pH decreases,
the columnar epithelium of the cervix
hypertrophies and is exposed to changed
local microbial flora and/or infection. This
leads to an increasing risk of urinary
tract infections as well as chorioamnio-
nitis and amniotic fluid infection during
the course of pregnancy and the following
delivery [2–4].
Since C. trachomatis, N. gonorrhoeae,
and bacterial vaginosis (BV) have been
associated with an increased risk of
febrile morbidity after surgical abor-
tion, routine screening is indicated prior
to the procedure in most populations
[5–6], but also considered in general for
pregnancy [1, 7–8]. Pregnancy loss and
preterm birth comprise the spectrum of
adverse pregnancy outcomes following
urogenital infections. BV in particular has
increasingly been recognized as a cause
of prematurity all over the world, e. g. in
Germany, Austria, Brazil, Greece, Sweden,
Denmark, the US, Iran, Korea [8–16].
2. METHODS
A systematic literature search was per-
formed in PubMed beginning in 2004
with the following key words: prevention
of prematurity, intravaginal pH-measure-
ment, genital infections, and the following
limitations: English abstract available,
non-systemic infection.
A total of 110 publications were iden-
tified, which were screened by title and
abstract. After exclusion of duplicates a
total of eight were included in the analy-
sis, supplemented by 27 citations known
to the author. It has to be considered,
however, that prevention of prematurity
289
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
caused by infection is a fairly new emerg-
ing task. Therefore the literature is still
very limited.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [17–18].
3. THE CURRENT CHALLENGE
Children born prematurely in general,
and especially children with low birth
weight, run a high risk of health and
development problems. Despite this fact
and despite all interventional efforts pre-
maturity rates have remained unchanged
for years, e.g. at about 6–8% throughout
Germany. In contrast, both perinatal mor-
bidity and mortality have been reduced
significantly over the last years. With
the current high standard of neonatal
medicine a further improvement of those
results can only be expected if we suc-
ceed in reducing prematurity as the main
contributor to perinatal morbidity and
mortality [19]. Because of the preventive
character of all measures this is not only
a medical, but also a social-political task.
Table 1 Effect of 6 Weeks of Oral Tetracycline Given Prior to 32 Weeks on Outcome of Pregnancy in 279 Nonbacteriuric
Women (12).
Measurement Tetracycline (N = 148)
Mean gestation (weeks)
Mean birth weight (g)
Premature liveborn
Stillborn
PROM
Postpartum fever
Neonatal resuscitation
Respiratory distress
a
Nonsignificant.
290
4. DEFINITION OF THE DISEASE
Textbooks for obstetrics name a number
of factors as causes for prematurity. The
type in question here is (the more and
more preventable) infection-based pre-
maturity. Currently the quantitatively
relevant, adjustable and scientifically
proven causes of prematurity are gen-
eral infections of the urogenital tract, as
well as infections of the vagina and cer-
vix uteri, in particular in the latter those
caused by Chlamydia trachomatis (LoE
2a). As a logical consequence e.g. since
April 1, 1995 screening for Chlamydia in
pregnancy is obligatory in Germany [7]
(GoR B).
Intriguing data implicating bacterial
infectious agents in prematurity were
first derived from a study performed
more than 40 years ago [20] investigat-
ing the role of urinary tract infection
in prematurity in 279 nonbacteriuric
women allocated to treatment with six
weeks of oral tetracycline at 1g per day
(today considered contraindicated in
pregnancy) or with placebo prior to 32
weeks of gestation (Table 1). The results
showed that the tetracycline–treated
Placebo (N = 131) p
39.1 38.1 < 0.025
3277 3141 NSa
% %
5.4 15.2 < 0.025
1.4 0.8
10 13 NS
6 12 < 0.001
8 19 < 0.005
7 < 0.05
 Prevention of prematurity by early diagnosis
group had significantly longer gestations,
fewer preterm infants, fewer episodes
of postpartum fever, and fewer neona-
tal complications in comparison with the
placebo-treated group (LoE 1b). Despite
the limitations of the study this benefit
suggested the presence of unidentified
microorganisms in the urogenital tract
(C. trachomatis or BV-associated) that
could have contributed to prematurity in
the placebo group. This also raises the
possibility that other as-yet unidentified
organisms may be associated with infec-
tion and prematurity, since many bac-
teria produce phospholipases that may
directly damage the membranes or lead
to prostaglandin production [1, 21]. This
process cannot be reversed at a late stage
by antibiotics, so the best strategy is pre-
vention of these conditions by early detec-
tion and treatment of lower urogenital or
genital infection (GoR B).
Pregnant women should be screened for
urinary tract infection during pregnancy
as well as for C. trachomatis, possibly
N. gonorrhoeae, syphilis and also facul-
tatively T. vaginalis on their first prena-
tal visit and treated if positive (GoR B).
Screening should be repeated in high risk
groups [1, 7], however, most recommen-
dations for management and therapy in
pregnancy lack the support of scientifi-
cally performed prospectively randomized
studies due to methodical and ethical
reasons.
5. CLINICAL EVALUATION: STARTING
POINT OF A BROAD SCALE
PREMATURITY PREVENTIONAL
REGIME
Bacterial vaginosis, an anaerobic dys-
biosis, has a significant prevalence in
pregnancy of up to 20% and a rela-
tive risk for miscarriage or prematu-
rity of 1.4–6.9% (LoE 2a). An adequate
treatment regime, especially in the
early stages of pregnancy, can lead to
| 4.6 |
evident reduction of prematurity (GoR B)
[8, 22–24]. The unquestionable efficacy
of the concept which pregnant women
actively take part in has recently been
investigated in the prospective Erfurt
and Thuringia trials [8]: The objective of
these trials was to prove the efficacy of
vaginal pH screening during pregnancy,
carried out twice per week by the woman
herself, because gynecologists’ examina-
tions in the alleged intervals (e.g. every
four weeks during early pregnancy) are
not considered to be sufficient. It was not
intended to investigate the well-studied
impact of bacterial vaginosis on prematu-
rity, to collect new epidemiological data,
to reassess diagnostic measures or to
compare different treatment regimes.
Briefly, the patients were recruited
into the program with the help of a sim-
ple explanatory leaflet at the end of
their 12th week of pregnancy. Patients
received examination gloves (CarePlan®
VpH, Selfcare, then Inverness GmbH,
Munich, now Unipath Diagnostics GmbH,
Cologne) and a simple documentation
sheet. Each patient was asked to consult
her gynaecologist immediately when risk
indicators or symptoms relevant for pre-
maturity occurred, especially when she
found an elevated pH value ≥ 4.7. The
sensitivity of a pH ≥ 4.7 with respect to
bacterial vaginosis is 97%; a pH value
≥ 4.7 is only 67 % specific and not sensi-
tive for other infections [25].
During any unscheduled consulta-
tion due to above mentioned indications
and after pH control, odour test and wet
mount microscopy, the gynaecologist had
to decide if the elevated pH was attribut-
able to:
- a physiological condition
- pH elevation without evident affection
or pathogen present
- bacterial vaginosis or
- a result indicating hospital assign-
ment, such as rupture of the
membranes.
291
Chapter |4| Prevention of recurrent urogenital tract infections in adult women

Accordingly, following the gynaecologic
assessment, the patient was assigned to:
- no therapy
- a therapy recommendation for a
preparation containing lactoba-
cilli (in the Erfurt and Thuringia
trial Gynoflor®, Nourypharma,
Oberschleißheim) i. vag.
- a treatment recommendation for
clindamycin cream (Sobelin-Creme®,
Pharmacia & Upjohn, Erlangen)
i. vag., or
- hospital assignment.
6. RISK ASSESSMENT AND
REDUCTION
381 women participated in this pilot
screening and treatment programme
[8]; 2341 women did not participate, and
served as a control group. An early prema-
turity rate of 0.3% amongst participants
was observed, compared to a 2.2% rate
amongst women who did not participate,
but whose physicians were informed of and
taking part in the programme and a 4.1%
rate in a group of pregnant women who
received only conventional prenatal care
(Table 2). Compliance with the test glove
and with the testing regime was rated as
outstanding by all parties involved. Many
women emphasized the value of the indi-
viduality of the self-precaution and as
result the change from being the object of
care during pregnancy to the subject.
Another six month trial was conducted
in the federal state of Thuringia start-
ing March 1, 2000. The objective of the
trial was to involve all pregnant women
throughout the federal state (about
16,000 per year) for a defined period of
time with the help of office based gynae-
cologists and to achieve a measureable
decrease in prematurity rates in the
annual perinatal state inquiry which had
previously been reported stable between
1992 and 1999 [8].
The method was to send office based
gynaecologists test glove kits (total 3833)
free of charge. Women who were at least
12 + 0 weeks pregnant were recruited
for the campaign. Due to the presumed
efficacy of the action it was hypotheti-
cally expected that there would be a
significant decrease in the prematu-
rity rate. Treatment with lactobacillae
or antibiotics was suggested, but was at
the discretion of the treating physician.
Acidification of the vagina with acid-
containing pharmaceutical preparations
was excluded however, because of the
lack of scientific evidence supporting this
treatment.
The evaluation of the perinatal inquiry
for the year 2000 in Thuringia (16.276
births) gave a clear result: the total
number of early premature births was
less in the 2nd half of the year accord-
ing to the initially formulated hypothesis
(Figure 1a). Similar results were obtained
when comparing the birth weights
(Figure 1b).

Table 2 Prematurity Prevention Campaign 1998: Delivery (controlled for gestational age) at the OB-Department Erfurt
(n = 2722).

Participants Controls A
(pH self (pH measured by Controls B
Delivery measurement) physician) (no measurement)
(gestational age) (n = 381) (n = 1001) (n = 1340)

> 37 + 0 91.9 % 90.7 % 85.4 %

32 + 0/36 + 6 7.9 % 7.1 % 10.4 %

< 32 + 0 0.3 % 2.2 % 4.1 %

292
 Prevention of prematurity by early diagnosis | 4.6 |

% % 6,92
9 8,5 7
8,19 1st 6 months 6,01
8 2nd 6 months
6
7
1st 6 months 5
6
2nd 6 months
5 4 Thuringia
4 Perintal Inquiry
3 2,67
3 Thuringia 2,04
1,58
2 0,99*** Perinatal Inquiry 2 1,29
1 0,97
1 0,61
0,38
0
� 32 � 0 week � 37 � 0 week ***p � .001 0
Weight in g < 1000 < 1500 < 2000 < 2500
p-value < .05 < .05 < .005 < .01
Figure 1a Thuringia Prematurity Prevention Campaign 2000
Distribution of Prematurity (n = 16,276; January-June: 7870; Figure 1b Thuringia Prematurity Prevention Campaign 2000
July-December: 8406). Distribution of Birth Weights 2000 (n = 16,582; January-June:
8148; July-December: 8434).

%
A detailed analysis of participants 79,7
80
reporting back (n = 607) vs. controls
70 65,6
(1. half year 2000, n = 7870)* revealed a
reduction in: 60
with
50 without
• prematurity < 32 + 0 wks. (0.3 % vs. PROM
40 34,4
1.58 %; p < .05)
30
• prematurity < 37 + 0 wks. (5.3 % vs. 20,2* Thuringia Perinatal Inquiry
20
8.5 %; p < .01)
10
• the incidence of newborns < 2500 g 0
(3.45 % vs. 6.92 %; p < .001). 1st 6 months 2nd 6 months p* , 0.05
(n 5 125) (n 5 84)
These data allow the conclusion that
with this strategy, even if only < 50% of Figure 2 Prematurity Prevention Campaign 2000: Share
of Premature Rupture Thuringia of Membranes for Early
pregnant women participated in a wider Prematurity (< 32 + 0 weeks).
territory, the number of early premature
births would be significantly reduced. have been scientifically studied to a great
One possible explanation for the suc- extent with regard to their quantitative
cess of this programme was that whereas and qualitative consequences, amongst
more than one third of early premature which the release of bacterial proteases,
births were connected with early rupture the release of phospholiphase A2 from
of membranes during the first half of the membranes, lysosomes and bacteria
year, this was only the case in one in five (Bacteroides and Prevotella spp.), and
during the second half (Figure 2). the resulting synthesis of prostagland-
ines can be relevant (LoE 2a). Another
7. DISCUSSION OF TREATMENT factor is the direct effect of bacterial
endotoxin as well as macrophage activa-
tion with the release of cytokines [24, 26].
The list of risk factors for prematurity
Furthermore, there are indications that
is lengthy. The majority of these fac-
fetal cytokines alone can trigger birth; in
tors are difficult to influence. Cervical
this situation without maternal reaction
and vaginal conditions are factors which
to infection, labour can be induced, which
* Hübner, J., VII. Meeting European Society for Infectious Diseases in
is lifesaving for both mother and child
OB/GYN (ESIDOG), 13.06.2003, Erfurt (LoE 2b) [21].

293
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
Bacterial vaginosis as dysbiosis rsp.
dysbalance with an increase in vagi-
nal anaerobic bacteria concentrations
by 1000-fold is without doubt a risk for
prematurity. The large American VIP
trial (in which enrolment was later in
the course of pregnancy) found a relative
rate of 1.6 and therefore as high as for
Chlamydia infections or similar to tri-
chomoniasis at 1.7 (LoE 2a) [22]. Aerobic
types of colpitis with an increase of the
pH value [27] as well as intra- and extra-
amnial infections with enteropharyngeal
pathogens are also thought to contribute
towards prematurity (LoE 2b) [28–29].
In the majority of trials concerning preg-
nancy, bacterial vaginosis has been suc-
cessfully treated with Clindamycin rsp. or
alternatively with Metronidazole [30–32].
Even when labour was already established
a significant prolongation of pregnancy
could be demonstrated in controlled trials
(LoE 1b) [26]. Dennemark et al. [33] were
able to show that by early intervention
either with lactobacillus preparations or
preferably with intravaginal Clindamycin
treatment a distinct reduction of prematu-
rity could be obtained (LoE 2a). In princi-
ple lactobacillus preparations cannot yet
be considered a scientifically proven rsp.
causal therapy, but the main objective of
treatment in both the Dennemark and the
Erfurt/Thuringia investigations was the
prolongation of pregnancy.
8. PRINCIPLES OF MANAGEMENT
The Erfurt and Thuringia programmes
represent for the first time a prospective,
controlled study. The main benefit is that
because of the active involvement of the
pregnant women pH changes could be
recognised as early as possible and as a
consequence a huge part of the disorders
relevant for late miscarriage or prema-
ture birth could be addressed with an
immediate adequate therapy. The results
confirm the positive consequences of the
applied measures in a statistically sound
294
way. As the investigation was carried
out in a whole federal state, the posi-
tive results can be regarded as a definite
breakthrough with respect to the avail-
ability of a practicable and widespread
prevention of prematurity. The compari-
son with other federal states, i.e. Bavaria
or Saxonia, shows that when evaluat-
ing the quality indicator of birth weight,
that the higher rates of prematurity for
Thuringia in 1999 can be changed to
an unmistakable reduction during the
2nd half of 2000 (Figure 3). The results
achieved in Thuringia in 2000 are the
best ever seen in any of the German
states in the past. However, following
discontinuation of the campaign the pre-
maturity rates in Thuringia (monitored
until 2005) returned to rates are as high
as prior to our state-wide programme in
general, as well as for our hospital in par-
ticular (Table 3).
Prevention of prematurity by screen-
ing, diagnosis and therapy of genital
infections is without any doubt an impor-
tant step for optimising and rational-
ising the health care system (GoR B).
The concepts and results presented are
encouraging that an improvement of the
situation with simultaneous cost reduc-
tion is indeed possible.
9. FURTHER RESEARCH
The efficacy of the regime is supported
and established in several scientifically
performed prospective studies.
The data of 7731 participating preg-
nant women as well as 135,394 controls
are under evaluation at present [27].
In this study, initiated by four German
insurance companies, reduction of pre-
maturity will be investigated as well as
possible financial savings: preliminary
data indicate about 300 Euros per any
pregnancy regardless of outcome, so the
possible implementation of the procedure
in a guideline is under discussion by the
German health authorities.
 Prevention of prematurity by early diagnosis | 4.6 |

%
Bremen 0,92
Northrhine 0,69
Lower Saxonia 0,62
Bavaria 0,6
Westfalia 0,59
1999
Saxonia-Anhalt 0,58
Hessen (1st 6 months) 0,57
Thuringia 0,53
Saxonia 0,46
Brandenburg 0,39
0 1

Thuringia 1st 6 months 0,61

Perinatal Inquiry
Bavaria 0,6
of the Federal
Saxonia 0,44 States 2000
Thuringia 2nd 6 months 0,38

0 1

Figure 3 Thuringia Prematurity Preventation Campaign 2000 Birth Weights < 1000g Compared to other Federal States.

Table 3 Distribution of Birthweights (%) State of Thuringia 2000–2002.

Year 1999 I/2000 II/2000 2001 2002 2003 2004 2005

N 16233 8162 8458 16408 15995 15436 16058 15633

< 1000 g 0.54 0.61* 0.38 0.46 0.63*** 0.62** 0.60** 0.56**

< 1500 g 1.22** 1.29* 0.97 1.09 1.32** 1.17* 1.15* 1.30**

< 2000 g 2.67*** 2.67* 2.03 2.36** 2.62*** 2.74*** 2.34** 2.60***

< 2500 g 6.76*** 6.91** 5.99 6.64*** 6.72*** 6.80*** 6.35** 6.88***

< 1000 g Perinatal- 1.5 1.0 1.5 1.6 1.5 1.4 1.7
center Erfurt

* p < 0.05; ** p < 0.01; *** p < 0.001.

As further scientific proof for the regime
of pH-measurement by pregnant women
themselves, as well as worldwide applica-
bility, a prospectively randomized study
will be initiated at the University of Cairo.
10. CONCLUSIONS
The investigated concept of pH self-
measurement leads to an efficient reduc-
tion of prematurity and is at the same
time a simple means for optimising and
rationalising diagnosis as well as ther-
apy. The chance to reduce the extremely
costly complications associated with
prematurity with minimal expense
comes with the fact that the immeasur-
able extraordinary strain on all parties
involved can be reduced in a beneficial
way. Can we as physicians, health care
providers and politicians take the liberty
to ignore these encouraging prospects?

295
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
REFERENCES
1. Hitti J and Watts DH, Bacterial Sexually
Transmitted Infections in Pregnancy, in
Sexually transmitted diseases, Holmes
KK, Editor. 2008, McGraw-Hill, Medical:
New York. p. 1529–1561.
2. Singer A, The uterine cervix from ado-
lescence to the menopause. Br J Obstet
Gynaecol, 1975. 82(2): 81–99.
3. Arya OP, Mallinson H, and Goddard AD,
Epidemiological and clinical correlates
of chlamydial infection of the cervix. Br J
Vener Dis, 1981. 57(2): 118–24.
4. Goplerud CP, Ohm MJ, and Galask RP,
Aerobic and anaerobic flora of the cervix
during pregnancy and the puerperium. Am
J Obstet Gynecol, 1976. 126(7): 858–68.
5. Sorensen JL, Thranov I, Hoff G, and
Dirach J, Early- and late-onset of pelvic
inflammatory disease among women with
cervical Chlamydia trachomatis infection
at the time of induced abortion: A follow-up
study. Infection, 1994(22): 242–246.
6. Larsson PG, Platz-Christensen JJ, Thejls
H, Forsum U, and Pahlson C, Incidence
of pelvic inflammatory disease after first-
trimester legal abortion in women with
bacterial vaginosis after treatment with
metronidazole: a double-blind, rand-
omized study. Am J Obstet Gynecol, 1992.
166(1 Pt 1): 100–3.
7. Hoyme UB, [Prenatal guidelines and
Chlamydia screening]. Z Geburtshilfe
Neonatol, 1997. 201(4): 113–4.
8. Hoyme UB and Saling E, Efficient pre-
maturity prevention is possible by pH-self
measurement and immediate therapy of
threatening ascending infection. Eur J
Obstet Gynecol Reprod Biol, 2004. 115(2):
148–53.
9. Kiss H, Petricevic L, and Husslein P,
Prospective randomised controlled trial
of an infection screening programme to
reduce the rate of preterm delivery. BMJ,
2004. 329(7462): 371.
10. Camargo RP, Simoes JA, Cecatti JG,
Alves VM, and Faro S, Impact of treat-
ment for bacterial vaginosis on prematu-
rity among Brazilian pregnant women: a
retrospective cohort study. Sao Paulo Med
J, 2005. 123(3): 108–12.
296
11. Daskalakis G, Papapanagiotou A,
Mesogitis S, Papantoniou N, Mavromatis
K, and Antsaklis A, Bacterial vaginosis
and group B streptococcal colonization
and preterm delivery in a low-risk popula-
tion. Fetal Diagn Ther, 2006. 21(2): 172–6.
12. Larsson PG, Fahraeus L, Carlsson B,
Jakobsson T, and Forsum U, Late miscar-
riage and preterm birth after treatment
with clindamycin: a randomised consent
design study according to Zelen. BJOG,
2006. 113(6): 629–37.
13. Svare JA, Schmidt H, Hansen BB, and
Lose G, Bacterial vaginosis in a cohort
of Danish pregnant women: prevalence
and relationship with preterm delivery,
low birthweight and perinatal infections.
BJOG, 2006. 113(12): 1419–25.
14. Hendler I, Andrews WW, Carey CJ,
Klebanoff MA, Noble WD, Sibai BM, Hillier
SL, Dudley D, Ernest JM, Leveno KJ,
Wapner R, Iams JD, Varner M, Moawad
A, Miodovnik M, O’Sullivan MJ, and Van
Dorsten PJ, The relationship between reso-
lution of asymptomatic bacterial vaginosis
and spontaneous preterm birth in fetal
fibronectin-positive women. Am J Obstet
Gynecol, 2007. 197(5): 488 e1–5.
15. Nejad VM and Shafaie S, The association
of bacterial vaginosis and preterm labor. J
Pak Med Assoc, 2008. 58(3): 104–6.
16. Lee SE, Romero R, Kim EC, and Yoon
BH, A high Nugent score but not a posi-
tive culture for genital mycoplasmas is a
risk factor for spontaneous preterm birth.
J Matern Fetal Neonatal Med, 2009.
22(3): 212–7.
17. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
18. Abrams P, Khoury S, and Grant A,
Evidence–based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
19. Institute of Medicine, Preterm birth:
Causes, consequences and preven-
tion. 2006, Washington, DC: National
Academic.
20. Elder HA, Santamarina BA, Smith S, and
Kass EH, The natural history of asympto-
matic bacteriuria during pregnancy: the
 Prevention of prematurity by early diagnosis
effect of tetracycline on the clinical course
and the outcome of pregnancy. Am J Obstet
Gynecol, 1971. 111(3): 441–62.
21. Romero R, Gomez R, Ghezzi F, Yoon BH,
Mazor M, Edwin SS, and Berry SM, A
fetal systemic inflammatory response is
followed by the spontaneous onset of pre-
term parturition. Am J Obstet Gynecol,
1998. 179(1): 186–93.
22. Hillier SL, Nugent RP, Eschenbach DA,
Krohn MA, Gibbs RS, Martin DH, Cotch
MF, Edelman R, Pastorek JG, 2nd, Rao
AV, and et al., Association between bacte-
rial vaginosis and preterm delivery of
a low-birth-weight infant. The Vaginal
Infections and Prematurity Study Group.
N Engl J Med, 1995. 333(26): 1737–42.
23. Saling E, Fuhr N, Placht A, and
Schumacher E, [[Initial results of “preven-
tive self-care by pregnant patients” for pre-
vention of premature labor]. Arch Gynecol
Obstet, 1995. 257(1–4): 178–85.
24. Martius JAH, Über die Bedeutung
der Bakteriellen Vaginose und
anderer Urogenitalinfektionen
in der Schwangerschaft für die
Frühgeburtlichkeit und die mütterli-
che peripartale Infektmorbidität. 1986,
Universität Würzburg.
25. Eschenbach DA, Gravett MG, Hoyme UB,
and Holmes KK, An association with pre-
maturity and postpartum complication,
in Bacterial vaginosis. WHO workshop
on anaerobic curved rods and bacterial
vaginosis, Mardh PA and Taylor-Robinson
D, Editors. 1984, Almqvist & Wiksell:
Stockholm. p. 213–218.
26. McGregor JA, French JI, and Seo K,
Adjunctive clindamycin therapy for
| 4.6 |
preterm labor: results of a double-blind,
placebo-controlled trial. Am J Obstet
Gynecol, 1991. 165(4 Pt 1): 867–75.
27. Donders GGG, Bacterial vaginosis dur-
ing pregnancy: screen and treat? Europ J
Obst Gynecol Reprod Biol 1999(3): 1–4.
28. Hill GB, Preterm birth: associations with
genital and possibly oral microflora. Ann
Periodontol, 1998. 3(1): 222–32.
29. Viehweg B, Junghans U, Stepan H, Voigt
T, and Faber R, Der Nutzen vaginaler
pH-Messungen für die Erkennung poten-
tieller Frühgeburten. Zentralbl Gynäkol
1997(119): 33–37.
30. Andres FJ, Parker R, Hosein I, and
Benrubi GI, Clindamycin vaginal cream
versus oral metronidazole in the treat-
ment of bacterial vaginosis: a prospective
double-blind clinical trial. South Med J,
1992. 85(11): 1077–80.
31. Gorlero F, Macciavello S, Paccagnella
F, Ferraiolo A, Gianrosso G, de Gecco L,
and Schito GC, Clindamycin phosphate
vaginal cream - a local approach to the
treatment of bacterial vaginosis. Report
of the 3rd International Symposium on
Vaginitis/Vaginosis. Clin Commun (Oxf)
1994.
32. Hillier SL, Krohn MA, Watts H, Wolner-
Hanssen P, and DA E, Microbiologic effi-
cacy of intravaginal clindamycin cream
for the treatment of bacterial vaginosis.
Obstet Gynecol, 1990(76): 407–413.
33. Dennemark N, Meyer-Wilmes M, and R
S, Screening and treatment of bacterial
vaginosis in the early second trimester of
pregnancy: a sufficient measure for pre-
vention of preterm deliveries? . Intern J
STD AIDS 1997(8): 38–40.
297
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 Chapter |5|

Asymptomatic bacteriuria
Chair: Lindsay E. Nicolle

CHAPTER OUTLINE
5.1 Introduction – The evolution of asymptomatic bacteriuria 300
5.2 Asymptomatic bacteriuria – to treat or not to treat 303
5.3 Asymptomatic bacteriuria with the model strain
Escherichia coli 83972 protects against symptomatic
urinary tract infections 314
|5.1|
Introduction – The evolution of
asymptomatic bacteriuria
Lindsay E. Nicolle
Professor, Department of Internal Medicine and Department of Medical Microbiology, University of Manitoba Health
Sciences Centre, Room GG443 – 820 Sherbrook Street,Winnipeg, MB R3A 1R9
INTRODUCTION
Studies published in the 1950’s which
initially defined quantitative bacteriu-
ria as ≥ 105 cfu/ml described a substan-
tial number of men and women with
urine cultures which met this criteria
but had no symptoms attributable to the
genitourinary tract [1]. When these cri-
teria for quantitative urine culture were
applied in studies of pregnant women,
it was rapidly and repeatedly confirmed
that this “asymptomatic bacteriuria”, if
untreated, was associated with a substan-
tially increased risk of pyelonephritis and
premature delivery later in pregnancy [2].
In addition, histopathologic evidence of
“chronic pyelonephritis” in a high propor-
tion of individuals with end stage renal
failure who had no history of symptomatic
urinary tract infection was attributed to
“occult bacteriuria” [1]. The confluence of
these observations generated a paradigm
which saw asymptomatic bacteriuria as
a stealthy and dangerous condition with
substantial negative outcomes. In fact,
Kass, the father of the quantitative urine
culture, wrote in 1962, “… there is now
clear evidence that bacteriuria is one of
the commonest human infections, that
it may be chronic and persistent, that it
may influence structure and function out-
side of the urinary tract, and that it plays
an important role in disease from the cra-
dle to the grave – from prematurity to
hypertension and renal failure” [3].
This paradigm was soon questioned
[4]. Case control studies and long term
prospective cohort studies initiated in the
1960’s and continued for decades in both
school children and non-pregnant adult
women reported no negative outcomes
associated with initial or subsequent
asymptomatic bacteriuria. More recently,
prospective, randomized clinical trials
enrolling adult women, schoolgirls, long
term care facility residents, spinal cord
injured patients, and diabetic women con-
sistently document no benefits with treat-
ment of asymptomatic bacteriuria [2].
 Introduction – The evolution of asymptomatic bacteriuria
The observations in these populations are
distinctly different from those in preg-
nant women, in whom the benefits of
treatment of asymptomatic bacteriuria
have been repeatedly and consistently
documented. The histopathological diag-
nosis of “chronic pyelonephritis”, on the
other hand, is now recognized as an end
stage of many inflammatory renal dis-
eases, attributable to urinary infection
rarely, and only in individuals with a his-
tory of symptomatic infection [4].
The paradigm has now fully shifted.
Asymptomatic bacteriuria is recognized
as benign, and antimicrobial treatment
of asymptomatic bacteriuria is discour-
aged [2]. These recommendations are
irrespective of the presence of pyuria,
which is a common accompaniment of
asymptomatic bacteriuria. The exception,
of course, remains pregnant women who
must be screened for bacteriuria early in
pregnancy and treated if positive. In addi-
tion, individuals who will undergo inva-
sive genitourinary procedures likely to be
associated with mucosal bleeding should
receive perioperative antimicrobial proph-
ylaxis to prevent bacteremia and sep-
sis complicating the procedure. Further
clinical trials are needed for some unique
populations such as immunocompromised
patients with solid organ or bone marrow
transplants and neutropenic patients, as
there is insufficient evidence addressing
outcomes in these groups.
It is now accepted that asymptomatic
bacteriuria is not harmful for most
patients, but we are moving beyond this
concept. Several studies suggest that
asymptomatic bacteriuria may be bene-
ficial. In school girls, healthy women,
diabetic women and spinal cord injured
patients, antimicrobial treatment given
for asymptomatic bacteriuria or other
infections is followed in the short term
by an increased risk for symptomatic uri-
nary infection [5–6]. One hypothesis to
explain this observation for adult women
is that antimicrobial use disrupts normal
vaginal flora, facilitating colonization
| 5.1 |
with potential uropathogens, which pre-
ceeds symptomatic urinary infection [6].
However, this explanation does not seem
likely to explain observations in children
or subjects with complicated urinary
tract infection. An alternate hypothesis
is that persistent asymptomatic bacte-
riuria with organisms of low virulence
prevents other, more virulent, organisms
from gaining access to the urinary tract
and establishing symptomatic infection.
Potential mechanisms for this would
include limiting access to uroepithelial
receptors or nutrients in the urine, or
production of inhibiting molecules. This
is “bacterial interference” [5].
The next conceptual shift to con-
sider is whether inducing asymptomatic
bacteriuria is therapeutic for persons
with recurrent urinary tract infections.
This approach is described in the paper
by Wullt and Sunden, together with
the status of clinical trials evaluating
this intervention. In selected patients
with complicated urinary infection and
impaired bladder emptying preliminary
clinical studies report that establishing
persistent asymptomatic bacteriuria with
the avirulent E. coli 83972 strain protects
the patient from symptomatic episodes
[7–8]. Thus, this approach seems attrac-
tive for some patients with recurrent
infection. Wullt et al have now completed
a randomized, cross-over trial which
should clarify potential efficacy and refine
some aspects of this approach; the results
from this trial will be of great interest.
The hurdles in development of this strat-
egy, however, are the relatively small
number of patients in whom prolonged
bacteriuria can be established, and con-
vincing patients and regulators that an
“avirulent” strain is safe.
Our perspective of asymptomatic bac-
teriuria, then, has shifted from one pole,
where bacteriuria was considered to be
uniformly harmful, to a neutral posi-
tion. If “bacterial interference” proves
to be safe and effective in comparative
clinical trials, opinion may shift further
301
Chapter |5| Asymptomatic bacteriuria
towards the completely opposite pole –
that asymptomatic bacteriuria is benefi-
cial. “Bacterial interference” is a further
step towards unveiling the many faces of
asymptomatic bacteriuria, a journey that
started 50 years ago.
REFERENCES
1. Kass EH, Asymptomatic infections of the
urinary tract. Trans Assoc Am Physicians,
1956. 69: 56–64.
2. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
3. Kass EH, Pyelonephritis and bacteriuria.
A major problem in preventive medicine.
Ann Intern Med, 1962. 56: 46–53.
4. Gleckman R, The controversy of treat-
ment of asymptomatic bacteriuria in
non-pregnant women – resolved. J Urol,
1976. 116(6): 776–7.
302
5. Sunden F, Hakansson L, Ljunggren E,
and Wullt B, Bacterial interference – is
deliberate colonization with Escherichia
coli 83972 an alternative treatment for
patients with recurrent urinary tract
infection? Int J Antimicrob Agents, 2006.
28 Suppl 1: S26–9.
6. Smith HS, Hughes JP, Hooton TM,
Roberts P, Scholes D, Stergachis A,
Stapleton A, and Stamm WE,
Antecedent antimicrobial use increases
the risk of uncomplicated cystitis in
young women. Clin Infect Dis, 1997.
25(1): 63–8.
7. Wullt B, Connell H, Rollano P, Mansson W,
Colleen S, and Svanborg C, Urodynamic
factors influence the duration of
Escherichia coli bacteriuria in deliber-
ately colonized cases. J Urol, 1998. 159(6):
2057–62.
8. Prasad A, Cevallos ME, Riosa S,
Darouiche RO, and Trautner BW, A bacte-
rial interference strategy for prevention
of UTI in persons practicing intermittent
catheterization. Spinal Cord, 2009. 47(7):
565–9.
|5.2|

Asymptomatic bacteriuria – to
treat or not to treat
Lindsay E. Nicolle
Professor, Department of Internal Medicine and Medical Microbiology, University of Manitoba,
Health Sciences Centre, Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9
Tel: (204) 787-7029, Fax: (204) 787-4826, e-mail: lnicolle@hsc.mb.ca

ABSTRACT evaluation to describe the natural history

Asymptomatic bacteriuria is common.
Among healthy adults, bacteriuria
increases with increasing age, and occurs
more frequently in women than men.
Individuals with underlying genitourinary
abnormalities such as patients with spinal
cord injuries or with indwelling catheters
also have a very high prevalence of bacte-
riuria. Bacteriuria in most populations is
benign. It has been shown to have adverse
outcomes in pregnant women, where it is
associated with pyelonephritis and pre-
mature birth, and in patients undergoing
traumatic genitourinary procedures asso-
ciated with mucosal bleeding, where there
is a high risk of bacteremia and sepsis.
In other populations, clinical trials have
consistently shown no benefits of screen-
ing for or treatment of asymptomatic bac-
teriuria. For some immunocompromised
persons, such as those with neutrope-
nia or renal transplant patients, further
and impact of bacteriuria is required.
Key words: asymptomatic, bacteriuria,
urinary infection
SUMMARY OF RECOMMENDATIONS
Diagnosis:
1. For women, the quantitative count of
≥ 105 cfu/ml of an organism in a voided
urine specimen identifies bacteriuria
[1] (GoR B).
2. For men, a culture from a voided urine
specimen with a quantitative count
≥ 105 cfu/ml identifies bacteriuria [2]
(GoR B).
2.1 For men with specimens collected
using an external condom cath-
eter ≥ 105 cfu/ml is the appropri-
ate quantitative criteria [3–4]
(GoR B).
Chapter |5| Asymptomatic bacteriuria
3. For patients with indwelling urethral
catheters a quantitative count of ≥ 105
cfu/ml identifies bacteriuria (GoR B).
3.1 For a urine specimen collected by in
and out catheter, a quantitative
count of ≥ 102 cfu/ml is consistent
with bacteriuria [1] (GoR B).
4. Pyuria in the absence of signs or
symptoms in a person with bacteriuria
should not be interpreted as sympto-
matic infection or as an indication for
antimicrobial therapy [1] (GoR B)
5. Screening for and treatment of
asymptomatic bacteriuria is recom-
mended for:
5.1 Pregnant women [1] (GoR A)
5.2 Prior to an invasive genitourinary
procedure where there is a risk of
mucosal bleeding [5–9] (GoR A).
6. Screening for or treatment of asymp-
tomatic bacteriuria is not recom-
mended for:
6.1 Premenopausal, non-pregnant
women [10] (GoR A)
6.2 Post-menopausal women [10]
(GoR A)
6.3 Diabetic women [11] (GoR A)
6.4 Healthy men [12] (GoR B)
6.5 Residents of long term care facili-
ties [13] (GoR A)
6.6 Patients with an indwelling ure-
thral catheter [1, 14–15] (GoR A)
6.7 Patients with nephrostomy tubes
or ureteric stents (GoR C)
6.8 Spinal cord injured patients
[16–19] (GoR B)
6.9 Patients with candiduria [20–21]
(GoR A)
7. Screening for or treatment of asymp-
tomatic bacteriuria in renal trans-
plant patients beyond the first 6
months is not recommended (GoR B).
8. No recommendation can be made with
respect to screening for or treatment
of bacteriuria in patients with neutro-
penia (GoR D).
304
1. INTRODUCTION
This chapter addresses the diagno-
sis and management of asymptomatic
bacteriuria in adult women and men.
Asymptomatic bacteriuria in pregnant
women and children is addressed in
other chapters, and will not be discussed
in detail here.
2. METHODS
This document incorporates and
updates the 2005 Infectious Diseases
Society of America Guideline for the
management of asymptomatic bacte-
riuria [1]. The update used a system-
atic literature search performed in
Medline, Cochrane, and Embase. Key
words included bacteriuria and asymp-
tomatic urinary infection. The limita-
tions used included adult with age over
18 years, clinical studies, English and
peer reviewed. A total of 100 publica-
tions were identified, and screened by
title and abstract. Eleven papers were
included in the review. The information
identified through the literature review
was supplemented by citations in pub-
lished reports as well as other papers
identified by the author.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[22–23].
3. DEFINITION OF THE DISEASE
Asymptomatic bacteriuria is the micro-
biologic diagnosis of urinary tract infec-
tion with isolation of bacteria from urine
specimens in appropriate quantitative
counts together with the absence of clini-
cal signs or symptoms referable to the
genitourinary tract.
 Asymptomatic bacteriuria – to treat or not to treat
4. EPIDEMIOLOGY
Asymptomatic bacteriuria is common in
women of all age groups, and increases
with increasing age (Table 1) [1].
Asymptomatic bacteriuria is uncom-
mon in younger men, but increases in
otherwise healthy older men over 65
years, likely attributable to prostatic
hypertrophy. A recent population-based
study of women and men over 80 years
in the community in a Swedish health
region reported a prevalence of 20% in
women and 5–10% in men in three sur-
veys repeated over 18 months [28].
Bacteriuria is very common in residents
of nursing homes, with 25–50% of women
and 15–40% of men having positive urine
cultures at any time [13]. Populations
with functional or structural abnormali-
ties of the genitourinary tract who are
at risk for complicated urinary tract
Table 1 Prevalence of asymptomatic bacteriuria in selected populations.
Women [1]:
premenopausal
55–75 years
≥ 70 years [2]
long-term care facility [13]
diabetic women
Men [13]:
≥ 70 years
long term care facility
Indwelling urinary devices
chronic indwelling catheter [24]
short-term indwelling catheter [24]
ileal neobladder [25]
Spinal cord injured [26–27]
sphincterotomy
intermittent catheterization
external condom catheter
| 5.2 |
infection also may have a high preva-
lence of bacteriuria. Spinal cord injured
patients have a prevalence of bacteriuria
of 50%, irrespective of voiding method
used [1]. Persons with long term (over 30
days) indwelling urethral catheters have
a prevalence of bacteriuria of 100%, while
short term indwelling catheters are asso-
ciated with acquisition of bacteriuria at
the rate of 3–7% per day [24]. Other uro-
logic devices such as nephrostomy tubes
or ureteric stents are also associated with
a high prevalence of bacteriuria while
they remain in situ.
5. RISK FACTORS
For pre-menopausal women, risk factors
for asymptomatic bacteriuria are the same
genetic and behavioral determinants asso-
ciated with recurrent acute uncomplicated
urinary infection [29]. The most important
Prevalence of bacteriuria
5–10%
10–20%
15–20%
25–50%
5–10%
5–10%
15–40%
100%
3–7%/day
57%
50%
50%
50%
305
Chapter |5| Asymptomatic bacteriuria
behavioral determinants are sexual inter-
course and use of spermicides for birth
control. For postmenopausal women, the
strongest associations are genetic, includ-
ing prior history of urinary tract infection
and being a nonsecretor of the blood group
substance [30–31].
Consistent alterations observed in the
vaginal flora following menopause are
loss of the predominant lactobacillus flora
which maintains the vaginal acid pH
with replacement by organisms such as
Escherichia coli or group B streptococci
[32]. This change is attributed to loss of
an estrogen effect; systemic or topical
estrogen therapy re-establishes the lacto-
bacilli and an acid vaginal pH. Thus, it
has been suggested that estrogen defi-
ciency contributes to the aging-associated
increase in bacteriuria. However, results
of clinical trials are conflicting. One pro-
spective, randomized trial reported topical
estrogen therapy decreased asymptomatic
as well as symptomatic infection in older
women in both the community and long
term care facilitates [33]. However,
another prospective, placebo controlled
study reported no decrease in asympto-
matic bacteriuria with systemic estrogen
replacement in women in a nursing home,
despite a decrease in vaginal pH [34].
An increased post-void residual vol-
ume has also been suggested to con-
tribute to the observed increase in
bacteriuria with age. However, clinical
studies in both noninstitutionalized [31]
and institutionalized [35] older popu-
lations report no independent associa-
tion of post-void residual volume with
bacteriuria in older men or women.
Incontinence is a consistent association
of asymptomatic bacteriuria in women,
but is unlikely causative [1, 13]. This
association reflects voiding impairment
which facilitates both incontinence and
bacteriuria.
In the long term care facility popu-
lation, bacteriuria is more common in
the most functionally impaired – those
with incontinence of bladder or bowel,
306
or dementia [13]. It is assumed the high
prevalence of bacteriuria is attributable
to voiding impairment associated with
chronic neurologic diseases. The very
high prevalence of bacteriuria observed
in some populations with functional or
structural genitourinary abnormalities is
also attributed to impaired voiding or to
persistence of bacteria in biofilm on ind-
welling devices in the genitourinary tract
(e.g. catheters, stents, and nephrostomy
tubes).
6. MORBIDITY AND MORTALITY
Asymptomatic bacteriuria may be harm-
ful for pregnant women, as discussed
more fully in an alternate chapter [1].
Persons with bacteriuria are also at risk
for bacteremia and sepsis when traumatic
genitourinary procedures are performed
[1]. In other populations, no harms have
been associated with asymptomatic
bacteriuria.
An individual identified with asymp-
tomatic bacteriuria is at increased risk
of subsequent symptomatic urinary tract
infection [1]. However, the asymptomatic
bacteriuria is likely not causative. This
suggests that the biologic determinants of
asymptomatic and symptomatic urinary
infection are similar. In healthy young
women a 8% risk of developing sympto-
matic urinary infection within one week
of new acquisition of bacteriuria was
reported [29]. Thus a brief period of bac-
teriuria may immediately precede some
symptomatic episodes in these women.
However, persistent asymptomatic bac-
teriuria does not precede symptomatic
infection with the same organism in the
absence of contributing factors such as
obstruction or genitourinary trauma. In
fact, asymptomatic bacteriuria in some
patients has been associated with a
decreased risk for symptomatic infection,
perhaps due to bacterial interference pre-
venting other organisms from establish-
ing infection within the bladder [36].
 Asymptomatic bacteriuria – to treat or not to treat
Table 2 Studies of asymptomatic bacteriuria and mortality.
Population (ref) Subjects
Greece, older women and 342
men institutionalized [37]
Wales and Jamaica women 1530
15 – 84 yr. [38]
Sweden, men and women >70 2010
years [39]
Finland, men and women >85 561
years [40]
US, women, >80 yr. [41] 1491
Canada, men mean age 91
78 years, institutionalized [42]
Swedish, random population 1462
based, women [43]
Asymptomatic bacteriuria is not asso-
ciated with increased mortality (Table 2)
[37–43]. Some early studies reported
decreased survival associated with
asymptomatic bacteriuria, but did not
adjust for comorbidity or functional sta-
tus, both of which are independently
associated with both bacteriuria and
increased mortality [37–38]. In elderly
populations asymptomatic bacteriuria is
correlated with impaired functional sta-
tus, which is itself an independent risk
factor for mortality [44]. Subsequent
studies in community and institutional-
ized populations which have adjusted for
this potential bias have not reported an
association of asymptomatic bacteriuria
with mortality (Table 2) [38–43].
7. MICROBIOLOGY
The most common organism isolated from
asymptomatic bacteriuria in women is
Escherichia coli [1]. This is also the spe-
cies most often isolated when prolonged
bacteriuria with the same organism
occurs [45–46]. A prospective study in
young women reported no differences in
| 5.2 |
Follow-up Mortality
10 years Significantly shorter survival for bacteriuric men or
women.
13 years RR 1.5 (0.96, 2.32) adjusted for age only
9 years Similar mortality with and without asymptomatic
bacteriuria, with stratification for risk factors.
5 years Bacteriuria had no prognostic significance for
mortality
10 years Multivariate: observational RR 1.1 clinical trial RR
0.92 (0.57, 1.47)
6 years No association of bacteriuria with mortality; OR at
5 years 1.2 (0.38, 3.9)
24 years No difference in mortality ASB vs not: 95% CI RR:
(0.74 – 2.52)
virulence characteristics between E. coli
strains isolated from asymptomatic or
symptomatic infection [29]. However,
other studies have reported strains of
E. coli isolated from women with asymp-
tomatic bacteriuria are characterized by
a lower prevalence of potential virulence
factors than strains from symptomatic
infection [47]. Gram-positive organisms,
including group B streptococcus, entero-
coccus species, and coagulase negative
staphylococci other than Staphylococcus
saprophyticus, are isolated more fre-
quently from women with bacteriuria
than symptomatic infection.
For men with asymptomatic bacte-
riuria the most common infecting organ-
isms are E. coli, Enterococcus spp and
coagulase negative staphylococci [48].
Bacteriuric men or women with urologic
abnormalities generally have a broader
spectrum of bacterial species or yeast
isolated. While E. coli may remain the
single most common organism, particu-
larly in women, the repeated courses
of antimicrobial therapy and urologic
interventions in health care settings
lead to isolation of more resistant organ-
isms such as Pseudomonas aeruginosa,
307
Chapter |5| Asymptomatic bacteriuria
Citrobacter species, and urease produc-
ing organisms such as Proteus mirabilis
and Providencia stuartii.
8. CLINICAL EVALUATION/DIAGNOSIS
8.1 Microbiologic criteria
The criteria for diagnosing asympto-
matic bacteriuria in women is two con-
secutive specimens with ≥ 105 cfu/ml of
an organism isolated (LoE 2a). This was
determined in initial studies evaluating
the quantitative urine culture, but the
specific timing of the second urine speci-
men was not specified [1]. About 10–15%
of initially bacteriuric women will have
a negative urine culture on repeat test-
ing. The failure to isolate bacteriuria
on the second specimen may reflect con-
tamination of the first specimen, but in
younger women in particular, transient
bacteriuria is common [11, 28–29]. Thus,
the longer the period of time between the
first and second urine specimen being
obtained, the more likely the second spec-
imen will be negative because of sponta-
neous resolution of bacteriuria. For men,
a single voided specimen with ≥ 105 cfu/
ml is sufficient to identify bacteriuria [2]
(LoE 2a). If a specimen is collected using
an external condom catheter, the appro-
priate criteria is ≥ 105 cfu/ml [3–4] (LoE
2a). For specimens collected by aspira-
tion of an indwelling catheter, ≥ 105 cfu/
ml is required to identify bacteriuria
(LoE 2b).
8.2 Pyuria
In younger populations, approximately
50% of women with asymptomatic bacte-
riuria have accompanying pyuria (1). In
older women and men, and in patients
with underlying genitourinary abnormal-
ities, pyuria is present in over 90% of per-
sons with asymptomatic bacteriuria [13,
24]. Thus pyuria does not discriminate
between symptomatic or asymptomatic
infection.
308
9. TREATMENT
9.1 Premenopausal women
Antimicrobial treatment of bacteriuria in
premenopausal women may decrease the
short term prevalence of asymptomatic
bacteriuria, but does not decrease the inci-
dence of subsequent symptomatic episodes
[1, 10]. Long term prospective cohort stud-
ies continuing for several decades have not
reported different outcomes for women ini-
tially stratified as bacteriuric or not bac-
teriuric [16, 49–51]. In fact, antimicrobial
treatment of asymptomatic bacteriuria
may be associated with an increased risk
for symptomatic infection immediately
post therapy [52]. This may be explained
by vaginal flora changes attributed to
antimicrobial therapy, but an alternate
explanation may be loss of bacterial inter-
ference when bacteriuria is disrupted by
antimicrobial therapy. Thus, asympto-
matic premenopausal women with bacte-
riuria should not be treated (LoE 1a).
9.2 Post menopausal women
Prospective, randomized comparative tri-
als [10] and prospective cohort studies
[37, 49–51] of asymptomatic bacteriuria
in healthy post-menopausal women have
not identified benefits with treatment
or harms with non-treatment (LoE 1b).
In particular, there is no decrease in the
occurrence of symptomatic urinary tract
infection following treatment of asympto-
matic bacteriuria [10].
9.3 Diabetic women
A prospective, randomized placebo con-
trolled trial of antibiotics or no antibiotics
for treatment of asymptomatic bacteriuria
in diabetic women of all ages reported no
benefits with treatment of asymptomatic
bacteriuria [11]. Subsequent episodes of
symptomatic cystitis or pyelonephritis
and hospitalization attributed to urinary
tract infection or to any other cause were
not decreased in women who received
 Asymptomatic bacteriuria – to treat or not to treat
antimicrobial therapy for bacteriuria.
There was, however, substantially greater
antimicrobial exposure in the treat-
ment group. A prospective cohort study
of women with type II diabetes reported
that asymptomatic bacteriuria was not
associated with an accelerated decline in
renal function [53]. Other cohort studies
have also reported no difference in mor-
tality or progression of complications of
diabetes in women stratified by bacteriu-
ria or no bacteriuria [54]. Thus asymp-
tomatic bacteriuria in diabetic women
should not be screened for or treated.
9.4 Men with asymptomatic
bacteriuria
There are no prospective, randomized tri-
als of treatment of otherwise healthy men
with asymptomatic bacteriuria. However, a
prospective cohort study of bacteriuric men
at a Veteran’s hospital ambulatory clinic
reported a low risk for subsequent symp-
tomatic infection and spontaneous clearing
of bacteriuria without antimicrobial treat-
ment for most episodes [12] (LoE 2b).
9.5 Elderly residents of long term
care facilities
Prospective, randomized trials of treat-
ment of asymptomatic bacteriuria in
residents of long term care facilities docu-
ment no decrease in symptomatic urinary
tract infection, no decrease in prevalence
or severity of chronic genitourinary symp-
toms, and no impact on survival with
antimicrobial therapy [1] (LoE 1a). There
are, however, negative outcomes with
attempts to treat asymptomatic bacte-
riuria including increased adverse effects
attributed to the antimicrobials, reinfec-
tion with organisms of increased antimi-
crobial resistance, and increased cost.
9.6 Individuals with indwelling
urinary catheters
Treatment of bacteriuria in subjects with
chronic indwelling catheters does not
| 5.2 |
decrease the incidence of symptomatic
infection [14–15]. While there is short
term interruption of bacteriuria, sub-
sequent reinfection is with organisms
of increased antimicrobial resistance.
Antimicrobial therapy given during the
first 3 to 4 days of catheterization or at
removal of a short-term catheter is asso-
ciated with a decreased prevalence of
asymptomatic bacteriuria [1]. However,
concerns with increasing antimicrobial
resistance associated with antimicrobial
use support recommendations that anti-
microbials for treatment of asymptomatic
bacteriuria be avoided in catheterized
patients (LoE 1b).
9.7 Spinal cord injured patients
Treatment of asymptomatic bacteriuria
does not decrease the prevalence of bac-
teriuria or subsequent symptomatic
infection in spinal cord injured patients
[16–19]. Reinfection occurs rapidly, so any
impact of antimicrobial therapy is lim-
ited. Attempts to treat asymptomatic bac-
teriuria are, however, associated with an
increased risk of reinfection with resist-
ant organisms (LoE 2a).
9.8 Urological procedures
Trauma to the genitourinary tract when
bacteriuria is present is associated with
a high risk of bacteremia and sepsis
[5]. Treatment of asymptomatic bacte-
riuria, with the antimicrobial initiated
immediately prior to the procedure, will
prevent these complications. Thus, it
is recommended that prior to an inva-
sive genitourinary procedure likely to be
associated with trauma (e.g. cystoscopy
in men, mucosal biopsy, stent insertion,
transurethral resection of the prostate)
antimicrobial therapy should be given
[5–9] (LoE 1b). Ideally the antimicrobial
therapy is targeted towards the infecting
organism. Clinical trials have repeatedly
documented that prophylaxis is effective
in preventing post-operative sepsis for
309
Chapter |5| Asymptomatic bacteriuria
men undergoing transurethral resection
of the prostate, but studies evaluating
other urologic procedures are limited [1].
It is assumed, however, that the risk of
sepsis is similar for any procedure likely
to be associated with mucosal bleeding,
and that antimicrobial therapy will have
a similar benefit for all these procedures.
9.9 Other patient groups
Renal transplant patients: Prospective
clinical trials have not addressed the
question of whether the treatment
of asymptomatic bacteriuria in renal
transplant patients is associated with
improved outcomes in patient morbid-
ity or mortality, or graft survival. In the
initial 6 months following transplant,
all patients receive prophylactic antimi-
crobial therapy, usually trimethoprim/
sulfamethoxazole [1]. This is effective in
preventing symptomatic and asympto-
matic urinary infection, as well as other
infections. Beyond 6 months, cohort stud-
ies do not report an association of asymp-
tomatic bacteriuria with graft survival.
Asymptomatic bacteriuria is common, but
tends to be identified in patients who are
also experiencing repeated symptomatic
urinary tract infection [55–56]. Thus,
these individuals are treated for sympto-
matic urinary infection, and screening for
or treatment of asymptomatic bacteriuria
have not yet been shown to have addi-
tional benefit (LoE 2b). Further clinical
studies of this population are needed.
9.10 Candiduria
A prospective randomized comparative
trial of hospitalized patients with asymp-
tomatic candiduria reported that fluco-
nazole treatment had only a short term
impact on the prevalence of candiduria,
and no improved clinical outcomes for the
treated group [20] (LoE 1b). Studies also
suggest no benefits with treatment of
asymptomatic bacteriuria in renal trans-
plant patients [21].
310
10. FURTHER RESEARCH
Unresolved questions include the man-
agement of asymptomatic bacteriuria in
renal transplant and other immunocom-
promised patients. In addition, further
studies to refine the presentations of
symptomatic infection in older individu-
als, especially residents in long term care
facilities, are necessary.
11. CONCLUSIONS
Asymptomatic bacteriuria is common in
women, and increases with age. In men
it is common at older ages. For healthy
women, the same risk factors reported
for recurrent acute uncomplicated uri-
nary infection are also associated with
asymptomatic bacteriuria. Screening and
treatment of asymptomatic bacteriuria is
indicated for pregnant women, and prior
to an invasive genitourinary procedure.
No benefits with screening or treatment
have been identified in other popula-
tions. Thus, for healthy men and women,
asymptomatic bacteriuria should not be
screened for and, if present, should not
be treated. There is also no evidence that
treatment of asymptomatic bacteriuria is
beneficial for persons with complicated
urinary infection.
REFERENCES
1. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
2. Gleckman R, Esposito A, Crowley M,
and Natsios GA, Reliability of a single
urine culture in establishing diagnosis of
asymptomatic bacteriuria in adult males.
J Clin Microbiol, 1979. 9(5): 596–7.
3. Ouslander JG, Greengold BA, Silverblatt
FJ, and Garcia JP, An accurate method
to obtain urine for culture in men with
 Asymptomatic bacteriuria – to treat or not to treat
external catheters. Arch Intern Med, 1987.
147(2): 286–8.
4. Nicolle LE, Harding GK, Kennedy J,
McIntyre M, Aoki F, and Murray D, Urine
specimen collection with external devices
for diagnosis of bacteriuria in elderly
incontinent men. J Clin Microbiol, 1988.
26(6): 1115–9.
5. Cafferkey MT, Falkiner FR, Gillespie
WA, and Murphy DM, Antibiotics for
the prevention of septicaemia in urol-
ogy. J Antimicrob Chemother, 1982. 9(6):
471–7.
6. Grabe M, Forsgren A, Bjork T, and
Hellsten S, Controlled trial of a short and
a prolonged course with ciprofloxacin in
patients undergoing transurethral pros-
tatic surgery. Eur J Clin Microbiol, 1987.
6(1): 11–7.
7. Olsen JH, Friis-Moller A, Jensen SK,
Korner B, and Hvidt V, Cefotaxime for
prevention of infectious complications in
bacteriuric men undergoing transurethral
prostatic resection. A controlled com-
parison with methenamine. Scand J Urol
Nephrol, 1983. 17(3): 299–301.
8. Grabe M, Forsgren A, and Hellsten S,
The effect of a short antibiotic course in
transurethral prostatic resection. Scand J
Urol Nephrol, 1984. 18(1): 37–42.
9. Allan WR and Kumar A, Prophylactic
mezlocillin for transurethral prostatec-
tomy. Br J Urol, 1985. 57(1): 46–9.
10. Asscher AW, Sussman M, Waters WE,
Evans JA, Campbell H, Evans KT, and
Williams JE, Asymptomatic significant
bacteriuria in the non-pregnant woman.
II. Response to treatment and follow-up.
Br Med J, 1969. 1(5647): 804–6.
11. Harding GK, Zhanel GG, Nicolle LE, and
Cheang M, Antimicrobial treatment in
diabetic women with asymptomatic bac-
teriuria. N Engl J Med, 2002. 347(20):
1576–83.
12. Mims AD, Norman DC, Yamamura RH,
and Yoshikawa TT, Clinically inapparent
(asymptomatic) bacteriuria in ambulatory
elderly men: epidemiological, clinical, and
microbiological findings. J Am Geriatr
Soc, 1990. 38(11): 1209–14.
13. Nicolle LE, Asymptomatic bacteriuria
in the elderly. Infect Dis Clin North Am,
1997. 11(3): 647–62.
| 5.2 |
14. Warren JW, Anthony WC, Hoopes JM,
and Muncie HL, Jr., Cephalexin for
susceptible bacteriuria in afebrile, long-
term catheterized patients. JAMA, 1982.
248(4): 454–8.
15. Leone M, Perrin AS, Granier I, Visintini
P, Blasco V, Antonini F, Albanese J, and
Martin C, A randomized trial of catheter
change and short course of antibiotics for
asymptomatic bacteriuria in catheterized
ICU patients. Intensive Care Med, 2007.
33(4): 726–9.
16. Waites KB, Canupp KC, and DeVivo MJ,
Eradication of urinary tract infection fol-
lowing spinal cord injury. Paraplegia,
1993. 31(10): 645–52.
17. Lewis RI, Carrion HM, Lockhart JL, and
Politano VA, Significance of asymptomatic
bacteriuria in neurogenic bladder disease.
Urology, 1984. 23(4): 343–7.
18. Mohler JL, Cowen DL, and Flanigan RC,
Suppression and treatment of urinary
tract infection in patients with an inter-
mittently catheterized neurogenic bladder.
J Urol, 1987. 138(2): 336–40.
19. Maynard FM and Diokno AC, Urinary
infection and complications during clean
intermittent catheterization following
spinal cord injury. J Urol, 1984. 132(5):
943–6.
20. Sobel JD, Kauffman CA, McKinsey D,
Zervos M, Vazquez JA, Karchmer AW, Lee
J, Thomas C, Panzer H, and Dismukes
WE, Candiduria: a randomized, double-
blind study of treatment with fluconazole
and placebo. The National Institute of
Allergy and Infectious Diseases (NIAID)
Mycoses Study Group. Clin Infect Dis,
2000. 30(1): 19–24.
21. Safdar N, Slattery WR, Knasinski V,
Gangnon RE, Li Z, Pirsch JD, and Andes D,
Predictors and outcomes of candiduria in
renal transplant recipients. Clin Infect Dis,
2005. 40(10): 1413–21.
22. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
23. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
311
Chapter |5| Asymptomatic bacteriuria
24. Warren JW, Catheter-associated urinary
tract infections. Infect Dis Clin North Am,
1997. 11(3): 609–22.
25. Suriano F, Gallucci M, Flammia GP,
Musco S, Alcini A, Imbalzano G, and
Dicuonzo G, Bacteriuria in patients with
an orthotopic ileal neobladder: urinary
tract infection or asymptomatic bacteriu-
ria? BJU Int, 2008. 101(12): 1576–9.
26. Bakke A and Digranes A, Bacteriuria in
patients treated with clean intermittent
catheterization. Scand J Infect Dis, 1991.
23(5): 577–82.
27. Waites KB, Canupp KC, and DeVivo MJ,
Epidemiology and risk factors for uri-
nary tract infection following spinal cord
injury. Arch Phys Med Rehabil, 1993.
74(7): 691–5.
28. Rodhe N, Molstad S, Englund L, and
Svardsudd K, Asymptomatic bacteriuria
in a population of elderly residents living
in a community setting: prevalence, char-
acteristics and associated factors. Fam
Pract, 2006. 23(3): 303–7.
29. Hooton TM, Scholes D, Stapleton
AE, Roberts PL, Winter C, Gupta K,
Samadpour M, and Stamm WE, A pro-
spective study of asymptomatic bacteriu-
ria in sexually active young women.
N Engl J Med, 2000. 343(14): 992–7.
30. Jackson SL, Boyko EJ, Scholes D,
Abraham L, Gupta K, and Fihn SD,
Predictors of urinary tract infection after
menopause: a prospective study. Am J
Med, 2004. 117(12): 903–11.
31. Raz R, Gennesin Y, Wasser J, Stoler Z,
Rosenfeld S, Rottensterich E, and Stamm
WE, Recurrent urinary tract infections in
postmenopausal women. Clin Infect Dis,
2000. 30(1): 152–6.
32. Pabich WL, Fihn SD, Stamm WE, Scholes
D, Boyko EJ, and Gupta K, Prevalence
and determinants of vaginal flora altera-
tions in postmenopausal women. J Infect
Dis, 2003. 188(7): 1054–8.
33. Raz R and Stamm WE, A controlled trial
of intravaginal estriol in postmenopau-
sal women with recurrent urinary tract
infections. N Engl J Med, 1993. 329(11):
753–6.
34. Ouslander JG, Greendale GA, Uman G,
Lee C, Paul W, and Schnelle J, Effects of
oral estrogen and progestin on the lower
312
urinary tract among female nursing home
residents. J Am Geriatr Soc, 2001. 49(6):
803–7.
35. Barabas G and Molstad S, No association
between elevated post-void residual vol-
ume and bacteriuria in residents of nurs-
ing homes. Scand J Prim Health Care,
2005. 23(1): 52–6.
36. Trautner BW, Hull RA, Thornby JI, and
Darouiche RO, Coating urinary catheters
with an avirulent strain of Escherichia
coli as a means to establish asympto-
matic colonization. Infect Control Hosp
Epidemiol, 2007. 28(1): 92–4.
37. Dontas AS, Tzonou A, Kasviki-Charvati
P, Georgiades GL, Christakis G, and
Trichopoulos D, Survival in a residential
home: an eleven-year longitudinal study.
J Am Geriatr Soc, 1991. 39(7): 641–9.
38. Evans DA, Kass EH, Hennekens CH,
Rosner B, Miao L, Kendrick MI, Miall
WE, and Stuart KL, Bacteriuria and
subsequent mortality in women. Lancet,
1982. 1(8264): 156–8.
39. Nordenstam GR, Brandberg CA, Oden
AS, Svanborg Eden CM, and Svanborg A,
Bacteriuria and mortality in an elderly
population. N Engl J Med, 1986. 314(18):
1152–6.
40. Heinamaki P, Haavisto M, Hakulinen T,
Mattila K, and Rajala S, Mortality in rela-
tion to urinary characteristics in the very
aged. Gerontology, 1986. 32(3): 167–71.
41. Abrutyn E, Mossey J, Berlin JA, Boscia J,
Levison M, Pitsakis P, and Kaye D, Does
asymptomatic bacteriuria predict mor-
tality and does antimicrobial treatment
reduce mortality in elderly ambulatory
women? Ann Intern Med, 1994. 120(10):
827–33.
42. Nicolle LE, Henderson E, Bjornson J,
McIntyre M, Harding GK, and MacDonell
JA, The association of bacteriuria with
resident characteristics and survival in
elderly institutionalized men. Ann Intern
Med, 1987. 106(5): 682–6.
43. Bengtsson C, Bengtsson U, Bjorkelund
C, Lincoln K, and Sigurdsson JA,
Bacteriuria in a population sample of
women: 24-year follow-up study. Results
from the prospective population-based
study of women in Gothenburg, Sweden.
Scand J Urol Nephrol, 1998. 32(4): 284–9.
 Asymptomatic bacteriuria – to treat or not to treat
44. High KP, Bradley S, Loeb M, Palmer R,
Quagliarello V, and Yoshikawa T, A new
paradigm for clinical investigation of
infectious syndromes in older adults:
assessment of functional status as a risk
factor and outcome measure. Clin Infect
Dis, 2005. 40(1): 114–22.
45. LiPuma JJ, Stull TL, Dasen SE, Pidcock
KA, Kaye D, and Korzeniowski OM, DNA
polymorphisms among Escherichia coli
isolated from bacteriuric women. J Infect
Dis, 1989. 159(3): 526–32.
46. Nicolle LE, Zhanel GG, and Harding GK,
Microbiological outcomes in women with
diabetes and untreated asymptomatic bac-
teriuria. World J Urol, 2006. 24(1): 61–5.
47. Svanborg C and Godaly G, Bacterial viru-
lence in urinary tract infection. Infect Dis
Clin North Am, 1997. 11(3): 513–29.
48. Cornia PB, Takahashi TA, and Lipsky
BA, The microbiology of bacteriuria in
men: a 5-year study at a Veterans’ Affairs
hospital. Diagn Microbiol Infect Dis,
2006. 56(1): 25–30.
49. Freedman LR, Natural history of urinary
infection in adults. Kidney Int Suppl,
1975. 4: S96–100.
50. Tencer J, Asymptomatic bacteriuria – a
long-term study. Scand J Urol Nephrol,
1988. 22(1): 31–4.
51. Alwall N, On controversial and open
questions about the course and compli-
cations of non-obstructive urinary tract
infection in adult women. Follow-up for
up to 80 months of 707 participants in
| 5.2 |
a population study and evaluation of a
clinical series of 36 selected women with a
history of urinary tract infection for up to
40 years. Acta Med Scand, 1978. 203(5):
369–77.
52. Smith HS, Hughes JP, Hooton TM,
Roberts P, Scholes D, Stergaehis A,
Stapleton A, and Stamm WE, Antecedent
antimicrobial use increases the risk of
uncomplicated cystitis in young women.
Clin Infect Dis, 1997. 25: 63–68.
53. Meiland R, Geerlings SE, Stolk RP,
Netten PM, Schneeberger PM, and
Hoepelman AI, Asymptomatic bacteriu-
ria in women with diabetes mellitus:
effect on renal function after 6 years
of follow-up. Arch Intern Med, 2006.
166(20): 2222–7.
54. Semetkowska-Jurkiewicz E, Horoszek-
Maziarz S, Galinski J, Manitius A, and
Krupa-Wojciechowska B, The clinical course
of untreated asymptomatic bacteriuria in
diabetic patients – 14-year follow-up. Mater
Med Pol, 1995. 27(3): 91–5.
55. Takai K, Tollemar J, Wilczek HE, and
Groth CG, Urinary tract infections
following renal transplantation. Clin
Transplant, 1998. 12(1): 19–23.
56. Lyerova L, Lacha J, Skibova J, Teplan V,
Vitko S, and Schuck O, Urinary tract
infection in patients with urological com-
plications after renal transplantation
with respect to long-term function and
allograft survival. Ann Transplant, 2001.
6(2): 19–20.
313
|5.3|

Asymptomatic bacteriuria with the

model strain Escherichia coli 83972
protects against symptomatic
urinary tract infections
Björn Wullt1,2, Fredrik Sundén1
1
Department of Urology, Skåne University Hospital, Malmö
2
Department of MIG, Institute of Laboratory Medicine, Lund University, Lund, Sweden, Word count: 1735
Address for correspondence: Björn Wullt, MD PhD FEBU, Department of Urology, Skåne University Hospital,
205 02 Malmö, Sweden, Tel: +46 46 171994, Fax: +46 46 2112595, bjorn.wullt@med.lu.se

ABSTRACT recurrent UTI. The model strain used

The increasing microbial antibiotic
resistance is a cause of major con-
cern and motivates the development of
alternatives to conventional antibiotic
treatment. In recurrent urinary tract
infections (UTI), “bacterial interfer-
ence” has gained interest as a possible
alternative treatment option. Clinical
trials observing patients with asympto-
matic bacteriuria has shown that a non-
treatment approach reduces the risk
for a subsequent symptomatic infec-
tion. This observation has prompted
clinical trials with deliberate coloniza-
tion of the human urinary tract as an
alternative approach in patients with
for urinary tract colonization, the ABU
isolate E. coli 83972, causes symptom-
free colonizations for long periods of
time in UTI prone patients and with
dysfunctional voiding. Patients in open
long-term colonization studies benefit
subjectively, and UTI treatments are
rare. Furthermore, placebo-controlled
studies demonstrate a significant delay
of UTI episodes in colonized patients
as compared to controls. This report
summarizes the clinical data on E. coli
839072 colonization trials.
Key words: Recurrent Urinary tract Infec-
tions, Bacterial Interference, Escherichia
coli 83972, Asymptomatic Bacteriuria
 Asymptomatic bacteriuria with the model strain
1. INTRODUCTION
Urinary tract infections are one of the
most common infections in mankind
and counts for about one tenth of all
antibiotics prescribed in primary care
[1]. Antibiotic treatment is effective in
sporadic infections, but when repeated
courses or long-term prophylactics are
given in recurrent or complicated cases,
the impact of side effects increases;
selection of microbial resistance, gastro-
intestinal disturbances and allergic
reactions. In addition, recent data on
increased frequency of multiple antibiotic
resistance and its relation to antibiotic
consumption in the society, stresses the
need for alternative approaches in infec-
tious diseases [2–3]. In UTI, alternatives
to antibiotic treatments include antibac-
terial molecules or peptides, vaccination
strategies, or “ecological therapy”. Recent
reports have demonstrated antibacte-
rial peptides within the urinary tract [4],
and their possible role in the treatment
of UTI may be promising in the future.
Vaccine strategies, using different E. coli
antigens, have shown interesting results
but have in general not been considered
effective enough [5].
“Ecological therapy” refers to bacte-
rial interference; the microbial interac-
tion by the competition of nutrients and
by the production of toxic molecules. This
causes a microbial balancing on colonized
surfaces as the skin and mucosal orifices,
which is considered a potent defense
against superinfecting pathogenic bacte-
ria [6]. Asymptomatic bacteriuria (ABU)
may be described as an example of bacte-
rial interference. ABU patients are colo-
nized during long periods of time in the
lower urinary tract with the same strain
[7], and if left untreated, superinfection
with other strains seems to be hindered
[8]. Based on these data a protocol for
deliberate colonization of the lower uri-
nary tract in patients with recurrent UTI
[9] has been developed, with the aim of
preventing symptomatic superinfections.
| 5.3 |
The strain used for colonization, the
apathogenic E. coli 83972, was originally
isolated from a girl with long term ABU
[9–10] and possesses a documented abil-
ity to colonize the human urinary tract
symptom-free for long periods of time
[9, 11–12].
Studies on deliberate E. coli 83972 colo-
nizations in UTI prone patients and with
bladder dysfunctions were initiated in the
early 1990’ies at the author’s institution
[11, 13]. The accumulated clinical experi-
ence in our centre now covers more than
70 patient-years in 44 patients. This report
describes the clinical outcome and protec-
tive effect of the colonization approach.
2. DELIBERATE E. COLI 83972
COLONIZATION; PATIENTS AND
PROTOCOL
All patients included in colonization tri-
als have had bladder dysfunctions (lower
motor neuron lesions or neuropathic blad-
ders due to spinal lesions) in combina-
tion with a history of recurrent UTI (3–4
UTI/year, the last two years), resistant to
optimal conventional measures including
repeated, or long-term low dose, antibi-
otic treatment. Urodynamics, cystoscopy
and upper urinary tract imaging has been
performed to detect treatable diseases
or dysfunctions. In patients with signifi-
cant residual urine Clean Intermittent
Caterization (CIC) has been initiated.
Patients with recurrent pyelonephritis,
upper urinary tract dysfunctions, renal
calculi, corticosteroid treatment, reduced
kidney function, severe co-morbidity, or
indwelling urethral catheter have not
been included.
The isolate used for colonization, E. coli
83972, was isolated from a girl for who
had carried this strain for three years
without subjective symptoms from the
lower urinary tract, and without causing
any kidney damage [9–10]. E. coli 83972
is extensively characterized genotypically
and phenotypically [14] and it belongs to
315
Chapter |5| Asymptomatic bacteriuria
non-pathogenic OKH serogroups [9]. Like
many ABU strains it carries the adhesin
gene clusters, including the pap and fim
gene sequences, but does not express
fimbriae or functional adhesions on its
cell surface, and it has been shown that
the pap and fim gene clusters carry sig-
nificant deletions [15–16]. E. coli 83972 is
sensitive to all common antibiotics used
for UTI and it carries a small plasmid,
enabling identification through plasmid
tests. The ability of the non adherent
ABU isolate E. coli 83972 to cause long
term bacteriuria in patients with dys-
functional voiding, but not in patients
with complete bladder emptying, is well
documented [11].
The colonization follows a standard-
ized protocol [9, 11]; appropriate antibiot-
ics is given to sterilize the urine and after
an antibiotic free interval the patient
is catheterized, and the bladder is emp-
tied. 30 ml of E. coli 83972 (105 cfu/ml) is
instilled in the bladder, and the catheter
is removed. The procedure is repeated
once daily for three days. The success
of the colonization attempt is proven by
repeated urine cultures, and the long-
term follow up is performed urine cul-
tures obtained by first weekly and later
monthly intervals.
3. OBSERVATIONAL STUDIES ON
E. COLI 83972 COLONIZATION;
SUMMARY AND RESULTS
During a 10-year (1995–2005) period
24 (14 females and 10 males, mean age
62, range 44–85 years) patients were
included in open trials to study the effect
of deliberate colonization with E. coli
83972. The aims were to determine uro-
dynamic factors crucial for stable coloni-
zation, and to investigate the influence
of bacterial adherence factors (using
genetically transformed variants of E.
coli 83972) on the host response and bac-
terial establishment. The result of these
studies are further discussed in chapter
316
on host responses in the urinary tract by
Wullt and Svanborg [17–19]. All patients
were followed long-term by monthly urine
cultures, and by regular interviews. The
patients were informed of urinary culture
findings, and if spontaneous clearance
was observed, given the choice to leave
the study or to be subjected to a repeated
colonization.
In total, E. coli 83972 bacteriuria was
registered for 602 months (or 50.2 years)
in the 24 patients. Bacteriuria was estab-
lished in one or more periods exceeding
three months in 16 of the 24 patients
(67%). Four patients were colonized for
periods between three months and one
year, on one or several occasions, and 12
patients were colonized for more than
one year, on one or several occasions. The
longest observed colonization period was
four years, which was recorded in three
patients.
Several important conclusions were
made on the data achieved. Incomplete
bladder emptying was defined as a
prerequisite for the success of bacte-
rial long-term establishment; transient
superinfections with uropathogens were
outcompeted by E. coli 83972; there were
no serious side effects such as febrile
UTI or pyelonephritis reported from any
of the patients [11, 13]. During coloniza-
tion with E. coli 83972, UTI requiring
antibiotic treatment was recorded in nine
cases (0.14 treatments per patient year),
none of these causing a febrile reaction or
raised CRP [13]. All patients with long-
term colonization reported subjective
improvement in terms of fewer symptoms
from the lower urinary tract, and reduc-
tion of UTI episodes. In case of sponta-
neous clearance of the bacteriuria, all
patients asked for a re-inoculation on one
or more occasions [13].
These observational studies demon-
strated the E. coli 83972 colonization
approach to be safe and without sig-
nificant side-effects, and the suggested
protective effect against UTI motivated
further randomized controlled trials.
 Asymptomatic bacteriuria with the model strain
4. PLACEBO-CONTROLLED STUDIES
ON E. COLI 83972 COLONIZATION;
SUMMARY AND RESULTS
To test the protective effect suggested in
the observational studies we conducted
a randomized, blinded placebo-controlled
study, including a cross-over to enable
group-wise and intra-individual analysis
[20]. After randomization, patients were
inoculated either with E. coli 83972 or
saline, and followed until the first report
of a UTI, or until 12 months follow-up
before cross-over. Group-wise and intra-
individual analysis from the 20 patients
who fulfilled the protocol demonstrates a
significant delay of reported UTI events
in the colonization-arm as compared to
the control-arm. In addition, a second
randomized study [21], but without cross-
over, independently performed, have in
a group-wise analysis demonstrated that
patients initially colonized had a signifi-
cant delay in reporting UTI as compared
to patients in a placebo-arm.
We conclude that randomized studies
independently have verified the protec-
tive effect against UTI of E. coli 83972
colonization in patients with dysfunc-
tional voiding and recurrent infections.
5. DISCUSSION
Increasing microbial resistance [2]
enforces the medical community to use
antibiotic treatment only on strict indica-
tions and to find alternative treatments.
In this review we have demonstrated that
deliberate colonization of the lower uri-
nary tract with E. coli 83972 in patients
with dysfunctional voiding and recur-
rent UTI is safe and without serious
side-effects, and that it protects against
symptomatic infection episodes. This
has been shown by repeated observa-
tional studies [12–13] and by two inde-
pendent controlled studies [20–21]. The
positive effect by the E. coli 83972 coloni-
zation approach indirectly underlines the
| 5.3 |
importance of not treating spontaneously
developed ABU in patients with dysfunc-
tional lower urinary tracts. However, in
patients who do not develop ABU and, in
spite of a strict treatment regimen, are
subjected to repeated courses of antibiot-
ics due to recurrent UTI, the colonization
approach should be considered a possible
treatment alternative.
Further development of the coloniza-
tion approach is warranted, mainly due
to two issues. A few patients fail to estab-
lish E. coli 83972 bacteriuria in spite of
repeated attempts, and spontaneous
clearance of the bacteriuria may occur
in any patient at any time during colo-
nization [11, 13]. The underlying mecha-
nisms explaining colonization resistance
or spontaneous clearance are unknown.
In addition, in rare cases, patients have
reported UTI symptoms while being col-
onized with E. coli 83972. To study this,
the colonization approach in itself offers
an excellent research-model of host/
parasite interaction in the human uri-
nary tract (see also the chapter on host
response in the urinary tract by Wullt
and Svanborg). This research should aim
at identifying molecular mechanisms in
bacterial adaptation and mucosal toler-
ance in vivo in the human urinary tract.
In the future, possibly discrete altera-
tions of bacterial geno- or phenotypic
characteristics could be performed to
enhance long-term colonization success in
the individually selected patient.
6. CONCLUSIONS
ABU in patients with incomplete blad-
der emptying and UTI susceptibility
should not be treated due the protective
effect against symptomatic superinfec-
tions. If ABU does not develop sponta-
neously protective ABU may be induced
by deliberate inoculation with the
apathogenic isolate E. coli 83972. The
increasing microbial multi-resistance in
gram-negative uropathogens will make
317
Chapter |5| Asymptomatic bacteriuria
the development of alternative therapies,
including the E. coli 83972 bacteriuria
approach, more important in the future.
REFERENCES
1. Andre, M., et al., Diagnosis-prescribing
surveys in 2000, 2002 and 2005 in
Swedish general practice: Consultations,
diagnosis, diagnostics and treatment
choices. Scand J Infect Dis, 2008: p. 1–7.
2. Goossens, H., et al., Outpatient antibiotic
use in Europe and association with resist-
ance: a cross-national database study.
Lancet, 2005. 365(9459): p. 579–87.
3. Pitout, J.D. and K.B. Laupland,
Extended-spectrum beta-lactamase-
producing Enterobacteriaceae: an emerg-
ing public-health concern. Lancet Infect
Dis, 2008. 8(3): p. 159–66.
4. Chromek, M., et al., The antimicrobial
peptide cathelicidin protects the urinary
tract against invasive bacterial infection.
Nat Med, 2006. 12(6): p. 636–41.
5. Naber, K.G., et al., Immunoactive prophy-
laxis of recurrent urinary tract infections:
a meta-analysis. Int J Antimicrob Agents,
2009. 33(2): p. 111–9.
6. Falagas, M.E., P.I. Rafailidis, and G.C.
Makris, Bacterial interference for the
prevention and treatment of infections.
Int J Antimicrob Agents, 2008. 31(6):
p. 518–22.
7. Hansson, S., et al., Untreated asympto-
matic bacteriuria in girls: I – Stability of
urinary isolates. Bmj, 1989. 298(6677):
p. 853–5.
8. Hansson, S., et al., Untreated asympto-
matic bacteriuria in girls: II – Effect of
phenoxymethylpenicillin and erythromy-
cin given for intercurrent infections. Bmj,
1989. 298(6677): p. 856–9.
9. Andersson, P., et al., Persistence of
Escherichia coli bacteriuria is not deter-
mined by bacterial adherence. Infect
Immun, 1991. 59(9): p. 2915–21.
10. Lindberg, U., Asymptomatic bacteriuria
in schoolgirls. V. The clinical course and
response to treatment. Acta Paediatr.
Scand., 1975. 64: p. 718–724.
318
11. Wullt, B., et al., Urodynamic factors
influence the duration of Escherichia coli
bacteriuria in deliberately colonized cases.
J Urol, 1998. 159(6): p. 2057–62.
12. Darouiche, R.O., et al., Pilot trial of bacte-
rial interference for preventing urinary
tract infection. Urology, 2001. 58(3):
p. 339–44.
13. Sunden, F., et al., Bacterial interference –
is deliberate colonization with Escherichia
coli 83972 an alternative treatment for
patients with recurrent urinary tract
infection? Int J Antimicrob Agents, 2006.
28 Suppl 1: p. S26–9.
14. Hull, R.A., et al., Virulence properties of
Escherichia coli 83972, a prototype strain
associated with asymptomatic bacteriuria.
Infect Immun, 1999. 67(1): p. 429–32.
15. Klemm, P., et al., Molecular
Characterization of the Escherichia coli
83972 Asymptomatic Bacteriuria Strain:
the Taming of a Pathogen. Infection and
Immunity, 2006. Jan: p. 781–785.
16. Zdziarski, J., et al., Molecular basis of
commensalism in the urinary tract: low
virulence or virulence attenuation? Infect
Immun, 2008. 76(2): p. 695–703.
17. Wullt, B., et al., P fimbriae enhance the
early establishment of escherichia coli in
the human urinary tract. Mol Microbiol,
2000. 38(3): p. 456–64.
18. Wullt, B., et al., P-fimbriae trigger
mucosal responses to Escherichia coli in
the human urinary tract. Cell Microbiol,
2001. 3(4): p. 255–64.
19. Bergsten, G., et al., PapG-dependent
adherence breaks mucosal inertia and
triggers the innate host response. J Infect
Dis, 2004. 189(9): p. 1734–42.
20. Sundén, F., et al., Deliberately induced
E. coli 83972 bacteriuria protects against
recurrent lower urinary tract infections
in patients with incomplete bladder emp-
tying. A blinded randomized placebo-
controlled cross-over study. In press,
J Urol, July, 2010.
21. Darouiche, R.O., et al., Bacterial inter-
ference for prevention of urinary tract
infection: a prospective, randomized,
placebo-controlled, double-blind pilot
trial. Clin Infect Dis, 2005. 41(10):
p. 1531–4.
 Chapter |6|

Urinary tract infections

in children
Chair: Rien J.M. Nijman

CHAPTER OUTLINE
6.1 Introduction 320
6.2 Classification of urinary tract infections in children 323
6.3 Diagnostic work-up of urinary tract infections in children 328
6.4 Antimicrobial therapy of urinary tract infections in children 344
6.5 Non-operative urological management of
urinary tract infections in children 363
6.6 Medical therapy versus surgery in vesicoureteral
reflux from the view of the paediatrician 374
6.7 Vesico-ureteral reflux: An American pediatric
urologic perspective 392
|6.1|
Introduction
Rien J.M. Nijman
Professor and chair department of Urology, University Medical Centre Groningen, Hanzeplein 1
9713 GZ Groningen, The Netherlands
Tel: +31 50 3613248, Fax: +31 50 3619607, Email: j.m.nijman@uro.umcg.nl
Urinary tract infection in children affects
3% of children every year. Throughout
childhood the risk of a UTI is 8% for girls
and 2% for boys. Sexually active girls
experience more UTIs than sexually inac-
tive girls. However, during the first year
of life, more boys than girls get UTIs,
with a tenfold increased risk for uncir-
cumcised compared to circumcised boys.
Especially in children younger than
two years, UTIs have been associated
with significant morbidity and long-term
medical problems, such as hyperten-
sion, impaired renal function and chronic
kidney disease. Prompt diagnosis and
treatment are critical in preventing the
possible pathologic sequelae of UTIs.
Paediatric UTIs should be considered
as complicated until proved otherwise.
Genitourinary abnormalities should be
considered subsequent to a diagnosis of
UTI, and early diagnosis and accurate
management should provide an improved
long-term prognosis.
Classic symptoms of cystitis include
urinary frequency, urgency, dysuria, hae-
maturia, suprapubic pain, sensation of
incomplete emptying, and even inconti-
nence. In neonates and young children
often non-specific symptoms are the first
indication that a UTI may be present.
These can include poor feeding, irrita-
bility, lethargy, vomiting, diarrhoea, ill
appearance, and abdominal distension.
Fever and flank pain are unusual symp-
toms for lower UTI.
Pyelonephritis in the older child typi-
cally begins as a lower UTI that proceeds
to an upper UTI as the infections ascends.
In neonates and the young child pyelone-
phritis can also result from hematoge-
nous spread of infection (e.g. bacteremia).
Symptoms that occur with upper UTIs
overlap those for cystitis, in part because
cystitis is common in both. In upper
UTIs, flank pain and fevers (>39° C) are
more pronounced and important.
In this chapter specific infections like
fungal infections, tuberculosis, schisto-
somiasis, viral UTI and xantogranuloma-
tous pyelonephritis are not described but
referred to in different textbooks.
The main focus will be on classification,
diagnostic work-up and the relationship

of UTI and vexicoureteral reflux and sub-
sequent treatment of these problems.
Also specific congenital and acquired
diseases that may cause UTI are not
included, partly because they do not need
further discussion and partly because
these anomalies are not addressed in
the literature with particular reference
to UTI.
An interesting topic that will be dis-
cussed extensively is the use of pro-
phylactic antibiotics in children with
recurrent UTI and/or low grade reflux.
There is growing evidence that the use of
antibiotic prophylaxis may not be recom-
mended in these children.
Bladder dysfunction and dysfunctional
voiding is an issue that needs special
attention. In most studies urinary incon-
tinence is the main outcome parameter,
while UTI is a frequent problem in many
of these children. Why does an overac-
tive bladder cause UTI? Is it the high
intermittent pressure in the bladder or
the relatively high voiding pressure with
subsequent damage to the urethral epi-
thelium causing infection or does it have
to do with the fact that during increased
bladder pressure the bladder neck opens
and closes again with the so-called milk-
ing back phenomenon as a consequence
that is responsible for recurrent UTI? In
children with dysfunctional voiding and
post void residual urine, it is believed
that the incomplete emptying is responsi-
ble for the UTI, but not all children with
residual urine develop UTIs. The changed
bladder dynamics may play a role, but at
the same time bladder urothelium may be
different as well, allowing an increased
bacterial colonisation. Although we have
acquired much knowledge about these
problems, there are still many unre-
solved issues and the actual answers are
lacking.
Although the occurrence of a UTI, espe-
cially in the very young, may have a seri-
ous impact on the child and its parents, it
is important to realise that it serves as a
‘revealing’ symptom rather than a serious
Introduction | 6.1 |
disease. It often is the first sign of under-
lying pathology requiring prompt diag-
nosis and treatment, but the long term
results are usually good. While the same
pathology, not presenting with a UTI and
therefore undiscovered for a longer time,
may in the end have a much worse long-
term outcome.
Because children with UTI are usually
first seen by a GP or paediatrician before
being referred to a paediatric urologist,
both specialist’s views and recommenda-
tions are included in this chapter. At first
sight this may cause some confusion,
because of the apparent contradictions
and overlap. But it also provides a bal-
anced overview, with emphasis on differ-
ent issues.
• UTI is one of the most common bacte-
rial infections in children.
• If there is clinical suspicion or a
positive urinalysis, a urine cul-
ture should always be obtained for
diagnosis.
• After a maximum of two UTI epi-
sodes in a girl and one episode in a
boy, further investigations should be
undertaken.
• A DMSA scan is the gold standard to
determine renal scarring.
• The main objective of the treatment
is the elimination of symptoms in the
acute episode and the prevention of
renal impairment in the long term.
• Prophylactic antibiotics may be used
to reduce the risk of recurrent UTI,
but there is growing evidence that
efficacy is poor, except in children
with dilating VUR and other forms of
obstructive uropathy.
REFERENCES
1. Qigley R. Diagnosis of urinary tract infec-
tions in children. Current Opinion in
Pediatrics 2009; 21: 194–198.
2. Riccabona M. Urinary tract infections
in children. Current Opinion in Urology
2003; 13: 59–62.
321
Chapter |6| Urinary tract infections in children
3. Mori R, Lakhanpaul M, Verrier-Jones K.
Diagnosis and management of urinary
tract infection in children: summary of
NICE guidance. BMJ 2007; 335: 395–7.
4. Kass EJ, Kernen KM, Carey JM.
Paediatric urinary tract infection and the
necessity of complete urological imaging.
BJU Int 2000; 86(1):94–6.
322
5. Luk WH, Woo YH, Au-Yeung AWS, and
Chan JCS. Imaging in pediatric urinary
tract infection: A 9-year local experience.
AJR 2009; 192: 1253–60.
6. Zorc JJ, Kiddoo DA, and Shaw KN.
Diagnosis and management of pediatric
urinary tract infections. Clin Microbiol
Rev 2005; 18: 417–22.
|6.2|

Classification of urinary tract

infections in children
Chang-Hee Han, Sang Don Lee
Chang Hee Han, MD, Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea
Tel: +82-31-820-3546, Fax: +82-31-847-6133, E-mail: urohan@catholic.ac.kr
Sang Don Lee, MD, Department of Urology, School of Medicine, Pusan National University, Yangsan, Korea
Tel: +82-55-360-2671, Fax: +82-55-360-2164, E-mail: lsd@pusan.ac.kr

ABSTRACT or the existence of complicating factors

In infants and children, urinary tract
infection (UTI) is one of the most com-
mon bacterial infections. The ultimate
goal of treatment is the preservation of
kidney function. Many classification sys-
tems have been introduced to differenti-
ate children with UTI whose kidneys are
at risk or not. The classification system
presented here is synthesized from other
systems and may be used in practice to
reach this aim.
Key words: UTI, child, classification
SUMMARY OF RECOMMENDATIONS
Classification according to the site of
infection (lower tract versus upper tract),
the number of episodes (first versus recur-
rent), the severity (simple versus severe),
(uncomplicated versus complicated) is
useful to differentiate children with UTI
whether they are at risk of renal damage
or not (GoR B).
1. INTRODUCTION
The classification of urinary tract infec-
tion (UTI) is complex for historical rea-
sons, and many classification systems
exist. UTIs can be classified by the site
of infection (lower tract versus upper
tract), by the number of episodes (first
versus recurrent), by severity (simple ver-
sus severe), by the presence of symptoms
(asymptomatic versus symptomatic), or
by the existence of complicating factors
(uncomplicated versus complicated)
(Table 1). Such classifications imply sever-
ity of infection when, in fact, this cannot
Chapter |6| Urinary tract infections in children
Table 1 Classifications of urinary tract infections (UTIs) in
children.
1. Classification according to site
Lower urinary tract (cystitis)
Upper urinary tract (pyelonephritis)
2. Classification according to episode (risk of
complication)
First infection
Recurrent infection
Unresolved
Persistence infection
Reinfection
3. Classification according to severity (risk of
complication)
Simple UTIs
Severe UTIs
4. Classification according to symptoms
Asymptomatic bacteriuria
Symptomatic bacteriuria
5. Classification according to complicating factor (risk of
complication)
Uncomplicated UTIs
Complicated UTIs
be documented clinically and “milder”
infections may require less rigorous
evaluation.
2. METHODS
We performed a systemic literature
search in Medline from 1989 to 2008
using the key word UTI with the follow-
ing limitations: English publications,
human studies, review, 0–18 years old.
A total of 86 publications were found and
screened by title and abstract. Finally
30 publications were included into this
review. We also reviewed textbooks to
provide relevant background and context
for this analysis.
All studies were rated according to
the level of evidence and the recommen-
dations graded to strength according to
ICUD standards [1–2].
324
3. CLASSIFICATIONS
For practical purposes five classification
systems, based on the natural history and
subsequent evaluation and management
which imply the complication possibility,
are widely used.
3.1 Classification according to
site of UTIs
Understanding and appropriately differ-
entiating cystitis from pyelonephritis is
crucial and imperative for two reasons:
a) to permit identification, treatment, and
evaluation of children who are at risk for
kidney damage; and b) to avoid unneces-
sarily evaluating and treating children
who are not at risk.
3.1.1 Cystitis
Cystitis is an inflammatory condition of
the urinary bladder. General signs and
symptoms of cystitis include dysuria, fre-
quency, urgency, malodorous urine, enu-
resis, haematuria, and suprapubic pain.
3.1.2 Pyelonephritis
Pyelonephritis is a diffuse pyogenic infec-
tion of the renal pelvis and parenchyma.
The onset of pyelonephritis is generally
abrupt. Clinical signs and symptoms
include fever (38.5°C or greater), chills,
along with costovertebral angle or flank
pain and tenderness. Older children may
report cystitis symptoms, such as strong
smelling urine, dysuria, urgency, and
frequency along with the fever and flank
pain. Infants and children may have
nonspecific signs such as poor appetite,
failure to thrive, lethargy, irritability,
vomiting or diarrhoea.
3.2 Classification according to the
number of UTI episodes
These infections are categorized as first
infection and recurrent infection. The
recurrent UTIs can be subcategorized
 Classification of urinary tract infections in children
further as unresolved bacteriuria, bacte-
rial persistence, or reinfection [3–6].
3.2.1 First infection
This is simply the first UTI that is diag-
nosed. In infants and children, first infec-
tions are considered complicated because
of the potential association with anatomic
anomalies. A high prevalence of anatomic
anomalies occurs in children and may pre-
dispose them to complications of UTI and
potential renal damage. Therefore, infants
and children with first infections should
undergo anatomical evaluation [4].
3.2.2 Recurrent infection
3.2.2.1 Unresolved infection
Unresolved infection indicates that initial
therapy has been inadequate in eliminat-
ing bacterial growth in the urinary tract.
It may be caused by inadequate therapy
related to bacterial resistance to the
selected therapeutic agent, inadequate
antimicrobial urinary concentration
owing to poor renal concentration or gas-
trointestinal malabsorption, or an infec-
tion involving multiple organisms with
differing antimicrobial susceptibilities. It
can usually be treated successfully once
proper culture and antimicrobial sensitiv-
ity patterns are available.
3.2.2.2 Bacterial persistence
Bacterial persistence is different from
unresolved infection. It is caused by re-
emergence of bacteria from a site within
the urinary tract and may be due to a
nidus for persistent infection that cannot
be eradicated. As a result, the same path-
ogen is identified in recurrent infections,
but episodes of sterile urine may occur
during and shortly following antimicro-
bial treatment. Bacterial micro-organisms
reside in an isolated portion (or anomaly)
of the urinary tract where the pathogens
are shielded from the current treatment,
resulting in a persistent nidus of infection
(e.g. infected stones, Table 2) [3]. Sources
of urinary tract bacterial persistence are
| 6.2 |
Table 2 Surgically correctable causes of bacterial
persistence in children.
Infection stones
Infected nonfunctioning or poorly functioning kidneys or
renal segments
Infected ureteral stumps after nephrectomy
Vesicointestinal or rectourethral fistula
Vesicovaginal fistula
Infected necrotic papillae in papillary necrosis
Unilateral medullary sponge kidney
Infected urachal cyst
Infected urethral diverticulum or periurethral gland
Dilating vesicoureteral reflux
Obstructive uropathy (urethral valves, UPJ obstruction etc)
usually found early in children because
imaging is performed after the first UTI.
The treatment options are more compli-
cated and often require surgical correc-
tion of underlying abnormalities with
extirpation of the nidus.
3.2.2.3 Reinfection
Re-infection is different from bacterial
persistence. In re-infection, each episode
can be caused by a variety of new infect-
ing organisms, whereas in bacterial per-
sistence, the same infecting organism
is always isolated. Re-infection most
frequently occurs by the faecal-perineal-
urethral route in girls and periurethral
colonization in boys. Confusion in this
form of pathogenesis sometimes occurs
because Escherichia coli, the most com-
mon general pathogenic species, occur in
many different serotypes; thus, recurrent
Escherichia coli UTI does not equate to
infection with the same organism. With
serotyping, re-infection can be estab-
lished, but this is rarely done in the rou-
tine clinical setting.
3.3 Classification according to
severity of UTIs
From the clinical point of view, sim-
ple and severe forms of UTIs should be
325
Chapter |6| Urinary tract infections in children

differentiated because to some extent the (pyelonephritis). Cystitis may represent

severity of symptoms dictates the degree
of urgency with which investigation and
treatment are to be undertaken (Table 3).
3.3.1 Simple UTI
A child with a simple UTI may have only
mild pyrexia, but is able to take fluids and
oral medication. The child is only slightly
or not dehydrated and has a good expected
level of compliance. When a low level of
compliance is expected, such a child should
be managed as one with a severe UTI.
3.3.2 Severe UTI
Severe UTI is related to the presence of
fever of > 39ºC, the feeling of being ill,
persistent vomiting, and moderate or
severe dehydration.
3.4 Classification according to
symptoms
This classification system is based on the
existence of local or systemic symptoms.
early recognition of an infection destined
to become pyelonephritis, or bacterial
growth controlled by a balance of viru-
lence and host response.
3.5 Classification according to
complicating factor
Useful criteria for distinguishing compli-
cated from uncomplicated UTI is summa-
rized in Table 4 [7].
3.5.1 Uncomplicated UTI
Uncomplicated UTI describes infection
in a patient with a morphologically and
functionally normal urinary tract. This
category includes mostly isolated or
recurrent bacterial cystitis and is usu-
ally associated with a narrow spectrum
of infecting pathogens which are eas-
ily eradicated by a short course of oral
antimicrobial agents. Patients can be
managed on an outpatient basis, with
emphasis on documenting resolution

3.4.1 Asymptomatic bacteriuria Table 4 Clinical classification of pediatric urinary tract

infections (UTIs) according to complicating factor.
Asymptomatic bacteriuria indicates
attenuation of uropathogenic bacteria by History Complicated Uncomplicated
the host, or colonization of the bladder by UTI UTI
nonvirulent bacteria incapable of activat- Age <3 mo >3 mo
ing a symptomatic response.
Systemic symptoms + –
Known urologic + –
3.4.2 Symptomatic bacteriuria (UTI) anomaly
Symptoms associated with UTI include Physical
+ –
irritative voiding symptoms, suprapu- examination
bic pain (cystitis), fever and malaise Fever
+ –
+ –
Flank pain
Table 3 Clinical classification of pediatric urinary tract Abdominal or flank
infections (UTIs) according to severity. mass + –
Laboratory findings + –
Severe UTI Simple UTI
Unusual pathogen + –
Fever >38.5°C Mild pyrexia
Azotemia +
Persistent vomiting Good fluid intake Leukocytosis
Serious dehydration Slight dehydration Radiologic
indication
Poor treatment compliance Good treatment
compliance of obstruction

326
 Classification of urinary tract infections in children
of their bacteriuria followed by elective
evaluation for potential anatomic or func-
tional abnormalities of the urinary tract.
3.5.2 Complicated UTI
All neonates, most patients with clini-
cal evidence of pyelonephritis, and all
children with known mechanical or func-
tional obstructions of the urinary tract
are considered to have complicated UTI.
Mechanical obstruction is commonly due to
the presence of posterior urethral valves,
strictures or stones. Functional obstruction
often results from neurogenic bladder dys-
function or dilating vesicoureteral reflux.
Patients with complicated UTI require
hospitalization and parenteral antibiotics.
Prompt anatomic evaluation of the urinary
tract is critical to exclude the presence of
significant abnormalities. If mechanical
or functional abnormalities are present
adequate drainage of the infected urinary
tract is necessary.
4. FURTHER RESEARCH
Large epidemiological studies have fur-
thered our understandings of paediatric
UTI. The goal of current practice is the
early detection of urinary tract pathology
and prevention of renal damage. For this
purpose several classification systems
have been introduced. However, most
of the various aspects used for the clas-
sification of UTI in children are not yet
validated in prospective clinical studies,
which should be done in the future
5. CONCLUSIONS
For practical purposes four classification
systems (lower tract versus upper tract,
| 6.2 |
first versus recurrent, simple versus
severe and uncomplicated or complicated
UTI) are widely used. Such classifications
are based on the natural history and sub-
sequent evaluation and management
which imply the complication possibility.
REFERENCES
1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of
the main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
3. Shortliffe LMD, Infection and inflamma-
tion of the pediatric genitourinary tract in
Campbell-Walsh urology, Campbell MF,
Wein AJ, and Kavoussi LR, Editors. 2007,
Saunders Elsevier: Philadelphia, Pa. ;
[Edinburgh]. p. 3232–3268.
4. Shortliffe LMD, Shinghal R, and Seto
EH, Pediatric urinary tract infections,
in Pediatric urology, Gearhart JP, Rink
RC, and Mouriquand PDE, Editors.
2001, W.B. Saunders Co: Philadelphia.
p. 237–258.
5. Schaeffer AJ, Urinary tract infections, in
Adult and pediatric urology, Gillenwater
JY, Grayhack JT, Howards SS, and
Mitchell ME, Editors. 2002, Lippincott
Williams & Wilkins: Philadelphia, Pa. ;
London. p. 211–272.
6. Ma JF and Shortliffe LM, Urinary tract
infection in children: etiology and epide-
miology. Urol Clin North Am, 2004. 31(3):
517–26, ix–x.
7. Burns MW, Burns JL, and Krieger
JN, Pediatric urinary tract infection.
Diagnosis, classification, and significance.
Pediatr Clin North Am, 1987. 34(5):
1111–20.
327
|6.3|

Diagnostic work-up of urinary

tract infections in children
Martin Westenfelder, Rolf Beetz
Prof. Dr. med. Martin Westenfelder, Zentrum für Kinderurologie und plastisch rekonstruktive Urologie, HELIOS Klinikum
Krefeld, Lutherplatz 40, 47805 Krefeld
Tel. +49 2151 32 2281, Fax +49 2151 32 2018, E-Mail: martin.westenfelder@helios-kliniken.de
PD Dr. med. Rolf Beetz, Paediatric Nephrology, Center for Paediatric and Adolescent Medicine, University Medical Clinic,
Langenbeckstr.1, 55131 Mainz
Phone +41-6131-17 3937, Fax +41-6131-17 6426, e-mail: beetz@kinder.klinik.uni-mainz.de

ABSTRACT At this point, in most cases, it should

Diagnosis of UTI in children should be
straightforward, clarifying the existence
of infection and the risk of a given infec-
tion. It is initially important to consider
clinical signs and symptoms, to get the
medical history (primary-, secondary-,
febrile-, a febrile- infection, constipation)
and, following inspection of the genitalia,
to carefully collect a specimen of urine.
This is followed by a thorough inves-
tigation with analysis of the freshly
obtained native urine using dipstick
and (preferably) a phase contrast micro-
scope which reveals the whole spectrum
of corpuscular elements occurring dur-
ing infection: bacteria, leucocytes, eryth-
rocytes, epithelial cells from bladder or
kidney, leukocyte cylinders (indicative for
pyelonephritis), elements which indicate
contamination and bacteriological culture
of urine (and blood).
be clear whether there is a significant
infection and a clinical risk associated. If
infection is verified, calculated antibacte-
rial treatment can be started.
The main problems arise when clinical
signs and symptoms are misinterpreted,
genitalia are not inspected and urine is
not collected properly. Whereas unnec-
essary antimicrobial treatment is a nui-
sance, disturbing medical history and
correct diagnosis, the delay of necessary
antimicrobial treatment can be delete-
rious. There is no need to restrict treat-
ment until results of bacteriological and
serological tests confirm infection.
At least in infants and young children,
ultrasonography of kidneys and uri-
nary tract as part of primary diagnostics
should be performed to rule out urinary
obstruction, calculi and/or pyonephrosis,
especially if pre- or postnatal ultrasound
screening has not been done before. This
 Diagnostic work-up of urinary tract infections in childrens
is also true in cases where antibiotic
treatment does not lead to efficient reso-
lution of symptoms.
Secondary diagnosis of the etiol-
ogy of a given UTI in children should
be planned carefully to prevent over- or
underdiagnosis.
Vesicoureteral reflux is regarded a risk
factor for renal damage with urinary
tract infections. Therefore, its detection
has an impact on further treatment and
prophylactic strategies.
Whether a DMSA-scan should be done
primarily to verify parenchymal involve-
ment justifying X- ray investigations such
as VCUG or whether VCUG should be the
primary investigation to identify reflux
is still controversial. Pyelectasy, rarified
parenchyma, dilated ureters, thick walled
bladders, residual urine and renal dupli-
cation require detailed morphological and
functional investigations of the urinary
tract in order to obtain a clear diagno-
sis. Only after this does it become clear
whether it is a complicated or uncompli-
cated infection requiring prophylaxis or
surgery.
We are still a long way from under-
standing all mechanisms leading to UTI;
however we are well able to prevent paren-
chymal loss if infection is detected early.
Key words: diagnosis of UTI in chil-
dren, urine analysis, leukocyte esterase,
quantification of bacteriuria, imaging of
the urinary tract, radionuclide studies,
urodynamic evaluation, endoscopy, inves-
tigative strategies in UTI
SUMMARY OF RECOMMENDATIONS
1. Considering that clinical signs and
symptoms vary with age, differentiat-
ing between a first (primary) episode
and recurrent infection is important
(GoR C).
2. Further investigation such as ultra-
sonography, VCUG and possibly
Isotope-studies should be undertaken
| 6.3 |
after two UTI episodes in girls and
one in boys (GoR B).
3. In children wearing diapers it is first
recommended to inspect and clean the
genitalia, apply a urinary collecting
bag and proceed with further investi-
gations (GoR C).
4. Urine analysis reveals infecting bac-
teria (through culture) and an inflam-
matory response (microscope and
dipstick test). However, urine has to
be collected under defined conditions
and investigated without delay. Plastic
bag- and midstream urine require
cautious interpretation, whereas urine
obtained by suprapubic aspiration or
catheterization give reliable results
(GoR B).
5. C-reactive protein (CRP), urinary
N-acetyl-ß-glucosaminidase (NAG)
and Serum-Procalcitonin are widely
used as markers for pyelonephritis
(GoR B) but have a lower sensitivity
and specifity than the DMSA-scan.
6. Presence or absence of severe anoma-
lies of the kidneys and urinary tract
can be predicted with high accuracy
by ultrasonography (GoR A).
7. When indicated, VCUG is used to
detect VUR and to visualize the blad-
der and urethra. VUR can also be
detected by sonographic techniques
using contrast medium or direct and
isotopic cystography with comparable
sensitivity.
8. Radionuclide studies are used to
investigate: i) renal function and
obstruction (mercaptoacetyltriglycine
(MAG-3) or ii) parenchymal loss and
scar formation DMSA-Scan: Tc-99m or
iii) reflux, indirect radionuclide cystog-
raphy (GoR B).
9. Excretory urography is needed only
in those cases where morphology can-
not be clarified by other techniques,
e.g. renal duplication, and where MRI
of the urinary tract is not available
(GoR C).
329
Chapter |6| Urinary tract infections in children
10. Urodynamic evaluation is used
when voiding disorders or bladder
hypo/hyperactivity is suspected.
In most cases, it can be restricted
to uroflowmetry, flow- EMG and
sonographic measurement of resid-
ual urine, whereas a neurogenic
bladder requires complete evaluation
(GoR B).
11. Endoscopy has no place in the evalu-
ation of acute infections (GoR C).
Only in a limited number of chil-
dren may it be helpful to clarify the
underlying pathology.
1. INTRODUCTION
Bacterial UTIs only occur when special-
ized (mostly virulent) uropathogenic
bacteria invade the urinary tract (UT),
multiply faster than they are eliminated
and induce an inflammatory response.
This is usually prevented by a multitude
of mechanisms which interfere with inva-
sion, multiplication and damaging inflam-
matory reactions such as scar formation
in the kidney.
In principle, UTI in children and adults
are comparable; however there are sig-
nificant differences requiring a different
approach concerning the imminence and
urgency of detecting the risk involved in
a given UTI.
UTI in children is less common than in
adults and more common in boys (3.7%)
than in girls (2%) in the first year of life
[1] (LoE 3). By one year of age, 2.7% of
boys and 0.7% of girls have had bacteriu-
ria [2] (LoE 3).
This is partially due to primary infec-
tions especially during the first three
months, which occur in the presence of
severe congenital anomalies as megau-
reters, vesicoureteral reflux (VUR) and
urethral valves, intensified when combined
with phimosis. During that period uncir-
cumcised boys have a 10 times greater
risk than circumcised boys of having a
330
UTI [3–4] (LoE 3 and 2a). The incidence
changes after the first year, being 3% in
girls and 1.1% in boys [5] (LoE 3). Young
age and the length of the urethra therefore
are not main risk factors for UTI.
The outcome of a UTI is usually
benign, but it can progress to renal
scarring especially when pyelonephri-
tis remains untreated over several days
[6–7]. Although older children may have
less risk of scarring from infection than
those younger than five years of age, vul-
nerability for scarring persists at least
until puberty (10 to 15 years) [8–9] (LoE
3 and 2a). In most children with UTI in
whom renal scars are found, the scars are
found on the first set of imaging studies
and remain unchanged regardless of the
child’s future clinical course [10] (LoE
2b). Therefore dependent on age, sex and
whether the infection is febrile or non-
febrile, primary (first presenting clinical
infection) or secondary (second or recur-
rent infection), the urgency of diagnosis
varies.
2. METHODS
A systematic literature search was
performed up to 1997 in MEDLINE,
Cochrane and in specific literature using
the following key words: UTI in children,
incidence, aetiology, pathogenesis, course
of, diagnosis, with the following limita-
tions: children up to 14 years; an English
abstract had to be available. The authors
also had continuously observed the rele-
vant literature concerning the topic dur-
ing the last 30 years. Only peer reviewed
articles were included. A total of more
than 200 publications were identified,
which were screened by title and abstract.
After exclusion of duplicates and insignif-
icant articles, a total of 64 were included
into the review.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [11–12]
 Diagnostic work-up of urinary tract infections in childrens
3. MEDICAL HISTORY AND CLINICAL
FINDINGS
The process leading to the diagnosis of UTI
should be straightforward. Clinical appear-
ance in combination with medical history,
physical examination and ultrasound, com-
pleted by urine analysis, leads to the sus-
picion of UTI. If the child is in diapers it is
helpful to inspect and clean the genitalia
and apply a urinary collection bag before
further investigations. Often the bladder
is emptied during investigation and urine
can be analyzed immediately.
3.1 Medical history
The most important questions are
whether this is a primary (first) or sec-
ondary (recurring) infection and if there
are indications for possible malforma-
tions of the UT e.g. pre- or postnatal
ultrasound screening, family history and
whether there is constipation or signs of
voiding dysfunction.
3.2 Clinical signs and symptoms
These may vary with age and severity of
the disease. Neonates with pyelonephritis
or even urosepsis may present with non-
specific symptoms, i.e. failure to thrive,
jaundice, hyperexcitability and without
any fever. In small children, UTI may
present as gastroenteritis with jaundice,
vomiting, not drinking, diarrhea, exsicca-
tion. 13.6% of patients with fever have a
UTI [13] (LoE 3). Among febrile infants
(younger than eight weeks of age), the
prevalence of UTI has been found to be
13.6%, with the majority of infections
occurring in male infants. Fever accounts
for about 20% of paediatric office vis-
its [14] (LoE 4) and UTI causes 4.1% to
7.5% of these febrile episodes [15] (LoE
4). Septic shock is unusual, even with
very high fever. Signs of a UTI may be
vague and unspecific in small children,
but later on, when they are older than
two years, frequent voiding, dysuria and
| 6.3 |
suprapubic, abdominal or lumbar pain
may be present.
Bacterial epididymitis is rare and
only occurs in combination with signifi-
cant UTI or renal duplication and ectopic
ureters, or due to urethral strictures.
However, scrotal pain and inflammation
in a boy is primarily indicative for testic-
ular torsion, or torsion of a hydatide.
3.3 Physical examination
Physical examination includes a gen-
eral examination of throat, lymph nodes,
abdomen (constipation) and temperature.
The absence of fever does not exclude
UTI. Examination may reveal a palpable
and painful kidney, palpable bladder, phi-
mosis, labial adhesion, vulvitis, epididy-
mo-orchitis, and stigmata of spina bifida
or sacral agenesis.
4. URINE ANALYSIS
Diagnosis of urinary tract infection
depends on detection of bacteria and an
inflammatory response in the urinary
tract, preferably by a significant positive
urine culture [16–17] (LoE 4 and 1a).
4.1 Urine sampling
Urine has to be collected under defined
conditions and investigated without
delay.
4.1.1 Midstream urine (MSU)
In toilet-trained children and adoles-
cents, mid stream urine can be obtained.
The child is instructed to spread the labia
(for girls) or retract the foreskin (for non-
circumcised boys), to clean the urethral
meatus and perineum with gauze and liq-
uid soap twice, to urinate into the toilet,
and, midway through urination, to col-
lect the urine in a sterile container [18].
Urine contamination rates are higher in
midstream urine that is collected from
toilet-trained children when obtained
331
Chapter |6| Urinary tract infections in children
without perineal/genital cleaning [18].
Collection after cleaning the genitalia is
reliable when dipstick test and (phase
contrast) microscopy is taken into consid-
eration [19] (LoE 1a).
4.1.2 Urine sampling in infants and
non-toilet trained children
Obtaining urine samples from non-toilet
trained children (i.e., younger than three
years of age) involves four main methods
with varying contamination rates and
invasiveness.
4.1.2.1 Plastic bag attached to the cleaned
genitalia
This technique is most often used in daily
practice for infants and young children
who are not toilet-trained. If an ultra-
sonography is planned as a part of the
initial diagnostic, the urine collection bag
should be applied before performing it,
since the bladder may be emptied during
the investigation.
Dipstick negative for both leucocytes
and nitrite or microscopic analysis nega-
tive for both pyuria and bacteriuria of a
bag urine specimen may reasonably be
used to rule out urinary tract infection
[20]. However, prospective studies show
a high incidence of false-positive results,
ranging from 85–99% [16, 19] (LoE 1a
and 4) if the genitalia are not cleaned
and if the culture is delayed. In respect
to bacteriuria it is only helpful when the
culture is negative [16, 19] (LoE 1a and
4) and has a positive predictive value of
15% [21] (LoE 4). However, in combina-
tion with (phase contrast) microscopy
and dipstick test, accuracy and predictive
value is approximately 80% higher [21]
(LoE 4). Due to the high contamination
rate and the less than favorable risk pro-
file, the American Academy of Pediatrics
concluded that bag urine specimens are
not useful for diagnosing UTI and should
always be followed up with another
method in young children to confirm the
diagnosis [15]. However, urine obtained
332
from a bag urine collection is useful
for dipstick urinalysis and microscopic
evaluation [22]. Nevertheless, bag urine
specimens should not be used for culture,
where possible [23].
4.1.2.2 Clean-catch urine collection
Instead of bag urine, the clean catch
technique is equally non-invasive and
has been reported to have a false-pos-
itive rate of 5% and a false-negative
rate of 12% in infants [24]. The infant
is placed in the lap of a parent or nurs-
ing staff member, who holds a sterile
foil bowl underneath the infant’s genita-
lia. The infant is offered oral fluids, and
urine collection is awaited [24]. Some
authors have found a good association
in results of culture of urine obtained by
clean-catch urine collection and suprapu-
bic aspiration (24). However, this method
is time consuming and it needs proper
instruction of parents. Therefore, it can-
not be recommended as a routine method
for daily practice.
4.1.2.3 Bladder catheterization
Transurethral catheterization is reliable
but traumatic, especially in boys, and
bears the risk of nosocomial infection
[15, 25] (LoE 4). However, in experienced
hands this technique may be an alterna-
tive for suprapubic bladder aspiration,
even in newborns and non-toilet trained
infants and children [26].
4.1.2.4 Suprapubic bladder aspiration
Before attained bladder control the most
sensitive method for obtaining an uncon-
taminated urine sample is suprapubic
bladder aspiration. The success rate
regarding sufficient urine sample volumes
is best if ultrasound is used for the assess-
ment of bladder filling. In neonates, use of
ultrasound guidance simplifies suprapu-
bic aspiration and improves the diagnostic
yield of obtaining a urine specimen from
60% to almost 97% [27–28]. Complications
of suprapubic bladder aspiration are
extremely rare and have been reported to
 Diagnostic work-up of urinary tract infections in childrens
be 0.22%, ranging from transient haema-
turia to bowel perforation [29]
4.2 Microscopic urine investigation
This is a fast method to get information on
the intensity of a given infection. Freshly
obtained native urine (uncentrifuged) is
investigated (preferably) with a phase
contrast microscope. The whole spectrum
of corpuscular elements occurring dur-
ing infection can be identified: bacteria,
leucocytes, erythrocytes, epithelial cells
from bladder or kidney. Presence of leu-
kocyte cylinders is indicative for pyelone-
phritis. The microscopic identification of
bacteria in the urine is more sensitive and
specific for diagnosing UTI than identi-
fication of pyuria [30–31] (LoE 4 and 3).
Identification of bacteria under high dry
magnification (450× to 570×) represents
about 30,000 bacteria per millilitre. In
girls leucocyturia of up to 20 leucocytes/µl
are considered to be normal, up to 50/µl
are suggestive, and over 50/µl are indica-
tive for infection. In boys older than three
years leucocyte counts of more than 10/µl
are considered to be pathological [30–31]
(LoE 2b and 3). The analysis of urine sam-
ples obtained by catheter for the presence
of significant pyuria (>=10 white blood
cells/ mm3) can be used to guide decisions
regarding the need for urine culture in
young febrile children [32].
4.3 Dipstick test
Dipstick tests are readily available and
easy to perform. They provide informa-
tion about the presence of biochemical
markers in urine indicative for UTI [16]
(LoE 4). If both, nitrite and leukocyte
esterase tests are positive, in combination
with the clinical symptoms, UTI is most
likely [31, 33] (LoE 3 and 1a).
4.3.1 Nitrite
Nitrates from the metabolism of most
Gram-negative bacteria are degraded to
nitrite which can be detected. However, not
| 6.3 |
all uropathogens reduce nitrate to nitrite,
e.g. Enterococci, Pseudomonas aeruginosa.
When an infection is caused by Gram-
positive bacteria, the test may be negative
[16]) (LoE 4). In cases of high diuresis and/
or frequent voiding even nitrite-producing
pathogens may show a negative test result,
due to the short transit time in the blad-
der. Whereas contaminated urine, stored
too long at a higher temperature before
cultivation, may be falsely positive.
The nitrite test has a sensitivity of
only 45–60%, but a very good specificity
of 85–98% [16, 31] (LoE 4 and 3).
4.3.2 Leukocyte esterase
Leukocytes produce leukocyte esterase.
The test for leukocyte esterase has sen-
sitivity of 48–86% and a specificity of
17–93% [16, 31, 33–34] (LoE 4, 3, and
1a). Nitrite and leukocyte esterase test-
ing improve sensitivity and specificity,
but carry the risk of false-positive results
[33] (LoE 1a). Bacteriuria without pyuria
is found in 0.5% of mid stream specimens
and may be due to contaminated urine or
asymptomatic bacteriuria [33] (LoE 1a).
In febrile children with positive urine
culture and absence of pyuria urinalysis
should be repeated after 24 hours to clar-
ify the situation. Pyuria without bacteriu-
ria may be due to antimicrobial treatment,
urolithiasis, foreign bodies, past sur-
gery, infections caused by Mycobacterium
tuberculosis and other fastidious bacteria,
e.g. Chlamydia trachomatis.
Thus, neither bacteriuria nor pyuria are
reliable parameters for UTI [35] (LoE 2a).
However, according to Landau et al. [36]
(LoE 2a), pyuria in febrile children is indic-
ative of acute pyelonephritis. In neonates
and children under six months of age, pyu-
ria, bacteriuria and the nitrite test, sepa-
rately, have minimal predictive value for
UTI [37–38] (LoE 2b and 4). With a posi-
tive predictive value of 98%, pyuria with a
positive nitrite test is more reliable in older
children for the diagnosis of UTI than in
infants and younger children, [34] (LoE 3).
333
Chapter |6| Urinary tract infections in children
4.4 Microbiology
What constitutes a “significant” UTI is
unclear. It is controversial whether “colo-
nization” represents specimen contami-
nation or asymptomatic benign infection.
In severe UTI however more than 105
cfu/mL can be expected. Nevertheless
the count can vary and be related to the
method of specimen collection, diuresis,
time and temperature of storage until
cultivation occurs [17] (LoE 1a).
4.4.1 Significant bacteriuria
The classical definition of more than 105
cfu/mL of voided urine is still used [31,
38] (LoE 1a and 3) and is the traditional
definition for a clinically significant UTI
[39] (LoE 4).
Other studies have shown that 10,000
or fewer organisms on a voided specimen
may indicate a significant UTI [35, 40]
(LoE 2a and 2b). In MSU or in urine from
a collection- bag more than105 cfu/mL is
considered to be positive [21].
4.4.2 Urine obtained by catheterization
For urine obtained by catheterization, a
culture of 104 cfu/mL and more culture is
considered to be positive.
4.4.3 Urine obtained by suprapubic
aspiration
In urine obtained by suprapubic aspi-
ration any counts are considered to be
significant. However, counts lower than
10³ cfu/ml are unusual. The presence of
pyuria (more than 10 leucocytes per µl)
and bacteriuria in a fresh urine sample
will reinforce the clinical diagnosis of
UTI [31–32] (LoE 3). Mixed cultures are
indicative for contamination. In these
cases, it is better to repeat the culture or
to evaluate the presence of other signs,
such as pyuria, nitrites or other bio-
chemical markers than to draw immedi-
ate therapeutic consequences [17] (LoE
1a). Combining bacteriuria and pyuria in
febrile children, the findings of > 10 WBC/
334
mm3 and > 50,000 cfu/mL in a specimen
collected by catheterization are signifi-
cant for a UTI and discriminates between
infection and contamination [32, 34, 37]
(LoE 3 and 2b).
4.5 Strategy of urine sampling and
investigation in infants
Urine cultures by catheterization or
suprapubic aspiration are necessary to
detect urinary tract infections in infants
and non-toilet trained children. However,
these methods are inconvenient and are
not accepted in every situation by par-
ents and first care physicians. Strategies
to rule out a UTI from bag or clean catch
urine samples would be useful in daily
practice. The AAP practice parameter
for the diagnosis, treatment, and evalu-
ation of the initial UTI in febrile infants
and young children therefore suggests
two options for managing the infant or
young child (aged two months to two
years) with unexplained fever that is
assessed as not being so ill as to require
immediate antimicrobial therapy. One
option is immediate suprapubic bladder
puncture or catheterization; the other is
to “obtain a urine specimen by the most
convenient means and perform a uri-
nalysis. If the urinalysis suggests a UTI,
obtain and culture a urine specimen, col-
lected by suprapubic bladder aspiration
or transurethral catheterization” [15]. If
the urinalysis is negative, then the AAP
suggests that it is “reasonable to fol-
low the clinical course without initiating
microbiological therapy” [15]. There are
currently no new data to motivate any
changes to this recommendation.
5. LEVEL OF URINARY TRACT
INFECTION
The differential diagnosis between upper
(pyelonephritis) and lower urinary tract
infection (cystitis, urethritis) has clini-
cal implications, especially in infants and
 Diagnostic work-up of urinary tract infections in childrens
young children. In this age group, the
clinical presentation tends to be nonspe-
cific, and the risk of renal damage with
pyelonephritis is considered to be higher
than in older children. Additionally, con-
cepts of further imaging and treatment
are frequently based on the level of UTI
[15]. There are some parameters which
are used for level diagnosis:
Fever: It is estimated that 60–65% of
patients with a febrile UTI will have an
acute pyelonephritis [37].
C-reactive protein: Although non-
specific in febrile children with bacte-
riuria, C-reactive protein is often used
in daily practice to distinguish between
acute pyelonephritis and other causes of
bacteriuria. It is considered significant at
a concentration above 20 µg/mL.
Procalcitonin is also used for early
detection of renal parenchymal involve-
ment and detection of reflux [41–42] (LoE
2b and 2b).
Urinary N-acetyl-β-glucosaminidase
(NAG): This is a marker of tubular dam-
age. It is increased in a febrile UTI and
may become a reliable diagnostic test for
UTIs, although it is also elevated in VUR
[19] (LoE 1a).
DMSA-Scan (Dimercaptoproprionyl-
acid renal scintigram): Currently, this
investigation is considered as the gold
standard for the diagnosis of pyelonephri-
tis. Parenchymal hypoperfusion in zones
of inflammation are visualized by areas
of diminished activity of the tracer.
Colour-coded power doppler
sonography is also used for the detec-
tion of hypoperfused parenchymal areas
but has a lower sensitivity and specifity
than DMSA. [43].
The presence of fever, as well as the
increase of laboratory parameters like
CRP, erythrozyte sedimentation rate
(ESR) and white blood cell count are
frequently used as signs for kidney
involvement in daily clinical practice.
Many studies have shown a statistically
increased level of acute phase reactants
(WBC, CRP, and ESR) in patients with
| 6.3 |
acute pyelonephritis when compared
with those with acute cystitis. However,
although the sensitivity of these tests
are 80–100%, their specificity in chil-
dren under the age of two years was
lower than 28% in a study comparing
clinical and laboratory findings with the
finding of acute lesions DMSA-scan as
gold standard [44]. A relevant problem is
the cut off level for WBC, ESR, or WBC
that can afford discrimination between
acute pyelonephritis and cystitis. For
these reasons, some recommend DMSA
renal scintigram, when available, as the
test of choice to make the diagnosis of
acute pyelonephritis in young children
under the age of two with febrile UTI
[44]. In most clinics a DMSA-Scan is not
used as a diagnostic tool for determin-
ing the level of infection. Therefore, in
case of doubt one should treat a symp-
tomatic UTI in early childhood like a
pyelonephritis.
6. IMAGING OF THE URINARY TRACT
It is a common practice to investigate
with imaging studies in children after
urinary tract infection. Today, many
imaging techniques exist for the detection
of morphological anomalies of the kidneys
and urinary tract, of reflux and of acute
pyelonephritic lesions as well as for per-
sistent pyelonephritic scarring and renal
dysplasia.
6.1 Ultrasonography
Ultrasonography is an important pri-
mary imaging tool and bears no risk but
requires experience. It delivers immedi-
ate information on the anatomy of the
urogenital tract: size and configuration
of the renal parenchyma, kidney vol-
ume, the collecting system, dilated ure-
ters, pathology of the bladder urethra
and gonads [45–46] (LoE 2a). It gives
rough information on renal function,
severe infection, scars, and malforma-
tions of kidneys, ureters and the bladder.
335
Chapter |6| Urinary tract infections in children
Sometimes there are even signs of reflux
and ureteroceles. Presence or exclusion
of anomalies can be predicted with high
accuracy. Power-Doppler-Sonography
even allows evaluation of renal per-
fusion. To identify or verify parenchymal
hypoperfusion as a sign for pyelonephri-
tis or to detect permanent renal scars,
however, DMSA-scanning (technetium-
99m dimercaptosuccinic acid-scanning,
Tc-99m) is more sensitive [45, 47] (LoE
2a and 2b).
Some authors have stated that ultra-
sonography would not be necessary after
UTI if antenatal ultrasound screen-
ing resulted in normal findings [48].
However, due to frequent lack of rel-
evant findings in prenatal ultrasound,
it should not be used as a substitute
for ultrasound after UTI [49]. In recent
years questions have been raised about
the relatively low yield of abnormalities
found on renal ultrasound and the clini-
cal significance of those abnormalities
[34, 50–52]. The prevalence of abnormal-
ities ranged from 12% to 16%, with most
findings including dilated renal pelvis,
caliectasis, megaureter, and double col-
lecting systems.
6.1.1 Cystosonography
Contrast material-enhanced voiding
ultrasonography has been introduced
for the diagnoses of VUR without radio-
logical exposure [53–55] (LoE 1a and 2a).
By transurethral instillation of contrast
material (e.g. Levovist®), CO2 higher
than grade I reflux can be visualised [55].
Compared with VCUG as a gold standard
for reflux detection, contrast-enhanced
cysto-sonography reaches a sensitivity of
more than 86% and a specificity of more
than 92% [56]. Using sophisticated tech-
niques like “low-dose contrast-enhanced
harmonic ultrasound imaging” [56]
or “echo-enhanced colour doppler cys-
tosonography with stimulated acoustic
emission” [57] the sensitivity can further
be increased.
336
6.2 Radiological investigations
6.2.1 Voiding cystourethrography
VCUG is the most widely used radiologi-
cal exploration for the study of the lower
urinary tract and especially of VUR. It
is considered mandatory in the evalua-
tion of symptomatic UTI in children less
than one year of age. Its main drawbacks
are the risk of infection [58], if not car-
ried out by suprapubic puncture, the
need for retrograde filling of the blad-
der and the possible deleterious effect
of radiation on children [59] (LoE 3). In
recent years, tailored low-dose fluoro-
scopic VCUG with digital technique has
been used for the evaluation of VUR in
order to minimize radiological exposure
[60] (LoE 3). Voiding cystourethrography
is mandatory in the assessment of recur-
rent febrile childhood UTI, even in the
presence of normal ultrasonography. Up
to 23% and more, depending on the age
of these patients may reveal VUR [61]
(LoE 3). The timing of the VCUG after a
pyelonephritic episode does not influence
the results [62–66] (LoE 1).
6.2.2 Excretory urography
Intravenous pyelography remains a val-
uable tool in the evaluation of urinary
tract anomalies in children; however it
should be reserved when images need to
be morphologically clarified, e.g. renal
duplication [67] (LoE 3). Its use in UTI is
debatable unless preliminary imaging has
demonstrated abnormalities requiring
further investigation. The major disad-
vantages are exposure to contrast media
and radiation [46] (LoE 2a). Digital imag-
ing techniques should be used to reduce
radiation. The role is declining with the
increasing technical superiority of ultra-
sonography, MRI and CT [68] (LoE 3).
6.3 Radionuclide studies
6.3.1 DMSA-Scan
Tc-99m DMSA is a radiopharmaceutical
that is bound to the basement membrane
 Diagnostic work-up of urinary tract infections in childrens
of proximal renal tubular cells; half of the
dose remains in the renal cortex after six
hours. This technique is helpful in deter-
mining functional renal mass and ensures
an accurate diagnosis of cortical scarring
by showing areas of hypoactivity indi-
cating lack of function. A UTI interferes
with the uptake of this radiotracer by the
proximal renal tubular cells, and may
show areas of focal defect in the renal
parenchyma. A star-shaped defect in the
renal parenchyma may indicate an acute
episode of pyelonephritis. A focal defect
in the renal cortex usually indicates a
chronic lesion or a “renal scar” [69–71]
(LoE 4, 3 and 1a). A focal scarring or a
smooth uniform loss of renal substance as
demonstrated by Tc-99m DMSA has gen-
erally been regarded as being associated
with VUR (reflux nephropathy) [72–73]
(LoE 1a and 2a). However, Rushton et
al. [74] (LoE 2a) stated that significant
renal scarring may develop, regardless of
the existence or absence of VUR. Risdon
[75] (LoE 4) reported that Tc-99m DMSA
showed a specificity of 100% and sensitiv-
ity of 80% for renal scarring. The use of
Tc-99m DMSA scans can be helpful in the
early diagnosis of acute pyelonephritis.
About 50–85% of children will show posi-
tive findings in the first week. Minimal
parenchymal defects, when character-
ized by a slight area of hypoactivity, can
resolve with antimicrobial therapy [75–76]
(LoE 4 and 2b). However, defects lasting
longer than five months are considered to
be renal scarring [77] (LoE 2a). Tc-99m
DMSA scans are considered more sensi-
tive than excretory urography and ultra-
sonography in the detection of renal scars
[78–81] (LoE 2b, 2b, 2a and 3). It remains
questionable whether radionuclide scans
could substitute for ultrasonography as a
first-line diagnostic approach in children
with a UTI [53, 82–83] (LoE 3, 4 and 4).
6.3.2 Direct radionuclide cystography
After instillation of MAG 3 into the
bladder (by catheter or by suprapubic
| 6.3 |
puncture) reflux is visualized by a gamma
camera in a sitting or supine position.
This method is highly sensitive compa-
rable to radiologic VCUG but gives little
information about morphology.
6.3.3 Indirect radionuclide cystography
This investigation is performed by pro-
longing the period of scanning after the
injection of Tc-99m diethylene triamine
pentaacetate (DTPA) or as part of a
dynamic renography. It represents a mer-
captoacetyltriglycine (MAG-3) attractive
alternative to conventional cystography,
especially when following patients with
reflux, because of its lower dose of radia-
tion. Disadvantages are a poor image res-
olution and difficulty in detecting lower
urinary tract abnormalities [77–78].
6.3.4 Diuretic renography
Diuretic scintigraphy is the most com-
monly used diagnostic tool to detect
the severity and functional significance
of urine transport problems. 99m Tc –
MAG3 is the radionuclide of choice. It
is important to perform the study under
standardized circumstances (hydration,
transurethral catheter) between the
fourth and sixth week of life [82] (LoE 4).
Oral fluid intake is encouraged prior
to the examination. Fifteen minutes
before the injection of the radionuclide,
normal saline intravenous infusion at a
rate of 15 mL/kg over 30 min is manda-
tory with a subsequent maintenance rate
of 4 mL/kgh during the duration of the
investigation [84] (LoE 3). The recom-
mended dose of furosemide is 1mg/kg for
infants during the first year of life, while
0.5 mg/kg should be given in children
aged one to 16 years up to a maximum
dose of 40 mg.
6.4 Imaging strategies in UTI
After a maximum of two UTI episodes
in a girl and one episode in a boy, more
detailed investigation of the urinary tract
337
Chapter |6| Urinary tract infections in children
should be carried out to clarify the child’s
risk, but not in asymptomatic bacteriuria
[54, 68, 85–89] (LoE 1b, 2a, 2b, 2b, 2a, 4
and 2a).
Initial imaging guidelines from 1999
for febrile children up to the age of two
years by the American Academy of
Paediatrics involve a combination of
ultrasound and VCUG or isotope cystog-
raphy [15]. UK guidelines from 1991 were
similar for the infant and young child,
but also included renal cortical scintigra-
phy with DMSA [90].
During the last few years, efforts have
been made to come up with a more risk
oriented approach after urinary tract
infections instead of performing sono-
graphic and radiographic studies in
every child with a first urinary tract
infection. UTI guidelines from the
National Institute of Health and Clinical
Excellence (NICE) 2007 put forward a
selective approach for imaging, accord-
ing to risk factors including age, pres-
ence of atypical features (serious illness,
poor urine flow, presence of abdominal or
bladder mass, raised serum creatinine
level, septicaemia, non-E.coli organism
from urine culture and poor response
to suitable antibiotics) and presence of
symptomatic recurrence, with the aim of
applying imaging studies to the at-risk
group of infants in a more focused man-
ner (http://guidance.nice .org.uk/CG054)
[91]. However, while the NICE guidelines
may help to focus investigations in the
at-risk group, it may result in the under-
diagnosis of significant findings [92].
Debate continues about optimal imag-
ing strategies after first urinary tract
infection [49].
Today, most clinics would recommend
a cystogram if signs, symptoms and his-
tory indicate the possibility of reflux e.g.
in children with pyelonephritis, a family
history of reflux or recurrent infections
associated with signs of bladder dysfunc-
tion, signs for reflux or upper tract dilata-
tion in sonographic studies.
338
If reflux is seen, then a DMSA scan
would probably be required to assess the
extent of any renal damage. The goal of
this strategy is early detection of reflux
and prevention of ascending urinary tract
infections [93] (LoE 4).
7. URODYNAMIC EVALUATION
When voiding dysfunction is suspected,
e.g. incontinence, residual urine and
increased bladder wall thickness, then
urodynamic evaluation, restricted to
uroflowmetry, flow- EMG and residual
urine should be performed. Furthermore
fluid intake and bowel movement should
be recorded. Video-urodynamic studies,
including pressure flow studies and elec-
tromyography of the pelvic floor muscles
should be reserved for the evaluation
of children with bladder and voiding
problems not responding to standard
treatment, congenital anomalies and neu-
rogenic bladders.
8. ENDOSCOPY
Routine cystoscopy has no place in the
evaluation of acute infections. But in the
final process of diagnosis, some weeks
after bacterial eradication, it may be
helpful to clarify the diagnosis in a lim-
ited number of patients. With modern
imaging techniques the need for endo-
scopic investigations has been further
reduced. Endoscopy is used to manage
VUR, strictures, valves, foreign bodies,
stones etc.
9. FURTHER RESEARCH
Many open questions need to be clarified:
1. The significance of elimination dis-
orders of bladder and bowel in the
aetiology of UTI combined with the
various anomalies.
 Diagnostic work-up of urinary tract infections in childrens
2. The accuracy of radionuclide stud-
ies in young children (detection of
obstruction), and of detection of renal
“scars” in DMSA- scans carried out
over several months.
3. The accuracy of power ultrasonog-
raphy and indirect radionuclide
cystography compared to conventional
VCUG to detect VUR.
4. It is desirable to minimize the
number of invasive examinations and
radiation load to which children are
exposed. Alternative tests that offer a
potential advantage over the current
reference standards, such as ultra-
sound or laboratory-based tests, are
therefore required [53].
5. More research is needed to under-
stand the contribution of delayed
diagnosis and treatment of UTI,
dysfunctional elimination, and con-
genital renal dysplasia to the devel-
opment of renal scarring in children
after UTI [49].
10. CONCLUSIONS
Differentiation between a first (primary)
episode and recurrent infection is important.
Diagnosis of a primary UTI in children
should be straightforward, clarifying the
existence of an infection and the risk of a
given infection.
Clinical signs and symptoms, medical
history, investigation of a carefully col-
lected specimen of urine following inspec-
tion of the genitalia and ultrasonograpy
will give the answer. Clinical signs and
symptoms vary with age. Under well-or-
ganized conditions the diagnostic evalua-
tion will take about 30 minutes leading to
a calculated antimicrobial treatment.
Diagnosis of a recurrent UTI in chil-
dren should be planned carefully to pre-
vent over- or underdiagnosis, clarifying
the cause of infection and the presence of
parenchymal damage.
| 6.3 |
REFERENCES
1. Kunin CM, Deutscher R, and Paquin
A, Jr., URINARY TRACT INFECTION
IN SCHOOL CHILDREN: AN
EPIDEMIOLOGIC, CLINICAL AND
LABORATORY STUDY. Medicine
(Baltimore), 1964. 43: 91–130.
2. Wettergren B, Fasth A, and Jacobsson
B, UTI during the first year of life in a
Göteborg area 1977–79. Pediatr Res,
1980. 14: 981.
3. Rushton HG and Majd M, Pyelonephritis
in male infants: how important is the
foreskin? J Urol, 1992. 148(2 Pt 2): 733–6;
discussion 737–8.
4. Wiswell TE and Hachey WE, Urinary
tract infections and the uncircumcised
state: an update. Clin Pediatr (Phila),
1993. 32(3): 130–4.
5. Winberg J, Andersen HJ, Bergstrom T,
Jacobsson B, Larson H, and Lincoln K,
Epidemiology of symptomatic urinary
tract infection in childhood. Acta Paediatr
Scand Suppl, 1974(252): 1–20.
6. Doganis D, Siafas K, Mavrikou M,
Issaris G, Martirosova A, Perperidis G,
Konstantopoulos A, and Sinaniotis K,
Does early treatment of urinary tract
infection prevent renal damage?
Pediatrics, 2007. 120(4): e922–8.
7. Hewitt IK, Zucchetta P, Rigon L, Maschio
F, Molinari PP, Tomasi L, Toffolo A,
Pavanello L, Crivellaro C, Bellato S,
and Montini G, Early treatment of acute
pyelonephritis in children fails to reduce
renal scarring: data from the Italian
Renal Infection Study Trials. Pediatrics,
2008. 122(3): 486–90.
8. Smellie JM, Ransley PG, Normand IC,
Prescod N, and Edwards D, Development
of new renal scars: a collaborative study.
Br Med J (Clin Res Ed), 1985. 290(6486):
1957–60.
9. Shimada K, Matsui T, Ogino T, and
Ikoma F, New development and progres-
sion of renal scarring in children with pri-
mary VUR. Int Urol Nephrol, 1989. 21(2):
153–8.
10. Verber IG and Meller ST, Serial 99mTc
dimercaptosuccinic acid (DMSA) scans
after urinary infections presenting before
339
Chapter |6| Urinary tract infections in children
the age of 5 years. Arch Dis Child, 1989.
64(11): 1533–7.
11. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
12. Abrams P, Khoury S, and Grant A,
Evidence-based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–684.
13. Lin DS, Huang SH, Lin CC, Tung YC,
Huang TT, Chiu NC, Koa HA, Hung HY,
Hsu CH, Hsieh WS, Yang DI, and Huang
FY, Urinary tract infection in febrile
infants younger than eight weeks of Age.
Pediatrics, 2000. 105(2): E20.
14. Eggli DF and Tulchinsky M, Scintigraphic
evaluation of pediatric urinary tract infec-
tion. Semin Nucl Med, 1993. 23(3): 199–218.
15. Practice parameter: the diagnosis, treat-
ment, and evaluation of the initial uri-
nary tract infection in febrile infants
and young children. American Academy
of Pediatrics. Committee on Quality
Improvement. Subcommittee on Urinary
Tract Infection. Pediatrics, 1999. 103(4 Pt
1): 843–52.
16. Ma JF and Shortliffe LM, Urinary tract
infection in children: etiology and epide-
miology. Urol Clin North Am, 2004. 31(3):
517–26, ix-x.
17. Zorc JJ, Kiddoo DA, and Shaw KN,
Diagnosis and management of pediatric
urinary tract infections. Clin Microbiol
Rev, 2005. 18(2): 417–22.
18. Vaillancourt S, McGillivray D, Zhang
X, and Kramer MS, To clean or not
to clean: effect on contamination rates
in midstream urine collections in toilet-
trained children. Pediatrics, 2007. 119(6):
e1288–93.
19. Koch VH and Zuccolotto SM, [Urinary
tract infection: a search for evidence].
J Pediatr (Rio J), 2003. 79 Suppl 1:
S97–106.
20. Whiting P, Westwood M, Watt I, Cooper
J, and Kleijnen J, Rapid tests and urine
sampling techniques for the diagnosis of
urinary tract infection (UTI) in children
under five years: a systematic review.
BMC Pediatr, 2005. 5(1): 4.
340
21. Cavagnaro F, [Urinary tract infection in
childhood]. Rev Chilena Infectol, 2005.
22(2): 161–8.
22. Bag urine specimens still not appropriate
in diagnosing urinary tract infections in
infants. Can J Infect Dis Med Microbiol,
2004. 15(4): 210–1.
23. Al-Orifi F, McGillivray D, Tange S, and
Kramer MS, Urine culture from bag speci-
mens in young children: are the risks too
high? J Pediatr, 2000. 137(2): 221–6.
24. Ramage IJ, Chapman JP, Hollman AS,
Elabassi M, McColl JH, and Beattie TJ,
Accuracy of clean-catch urine collection in
infancy. J Pediatr, 1999. 135(6): 765–7.
25. Hellerstein S, Urinary tract infection in
children: pathophysiology, risk factors
and management. Infect Med, 2002. 19:
554–560.
26. Austin BJ, Bollard C, and Gunn TR,
Is urethral catheterization a successful
alternative to suprapubic aspiration in
neonates? J Paediatr Child Health, 1999.
35(1): 34–6.
27. Buys H, Pead L, Hallett R, and Maskell
R, Suprapubic aspiration under ultra-
sound guidance in children with fever
of undiagnosed cause. BMJ, 1994.
308(6930): 690–2.
28. Kiernan SC, Pinckert TL, and Keszler
M, Ultrasound guidance of suprapubic
bladder aspiration in neonates. J Pediatr,
1993. 123(5): 789–91.
29. Hildebrand WL, Schreiner RL, Stevens
DC, Gosling CG, and Sternecker CL,
Suprapubic bladder aspiration in infants.
Am Fam Physician, 1981. 23(5): 115–8.
30. Hallander HO, Kallner A, Lundin A, and
Osterberg E, Evaluation of rapid methods
for the detection of bacteriuria (screen-
ing) in primary health care. Acta Pathol
Microbiol Immunol Scand B, 1986. 94(1):
39–49.
31. Lohr JA, Use of routine urinalysis in mak-
ing a presumptive diagnosis of urinary
tract infection in children. Pediatr Infect
Dis J, 1991. 10(9): 646–50.
32. Hoberman A, Wald ER, Reynolds EA,
Penchansky L, and Charron M, Is urine
culture necessary to rule out urinary
tract infection in young febrile children?
Pediatr Infect Dis J, 1996. 15(4): 304–9.
 Diagnostic work-up of urinary tract infections in childrens
33. Deville WL, Yzermans JC, van Duijn
NP, Bezemer PD, van der Windt DA, and
Bouter LM, The urine dipstick test useful
to rule out infections. A meta-analysis of
the accuracy. BMC Urol, 2004. 4: 4.
34. Hoberman A and Wald ER, Urinary
tract infections in young febrile children.
Pediatr Infect Dis J, 1997. 16(1): 11–7.
35. Stamm WE, Measurement of pyuria and
its relation to bacteriuria. Am J Med,
1983. 75(1B): 53–8.
36. Landau D, Turner ME, Brennan J, and
Majd M, The value of urinalysis in differ-
entiating acute pyelonephritis from lower
urinary tract infection in febrile infants.
Pediatr Infect Dis J, 1994. 13(9): 777–81.
37. Hoberman A, Chao HP, Keller DM,
Hickey R, Davis HW, and Ellis D,
Prevalence of urinary tract infection in
febrile infants. J Pediatr, 1993. 123(1):
17–23.
38. Piercey KR, Khoury AE, McLorie GA,
and Churchill BM, Diagnosis and man-
agement of urinary tract infections. Curr
Opin Urol, 1993. 3: 25–29.
39. Kass EH and Finland M, Asymptomatic
infections of the urinary tract. J Urol,
2002. 168(2): 420–4.
40. Bollgren I, Engstrom CF, Hammarlind
M, Kallenius G, Ringertz H, and Svenson
SB, Low urinary counts of P-fimbriated
Escherichia coli in presumed acute
pyelonephritis. Arch Dis Child, 1984.
59(2): 102–6.
41. Pecile P and Romanello C, Procalcitonin
and pyelonephritis in children. Curr Opin
Infect Dis, 2007. 20(1): 83–7.
42. Kotoula A, Gardikis S, Tsalkidis
A, Mantadakis E, Zissimopoulos A,
Kambouri K, Deftereos S, Tripsianis G,
Manolas K, Chatzimichael A, and Vaos G,
Procalcitonin for the early prediction of
renal parenchymal involvement in chil-
dren with UTI: preliminary results. Int
Urol Nephrol, 2009. 41(2): 393–9.
43. Halevy R, Smolkin V, Bykov S,
Chervinsky L, Sakran W, and Koren A,
Power Doppler ultrasonography in the
diagnosis of acute childhood pyelonephri-
tis. Pediatr Nephrol, 2004. 19(9): 987–91.
44. Garin EH, Olavarria F, Araya C,
Broussain M, Barrera C, and Young L,
| 6.3 |
Diagnostic significance of clinical and
laboratory findings to localize site of uri-
nary infection. Pediatr Nephrol, 2007.
22(7): 1002–6.
45. Kass EJ, Fink-Bennett D, Cacciarelli AA,
Balon H, and Pavlock S, The sensitivity
of renal scintigraphy and sonography in
detecting nonobstructive acute pyelone-
phritis. J Urol, 1992. 148(2 Pt 2): 606–8.
46. Huang HP, Lai YC, Tsai IJ, Chen SY, and
Tsau YK, Renal ultrasonography should
be done routinely in children with first
urinary tract infections. Urology, 2008.
71(3): 439–43.
47. Pickworth FE, Carlin JB, Ditchfield
MR, de Campo MP, de Campo JF, Cook
DJ, Nolan T, Powell HR, Sloane R, and
Grimwood K, Sonographic measurement
of renal enlargement in children with
acute pyelonephritis and time needed for
resolution: implications for renal growth
assessment. AJR Am J Roentgenol, 1995.
165(2): 405–8.
48. Miron D, Daas A, Sakran W, Lumelsky D,
Koren A, and Horovitz Y, Is omitting post
urinary-tract-infection renal ultrasound
safe after normal antenatal ultrasound?
An observational study. Arch Dis Child,
2007. 92(6): 502–4.
49. Keren R, Imaging and treatment strate-
gies for children after first urinary tract
infection. Curr Opin Pediatr, 2007. 19(6):
705–10.
50. Zamir G, Sakran W, Horowitz Y, Koren
A, and Miron D, Urinary tract infection:
is there a need for routine renal ultra-
sonography? Arch Dis Child, 2004. 89(5):
466–8.
51. Giorgi LJ, Jr., Bratslavsky G, and Kogan
BA, Febrile urinary tract infections in
infants: renal ultrasound remains neces-
sary. J Urol, 2005. 173(2): 568–70.
52. Jahnukainen T, Honkinen O, Ruuskanen
O, and Mertsola J, Ultrasonography after
the first febrile urinary tract infection in
children. Eur J Pediatr, 2006. 165(8):
556–9.
53. Westwood ME, Whiting PF, Cooper J,
Watt IS, and Kleijnen J, Further investi-
gation of confirmed urinary tract infection
(UTI) in children under five years: a sys-
tematic review. BMC Pediatr, 2005. 5(1): 2.
341
Chapter |6| Urinary tract infections in children
54. Piaggio G, Degl’ Innocenti ML,
Toma P, Calevo MG, and Perfumo F,
Cystosonography and voiding cystoure-
thrography in the diagnosis of vesi-
coureteral reflux. Pediatr Nephrol, 2003.
18(1): 18–22.
55. Darge K, Voiding urosonography with
US contrast agents for the diagnosis
of vesicoureteric reflux in children. II.
Comparison with radiological examina-
tions. Pediatr Radiol, 2008. 38(1): 54–63;
quiz 126–7.
56. Darge K, Moeller RT, Trusen A, Butter F,
Gordjani N, and Riedmiller H, Diagnosis
of vesicoureteric reflux with low-dose con-
trast-enhanced harmonic ultrasound imag-
ing. Pediatr Radiol, 2005. 35(1): 73–8.
57. Riccabona M, Mache CJ, and Lindbichler
F, Echo-enhanced color Doppler cys-
tosonography of vesicoureteral reflux in
children. Improvement by stimulated
acoustic emission. Acta Radiol, 2003.
44(1): 18–23.
58. Rachmiel M, Aladjem M, Starinsky R,
Strauss S, Villa Y, and Goldman M,
Symptomatic urinary tract infections
following voiding cystourethrography.
Pediatr Nephrol, 2005. 20(10): 1449–52.
59. Haycock GB, A practical approach to
evaluating urinary tract infection in chil-
dren. Pediatr Nephrol, 1991. 5(4): 401–2;
discussion 403.
60. Kleinman PK, Diamond DA, Karellas A,
Spevak MR, Nimkin K, and Belanger P,
Tailored low-dose fluoroscopic voiding
cystourethrography for the reevaluation
of vesicoureteral reflux in girls. AJR Am J
Roentgenol, 1994. 162(5): 1151–4; discus-
sion 1155–6.
61. Kass EJ, Kernen KM, and Carey JM,
Paediatric urinary tract infection and the
necessity of complete urological imaging.
BJU Int, 2000. 86(1): 94–6.
62. Doganis D, Mavrikou M, Delis D,
Stamoyannou L, Siafas K, and Sinaniotis
K, Timing of voiding cystourethrography
in infants with first time urinary infection.
Pediatr Nephrol, 2009. 24(2): 319–22.
63. Sathapornwajana P, Dissaneewate P,
McNeil E, and Vachvanichsanong P,
Timing of voiding cystourethrogram after
urinary tract infection. Arch Dis Child,
2008. 93(3): 229–31.
342
64. Mahant S, To T, and Friedman J, Timing
of voiding cystourethrogram in the inves-
tigation of urinary tract infections in chil-
dren. J Pediatr, 2001. 139(4): 568–71.
65. McDonald A, Scranton M, Gillespie R,
Mahajan V, and Edwards GA, Voiding
cystourethrograms and urinary tract
infections: how long to wait? Pediatrics,
2000. 105(4): E50.
66. Craig JC, Knight JF, Sureshkumar
P, Lam A, Onikul E, and Roy LP,
Vesicoureteric reflux and timing of mic-
turating cystourethrography after urinary
tract infection. Arch Dis Child, 1997.
76(3): 275–7.
67. Kangarloo H, Gold RH, Fine RN,
Diament MJ, and Boechat MI, Urinary
tract infection in infants and children
evaluated by ultrasound. Radiology, 1985.
154(2): 367–73.
68. Huang JJ, Sung JM, Chen KW, Ruaan
MK, Shu GH, and Chuang YC, Acute bac-
terial nephritis: a clinicoradiologic cor-
relation based on computed tomography.
Am J Med, 1992. 93(3): 289–98.
69. Kass EJ, Imaging in acute pyelonephritis.
Curr Opin Urol, 1994. 4(1): 39–44.
70. Stutley JE and Gordon I, Vesico-ureteric
reflux in the damaged non-scarred kidney.
Pediatr Nephrol, 1992. 6(1): 25–9.
71. Britton KE, Renal radionuclide studies, in
Textbook of genitourinary surgery, Whitfield
HN, Hendry WF, and Kirby RS, Editors.
1998, Blackwell Science: Oxford. p. 76–103.
72. Rosenberg AR, Rossleigh MA, Brydon MP,
Bass SJ, Leighton DM, and Farnsworth
RH, Evaluation of acute urinary tract
infection in children by dimercaptosuc-
cinic acid scintigraphy: a prospective
study. J Urol, 1992. 148(5 Pt 2): 1746–9.
73. Jakobsson B, Soderlundh S, and Berg U,
Diagnostic significance of 99mTc-dimer-
captosuccinic acid (DMSA) scintigraphy
in urinary tract infection. Arch Dis Child,
1992. 67(11): 1338–42.
74. Rushton HG, Majd M, Jantausch B,
Wiedermann BL, and Belman AB, Renal
scarring following reflux and nonreflux
pyelonephritis in children: evaluation
with 99mtechnetium-dimercaptosuccinic
acid scintigraphy. J Urol, 1992. 147(5):
1327–32.
 Diagnostic work-up of urinary tract infections in childrens
75. Risdon RA, The small scarred kidney of
childhood. A congenital or an acquired
lesion? Pediatr Nephrol, 1987. 1(4):
632–7.
76. Risdon RA, Godley ML, Gordon I, and
Ransley PG, Renal pathology and the
99mTc-DMSA image before and after
treatment of the evolving pyelonephritic
scar: an experimental study. J Urol, 1994.
152(4): 1260–6.
77. Jakobsson B and Svensson L, Transient
pyelonephritic changes on 99mTechne-
tium-dimercaptosuccinic acid scan for
at least five months after infection. Acta
Paediatr, 1997. 86(8): 803–7.
78. Rushton HG, Majd M, Chandra R, and
Yim D, Evaluation of 99mtechnetium-
dimercapto-succinic acid renal scans in
experimental acute pyelonephritis in pig-
lets. J Urol, 1988. 140(5 Pt 2): 1169–74.
79. Bircan ZE, Buyan N, Hasanoglu E,
Ozturk E, Bayhan H, and Isik S,
Radiologic evaluation of urinary tract
infection. Int Urol Nephrol, 1995. 27(1):
27–32.
80. Elison BS, Taylor D, Van der Wall
H, Pereira JK, Cahill S, Rosenberg
AR, Farnsworth RH, and Murray IP,
Comparison of DMSA scintigraphy with
intravenous urography for the detection
of renal scarring and its correlation with
vesicoureteric reflux. Br J Urol, 1992.
69(3): 294–302.
81. MacKenzie JR, Fowler K, Hollman AS,
Tappin D, Murphy AV, Beattie TJ, and
Azmy AF, The value of ultrasound in the
child with an acute urinary tract infec-
tion. Br J Urol, 1994. 74(2): 240–4.
82. O’Reilly P, Aurell M, Britton K, Kletter K,
Rosenthal L, and Testa T, Consensus on
diuresis renography for investigating the
dilated upper urinary tract. Radionuclides
in Nephrourology Group. Consensus
Committee on Diuresis Renography. J
Nucl Med, 1996. 37(11): 1872–6.
83. Mucci B and Maguire B, Does routine
ultrasound have a role in the investiga-
tion of children with urinary tract infec-
tion? Clin Radiol, 1994. 49(5): 324–5.
84. Choong KK, Gruenewald SM, Hodson
EM, Antico VF, Farlow DC, and Cohen
RC, Volume expanded diuretic renography
in the postnatal assessment of suspected
| 6.3 |
uretero-pelvic junction obstruction. J Nucl
Med, 1992. 33(12): 2094–8.
85. De Sadeleer C, De Boe V, Keuppens F,
Desprechins B, Verboven M, and Piepsz
A, How good is technetium-99m mercap-
toacetyltriglycine indirect cystography?
Eur J Nucl Med, 1994. 21(3): 223–7.
86. Majd M, Rushton HG, Jantausch B, and
Wiedermann BL, Relationship among
vesicoureteral reflux, P-fimbriated
Escherichia coli, and acute pyelonephri-
tis in children with febrile urinary tract
infection. J Pediatr, 1991. 119(4): 578–85.
87. Melis K, Vandevivere J, Hoskens C,
Vervaet A, Sand A, and Van Acker KJ,
Involvement of the renal parenchyma
in acute urinary tract infection: the
contribution of 99mTc dimercaptosuccinic
acid scan. Eur J Pediatr, 1992. 151(7):
536–9.
88. Smellie JM and Rigden SP, Pitfalls in
the investigation of children with urinary
tract infection. Arch Dis Child, 1995.
72(3): 251–5; discussion 255–8.
89. Smellie JM, Rigden SP, and Prescod NP,
Urinary tract infection: a comparison of
four methods of investigation. Arch Dis
Child, 1995. 72(3): 247–50.
90. Guidelines for the management of
acute urinary tract infection in child-
hood. Report of a Working Group of
the Research Unit, Royal College of
Physicians. J R Coll Physicians Lond,
1991. 25(1): 36–42.
91. Baumer JH and Jones RW, Urinary tract
infection in children, National Institute
for Health and Clinical Excellence. Arch
Dis Child Educ Pract Ed, 2007. 92(6):
189–92.
92. Tse NK, Yuen SL, Chiu MC, Lai WM,
and Tong PC, Imaging studies for first
urinary tract infection in infants less than
6 months old: can they be more selective?
Pediatr Nephrol, 2009. 24(9): 1699–703.
93. Beetz R, Bachmann H, Gatermann S,
Keller H, Kuwertz-Broking E, Misselwitz
J, Naber KG, Rascher W, Scholz
H, Thuroff JW, Vahlensieck W, and
Westenfelder M, [Urinary tract infections
in infants and children – a consensus
on diagnostic, therapy and prophylaxis].
Urologe A, 2007. 46(2): 112, 114–8,
120–3.
343
|6.4|

Antimicrobial therapy of urinary

tract infections in children
Rolf Beetz, Martin Westenfelder
PD Dr. med. Rolf Beetz, Paediatric Nephrology, Center for Paediatric and Adolescent Medicine
University Medical Clinic, Langenbeckstr.1, 55131 Mainz
Phone +41-6131-17 3937, Fax +41-6131-17 6426, e-mail: beetz@kinder.klinik.uni-mainz.de
Prof. Dr. med. Martin Westenfelder, Zentrum für Kinderurologie und plastisch rekonstruktive Urologie
HELIOS Klinikum Krefeld, Lutherplatz 40, 47805 Krefeld
Tel. +49 2151 32 2281, Fax +49 2151 32 2018, E-Mail: martin.westenfelder@helios-kliniken.de

ABSTRACT factors. In early infancy, a combination of

The main objectives in childhood urinary
tract infections are rapid recovery from
complaints, prevention of urosepsis and
infection-related complications as well as
the prevention of renal parenchymal dam-
age. Calculated antibiotic therapy should
take the local resistance-rates of uropath-
ogens into consideration. The current situ-
ation of bacterial resistances differs from
region to region. In E.coli, resistance rates
against cephalosporines, aminoglycosides,
nitrofurantoin und chinolones have been
relatively low. In contrast, resistance
rates against ampicillin have increased
over the last 20 years. A similar trend has
been observed for TMP/SMX. The choice
of appropriate antibiotics, the duration
of therapy and the form of application
depend on age, severity of clinical symp-
toms and the presence of complicating
aminoglycoside/ampicillin or ceftazidime/
ampicillin is commonly recommended
as first line treatment in pyelonephritis.
Pyelonephritis in young infants should
always be treated in a paediatric clinic. In
later infancy and childhood, an oral third
generation cephalosporin can be used.
Key words: antimicrobial therapy, pro-
phylaxis, pyelonephritis, cystitis, asymp-
tomatic bacteriuria, voiding dysfunction,
resistance, recurrence, urinary tract
infections, children, infants
SUMMARY OF RECOMMENDATIONS
1. In newborns and young infants with
pyelonephritis, parenteral anti-
biotic therapy is initiated with a
combination of a third generation
cephalosporin and ampicillin or with
 Antimicrobial therapy of urinary tract infections in children
aminoglycoside and ampicillin (GoR
A). Infants of this age should be
treated in the hospital (GoR C).
2. In infants after the age of two to six
months and without further compli-
cating factors (i.e. urinary tract abnor-
malities and neurogenic bladder),
pyelonephritis can be treated by oral
third generation cephalosporines or
with short courses (two to four days)
of IV therapy, followed by oral therapy
[1] (GoR A). However, if enterococci
infection is suspected, amoxycillin or
ampicillin should be added (GoR C).
3. In case of cystitis in older children,
oral antibiotic therapy is sufficient
(GoR A). It is suggested to use a sec-
ond or third generation cephalosporin
as the first line agent (GoR B).
4. Due to worldwide increasing and quite
high resistance-rates of E.coli against
ampicillin, this substance should
not be used any longer as first line
medication for urinary tract infections
(GoR B). This is also true for co-
trimoxazole and respectively trimetho-
prim in regions in which resistance
rates of E.coli exceed 20% (GoR B).
5. The duration of antibiotic therapy
is seven to 14 days in newborns and
small infants (GoR B), seven to 10
days in the case of pyelonephritis in
older infants and children [2] (GoR
B), and three to five days in cysti-
tis (GoR A). If further diagnostics
(i.e. VCUG, diuretic renography)
are planned after pyelonephritis,
prophylactic dosages of the appropri-
ate antibiotic should be given until
the results of the imaging tests are
available (GoR C).
6. Asymptomatic bacteriuria does not usu-
ally need antibiotic therapy (GoR A).
7. In children with high grade reflux,
severe urinary obstruction and fre-
quently recurrent pyelonephritis
chemoprophylaxis should be consid-
ered in order to decrease the rate of
| 6.4 |
recurrences and the risk of renal scar-
ring (GoR B).
8. Prophylaxis should not be restricted to
the use of antibiotics or other prophy-
lactic agents but must also include the
efficient management of bladder and/or
bowel dysfunction, as well as the treat-
ment of predisposing factors (GoR B).
1. INTRODUCTION
The main objectives in childhood urinary
tract infections are rapid recovery from
complaints, prevention of related com-
plications, such as urosepsis, urolithiasis
and renal abscess, as well as the preven-
tion of permanent renal parenchymal
damage. To achieve these aims, urinary
tract infections must be recognized and
treated during the early stage of the dis-
ease. Antibiotics should be both highly
effective in eliminating usual uropatho-
gens and well tolerated by infants and
children. This especially applies to
pyelonephritic episodes. The choice of an
appropriate antibiotic, considering the
increasing resistance rates against some
of the conventional agents, is most impor-
tant. The unnecessary usage of ‘reserve’
antibiotics should be avoided in simple
urinary tract infections.
This part of the chapter focuses on the
therapy and prophylaxis of urinary tract
infections in infants and children.
2. METHODS
A systematic literature search was per-
formed for the last 10 years in MEDLINE
and Cochrane library with the follow-
ing key words: urinary tract infections,
therapy, prophylaxis. Limitations were
children 0–14 years. An English abstract
had to be available. The authors also had
continuously observed the relevant litera-
ture concerning the topic during the last
twenty years. Only peer reviewed articles
were included.
345
Chapter |6| Urinary tract infections in children

A total of more than 300 publications
were identified, which were screened by
title and abstract, and more than 80 stud-
ies were included in the analysis.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [3–4].
3. GENERAL ASPECTS OF
ANTIMICROBIAL THERAPY
IN CHILDHOOD
3.1 Choice of antibiotic
3.1.1 Aspects of calculated therapy
An acute, symptomatic urinary tract
infection mostly requires antibacterial
therapy before the pathogen is known
and the results of a resistance test are
available. Therefore, the selection of the
antibiotic(s) is “calculated” from the high-
est pathogen probability. Prior to the
therapy’s initiation, a urine culture (in
case of highly feverish infections, fore-
most in infancy, also a blood culture)
should be taken to be able to modify the
therapy, if applicable.
As in adulthood, E.coli are by far the
most prevalent pathogens of urinary tract
infections in children (Table 1). The path-
ogen probability is dependent on age and
gender: the percentage rate of Enterococcus
infections is higher in early infancy than
at a later age [5–6]. In a recent study, 20%
of uropathogens in boys from birth to four
years years and 15% in girls at the same
age were Enterococci [5]. This accounts
inter alia for the combination therapy of
third-generation cephalosporines, respec-
tively amino glycosides, with ampicillin in
the infant age group (LoE 2a).
In case of pre-existing abnormalities
or dysfunctions of the urinary tract (so
called complicated urinary tract infec-
tions), after earlier urinary tract infec-
tions, and under antibacterial prophylaxis
non-E.coli strains are more often to be
reckoned with (Table 1). This is also true
for nosocomial urinary tract infections.
In association with secondary urolithi-
asis (magnesium ammonium phosphate

Table 1 Organisms isolated from the urinary tracts of children in the community and those with an underlying renal problem.

Isolates from children in the Isolates from children with

community underlying renal problems

Escherichia coli 63.0% 40.3%

Proteus spp. 5.8% 3.7%

Klebsiella spp. 3.3% 7.6%

Enterobacter sp.. 1.2% 3.8%

Morganella morganii 0.9% 1.3%

Pseudomonas spp. 2.1% 10.8%

Stenotrophomonas maltophilia 0% 0.7%

Other Gram negative bacilli 1.0% 2.1%

Staphylococcus aureus 0.9% 2.9%

Other staphylococci 0.6% 3.7%

Enterococcus spp. 19.3% 20.2%

Non-faecal streptococci 1.9% 2.8%

from: Ladhani S, Gransden W 2003.

346
 Antimicrobial therapy of urinary tract infections in children | 6.4 |

calculi), Proteus bacteria are most likely
to be found. Urinary tract infections with
Proteus species are more often found in
male infants than in girls because of fre-
quent colonization of the prepuce.
The pathogen’s responsiveness to anti-
biotics depends on the natural resist-
ance and the actual resistance situation,
which can differ largely from region to
region. E.coli show the least resistance
against second and third generation
cephalosporines, amino glycosides, nitro-
furantoin and quinolones,. In contrast,
the resistance to ampicillin grew consid-
erably in many places over the past 20
years and concerns over 50% of the E.coli
in some regions. A similar trend becomes
apparent in childhood concerning co-tri-
moxazole and trimethoprim respectively
[6–15] (Table 2).
After antibacterial pre-treatment and
during antibacterial prophylaxis, the risk
of resistant uropathogens is especially
high [10].
3.1.2 Specific problems in the choice
of antibiotic in childhood
Not all available antibiotics are approved
by the national health authorities in
infancy and childhood. Trimethoprim
is contraindicated in premature infants
and newborns. Usage limitations exist
for infants under six weeks (due to the
lack of adequate experience). Because of
the danger of haemolytic anaemia, nitro-
furantoin is contraindicated for young
infants until the third month of age.
In Germany, ciprofloxacin is only
approved for the treatment of compli-
cated urinary tract infections from the
age of one to two years onward. The
American Academy of Paediatrics (AAP)
Committee on Infectious Diseases rec-
ommends that the use of ciprofloxacin
for UTI in children be limited to urinary
tract infections caused by Pseudomonas
aeruginosa or other multi-drug resistant,
Gram-negative bacteria. Circumstances
in which fluorquinolones may be useful

Table 2 Resistance rates of E.coli in urinary tract infections in children observed in isolates from different European regions
(in %). The data were collected in different age groups and with first or recurrent UTIs. They are not comparable to each
other. The numbers are useful to demonstrate trends.

Heidelberg, London, Kreta, Innsbruck, Istanbul, Tel Aviv, Toulouse,

Germany England Greece Austria Turkey Israel France
Schmitt CP Ladhani S Anatoliaki M Prelog M Gökce I Marcus N Prere M-F
2007 2003 2007 2008* 2006 2005 2004

Amoxicillin/ 44 51,1 56,4 64,8 62 62 53

Ampicillin

Amoxicillin- 10 15,5 6,9 43 8 7

Clavulanic acid

TMP/Sulfa- 34 27,6 27,3 35,5 33 38 22

methozazole

Cefaclor 5 22,5 2,8** 37**

Cefuroxime 2 0,9 3,1 2,8 19 1

Ceftazidime 0 1,0 0 1

Ceftriaxone 1,6 1,0 9 0 0

Ciprofloxacin 3 0 3

Nitrofurantoin 5,9 2,6 3,4 15 3 7

*only children > 25 months of age.

**Cefazolin.

347
Chapter |6| Urinary tract infections in children

include those in which 1) the infection is
caused by multidrug-resistant pathogens
for which there is no safe and effective
alternative and 2) parenteral therapy is
not feasible and no other effective oral
agent is available [16] (LoE 4).
The dosage of all substances is depend-
ent on age and body weight (Table 3).
with the Schwartz formula (Table 4)
[17–19].
Drug monitoring is essential in the
deployment of amino glycosides.
Nitrofurantoin is not deployable when
the GFR is less than 50% of the norm,
because insufficient renal elimination does
not allow sufficient urine concentration.

3.1.3 Kidney function 3.2 Form of application

In case of impaired renal function, the The decision for oral or parenteral ther-
dosage is adjusted to the glomerular filtra- apy complies with age, severity of the
tion rate, which can be calculated from the illness, and prerequisites for oral appli-
current serum creatinine and body length cation (Table 5). Because of the increased

Table 3 Frequently used antibacterial substances for the therapy of urinary tract infections in infants and children
up to 12 years.*

Chemotherapeutics Daily dosage Application Comments

Parenteral Cephalosporines
Group 3a, e.g. Cefotaxim 100–200 mg/kg i.v. in 2–3 D
(Adolesc.: 3–6 g)
i.v. in 2–3 D
Group 3b, e.g. Ceftazidim 100–150 mg/kg
(Adolesc.: 2–6 g)

Oral-Cephalosporine
Group 3, e.g. Ceftibuten 9 mg/kg p.o. in 1–2 D
(Adolesc.: 0,4 g)
Group 3, e.g. Cefixim 8–12 mg/kg p.o. in 1–2 D
(Adolesc.: 0,4 g)
Group 2, e.g. Cefpodoximproxetil 8–10 mg/kg p.o. in 1–2 D
(Adolesc.: 0,4 g) p.o. in 2 D
Group 2, e.g. Cefuroximaxetil 20–30 mg/kg p.o. in 3 D
(Adolesc.: 0,5–1 g)
Group 1, e.g. Cefaclor 50–100 mg/kg p.o. in 2–3 D
(Adolesc.: 1,5–4 g)

Trimethoprim or 5–6 mg/kg p.o. in 2 D

Trimethoprim/Sulfamethoxazol 5–6 mg/kg (TMP-Anteil) p.o. in 2 D
(Adolesc.: 320 mg)

Ampicillin 100–200 mg/kgKG i.v. in 3 D Ampicillin and Amoxicillin

are not eligible for calculated
(Adolesc.: 3–6 g) i.v. in 3–4 D
monotherapy
Amoxicillin 50–100 mg/kg p.o. in 2–3 D1
(Adolesc.: 1,5–6 g) p.o. in 2–3 D

348
 Antimicrobial therapy of urinary tract infections in children | 6.4 |

Chemotherapeutics Daily dosage Application Comments

Amoxicillin/Clavulanic acid 60–100 mg/kg i.v. in 3 D

(parenteral) (Adolesc.: 3,6–6,6 g)
i.v. in 3 D
45–60 mg/kg
Amoxicillin/Clavulanic acid (oral) p.o. in 3 D
(Amoxicillin-fraction)
(Adolesc.: 1500 + 375 mg) p.o.in 3 D

Tobramycin 5 mg/kg i.v. in 1 D Drug monitoring

(Adolesc.: 3–5 mg/kg, max. 0,4 g)
Gentamicin 5 mg/kg
i.v. in 1 D
(Adolesc.: 3–5 mg/kg, max. 0,4g)

Ciprofloxacin Children and adolesc. i.v. in 3 D Approved in most European

(1–17 years of age): 20–30 mg/kg
(max. D: 400 mg) (parenterally)
Children and adolesc.
(1–17 years of age): 20–40 mg/kg
(max. D 750 mg) (orally)
countries as second-or third
line medication for compli-
cated UTIs,
p.o. in 2 D “reserve-antibiotic“ !

Nitrofurantoin 3–5 mg p.o. in 2 D Contraindicated in the case of

renal insufficiency

*Dosage for adolescents in paracentesis, if differing.

1
Infants 2 D, children 1–12 ys. 3 D.

Table 4 Calculation of the glomerular filtration rate according to the Schwartz formula
(Schwartz 1976, 1984, 1985).
Glomerular filtration rate (mL/min x 1.73 m2) = k x L / Crea.S
k = correcting factor (see table); L = body length in cms; Crea S = serum creatinine (mg/dL)
Correcting factors for the Schwartz formula

Age group Age (years) k (mean)* k (mean)**

Term newborns and infants <1 0.45 40

Children 2–12 0.55 48

Female adolescents > 12 0.55 48

Male adolescents > 12 0.70 62

*factor k for Creatinine in mg/dL.

**factor k for Creatinine in mmol/L.

incidence of urosepsis and severe pyelone- cephalosporines enables a relatively safe

phritis, newborns and infants under two
months of age are in need of parenteral
antibiotic therapy (LoE 4).
The intention to convert the recom-
mended inpatient initial treatment of
pyelonephritis in later infancy and child-
hood to ambulant per oral therapy has
resulted for various reasons. The avail-
ability of potent, orally applicable group 3
oral therapy for urinary tract infections.
The cost savings make ambulant therapy
of urinary tract infections attractive and
it adds to the prevention of nosocomial
infections.
Alternative options to ambulatory man-
agement include outpatient parenteral
therapy for patients with acute pyelone-
phritis. Several studies have demonstrated

349
Chapter |6| Urinary tract infections in children
Table 5 Indications for parenteral application of antibacterial medication in UTI.
•  Newborns and young infants (< 4–6 months of age)
•  Clinical suspicion of urosepsis
•  Critically ill condition
•  Refusal of fluids or/and food and/or oral medication
•  Vomiting, diarrhoea
•  Non-compliance
•  complicated pyelonephritis (e.g. urinary obstruction)
that once-daily parenteral administration
of gentamicin or ceftriaxon in a day treat-
ment centre is safe, effective and cost-
effective in children with UTI [20]
(LoE 1b).
Children with urinary tract abnor-
malities have been excluded from all
randomised studies comparing the equal-
ity of an oral therapy to the parental
treatment. Thus, the responsible pae-
diatrician should at least establish by
ultrasonography whether a urinary tract
deformity is existent, before dismissing
hospitalization.
4. THERAPY OF PYELONEPHRITIS
4.1 Pyelonephritis in newborns
and early infancy
In newborns and young infants, a febrile
urinary tract infection proceeds consider-
ably more frequently in the form of uro-
sepsis than in older children. Positive
blood cultures are found in approxi-
mately 20%. Electrolyte disorders with
hyponatremia and hyperkalemia may
occur; most likely because of temporary
pseudo-hypoaldosteronism. For these
reasons, newborns and infants in the
first two to six months of life initially
require parenteral antibacterial therapy
under inpatient conditions (Table 6). The
combination treatment with ampillicin
and an amino-glycoside (Tobramycin®,
Gentamicin®) respectively a group 3
cephalosporin, achieves great therapeutic
350
 
safety (high efficacy of aminoglycosides,
respectively cephalosporines against com-
mon uropathogens; enterococcus gap is
closed with ampillicin) (LoE 3).
When applying amino-glycosides, a
single daily dose is safe and effective
[1, 21–22] (LoE 1a).
After defervescence, and after the
microbiological resistance results are
known, a parenteral, calculated therapy
can be changed over to a targeted resist-
ance-appropriate medication.
4.2 Therapy of pyelonephritis in
late infancy and childhood
In case of pyelonephritis beyond early
infancy, the incidence of parenchymal
scars in DMSA scan after a three-day
antibacterial intravenous therapy, fol-
lowed by a five-day oral treatment, equals
the incidence after an eight-day intrave-
nous treatment regimen [23] (LoE 1b).
According to more recent studies, an
exclusively oral therapy with a group 3
cephalosporin (e.g. cefixim, ceftibuten)
is equal to the usual two to four days
intravenous therapy followed by an oral
treatment. This is true for the duration
of fever, as well as for the development
of persistent renal scars [22, 24–25].
Similar data has been shown for amoxi-
cillin-clavulanate [26] (LoE 1a). However,
amoxicillin-clavulanate is associated with
increasing rates of resistance.
Hence, in case of pyelonephritis in
infancy and childhood, the antibacte-
rial treatment with an oral group 3
 Antimicrobial therapy of urinary tract infections in children | 6.4 |

Table 6 Recommendations for calculated antibacterial therapy of pyelonephritis dependent on age and
severity of the infection.

Duration of Level of
Diagnosis Proposal Application therapy Evidence

Pyelonephritis during Ceftazidim + Ampicil- 3–7 days parenterally, for 10 (–14) days IV
the first 0–6 months lin1 or Aminoglycoside at least 2 days after after de-
of life + Ampicillin1 vervescence, then oral therapy2
In newborns: parenteral Newborns 14–21
therapy for 7–14 days, then days
oral therapy2

Uncomplicated Cephalosporine Orally (initially parenterally, if (7–)10 days I

pyelonephritis after group 32 necessary)
6 months of age

Complicated pye- Ceftazidime + 7 days parenterally, then oral 10–14 days IV

lonephritis/ urosepsis Ampicillin1 or therapy2
(all ages) Aminoglycoside +
Ampicillin1

after receipt of microbiological findings (pathogen, resistance) adaption of therapy.

1

i.v.: e.g. Cefotaxim; orally: e.g. Cefpodoximproxetil, Ceftibuten, Cefixim.

2

cephalosporin can be carried out after paediatric UTIs with antibiotics for seven
thorough consideration, if a good compli- to 14 days [2]
ance is to be expected and medical sur-
veillance and therapy are warranted, and 4.3 Therapy of complicated
if urinary tract abnormalities have been pyelonephritis
excluded (Table 6) [1].
In complicated UTI non-E.coli uropath-
The conclusion that ambulant treat-
ogens, such as Proteus mirabilis,
ment is to be equated with an inpatient
Klebsiella spp., Indol-pos. Proteus spp.,
therapy cannot be drawn without further
Pseudomonas aeruginosa, Enterococci
consideration. Adequate surveillance,
and Staphylococci are more often to be
medical supervision and, if necessary,
anticipated. Parenteral treatment with
adjustment of the therapy must be guar-
broad-spectrum antibiotics is to be pre-
anteed. To what extent this can be guar-
ferred over oral therapy. A temporary uri-
anteed in everyday practice by ambulant
nary diversion (suprapubic cystostomy
treatment in infancy and childhood, has
or percutaneous nephrostomy) might be
not been investigated so far. If the deci-
required in case of failure in obstructive
sion is made in favour of ambulant treat-
uropathies (i.e. severe pyonephrosis with
ment, the first oral administration of
urethral valves, obstructive megaureter
the antibiotic in the clinic, respectively
or ureteropelvic junction obstruction).
the medical practice, should be applied
in double dosage, to test compliance and
tolerance to the preparation. Also, close 4.4 Acute focal bacterial nephritis
contact with the family is advised in the (“lobar nephronia”)
initial phase of the therapy [27]. Acute focal bacterial nephritis (“lobar
Regarding the optimal duration of ther- nephronia”) is a localized bacterial infec-
apy, a meta-analysis provided an empiri- tion of the kidney presenting as an inflam-
cal basis for the current widespread matory mass without abscess formation,
and recommended practice of treating which may represent a relatively early

351
Chapter |6| Urinary tract infections in children
stage of renal abscess. For the majority
of children, the pathogenesis is related to
ascending infection due to pre-existing
uropathy, especially vesicorenal reflux or
urinary obstruction. Prolonged intrave-
nous antibiotic treatment is sufficient in
most cases [28]; three weeks of intrave-
nous and oral therapy tailored to the path-
ogen noted in cultures seems to be superior
to shorter treatment [29] (LoE 2 a).
4.5 Therapy of cystitis and
cystourethritis
Symptomatic nonfebrile UTIs with
dysuria, alguria, pollakisuria, lower
abdominal pain and/or onset of second-
ary urinary incontinence require a treat-
ment which guarantees high urine levels
of the antibiotic used. In this respect,
nitrofurantoin could be one of the most
appropriate substances – it has, however,
limitations due to frequent gastrointes-
tinal intolerance reactions. Currently,
trimethoprim or trimethoprim/sulfo-
methoxazole and related substances are
regarded substances of first choice in
uncomplicated cystitis. Increasing resist-
ance rates, especially of E.coli against
trimethoprim, in some regions justifies
empirical calculated therapy with an oral
Table 7 Recommendations for antibacterial treatment in cystitis und cystourethritis (Dosages for children up
to 12 years of age).
Chemotherapeutics
Oral Cephalosporines
Group 1, e.g. Cefaclor
Group 1, e.g. Cefalexin
Group 2, e.g. Cefuroximaxetil
Group 2, e.g. Cefpodoximproxetil
Group 3, e.g. Ceftibuten
Trimethoprim
Trimethoprim/Sulfamethoxazol
Amoxicillin/Clavulanic acid
Nitrofurantoin
352
cephalosporin in these areas. In principle,
simple antibiotics should be preferred
to highly effective ‘reserve’ antibiotics in
uncomplicated cystitis to avoid further
development of resistance in the popula-
tion (Table 7).
The recommended duration of therapy
is three to five days. A recent Cochrane
review has shown equivalence of a two to
four day oral antibacterial therapy com-
pared to a seven to 14-day therapy for
lower UTIs [30] (LoE 1a). Single doses or
one-day therapies are accompanied with
higher rates of relapse or recurrence.
4.6 Therapy of renal carbuncle and
abscess
Renal cortical abscesses (“carbuncles”)
are caused by haematogenous spread
originating from another focus of bacte-
rial infection (e.g. skin infection such as
infected wounds, furunculosis or skin
abscess) the most frequent pathogen being
staphylococcus aureus. In most of these
cases urine cultures are sterile. Mostly,
a prolonged parenteral calculated com-
bination therapy including β-lactamase
resistant antibiotics targeting staphyloco-
ccus aureus is sufficiently effective. More
rarely, additional percutaneous drainage,
Daily dosage Application
50 (-100) mg/kgbw p.o. in 2–3 D
50 mg/kgbw p.o. in 3–4 D
20–30 mg/kgbw p.o. in 2 D
8–10 mg/kgbw p.o. in 2 D
9 mg/kgbw p.o. in 1 D
5–6 mg/kgbw p.o. in 2 D
5–6 mg/kgbw /TMP-fraction) p.p. in 3 D
37.5–75 mg/kgbw (Amoxicillin-fraction) p.o. in 3 D
3–5 mg/kgbw p.o. in 2 D
 Antimicrobial therapy of urinary tract infections in children
open surgical revision or nephrectomy are
required [31].
Renal corticomedullary abscesses are
sometimes observed as complications of
ascending UTIs with vescicorenal (intra-
renal) reflux or in urinary tract obstruc-
tion. These abscesses often are preceded
by pyelonephritis or by focal bacterial
nephritis (“lobar nephronia”) caused by
Gram-negative bacteria, e.g. E.coli [32].
4.7 Asymptomatic bacteriuria
Infants and children with asymptomatic
bacteriuria (ABU) have a low risk of
developing pyelonephritis. ABU is com-
monly caused by low virulent uropatho-
gens almost leading to a colonisation
– not, however, to an infection. They can
even protect the urinary tract from inva-
sion by bacteria of higher virulence. It
has been shown that the rate of pyelone-
phritic episodes was higher in girls who
were treated for asymptomatic bacteriu-
ria than in those who stayed untreated,
in spite of bacteriuria [33]. In most cases,
asymptomatic bacteriuria resolves spon-
taneously after a few weeks or months.
Asymptomatic bacteriuria in patients
without accompanying uropathy, bladder
dysfunction or history of pyelonepritic
episodes does not need antibacterial ther-
apy at all (LoE 2a). If antibacterial ther-
apy becomes necessary for other reasons,
e.g. otitis media or pneumonia, a sympto-
matic UTI can happen thereafter due to a
shift to a more virulent uropathogen [34].
5. CONTROL OF THERAPEUTIC
SUCCESS
Under successful treatment the urine
usually becomes sterile after 24 hours,
and leukocyturia normally disappears
within three to four days. Normal body
temperature can be expected within 24 to
48 hours after the start of therapy in 90%
of cases. CRP mostly normalizes after
four to five days.
| 6.4 |
In cases of prolonged fever and failure
to recover, one should consider a resistant
uropathogen or the presence of a congeni-
tal uropathy or an acute urinary obstruc-
tion (e.g. due to a urinary calculus), which
urgently demands ultrasonography.
6. PROPHYLAXIS
6.1 Chemoprophylaxis
Early diagnosis and therapy are the most
effective prophylactic measures against
renal scarring in every case of pyelone-
phritis in infancy and childhood.
Approximately 1% of boys and 3–5%
of girls suffer from at least one UTI dur-
ing childhood [35]. After their first symp-
tomatic UTI, 30%-50% are prone to at
least one recurrence [36–37]. The recur-
rence rate is directly correlated with the
number of preceding UTIs [38]. In boys,
early recurrences are as frequent as in
girls; later the recurrence rate is much
lower in boys than in girls. The suscepti-
bility for recurrences is highest within the
first two to six months after a UTI [39].
The longer the infection-free interval, the
lower the risk for further recurrences [38].
A long-term antibacterial prophylaxis
should be considered in cases of high sus-
ceptibility to UTIs and risk of acquired
renal damage. These are, for instance,
patients with dilating vesicorenal reflux,
with recurrent pyelonephritic episodes or
with significant urinary tract obstruction
(e.g. high grade megaureters, urethral
valves). However, the role of vesicorenal
reflux as a predisposing factor for UTI
recurrence is controversial. Nuutinen
and Uhari found that recurrence-free
survival was significantly shorter and
recurrent UTIs occurred more often in
the children with grade 3–5 VUR than in
those with grade 0–2 VUR and concluded
grade 3–5 VUR to be a risk factor for
recurrent UTI [36].
Antimicrobials selected for prophylaxis
should fulfil the following demands [40]:
353
Chapter |6| Urinary tract infections in children

• Effectiveness against the majority of
uropathogens
• Cause a minimum of serious side
effects
• Cause minimal bacterial resistance
• Make little ecological impact on indig-
enous bacterial flora
Usually, the substance is given daily in
the evening shortly before going to sleep.
A quarter of the regular therapeutic dos-
age is sufficient (Table 8).
For many years, trimethoprim or cot-
rimoxazole and nitrofurantoin have been
the substances most used for antibacte-
rial prophylaxis of UTI in children. Due
to the fact that in many countries the use
of both substances is restricted in early
infancy, oral cephalosporines are pre-
ferred in this age group.
In comparative studies, nitrofurantoin
produced significantly more side effects
than trimethoprim. The differences were
due to higher rates of complaints of gas-
trointestinal symptoms like nausea or
vomiting, as well as of bad taste of the
mixture [41]. In adults, the use of nitro-
furantoin is limited because of the rela-
tively high frequency of severe adverse
reactions, especially including pulmonary
fibrosis and polyneuropathy [42]. The sit-
uation in childhood appears to be mark-
edly different. Corragio et al. in 1989
reviewed the serious adverse reaction
reports submitted to the Food and Drug
Administration since 1953. There were
only 26 cases of serious reactions to
nitrofurantoin in children and adoles-
cents who were younger than 20 years
of age in the United States. Neurologic
and hepatic reactions occurred in seven
and nine patients respectively, which
equated to 0.8 and 1.0 cases/million uses
respectively [43]. On the basis of these
data and of clinical experience, it may
be concluded that nitrofurantoin is a
safe and effective antibiotic for prophy-
laxis in children with recurrent UTI.
In spite of its potential side effects, the
value of nitrofurantoin as an alternative
to trimethoprim in children will prob-
ably undergo a renaissance, since bac-
terial resistance to trimethoprim has
been shown to increase rapidly in many
regions of the world.
6.1.1 The problem of non-compliance
Patient compliance is one of the big-
gest problems with antibacterial proph-
ylaxis. Daschner and Marget tested
compliance with long-term antibiotic
therapy by checking urine in 93 children
with recurrent UTIs. Only 32.2 % of the
children took the prescribed drugs at
regular intervals, 19% did not take the
antibiotics at all [44]. Similar results
have been shown in children with vesi-
coureteric reflux [45]. Rational and

Table 8 Usable substances for antibacterial prophylaxis.

Substance* Prophylactic dosage (mg/kgbw/d) Limitations in young infants

Trimethoprrim 1 until 6 weeks of age

Nitrofurantoin 1 Until 3 months of age

Cefaclor 10 No age limitations

Cefixim 2 Preterms and newborns

Ceftibuten 2 **

Cefuroximaxetil 5 **

*Substances of first choice are Nitrofurantoin and Trimethoprim. In exceptional cases oral cephalosporine can be used.
**In Germany, Ceftibuten are not approved for infants under 3 months of age.

354
 Antimicrobial therapy of urinary tract infections in children
understandable information for parents
on the aims and necessity of prophy-
laxis and its control is inevitable for its
success.
6.1.2 Current controversies in
antibacterial prophylaxis
The efficacy of antibacterial prophylaxis
per se has been questioned in several
reviews [46–49]. Garin et al came to the
conclusion that “the current available
data do not support a role for continuous
urinary antibiotic prophylaxis in the pre-
vention of renal scars in patients with
vesicoureteric reflux“ [50]. Likewise,
Larcombe stated that the long-term
benefits of prophylaxis have not been
adequately evaluated, even for children
with VUR [46]. In an actual Cochrane
review, Williams et al. concluded that
there is considerable uncertainty about
the effectiveness of long-term, low-dose
antibiotic administration for the pre-
vention of UTI in children [49]. Finally,
Le Saux et al criticized the low qual-
ity of available evidence for using anti-
bacterial prophylaxis to prevent UTI
in children with normal urinary tracts
or neurogenic bladder [47]. In addition,
they found a surprising lack of evidence
for children with reflux.
Most of the authors of these articles
criticize the lack of evidence for using
antibacterial prophylaxis due to the low
quality of clinical trials and the small
number of patients. Indeed, several
authors of reviews came to the conclusion
that it is not clear whether any interven-
tion for children with primary VUR – a
domain for antibiotic prophylaxis – does
more harm than good [48, 51]. Therefore,
several authors demand new, well-
designed randomised trials focusing on
groups with different risk stratifications
[47, 51–52]. Recently published results
of prospective, randomised studies do
not support the efficacy of antibacterial
prophylaxis in low-grade vesicoureteral
reflux [53–56] (LoE 1b). However, several
| 6.4 |
randomised, controlled, prospective stud-
ies on antibacterial prophylaxis with
VUR are in progress [57–58]; (see also
chapter “vesicoureteral reflux”).
6.2 Other agents used for
prophylaxis
6.2.1 “Urine disinfectants”
Nitroxolin (5-nitro-8-hydroxyquinoline)
is a derivate of nitrochinolinol with
bacteriostatic and bactericide effects
against many Gram-positive and Gram-
negative pathogens. In addition, the
substance has been demonstrated to
inhibit bacterial adherence to epithe-
lial cells or solid surfaces, probably by
chelating effects with various metal-
lic divalent cations [59–60]. Nitroxolin
has been used since 1962 in the treat-
ment of UTI. However, more than half
of the very few publications originally
came from France, probably due to the
more popular usage of nitroxolin in that
country. For children, there is no data
available concerning its prophylactic
efficiency compared to other antibacte-
rial substances or to placebo.
6.2.2 “Urine acidification”
The bacteriostatic effect of acid urine is
the main argument for acidifying sub-
stances in UTI prophylaxis, especially
those produced by weak organic acids.
L-methionin is the only essential amino
acid which contains sulphur. Its metabo-
lisation to hydrogen sulfide and sulfu-
ric acid sets H-ions free leading to an
acidification of the urine. Another effect
of L-Methionin is the inhibition of bac-
terial adherence at uroepithelial cells
[61]. In children with ammonium mag-
nesium phosphate stones due to bacte-
riuria (e.g. Proteus mirabilis) in alkaline
urine, where stone fragments cannot be
removed completely, antibacterial prophy-
laxis in combination with urine acidifica-
tion by L-methionin (urine pH 5.6 to 6.2)
is most appropriate [62–63].
355
Chapter |6| Urinary tract infections in children
6.2.3 Cranberry
Syrup or juice from vaccinium macro-
carpon, a certain cranberry species, has
been used for centuries as a homespun
remedy for urinary tract infection, and
has undergone a renaissance in UTI
prophylaxis over the last 10 years. Its
effect is possibly based on the inhibition
of uropathogen E.coli at the uroepithel
[64]. In adults, the protective effects of
cranberry juice on recurrence rates of
UTIs is proven [65]. In children, there
are no similar study results available.
Two studies in children with neurogenic
bladders demonstrated no influence of
cranberry juice on UTI recurrence rates
[66–67].
6.3 Treatment of bladder
dysfunction and obstipation
Normalization of micturition disorders
or bladder overactivity is a paramount
measure to lower the recurrence rate of
UTIs in a child [68]. If there are signs
of bladder dysfunction in infection-free
intervals (e.g. pollakisuria, incontinence,
micturition abnormalities), further diag-
nostics and effective treatment are pre-
requisites for therapeutic success [69–70]
(LoE 2a). By a standardized history and
by non-invasive investigations (e.g. blad-
der and bowel diary, ultrasound including
measurement of residual urine, uroflow-
metry, pelvic floor electromyogram), most
types of urinary incontinence and bladder
dysfunction in children are easily detect-
able [71].
Often, dysfunctional voiding is associ-
ated with constipation. It is well known
that treatment of constipation leads to
decreasing urinary continence and avoid-
ance of UTI recurrences [72–75] (LoE 1b).
6.4 Vaccination
Experimental trials in animals using
vaccines against Pili-antigens of E.coli
or blockade of adherence receptors on
uroepithelial cells cannot be transferred
356
to humans so far. However, there is some
experience with lysates attained from
inactivated uropathogenic strains, which
are applied orally or parenterally.
6.4.1 Oral vaccines
There is some evidence that these prep-
arations stimulate B-lymphozytes and
NK cells as well as cells within the
Peyer’s plaques. Stimulation of intesti-
nal IgA-secretion is said also to lead to
higher secretory IgA levels in urine. In
adults, prophylaxis with Urovaxom®
seemed to be effective in a few placebo-
controlled studies [76]. In children, only
one controlled, randomized study was
published which showed a protective
effect comparable with that of nitro-
furantoin [77].
6.4.2 Parenteral vaccines
After injection of inactivated uropath-
ogens, Nayir et al. found increasing
sIgA-levels in the urine of children.
After the first injection the IgA-levels
fell but increased again after a booster.
Children in the vaccinated group suf-
fered from fewer UTIs than those in the
non-vaccinated group [78]. In Germany,
a parenteral vaccine is on the market
(StroVac®), containing 109 inactivated
uropathogens (E.coli, Morganella mor-
gani, Proteus mirabilis, Klebsiella pneu-
moniae, Enterococcus faecalis). It is not
approved for children below the age of
five years. In children between five and
15 years no sufficient experience exists,
and experimental data concerning its
usage during growth phase in mammals
is not available.
6.4.3 Autogene vaccines
These are uropathogens attained from
the urine of an individual patient with
an acute urinary tract infection, pre-
pared solely for the use in this individual
person. After culture from a urine sam-
ple, and after inactivation, the antigen
 Antimicrobial therapy of urinary tract infections in children
is injected subcutaneously in increas-
ing concentrations in weekly or monthly
intervals. Despite being known for over
100 years, this method of “autogenic vac-
cination” is not established. However, in
some countries (e.g. Germany since 2005)
its use is officially approved. Data on chil-
dren do not exist.
6.5 Primary prevention
6.6.1 Breast milk feeding
Breast milk feeding significantly protects
against UTIs, at least during the first
months of life. In a case control study,
the protective effect of breast feeding was
highest soon after birth and declined to
zero up to the seventh month of life. It
contributed to a diminished rate of UTIs
even after weaning, demonstrating a
prolonged effectiveness [79]. In another
case control study only 16% of the infants
suffering from UTI had been breast-fed
whereas 55% of the control group without
UTI were breast-fed at least until three
days before the end of the observation
period [80] (LoE 3).
6.6.2 Circumcision
Circumcised male infants have a three
to 10-fold diminished risk for UTI than
non-circumcised boys. Colonisation with
uropathogens such as E.coli, Klebsiella-
Enterobacter, Proteus mirabilis and
Pseudomonas aeruginosa in urethral and
periurethral swabs from non-circumcised
boys is much more frequent than in cir-
cumcised controls [81]. There is good
evidence that circumcision lowers the
risk of urinary tract infections, not only
in infants but also in toddlers [81–83].
However, the authors of a recent meta-
analysis came to the conclusion that 111
circumcisions would be necessary in the
whole male newborn population to avoid
one UTI. The number to treat (NTT)
is much lower in high risk patients: a
number of 11 for boys with recurrent
urinary tract infections and a number of
| 6.4 |
three for boys with dilating vesicorenal
reflux were calculated in the same study
[84] (LoE 1a).
There has never been a recommenda-
tion for routine circumcision in Western
European countries. This is also true for
the current guidelines of the American
Academy of Paediatrics [85]. However,
many paediatric urologists consider a
“prophylactic” circumcision in high risk
male patients, e.g. infants with urethral
valves, with high grade VUR or with
severe neurogenic bladder [86].
7. FURTHER RESEARCH
Whereas the treatment strategies for UTI
are well established, the problem of effec-
tive prevention in infants and children
susceptible for recurrent UTI’s continues
to be unsolved. However, the identifica-
tion of children at risk for pyelonephritic
scarring is a prerequisite for targeted
prophylaxis. Genetics, biomarkers and
urinary proteomics will play a decisive
role in this respect.
Due to the widespread use of antibiot-
ics, resistance rates in uropathogens are
growing worldwide. The surveillance of
bacterial resistance and the rational use
of antibiotics to avoid its further increase
in different populations might be one of
the most important challenges in future
research.
Recent advances in the understanding
of innate and adaptive immunity of the
urinary tract have provided new insights
into the interaction between the urinary
tract and pathogens, which may impact
clinical practice. Basic research in host
defence mechanisms and identification
of susceptible patients will enable novel
strategies to prevent infections and mini-
mize renal damage [87]. In this context,
the influence of bladder and bowel func-
tion on the susceptibility to UTI and
measures for the treatment of their dys-
function might especially be of clinical
interest.
357
Chapter |6| Urinary tract infections in children
8. CONCLUSIONS
The main objectives in childhood urinary
tract infections are rapid recovery from
complaints, prevention of urosepsis and
infection-related complications, and the
prevention of renal parenchymal damage.
Evidence-based data exist for the use of
antibiotics for the treatment of children
with acute pyelonephritis and those with
lower UTIs. The choice of the appropri-
ate antibiotics, the duration of therapy
and the form of application depend on
age, severity of clinical symptoms and
the presence of complicating factors.
Additionally, the regional resistance rates
of uropathogens have to be considered
when calculated antibacterial therapy is
initiated.
In infants and children susceptible
to pyelonephritis and UTI recurrences,
effective prophylactic measures are eli-
gible. Prophylaxis should always include
the efficient management of bladder and/
or bowel dysfunction, as well as the treat-
ment of other predisposing factors. Due
to the lack of evident data, doubts have
arisen concerning the efficacy of antibac-
terial prophylaxis in infants and children
at risk of pyelonephritis and UTI recur-
rences. At present, numerous clinical
studies regarding this topic in children
with vesicoureteral reflux are in process.
Until their results are available, over-
treatment and undertreatment should be
approached with caution [58].
REFERENCES
1. Bloomfield P, Hodson EM, and Craig JC,
Antibiotics for acute pyelonephritis in
children. Cochrane Database Syst Rev,
2005(1): CD003772.
2. Keren R and Chan E, A meta-analysis of
randomized, controlled trials comparing
short- and long-course antibiotic therapy
for urinary tract infections in children.
Pediatrics, 2002. 109(5): E70–0.
3. US Department of Health and Human
Services, Public Health Service, and
358
Agency for Health Care Policy and
Research, 1992: 115–127.
4. Abrams P, Khoury S, and Grant A,
Evidence-based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–684.
5. Gaspari RJ, Dickson E, Karlowsky J, and
Doern G, Antibiotic resistance trends in
paediatric uropathogens. Int J Antimicrob
Agents, 2005. 26(4): 267–71.
6. Haller M, Brandis M, and Berner R,
Antibiotic resistance of urinary tract path-
ogens and rationale for empirical intra-
venous therapy. Pediatr Nephrol, 2004.
19(9): 982–6.
7. Anatoliotaki M, Galanakis E, Schinaki
A, Stefanaki S, Mavrokosta M, and
Tsilimigaki A, Antimicrobial resistance
of urinary tract pathogens in children in
Crete, Greece. Scand J Infect Dis, 2007.
39(8): 671–5.
8. Gokce I, Alpay H, Biyikli N, and
Ozdemir N, Urinary tract pathogens and
their antimicrobial resistance patterns in
Turkish children. Pediatr Nephrol, 2006.
21(9): 1327–8.
9. Ladhani S and Gransden W, Increasing
antibiotic resistance among urinary tract
isolates. Arch Dis Child, 2003. 88(5):
444–5.
10. Lutter SA, Currie ML, Mitz LB, and
Greenbaum LA, Antibiotic resistance pat-
terns in children hospitalized for urinary
tract infections. Arch Pediatr Adolesc
Med, 2005. 159(10): 924–8.
11. Marcus N, Ashkenazi S, Yaari A,
Samra Z, and Livni G, Non-Escherichia
coli versus Escherichia coli community-
acquired urinary tract infections in chil-
dren hospitalized in a tertiary center:
relative frequency, risk factors, antimi-
crobial resistance and outcome. Pediatr
Infect Dis J, 2005. 24(7): 581–5.
12. Pape L, Gunzer F, Ziesing S, Pape A,
Offner G, and Ehrich JH, [Bacterial path-
ogens, resistance patterns and treatment
options in community acquired pediatric
urinary tract infection]. Klin Padiatr,
2004. 216(2): 83–6.
13. Prelog M, Schiefecker D, Fille M,
Wurzner R, Brunner A, and Zimmerhackl
LB, Febrile urinary tract infection in
 Antimicrobial therapy of urinary tract infections in children
children: ampicillin and trimethoprim
insufficient as empirical mono-therapy.
Pediatr Nephrol, 2008. 23(4): 597–602.
14. Prere MF, Licznar P, Decramer S, and
Fayet O, [E.coli from urinary tract infec-
tions and acute pyelonephritis of children:
1% of strains are resistant to a subset of
third generation cephalosporins]. Pathol
Biol (Paris), 2004. 52(8): 497–500.
15. Schmitt CP, Keimspektrum und
Resitenzlage bei Harnwegsinfektionen im
Kindesalter. Monatsschr Kinderheilkd,
2007. 155(3): 228–233.
16. The use of systemic fluoroquinolones.
Pediatrics, 2006. 118(3): 1287–92.
17. Schwartz GJ, Feld LG, and Langford DJ,
A simple estimate of glomerular filtra-
tion rate in full-term infants during the
first year of life. J Pediatr, 1984. 104(6):
849–54.
18. Schwartz GJ and Gauthier B, A simple
estimate of glomerular filtration rate in
adolescent boys. J Pediatr, 1985. 106(3):
522–6.
19. Schwartz GJ, Haycock GB, Edelmann
CM, Jr., and Spitzer A, A simple estimate
of glomerular filtration rate in children
derived from body length and plasma cre-
atinine. Pediatrics, 1976. 58(2): 259–63.
20. Gauthier M, Chevalier I, Sterescu A,
Bergeron S, Brunet S, and Taddeo D,
Treatment of urinary tract infections
among febrile young children with daily
intravenous antibiotic therapy at a day
treatment center. Pediatrics, 2004. 114(4):
e469–76.
21. Contopoulos-Ioannidis DG, Giotis ND,
Baliatsa DV, and Ioannidis JP, Extended-
interval aminoglycoside administration
for children: a meta-analysis. Pediatrics,
2004. 114(1): e111–8.
22. Hodson EM, Willis NS, and Craig JC,
Antibiotics for acute pyelonephritis in
children. Cochrane Database Syst Rev,
2007(4): CD003772.
23. Bouissou F, Munzer C, Decramer S,
Roussel B, Novo R, Morin D, Lavocat
MP, Guyot C, Taque S, Fischbach M,
Ouhayoun E, and Loirat C, Prospective,
randomized trial comparing short and
long intravenous antibiotic treatment
of acute pyelonephritis in children:
dimercaptosuccinic acid scintigraphic
| 6.4 |
evaluation at 9 months. Pediatrics, 2008.
121(3): e553–60.
24. Hoberman A, Wald ER, Hickey RW,
Baskin M, Charron M, Majd M, Kearney
DH, Reynolds EA, Ruley J, and Janosky
JE, Oral versus initial intravenous ther-
apy for urinary tract infections in young
febrile children. Pediatrics, 1999.
104(1 Pt 1): 79–86.
25. Neuhaus TJ, Berger C, Buechner K,
Parvex P, Bischoff G, Goetschel P,
Husarik D, Willi U, Molinari L, Rudin
C, Gervaix A, Hunziker U, Stocker S,
Girardin E, and Nadal D, Randomised
trial of oral versus sequential intrave-
nous/oral cephalosporins in children
with pyelonephritis. Eur J Pediatr, 2008.
167(9): 1037–47.
26. Montini G, Toffolo A, Zucchetta P,
Dall’Amico R, Gobber D, Calderan A,
Maschio F, Pavanello L, Molinari PP,
Scorrano D, Zanchetta S, Cassar W,
Brisotto P, Corsini A, Sartori S, Da Dalt
L, Murer L, and Zacchello G, Antibiotic
treatment for pyelonephritis in children:
multicentre randomised controlled non-
inferiority trial. BMJ, 2007. 335(7616):
386.
27. Mak RH and Wong JH, Are oral antibiot-
ics alone efficacious for the treatment of
a first episode of acute pyelonephritis in
children? Nat Clin Pract Nephrol, 2008.
4(1): 10–1.
28. Klar A, Hurvitz H, Berkun Y, Nadjari M,
Blinder G, Israeli T, Halamish A, Katz A,
Shazberg G, and Branski D, Focal bacte-
rial nephritis (lobar nephronia) in chil-
dren. J Pediatr, 1996. 128(6): 850–3.
29. Cheng CH, Tsau YK, and Lin TY,
Effective duration of antimicrobial
therapy for the treatment of acute lobar
nephronia. Pediatrics, 2006. 117(1):
e84–9.
30. Michael M, Hodson EM, Craig JC,
Martin S, and Moyer VA, Short versus
standard duration oral antibiotic ther-
apy for acute urinary tract infection in
children. Cochrane Database Syst Rev,
2003(1): CD003966.
31. Jemni L, Mdimagh L, Jemni-Gharbi
H, Jemni M, Kraiem C, and Allegue M,
[Kidney carbuncle: diagnostic, bacterio-
logical and therapeutic considerations.
359
Chapter |6| Urinary tract infections in children
Apropos of 11 cases]. J Urol (Paris), 1992.
98(4): 228–31.
32. Shimizu M, Katayama K, Kato E,
Miyayama S, Sugata T, and Ohta K,
Evolution of acute focal bacterial nephri-
tis into a renal abscess. Pediatr Nephrol,
2005. 20(1): 93–5.
33. Hansson S, Jodal U, Noren L, and
Bjure J, Untreated bacteriuria in
asymptomatic girls with renal scarring.
Pediatrics, 1989. 84(6): 964–8.
34. Hansson S, Jodal U, Lincoln K, and
Svanborg-Eden C, Untreated asympto-
matic bacteriuria in girls: II--Effect of
phenoxymethylpenicillin and erythro-
mycin given for intercurrent infections.
BMJ, 1989. 298(6677): 856–9.
35. Winberg J, Bollgren I, Kallenius G,
Mollby R, and Svenson SB, Clinical
pyelonephritis and focal renal scarring.
A selected review of pathogenesis, preven-
tion, and prognosis. Pediatr Clin North
Am, 1982. 29(4): 801–14.
36. Nuutinen M and Uhari M, Recurrence
and follow-up after urinary tract infection
under the age of 1 year. Pediatr Nephrol,
2001. 16(1): 69–72.
37. Winberg J, Bergstrom T, and Jacobsson B,
Morbidity, age and sex distribution, recur-
rences and renal scarring in symptomatic
urinary tract infection in childhood.
Kidney Int Suppl, 1975. 4: S101–6.
38. McCracken GH, Jr., Recurrent urinary
tract infections in children. Pediatr Infect
Dis, 1984. 3(3 Suppl): S28–30.
39. Kasanen A, Sundquist H, Elo J, Anttila
M, and Kangas L, Secondary prevention
of urinary tract infections. The role of
trimethoprim alone. Ann Clin Res, 1983.
15(Suppl 36): 1–36.
40. Bollgren I, Antibacterial prophylaxis in
children with urinary tract infection. Acta
Paediatr Suppl, 1999. 88(431): 48–52.
41. Brendstrup L, Hjelt K, Petersen KE,
Petersen S, Andersen EA, Daugbjerg
PS, Stagegaard BR, Nielsen OH,
Vejlsgaard R, Schou G, and et al.,
Nitrofurantoin versus trimethoprim
prophylaxis in recurrent urinary tract
infection in children. A randomized,
double-blind study. Acta Paediatr Scand,
1990. 79(12): 1225–34.
360
42. Holmberg L, Boman G, Bottiger LE,
Eriksson B, Spross R, and Wessling
A, Adverse reactions to nitrofurantoin.
Analysis of 921 reports. Am J Med, 1980.
69(5): 733–8.
43. Coraggio MJ, Gross TP, and Roscelli JD,
Nitrofurantoin toxicity in children.
Pediatr Infect Dis J, 1989. 8(3): 163–6.
44. Daschner F and Marget W, Treatment
of recurrent urinary tract infection in
children. II. Compliance of parents and
children with antibiotic therapy regi-
men. Acta Paediatr Scand, 1975. 64(1):
105–8.
45. Westenfelder M, Vahlensieck W, and
Reinhartz U, Patient compliance and
efficacy of low-dose, long-term prophy-
laxis in patients with recurrent urinary
tract infection. Chemioterapia, 1987.
6(2 Suppl): 530–2.
46. Larcombe J, Urinary tract infection in
children. BMJ, 1999. 319(7218): 1173–5.
47. Le Saux N, Pham B, and Moher D,
Evaluating the benefits of antimicrobial
prophylaxis to prevent urinary tract
infections in children: a systematic
review. CMAJ, 2000. 163(5): 523–9.
48. Linshaw MA, Controversies in childhood
urinary tract infections. World J Urol,
1999. 17(6): 383–95.
49. Williams G, Lee A, and Craig J,
Antibiotics for the prevention of urinary
tract infection in children: A systematic
review of randomized controlled trials.
J Pediatr, 2001. 138(6): 868–74.
50. Garin EH, Campos A, and Homsy Y,
Primary vesicoureteral reflux: review of
current concepts. Pediatr Nephrol, 1998.
12(3): 249–56.
51. Wheeler D, Vimalachandra D,
Hodson EM, Roy LP, Smith G, and Craig
JC, Antibiotics and surgery for vesicouret-
eric reflux: a meta-analysis of randomised
controlled trials. Arch Dis Child, 2003.
88(8): 688–94.
52. Jodal U and Lindberg U, Guidelines for
management of children with urinary
tract infection and vesico-ureteric reflux.
Recommendations from a Swedish state-
of-the-art conference. Swedish Medical
Research Council. Acta Paediatr Suppl,
1999. 88(431): 87–9.
 Antimicrobial therapy of urinary tract infections in children
53. Garin EH, Olavarria F, Garcia Nieto V,
Valenciano B, Campos A, and Young L,
Clinical significance of primary vesi-
coureteral reflux and urinary antibiotic
prophylaxis after acute pyelonephritis:
a multicenter, randomized, controlled
study. Pediatrics, 2006. 117(3): 626–32.
54. Montini G, Rigon L, Zucchetta P,
Fregonese F, Toffolo A, Gobber D,
Cecchin D, Pavanello L, Molinari PP,
Maschio F, Zanchetta S, Cassar W,
Casadio L, Crivellaro C, Fortunati P,
Corsini A, Calderan A, Comacchio S,
Tommasi L, Hewitt IK, Da Dalt
L, Zacchello G, and Dall’Amico R,
Prophylaxis after first febrile urinary tract
infection in children? A multicenter, ran-
domized, controlled, noninferiority trial.
Pediatrics, 2008. 122(5): 1064–71.
55. Pennesi M, Travan L, Peratoner L,
Bordugo A, Cattaneo A, Ronfani L,
Minisini S, and Ventura A, Is antibi-
otic prophylaxis in children with vesi-
coureteral reflux effective in preventing
pyelonephritis and renal scars? A rand-
omized, controlled trial. Pediatrics, 2008.
121(6): e1489–94.
56. Roussey-Kesler G, Gadjos V, Idres N,
Horen B, Ichay L, Leclair MD, Raymond
F, Grellier A, Hazart I, de Parscau L,
Salomon R, Champion G, Leroy V,
Guigonis V, Siret D, Palcoux JB, Taque S,
Lemoigne A, Nguyen JM, and Guyot C,
Antibiotic prophylaxis for the prevention of
recurrent urinary tract infection in children
with low grade vesicoureteral reflux: results
from a prospective randomized study. J
Urol, 2008. 179(2): 674–9; discussion 679.
57. Esbjorner E, Hansson S, and Jakobsson
B, Management of children with dilat-
ing vesico-ureteric reflux in Sweden. Acta
Paediatr, 2004. 93(1): 37–42.
58. Greenfield SP, Chesney RW, Carpenter M,
Moxey-Mims M, Nyberg L, Hoberman A,
Keren R, Matthews R, and Mattoo T,
Vesicoureteral reflux: the RIVUR study
and the way forward. J Urol, 2008.
179(2): 405–7.
59. Oliviereo L, Perdiz M, and Bourlioux
P, Role direct de la nitroxiline dans
l’inhibtion e l’adherence bacterienne sur
sonde urinaire. Pathol Biol (Paris), 1990.
38: 455–458.
| 6.4 |
60. Pelletier C, Prognon P, and Bourlioux P,
Roles of divalent cations and pH in mech-
anism of action of nitroxoline against
Escherichia coli strains. Antimicrob
Agents Chemother, 1995. 39(3): 707–13.
61. Funfstuck R, Straube E, Schildbach O,
and Tietz U, [Prevention of reinfection
by L-methionine in patients with recur-
rent urinary tract infection]. Med Klin
(Munich), 1997. 92(10): 574–81.
62. Hess B and Ackermann D, [Preventive
measures in stones due to infection, uric
acid and cystine]. Ther Umsch, 1992.
49(1): 44–8.
63. Hesse A and Heimbach D, Causes of phos-
phate stone formation and the importance
of metaphylaxis by urinary acidifica-
tion: a review. World J Urol, 1999. 17(5):
308–15.
64. Lowe FC and Fagelman E, Cranberry
juice and urinary tract infections: what
is the evidence? Urology, 2001. 57(3):
407–13.
65. Jepson RG and Craig JC, Cranberries
for preventing urinary tract infections.
Cochrane Database Syst Rev, 2008(1):
CD001321.
66. Foda MM, Middlebrook PF, Gatfield CT,
Potvin G, Wells G, and Schillinger JF,
Efficacy of cranberry in prevention of uri-
nary tract infection in a susceptible pedi-
atric population. Can J Urol, 1995. 2(1):
98–102.
67. Schlager TA, Anderson S, Trudell J, and
Hendley JO, Effect of cranberry juice on
bacteriuria in children with neurogenic
bladder receiving intermittent catheteri-
zation. J Pediatr, 1999. 135(6): 698–702.
68. Winberg J, What antibiotics should be
used for prophylaxis against recurrent
urinary tract infections in childhood?
Pediatr Nephrol, 1990. 4: 244.
69. Koff SA, Wagner TT, and Jayanthi VR,
The relationship among dysfunctional
elimination syndromes, primary vesi-
coureteral reflux and urinary tract
infections in children. J Urol, 1998.
160(3 Pt 2): 1019–22.
70. van Gool JD, Kuitjen RH, Donckerwolcke
RA, Messer AP, and Vijverberg M,
Bladder-sphincter dysfunction, urinary
infection and vesico-ureteral reflux with
361
Chapter |6| Urinary tract infections in children
special reference to cognitive bladder
training. Contrib Nephrol, 1984. 39:
190–210.
71. Neveus T, von Gontard A, Hoebeke P,
Hjalmas K, Bauer S, Bower W, Jorgensen
TM, Rittig S, Walle JV, Yeung CK, and
Djurhuus JC, The standardization of
terminology of lower urinary tract func-
tion in children and adolescents: report
from the Standardisation Committee of
the International Children’s Continence
Society. J Urol, 2006. 176(1): 314–24.
72. De Paepe H, Renson C, Van Laecke E,
Raes A, Vande Walle J, and Hoebeke P,
Pelvic-floor therapy and toilet training in
young children with dysfunctional void-
ing and obstipation. BJU Int, 2000. 85(7):
889–93.
73. Loening-Baucke V, Urinary incontinence
and urinary tract infection and their reso-
lution with treatment of chronic constipa-
tion of childhood. Pediatrics, 1997.
100(2 Pt 1): 228–32.
74. O’Regan S and Yazbeck S, Constipation: a
cause of enuresis, urinary tract infection
and vesico-ureteral reflux in children.
Med Hypotheses, 1985. 17(4): 409–13.
75. O’Regan S, Yazbeck S, and Schick E,
Constipation, bladder instability, urinary
tract infection syndrome. Clin Nephrol,
1985. 23(3): 152–4.
76. Bauer HW, Rahlfs VW, Lauener PA, and
Blessmann GS, Prevention of recurrent
urinary tract infections with immuno-
active E. coli fractions: a meta-analysis of
five placebo-controlled double-blind stud-
ies. Int J Antimicrob Agents, 2002. 19(6):
451–6.
77. Lettgen B, Prophylaxe rezidivierender
Harnwegsinfektionen bei Mädchen. Curr
Ther Res, 1996. 27: 463–475.
78. Nayir A, Emre S, Sirin A, Bulut A, Alpay
H, and Tanman F, The effects of vac-
cination with inactivated uropathogenic
362
bacteria in recurrent urinary tract infec-
tions of children. Vaccine, 1995. 13(11):
987–90.
79. Marild S, Hansson S, Jodal U, Oden
A, and Svedberg K, Protective effect of
breastfeeding against urinary tract infec-
tion. Acta Paediatr, 2004. 93(2): 164–8.
80. Miller JL and Krieger JN, Urinary tract
infections cranberry juice, underwear,
and probiotics in the 21st century. Urol
Clin North Am, 2002. 29(3): 695–9.
81. Wiswell TE, Miller GM, Gelston HM, Jr.,
Jones SK, and Clemmings AF, Effect of
circumcision status on periurethral bacte-
rial flora during the first year of life.
J Pediatr, 1988. 113(3): 442–6.
82. Craig JC, Knight JF, Sureshkumar P,
Mantz E, and Roy LP, Effect of circumci-
sion on incidence of urinary tract infection
in preschool boys. J Pediatr, 1996. 128(1):
23–7.
83. Herzog LW, Urinary tract infections and
circumcision. A case-control study. Am
J Dis Child, 1989. 143(3): 348–50.
84. Singh-Grewal D, Macdessi J, and Craig J,
Circumcision for the prevention of uri-
nary tract infection in boys: a systematic
review of randomised trials and obser-
vational studies. Arch Dis Child, 2005.
90(8): 853–8.
85. Practice parameter: the diagnosis, treat-
ment, and evaluation of the initial uri-
nary tract infection in febrile infants
and young children. American Academy
of Pediatrics. Committee on Quality
Improvement. Subcommittee on Urinary
Tract Infection. Pediatrics, 1999.
103(4 Pt 1): 843–52.
86. Malone PS, Circumcision for preventing
urinary tract infection in boys: European
view. Arch Dis Child, 2005. 90(8): 773–4.
87. Mak RH and Kuo HJ, Pathogenesis of uri-
nary tract infection: an update. Curr Opin
Pediatr, 2006. 18(2): 148–52.
|6.5|

Non-operative urological
management of urinary tract
infections in children
Stephen Shei-Dei Yang1, Shang-Jen Chang2
1
Professor of Urology, School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan.
Chief of Surgeons, Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan. No. 289 Chienkuo Road, Xindian City,
Taipei, Taiwan. 231. Fax: +886–2-66289009, Tel: +886–2-66289779 Ext: 5708, urolyang@tzuchi.com.tw
2
Lecturer of Urology, School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan, Attending physician,
Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan. No. 289 Chienkuo Road, Xindian City, Taipei, Taiwan. 231
Fax: +886–2-66289009, Tel: +886–2-66289779 Ext: 5708, krissygnet@yahoo.com.tw

ABSTRACT included behavioural modification (timed

With growing antibiotics failure due to
emerging resistance of bacteria, non-
operative management of paediatric
UTI plays a more and more important
role because of its non-invasive char-
acteristics and little adverse effects.
We searched PubMed (January 1990
to February 2009) for management of
UTI in children other than surgical cor-
rection and antibiotics. Risk factors for
paediatric UTI include poor fluid intake,
infrequent voiding, constipation, dysfunc-
tional voiding, phimosis, and VUR. The
purpose of non-operative management
in paediatric UTI mainly aims to reduce
recurrence of UTI. The proposed non-
operative management of paediatric UTI
voiding, adequate fluids intake), topical
steroid for phimosis, dietary supplements
(breast milk, cranberry, probiotics),
biofeedback training for dysfunctional
voiding, anticholinergics for reducing
intravesical pressure, alpha-blockers in
dysfunctional voiding and neurogenic
bladder, and intermittent catheterization
for children with large PVR. However,
the published reports usually included
small number of patients, and were
lacking of randomization and control-
led group. Further well designed studies
are warranted to support the concepts of
non-operative management for paediat-
ric UTI.
Key words: children, prophylaxis, uri-
nary tract infection, treatment
Chapter |6| Urinary tract infections in children
SUMMARY OF RECOMMENDATIONS
1. In boys with non-retractile prepuce
and UTI, topical steroids for phimosis
are recommended (GoR B, LoE 1b).
2. In children with voiding postponement
and/or infrequent voiding and urinary
tract infection, timed voiding schedule
and optimal fluid intake are recom-
mended (GoR B, LoE 2).
3. In children with dysfunctional void-
ing are at risk of getting urinary tract
infection, biofeedback relaxation of
pelvic floor may be helpful in reduc-
ing urinary tract infection (GoR B,
LoE 2.).
4. In children with neurogenic or
non-neurogenic bladder with large
post void residual urine (PVR),
clean intermittent catheterization is
recommended for reducing sympto-
matic urinary tract infection (GoR B,
LoE 2).
5. Although constipation is common in
children, aggressive management
of constipation may reduce the risk
of recurrent urinary tract infections
(GoR B, LoE 2)
6. Breast milk feeding reduces the
risk of urinary tract infection in
infants under the age of seven
months, especially in girls (GoR B,
LoE 2).
7. Dietary supplements including cran-
berry juice and probiotics have not
been found to be effective in reduc-
ing urinary tract infection in children
(GoR C, LoE 3), despite the proven
efficacy in adult women.
8. Anticholinergics and alpha-block-
ers in children with high voiding
pressure have not been found to
be effective in reducing the recur-
rence rate of urinary tract infection:
they are recommended as optional
under the expert’s opinion (GoR C,
LoE 4).
364
1. INTRODUCTION
Because more than 30% of children with
UTI have recurrence of UTI, with most
episodes recurring within six months
after the first UTI [1], the aim of non-
operative management is to reduce the
recurrence of UTI in children following
antibiotic treatment.
We did a systematic search of PubMed
(January 1990 to February 2009) for the
management of UTI in children other
than surgical correction and antibiotic
treatment. Recognized risk factors for the
occurrence and/or recurrence of UTI are:
phimosis, increased post-void residual
urine (PVR), infrequent voiding, void-
ing dysfunction, and constipation. The
proposed non-operative management of
paediatric UTI included behavioural mod-
ification (timed voiding, adequate fluid
intake), topical steroid application for phi-
mosis, dietary supplements (breast milk,
cranberry, probiotics), biofeedback train-
ing for dysfunctional voiding, anticholin-
ergics for reducing intravesical pressure,
alpha-blockers in dysfunctional voiding
and neurogenic bladder, and clean inter-
mittent catheterization for children with
large PVR. Details are discussed below.
2. METHODS
We performed a literature search in
PubMed from January 1990 to February
2009 using the terms: risk factor, prepuce/
phimosis, steroid cream/steroid, behavio-
ral therapy, urotherapy, biofeedback/pel-
vic floor exercise, adrenergic antagonist,
anticholinergics, diet/dietary, dysfunc-
tional voiding/dysfunctional elimination
syndrome, constipation, dietary, clean
intermittent catheterization, probiotics/
lactobacillus, cranberry, breastfeeding,
breast milk, with infant/child/children/
paediatrics/paediatrics AND urinary tract
infection. Studies included in the review
were limited to human trials published in
English.
 Non-operative urological management of urinary tract
The major end point of this review was
the episodes of UTI development and
recurrence in children. The improvements
in voiding parameters such as decreased
voiding pressure, decreased post-void
residual urine was the surrogate end-
point of the review. With few randomized
controlled trials performed, evidence from
RCTs was given precedence.
2.1 Results of literature search
The literature search identified 62 rel-
evant references published in Pubmed
since January 1990. Case reports and
reviews were excluded. Finally, two
Cochrane Database Systemic Reviews,
three randomized controlled trials, and
three randomized crossover studies are
listed in Table 1. The remaining 54 stud-
ies included were nonrandomized case
controlled studies and mostly uncon-
trolled case series. A meta-analysis of the
studies was not performed due to the het-
erogeneity of the trials and the diversity
of the dosage and methods applied.
3. TOPICAL STEROIDS FOR PHIMOSIS
Circumcision reduces UTI, but with a
significant morbidity. Topical steroids
improve phimosis, but their role in the
prevention of UTI needs further study.
In boys, physiologic phimosis is an
important factor both in the development
or recurrence of UTI [10]. Children with
a non-retractile prepuce had a signifi-
cantly higher rate of recurrent UTI com-
pared to those with a retractile prepuce
[11]. Neonatal circumcision has been
confirmed to be effective in reducing the
risk of UTI [12]. There was a reduction of
90% UTI in circumcised boys when com-
pared with uncircumcised boys. However,
complications including haemorrhage
and infection occurred in 2% of patients
undergoing circumcision. One meta-
analysis suggested that the clinical bene-
fit of circumcision is likely only in boys at
| 6.5 |
high risk of UTI [12], while another study
suggested that circumcision during anti-
reflux surgery has no effect on the inci-
dence of postoperative UTI [13].
Jorgensen and Svensson [14] first
introduced the topical application of ster-
oid treating phimosis, several authors
subsequently reported success rates
ranging from 67% to 95%, and little
adverse effects. The fear that topical ster-
oids would affect the cortisol level in the
children was not observed [15]. Later,
comparable effectiveness of highly and
moderately potent steroids treating phi-
mosis was observed by Yang et al [16]. In
a small scale, prospective, randomized
study by Lee et al [3], topical use of
hydrocortisone twice daily on non-retrac-
tile prepuce for two to four weeks reduced
the rate of recurrent UTI in the follow-
ing year in infants with UTI (7.1% in the
treatment group vs. 29.6% in the control
group). Further studies evaluating neo-
natal application of steroid on foreskin to
reduce the risk of UTI in healthy infants
are warranted. The major shortcoming of
topical steroids on phimosis is that the
use of topical steroids in children with
pathological phimosis, thick scarred pre-
puce or severe balanoposthitis is less
beneficial, and circumcision should be
considered in these patients [17].
4. BEHAVIOURAL MODIFICATION
Clinically, we usually encourage chil-
dren with UTI and poor fluid intake to
increase fluid intake, although relevant
studies remain scarce. It is assumed that
an increased fluid intake may result in
shorter stasis time of urine in the blad-
der and better wash-out of bacteria from
the bladder. Infrequent voiding, poor
fluid intake, functional stool constipation,
and dysfunctional voiding were more fre-
quently disclosed in girls with recurrent
UTI than in control girls [18–19]. When
managing children with UTI, a frequency/
volume chart may help physicians and
365
Chapter |6| Urinary tract infections in children

Table 1

Subjects and
References Intervention Design Findings and Significance

Pediatr Nephrol. Probiotics prospective The incidence of recurrent UTI did not differ
2007 Sep;22(9): randomized significantly between the two groups (P > 0.05).
Lactobacillus acido-
1315–20 [2] controlled study The development of new renal scar was not
philus 10(8) CFU/g
significantly different between the two groups
1 g b.i.d. vs. antibi-
(P > 0.05).
otics prophylaxis

Pediatr Nephrol. Topical steroid + prospective the recurrent rate of UTI was 7.1% (2/28) in the
2006 Aug;21(8): physiotherapy vs. randomized infants with retractile prepuces, which was signifi-
1127–30. [3] vaseline controlled study cantly less than the rate (29.6%; 8/27) in infants
with nonretractile prepuces (P < 0.05).

Biol Neonate 2002: Seven days of A multicenter Seven days of Lactobacillus GG supplementa-
82(2):103–108 [4] Lactobacillus GG vs. Prospective, tion starting with the first feed is not effective in
placebo randomized- reducing the incidence of UTIs, NEC and sepsis in
controlled study preterm infants.

Paediatrics. 2001 New sterile catheter A prospective, A new, sterile catheter for each void did not
Oct;108(4):E71 [5] for intermittent randomized, decrease the high frequency of bacteriuria in
catheterization crossover trial patients with neurogenic bladder on intermittent
and reuse of a catheterization.
clean catheter
for intermittent
catheterization

J Pediatr. 1999 Cranberry vs. Double-blind, cranberry concentrate had no effect on bacteriuria
Dec;135(6): placebo placebo-controlled, in children underwent CIC
698–702 [6] crossover study

Can J Urol. 1995 Cranberry juice vs. randomized Liquid cranberry product, on a daily basis, at
Jan;2(1):98–102 [7] water single-blind the dosage employed, did not have any effect
cross-over study greater than that of water in preventing UTI in this
paediatric neuropathic bladder population

Cochrane Database Cranberries for pre- Cochrane Review There is some evidence that cranberry juice may
Syst Rev. 2008Jan venting urinary tract decrease the number of symptomatic UTIs over
23;(1):CD001321 [8] infections a 12 month period, particularly for women with
recurrent UTIs. It’s effectiveness for other groups is
less certain.

Cochrane Database Long-term bladder Cochrane Review Intermittent catheterization is a critical aspect of
Syst Rev 2007:(4): management by healthcare for individuals with incomplete emptying
CD006008. [9] intermittent cath- who are otherwise unable to void adequately to
eterization in adults protect bladder and renal health. There is a lack of
and children. evidence to state that incidence of UTI is affected
by use of sterile or clean technique, coated or
uncoated catheters, single (sterile) or multiple use
(clean) catheters, self-catheterization or catheteriza-
tion by others, or by any other strategy.

parents monitor the voiding frequency time of bacteria multiplication in the

and fluid intake in these children.
Increased post-void residual urine
(PVR) has long been linked to the devel-
opment and recurrence of UTI [20].
Infrequent voiding may result in longer
bladder, and increased PVR that was
frequently observed in urinary bladder
overdistension [21]. Bladder overdis-
tension is defined as a bladder capacity
(voided volume +PVR) larger than 115%

366
 Non-operative urological management of urinary tract
of expected bladder capacity. At a blad-
der capacity reaching overdistension,
more than one-third of voidings resulted
in an abnormal uroflow pattern and PVR
>20ml [21]. A timed voiding schedule is
advised in infrequent voiders to decrease
the urinary stasis time and to avoid blad-
der overdistension. However, the optimal
amount of fluid intake is not known.
Good toilet posture also plays a role,
enabling optimal relaxation of the pelvic
floor muscle and hence reducing dysfunc-
tional voiding and PVR. In postures with
adequate bilateral foot support, the relax-
ation was observed in 94% recorded from
the pelvic floor muscles. EMG amplitudes
from the pelvic floor and adductor mus-
cles were significantly higher in postures
with unsupported legs compared to pos-
tures with supported legs [22–23].
5. BIOFEEDBACK RELAXATION OF
PELVIC FLOOR MUSCLES
Children with increased sphincteric
activity during detrusor contraction, i.e.
dysfunctional voiding, have a higher rate
of UTI recurrence [24–25]. Biofeedback
relaxation of pelvic floor muscles is help-
ful in improving voiding symptoms and
urodynamic parameters in children with
dysfunctional voiding [26]. In a study of
girls with recurrent UTI who underwent
a training program including voiding and
drinking schedule, pelvic-floor relaxa-
tion biofeedback, instructions on toilet
behaviour and biofeedback uroflowmetry,
the program was effective in preventing
recurrence of UTI in 35 of 42 (83%) chil-
dren [27]. In a prospective, randomized
study comparing pelvic floor exercise and
biofeedback therapy in treating children
with dysfunctional elimination syndrome,
both groups of patients showed a low rate
of relapsed UTI (3.8% and 10%). Although
no differences in effectiveness between
different programs were detected, only
children who received biofeedback ther-
apy had a significantly reduced PVR.
| 6.5 |
Children with voiding dysfunction and
vesicoureteral reflux usually have a high
breakthrough infection rate of 34% to
43% [28]. Of 37 children with previous
history of UTI, VUR and non-neurogenic
voiding dysfunction who underwent a
biofeedback training program only 19%
had breakthrough UTI during a mean
follow-up of 21 months [29]. Similarly,
breakthrough infection was reduced to
10% after combined conservative medical
and computer game assisted pelvic floor
muscle retraining program in a mean fol-
low-up period of 24 months [28].
6. CLEAN INTERMITTENT
CATHETERIZATION FOR LARGE PVR
Since the first introduction of clean inter-
mittent catheterization (CIC) by Lapides
et al [30], CIC has gained wide acceptance
in treating patients with a neurogenic
bladder to improve bladder emptying, to
achieve continence, to prevent upper tract
damage and avoid symptomatic UTI. It
is also considered a viable therapeutic
option for the treatment of children with
nonneurogenic dysfunctional voiding and
large PVR [27]. During the catheteriza-
tion procedure, some bacteria may be
introduced into the bladder and therefore
the most common complication of CIC
is UTI. In a long term follow-up study
of 14 children who were on CIC, 70% of
urine samples were positive for bacteru-
ria, but only five symptomatic UTIs were
observed during the 323 patient-weeks.
Therefore, the author concluded that CIC
may cause asymptomatic pyuria while
reducing the possibility of febrile UTI in
children with a neurogenic bladder [30].
The factors affecting UTI were catheteri-
zation frequency and the avoidance of
bladder overfilling. The compliance of
CIC was good. In a five-year follow-up in
86 children with congenital neurogenic
bladder, only four (4.6%) discontinued the
CIC program because of discomfort asso-
ciated with introducing the catheter.
367
Chapter |6| Urinary tract infections in children
Because there are various techniques
in practice, and different catheters, a
recent Cochrane review [9] concluded that
there is a lack of evidence to state that
incidence of UTI is affected by use of ster-
ile or clean technique, coated or uncoated
catheters, single or multiple use cath-
eters, self-catheterization or catheteriza-
tion by others, or by any other strategy.
7. INTENSIVE BOWEL REGIMEN FOR
CONSTIPATION
Constipation in children is common. The
American Academy of Paediatrics defined
constipation as “a delay or difficulty
in defecation, present for two or more
weeks”, while some preferred the Bristol
stool scale in the diagnosis of constipa-
tion in children [31]. Others advocated
defining constipation as ≤2 defecations
per week, the Rome III criteria [32]. It is
postulated that chronic retention of faecal
mass above the anal verge makes children
maintain a high anal sphincter tone. The
high anal tone leads to pelvic floor (over)
activity and impaired emptying function
of the bladder and elevated PVR which
is an important factor in developing UTI
[33]. Another theory is that constipation
may increase uropathogenic organisms
in the gastrointestinal tract which then
leads to more UTI [34]. Previous studies
have documented a correlation between
constipation and UTI. Romanczuk et
al [35] evaluated 180 children suffer-
ing from recurrent UTIs and found that
treatment of chronic constipation may
reduce pyuria, bacteuria and inconti-
nence in these children. In a study of 234
children treated for chronic constipation,
relief of constipation was obtained in 52%
of patients without urinary tract anom-
aly and resulted in disappearance of UTI
[36]. Koff et al [25] evaluated 143 chil-
dren with primary vesicoureteral reflux
and UTI, 66 had dysfunctional elimina-
tion syndrome of which 50% had consti-
pation as the most prominent symptom.
368
Of the 66 with dysfunctional elimination
syndrome, 82% needed surgical reim-
plantation, while only 18% had sponta-
neous resolution of reflux. Therefore, the
importance of managing constipation and
voiding dysfunction concurrently cannot
be overemphasized. A recent study found
that children with history of UTI had
more symptoms of constipation than those
without UTI, although poor correlation
between history of constipation and faecal
loading on radiological film was observed.
The author found it difficult to define con-
stipation in children. Apart from history
from parents, the Bristol stool form scale
had been shown to be appreciated by
children. In children with recurrent UTI
and constipation, we should have a bowel
movement diary and a frequency/volume
chart. Then, physicians and/or parents
can monitor the condition from the chil-
dren and supervise them. Treatment of
constipation includes osmotic laxatives,
stimulant laxatives, increasing fluids
intake, biofeedback and psychological
intervention, all are effective in the man-
agement of constipation [37].
8. DIETARY SUPPLEMENT
8.1 Breast milk
The protective role of breast milk may be
attributed to the specific contents within
the breast milk, including immunoglobu-
lin A [38], antiadhesive oligosaccharide
[39] and lactoferrin [38]. The antibacte-
rial effect and selection of low uropatho-
genic bacteria play the role. Marid et al
observed that shorter duration of breast-
feeding was associated with higher risk of
UTI in children [40]. Recently, the same
group concluded that ongoing breastfeed-
ing and a longer duration of breastfeeding
resulted in a lower risk of infection after
weaning, especially in girls [41]. The pro-
tective role of breastfeeding was strong-
est directly after birth, then it decreased
after seven months of age.
 Non-operative urological management of urinary tract
8.2 Cranberry
From a meta analysis by Jepson and
Craig, there is some evidence supporting
the use of cranberry in reduction of UTI
episodes among women with recurrent
UTI, while there are few randomized tri-
als evaluating the effectiveness of cran-
berry in children [8]. In an open label
randomized study, 150 women with uri-
nary tract infection of E.coli were ran-
domly allocated to receive cranberry
juice, lactobacillus drink, or no interven-
tion. About a 20% reduction in absolute
risk in the cranberry group compared
with the control group was observed [42].
However, the evidence of the role of cran-
berry in prevention of UTI in children
is still inconclusive, although cranberry
juice consumption provides significant
anti-adherence activity against different
E.coli uropathogenic strains in the urine
compared with placebo [43]. Schlager et
al conducted a double-blind, placebo-con-
trolled, crossover study to determine the
effect of cranberry juice on pyuria and
symptomatic UTI in children with neuro-
genic bladder needing clean intermittent
catheterization [6]. They found that cran-
berry concentrate had no effect on bacte-
riuria in the study population, although
this may be partly due to host suscepti-
bility to infection. Foda et al conducted a
randomized single-blind cross-over study
to compare cranberry juice and water,
and no difference in infection of the inter-
vention periods were observed [7]. These
two studies only enrolled a small number
of children. More studies are required to
elucidate the role of cranberry in preven-
tion of paediatric UTI.
8.3 Probiotics
The term probiotics is defined as “live
microorganisms which when admin-
istered in adequate amounts confer a
health benefit on the host” [44]. The con-
cept of probiotics developed from normal
flora that exist in the gastrointestinal
tract and genital area. The introduction of
| 6.5 |
probiotics in the prevention of recurrent
UTI was largely due to antibiotic failure
and increased evidence of the efficacy
of probiotics [44]. Several studies have
shown the effectiveness of some lactoba-
cilli strains in reducing UTI in women
through improving vaginal ecology
[45–46]. However, controversy exists over
the efficacy of probiotics in prevention of
paediatric UTI. Dani et al [4] adminis-
tered Lactobacillus GG in neonates with
UTI, sepsis, and necrotizing enterocolitis:
no significant effect of Lactobacillus GG
in reduction of UTI was noted. A prospec-
tive, randomized controlled study com-
pared the conventional antibiotics and
probiotics in treating children with pri-
mary VUR, the incidence of recurrent UTI
was comparable in both groups of chil-
dren [2]. Long-term effects of probiotics
in children need further evaluation. Also,
which strains of lactobacillus are more
helpful in preventing paediatric UTI need
further elucidation [47]. Despite the pos-
sible clinical effects of probiotics on UTI
in children, two cases with bacteremia of
lactobacilli were reported [48].
9. MEDICATIONS OTHER THAN
ANTIBIOTICS
9.1 Alpha-blockers
There were several studies to show
the effectiveness of alpha blockers to
improve voiding dysfunction and reduce
PVR [49–51]. However, none of these
studies correlated the alpha-blockers to
reduction of UTI. In children with dys-
functional voiding or neurogenic blad-
der, alpha-blockers may relieve bladder
outlet obstruction and improve urody-
namic parameters such as uroflow rate
and post-void residual urine. Yang et al
evaluated the effectiveness of doxazosin
in 16 boys with low flow rate and uri-
nary incontinence. The symptoms and
flow rate improved in half of the chil-
dren after medical treatment, although
369
Chapter |6| Urinary tract infections in children
no placebo control group was compared
[51]. In a randomized, double-blind,
placebo-controlled study, doxazosin did
not demonstrate a significant objective
benefit (including incontinent episodes,
voiding parameters, and PVR), but pro-
duced a significant subjective benefit in
the treatment of urinary incontinence
secondary to voiding dysfunction [52].
Yucel et al [53] conducted a small scale,
prospective, open-label, randomized
study to compare the efficacy of bio-
feedback therapy and alpha-blockers
for children with dysfunctional voiding
and urinary tract infection. The peak
flow rates, PVR, and urge incontinence
improved in both groups without statis-
tical difference while these patients also
received behavioural therapy, anticholin-
ergics and antibiotics prophylaxis. There
existed no long-term effects of alpha-
blocker on paediatric dysfunctional void-
ing and UTI, further evaluation should
be warranted.
9.2 Anticholinergics
Theoretically, anticholinergics may
relieve the symptoms of frequency,
urgency, and urgency incontinence in
children with UTI. However, the fear that
anticholinergics may increase PVR and
hence increase the rate of UTI was still a
major concern for most paediatric urolo-
gists [54]. The rationale of anticholiner-
gics in treating children with UTI lies in
the fact that anticholinergics can inhibit
bladder contractions and reduce bladder
pressure. Some studies advocated add-
ing anticholinergics in treating VUR with
bladder overactivity. In their opinion,
anticholinergics can reduce bladder pres-
sure and lower the rate of breakthrough
UTI [55–56]. In children with spinal
cord injury, Generao el al [57] suggested
early clean intermittent catheteriza-
tion and use of anticholinergics to pre-
vent upper tract deterioration, improve
continence and decrease infections.
However, the design of these studies
370
lacks a well-controlled group. In a multi-
center, open-label extension of a 12-week,
double-blind, placebo-controlled study of
tolterodine ER in children with urge uri-
nary incontinence [54] UTI was the most
commonly reported adverse effect which
occurred in 7% of children during that
open-label treatment. Although only 0.9%
of UTI was considered by investigator
to be treatment related, the role of anti-
cholinergics on paediatric UTI needs fur-
ther evaluation.
10. FURTHER RESEARCH
Despite clinical importance of urinary
tract infection in children, there is a
lack of large scale, well designed, and
randomized controlled trials on the top-
ics about non-operative management.
Although some dietary supplements
were proven to be effective in adults,
more studies in children are warranted.
Besides, further studies on the impact
of life style modification and the optimal
fluid intake on paediatric UTI should be
performed.
11. CONCLUSIONS
Several non-operative means are avail-
able for reducing the recurrence of UTI.
Except for those with anatomical anom-
aly, non-operative urological management
for the above mentioned risk factors may
reduce the recurrence rate of UTI. The
common shortcomings of these studies
on non-operative means are small sam-
ple size, lack of randomization, ill-defined
severity of disease and other confounding
factors. Since these non-operative meth-
ods usually bear little risks to the chil-
dren, and the long-term sequelae of UTI
may be detrimental, efforts to apply these
non-operative methods are still recom-
mended to reduce the recurrence of UTI
(Table 1).
 Non-operative urological management of urinary tract
REFERENCES
1. Nuutinen M and Uhari M, Recurrence
and follow-up after urinary tract infection
under the age of 1 year. Pediatr Nephrol,
2001. 16(1): 69–72.
2. Lee SJ, Shim YH, Cho SJ, and Lee JW,
Probiotics prophylaxis in children with
persistent primary vesicoureteral reflux.
Pediatr Nephrol, 2007. 22(9): 1315–20.
3. Lee JW, Cho SJ, Park EA, and Lee SJ,
Topical hydrocortisone and physiotherapy
for nonretractile physiologic phimosis
in infants. Pediatr Nephrol, 2006. 21(8):
1127–30.
4. Dani C, Biadaioli R, Bertini G, Martelli E,
and Rubaltelli FF, Probiotics feeding in
prevention of urinary tract infection, bac-
terial sepsis and necrotizing enterocolitis
in preterm infants. A prospective double-
blind study. Biol Neonate, 2002. 82(2):
103–8.
5. Schlager TA, Clark M, and Anderson S,
Effect of a single-use sterile catheter for
each void on the frequency of bacteriuria
in children with neurogenic bladder on
intermittent catheterization for bladder
emptying. Pediatrics, 2001. 108(4): E71.
6. Schlager TA, Anderson S, Trudell J, and
Hendley JO, Effect of cranberry juice
on bacteriuria in children with neuro-
genic bladder receiving intermittent
catheterization. J Pediatr, 1999. 135(6):
698–702.
7. Foda MM, Middlebrook PF, Gatfield CT,
Potvin G, Wells G, and Schillinger JF,
Efficacy of cranberry in prevention of uri-
nary tract infection in a susceptible pedi-
atric population. Can J Urol, 1995. 2(1):
98–102.
8. Jepson RG and Craig JC, Cranberries
for preventing urinary tract infections.
Cochrane Database Syst Rev, 2008(1):
CD001321.
9. Moore KN, Fader M, and Getliffe K,
Long-term bladder management by inter-
mittent catheterisation in adults and
children. Cochrane Database Syst Rev,
2007(4): CD006008.
10. Hiraoka M, Tsukahara H, Ohshima Y,
and Mayumi M, Meatus tightly covered
by the prepuce is associated with urinary
| 6.5 |
infection. Pediatr Int, 2002. 44(6):
658–62.
11. Shim YH, Lee JW, and Lee SJ, The risk
factors of recurrent urinary tract infection
in infants with normal urinary systems.
Pediatr Nephrol, 2009. 24(2): 309–12.
12. Singh-Grewal D, Macdessi J, and Craig J,
Circumcision for the prevention of uri-
nary tract infection in boys: a systematic
review of randomised trials and obser-
vational studies. Arch Dis Child, 2005.
90(8): 853–8.
13. Kwak C, Oh SJ, Lee A, and Choi H, Effect
of circumcision on urinary tract infection
after successful antireflux surgery. BJU
Int, 2004. 94(4): 627–9.
14. Jorgensen ET and Svensson A, The treat-
ment of phimosis in boys, with a potent
topical steroid (clobetasol propionate
0.05%) cream. Acta Derm Venereol, 1993.
73(1): 55–6.
15. Golubovic Z, Milanovic D, Vukadinovic V,
Rakic I, and Perovic S, The conservative
treatment of phimosis in boys. Br J Urol,
1996. 78(5): 786–8.
16. Yang SS, Tsai YC, Wu CC, Liu SP, and
Wang CC, Highly potent and moder-
ately potent topical steroids are effec-
tive in treating phimosis: a prospective
randomized study. J Urol, 2005. 173(4):
1361–3.
17. Orsola A, Caffaratti J, and Garat JM,
Conservative treatment of phimosis in
children using a topical steroid. Urology,
2000. 56(2): 307–10.
18. Stauffer CM, van der Weg B, Donadini R,
Ramelli GP, Marchand S, and Bianchetti
MG, Family history and behavioral
abnormalities in girls with recurrent uri-
nary tract infections: a controlled study. J
Urol, 2004. 171(4): 1663–5.
19. Mazzola BL, von Vigier RO, Marchand S,
Tonz M, and Bianchetti MG, Behavioral
and functional abnormalities linked with
recurrent urinary tract infections in girls.
J Nephrol, 2003. 16(1): 133–8.
20. Shaikh N, Abedin S, and Docimo SG, Can
ultrasonography or uroflowmetry predict
which children with voiding dysfunction
will have recurrent urinary tract infec-
tions? J Urol, 2005. 174(4 Pt 2): 1620–2;
discussion 1622.
371
Chapter |6| Urinary tract infections in children
21. Yang SS and Chang SJ, The effects of
bladder over distention on voiding func-
tion in kindergarteners. J Urol, 2008.
180(5): 2177–82; discussion 2182.
22. Wennergren HM, Oberg BE, and
Sandstedt P, The importance of leg sup-
port for relaxation of the pelvic floor
muscles. A surface electromyograph study
in healthy girls. Scand J Urol Nephrol,
1991. 25(3): 205–13.
23. De Paepe H, Renson C, Hoebeke P,
Raes A, Van Laecke E, and Vande Walle
J, The role of pelvic-floor therapy in the
treatment of lower urinary tract dysfunc-
tions in children. Scand J Urol Nephrol,
2002. 36(4): 260–7.
24. Shortliffe LM, The management of uri-
nary tract infections in children without
urinary tract abnormalities. Urol Clin
North Am, 1995. 22(1): 67–73.
25. Koff SA, Wagner TT, and Jayanthi VR,
The relationship among dysfunctional
elimination syndromes, primary vesi-
coureteral reflux and urinary tract
infections in children. J Urol, 1998.
160(3 Pt 2): 1019–22.
26. Shei Dei Yang S and Wang CC,
Outpatient biofeedback relaxation of the
pelvic floor in treating pediatric dysfunc-
tional voiding: a short-course program is
effective. Urol Int, 2005. 74(2): 118–22.
27. De Paepe H, Hoebeke P, Renson C, Van
Laecke E, Raes A, Van Hoecke E, Van
Daele J, and Vande Walle J, Pelvic-floor
therapy in girls with recurrent urinary
tract infections and dysfunctional void-
ing. Br J Urol, 1998. 81 Suppl 3: 109–13.
28. Herndon CD, DeCambre M, and
McKenna PH, Changing concepts con-
cerning the management of vesicoureteral
reflux. J Urol, 2001. 166(4): 1439–43.
29. Khen-Dunlop N, Van Egroo A,
Bouteiller C, Biserte J, and Besson R,
Biofeedback therapy in the treatment
of bladder overactivity, vesico-ureteral
reflux and urinary tract infection. J
Pediatr Urol, 2006. 2(5): 424–9.
30. Schlager TA, Dilks S, Trudell J, Whittam
TS, and Hendley JO, Bacteriuria in chil-
dren with neurogenic bladder treated
with intermittent catheterization: natural
history. J Pediatr, 1995. 126(3): 490–6.
372
31. Heaton KW, Radvan J, Cripps H,
Mountford RA, Braddon FE, and Hughes
AO, Defecation frequency and timing,
and stool form in the general population:
a prospective study. Gut, 1992. 33(6):
818–24.
32. Tack J, Talley NJ, Camilleri M,
Holtmann G, Hu P, Malagelada JR, and
Stanghellini V, Functional gastroduode-
nal disorders. Gastroenterology, 2006.
130(5): 1466–79.
33. Franco I, Overactive bladder in children.
Part 1: Pathophysiology. J Urol, 2007.
178(3 Pt 1): 761–8; discussion 768.
34. Giramonti KM, Kogan BA, Agboola OO,
Ribons L, and Dangman B, The asso-
ciation of constipation with childhood
urinary tract infections. J Pediatr Urol,
2005. 1(4): 273–8.
35. Romanczuk W and Korczawski R,
Chronic constipation: a cause of recurrent
urinary tract infections. Turk J Pediatr,
1993. 35(3): 181–8.
36. Loening-Baucke V, Urinary incontinence
and urinary tract infection and their
resolution with treatment of chronic con-
stipation of childhood. Pediatrics, 1997.
100(2 Pt 1): 228–32.
37. Rubin G and Dale A, Chronic constipa-
tion in children. BMJ, 2006. 333(7577):
1051–5.
38. Goldblum RM, Schanler RJ, Garza C,
and Goldman AS, Human milk feed-
ing enhances the urinary excretion of
immunologic factors in low birth weight
infants. Pediatr Res, 1989. 25(2): 184–8.
39. Gothefors L, Olling S, and Winberg J,
Breast feeding and biological properties
of faecal E. coli strains. Acta Paediatr
Scand, 1975. 64(6): 807–12.
40. Marild S, Jodal U, and Mangelus L,
Medical histories of children with acute
pyelonephritis compared with controls.
Pediatr Infect Dis J, 1989. 8(8): 511–5.
41. Marild S, Hansson S, Jodal U, Oden
A, and Svedberg K, Protective effect of
breastfeeding against urinary tract infec-
tion. Acta Paediatr, 2004. 93(2): 164–8.
42. Kontiokari T, Sundqvist K, Nuutinen
M, Pokka T, Koskela M, and Uhari
M, Randomised trial of cranberry-
lingonberry juice and Lactobacillus
 Non-operative urological management of urinary tract
GG drink for the prevention of urinary
tract infections in women. BMJ, 2001.
322(7302): 1571.
43. Di Martino P, Agniel R, David K, Templer
C, Gaillard JL, Denys P, and Botto H,
Reduction of Escherichia coli adherence
to uroepithelial bladder cells after con-
sumption of cranberry juice: a double-
blind randomized placebo-controlled
cross-over trial. World J Urol, 2006. 24(1):
21–7.
44. Reid G, The potential role of probiotics in
pediatric urology. J Urol, 2002. 168(4 Pt
1): 1512–7.
45. Bruce AW and Reid G, Intravaginal instil-
lation of lactobacilli for prevention of
recurrent urinary tract infections. Can J
Microbiol, 1988. 34(3): 339–43.
46. Cadieux P, Burton J, Gardiner G,
Braunstein I, Bruce AW, Kang CY, and
Reid G, Lactobacillus strains and vaginal
ecology. JAMA, 2002. 287(15): 1940–1.
47. Reid G and Bruce AW, Probiotics to pre-
vent urinary tract infections: the ration-
ale and evidence. World J Urol, 2006.
24(1): 28–32.
48. Land MH, Rouster-Stevens K, Woods CR,
Cannon ML, Cnota J, and Shetty AK,
Lactobacillus sepsis associated with pro-
biotic therapy. Pediatrics, 2005. 115(1):
178–81.
49. Austin PF, Homsy YL, Masel JL, Cain
MP, Casale AJ, and Rink RC, alpha-
Adrenergic blockade in children with
neuropathic and nonneuropathic voiding
dysfunction. J Urol, 1999. 162(3 Pt 2):
1064–7.
50. Cain MP, Wu SD, Austin PF,
Herndon CD, and Rink RC, Alpha blocker
therapy for children with dysfunctional
voiding and urinary retention. J Urol,
| 6.5 |
2003. 170(4 Pt 2): 1514–5; discussion
1516–7.
51. Yang SS, Wang CC, and Chen YT,
Effectiveness of alpha1-adrenergic block-
ers in boys with low urinary flow rate
and urinary incontinence. J Formos Med
Assoc, 2003. 102(8): 551–5.
52. Kramer SA, Rathbun SR, Elkins D,
Karnes RJ, and Husmann DA, Double-
blind placebo controlled study of
alpha-adrenergic receptor antagonists
(doxazosin) for treatment of voiding
dysfunction in the pediatric population.
J Urol, 2005. 173(6): 2121–4; discussion
2124.
53. Yucel S, Akkaya E, Guntekin E, Kukul E,
Akman S, Melikoglu M, and Baykara M,
Can alpha-blocker therapy be an alterna-
tive to biofeedback for dysfunctional void-
ing and urinary retention? A prospective
study. J Urol, 2005. 174(4 Pt 2): 1612–5;
discussion 1615.
54. Nijman RJ, Borgstein NG, Ellsworth P,
and Siggaard C, Long-term tolerability
of tolterodine extended release in chil-
dren 5–11 years of age: results from a
12-month, open-label study. Eur Urol,
2007. 52(5): 1511–6.
55. Willemsen J and Nijman RJ,
Vesicoureteral reflux and videourody-
namic studies: results of a prospec-
tive study. Urology, 2000. 55(6):
939–43.
56. Chandra M and Maddix H, Urodynamic
dysfunction in infants with vesicoureteral
reflux. J Pediatr, 2000. 136(6): 754–9.
57. Generao SE, Dall’era JP, Stone AR, and
Kurzrock EA, Spinal cord injury in chil-
dren: long-term urodynamic and uro-
logical outcomes. J Urol, 2004. 172(3):
1092–4, discussion 1094.
373
|6.6|
Medical therapy versus surgery
in vesicoureteral reflux from the
view of the paediatrician
Rolf Beetz
Paediatric Nephrology, Center for Paediatric and Adolescent Medicine, University Medical Clinic
Langenbeckstr.1, 55131 Mainz
Phone: +41-6131-17 3937, Fax: +41-6131-17 6426, e-mail: beetz@kinder.klinik.uni-mainz.de
ABSTRACT
Up to 30(–50) % of children present-
ing with their first urinary tract infec-
tion (UTI) are subsequently diagnosed
with vesicoureteral reflux (VUR) [1–2].
The main goal of any therapy in vesi-
coureteral reflux is the prevention of
acquired parenchymal damage by ascend-
ing urinary tract infections with their
potential sequelae such as hypertension
and/or chronic kidney failure. However, in
many cases of dilating VUR, renal dam-
age is already present at diagnosis and is
a congenital kidney malformation associ-
ated with VUR rather than an acquired
lesion.
To prevent future renal scarring, two
treatment options are available. Due to
the fact that low to medium grade VUR
may spontaneously resolve, the cur-
rent standard of care for most children,
at least initially, is long term antibacte-
rial prophylaxis to prevent UTI. Another
option, presumably indicated in high
grade VUR, is surgical correction in order
to prevent the ascension of bacteria to
the kidney. Until recently, open surgery
was the only treatment option. Currently,
endoscopic injection with dextranomer/
hyaluronic acid copolymer is widely used
[3]. However, in lower to mild reflux
grades no treatment at all seems to be
quite a secure strategy if pyelonephritis
episodes are promptly treated.
The wide spectrum of treatment
options provides the opportunity for
sophisticated therapeutic and prophy-
lactic strategies. However, in spite of
several national guidelines published or
being in process no consensus has been
found yet regarding the best therapy
for different grades of reflux and renal
involvement.
 Medical therapy versus surgery in vesicoureteral reflux
A risk oriented therapy for infants
and children with reflux should account
for its complexity. This probably requires
an extended classification. It should not
only include reflux grades but also fac-
tors like bladder dysfunction, age, sex,
urinary tract infections and scarring
as decision criteria for treatment and
prophylaxis.
To a lesser extent, conservative and
surgical concepts should not compete
against each other but complement one
another. Interdisciplinary cooperation
should result in a differentiated concept
of therapy and prophylaxis of reflux and
urinary tract infection.
Key words: reflux, prophylaxis,
pyelonephritis, voiding dysfunction,
resistance, recurrence, urinary tract
infections, children, infants.
SUMMARY OF RECOMMENDATIONS
Preliminary note: the following recom-
mendations apply to cases with the his-
tory of at least one symptomatic UTI
before or after the diagnosis of VUR.
1. Due to its high spontaneous matura-
tion rate, most of the children with
reflux grades I-II should be treated
conservatively (GoR A).
2. Antibacterial prophylaxis in low grade
reflux (grade I-II according to the
International Reflux Classification)
is not superior to pure surveillance
without medication. In low grade
reflux without frequent recurrences of
pyelonephritis, antibacterial prophy-
laxis therefore is not generally recom-
mended (GoR A).
3. In VUR grade III-IV, surgical reflux
correction and long term antibacte-
rial prophylaxis show no difference
regarding the risk of renal damage.
The individual decision for surgical
or conservative treatment of dilating
VUR should depend on multiple terms
and conditions such as age and sex,
| 6.6 |
laterality and degree of reflux, bladder
function, recurrences of symptomatic
UTIs, pre-existing renal scars and the
expectations of parents (GoR B).
4. VUR grade V is commonly regarded as
requiring surgical treatment because
spontaneous resolution is very rare
(GoR C).
5. If dilating VUR persists during long
term antibacterial prophylaxis, the
disadvantages of antibiotics such as
side effects or the development of bac-
terial resistance limit its practicabil-
ity. In these cases surgery should be
considered (GoR C).
6. Bladder dysfunction increases the
risk of urinary tract infections and
can lead to significant delay in reflux
maturation. Its detection by careful
history and its efficient treatment
therefore is mandatory in affected
children (GoR B).
7. Therapeutic delay increases the risk
of pyelonephritis and subsequent
renal scarring. Diagnosis and treat-
ment of febrile urinary tract infection
therefore should be initiated promptly
and effectively (GoR A).
8. In patients with VUR, symptomatic
UTI is caused more often by non-E.
coli than in uncomplicated infections.
This has to be considered with calcu-
lated antibacterial therapy (GoR B).
1. INTRODUCTION
Scarcely another topic in paediatric urol-
ogy has been discussed more controver-
sially than vesicoureteral reflux. Despite
growing knowledge on the interrelations
between reflux, urinary tract infection
and renal scars, the significance of reflux
in the pathogenesis of pyelonephritis
and renal damage remains contentious.
Over the last decade vesicorenal reflux
and reflux nephropathy have been rec-
ognized as being parts of a multifactorial
disturbance of ureterorenal development;
375
Chapter |6| Urinary tract infections in children
“CAKUT“ (congenital anomalies of kid-
neys and urinary tract) [4–5].
Over 30% of children with urinary
tract infection and presenting with a
radiologically detected vesicoureteral
reflux (VUR), show renal scars in the
ipsilateral kidney [6]. In contrast, these
parenchymal changes rarely exist in the
non-refluxing contralateral kidney of the
same child [7–8]. Radiologically detect-
able scars have therefore been classified
as “reflux nephropathy” [9]. The pro-
portion of renal units with reflux neph-
ropathy correlates with the reflux grade.
Basically, there are two conditions poten-
tially leading to renal damage in associa-
tion with VUR:
1.1 “Congenital reflux nephropathy”
Approximately one third of newborns
with sonographically presumed and
VCUG proven VUR present with paren-
chymal defects in DMSA scans [10–11].
This congenital association of VUR and
renal damage can probably be explained
by a disorganisation of ureteral develop-
ment in early embryonal stage [12]. If
the ureteral bud arises aberrantly from
its typical origin at the Wolff-duct, it can
connect to undifferentiated parts of the
metanephrogenic blastema, thus inducing
dysplastic renal parenchyma. Dilating
reflux predominantly is detected in boys,
with dilating ureters or renal pelvices
being noticed by ultrasound. As the pro-
portion of renal units with parenchymal
damage increases with reflux grade, this
might explain why male infants are more
often affected by congenital reflux neph-
ropathy than girls.
1.2 Acquired pyelonephritic renal
damage associated with VUR
The emerging development of renal scars
is usually associated with the occurrence
of a pyelonephritic episode [13]. A vesico-
renal reflux is said to favour the ascen-
sion of uropathogens up to the kidney.
However, there is growing uncertainty
376
over the pathogenic importance of VUR in
the development of pyelonephritic scars.
Systematic studies using DMSA-scans
demonstrated that pyelonephritic scars
can develop in comparable numbers in
infants and children with or without
reflux [14]. These results throw a new
light on VUR: pyelonephritis, not reflux
itself, is the crucial mechanism leading
to parenchymal damage in acquired renal
scarring.
The following factors increase the risk
for acquired renal damages:
• Recurrent pyelonephritis
• Therapeutic delay of pyelonephritis
• High grade vesicorenal reflux
While it is well known that infants and
young children bear a particular risk for
pyelonephritic damage [15], renal scars
can also develop during later childhood
and adolescence [13, 16–17]. In recent
years it has become obvious that the indi-
vidual risk for pyelonephritic scars might
be partially genetically determined [18].
From the view of the paediatrician, the
main goal of any therapy is the preven-
tion of acquired parenchymal damage by
ascending urinary tract infections [19].
Today, there are different ways to achieve
this aim. Strategies with the lowest inva-
siveness and greatest efficacy in this
respect will become accepted in future.
2. METHODS
A systematic literature search was
performed for the last 10 years in
MEDLINE and the Cochrane library
with the following key words: urinary
tract infections, therapy, prophylaxis.
Limitations were children aged 0–14
years. An English abstract had to be
available. The authors had also continu-
ously observed the relevant literature
concerning the topic over the last twenty
years. Only peer reviewed articles were
included. More than 300 publications
 Medical therapy versus surgery in vesicoureteral reflux
were identified, which were screened by
title and abstract and more than 100
were included in this analysis.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[20–21]
3. THERAPEUTIC STRATEGIES IN
VESICOURETERAL REFLUX
The main goal of therapy is the preven-
tion of parenchymal damage. In primary
reflux, ascending urinary tract infec-
tions are responsible for acquired renal
damage. Without urinary tract infection,
primary VUR does not usually cause
scarring.
Today, there are two principal thera-
peutic options for primary VUR. The
“conservative” concept relies on the spon-
taneous resolution of reflux which mainly
depends on reflux grade, but is also influ-
enced by the presence of bladder func-
tional status and age at presentation.
Surgical therapy relies on the hypothesis
that the risk for pyelonephritis would be
significantly lower after the cessation of
reflux.
3.1 Long term observation and
antibacterial prophylaxis
For a long time there has been an agree-
ment in principle about the fact that chil-
dren with pyelonephritis and VUR are at
risk for developing renal scars and that
this risk correlates with the degree of
reflux [6, 22–23]. This is especially true
for young infants with dilating vesico-
renal reflux [24]. The pre-existence of
parenchymal defects further increases
this risk [25].
The proportion of refluxing ureters
in the population as well as the degree
of reflux in persistently refluxing renal
units decreases with growing age. This
phenomenon of “reflux maturation”
| 6.6 |
encourages a strategy of “watchful wait-
ing“ [26]. Conservative strategies today
rely on this concept using antibacterial
long term prophylaxis to decrease the
risk of UTI recurrences as long as reflux
has not been resolved or downgraded.
The indications for antibacterial proph-
ylaxis differ from country to country and
from clinic to clinic. The guidelines of
the American Academy of Paediatrics
recommend antibacterial prophylaxis
independent of reflux grade in all cases,
if there is no absolute indication for sur-
gical repair [27]. This recommendation
was adopted in a recent German consen-
sus paper and advised after diagnosis
of VUR following a pyelonephritis up to
the fifth year of life in girls and the sec-
ond year of life in boys [28]. In a Swedish
guideline published in 1999, antibacte-
rial prophylaxis is used exclusively with
reflux grade III-V and continued for one
year. Thereafter prophylaxis is continued
if the reflux is not downgraded to grade
0-II [29].
Today, nitrofurantoin and trimetho-
prim are the first choice substances used
for antibacterial prophylaxis of UTI’s.
Cefaclor also has its place in long term
antibacterial prophylaxis [30].
However, the reliability of intake is
uncertain. In an observation study, only
two-thirds of the paediatric patients
took the antibacterial medication reg-
ularly [31]. A recent analysis of over
35,000 VUR patients evaluated the ratio
of total days of antibiotic fill over the
12-month period following VUR diagno-
sis. The average rate of compliance dur-
ing this time frame was 41.4%, meaning
that, on average, patients had enough
antibacterial therapy to last 41.4% of
the year [32]. “Breakthrough infections”
can frequently be ascribed to poor com-
pliance. Therefore, it is imperative that
parents and patients are fully informed
on the use of antibacterial prophylaxis
before commencement and encour-
aged to continue treatment as long as
necessary.
377
Chapter |6| Urinary tract infections in children
3.1.1 Duration of antibacterial
prophylaxis with vesicoureteral
reflux
The optimal duration of long-term anti-
bacterial prophylaxis is as unclear as
its indication. Following the rationales
for antibacterial prophylaxis mentioned
above, it should be continued until the
risk of pyelonephritic recurrences is
diminished and/or the risk of renal scars
is “outgrown”.
In children with vesicorenal reflux,
prophylaxis is usually discontinued after
resolving reflux, proven by repeated
VCUs, or after successful reflux surgery.
The situation is more difficult in cases
with long-lasting, high-grade reflux with-
out breakthrough infections, and in which
continuation of conservative treatment is
intended.
The decision to discontinue antibacte-
rial prophylaxis is quite easy in boys with
vesicoureteric reflux. Long-term prophy-
laxis in boys over one year of age with
conservatively monitored vesicoureteric
reflux has been questioned because the
risk of recurrence is extremely low in
boys at this age [33–34].
In girls with vesicorenal reflux, the
decision for stopping antibacterial proph-
ylaxis is comparatively more difficult.
The above-average susceptibility for UTIs
often continues over many years into
adulthood [35]. With growing restraint
in surgical correction, the situation has
Table 1 Frequency of non-neurogenic bladder dysfunction in children with vesicoureteral reflux
(Diagnosis by urodynamic study).
Source Patients (n)
Taylor et al. 1982 [104] 37
Koff u. Murtagh 1983 [105] 62
Nielsen et al. 1984 [106] 41
Secura 1989 [107] 53
Scholtmeijer et al. 1994 [108] 101
378
become more complicated over the last 10
years. It is widely accepted that the risk
for pyelonephritic renal scars decreases
with increasing age. This has caused a
recommendation for the cessation of anti-
bacterial prophylaxis in later childhood,
despite continuing low grade reflux [29,
36]. Several recent studies seem to sup-
port this concept with low grade reflux
[33, 37–38]. However, the extent of the
risk of acquired scarring actually out-
growing with age remains unclear. There
are clinical and experimental data which
demonstrate the risk of renal scarring in
later childhood and adolescents [13, 39].
The cessation of antibacterial prophy-
laxis is an individual decision which
must consider the duration of the previ-
ous infection-free period, the degree of
reflux, pre-existing parenchymal damage
and the existence of bladder dysfunction.
Last but not least, the decision depends
on the compliance and reliability of the
family.
3.1.2 Importance of Bladder Dysfunction
in Vesicoureteral Reflux
Vesicoureteral reflux, urinary tract infec-
tions and bladder dysfunction are fre-
quently associated [40–42] (Table 1).
Overall it is estimated that bladder dys-
function exists in about 50% of children
with VUR [43]. Bladder function influ-
ences the spontaneous regression rate
Types of bladder dysfunction (%)
Detrusor-hyperactivity Detrusor-Sphincter-Dyscoordination
75 not investigated
55 not investigated
50 25
75 68
40 not investigated
 Medical therapy versus surgery in vesicoureteral reflux
of reflux [42, 44–46]. These observations
support the current trend of a differenti-
ated view of the phenomenon “reflux“:
not only are reflux grade or the configura-
tion of ureteral insertion into the bladder
crucial prognostic factors in the natural
history of reflux, but bladder function is
also an important predictive parameter
for spontaneous reflux maturation, sus-
ceptibility for pyelonephritic episodes
and for renal damaging. This awareness
has implications for conservative reflux
therapy. It must include the treatment
of pre-existing bladder dysfunction to be
successful in the long run [47].
3.1.3 Reflux control during observation
Commonly, annual controls of reflux
are recommended during conservative
treatment. However, the extension of
these intervals would have no unaccept-
able influence on the duration of prophy-
laxis. Thompson et al. demonstrated via
a mathematical model that two-year
intervals with low-grade refluxes would
decrease the number of VCUs by 42%,
whereas the duration of antibacterial
prophylaxis would only be prolonged by
16%. In high-grade reflux, a three-year
interval would decrease the number of
VCUs by 63%, whereas the duration of
prophylaxis would only be prolonged by
10% [48]. Therefore, the frequency of
repeated VCUs should be based individu-
ally on reflux grade with preference to
longer intervals.
Table 2 Prospective randomised Pioneer Studies on antibacterial prophylaxis in children.
Authors, year of
publication Age of probands
Stansfeld JM et al, 1975 [60] 6 months-14 years
SavageDC et al, 1975[58] 5–7 years
Lohr JA et al, 1977[55] 3–13 years
Smellie JM et al, 1978[57] 2–12 years
| 6.6 |
3.1.4 Effectiveness of antibacterial
prophylaxis
Antibacterial prophylaxis has been shown
to be safe and has been repeatedly docu-
mented as decreasing symptomatic recur-
rences of uncomplicated recurrent UTI
in women [49–53]. Most of these studies
show a remarkably consistent re-infection
rate of 2.0–3.0 per patient year, reduced
to 0.1–0.2 per patient year with prophy-
laxis (LoE 1a).
However, the evidence that antibac-
terial prophylaxis works in uncompli-
cated UTI in young women does not
mean that it is also effective for the
prevention of recurrent UTIs in chil-
dren [54]. Furthermore, prophylaxis
in adults is preferably carried out to
reduce the rate of cystitis in women,
whereas in children efforts are made
to avoid pyelonephritic episodes, which
might lead to renal scars. The question
of whether antibacterial prophylaxis is
effective in children therefore, presum-
ably has to be focussed on the develop-
ment of renal scars with and without
medication.
There is some evidence from a number
of studies that antibiotics may prevent
recurrent UTI in children, particularly
during the period of prophylaxis. Previous
pioneer trials in children have demon-
strated the combination of trimethoprim-
sulfamethoxazole, trimethoprim and
nitrofurantoin to be effective prophylactic
drugs [55–60] (Table 2).
Duration of
Study design prophylaxis
Cotrimoxazole vs. Placebo 6 months
Cotrimoxazole or Nitrofurantoin vs. 10 weeks
control
Nitrofurantoin vs. Placebo 6 months
Cotrimoxazole or Nitrofurantoin vs. 6–12 months
control
379
Chapter |6| Urinary tract infections in children
However, in recent years doubts have
arisen concerning the rationale of the
widespread use of long-term antibac-
terial prophylaxis in paediatric urol-
ogy. The established indications and
the efficacy of antibacterial prophylaxis
per se have been questioned in several
reviews [61–65]. Williams et al. stated
in a recent Cochrane review that there is
considerable uncertainty about whether
long-term, low-dose antibiotic administra-
tion prevents UTI in children [65]. Most
of the authors of these articles criticize
the lack of evidence for using antibac-
terial prophylaxis, due to the low qual-
ity and small patient groups of available
clinical trials. Indeed, recommendations
offering continuous antibiotic prophylaxis
in children are based on limited scientific
data.
Recently published results of a pro-
spective, randomised controlled study
comparing the effects of antibacterial
prophylaxis on patients with and with-
out vesicoureteral reflux also question the
effectiveness of antibacterial prophylaxis
in children with low-grade reflux [66]. In
this study, after an acute pyelonephritis,
218 patients of three months to 18 years
of age, with or without mild vesicoureteral
reflux, randomised to a group with and a
group without antibacterial prophylaxis,
were followed over a period of one year.
Table 3 Current prospective randomised studies on antibacterial prophylaxis in children.
Author, year of Characteristics of
publication probands
Garin EH et al, 2006 VUR 0-III
[66]
Roussey-Kelser G VUR I-III
et al, 2008 [67]
Pennesi M et al, VUR II-IV
2008 [69]
Montini G et al, VUR 0-III
2008 [68]
* n.s. = not significantly different from Placebo.
380
Initially a DMSA scan was performed
and repeated after six months or after
a febrile urinary tract infection. There
were no differences between the groups
concerning the recurrence or severity of
UTIs, or the development of renal scars.
The authors concluded that neither mild
reflux nor antibacterial prophylaxis influ-
ence the rates of pyelonephritis and renal
scarring [66].
A French working group observed the
influence of antibacterial prophylaxis
with cotrimoxazol on the frequency of
UTI in 225 children aged one month up
to three years with vesicoureteral reflux
grade I-III during an observation period
of 18 months. Concerning sex, age and
reflux grade there were no differences
between treated patients and the control
group. During the observation period,
the rate and severity of UTI was not sig-
nificantly different between both groups.
Only in boys with reflux grade III could
a significant reduction of recurrences be
demonstrated in the treatment group
[67]. These results were actually sup-
ported by two Italian studies [68–69]. In
summary, the four randomised control-
led studies cited above allow the conclu-
sion that antibiotic prophylaxis would not
be indicated for children following a first
febrile UTI if no or only mild grade I or II
reflux is present [70] (Table 3). However,
Antibiotic/control Influence of prophylaxis on
UTI recurrence Renal scarring
TP/MMZ or Nitrofurantoin n.s. n.s.
vs no prophylaxis
TMP/SMZ vs no n.s. n.s.
prophylaxis
TMP/SMZ vs no n.s. n.s.
prophylaxis
Amoxy-Clav or TMP/ n.s. n.s.
SMZ vs no prophylaxis
 Medical therapy versus surgery in vesicoureteral reflux
for higher grade reflux, no definite conclu-
sions can be drawn from current studies.
At this time, three randomised pro-
spective studies are in progress, hopefully
resulting in answers to current questions
concerning antibacterial prophylaxis with
VUR:
One of these studies has been initiated
in Sweden by the Gothenburg group. In
over 200 children under the age of two
years with reflux grade III and IV, three
treatment options were compared: low-
dose antibacterial prophylaxis, early
therapy of recurrences in cases with-
out antibacterial prophylaxis and early
endoscopic reflux correction by subu-
reteral injection of Deflux®. Preliminary
results demonstrate significant superior-
ity of antibacterial prophylaxis compared
to surveillance without prophylaxis
regarding the risk of new renal scar-
ring (Presentation at the International
Conference on Vesicoureteral Reflux in
Children, Göteborg, Sweden, June 4–6,
2009). The results are expected to be
published in late 2009. They will pre-
sumably change established concepts
of reflux treatment in the future [71].
A second study performed in Australia,
called PRIVENT-study (Prevention of
Recurrent urinary tract Infection in
children with Vesicoureteric reflux and
Normal renal tracts Trial) enclosing
nearly 600 with VUR I-IV in the age of
two to 72 months has just been finished
(http://www.kidney-research. org/privent.
php). The third study is the American
RIVUR study (Randomized Intervention
for children with VesicoUreteral Reflux)
which was started in 2007 [72]. This
multicentric, randomised, placebo-con-
trolled study was designed to examine
the effectiveness of antibacterial prophy-
laxis in children with reflux who had suf-
fered from UTI. The study was initiated
by the National Institute of Diabetes and
Digestive and Kidney Disease (http://
www.rivur.net). 15 clinical centres are
participating in this study. The primary
end-point is the occurrence of febrile/
| 6.6 |
symptomatic urinary tract infections.
Secondary end-points are the develop-
ment of renal scars and of bacterial
resistance. 600 children at the age of
two to 72 months with reflux grades I-IV
after their first UTI will be included. One
of the first statements by the authors of
this study closed with the following sen-
tence: “It is time that we recognize the
need to base our decisions on data that
is obtained from studies relatively free of
bias. However, until these data are avail-
able, under diagnosis and under treat-
ment should be approached with caution”
[73].
Indeed it would be unwise to abruptly
leave empirically based and well-prac-
ticed, commonly accepted strategies for
some current study results. Many fac-
tors involved in clinical course and prog-
nosis must be drawn into consideration
including age, sex, degree of reflux, asso-
ciated malformations, bladder function,
bacterial characteristics, localization of
infection and treatment. This can only
be done by dividing the children into dif-
ferent study groups and simultaneously
stratifying them according to the most
important factors [24]. To make antibac-
terial prophylaxis work, excludable pre-
disposing factors for recurrent UTI have
to be removed or taken into considera-
tion by careful stratification. This is not
only true for daily practice but also for
each prospective study, which aims to
test the benefit of antibacterial prophy-
laxis on UTI recurrence rates and renal
scars. Otherwise, the study results may
be influenced by more or less meaningful
susceptibility factors.
3.1.5 Treatment of symptomatic urinary
tract infection
In patients with VUR, symptomatic UTI
more often is caused by non-E.coli than
in uncomplicated infections. Under anti-
bacterial prophylaxis, breakthrough
UTIs are usually caused by resistant
uropathogens. This has to be considered
381
Chapter |6| Urinary tract infections in children
if calculated antibacterial therapy has to
be initiated.
Significant delays in initiating antibacte-
rial therapy increase the risk of renal scar-
ring in experimental as well as in clinical
settings [13, 74–78]. However, in a recent
study in infants and children one month
to seven years of age who had presented
with acute pyelonephritis proved by paren-
chymal perfusion defects in DMSA-scans,
the incidence of persistent scars in a sec-
ond DMSA-scan was not dependent on the
start of therapy within a range from < one
to five days after onset of symptoms [79].
This does not mean that delay of therapy
is without consequences. Indeed, a similar
study performed in infants up to one year
of age, acute parenchymal changes were
found in 41% of those children who were
treated within 24 hours and in 75% of the
cases with a therapeutic delay of more
than four days. In 51% of all of them, per-
sistent renal damage was detected in the
second DMSA-scan independent from the
start of therapy. This clearly indicates that
early therapy protects against the develop-
ment of severe pyelonephritis. However, if
pyelonephritic parenchymal changes have
occurred, therapeutic delay is no longer
crucial for the risk of renal scarring [80].
In summary, early diagnosis and imme-
diate therapy of UTI might be one of the
most effective strategies in the prevention
of renal scarring in patients with VUR and
UTI recurrences.
3.1.6 Should asymptomatic bacteriuria
be treated in patients with
vesicoureteral reflux?
Several prospective studies in girls dem-
onstrated that asymptomatic bacteriuria
(ABU) leads neither to renal scarring nor
retardation of kidney growth in young
girls in the long term [81–84]. The bac-
teria tend to be of low virulence and do
not harm the kidney. Antibacterial treat-
ment of ABU in girls did not have any
benefit but was associated with a higher
incidence of pyelonephritic episodes than
382
in untreated patients [85]. Asymptomatic
bacteriuria is commonly a benign condi-
tion even with VUR [86]. Treating ABU
therefore might be rarely indicated even
in the presence of VUR [86].
3.2 Surgical therapy
The surgical concept is based on the
assumption that ascension of uropatho-
gens to the kidney leading to pyelonephri-
tis can be avoided by reflux correction, in
spite of continuing susceptibility to bacte-
rial growth in the bladder.
Commonly accepted indications for sur-
gical reflux correction are:
• Recurrent pyelonephritis in spite
of antibacterial prophylaxis (break-
through infections)
• Poor compliance with antibacterial
prophylaxis
• Progression of pyelonephritic scars
• High grade reflux (grade IV-V) with
low chance of spontaneous reflux
resolution
• Persistent high grade reflux in adoles-
cent girls without tendency to resolve
spontaneously
• Refusal of antibacterial prophylaxis
by parents and/or patient and desire
for surgical correction with high grade
reflux
The principle of all variants in open
reflux correction is the prolongation of
the submucosal section of the refluxing
ureter. The success of operation depends,
amongst other things, on the reflux
grade. The success rate of open surgical
techniques is about 96% in experienced
hands [27].
Endoscopic reflux correction with sub-
ureteral injection of bulking substances
has become a serious concurrence to open
reflux correction due to modern material
like NASHATM/Dx (stabilized, non-animal
hyaluronic acid/dextranomer) (Dx/HA,
Deflux®, Q-Med AB, Uppsala, Sweden)
and new techniques (subureteral injection
 Medical therapy versus surgery in vesicoureteral reflux
techniques = HIT). An important critique
of this new method is the lower success
rate concerning cessation of reflux. In
a recent meta-analysis of endoscopical
techniques the success rate was 85%, on
occasion achieved only with two or more
repeated injections [87]. However, most
of studies included used the bulking
agents polytetrafluorethylene, collagen or
other materials. With exclusive usage of
NASH (Deflux®), extremely experienced
surgeons achieved growing success rates
similar to open techniques [88]. The costs
of endoscopic correction are no less than
with open surgery or long term prophy-
laxis [89].
Some reports exist of a decreased inci-
dence of UTI after Deflux® procedure
[90]. In a retrospective analysis of a
database, significantly fewer UTIs were
reported after endoscopic injection with
Dx/HA compared with children receiving
antibacterial prophylaxis [3]. However,
these results should be assessed with
caution. Evident data from prospective-
randomised studies concerning long term
results are missing, especially concerning
the incidence of postoperative UTI, renal
scarring and late reflux recurrences.
Since NASHA (Deflux®) was approved by
the FDA (Food and Drug Administration)
in 2001, there is a trend towards increas-
ing numbers of surgical reflux correc-
tions in the USA [91]. Interestingly, this
is due to the increasing number of endo-
scopic interventions, whereas the number
of open reflux corrections remains sta-
ble [91]. Obviously Deflux® injection has
become not only an alternative to open
Table 4 New renal scars detected during an observation period of 5 years in children with VUR grade III-IV who were
randomised to surgical or conservative therapy.
Study Patients (n)
Birmingham Reflux Study [92]
International Reflux Study [109]
| 6.6 |
procedures, but also to conservative
reflux management, thereby assuming a
position between surgical and conserva-
tive strategies. In several centres, endo-
scopic techniques are even used in very
low degrees of reflux. For the paediatri-
cian this situation has become more dif-
ficult than before the Deflux® era: today,
the endoscopically treated group consists
of children who formerly would clearly
have been treated conservatively as well
as children who would have received open
surgery. These trends require new algo-
rithms for reflux therapy, which include
the new techniques. Future experience
will show their significance in relation-
ship to traditional strategies.
4. SIGNIFICANCE OF DIFFERENT
THERAPEUTIC STRATEGIES
Due to high spontaneous resolution rates,
conservative treatment is widely accepted
in VUR grade I-II.
In dilating reflux (grade III-IV), the
results of randomised prospective stud-
ies demonstrated that conservative and
surgical therapy were equivalent if renal
scarring was taken as an end-point [43,
92] (Table 4). The closing report of the
International Reflux Study was pub-
lished in 2006 [43]. This study dealing
with reflux therapy is the largest to date,
and included infants and children up to
11 years of age with VUR grade III-IV
being detected after UTI. One group
was followed with antibacterial proph-
ylaxis, and surgical reflux correction
Patients with new renal scars
Surgical Conservative Total
group (n) group (n) (n)
161 4 5 9 (6 %)
302 20 19 29 (13 %)
383
Chapter |6| Urinary tract infections in children
was performed in one group. New renal
scars were defined as primary end-point.
During the first five year period, 19 new
scars developed in the conservative group
and 21 in the operative group. In the sec-
ond five year period only two new scars
were detected. Renal growth and recur-
rence rate of UTIs were almost identical.
However, more pyelonephritic episodes
were registered in the non-operated
group. The incidence of new renal scars
was similar in both groups despite higher
rates of pyelonephritic episodes in the
conservative group.
The children included in the Inter-
national Reflux Study were observed with
special care. Breakthrough infections
were treated promptly. To reproduce
results in daily practice, high compliance
by parents and patients, as well as higher
than average efforts by the doctor respon-
sible are prerequisites in the conserva-
tive treatment of reflux. Unfortunately,
consequent long term follow-up is not
possible in every case. In a retrospective
study with American children, 34% of the
patients were already lost to follow-up
after diagnosis of reflux. 80% were not
seen again after their one-year follow-up
visit. Neither specialisation of the phy-
sician, nor health insurance, income,
education or living conditions had any
influence on compliance. Only the age
of the mother correlated positively with
compliance [2].
4.1 Which therapy for which
patient?
The individual decision for surgical or
conservative treatment depends on mul-
tiple terms and conditions such as age
and sex of the patient, bladder function,
degree and laterality of reflux, recur-
rences of symptomatic UTIs, pre-existing
renal scars and the expectations of par-
ents [93]. Last but not least, the avail-
ability of a paediatric urologist with
experience in surgical reflux correction
may play an important role [94].
384
For instance, in a six-year-old girl with
primary VUR grade III detected after her
first febrile UTI presenting with no evi-
dence of renal scarring or kidney involve-
ment, conservative treatment is justified.
In contrast, in a female infant with febrile
UTIs in spite of antibacterial prophylaxis
(“breakthrough infections”), high grade
reflux and renal scarring detected in a
DMSA-scan, surgical correction has to be
recommended.
However, in patients with pre-existing
reflux nephropathy and dilating reflux,
the main factor that determines outcome
seems to be the extent of renal parenchy-
mal reduction and the degree of functional
impairment at the time of diagnosis. In a
prospective study in children with bilateral
severe VUR and bilateral nephropathy,
Smellie et al. did not find any differences
in renal growth, function, or scarring at
five years, or renal function at 10 years
after randomisation between the conserv-
atively followed group and the patients
after surgical reflux correction [95].
5. POST-OPERATIVE TREATMENT
AND CARE AFTER CESSATION OF
REFLUX
Two groups of patients need long-term
follow-up even after successful surgical
correction or spontaneous cessation of
reflux:
5.1 Patients with continuing
susceptibility for UTIs
Many patients who have become con-
spicuous with UTI before surgical repair
or spontaneous cessation of reflux, con-
tinue to suffer recurrences [96]. In a
long-term follow-up study with an obser-
vation period of more than 20 years after
surgical reflux repair, more than 70% of
the patients developed at least one symp-
tomatic UTI. The infection, however,
was mostly restricted to the lower uri-
nary tract [35]. Women with a history of
 Medical therapy versus surgery in vesicoureteral reflux
previous UTIs have a high incidence of
bacteriuria in pregnancy, and those with
renal scarring and persistent reflux are
prone to develop acute pyelonephritis
[97]. Because pyelonephritis can lead to
risks for mother and foetus, special care
is recommended during pregnancy, and
urine diagnostics are necessary if symp-
toms suspicious of UTI appear.
5.2 Patients with reflux
nephropathy
Over 20% of patients have renal scars at
the time of reflux diagnosis. They are at
risk of developing renal arterial hyper-
tension [98]. Girls can also suffer from
complications in pregnancy. Renal insuf-
ficiency can result from severe bilateral
reflux nephropathy.
5.2.1 Arterial hypertension
The incidence of renal arterial hyper-
tension is about 12–14% in young adults
with unilateral renal scars and 18% with
bilateral changes [7]. With increasing age,
the incidence can increase up to over 40%
[99]. Lifelong control of blood pressure
and, if necessary, treatment of arterial
hypertension are therefore recommended
in patients with reflux nephropathy.
5.2.2 Renal insufficiency
In most cases of unilateral reflux neph-
ropathy, the hypertrophy of non-affected
parenchyma compensates for the loss of
functioning nephrons in scarred areas
resulting in normal or only moderately
reduced whole kidney function [45]. Silva
et al. in a retrospective study of 735
patients with primary VUR found that
only 3% progressed to chronic renal insuf-
ficiency with an average GFR of 31.2 ml/
min [100]. Interestingly, in a retrospective
study performed by the same authors,
variables independently associated with
chronic kidney disease were not only
VUR grade V and bilateral renal damage
but also a delay of the diagnosis of VUR
more than 12 months after UTI [101].
| 6.6 |
With bilateral severe reflux nephropa-
thy, the risk of progressive renal insuf-
ficiency demands repeated controls of
serum creatinine and calculated glomeru-
lar filtration rate. Adequate treatment of
hypertension and lowering proteinuria by
ACE inhibitors can probably slow down
the progress of functional loss.
5.2.3 Complications in pregnancy
Reflux nephropathy and increased sus-
ceptibility to UTI’s seem to be risk factors
for EPH-gestosis during pregnancy [102];
mild renal insufficiency can probably
worsen to higher CKD-levels [103].
6. FURTHER RESEARCH
Today, several therapeutic options can be
chosen for the therapy of vesicoureteral
reflux. They include long term antibac-
terial prophylaxis, open reflux surgery,
endoscopic therapy and – last but not
least- “watchful waiting” without medi-
cation. However, controversies exist
about the optimal treatment, especially
in higher grades of reflux regarding the
risk of recurrent pyelonephritis as well
as acquired renal scarring. Therefore,
there is an urgent need for randomized
prospective controlled studies in this
field.
In future studies, many factors involved
in clinical course and prognosis must be
drawn into consideration including grade
of reflux, age, sex, malformations, blad-
der function, bacterial characteristics,
localization of infection and pre-existing
renal damage. This can only be done by
dividing the children into different study
groups and, simultaneously, by stratify-
ing them according to the most important
factors. Another point is the definition of
the risk of recurrence. It is highly depend-
ent on the number of previous UTIs. This
means that the randomisation should
include a stratification of the number of
recurrences before the start of the study.
Information on patient compliance will
385
Chapter |6| Urinary tract infections in children
also be of importance for the interpreta-
tion of study results regarding the effi-
cacy of antibacterial prophylaxis.
Fortunately, numerous prospective
multicentre studies are in progress. Until
their results are available, overtreatment
and undertreatment should be avoided as
far as possible.
7. CONCLUSIONS
Strategies using antibacterial prophy-
laxis and surgical treatment are proven
to be equivalent in randomised studies
with reflux grade III and IV regarding
renal scarring. To be effective, non-op-
erative prevention of pyelonephritis and
renal damage should not be restricted
to the use of antibiotics but must also
include the efficient management of blad-
der and/or bowel dysfunction, as well as
the treatment of predisposing factors.
However, as antibacterial prophylaxis
has been questioned to be effective pre-
venting symptomatic UTI’s and pyelone-
phritic damages by current results of
several clinical studies, the concept of
reflux treatment has to be renewed.
Endoscopic reflux correction with subu-
reteral injection of bulking substances
might become an important part of this
concept if ongoing studies show superior-
ity over antibacterial prophylaxis. Future
concepts will be critically influenced by
the results of the randomised multicenter
studies that are in progress.
In fact, vesicoureteric reflux is a com-
plex topic. A risk oriented therapy should
account for this complexity. This obvi-
ously requires an extended classification.
It should include factors like bladder
dysfunction, age, sex, urinary tract infec-
tions and scarring as decision criteria for
treatment and prophylaxis. Thus, one of
the future challenges in this field will be
the identification of risk factors for renal
scars enabling a better selection of chil-
dren who may really benefit from prophy-
laxis or reflux correction.
386
REFERENCES
1. Practice parameter: the diagnosis, treatment,
and evaluation of the initial urinary tract
infection in febrile infants and young chil-
dren. American Academy of Pediatrics.
Committee on Quality Improvement.
Subcommittee on Urinary Tract Infection.
Pediatrics, 1999. 103(4 Pt 1): 843–52.
2. Greenfield SP and Wan J, Vesicoureteral
reflux: practical aspects of evaluation
and management. Pediatr Nephrol, 1996.
10(6): 789–94.
3. Elder JS, Shah MB, Batiste LR, and
Eaddy M, Part 3: Endoscopic injection
versus antibiotic prophylaxis in the reduc-
tion of urinary tract infections in patients
with vesicoureteral reflux. Curr Med Res
Opin, 2007. 23 Suppl 4: S15–20.
4. Nakai H, Asanuma H, Shishido S, Kitahara
S, and Yasuda K, Changing concepts in uro-
logical management of the congenital anom-
alies of kidney and urinary tract, CAKUT.
Pediatr Int, 2003. 45(5): 634–41.
5. Nakanishi K and Yoshikawa N, Genetic
disorders of human congenital anomalies
of the kidney and urinary tract (CAKUT).
Pediatr Int, 2003. 45(5): 610–6.
6. Smellie JM, Edwards D, and Hunter N,
VUR and renal scarring. Kidney Int,
1975. 8: 65–72.
7. Beetz R, Schulte-Wissermann H, Troger
J, Riedmiller H, Mannhardt W, Schofer O,
and Hohenfellner R, Long-term follow-up
of children with surgically treated vesi-
corenal reflux: postoperative incidence of
urinary tract infections, renal scars and
arterial hypertension. Eur Urol, 1989.
16(5): 366–71.
8. Polito C, Rambaldi PF, Mansi L, Di Toro
R, and La Manna A, Unilateral vesi-
coureteric reflux: Low prevalence of con-
tralateral renal damage. J Pediatr, 2001.
138(6): 875–9.
9. Smellie JM and Normand IC, Reflux
Nephropathy in Childhood, in Reflux
Nephropathy, Hodson J and Kincaid-
Smith P, Editors. 1979, Masson
Publishing USA: New York. p. 14–20.
10. Tsai JD, Huang FY, and Tsai TC,
Asymptomatic vesicoureteral reflux detected
by neonatal ultrasonographic screening.
Pediatr Nephrol, 1998. 12(3): 206–9.
 Medical therapy versus surgery in vesicoureteral reflux
11. Yeung CK, Godley ML, Dhillon HK,
Gordon I, Duffy PG, and Ransley PG, The
characteristics of primary vesico-ureteric
reflux in male and female infants with
pre-natal hydronephrosis. Br J Urol,
1997. 80(2): 319–27.
12. Najmaldin A, Burge DM, and Atwell JD,
Reflux nephropathy secondary to intrau-
terine vesicoureteric reflux. J Pediatr
Surg, 1990. 25(4): 387–90.
13. Smellie JM, Ransley PG, Normand IC,
Prescod N, and Edwards D, Development
of new renal scars: a collaborative study.
Br Med J (Clin Res Ed), 1985. 290(6486):
1957–60.
14. Garin EH, Campos A, and Homsy Y,
Primary vesicoureteral reflux: review of
current concepts. Pediatr Nephrol, 1998.
12(3): 249–56.
15. Vernon SJ, Coulthard MG, Lambert HJ,
Keir MJ, and Matthews JN, New renal
scarring in children who at age 3 and 4
years had had normal scans with dimer-
captosuccinic acid: follow up study. BMJ,
1997. 315(7113): 905–8.
16. Benador D, Benador N, Slosman D,
Mermillod B, and Girardin E, Are younger
children at highest risk of renal seque-
lae after pyelonephritis? Lancet, 1997.
349(9044): 17–9.
17. Jakobsson B, Jacobson SH, and Hjalmas
K, Vesico-ureteric reflux and other risk
factors for renal damage: identifica-
tion of high- and low-risk children. Acta
Paediatr Suppl, 1999. 88(431): 31–9.
18. Ozen S, Alikasifoglu M, Saatci U,
Bakkaloglu A, Besbas N, Kara N, Kocak
H, Erbas B, Unsal I, and Tuncbilek E,
Implications of certain genetic poly-
morphisms in scarring in vesicoureteric
reflux: importance of ACE polymorphism.
Am J Kidney Dis, 1999. 34(1): 140–5.
19. Gargollo PC and Diamond DA, Therapy
insight: What nephrologists need to
know about primary vesicoureteral reflux.
Nat Clin Pract Nephrol, 2007. 3(10): 551–63.
20. US Department of Health and Human
Services PHS, Agency for Health Care
Policy and Research, 1992: 115–127.
21. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
| 6.6 |
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
22. Hoberman A, Charron M, Hickey RW,
Baskin M, Kearney DH, and Wald ER,
Imaging studies after a first febrile
urinary tract infection in young children.
N Engl J Med, 2003. 348(3): 195–202.
23. Rushton HG, Urinary tract infections in
children. Epidemiology, evaluation, and
management. Pediatr Clin North Am,
1997. 44(5): 1133–69.
24. Jodal U and Hansson S, Urinary tract
infection, in Pediatric Nephrology,
Holliday MA, Barratt TM, and Avner
ED, Editors. 1994, Williams & Wilkins:
Baltimore. p. 950–962.
25. Merrick MV, Notghi A, Chalmers N,
Wilkinson AG, and Uttley WS, Long-term
follow up to determine the prognostic
value of imaging after urinary tract infec-
tions. Part 2: Scarring. Arch Dis Child,
1995. 72(5): 393–6.
26. Edwards D, Normand IC, Prescod N, and
Smellie JM, Disappearance of vesicouret-
eric reflux during long-term prophylaxis
of urinary tract infection in children. Br
Med J, 1977. 2(6082): 285–8.
27. Elder JS, Peters CA, Arant BS, Jr., Ewalt
DH, Hawtrey CE, Hurwitz RS, Parrott
TS, Snyder HM, 3rd, Weiss RA, Woolf SH,
and Hasselblad V, Pediatric Vesicoureteral
Reflux Guidelines Panel summary report
on the management of primary vesi-
coureteral reflux in children. J Urol, 1997.
157(5): 1846–51.
28. Beetz R, Bachmann H, Gatermann S,
Keller H, Kuwertz-Broking E, Misselwitz
J, Naber KG, Rascher W, Scholz
H, Thuroff JW, Vahlensieck W, and
Westenfelder M, [Urinary tract infections
in infants and children – a consensus
on diagnostic, therapy and prophylaxis].
Urologe A, 2007. 46(2): 112, 114–8, 120–3.
29. Jodal U and Lindberg U, Guidelines for
management of children with urinary
tract infection and vesico-ureteric reflux.
Recommendations from a Swedish state-
of-the-art conference. Swedish Medical
Research Council. Acta Paediatr Suppl,
1999. 88(431): 87–9.
30. Kaneko K, Ohtomo Y, Shimizu T,
Yamashiro Y, Yamataka A, and Miyano T,
Antibiotic prophylaxis by low-dose cefaclor
387
Chapter |6| Urinary tract infections in children
in children with vesicoureteral reflux.
Pediatr Nephrol, 2003. 18(5): 468–70.
31. Westenfelder M, Vahlensieck W, and
Reinhartz U, Patient compliance and
efficacy of low-dose, long-term prophy-
laxis in patients with recurrent urinary
tract infection. Chemioterapia, 1987. 6(2
Suppl): 530–2.
32. Hensle TW, Hyun G, Grogg AL, and Eaddy
M, Part 2: Examining pediatric vesi-
coureteral reflux: a real-world evaluation
of treatment patterns and outcomes. Curr
Med Res Opin, 2007. 23 Suppl 4: S7–13.
33. Thompson RH, Chen JJ, Pugach J,
Naseer S, and Steinhardt GF, Cessation
of prophylactic antibiotics for managing
persistent vesicoureteral reflux. J Urol,
2001. 166(4): 1465–9.
34. Winberg J, Management of primary vesico-
ureteric reflux in children – operation
ineffective in preventing progressive renal
damage. Infection, 1994. 22 Suppl 1: S4–7.
35. Beetz R, Mannhardt W, Fisch M, Stein
R, and Thuroff JW, Long-term followup
of 158 young adults surgically treated
for vesicoureteral reflux in childhood: the
ongoing risk of urinary tract infections. J
Urol, 2002. 168(2): 704–7; discussion 707.
36. Al-Sayyad AJ, Pike JG, and Leonard MP,
Can prophylactic antibiotics safely be dis-
continued in children with vesicoureteral
reflux? J Urol, 2005. 174(4 Pt 2): 1587–9;
discussion 1589.
37. Cooper CS, Chung BI, Kirsch AJ,
Canning DA, and Snyder HM, 3rd, The
outcome of stopping prophylactic antibiot-
ics in older children with vesicoureteral
reflux. J Urol, 2000. 163(1): 269–72; dis-
cussion 272–3.
38. Georgaki-Angelaki H, Kostaridou S,
Daikos GL, Kapoyiannis A, Veletzas
Z, Michos AG, and Syriopoulou VP,
Long-term follow-up of children with
vesicoureteral reflux with and without
antibiotic prophylaxis. Scand J Infect Dis,
2005. 37(11–12): 842–5.
39. Coulthard MG, Flecknell P, Orr H, Manas
D, and O’Donnell M, Renal scarring
caused by vesicoureteric reflux and uri-
nary infection: a study in pigs. Pediatr
Nephrol, 2002. 17(7): 481–4.
40. Sillen U, Vesicoureteral reflux in infants.
Pediatr Nephrol, 1999. 13(4): 355–61.
388
41. Snodgrass W, Relationship of voiding
dysfunction to urinary tract infection and
vesicoureteral reflux in children. Urology,
1991. 38(4): 341–4.
42. Yeung CK, Sreedhar B, Sihoe JD, and Sit
FK, Renal and bladder functional status
at diagnosis as predictive factors for the
outcome of primary vesicoureteral reflux
in children. J Urol, 2006. 176(3): 1152–6;
discussion 1156–7.
43. Jodal U, Smellie JM, Lax H, and Hoyer
PF, Ten-year results of randomized
treatment of children with severe vesi-
coureteral reflux. Final report of the
International Reflux Study in Children.
Pediatr Nephrol, 2006. 21(6): 785–92.
44. Koff SA, Wagner TT, and Jayanthi VR,
The relationship among dysfunctional
elimination syndromes, primary vesi-
coureteral reflux and urinary tract infec-
tions in children. J Urol, 1998. 160(3 Pt
2): 1019–22.
45. Wennerstrom M, Hansson S, Jodal U,
Sixt R, and Stokland E, Renal function
16 to 26 years after the first urinary tract
infection in childhood. Arch Pediatr
Adolesc Med, 2000. 154(4): 339–45.
46. Upadhyay J, Bolduc S, Bagli DJ, McLorie
GA, Khoury AE, and Farhat W, Use of the
dysfunctional voiding symptom score to
predict resolution of vesicoureteral reflux
in children with voiding dysfunction. J
Urol, 2003. 169(5): 1842–6; discussion
1846; author reply 1846.
47. Kibar Y, Ors O, Demir E, Kalman S,
Sakallioglu O, and Dayanc M, Results
of biofeedback treatment on reflux
resolution rates in children with dysfunc-
tional voiding and vesicoureteral reflux.
Urology, 2007. 70(3): 563–6; discussion
566–7.
48. Thompson M, Simon SD, Sharma V, and
Alon US, Timing of follow-up voiding
cystourethrogram in children with pri-
mary vesicoureteral reflux: development
and application of a clinical algorithm.
Pediatrics, 2005. 115(2): 426–34.
49. Albert X, Huertas I, Pereiro, II, Sanfelix
J, Gosalbes V, and Perrota C, Antibiotics
for preventing recurrent urinary tract
infection in non-pregnant women.
Cochrane Database Syst Rev, 2004(3):
CD001209.
 Medical therapy versus surgery in vesicoureteral reflux
50. Brumfitt W and Hamilton-Miller JM,
Efficacy and safety profile of long-term
nitrofurantoin in urinary infections:
18 years’ experience. J Antimicrob
Chemother, 1998. 42(3): 363–71.
51. Rubin RH, Shapiro ED, Andriole VT,
Davis RJ, and Stamm WE, Evaluation
of new anti-infective drugs for the treat-
ment of urinary tract infection. Infectious
Diseases Society of America and the Food
and Drug Administration. Clin Infect Dis,
1992. 15 Suppl 1: S216–27.
52. Stapleton A and Stamm WE, Prevention
of urinary tract infection. Infect Dis Clin
North Am, 1997. 11(3): 719–33.
53. Nicolle LE and Ronald AR, Recurrent
urinary tract infection in adult women:
diagnosis and treatment. Infect Dis Clin
North Am, 1987. 1(4): 793–806.
54. Norrby SR, Design of clinical trials in
patients with urinary tract infections.
Infection, 1992. 20 Suppl 3: S181–8; dis-
cussion S189–92.
55. Lohr JA, Nunley DH, Howards SS, and
Ford RF, Prevention of recurrent urinary
tract infections in girls. Pediatrics, 1977.
59(4): 562–5.
56. Smellie JM, Gruneberg RN, Normand
IC, and Bantock HM, Trimethoprim-
sulfamethoxazole and trimethoprim alone
in the prophylaxis of childhood urinary
tract infection. Rev Infect Dis, 1982. 4(2):
461–6.
57. Smellie JM, Katz G, and Gruneberg RN,
Controlled trial of prophylactic treat-
ment in childhood urinary-tract infection.
Lancet, 1978. 2(8082): 175–8.
58. Savage DC, Howie G, Adler K, and Wilson
MI, Controlled trial of therapy in covert
bacteriuria of childhood. Lancet, 1975.
1(7903): 358–61.
59. Smellie JM, Gruneberg RN, Bantock HM,
and Prescod N, Prophylactic co-trimoxa-
zole and trimethoprim in the management
of urinary tract infection in children.
Pediatr Nephrol, 1988. 2(1): 12–7.
60. Stansfeld JM, Duration of treatment for
urinary tract infections in children. Br
Med J, 1975. 3(5975): 65–6.
61. Larcombe J, Urinary tract infection in
children. BMJ, 1999. 319(7218): 1173–5.
62. Le Saux N, Pham B, and Moher D,
Evaluating the benefits of antimicrobial
| 6.6 |
prophylaxis to prevent urinary tract infec-
tions in children: a systematic review.
CMAJ, 2000. 163(5): 523–9.
63. Linshaw MA, Controversies in childhood
urinary tract infections. World J Urol,
1999. 17(6): 383–95.
64. Wheeler D, Vimalachandra D, Hodson
EM, Roy LP, Smith G, and Craig JC,
Antibiotics and surgery for vesicoureteric
reflux: a meta-analysis of randomised con-
trolled trials. Arch Dis Child, 2003. 88(8):
688–94.
65. Williams G, Lee A, and Craig J,
Antibiotics for the prevention of urinary
tract infection in children: A systematic
review of randomized controlled trials. J
Pediatr, 2001. 138(6): 868–74.
66. Garin EH, Olavarria F, Garcia Nieto
V, Valenciano B, Campos A, and Young
L, Clinical significance of primary vesi-
coureteral reflux and urinary antibiotic
prophylaxis after acute pyelonephritis: a
multicenter, randomized, controlled study.
Pediatrics, 2006. 117(3): 626–32.
67. Roussey-Kesler G, Gadjos V, Idres N,
Horen B, Ichay L, Leclair MD, Raymond
F, Grellier A, Hazart I, de Parscau
L, Salomon R, Champion G, Leroy V,
Guigonis V, Siret D, Palcoux JB, Taque S,
Lemoigne A, Nguyen JM, and Guyot C,
Antibiotic prophylaxis for the prevention
of recurrent urinary tract infection in chil-
dren with low grade vesicoureteral reflux:
results from a prospective randomized
study. J Urol, 2008. 179(2): 674–9; discus-
sion 679.
68. Montini G, Rigon L, Zucchetta P,
Fregonese F, Toffolo A, Gobber D, Cecchin
D, Pavanello L, Molinari PP, Maschio
F, Zanchetta S, Cassar W, Casadio L,
Crivellaro C, Fortunati P, Corsini A,
Calderan A, Comacchio S, Tommasi L,
Hewitt IK, Da Dalt L, Zacchello G, and
Dall’Amico R, Prophylaxis after first
febrile urinary tract infection in children?
A multicenter, randomized, controlled,
noninferiority trial. Pediatrics, 2008.
122(5): 1064–71.
69. Pennesi M, Travan L, Peratoner L,
Bordugo A, Cattaneo A, Ronfani L,
Minisini S, and Ventura A, Is antibi-
otic prophylaxis in children with vesi-
coureteral reflux effective in preventing
389
Chapter |6| Urinary tract infections in children
pyelonephritis and renal scars? A rand-
omized, controlled trial. Pediatrics, 2008.
121(6): e1489–94.
70. Montini G and Hewitt I, Urinary tract
infections: to prophylaxis or not to prophy-
laxis? Pediatr Nephrol, 2009.
71.Esbjorner E, Hansson S, and Jakobsson B,
Management of children with dilating
vesico-ureteric reflux in Sweden. Acta
Paediatr, 2004. 93(1): 37–42.
72. Keren R, Carpenter MA, Hoberman
A, Shaikh N, Matoo TK, Chesney RW,
Matthews R, Gerson AC, Greenfield SP,
Fivush B, McLurie GA, Rushton HG,
Canning D, Nelson CP, Greenbaum L,
Bukowski T, Primack W, Sutherland R,
Hosking J, Stewart D, Elder J, Moxey-
Mims M, and Nyberg L, Rationale
and design issues of the Randomized
Intervention for Children With
Vesicoureteral Reflux (RIVUR) study.
Pediatrics, 2008. 122 Suppl 5: S240–50.
73. Greenfield SP, Chesney RW, Carpenter
M, Moxey-Mims M, Nyberg L, Hoberman
A, Keren R, Matthews R, and Mattoo T,
Vesicoureteral reflux: the RIVUR study and
the way forward. J Urol, 2008. 179(2): 405–7.
74. Glauser MP, Meylan P, and Bille J, The
inflammatory response and tissue dam-
age. The example of renal scars following
acute renal infection. Pediatr Nephrol,
1987. 1(4): 615–22.
75. Hiraoka M, Hashimoto G, Tsuchida S,
Tsukahara H, Ohshima Y, and Mayumi M,
Early treatment of urinary infection pre-
vents renal damage on cortical scintigra-
phy. Pediatr Nephrol, 2003. 18(2): 115–8.
76. Miller T and Phillips S, Pyelonephritis:
the relationship between infection, renal
scarring, and antimicrobial therapy.
Kidney Int, 1981. 19(5): 654–62.
77. Ransley PG and Risdon RA, Reflux neph-
ropathy: effects of antimicrobial therapy
on the evolution of the early pyelonephritic
scar. Kidney Int, 1981. 20(6): 733–42.
78. Slotki IN and Asscher AW, Prevention of
scarring in experimental pyelonephritis
in the rat by early antibiotic therapy.
Nephron, 1982. 30(3): 262–8.
79. Hewitt IK, Zucchetta P, Rigon L, Maschio
F, Molinari PP, Tomasi L, Toffolo A,
Pavanello L, Crivellaro C, Bellato S,
and Montini G, Early treatment of acute
390
pyelonephritis in children fails to reduce
renal scarring: data from the Italian
Renal Infection Study Trials. Pediatrics,
2008. 122(3): 486–90.
80. Doganis D, Siafas K, Mavrikou M,
Issaris G, Martirosova A, Perperidis
G, Konstantopoulos A, and Sinaniotis
K, Does early treatment of urinary
tract infection prevent renal damage?
Pediatrics, 2007. 120(4): e922–8.
81. Aggarwal VK, Verrier Jones K, Asscher
AW, Evans C, and Williams LA, Covert
bacteriuria: long term follow up. Arch Dis
Child, 1991. 66(11): 1284–6.
82. Savage DC, Natural history of covert bac-
teriuria in schoolgirls. Kidney Int Suppl,
1975. 4: S90–5.
83. Wettergren B, Hellstrom M, Stokland E,
and Jodal U, Six year follow up of infants
with bacteriuria on screening. BMJ, 1990.
301(6756): 845–8.
84. Martinell J, Claesson I, Lidin-Janson G,
and Jodal U, Urinary infection, reflux and
renal scarring in females continuously fol-
lowed for 13–38 years. Pediatr Nephrol,
1995. 9(2): 131–6.
85. Hansson S, Jodal U, Noren L, and Bjure
J, Untreated bacteriuria in asymptomatic
girls with renal scarring. Pediatrics,
1989. 84(6): 964–8.
86. Linshaw M, Asymptomatic bacteriuria
and vesicoureteral reflux in children.
Kidney Int, 1996. 50(1): 312–29.
87. Elder JS, Diaz M, Caldamone AA,
Cendron M, Greenfield S, Hurwitz R,
Kirsch A, Koyle MA, Pope J, and Shapiro
E, Endoscopic therapy for vesicoureteral
reflux: a meta-analysis. I. Reflux resolu-
tion and urinary tract infection. J Urol,
2006. 175(2): 716–22.
88. Puri P, Pirker M, Mohanan N, Dawrant M,
Dass L, and Colhoun E, Subureteral dex-
tranomer/hyaluronic acid injection as first
line treatment in the management of high
grade vesicoureteral reflux. J Urol, 2006.
176(4 Pt 2): 1856–9; discussion 1859–60.
89. Benoit RM, Peele PB, and Docimo SG,
The cost-effectiveness of dextranomer/
hyaluronic acid copolymer for the
management of vesicoureteral reflux. 1:
substitution for surgical management. J
Urol, 2006. 176(4 Pt 1): 1588–92; discus-
sion 1592.
 Medical therapy versus surgery in vesicoureteral reflux
90. Wadie GM, Tirabassi MV, Courtney RA,
and Moriarty KP, The deflux procedure
reduces the incidence of urinary tract
infections in patients with vesicoureteral
reflux. J Laparoendosc Adv Surg Tech A,
2007. 17(3): 353–9.
91. Lendvay TS, Sorensen M, Cowan CA,
Joyner BD, Mitchell MM, and Grady
RW, The evolution of vesicoureteral reflux
management in the era of dextranomer/
hyaluronic acid copolymer: a pediatric
health information system database study.
J Urol, 2006. 176(4 Pt 2): 1864–7.
92. Prospective trial of operative versus
non-operative treatment of severe vesi-
coureteric reflux in children: five years’
observation. Birmingham Reflux Study
Group. Br Med J (Clin Res Ed), 1987.
295(6592): 237–41.
93. Capozza N, Lais A, Matarazzo E, Nappo
S, Patricolo M, and Caione P, Treatment
of vesico-ureteric reflux: a new algorithm
based on parental preference. BJU Int,
2003. 92(3): 285–8.
94. Smellie JM, Tamminen-Mobius T, Olbing
H, Claesson I, Wikstad I, Jodal U, and
Seppanen U, Five-year study of medical
or surgical treatment in children with
severe reflux: radiological renal find-
ings. The International Reflux Study in
Children. Pediatr Nephrol, 1992. 6(3):
223–30.
95. Smellie JM, Barratt TM, Chantler C,
Gordon I, Prescod NP, Ransley PG, and
Woolf AS, Medical versus surgical treat-
ment in children with severe bilateral
vesicoureteric reflux and bilateral neph-
ropathy: a randomised trial. Lancet,
2001. 357(9265): 1329–33.
96. Marchand M, Kuffer F, and Tonz M,
Long-term outcome in women who under-
went anti-reflux surgery in childhood. J
Pediatr Urol, 2007. 3(3): 178–83.
97. Martinell J, Jodal U, and Lidin-Janson G,
Pregnancies in women with and without
renal scarring after urinary infections
in childhood. BMJ, 1990. 300(6728):
840–4.
98. Simoes e Silva AC, Silva JM, Diniz JS,
Pinheiro SV, Lima EM, Vasconcelos MA,
Pimenta MR, and Oliveira EA, Risk of
hypertension in primary vesicoureteral
reflux. Pediatr Nephrol, 2007. 22(3): 459–62.
| 6.6 |
99. Kincaid-Smith PS, Bastos MG, and
Becker GJ, Reflux nephropathy in the
adult. Contrib Nephrol, 1984. 39: 94–101.
100. Silva JM, Santos Diniz JS, Marino VS,
Lima EM, Cardoso LS, Vasconcelos MA,
and Oliveira EA, Clinical course of 735
children and adolescents with primary
vesicoureteral reflux. Pediatr Nephrol,
2006. 21(7): 981–8.
101. Silva JM, Diniz JS, Silva AC, Azevedo
MV, Pimenta MR, and Oliveira EA,
Predictive factors of chronic kidney
disease in severe vesicoureteral reflux.
Pediatr Nephrol, 2006. 21(9): 1285–92.
102. Austenfeld MS and Snow BW,
Complications of pregnancy in women
after reimplantation for vesicoureteral
reflux. J Urol, 1988. 140(5 Pt 2): 1103–6.
103. Becker GJ, Ihle BU, Fairley KF, Bastos
M, and Kincaid-Smith P, Effect of preg-
nancy on moderate renal failure in reflux
nephropathy. Br Med J (Clin Res Ed),
1986. 292(6523): 796–8.
104. Taylor CM, Corkery JJ, and White RH,
Micturition symptoms and unstable
bladder activity in girls with primary
vesicoureteric reflux. Br J Urol, 1982.
54(5): 494–8.
105. Koff SA and Murtagh DS, The uninhib-
ited bladder in children: effect of treat-
ment on recurrence of urinary infection
and on vesicoureteral reflux resolution. J
Urol, 1983. 130(6): 1138–41.
106. Nielsen JB, Djurhuus JC, and Jorgensen
TM, Lower urinary tract dysfunction
in vesicoureteral reflux. Urol Int, 1984.
39(1): 29–31.
107. Secura H, Vesicourteral reflux and void-
ing dysfunction: a prospective study. J
Urol, 1989. 142: 494–501.
108. Scholtmeijer RJ and Nijman RJ,
Vesicoureteric reflux and videourody-
namic studies: results of a prospective
study after three years of follow-up.
Urology, 1994. 43(5): 714–8.
109. Olbing H, Claesson I, Ebel KD,
Seppanen U, Smellie JM, Tamminen-
Mobius T, and Wikstad I, Renal scars
and parenchymal thinning in children
with vesicoureteral reflux: a 5-year
report of the International Reflux Study
in Children (European branch). J Urol,
1992. 148(5 Pt 2): 1653–6.
391
|6.7|

Vesico-ureteral reflux: An American

pediatric urologic perspective
Richard Grady1, Martin Koyle2
1
Associate Professor, Department of Urology, The University of Washington School of Medicine, Attending
Pediatric Urologist, Director of Clinical Research, Division of Pediatric Urology, Seattle Children’s Hospital, 4800
Sandpoint Way NE, Seattle, Washington USA 98105, (206) 987–2130 Office, richard.grady@seattlechildrens.org
2
Professor and Chief, Department of Urology, Michael E. Mitchell Endowed Chair of Pediatric Urology, The University
of Washington School of Medicine, Chief, Division of Pediatric Urology, Seattle Children’s Hospital, 4800 Sandpoint
Way NE, Seattle, Washington USA 98105, (206) 987–1461 Office, martin.koyle@seattlechildrens.org

ABSTRACT in distinguishing renal dysplasia from

VUR is a heterogenous condition. As a
result, the sequelae of this condition
depend on a variety of factors includ-
ing an affected individual’s underlying
propensity for UTI and renal scarring.
In aggregate, the presence of VUR, espe-
cially higher grades of VUR is associated
with an increased incidence of both condi-
tions. However, at this point in time we do
not have the ability to stratify risk in this
patient group as well as we would like to
do. The available data for UTI and VUR
suggests that surgical or endoscopic treat-
ment of VUR reduces the incidence of
pyelonephritis but does not eliminate it.
The available data for renal scarring sug-
gests that surgical correction likely does
not prevent scar progression or the forma-
tion of new renal scars. Information on
this area is complicated by the difficulties
renal scarring with current imaging
modalities. The available data suggests
that a real but modest positive treatment
effect likely exists for the prevention of
end-stage renal disease due to reflux
nephropathy when acquired renal scar-
ring is the primary cause of renal failure.
Key words: urinary tract infection, chil-
dren, vesico-ureteral reflux
SUMMARY OF RECOMMENDATIONS
1. Use antibiotics to treat acute UTI in
children and reconsider the use of
antibiotic prophylaxis to prevent UTI
in children with recurrent UTI or
moderate to low grade VUR (GoR A).
2. Surgical intervention should be used
to treat VUR in the setting of recur-
rent pyelonephritis because it has
 Vesico-ureteral reflux: An American pediatric urologic perspective
been shown to decrease the incidence
of pyelonephritis (GoR A).
3. Intervention to treat VUR may have
a modest beneficial effect on reduc-
ing the incidence of acquired renal
scarring and end-stage renal disease
due to this (GoR C). Surgical interven-
tion could be used to prevent acquired
new renal scarring but no high grade
evidence exists to justify the use of
surgical intervention to prevent new
renal scarring or end-stage renal
disease.
1. INTRODUCTION
This chapter will focus on the diagnosis,
evaluation and management of vesico-
ureteral reflux ( VUR) in children. The
management of VUR in children has
come under increased scrutiny due to
concerns of over-treatment and to con-
cerns regarding lack of efficacy of some
current therapeutic options. For exam-
ple, recent clinical trials have demon-
strated that antibiotic prophylaxis does
not decrease urinary tract infections in
children with a history of low-grade (non-
dilating) VUR or recurrent UTI [1–2].
Other studies have failed to demonstrate
that treatment of VUR impacts long-term
renal scarring. As a result, the treatment
of VUR is in an area of potential sea
change. A number of recent randomized
clinical trials evaluating VUR treatment
are now available. These studies signifi-
cantly increase the strength of evidence
available.
The initial rationale for diagnosis and
treatment of VUR concerned the potential
of ref lux to exert a “water-hammer effect”
on the kidney producing renal damage
even in sterile urine conditions [3–4].
Concerns for a “water-hammer” effect of
VUR in a child with a relatively normally
functioning bladder have abated and the
concerns regarding VUR largely focus on
its association with ascending urinary
tract infection [5]. Currently, the primary
| 6.7 |
rationale to treat VUR remains the pre-
vention of pyelonephritis and its poten-
tial consequences, most notably renal
scarring. This is especially the case for
younger child with “immature” kidneys
that have been considered at increased
risk for acquired renal scarring secondary
to pyelonephritis [6].
2. METHODS
A systematic literature search was per-
formed in Medline from 1969 to 2008
using the following key words: vesi-
coureteral reflux* AND treatment with
the following limitations: English pub-
lications, human studies, clinical trials,
meta-analyses, review, randomized clini-
cal trial, comparative study, ages birth to
45 years old.
A total of 339 publications were found
and screened by title and abstract.
Finally 59 publications were included into
this review and supplemented by publica-
tions mentioned in the selected publica-
tions or known by the author.
The studies were rated according to
level of evidence and the grade of rec-
ommendation graded according to ICUD
standards [7–8].
3. EPIDEMIOLOGY
Urinary tract infections (UTI) are clini-
cally significant in children because they
are so common. Up to 8% of children will
experience at least one UTI between the
ages of one month and 11 years. A sig-
nificant percentage of febrile infections
are associated with VUR, especially in
children evaluated before toilet training
[9]. In the current antibiotic era, the vast
majority of these infections are treat-
able. It is important to remember that
100 years ago childhood kidney infec-
tions carried a mortality of up to 25%
and left many children with chronic kid-
ney disease. At the turn of the century,
393
Chapter |6| Urinary tract infections in children
Goppert-Kattewitz noted the acute mor-
tality of pyelonephritis in young children
at 20%. Another 20% failed to recover
completely and subsequently died, pre-
sumably secondary to renal failure [10]
After sulfonamide antibiotics became
available in the 1940s, mortality dropped
to 2% in children hospitalized for non-
obstructive UTI [11]. Currently, mortal-
ity secondary to UTI approaches 0% for
otherwise healthy children in the United
States
4. UTI IN THE SETTING OF VUR
Febrile UTI in the setting of VUR is con-
cerning in younger children because such
kidneys may be more prone to renal scar-
ring secondary to ascending infections
[9, 12–14]. As a consequence current
management of pyelonephritis focuses
on prompt diagnosis and treatment to
accomplish:
• Prompt diagnosis and elimination of
the acute symptoms of infection
• Prevention of recurrent UTI
• Prevention of acquired new renal
scarring
• Treatment of associated urologic abnor-
malities including vesicoureteral
reflux to decrease the risk for future
renal infections
It is this last focal point that is cur-
rently used to justify the evaluation of
children for VUR because approximately
35–50% of children diagnosed with
pyelonephritis will have VUR.
5. RATIONALE FOR SURGICAL OR
ENDOSCOPIC TREATMENT OF VUR
TO DECREASE PYELONEPHRITIS
Several randomized clinical studies have
noted moderate to high grade (III-V)
VUR to be independently associated
with an increased risk for recurrent UTI
in children. Lower grades of VUR do not
394
appear to confer the same risk for fur-
ther UTI [1, 15–16] (LoE 1b). Antibiotic
prophylaxis has been used as a main-
stay of treatment in the setting of VUR
for decades. A Cochrane meta-analysis
in 2006 discussed five placebo control-
led studies evaluating the utility of this
treatment. Study design was suboptimal
in these studies but did provide evidence
to support this practice [17]. Recently
Roussey Kesler and their co-investigators
conducted a randomized controlled study
demonstrating limited therapeutic ben-
efit for antibiotic prophylaxis to prevent
UTI in infant boys and girls with grades
I-III VUR [2]. The North East Italy
Prophylaxis in VUR study group found
no benefit to antibiotic prophylaxis for
children less than 30 months of age with
grades II-IV VUR in preventing pyelone-
phritis or renal scarring [18]. In another
randomized controlled trial, Conway et
al found limited clinical efficacy of daily
antibiotic therapy to decrease the inci-
dence of UTI in children prone to UTI
[1]. Bacterial antibiotic resistance and
poor adherence to daily antibiotic ther-
apy remain possible explanations for lack
of efficacy in these two studies. In con-
trast, a recent prospective randomized
controlled study from the prevention
of Recurrent Urinary Tract Infection
in Children with Vesicoureteric Ref lux
and Normal Renal Tracts (PRIVENT)
Investigators group in Australia and New
Zealand demonstrated a modest but sig-
nificant decrease in urinary tract infec-
tions in children taking trimethoprim/
sulfamethoxazole compared to placebo
[19]. The level of evidence surrounding
the use of antibiotic prophylaxis for mod-
erate to low grade VUR is LoE 1a.
In contrast, surgical treatment of VUR
has been shown to reduce the incidence
of pyelonephritis in the post-operative
period compared to a treatment group of
patients using antibiotic prophylaxis [20].
A meta-analysis comparing surgical treat-
ment of reflux with long-term antibiotic
therapy noted a 60% reduction in febrile
 Vesico-ureteral reflux: An American pediatric urologic perspective
UTI by five years in the surgical therapy
group.[21] This analysis includes two
randomized studies comparing antibiotic
prophylaxis to surgical correction of VUR
[20, 22] (LoE 1a). A Cochrane analysis in
2007 also found a modest but significant
reduction in episodes of pyelonephritis
after surgical correction for VUR [23].
Haggerty et al also found that endoscopic
therapy to treat occult VUR using a dex-
tranomer polymer was been associated
with a decrease in UTI post-injection
[24]. The latter study, however, was non-
randomized and retrospective in nature
(LoE 2b). Elmore and co-workers recently
reported a series of children successfully
treated endoscopically for VU reflux who
had a lower incidence of UTI post-oper-
atively than a control group of patients
who had undergone ureteral reimplanta-
tion suggesting that endoscopic treatment
of VUR may reduce the risk for UTI after
VUR correction even more successfully
than after open ureteral reimplantation
[25] (LoE 2b).
Prior surgical correction of VUR does
not eliminate the risk for UTI during
pregnancy but may lower it. Bukowski
and co-workers found renal scarring
acted as an independent predictor for
an increased risk for pyelonephritis
during pregnancy. Women with renal
scarring who had undergone previous
ureteral reimplantation were at less risk
than those who had not. However, for
women without renal scarring no change
in pyelonephritis incidence was noted
between adult women during pregnancy
who had undergone correction of VUR as
children versus those who had persist-
ent VUR [26]. Other studies have dem-
onstrated that adult women who had
previously undergone surgical correction
for VUR as children remain at increased
risk for UTI during pregnancy [27–28]
(LoE 3). Still, the primary maternal fac-
tor associated with maternal morbid-
ity is a pre-existing reduction in renal
function as assessed by glomerular fil-
tration rate.
| 6.7 |
6. RATIONALE FOR SURGICAL OR
ENDOSCOPIC TREATMENT OF VUR
TO PREVENT RENAL SCARRING
The rationale for treatment of VUR to
decrease renal scarring arose from clini-
cal studies demonstrating an increased
risk of renal scarring in children follow-
ing pyelonephritis. From the 1960s to the
present, the perceived risk of significant
renal scarring following pyelonephritis
in childhood has become more controver-
sial. Wennerstrom and co-workers pro-
spectively followed 1221 children after
their first UTI. As part of this long-term
study, they evaluated patients with docu-
mented scarring by urography later and
compared this group to an age-matched
control group who had no evidence of
scarring following their first UTI. On fol-
low-up investigation 16 to 26 years later,
both groups underwent DMSA scans to
assess scarring and 51Cr-EDTA inves-
tigation to measure glomerular filtra-
tion rate (GFR). Median GFRs in these
two groups were comparable. However,
patients with initial bilateral renal scar-
ring demonstrated a significant drop in
GFR on follow-up evaluation. The GFR
of scarred kidneys also declined on fol-
low-up investigation [29]. Wennerstrom
also evaluated this same group for hyper-
tension and found no difference between
patients with renal scarring and those
without renal scarring. Plasma renin lev-
els, aldosterone, and angiotensin II levels
were similarly unaffected although atrial
natriuretic peptide was significantly ele-
vated in patients with renal scars [29].
These studies demonstrated that global
renal function remain intact for patients
with renal scarring after UTI but that
the effects of renal scarring do adversely
affect kidneys over time. The strength of
evidence of these studies is (LoE 3).
A second report found that scarring in
boys occurred more often in the presence
of VUR (61%) – especially high grade or
dilated VUR. The parenchymal loss was
global in many of the boys. In contrast,
395
Chapter |6| Urinary tract infections in children
girls with renal scarring demonstrated
focal scarring and only had VUR in 23%
of the cases. Furthermore, acquired renal
scarring only occurred in the setting of
recurrent febrile UTI [29]. These findings
support the concept that high grade VUR
is associated with developmental renal
abnormalities that occur during embryo-
genesis and that VUR in the absence of
UTI does not damage kidneys. In this
setting what may be considered renal
scarring may, in fact, be renal dysplasia.
The data also highlight the increased risk
of renal scarring with recurrent febrile
UTI in childhood. Other studies have
demonstrated an increased risk for renal
scarring with UTI and VUR independ-
ent of the grade of VUR [9]. Soylu found
high grade VUR was a predictor of renal
scarring but that only previous renal
scarring was a predictor for the develop-
ment of new renal scarring [13] (LoE 3).
Importantly, these studies suggest that
some children with VUR may have renal
abnormalities such as renal dysplasia
that occur independent of pyelonephritis
and are may be congenital.
So, while clinical evidence demon-
strates an increased association between
high grade VUR and renal scarring (per-
haps more accurately renal dysplasia),
it is not clear that surgical treatment of
VUR decreases the incidence or number
of renal scars following treatment. The
IRS found no difference in renal scar-
ring between groups of children treated
with antibiotic prophylaxis compared
to surgical correction based on intrave-
nous urographic data for scarring [20,
22]. However, some retrospective stud-
ies using DMSA nuclear medicine stud-
ies show a decreased incidence of renal
scarring following ureteral reimplanta-
tion when compared to historic data [30].
In contrast, other studies using DMSA
renal scinitgraphy to document renal
scarring have found no effect of ureteral
reimplantation or endoscopic injection on
the progression of existing renal scars or
the formation of new renal scars.[31–32]
396
Currently studies with the best level of
evidence (LoE 1b) show a lack of treat-
ment effect for surgical or endoscopic cor-
rection of VUR to prevent renal scarring.
Prospective studies such as the multi-
institutional RIVUR study funded by the
National Institutes of Health may help
provide more robust data in the future
to determine in surgical intervention
improves renal scarring outcomes [33].
7. RATIONALE FOR TREATMENT TO
PREVENT END STAGE RENAL
DISEASE SECONDARY TO REFLUX
NEPHROPATHY
Two other publications drew different con-
clusions about the epidemiology of reflux
nephropathy. Craig et al retrospectively
reviewed the dialysis and transplant regis-
try in Australia and New Zealand between
1971 and 1998. They found no change in
the incidence of reflux nephropathy as a
cause of end-stage renal disease during
this time when comparing subjects 25–34
years of age, 15–24 years of age and five to
14 years of age. The authors conclude that
treatment to prevent UTI in the setting
of VUR has not been associated with the
expected decrease in ESRD due to reflux
nephropathy. They suggest that ESRD
due to reflux nephropathy may represent
congenital dysplasia/hypoplasia that are
not amenable to postnatal intervention.
In contrast, Hansson and colleagues
reviewed the results of a quality assur-
ance project in Sweden. This study sug-
gests that the long-standing interest in
Sweden in the early detection of UTI
in children has led to a high diagnostic
rate for UTI. This was associated with a
decrease in long-term consequences (scar-
ring and reflux nephropathy-associated
ESRD) in that country [34]. Hansson’s
conclusions are supported by Nuutinen
et al who analyzed the data from chil-
dren with acute UTI and compared it to
data in the kidney transplant registry for
England, Wales, and Finland [35] (LoE 3).
 Vesico-ureteral reflux: An American pediatric urologic perspective
8. FURTHER RESEARCH
The accurate identification of children
with upper urinary tract involvement
during a urinary tract infection remains
a significant research question. In addi-
tion, the identification of children who are
at risk of renal scarring is an important
concern. Currently, imaging modalities
such as DMSA (dimercaptosuccinic acid)
nuclear imaging and biochemical marker
analysis using procalcitonin appear prom-
ising tools.
The utility of antibiotic prophylaxis
to prevent urinary tract infections in
children with recurrent urinary tract
infections or vesico-ureteral reflux is cur-
rently incompletely answered as is the
role of endoscopic therapy in the treat-
ment of vesico-ureteral reflux. The ongo-
ing RIVUR study may shed some further
light on these questions in particular.
9. CONCLUSIONS
Management of vesico-ureteral reflux is
currently experiencing a sea change. The
utility of antibiotic prophylaxis, in par-
ticular, appears more modest than pre-
viously believed. The beneficial effect of
surgical or endoscopic treatment of VUR
and/or antimicrobial prophylaxis to reduce
the incidence of pyelonephritic episodes
associated with VUR may, in fact, only be
possible in health care systems with uni-
versal and consistent access to treatment
and preventative care for children with
UTI and may explain why some health
care systems with more uneven access to
care and more mobile populations have
not demonstrated these beneficial results
of a reduction in episodes of pyelonephri-
tis, renal scarring, or end-stage renal
disease. Given the current state of knowl-
edge on VUR, and the evaluation and
treatment of urinary tract infection in
children, we anticipate that recommen-
dations on the management of VUR will
continue to evolve over the next decade.
| 6.7 |
REFERENCES
1. Conway PH, Cnaan A, Zaoutis T, Henry
BV, Grundmeier RW, and Keren R,
Recurrent urinary tract infections in
children: risk factors and association with
prophylactic antimicrobials. Jama, 2007.
298(2): 179–86.
2. Roussey-Kesler G, Gadjos V, Idres N,
Horen B, Ichay L, Leclair MD, Raymond
F, Grellier A, Hazart I, de Parscau
L, Salomon R, Champion G, Leroy V,
Guigonis V, Siret D, Palcoux JB, Taque S,
Lemoigne A, Nguyen JM, and Guyot C,
Antibiotic prophylaxis for the prevention
of recurrent urinary tract infection in chil-
dren with low grade vesicoureteral reflux:
results from a prospective randomized
study. J Urol, 2008. 179(2): 674–9; discus-
sion 679.
3. Ransley PG, Risdon RA, and Godley ML,
High pressure sterile vesicoureteral reflux
and renal scarring: an experimental study
in the pig and minipig. Contrib Nephrol,
1984. 39: 320–43.
4. Lenaghan D, Cass AS, Cussen LJ, and
Stephens FD, Long-term effect of vesi-
coureteral reflux on the upper urinary
tract of dogs. 1. Without urinary infection.
J Urol, 1972. 107(5): 755–7.
5. Smellie JM, Barratt TM, Chantler C,
Gordon I, Prescod NP, Ransley PG, and
Woolf AS, Medical versus surgical treat-
ment in children with severe bilateral
vesicoureteric reflux and bilateral neph-
ropathy: a randomised trial. Lancet,
2001. 357(9265): 1329–33.
6. Olbing H, Claesson I, Ebel KD, Seppanen
U, Smellie JM, Tamminen-Mobius T,
and Wikstad I, Renal scars and paren-
chymal thinning in children with vesi-
coureteral reflux: a 5-year report of the
International Reflux Study in Children
(European branch). J Urol, 1992.
148(5 Pt 2): 1653–6.
7. U.S. Department of Health and Human
Services PHS, Agency for Health Care
Policy and Research, 1992: 115–127.
8. P. Abrams SK, A. Grant, Evidence-based
medicine overview of the main steps for
developing and grading guideline recom-
mendations. Progress in Urology 2007.
17(3): 681–4.
397
Chapter |6| Urinary tract infections in children
9. Oh MM, Jin MH, Bae JH, Park HS,
Lee JG, and Moon du G, The role of
vesicoureteral reflux in acute renal
cortical scintigraphic lesion and
ultimate scar formation. J Urol, 2008.
180(5): 2167–70.
10. Goppert-Kattewitz F, Uber die eitri-
gen Erkrankungen der Harnwege im
Kindersalter. . Ergebinesse uber innern
Medizin und Kinderheilkund, 1908.
2: 30–73.
11. Lindblad B, Ekengren, K, . , The long-
term prognosis of non-obstructive urinary
tract infection in infancy and childhood
after the advent of sulphonamides. Acta
Pediatrica Scandinavica, 1969. 58: 25–32.
12. Faust WC, Diaz M, and Pohl HG,
Incidence of post-pyelonephritic renal
scarring: a meta-analysis of the dimer-
capto-succinic acid literature. J Urol,
2009. 181(1): 290–7; discussion 297–8.
13. Soylu A, Demir BK, Turkmen M,
Bekem O, Saygi M, Cakmakci H, and
Kavukcu S, Predictors of renal scar in
children with urinary infection and vesi-
coureteral reflux. Pediatr Nephrol, 2008.
23(12): 2227–2232.
14. Lee JH, Son CH, Lee MS, and Park YS,
Vesicoureteral reflux increases the risk of
renal scars: a study of unilateral reflux.
Pediatr Nephrol, 2006. 21(9): 1281–4.
15. Panaretto K, Craig J, Knight J, Howman-
Giles R, Sureshkumar P, and Roy L, Risk
factors for recurrent urinary tract infec-
tion in preschool children. J Paediatr
Child Health, 1999. 35(5): 454–9.
16. Garin EH, Olavarria F, Garcia Nieto
V, Valenciano B, Campos A, and Young
L, Clinical significance of primary vesi-
coureteral reflux and urinary antibiotic
prophylaxis after acute pyelonephritis:
a multicenter, randomized, controlled
study. Pediatrics, 2006.
117(3): 626–32.
17. Williams GJ, Wei L, Lee A, and Craig
JC, Long-term antibiotics for preventing
recurrent urinary tract infection in chil-
dren. Cochrane Database Syst Rev, 2006.
3: CD001534.
18. Pennesi M, Travan L, Peratoner L,
Bordugo A, Cattaneo A, Ronfani L,
Minisini S, and Ventura A, Is anti-
biotic prophylaxis in children with
398
vesicoureteral reflux effective in pre-
venting pyelonephritis and renal scars?
A randomized, controlled trial. Pediatrics,
2008. 121(6): e1489–94.
19. Craig JC, Simpson JM, Williams GJ,
Lowe A, Reynolds GJ, McTaggart SJ,
Hodson EM, Carapetis JR, Cranswick
NE, Smith G, Irwig LM, Caldwell PH,
Hamilton S, and Roy LP, Antibiotic
prophylaxis and recurrent urinary tract
infection in children. N Engl J Med, 2009.
361(18): 1748–59.
20. Weiss R, Duckett J, and Spitzer A,
Results of a randomized clinical trial of
medical versus surgical management of
infants and children with grades III and
IV primary vesicoureteral reflux (United
States). The International Reflux Study
in Children. J Urol, 1992. 148(5 Pt 2):
1667–73.
21. Wheeler D, Vimalachandra D, Hodson
EM, Roy LP, Smith G, and Craig JC,
Antibiotics and surgery for vesicoureteric
reflux: a meta-analysis of randomised
controlled trials. Arch Dis Child, 2003.
88(8): 688–94.
22. Jodal U, Koskimies O, Hanson E, Lohr
G, Olbing H, Smellie J, and Tamminen-
Mobius T, Infection pattern in children
with vesicoureteral reflux randomly
allocated to operation or long-term anti-
bacterial prophylaxis. The International
Reflux Study in Children. J Urol, 1992.
148(5 Pt 2): 1650–2.
23. Hodson EM, Wheeler DM, Vimalchandra
D, Smith GH, and Craig JC,
Interventions for primary vesicoureteric
reflux. Cochrane Database Syst Rev,
2007(3): CD001532.
24. Hagerty J, Maizels M, Kirsch A, Liu D,
Afshar K, Bukowski T, Caione P, Homsy
Y, Meyer T, and Kaplan W, Treatment of
occult reflux lowers the incidence rate of
pediatric febrile urinary tract infection.
Urology, 2008. 72(1): 72–6.
25. Elmore JM, Kirsch AJ, Heiss EA,
Gilchrist A, and Scherz HC, Incidence
of urinary tract infections in children
after successful ureteral reimplanta-
tion versus endoscopic dextranomer/
hyaluronic acid implantation. J Urol,
2008. 179(6): 2364–7; discussion
2367–8.
 Vesico-ureteral reflux: An American pediatric urologic perspective
26. Bukowski TP, Betrus GG, Aquilina JW,
and Perlmutter AD, Urinary tract infec-
tions and pregnancy in women who
underwent antireflux surgery in child-
hood. J Urol, 1998. 159(4): 1286–9.
27. Mansfield JT, Snow BW, Cartwright PC,
and Wadsworth K, Complications of preg-
nancy in women after childhood reim-
plantation for vesicoureteral reflux: an
update with 25 years of followup. J Urol,
1995. 154(2 Pt 2): 787–90.
28. Marchand M, Kuffer F, and Tonz M,
Long-term outcome in women who under-
went anti-reflux surgery in childhood.
J Pediatr Urol, 2007. 3(3): 178–83.
29. Wennerstrom M, Hansson S, Jodal U,
Sixt R, and Stokland E, Renal function
16 to 26 years after the first urinary
tract infection in childhood. Arch Pediatr
Adolesc Med, 2000. 154(4): 339–45.
30. Webster RI, Smith G, Farnsworth RH,
Rossleigh MA, Rosenberg AR, and Kainer
G, Low incidence of new renal scars after
ureteral reimplantation for vesicoureteral
reflux in children: a prospective study.
J Urol, 2000. 163(6): 1915–8.
31. Piepsz A, Tamminen-Mobius T, Reiners
C, Heikkila J, Kivisaari A, Nilsson NJ,
Sixt R, Risdon RA, Smellie JM, and
| 6.7 |
Soderborg B, Five-year study of medical
or surgical treatment in children with
severe vesico-ureteral reflux dimercap-
tosuccinic acid findings. International
Reflux Study Group in Europe. Eur
J Pediatr, 1998. 157(9): 753–8.
32. Capozza N and Caione P, Dextranomer/
hyaluronic acid copolymer implantation
for vesico-ureteral reflux: a randomized
comparison with antibiotic prophylaxis.
J Pediatr, 2002. 140(2): 230–4.
33. Chesney RW, Carpenter MA, Moxey-
Mims M, Nyberg L, Greenfield SP,
Hoberman A, Keren R, Matthews R, and
Matoo TK, Randomized Intervention
for Children With Vesicoureteral Reflux
(RIVUR): background commentary of
RIVUR investigators. Pediatrics, 2008.
122 Suppl 5: S233–9.
34. Jakobsson B, Esbjorner E, and
Hansson S, Minimum incidence and
diagnostic rate of first urinary tract
infection. Pediatrics, 1999. 104(2 Pt 1):
222–6.
35. Nuutinen M, Uhari M, Murphy MF, and
Hey K, Clinical guidelines and hospital
discharges of children with acute urinary
tract infections. Pediatr Nephrol, 1999.
13(1): 45–9.
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 Chapter |7|

Urinary tract infections

in nephropathies,
transplant patients and
immunosupression
Chair: Michael C. Bishop

CHAPTER OUTLINE
7.1 Introduction 402
7.2 Emphysematous pyelonephritis 404
7.3 Renal abscesses 413
7.4 Polycystic renal disease 419
7.5 Urinary tract infections in renal insufficiency and dialysis 426
7.6 Urogenital infections in renal transplant
patients – causes and consequences 438
|7.1|
Introduction
Michael C. Bishop
Prof. Michael C. Bishop, MD,FRCP,FRCS, Consultant Urologist, Nottingham Woodthorpe Hospital,
748, Mansfield Rd., Nottingham NG5 3FZ., Great Britain
mbish@btopenworld.com
The social and economic burden of
chronic illness due to progressive renal
disease is considerable and increasing in
the industrialised nations, mainly as a
result of the rising incidence of cardiovas-
cular disease and diabetes. However, the
process may be spreading to the develop-
ing World, particularly where there are
aspirations to adopt a Western lifestyle.
Whilst recurrent uncomplicated cystitis
and even severe pyelonephritis will virtu-
ally never cause permanent renal dam-
age some patients with end stage renal
failure will report life-long symptomatic
UTIs and this could be a preventable
component of chronic debilitating illness.
This section examines some important
questions on the causative links between
UTI and chronic renal insufficiency, the
susceptibility of uraemic patients to UTI,
whether it hastens the progression to end
stage renal failure and the significance
of UTI in relation to graft function after
renal transplantation.
The association between UTI and
chronic renal disease may be interest-
ing from a basic scientific aspect: are
host defences and immune competence
progressively impaired in uraemia and
is there a corresponding loss of bacterial
virulence factors, as is to be found in the
strains responsible for asymptomatic bac-
teriuria, and even for the broad category
of complicated UTI? Is there loss of epi-
thelial integrity in the whole urinary
tract of the uraemic individual, promot-
ing the development of intracellular bac-
terial communities and biofilm?
Fünfstück and colleagues have con-
sidered what contribution UTI has made
specifically to the cause of chronic renal
disease and whether UTI will hasten the
progression of renal functional impair-
ment. Intuitively, damaged renal paren-
chyma from whatever cause would not be
expected to tolerate recurrent acute infec-
tion with the resilience shown by normal
adult kidneys. And yet is there evidence
that UTI is more likely to cause per-
manent injury in patients with chronic
renal failure than in normal individuals.
However, the clinician should be espe-
cially vigilant to exclude obstruction
which in combination with infection will

predictably cause rapid destruction of
residual functioning renal tissue.
Other pre-existing non-obstructive
structural uropathies and lower urinary
tract dysfunction are obvious risk fac-
tors in promoting infection but again it
is questionable if they are more likely to
cause kidney damage than in the normal
individual, with the possible very contro-
versial exception of vesicoureteric reflux.
Of course, irreversible damage will very
occasionally occur as part of circulatory
multiorgan failure induced by urosepsis.
The term ADPKD covers a family of
systemic disorders characterised by vari-
able but usually inexorable progression to
end-stage renal disease and a propensity
to renal tract infection, within the cysts,
the pelvicaliceal system particularly if
the cysts cause intrarenal or pelviuret-
eric obstruction and in the renal paren-
chyma. Perepanova and Apolikhin rightly
emphasise the importance of control-
ling this infection well before the patient
undergoes transplantation and immuno-
suppression. Very occasionally even bilat-
eral nephrectomy will be indicated, as for
extreme cases of endstage obstructve and
reflux nephropathy, as a last resort. Some
of the very limited high level evidence
available in this section confirms the effi-
cacy of fluoroquinolones in controlling
cyst infection, even when administered
empirically.
Despite good evidence from RCT’s con-
firming the benefits of antibiotic prophy-
laxis in the first six months after renal
transplantation, UTI is still an ongoing
problem. Shoskes and Saad have under-
taken a useful detailed analysis of its
impact on graft function and of the allied
problem of the effect of immunosup-
pression on susceptibility to UTI. It is
not surprising that the evidence is often
confounded by a multitude of co-morbid
factors including diabetes through its
wide-ranging effects on the host response
Introduction | 7.1 |
to infection and on bladder function,
progressive chronic immunological injury,
potentially nephrotoxic immunosuppres-
sive agents and the relatively frequent
need for catheters and stents. UTI can
be induced by other organisms to which
immunosuppressed patients are particu-
larly susceptible (viruses, yeasts) and
which may be difficult to identify. They
may also be more relevant than conven-
tional bacterial pathogens in the context
of transplant functional deterioration,
through direct toxic effects and indirectly
by inducing rejection.
Asymptomatic bacteriuria is a conun-
drum, particularly in the small group of
patients who have undergone enterocysto-
plasty and need to void by intermittent
catheterisation. As in virtually all other
situations there still seems to be little or
no evidence to support long term antibi-
otic prophylaxis in favour of short course
high dose treatment of proven infection.
Finally this section concludes with a
discussion of the somewhat disconnected
topic of emphysematous pyelonephritis
(EPN) and renal abscess. Ishikawa has
presented an interesting analysis of risk
factors which may be predictive of success
from conservative management, using
antibiotics and percutaneous aspiration.
Much of the data are historic and it is
likely that contemporary studies would
show that mortality is much reduced with
better management of sepsis and diabe-
tes which of course affect the majority of
patients with EPN.
To some extent, the old surgical adage
that pus needs to be released urgently
can be revised, at least for smaller renal
abscesses which evidence suggests can
resolve spontaneously with antibiotic
treatment alone. It must not be forgot-
ten that EPN and renal abscess can still
occur as a result of obstruction and its
relief constitutes one of the few surgical
emergencies in urology.
403
|7.2|
Emphysematous pyelonephritis
Kiyohito Ishikawa
Address of Corresponding Author: Department of Urology, Fujita Health University School of Medicine, 1–98,
Dengakugakubo, Kutsukake, Totoake, Aichi, 470–1192, Japan
e-mail address: kiyo@fujita-hu.ac.jp

ABSTRACT indicator of septic disseminated intravas-

Emphysematous pyelonephritis (EPN)
represents a life-threatening infection of
the renal parenchyma by gas-forming bac-
teria. Poorly controlled diabetes mellitus
is present in up to 90% of patients. It car-
ries a mortality rate of approximately 20%
The literature on EPN has been
reviewed to develop a pathway to guide
management of this rare condition. An
analysis of 23 risk factors has facilitated
the early identification of patients for
whom relatively conservative forms of
treatment will be appropriate. Rarely,
where the disease has an exceptionally
fulminant course, urgent nephrectomy is
lifesaving. All patients will require vigor-
ous intravenous fluid replacement, broad-
spectrum antibiotics and diabetic control.
Percutaneous drainage (PCD) is some-
times urgently required. Paradoxically,
more localized parenchymal infection with
little or no fluid collection (Wan “Type 1”)
may be predictive of poor outcome. The
sinister implications of two other factors,
thrombocytopaenia, presumably as an
cular coagulopathy (DIC), and bilateral
disease are predictable.
Key words: Emphysematous pyelone-
phritis, gas-forming bacteria, diabetes
mellitus, sepsis, nephrectomy
SUMMARY OF RECOMMENDATIONS
1. Diagnosis
1.1 Plain radiography is recom-
mended to demonstrate gas
bubbles over the affected kidney
in approximately 85% of cases
(GoR B).
1.2 Ultrasonography is useful for the
diagnosis of urinary tract obstruc-
tion, but insensitive for the detec-
tion of renal gas (GoR C).
1.3 Modern multislice CT gives bet-
ter resolution and administration
of intravenous contrast reveals
asymmetric enhancement of renal
tissue (GoR B).
 Emphysematous pyelonephritis | 7.2 |

EPN

Initial KUB and renal echography Sussequent abdominal CT scan

Classes 1 and 2 Classes 3A and 3B Class 4

Low risk group (Bilateral) PCD

Fluid, Electrolyte, and
(0 or 1 risk factor)
Glucose control,
Antibiotics and PCD High risk group Failure
(^ 2 risk factors)

Survival Failure Intensive care followed by nephrectomy

Survival or Not

Figure 1 The Flowchart for management of EPN. The diagnostic steps and managements are recommended to [A, IIb], which
means “it is strongly recommended, and they are evidenced from well-designed quasi-experimental study”.

2. Treatment (recommendations are as a result of obstruction of the corre-

based on the classification devised by
Huang and Tseng (Figure-1) [1])
2.1 Class 1 or 2 EPN patients: treat
with percutaneous drainage (PCD)
and/or relief of urinary tract
obstruction (if present) in combi-
nation with antibiotic treatment
(GoR C).
2.2 Class 3 or 4 EPN patients with
less than one risk factor: treat
with PCD and/or relief of the
urinary tract obstruction (if
present) in combination with
antibiotic treatment (GoR C).
2.3 Class 3 or 4 EPN patients with
more than two risk factors should
undergo timely nephrectomy
(GoR C).
1. INTRODUCTION
Emphysematous pyelonephritis (EPN) is
a life-threatening necrotizing infection of
the kidney characterized by accumulation
of gas in the renal parenchyma and the
surrounding tissue [2–3]. It is most com-
monly seen in patients with poorly con-
trolled Type 1 diabetes mellitus (DM) but
not exclusively so. It may also develop
sponding reno-ureteral unit, debilitating
alcoholism and immunodeficiency [4–5].
Predictably, EPN is prone to be compli-
cated by the mortal effects of systemic
sepsis [6]. Four components of gas for-
mation in EPN have been proposed: the
presence of pathogenic Gram-negative,
gas-forming facultative bacteria such
as Escherichia coli; a defective immune
response, e.g. due to diabetes, alcohol-
ism or cancer, allowing bacterial multi-
plication; high tissue glucose levels that
help facultative anaerobes to ferment
glucose and produce carbon dioxide and
hydrogen; and ischemia of local tissue,
due to severe inflammation, microan-
giopathy or urinary tract obstruction,
all of which may impair tissue perfusion
and transportation of gas to the blood
stream, allowing gas accumulation [5].
Escherichia coli (58%), Klebsiella pneu-
moniae (24%) and mixed flora (10%) have
been cultured from patients with EPN
[7]. Proteus mirabilis, Enterobacter aero-
genes and Candida sp. have also been
implicated [2].
During the last three decades there
have been many publications on EPN
reporting wide variations in mortal-
ity and risk factors [8–11]. We have
attempted to develop recommendations
405
Chapter |7| Urinary tract infections in nephropathies

for management of EPN based on an in-
depth analysis of the published work [12].
2. METHODS
2.1 Data sources
We performed a systematic search of
PubMed (September 1965 to August
2008) to find articles providing data on
risk factors of mortality in patients with
EPN. We used the keywords “pyelonephri-
tis and (predict or prediction or prognosis
or hospitalization or outcome or mortality
or prognostic or risk factor or severity or
survival)” and the search was limited to
articles written in English and Japanese.
The 1503 published reports found were
screened by their title. The full text of
30 selected articles were read and 22
studies in the following categories were
excluded: 1) case reports and case series
of less than 5 patients, 2) review articles,
editorial and letters, 3) studies for which
abstracts were not available, 4) studies
involving paediatric patients, 5) antibi-
otic efficacy studies, 6) studies that were
irrelevant to our specific subjects and 7)
studies written in languages other than
English and Japanese. A total of eight
articles were finally used in the analysis.
2.2 Rating system
The studies were rated according to the
level of evidence and the strength of rec-
ommendations according to the ICUD
standards (see preface) [12–13].
2.3 Classification
The three commonly adopted schemes of
classification are shown in Table 1.
2.4 Statistical Methods
All-cause mortality was the only outcome
considered in this analysis. We compared

Table 1 Classification of emphysematous pyelonephritis.

Classification system Basis for classification Defining features

Michaeli et al. (2) Plain film X-ray

Stage 1 Gas present in the renal parenchyma or perinephric tissues

Stage 2 Gas present in the kidney and its surroundings

Stage 3 Extension of gas through Gerota’s fascia and/or bilateral disease

Huang and Tseng (1) CT

Class 1 Gas present in the collecting system only

Class 2 Gas present in the renal parenchyma, without extension into the
extrarenal space

Class 3A Extension of gas or abscess into the perinephric space

Class 3B Extension of gas or abscess into the pararenal space

Class 4 Bilateral EPN, or EPN in a solitary kidney

Wan et al. (18) Radiograpy, US and CT

Type 1 Parenchymal destruction with either lack of fluid collection or

presence of streky or mottled gas

Type 2 Renal or perirenal fluid collection with bubbly or loculated gas

or gas in the collecting system

406
 Emphysematous pyelonephritis | 7.2 |

the proportions of patients who died 4. MORTALITY AND RISK FACTORS

according to a list of identifiable risk fac-
tors. Pooled odds ratios and 95% confi-
dence intervals were calculated to quantify
the risk of mortality for the factors men-
tioned in more than two of the selected
studies by using the Mantel-Haenszel
fixed effect [14] and the DerSimonian-
Laird random effects models. For the risk
factors evaluated in one or two studies the
risk of mortality was quantified by using
the chi-square test or Fisher’s exact test
with a p-value less than 0.05 considered
statistically significant.
3. OVERVIEW OF STUDIES REVIEWED
In Table 2 we summarize the characteris-
tics of the eight selected studies, compris-
ing 311 patients with EPN, included in
the meta-analysis [1, 15–19]. All reports
were designed as retrospective cohort
studies. Five of the eight eligible studies
originated from Asia.
The majority (84.2%) of total 273
patients with EPN were female. In addi-
tion, 93.3% of total 311 patients had diabe-
tes mellitus. In three of the eight reports
all patients were diabetic [18, 20–21].
Mortality ranged from 10% to 42% in the
studies included in the meta-analysis
(Table 3). Overall 17.3% (62/358) of the
enrolled patients with EPN died. The
majority of the selected reports referred
to all-cause mortality (1,15–18,20,22).
One Japanese study provided informa-
tion with regard to the specific end-point
(nephrectomy) for the evaluation of mor-
tality [22].
In Table 3 we present in detail the risk
factors for mortality of patients with EPN
that were analyzed in each of the selected
study cohorts. In Table 4 we show data
regarding the association between the
specified risk factors and mortality (sum-
mary odds ratio and p-values).
Of 23 factors identified from the eligi-
ble articles as potentially high risk, seven
were described in three or more and in
our analysis only four factors were asso-
ciated with increased risk of mortality.
These were: conservative mode of treat-
ment alone (OR 3.66, 95% CI 2.01–6.66),
bilateral EPN (OR 5.36, 95% CI 1.41–
20.33), type 1 EPN (OR 2.53, 95% CI
1.13–5.65), and thrombocytopenia (OR
22.68, 95% CI 4.4–116.32).

Table 2 Main characteristics of studies inclused in the meta-analysis.

No. Pts No. Males/Pts No. Pts With DM/Total

Reference Country Enrolled Enrolled(%) No. Enrolled(%)

Abdul-Halim et al. (15) Kuwait 7 1/7(14) 7/7(100)

Tang at al. (16) Taiwan 21 1/21(5) 21/21(100)

Huang and Tseng (1) Taiwan 48 7/48(15) 46/48(96)

Kuo et al. (17) Taiwan 28 3/28(11) 25/28(89)

Wan et al. (18) Australia 38 Not available 37/38(97)

Shokeir at al. (19) Egypt 20 5/20(25) 16/20(80)

Ahlering et al. (20) United States 13 3/13(23) 13/13(100)

Masago et al. (21) Japan 136 23/136(16) 125/136(91)

Retrosepctive study design for all.

407
Chapter |7| Urinary tract infections in nephropathies

Table 3 Risk factors for all cause mortality in patients with EPN inclused in selested studies.

Abdul- Huang Kondo

Halim Tang and Kuo Wan Shokeir Ahlering et al.
et al.(15) et al.(16) Tseng(1) et al.(17) et al.(18) et al.(19) et al.(20) (22)

Conservative 0/0 vs 1/7 2/6 vs 4/15 2/5 vs 7/43 0/0 vs 3/28 6/9 vs 9/29 1/1 vs 3/19 2/6 vs 2/5 12/45 vs
mode of treat- 7/138
ment alone

Bilateral EPN 0/0 vs 1/7 2/4 vs 7/44 0/1 vs 3/27 1/1 vs 3/19 ?/7 vs ?/129

Type 1 EPN 1/7 vs 5/14 5/14 vs 4/34 1/14 vs 2/14 11/16 vs 4/22

DM 1/7 vs 0/0 6/21 vs 0/0 2/25 vs 1/3 5/12 vs 0/0

Thrombocytopenia 1/1 vs 0/6 8/22 vs 1/26 7/7 vs 8/31

Nephrolithiasis 3/12 vs 6/36 0/2 vs 3/26 not significant 0/1 vs 5/11

E. coli or K. 1/20 vs 2/8 13/31 vs 2/7 5/11 vs 0/1

pneumoniae

Comparison of proportions of patients who died among with or without a specific resk factor.

Table 4 Summary risk factors for all cause mortality in patients with EPN.

No. Studies No. Pts in Studies Summary

Reporting Data Reporting Data OR(95%CI) p-value

Conservative mode of 8 358 3.66(2.01–6.66) <0.001

treatment alone

Bilateral EPN 5 116 5.36(1.41–20.33) 0.01

Type 1 EPN 4 135 2.53(1.13–5.65) 0.02

DM 4 69 0.32(0.05–1.99) Not significant

Thrombocytopenia 3 93 22.68(4.4–116.32) <0.001

Nephrolithiasis 3 89 1.25(0.34–4.52) Not significant

E. coli or K. 3 79 0.99(0.29–3.40) Not significant

pneumoniae

Conservative mode of treatment approximately 85% of cases. However,

included fluid resuscitation, administra-
tion of antimicrobial agents and control of
diabetes mellitus. Percutaneous drainage
(PCD) was not considered part of the cat-
egory conservative treatment alone (GoR
B, LoE 2b).
5. DIAGNOSIS
Plain radiography will demonstrate
gas bubbles over the affected kidney in
this is frequently misinterpreted as bowel
gas. There may be a diffuse, mottled
appearance in the affected kidney, with
radially oriented gas, corresponding to
the configuration of the renal pyramids.
A crescent-shaped gas collection within
Gerota’s fascia demonstrates extension
into perirenal tissues and indicates an
advanced stage of renal necrosis [23].
Ultrasonography is also useful for the
diagnosis of urinary tract obstruction,
but is operator-dependent and insensitive

408

for the detection of renal gas. However,
modern multislice CT gives better resolu-
tion and nowadays few clinicians would
be confident in taking management deci-
sions without access to CT [24]. The
use of intravenous contrast may reveal
asymmetric enhancement of renal tis-
sue or delayed excretion and during the
nephrogram phase, areas of abscess for-
mation or focal tissue necrosis may be
identified [23]. A classification system
has been suggested based on CT findings,
and image-guided drainage offers effec-
tive treatment often avoiding emergency
nephrectomy [25]. CT remains the cor-
nerstone of imaging but new and rapidly
evolving MR sequences may also contrib-
ute to the more accurate evaluation of the
patient with acute pyelonephritis [24],
whilst providing a more cost-effective and
radiation-free alternative to CT.
6. CLASSIFICATION (TABLE 1)
A number of staging systems for EPN
exist (Table 1). Unlike that of Michaeli
et al. [2] the system proposed by Huang
and Tseng [1] has important prognos-
tic and therapeutic implications. In a
retrospective study of 38 patients, Wan
et al. [7] identified two types of EPN
based on fluid and gas pattern, and cor-
related findings with clinical course and
prognosis (GoR C, LoE 3). The mortal-
ity rates almost completely matched the
degree of parenchymal destruction. Type
1 disease had a substantially higher mor-
tality rate (69%), more extensive paren-
chymal destruction and a more fulminant
clinical course. Type 2 had a lower mor-
tality rate (18%) and more indolent clini-
cal course. It is unclear whether these
two subtypes represent stages in the evo-
lution of EPN or different pathophysi-
ological responses.
Wan et al. hypothesized that the clin-
icopathological differences between types
1 and 2 EPN by the pathological findings
are probably related to the difference in
Emphysematous pyelonephritis | 7.2 |
severity of vascular insufficiency in the
kidney and immunodeficiency especially
in patients with DM [19] (GoR C, LoE 3).
We confirmed that Wan’s classification
correlated well with the clinical course
and was predictive of outcome. However,
the more elaborate classification of
Huang and Tseng [1] was more conven-
iently applied to a flowchart for manage-
ment of EPN (Fig 1) (GoR A, LoE 2b).
7. TREATMENT
Treatment of patients with EPN remains
a controversial issue. Historically
nephrectomy was regarded as the main
treatment of patients with this life-
threatening infection [2] to be performed
as soon as possible after vigorous resus-
citation, administration of antimicrobial
agents, and control of blood glucose and
electrolytes. Early data showed mortal-
ity for patients who underwent nephrec-
tomy to be 20%, compared with 80% for
patients treated solely medically [26].
Even as recently as the 1990’s the dan-
gers of delayed nephrectomy were re-
emphasized [17–18]. These papers still
describe an accumulated experience
beginning many years before, when
patients would not have had the benefit
of modern intensive care, advanced imag-
ing techniques or interventional radiol-
ogy. Furthermore, patients assigned to
a “medical” group will often have been
regarded as unfit to undergo major sur-
gery and will therefore have had a poor
prognosis at the outset.
In the last decade the emphasis has
changed such that for a proportion of
patients a more conservative approach
may be appropriate. Mortality as low
as 8% has been reported with a staged
approach combining CT-guided percutane-
ous drainage (PCD) in combination with
antibiotic and supportive therapy [27].
Best and colleagues [28] reported success-
ful treatment of gas-filled renal abscesses
in diabetic patients with medical
409
Chapter |7| Urinary tract infections in nephropathies
treatment alone. Medical therapy is now
considered a valid alternative to surgical
intervention [29], and management should
be tailored according to disease severity
and radiographic findings (GoR C, LoE 3).
There is some indication from the
Japanese literature that the intro-
duction of new antibiotics including
acylaminopenicillins, with more effective
control of Pseudomonas and resistant
Enterobacteriaceae was also of key impor-
tance in improved results of treatment of
EPN. Kondo et al. [22] reviewed the out-
come of 183 Japanese patients with EPN
in relation to the introduction of carbeni-
cillin in 1989, 68 patients treated before
1989 (Group 1) were compared with 115
patients treated after 1989 (Table 5). For
the comparison of prognosis between two
groups the mortality rate was quanti-
fied by using the chi-square test with a
p-value less than 0.05 considered statis-
tically significant. Overall mortality in
Group 1 was 16% and fell significantly to
7% for Group 2.
Huang and Tseng proposed a clinical
classification which appeared to identify
categories of patients who might avoid
nephrectomy except where the disease
is rapidly progressive and fulminant, by
using the lesser procedure of PCD of the
kidney where it is obstructed and/or of
the abscess itself [1, 30].
Table 5 Treatment and prognosis of EPN: Comparision of Prognosis between early (-1988) and recent period (1989–1999).
Year –1988
No. cases No. death(%)
Conservative therapy 21 8(38%)
alone
Drainage + 6 0
Nephrectomy
Drainage alone 14 0 24
Nephrectomy alone 23 2(9%)
Others 4 1
Total 68 11(16%)
410
8. DISCUSSION
Our recommendations are based on
the flowchart for management of EPN
devised by Huang and Tseng (Fig 1) [1].
Although there were no significant dif-
ferences in the clinical features between
the categories, there was a progressive
tendency toward an increasing likeli-
hood of failure of PCD and risk of mortal-
ity from classes 1 to 4. The patients with
class 1 EPN had the best prognosis, and
all of them survived after PCD and/or
relief of the urinary tract obstruction (if
present) combined with antibiotic treat-
ment. In class 2 EPN, all patients treated
with PCD and antibiotics were cured.
Therefore, PCD and relief of the urinary
tract obstruction combined with antibi-
otic treatment is the choice of modality
for limited disease (class 1 or 2).
Analysis, particularly of the older lit-
erature, confirmed that patients in the
category “conservative treatment not
including PCD” also had a poor progno-
sis. This can be explained by the fact that
they will have suffered additional co-mor-
bidity precluding emergency major sur-
gery (nephrectomy) and even PCD. Some
might have undergone delayed nephrec-
tomy as an act of desperation, no doubt
contributing to their death. The delay
can hardly be regarded as causal and it
1989–1999 P value
No. cases No. death(%) (X2 test)
24 4(17%) 0.01
18 1(6%) 0.56
2(8%) 0.27
49 1(2%) 0.19
115 8(7%) <0.05

Table 6 Timing of nephrectomy of reported cases.
Day of nephrectomy (days after the 0–7
initial treatment)
No. patients(%) 24(36)
would obviously be misleading to derive a
general conclusion from this self- select-
ing group that delayed nephrectomy can
reduce survival chances [17–18].
We reviewed the management of
extensive EPN with gas or abscess exten-
sion beyond the renal capsule and bilat-
eral EPN (class 3 or 4) in relation to
the presence or absence of one or more
of the 23 designated risk factors. Our
study showed that 17 (85%) of the 20
patients with one or no risk were suc-
cessfully treated with PCD combined
with antibiotic treatment; compared with
the patients with two or more risk fac-
tors who had a significantly higher fail-
ure rate (92% vs 15%, p<0.01). For these
patients timely nephrectomy would have
provided the best management outcome.
Table 6 shows timing of nephrectomy of
all cases reported [22].
Bilateral EPN may be reasonably con-
sidered a more severe infection than uni-
lateral EPN. Data presented in the past
were not sufficient to determine whether
bilateral EPN was necessarily associated
with a poor outcome. However, our results
clearly show that bilateral EPN is a risk
factor predictive of both failure of PCD
and increased mortality (GoR A, LoE 1a).
Of course co-morbidity is a confounding
factor insofar as patients with bilateral
EPN are often too sick to undergo general
anesthesia and, therefore, are treated
conservatively, with poor results [20].
In summary, we suggest that even for
patients with extensive EPN (class 3 or 4)
provided they show no more than one risk
factor, PCD in combination with antibiotic
treatment may be attempted. However,
nephrectomy will still be required for
the few failing to respond to these meas-
ures and of course for fulminant disease
Emphysematous pyelonephritis | 7.2 |
8–14 15–21 22–28 >29 Total
12(18) 3(4) 8(12) 20(30) 67
and/or where there are two or more iden-
tifiable risk factors [A, 2b].
9. FURTHER RESEARCH
In some articles there is limited evidence
that increased serum creatinine level,
disturbance of consciousness and hypo-
tension (systolic blood pressure less than
90 mmHg) may also impact the survival
of EPN patients [1, 31]. Thus, further
research on these factors seems warranted
to confirm the potential detrimental effect
on the outcome of patients with EPN.
10. CONCLUSIONS
In this study, mortality of EPN was 17.3%
(62 of 358). It also demonstrated that
whilst a conservative approach to treat-
ment was generally effective, bilateral
EPN, type 1 EPN, and thrombocytopenia
were significant risk factors associated
with a higher than average mortality. In
such circumstances timely nephrectomy
might still be preferable as a life-saving
procedure.
REFERENCES
1. Huang, J.J. and C.C. Tseng,
Emphysematous pyelonephritis: clinico-
radiological classification, management,
prognosis, and pathogenesis. Arch Intern
Med, 2000. 160(6): p. 797–805.
2. Michaeli, J., et al., Emphysematous
pyelonephritis. J Urol, 1984. 131(2):
p. 203–8.
3. Pontin, A.R., et al., Emphysematous
pyelonephritis in diabetic patients.
Br J Urol, 1995. 75(1): p. 71–4.
411
Chapter |7| Urinary tract infections in nephropathies
4. Schultz, E.H., Jr. and E.H. Klorfein,
Emphysematous pyelonephritis. J Urol,
1962. 87: p. 762–6.
5. Huang, J.J., K.W. Chen, and M.K. Ruaan,
Mixed acid fermentation of glucose as a
mechanism of emphysematous urinary
tract infection. J Urol, 1991. 146(1):
p. 148–51.
6. Kaiser, E. and R. Fournier,
[Emphysematous pyelonephritis: diag-
nosis and treatment]. Ann Urol (Paris),
2005. 39(2): p. 49–60.
7. Wan, Y.L., et al., Acute gas-producing bac-
terial renal infection: correlation between
imaging findings and clinical outcome.
Radiology, 1996. 198(2): p. 433–8.
8. Menif, E., et al., [Emphysematous
pyelonephritis: report of 3 cases]. Ann
Urol (Paris), 2001. 35(2): p. 97–100.
9. Touiti, D., et al., [Emphysematous
pyelonephritis: report of 3 cases]. Prog
Urol, 2001. 11(4): p. 703–6.
10. Klein, F.A., Smith MJ, and Vick CW,
Emphysematous pyelonephritis: diagnosis
and treatment. South Med J 1986. 79:
p. 41–46.
11. Cohen, C., Emphysematous pyelonephri-
tis. A report of 2 cases. S Afr Med J, 1983.
63(5): p. 166–7.
12. Abrams, P., S. Khoury, and A. Grant,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): p. 681–4.
13. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
p. 115–127.
14. Mantel, N. and W. Haenszel, Statistical
aspects of the analysis of data from retro-
spective studies of disease. J Natl Cancer
Inst, 1959. 22(4): p. 719–48.
15. Kuo, Y.T., et al., Emphysematous pyelone-
phritis: imaging diagnosis and follow-
up. Kaohsiung J Med Sci, 1999. 15(3):
p. 159–70.
16. Wan, Y.L., et al., Predictors of outcome in
emphysematous pyelonephritis. J Urol,
1998. 159(2): p. 369–73.
17. Shokeir, A.A., et al., Emphysematous
pyelonephritis: a 15-year experience with
20 cases. Urology, 1997. 49(3): p. 343–6.
412
18. Ahlering, T.E., et al., Emphysematous
pyelonephritis: a 5-year experience with 13
patients. J Urol, 1985. 134(6): p. 1086–8.
19. Masago, T., et al., Experiences of emphyse-
matous pyelonephritis 2 cases. Jpn J Urol
Surg, 2007. 20: p. 1323–1326.
20. Abdul-Halim, H., et al., Severe emphyse-
matous pyelonephritis in diabetic patients:
diagnosis and aspects of surgical manage-
ment. Urol Int, 2005. 75(2): p. 123–8.
21. Tang, H.J., et al., Clinical characteristics of
emphysematous pyelonephritis. J Microbiol
Immunol Infect, 2001. 34(2): p. 125–30.
22. Kondo, T., et al., [A case of emphyse-
matous pyelonephritis improved with
conservative therapy – indication for
conservative therapy]. Hinyokika Kiyo,
2000. 46(5): p. 335–8.
23. Stunell, H., et al., Imaging of acute
pyelonephritis in the adult. Eur Radiol,
2007. 17(7): p. 1820–8.
24. McHugh, T.P., S.E. Albanna, and
N.J. Stewart, Bilateral emphysematous
pyelonephritis. Am J Emerg Med, 1998.
16(2): p. 166–9.
25. Turney, J.H., Renal conservation for
gas-forming infections. Lancet, 2000.
355(9206): p. 770–1.
26. Evanoff, G.V., et al., Spectrum of gas
within the kidney. Emphysematous
pyelonephritis and emphysematous pyeli-
tis. Am J Med, 1987. 83(1): p. 149–54.
27. Chen, M.T., et al., Percutaneous drain-
age in the treatment of emphysematous
pyelonephritis: 10-year experience. J Urol,
1997. 157(5): p. 1569–73.
28. Best, C.D., et al., Clinical and radiologi-
cal findings in patients with gas form-
ing renal abscess treated conservatively.
J Urol, 1999. 162(4): p. 1273–6.
29. Tahir, H., et al., Successful medical treat-
ment of acute bilateral emphysematous
pyelonephritis. Am J Kidney Dis, 2000.
36(6): p. 1267–70.
30. Tseng, C.C., et al., Host and bacterial
virulence factors predisposing to emphyse-
matous pyelonephritis. Am J Kidney Dis,
2005. 46(3): p. 432–9.
31. Falagas, M.E., et al., Risk factors for mor-
tality in patients with emphysematous
pyelonephritis: a meta-analysis. J Urol,
2007. 178(3 Pt 1): p. 880–5; quiz 1129.
|7.3|
Renal abscesses
Kiyohito Ishikawa
Department of Urology, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake,
Totoake, Aichi, 470-1192, Japan
e-mail address: kiyo@fujita-hu.ac.jp
ABSTRACT
Renal abscesses result from a severe
infection leading to liquefaction of renal
tissue. They are quite frequently multiple
and arise in areas of interstitial inflam-
mation. An abscess can rupture through
the renal capsule into the perinephric
space, forming a perinephric abscess.
When it extends beyond Gerota’s fascia,
it may spread throughout the retroperito-
neal space limited anteriorly via the pre-
vertebral fascia and point in the inguinal
region or between the paraspinal muscle
masses overlying the kidney below the
12th rib in the costovertebral, renal angle.
Patients with diabetes and intravenous
drug abusers are at risk of developing
renal abscess.
Ultrasonography CT and MRI are
helpful in distinguishing abscess from
other inflammatory renal disease and in
deciding on the management. Intensive
antibiotic therapy alone may be effec-
tive for treatment of renal or perinephric
abscesses smaller than 5 cm.
Keywords: renal abscesses, Gram-
negative bacteria, antibiotic therapy
SUMMARY OF RECOMMENDATIONS
Diagnosis
1. Ultrasonography and CT are helpful
in distinguishing abscess from other
inflammatory renal disease (GoR C).
2. Abscesses are characteristically well
defined on CT both before and after
contrast agent enhancement (GoR C).
3. Rupture of a renal abscess with peri-
toneal extension is better appreci-
ated by MRI (GoR C).
4. Dilatation of the pelvicaliceal system
may indicate coexisting obstruction
(GoR C).
Treatment
5. The management of renal abscess
must first include appropriate
antibiotic therapy (GoR B).
Chapter |7| Urinary tract infections in nephropathies
6. Ampicillin or vancomycin in com-
bination with an aminoglycoside or
third-generation cephalosporin is
recommended as antibiotics (GoR B)
7. Antibiotic therapy must be continued
for at least four weeks (GoR B)
8. Coexisting upper urinary tract obstruct
ion is a surgical emergency and requi-
res drainage, preferably by percutane-
ous nephrostomy (PCD) (GoR B)
Other management
9. If the patient does not respond with
48 hours of treatment, PCD under
CT or ultrasound guidance is indi-
cated (GoR B).
10. The drained fluid should be cultured
for the causative organisms (GoR B).
11. If the abscess still does not resolve,
then open surgical drainage or
nephrectomy may be necessary
(GoR B).
Follow-up
12. Follow-up imaging is needed to
confirm resolution of the abscesses
(GoR B)
13. Evaluation for underlying urinary
tract abnormalities, such as stone
or obstruction, should be performed
after appropriate antibiotic treat-
ment has been initiated (GoR B).
1. INTRODUCTION
A renal abscess results from a severe
infection leading to liquefaction and per-
manent loss of renal tissue. It can rup-
ture into the perinephric space and then
extend beyond Gerota’s fascia to spread
widely through the retroperitoneum.
Historically, most renal/perinephric
abscesses result from hematogenous
spread of staphylococci, in particular
from infected skin lesions. Diabetes mel-
litus (DM) and intravenous drug abuse
are prominent causative factors. With
414
the development of effective antibiot-
ics and better management of disease
such as diabetes and renal failure, renal
or perinephric abscesses due to Gram-
positive bacteria are less prevalent;
whereas those caused by Escherichia coli
or Proteus species are becoming more
common [1–2]. Abscesses forming in
the renal cortex are likely to arise from
hematogenous spread, whereas those at
the corticomedullary junction are caused
by ascending infection by Gram-negative
bacteria in conjunction with other under-
lying urinary tract abnormalities, such as
stones or obstruction.
60% of Gram-negative abscesses in
adults are associated with renal calculi or
damaged kidneys. Although the associa-
tion of pyelonephritis with vesicoureteral
reflux is well established, renal abscess
is only rarely a consequence of reflux and
then only in children [3].
The differential diagnosis includes
secondary infection in renal cysts which
can be simple or part of a complex sys-
temic problem (e.g. adult dominant poly-
cystic kidney disease). Occasionally an
abscess can follow secondary infection in
a cystic tumour and it may also form part
of chronic infection and inflammation
in the urinary tract e.g. genitourinary
tuberculosis.
2. METHODS
We performed a systematic search of
PubMed (January 1996 to August 2008).
We used the keywords “renal abscesses
and (perinephric abscess or retroperitoneal
abscess or intravenous drug or antibiotic
therapy or prognosis or hospitalization or
outcome or mortality or prognostic or risk
factor or severity or survival)”. The search
was limited to articles written in English
and Japanese. 619 published reports were
identified and screened by their title. The
full texts of 16 articles were read and 11
studies were excluded for several reasons.

Table-1 Main characteristics of renal abscesses included in the meta-analysis.
U/C
Reference No. Pts positive
Siegel. JF (4) 52 71%
Meng MV (5) 25 72%
Shu T (6) 70 67%
Coelho RF (7) 65 43%
Lee BE (8) 56
U/C: Urine culture B/C: Blood culture
AB: antibiotic therapy alone
PCD: Percutaneus drainage
Nx: Nephrectomy or open surgery
A total of five articles were included into
the analysis. (Table 1) [4–8].
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [9–10].
3. PRESENTATION AND CLINICAL
FINDINGS
The most common presenting symp-
toms in patients with renal-perinephric
abscesses include fever, flank or abdomi-
nal pain, chills, and dysuria. Patients
sometimes suffer from the effects of an
indolent illness for several weeks before
medical advice is sought. A flank mass
is palpable in some patients. Urinalysis
usually demonstrates white blood cells;
however, it may be normal in approxi-
mately 25% of cases [2]. Urine cultures
only identify the causative organisms in
about one-third of cases and blood culture
in only about half of cases [11].
4. IMAGING
Ultrasonography (US) and CT are help-
ful in distinguishing abscess from other
inflammatory renal disease. US is the
Renal abscesses | 7.3 |
B/C No. Pts
positive with DM Treatment
28% 25% 3cm< AB 3-5cm PCD >5 cm Nx
AB AV=1.8 cm PCD AV=11 cm PCD+Nx 30%
AB 74% PCD 26% Nx 0%
17% 28% AB 25% PCD 37.5% Nx 37.5%
45% AB 36% PCD or Nx 64%
DM: Diabetes mellitus
quickest and least expensive method to
demonstrate a renal abscess and will
usually be the initial form of imaging
screen. US can reveal either a hyper- or
hypoechoic focal mass or complex cystic
structure. There may be posterior acous-
tic enhancement, although early in
development poor transmission of sound
waves can be seen. Demonstrating a
lack of vascularity on Doppler imaging
is important in distinguishing a com-
plex abscess from a malignant process
[12–13].
CT appears to be the diagnostic proce-
dure of choice for renal abscess, because
it provides excellent delineation of the tis-
sue (GoR A, LoE4). With high sensitivity,
CT scans can demonstrate an enlarged
kidney with focal areas of hypoattenu-
ation early on during the course of the
infection. On CT, abscesses are charac-
teristically well defined both before and
after contrast agent enhancement [14].
Once the inflammatory wall forms around
the fluid collection, the abscess appears
as a mass with a rim of contrast enhance-
ment, the “ring” sign. Fluid levels may be
present with dependent debris. Septation
may be present within the abscess [15].
CT scans may also demonstrate thick-
ening of Gerota’s fascia, stranding of
the perinephric fat, or obliteration of
415
Chapter |7| Urinary tract infections in nephropathies
the surrounding soft-tissue planes [16].
Recently, modern multislice CT gives bet-
ter resolution and few clinicians would be
confident in management decisions with-
out access to CT. The improvements in
CT technique and increased use of cross-
sectional imaging have facilitated the
detection of small or previously undiag-
nosed renal masses. Helical CT technol-
ogy will further improve renal imaging
with decreasing volume-averaging arti-
facts, eliminating respiratory misreg-
istration artifacts and allowing image
acquisition during the peak intravenous
contrast enhancement. Helical CT image
acquisition has also led to improved data
sets available for three-dimensional imag-
ing [17].
Magnetic resonance imaging, because
of its lack of ionizing radiation, has
recently gained popularity as an imag-
ing modality in obstetrics and gynecol-
ogy. On MRI, a renal abscess is displayed
as a low-signal intensity inhomogeneous
mass on T1-weighted images and with
increased signal intensity on T2-weighted
images depending on the presence of pro-
tein, fluid, and cellular debris. Rupture of
a renal abscess with peritoneal extension
is better appreciated on MRI [15].
Both ultrasonography and/or CT per-
formed as the initial diagnostic investi-
gation will demonstrate dilatation of the
collecting system due to obstruction, and
the presence of other associated abnor-
malities e.g. renal and ureteric stones.
5. ANTIBIOTIC THERAPY
The appropriate management of renal
abscess must first include appropri-
ate antibiotic therapy (GoR B, LoE 4).
Because it is often very difficult to iden-
tify the correct causative organisms from
the urine or blood, empiric therapy with
broad-spectrum antibiotics (ampicil-
lin or vancomycin in combination with
an aminoglycoside or third-generation
cephalosporin) is usually recommended
416
[4, 18–21]. Where present, obstruction
must be relieved by PCD or a stent
inserted endoscopically.
Response to antibiotic therapy should
be obvious from reduction of the dimen-
sions of the abscess. In a review of 55
patients with a renal abscess antibiotic
therapy alone was successful in 85.9% of
cases. Factors predicting a less favorable
outcome were abscess diameter > 5 cm,
involvement by more than one organism,
presence of Gram-negative bacilli, dura-
tion of therapy less than four weeks, and
use of aminoglycoside as the only anti-
biotic [18].
Siegel et al. observed successful anti-
biotic therapy in 5/5 renal abscesses that
were 3 cm or less, in 2/3 renal abscesses
with a size of 3–5 cm, and in 1/3 renal
abscesses larger than 5 cm [4].
Palma et al. recommended that inten-
sive antibiotic therapy alone could be
effective for treatment of renal or perine-
phric abscesses smaller than 5 cm.
However, should clinical response be
unsatisfactory, open surgery or PCD
drainage should be carried out.
Several investigators [18–21] empha-
size the importance of continuing antibi-
otic therapy for at least four weeks, even
when there is excellent clinical improve-
ment within a few days (GoR B, LoE 4).
6. OTHER MANAGEMENTS
Occasionally, obstruction must be reli-
eved as a matter of extreme urgency as
pyonephrosis may coexist with the paran-
chymal infection. This is more certainly
achieved by percutaneous nephrostomy
but circumstances may dictate retrograde
placement of a ureteric catheter.
The patient who was not obstructed
but showing little or no response after
48 hours of treatment, will require PCD
under CT or ultrasound guidance is indi-
cated [4]. The drained fluid should be cul-
tured for the causative organisms. If the
abscess still does not resolve, then open

surgical drainage or nephrectomy may be
necessary (GoR B, LoE 4).
Follow-up imaging is needed to con-
firm resolution of the abscesses. These
patients will also require evaluation for
underlying non-obstructive urinary tract
abnormalities after the infection has
resolved. Concurrent stone disease will
require interval management particularly
if closely associated with development of
the abscess.
The management of infected cysts in
polycystic kidney disease is discussed else-
where in this section (Perepanova et al).
7. FURTHER RESEARCH
It is unlikely that “Renal Abscess” will
ever be the subject of a major research
endeavour. However, in time a consensus
based on small anecdotal studies will pro-
vide useful evidence on the use of more
contemporary antimicrobial agents and
the appropriate duration of therapy. It
is to be hoped that the need for surgical
intervention will continue to diminish. No
doubt new imaging strategies will have
an impact on earlier diagnosis, assist in
percutaneous drainage and in plotting
the resolution of the abscess.
8. CONCLUSIONS
This study shows that renal abscesses of
less than 5 cm in diameter can respond
successfully to antibiotic therapy alone
without intervention. Larger abscesses
always need surgical drainage. Evaluation
for underlying urinary tract abnormali-
ties, such as stone or obstruction, should
be performed after appropriate antibiotic
treatment has been initiated.
REFERENCES
1. Merimsky E and Feldman C, Perinephric
abscess: report of 19 cases. Int Surg, 1981.
66(1): 79–80.
Renal abscesses | 7.3 |
2. Thorley JD, Jones SR, and Sanford JP,
Perinephric abscess. Medicine (Baltimore),
1974. 53(6): 441–51.
3. Segura JW and Kelalis PP, Localized
renal parenchymal infections in children.
J Urol, 1973. 109(6): 1029–32.
4. Siegel JF, Smith A, and Moldwin R,
Minimally invasive treatment of renal
abscess. J Urol, 1996. 155(1): 52–5.
5. Meng MV, Mario LA, and McAninch JW,
Current treatment and outcomes of perine-
phric abscesses. J Urol, 2002. 168(4 Pt 1):
1337–40.
6. Shu T, Green JM, and Orihuela E,
Renal and perirenal abscesses in
patients with otherwise anatomically
normal urinary tracts. J Urol, 2004.
172(1): 148–50.
7. Coelho RF, Schneider-Monteiro ED,
Mesquita JL, Mazzucchi E, Marmo
Lucon A, and Srougi M, Renal and perine-
phric abscesses: analysis of 65 consecutive
cases. World J Surg, 2007. 31(2): 431–6.
8. Lee BE, Seol HY, Kim TK, Seong EY,
Song SH, Lee DW, Lee SB, and Kwak IS,
Recent clinical overview of renal and peri-
renal abscesses in 56 consecutive cases.
Korean J Intern Med, 2008. 23(3): 140–8.
9. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
11. Edelstein H and McCabe RE, Perinephric
abscess. Modern diagnosis and treatment
in 47 cases. Medicine (Baltimore), 1988.
67(2): 118–31.
12. Kawashima A and LeRoy AJ, Radiologic
evaluation of patients with renal infec-
tions. Infect Dis Clin North Am, 2003.
17(2): 433–56.
13. Demertzis J and Menias CO, State of the
art: imaging of renal infections. Emerg
Radiol, 2007. 14(1): 13–22.
14. Baumgarten DA and Baumgartner BR,
Imaging and radiologic management of
upper urinary tract infections. Urol Clin
North Am, 1997. 24(3): 545–69.
417
Chapter |7| Urinary tract infections in nephropathies
15. Puvaneswary M, Bisits A, and Hosken B,
Renal abscess with paranephric extension
in a gravid woman: ultrasound and mag-
netic resonance imaging findings. Australas
Radiol, 2005. 49(3): 230–2.
16. Dalla Palma L, Pozzi-Mucelli F, and
Ene V, Medical treatment of renal and
perirenal abscesses: CT evaluation. Clin
Radiol, 1999. 54(12): 792–7.
17. Toprak U, Erdogan A, Gulbay M,
Karademir MA, Pasaoglu E, and Akar
OE, Preoperative evaluation of renal
anatomy and renal masses with heli-
cal CT, 3D-CT and 3D-CT angiogra-
phy. Diagn Interv Radiol, 2005. 11(1):
35–40.
418
18. Bamberger DM, Outcome of medical
treatment of bacterial abscesses without
therapeutic drainage: review of cases
reported in the literature. Clin Infect Dis,
1996. 23(3): 592–603.
19. Schiff M, Jr., Glickman M, Weiss RM,
Ahern MJ, Touloukian RJ, Lytton B, and
Andriole VT, Antibiotic treatment of renal
carbuncle. Ann Intern Med, 1977. 87(3):
305–8.
20. Rives RK, Harty JI, and Amin M, Renal
abscess: emerging concepts of diagnosis
and treatment. J Urol, 1980. 124(4): 446–7.
21. Dembry LM and Andriole VT, Renal and
perirenal abscesses. Infect Dis Clin North
Am, 1997. 11(3): 663–80.
|7.4|
Polycystic renal disease
Tamara Perepanova, Oleg Apolikhin
State S.R. Institute of Urology, Moscow, Russia
Corresponding author: Tamara Perepanova, MD, Professor of Urology, S.R. Institute of Urology in Moscow
3-ja Parkovaja st, h.51, Moscow, 105425, Russia
Tel. +7-495-367.1717, perepanova2003@mail.ru
ABSTRACT
UTI occurs in 21–75% of patients with
autosomal dominant polycystic kidney
disease (ADPKD) during their lifetime.
Frequently urinary infection is the first
and leading symptom of the disease. The
urinary tract per se, renal parenchyma
and cysts may be involved in the inflam-
matory process. Renal infection is a com-
mon occurrence in ADPKD and often
leads to serious complications, includ-
ing perinephric abscess, septicemia,
and death. Important predisposing fac-
tors include age, female sex, and recent
instrumentation of the urinary tract.
Renal infections in ADPKD are most com-
monly caused by Gram-negative enteric
organisms. Diagnosis of these infections
may be difficult since some patients do
not have bacteriuria. CT or MRI (or both)
may be helpful in some patients with uri-
nary infection and is often superior to
sonography for detecting cysts in organs
other than the kidney. Eradication of cyst
infections with conventional antibiotic
therapy can be difficult despite proven in
vitro sensitivity of responsible organisms
to the agents administered.
Key words: Autosomal dominant poly-
cystic kidney disease (ADPKD) and UTI,
polycystic renal disease, pyelonephritis,
cyst infections, treatment ADPKD.
SUMMARY OF RECOMMENDATIONS
1. Uncomplicated lower urinary tract
infection (cystitis, urethritis) in
patients with
2. ADPKD should be managed accord-
ing to the same principles as in
patients with normal urinary tracts
(GoR B)
3. Renal infections of patients with
autosomal dominant polycystic kid-
ney disease (ADPKD) should be sub-
classified as pyonephrosis (infection
of the upper collecting system), acute
bacterial interstitial infection (infec-
tion of the renal parenchyma) or
Chapter |7| Urinary tract infections in nephropathies
pyocyst (infection confined to a cyst)
(GoR B).
4. Of these, pyocysts can be the most
diagnostically challenging and,
because of delay in starting effec-
tive treatment, can generate the
most severe infection with risk of
systemic spread. Therefore, serial
cultures of blood and urine are
essential before starting antibiotic
therapy (GoR B).
5. For the majority of infections com-
mon Enterobacteriaceae also respon-
sible for cystitis and pyelonephritits
(eg: E. coli, Klebsiella, Proteus and
Pseudomonas spp.) have to be con-
sidered (GoR B).
6. CT imaging, perhaps supple-
mented with MR, is optimal in the
evaluation of the febrile patient
with ADPKD, to detect infected
cysts, pyonephrosis and perine-
phric abscess (GoR B). However,
even modern imaging can still be
misleading.
7. Lipid-soluble antibiotics should be
selected in the treatment of infected
renal cysts. Of these, fluoroqui-
nolones are the most effective and
should be prescribed empirically
(GoR B).
8. Nephrectomy is still occasionally
necessary to prevent recurrent UTI
and its complications, particularly
if transplantation is imminent and
the infecting organisms are resistant
(GoR B).
9. Nephrectomy may also be recom-
mended if removal of infective
stones is impossible by conservative
surgery.
1. INTRODUCTION
UTI occurs in 21–75% of patients with
autosomal dominant polycystic kidney
disease (ADPKD) [1–3]. The incidence of
420
urinary tract infections and other com-
plications e.g. hypertension, is higher
for PKD1 gene defects as compared with
PKD2. Often both kidneys are involved
in infectious process. Frequently urinary
infection is the first and leading symp-
tom of the disease. It occurs more often
in women due to the ascending infec-
tion of lower urinary tract (urethritis,
cystitis), similarly to patients without
ADPKD [1–2, 4] (GoR B, LoE 3). The
severity of urinary tract infection var-
ies from subclinical bacteriuria, through
simple cystitis to acute pyelonephritis
and pyonephrosis. The more severe clini-
cal manifestations of upper tract UTI are
common and tend to occur after instru-
mental intervention and bladder cath-
eterization when there is an increased
risk of colonization by nosocomially
acquires hospital polyresistant bacterial
strains [5] (GoR C, LoE4). However, the
overall outcome of ADPKD patients on
maintenance chronic haemodialysis (HD)
and after renal transplantation is sur-
prisingly similar to that of HD patients
with other primary renal diseases [6]
(GoR B, LoE 3).
2. METHODS
A systematic literature search was
performed in PubMed, Medline, the
Cochrane data base and in books, jour-
nal articles (in English and Russian)
with the following key words: “auto-
somal dominant polycystic kidney dis-
ease (ADPKD) and UTI, polycystic renal
disease, pyelonephritis, cyst infections,
treatment ADPKD” and without limi-
tation on gender, age, clinical studies.
Only literature published after 1985 was
reviewed.
A total 368 English publications were
identified, which were screened by title
and abstract, and three Russian mono-
graphs. After peer review and exclusion
of duplicates a total of 111 were available
and included in the analysis.

The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [7–8].
3. CLINICAL MANIFESTATION
The urinary tract should always be sus-
pected as the most likely source of infec-
tion in the febrile patient with polycystic
renal disease. The urinary tracts per
se, renal parenchyma and cysts may be
involved in the inflammatory process.
Urinary tract infection associated with
ADPKD can occur secondarily in associa-
tion with a variety of urological problems
which are themselves more common in
ADPKD and can predispose to infection
e.g. nephrolithiasis, recurrent gross hae-
maturia requiring repeated endoscopy,
and obstruction of renal outflow (extrinsi-
cally by cysts, luminally by blood clot and
debris).
Renal infections can be subclassified as
pyonephrosis (infection of the obstructed
upper collecting system), acute bacte-
rial interstitial infection (infection of the
renal parenchyma), or pyocyst (infection
confined to a cyst). Pyocysts are poten-
tially the most serious of the three as
diagnosis may be difficult and delayed
by failure of a short course of antibiotics
given empirically to the febrile patient
with nonspecific symptoms to be curative
[3] (GoR B, LoE 2b). Pyocysts are in most
instances accompanied by previously
unreported loin pain and tenderness, and
positive blood cultures. Usually Gram-
negative enteric organisms are responsi-
ble, which suggests an ascending route of
infection.
The relentless substitution of the
functioning renal parenchyma with
cysts eventually leads to chronic renal
insufficiency. UTI may play a role in
the decline of renal function but the evi-
dence is surprisingly equivocal [9] (GoR
C, LoE 4).
Polycystic renal disease | 7.4 |
4. DIAGNOSIS
4.1 Clinical symptoms and
laboratory evaluation
Diagnosis of a simple UTI is made as
usual on the basis of positive bacterial
analysis of urine in combination with
one or more clinical symptoms – dysuria,
back pain with typical radiation, pyrexia
and even rigors. Pyuria, leukocytosis and
bacteriemia are usually present [3] (GoR
B, LoE 2b). Positive urine culture and
pyuria favour renal parenchymal infec-
tion but a positive blood culture with
discrete abdominal or flank tenderness,
sometimes with a negative urine culture
is consistent with infection in a cyst.
The majority of infections are caused by
the standard enterobacteriaceae respon-
sible for cystitis and pyelonephritits (e.g.
E. coli, Klebsiella, Proteus, Pseudomonas)
[2]. Multiresistant strains of Proteus and
pseudomonas, staphylococcus and strep-
tococcus can be cultured [3, 10–11] (GoR
B, LoE 2b). The presence of anaerobic
bacteria may relate to the low partial oxy-
gen pressure in the cyst contents (pO2<40
mmHg) [1].
Cysts can become secondarily infected
by the haematogenous route. S. aureus
infection from culture of cyst fluid and
blood has been reported in an intrave-
nous drug abuser and after staphylococ-
cal peritonitis in a peritoneal dialysis
patient [10, 12] (GoR B, LoE 2a)
4.2 Imaging
X-rays and tomograms may reveal evi-
dence of peri-renal infection and neph-
rolithiasis. Sonography is commonly
used as a preliminary form of imag-
ing but it can be very difficult to iden-
tify the development of an abscess
within a complex septate cyst contain-
ing echodense proteinaceous deposits
suspended in serosanguinous cystic
fluid. Invariably modern multislice CT
is regarded as mandatory to make the
421
Chapter |7| Urinary tract infections in nephropathies
diagnosis and plan further treatment,
though MRI may ultimately prove as
effective without risk of radiation expo-
sure [13] (GoR B, LoE 3). In the past, 67
Gallium isotope scintigraphy was used
to detect areas of inflammation [14–15].
The value was limited by excretion of
a significant fraction of the dose into
the bowel. Furthermore it was reli-
able in detecting only 50% of infected
cysts, though in one study it was help-
ful in identifying the focus of persistent
UTI in renal transplant recipients with
underlying ADPKD [15]. Sensitivity may
be improved with gallium SPECT [16].
Indium labeled leucocytes may have
offered advantages as a carrier but
these techniques are rarely used except
in the research environment [17] (GoR
C, LoE 3).
5. TREATMENT
The efficacy of antibiotic treatment may
depend on the liposolubility of the agents
used and whether or not they are ion-
ized at physiological pH. Intracystic pH
determines the extent to which basic
lipophilic antibiotics accumulate in the
fluid. Lipid-soluble antibiotics which are
relatively alkaline may be useful in the
treatment of infected renal cysts [18–19]
(GoR A, LoE 2b).
Cephalosporins, gentamicin and ampi-
cillin, which are standard treatments for
acute pyelonephritis are often ineffective
for cyst infection, possibly because the
betalactams and aminoglycazides require
active transport [2, 18]. Fluoroquinolones
are generally the most effective, as they
have high lipid solubility and accumu-
late in gradient cysts [20] (GoR A, LoE 3).
Cyst infection is assumed to be present
by default in patients with suspected
acute pyelonephritis who do not respond
to standard antibiotic regimes. However,
increasingly fluoroquinolones are used
non-selectively.
422
Much of the detail on antibiotic trans-
port has been derived from studies on
uninfected cysts. Very little is known of
the effect of infection on epithelial func-
tion. Not surprisingly, much of the selec-
tion of antibiotics has to be empirical and
occasionally patients with cyst infection
may still respond dramatically to tri-
methoprim/sulphamethoxazole and chlo-
ramphenicol where quinolones have been
ineffective.
After initial efficacy has been con-
firmed, a prolonged course (four to eight
weeks) of the antibiotic may be required
to sterilise a pyocyst [3]. Percutaneous
drainage of antibiotic-unresponsive pyo-
cysts may be required to obtain material
for diagnosis and with a therapeutic aim
[21] (GoR B, LoE 3).
6. NEPHRECTOMY
Nowadays, nephrectomy is rarely required
in the context of infection prevention.
However, bilateral nephrectomy is still
essential in patients whose confirmed
suppurative pyocysts have not been steri-
lised before renal transplantation and
immunosuppressive medication is admin-
istered. The risk of recurrent severe UTI
and cyst infection occurring after trans-
plantation is considerable in patients
with a history of infection pre-transplant
[3, 22] (GoR B, LoE 3). Other indications
include antibiotic resistant infection
in association with renal stones where
clearance cannot be achieved by standard
minimal access techniques; accelerated
drug resistant hypertension; acquired
renal cystic disease with risk of malig-
nancy and very rarely, persistent heavy
haematuria .
Minimal operative differences were
seen between unilateral or bilateral two-
stage nephrectomy or bilateral simultane-
ous open or retroperitoneal laparoscopic
nephrectomy. The optimal timing is still
debatable [23–25] (GoR B, LoE 3).

Patients with ESRF due to ADPKD are
effectively treated by long term dialysis
and renal transplantation, with graft and
patient survival scores similar to that of
the general renal transplant population
[26–27] (GoR B, LoE 2a).
7. EXTRARENAL INFECTION AND
ADPKD
Hepatic cysts occur in 58–83% patients
with ADPKD [28–29]. They are more prev-
alent and tend to be of larger in women
and in the elderly of both sexes [28] (GoR
B, LoE 2a). Cysts are isolated from the
biliary excretion system and therefore
are rarely infected; however, suppuration
with multiple abscess development is still
possible, particularly in renal graft recipi-
ents [30–31]. If so, bacteraemia is com-
mon and unlike non-cystic pyogenic liver
abscesses, a single bacterial species is
usually responsible, suggesting a haema-
togenous origin for the infection.
8. FURTHER RESEARCH
Further research should deal with the
search and creation of new antimicrobial
drugs and prevention of ascending route
of UTI, e.g. use urinary catheters and
stents with antiadhesive, antimicrobial
covering.
9. CONCLUSIONS
The urinary tract should always be sus-
pected as the most likely source of infec-
tion in the febrile patient with polycystic
renal disease. The severity of urinary
tract infection in patients with auto-
somal dominant polycystic kidney disease
(ADPKD) varies from subclinical bacte-
riuria, through simple cystitis to acute
pyelonephritis and pyonephrosis. Usually
Gram-negative enteric organisms are
Polycystic renal disease | 7.4 |
responsible, which suggests an ascending
route of infection. Instrumental inter-
vention and bladder catheterization are
risk factors of colonization by hospital
acquired polyresistant bacterial strains
and can lead to development of severe
UTI [5] (GoR C, LoE4). Cysts can become
secondarily infected via the haematog-
enous route.
CT imaging, perhaps supplemented
with MR, is optimal to detect infected
cysts, pyonephrosis and perinephric
abscess (GoR B).
Fluoroquinolones are generally the
most effective, as they have high lipid
solubility and accumulate in gradient
cysts [20] (GoR A, LoE 3). Percutaneous
drainage of antibiotic-unresponsive pyo-
cysts may be required to obtain material
for diagnosis and with a therapeutic aim
[21] (GoR B, LoE 3).
Bilateral nephrectomy is still essential
in patients whose confirmed suppurative
pyocysts have not been sterilised before
renal transplantation and immunosup-
pressive medication is administered.
REFERENCES
1. Conte F, [Treatment of urinary tract infec-
tion in the course of autosomal dominant
polycystic kidney disease: new advances].
Minerva Urol Nefrol, 1987. 39(3): 291–5.
2. Schwab SJ, Bander SJ, and Klahr S,
Renal infection in autosomal dominant
polycystic kidney disease. Am J Med,
1987. 82(4): 714–8.
3. Sklar AH, Caruana RJ, Lammers JE, and
Strauser GD, Renal infections in auto-
somal dominant polycystic kidney disease.
Am J Kidney Dis, 1987. 10(2): 81–8.
4. Milutinovic J, Fialkow PJ, Agodoa LY,
Phillips LA, Rudd TG, and Sutherland
S, Clinical manifestations of autosomal
dominant polycystic kidney disease in
patients older than 50 years. Am J Kidney
Dis, 1990. 15(3): 237–43.
5. Funk-Bretano JL, Vantelon J, and Lopez-
Alvarez R, Les accidents evolitifs de
la maladie polykystique des reins: 154
423
Chapter |7| Urinary tract infections in nephropathies
observations personelles. Presse Med,
1964. 72: 1583.
6. Christophe JL, van Ypersele de Strihou C,
and Pirson Y, Complications of autosomal
dominant polycystic kidney disease in 50
haemodialysed patients. A case-control
study. The U.C.L. Collaborative Group.
Nephrol Dial Transplant, 1996. 11(7):
1271–6.
7. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
9. Gabow PA, Chapman AB, Johnson AM,
Tangel DJ, Duley IT, Kaehny WD, Manco-
Johnson M, and Schrier RW, Renal
structure and hypertension in autosomal
dominant polycystic kidney disease.
Kidney Int, 1990. 38(6): 1177–80.
10. Chapman AB, Thickman D, and Gabow
PA, Percutaneous cyst puncture in the
treatment of cyst infection in autosomal
dominant polycystic kidney disease. Am J
Kidney Dis, 1990. 16(3): 252–5.
11. Tодоров B, Пенкова С, and Монов А, Към
проблема за хроничния пиелонефрит
при бъбречная поликистоза. Вътрешни
болести, 1989. 28(3): 77-81.13.
12. Bretan PN, Jr., Price DC, and McClure
RD, Localization of abscess in adult poly-
cystic kidney by indium-111 leukocyte
scan. Urology, 1988. 32(2): 169–71.
13 Gupta S, Seith A, Sud K, Kohli HS,
Singh SK, Sakhuja V, and Suri S, CT in
the evaluation of complicated autosomal
dominant polycystic kidney disease. Acta
Radiol, 2000. 41(3): 280–4.
14. Sweet R and Keane WF, Perinephric
abscess in patients with polycystic kidney
disease undergoing chronic hemodialysis.
Nephron, 1979. 23(5): 237–40.
15. Tsang V, Lui S, Hilson A, Moorhead J,
Fernando O, and Sweny P, Gallium-67
scintigraphy in the detection of infected
polycystic kidneys in renal transplant
recipients. Nucl Med Commun, 1989.
10(3): 167–70.
424
16. Amesur P, Castronuovo JJ, and
Chandramouly B, Infected cyst localiza-
tion with gallium SPECT imaging in
polycystic kidney disease. Clin Nucl Med,
1988. 13(1): 35–7.
17. Knochel JQ, Koehler PR, Lee TG, and
Welch DM, Diagnosis of abdominal
abscesses with computed tomography,
ultrasound, and 111In leukocyte scans.
Radiology, 1980. 137(2): 425–32.
18. Bennett WM, Elzinga L, Pulliam JP,
Rashad AL, and Barry JM, Cyst fluid
antibiotic concentrations in autosomal-
dominant polycystic kidney disease. Am J
Kidney Dis, 1985. 6(6): 400–4.
19. Schwab S, Hinthorn D, Diederich
D, Cuppage F, and Grantham J,
PH-dependent accumulation of clindamy-
cin in a polycystic kidney. Am J Kidney
Dis, 1983. 3(1): 63–6.
20. Hiyama L, Tang A, and Miller LG,
Levofloxacin penetration into a renal cyst
in a patient with autosomal dominant
polycystic kidney disease. Am J Kidney
Dis, 2006. 47(1): e9–13.
21. Elzinga LW, Barry JM, Torres VE, Zincke
H, Wahner HW, Swan S, and Bennett
WM, Cyst decompression surgery for auto-
somal dominant polycystic kidney disease.
J Am Soc Nephrol, 1992. 2(7): 1219–26.
22. Brazda E, Ofner D, Riedmann B,
Spechtenhauser B, and Margreiter R,
The effect of nephrectomy on the outcome
of renal transplantation in patients with
polycystic kidney disease. Ann Transplant,
1996. 1(2): 15–8.
23. Gill IS, Kaouk JH, Hobart MG, Sung
GT, Schweizer DK, and Braun WE,
Laparoscopic bilateral synchronous
nephrectomy for autosomal dominant
polycystic kidney disease: the initial expe-
rience. J Urol, 2001. 165(4): 1093–8.
24. Lopez-Corona E, Garcia-Gonzalez VM,
and Gabilondo F, [Results of nephrectomy
in patients with autosomal dominant
polycystic kidney disease]. Rev Invest
Clin, 2004. 56(4): 437–42.
25. Desai PJ, Castle EP, Daley SM, Swanson
SK, Ferrigni RG, Humphreys MR, and
Andrews PE, Bilateral laparoscopic
nephrectomy for significantly enlarged
polycystic kidneys: a technique to optimize

outcome in the largest of specimens. BJU
Int, 2008. 101(8): 1019–23.
26. Fitzpatrick PM, Torres VE, Charboneau
JW, Offord KP, Holley KE, and Zincke H,
Long-term outcome of renal transplanta-
tion in autosomal dominant polycystic
kidney disease. Am J Kidney Dis, 1990.
15(6): 535–43.
27. Perrone RD, Ruthazer R, and Terrin NC,
Survival after end-stage renal disease in
autosomal dominant polycystic kidney
disease: contribution of extrarenal com-
plications to mortality. Am J Kidney Dis,
2001. 38(4): 777–84.
28. Bae KT, Zhu F, Chapman AB, Torres
VE, Grantham JJ, Guay-Woodford LM,
Baumgarten DA, King BF, Jr., Wetzel
LH, Kenney PJ, Brummer ME, Bennett
WM, Klahr S, Meyers CM, Zhang X,
Thompson PA, and Miller JP, Magnetic
resonance imaging evaluation of hepatic
Polycystic renal disease | 7.4 |
cysts in early autosomal-dominant poly-
cystic kidney disease: the Consortium for
Radiologic Imaging Studies of Polycystic
Kidney Disease cohort. Clin J Am Soc
Nephrol, 2006. 1(1): 64–9.
29. Mosetti MA, Leonardou P, Motohara T,
Kanematsu M, Armao D, and Semelka
RC, Autosomal dominant polycystic
kidney disease: MR imaging evaluation
using current techniques. J Magn Reson
Imaging, 2003. 18(2): 210–5.
30. Desir G, Helman D, Herlich M, Turka L,
and Bia MJ, Haemophilus parainfluen-
zae liver abscess in a recipient of a renal
transplant who had polycystic disease.
JAMA, 1986. 255(14): 1878.
31. Telenti A, Torres VE, Gross JB, Jr., Van
Scoy RE, Brown ML, and Hattery RR,
Hepatic cyst infection in autosomal domi-
nant polycystic kidney disease. Mayo Clin
Proc, 1990. 65(7): 933–42.
425
|7.5|

Urinary tract infections in renal

insufficiency and dialysis
Reinhard Fünfstück1, Kurt G. Naber2, Michael C. Bishop3
1
Department of Internal Medicine I, Sophien and Hufeland Hospital, Weimar, Germany
2
Technical University Munich, Munich, Germany,
3
Department of Urology, Nottingham City Hospital, Nottingham, UK
Corresponding author: Reinhard Fünfstück, Prof. Dr., Sophien- und Hufeland-Klinikum Weimar,
Klinik für Innere Medizin I, Henry-van-de-Velde-Straße 2, D-99425 Weimar, Germany
Phone: ++49-3643-571100, Fax: ++49-3643-571102,
email: innere1@klinikum-weimar.de, r.fuenfstueck@klinikum-weimar.de

ABSTRACT predisposing factor such as obstruction,

Epidemiological studies demonstrate an
increasing number of patients suffer-
ing from a progressive deterioration of
renal function. It may be of some inter-
est to know whether infection in the uri-
nary tract (UTI) is more prevalent in such
patients, but it is of considerable impor-
tance to establish if UTI enhances the
rate of renal structural and functional
deterioration. Predisposing factors for UTI
in renal insufficiency include altered host
response and various anatomical and func-
tional abnormalities of the urinary tract
which might be responsible for both renal
damage and infection, e.g. vesicoureteral
reflux, nephro-urolithiasis, obstruction.
UTI in patients with normal kidney
function does not often cause chronic
renal disease in the absence of a major
calculus, reflux, abnormalities of the void-
ing mechanism, or diabetes mellitus. But
a severe acute infection such as pyelone-
phritis or urosepsis may have an adverse
influence on the course of coexisting
chronic kidney disease and enhance the
development of renal failure.
Escherichia coli remains the most com-
mon infecting microorganism. However, a
wide variety of other pathogens can also be
isolated. Urological interventions, cathe-
terization and repeated courses of antibiot-
ics may increase antimicrobial resistance.
The diagnosis of UTI in renal insuffi-
ciency and in dialysis patients is based on
standard clinical and laboratory criteria
but these may need modification: pyuria
is more often observed in patients with
oliguria and therefore of less significance.
Sometimes low bacterial colony counts
 Urinary tract infections in renal insufficiency and dialysis
(<104 CFU/ml) can also be consistent with
clinical infection.
The treatment strategies of UTI in
renal insufficiency and dialysis are based
on the same principles as in patients
with normal renal function. However,
dosages of drugs cleared renally must be
adjusted to the glomerular filtration rate
(GFR). Antimicrobials with the potential
to cause systemic toxicity and specifically
nephrotoxicity (e.g. aminoglycosides,
nitrofurantoin) should be used very criti-
cally. Antibiotics eliminated by the dialy-
sis procedure must be administered at
the end of the dialysis session. There are
no randomised trials on the optimal man-
agement of UTI in renal insufficiency.
Key words: urinary tract infection,
pyelonephritis, renal/kidney insufficiency,
renal dialysis, antibiotic therapy, end
stage renal disease
SUMMARY OF RECOMMENDATIONS
Classification
1. In patients with mild and moderate
renal insufficiency (without olguria)
and with a normal urinary tract, a
lower UTI (cystitis) can be classified
as uncomplicated, because such an
infection has no adverse impact on
renal function.
2. An acute episode of pyelonephritis in
patients with endstage renal disease,
where dialysis is imminent or on-go-
ing, or with significant urinary tract
abnormalities, should be classified as
complicated, because such patients
may be particularly susceptible to
severe urosepsis and hence progres-
sion of renal insufficiency.
Diagnosis
3. The diagnosis of UTI is mainly based
on typical symptoms, bacteriuria and
pyuria, as in patients with normal
renal function. (GoR A)
| 7.5 |
4. It is important to investigate for
specific factors predisposing to UTI
especially for treatable conditions,
e.g. upper urinary tract obstruction,
vesicoureteral reflux, urolithiasis,
polycystic kidney disease, prostatic
disorders (for details see text) (GoR A)
5. Consider co-medication commonly
administered to patients with
chronic renal disease which might
predispose them to UTI e.g. immuno-
suppressive therapy (GoR C).
Treatment
6. The choice of antimicrobial agents is
similar for patients with or without
chronic renal disease (GoR B)
7. Antibiotics with nephrotoxic adverse
effects, should if possible be avoided
but otherwise blood concentrations
must be carefully monitored (GoR B)
8. Drug dosing adjustments are neces-
sary in patients with renal insuffi-
ciency and on hemo- and peritoneal
dialysis treatment. (GoR B)
9. Patients with severe renal disease,
particularly those on dialysis, gener-
ally require longer treatment com-
pared to patients with lesser degrees
of renal impairment (GoR C), but the
optimal duration of treatment is not
known.
10. Treatment of asymptomatic bacte-
riuria (ASB) should be considered in
patients treated with immunosup-
pressive therapy as any infection
might increase the rate of progres-
sion of the renal disease. Otherwise
treatment is not indicated. (GoR C)
11. If symptomatic relapses occur fre-
quently, extended courses of therapy,
or long term suppressive antimicrobial
therapy may be necessary (GoR C).
Very occasionally nephrectomy
(+ ureterectomy) is the only option
to control life threatening recurrent
episodes of pyelonephritis (GoR C).
427
Chapter |7| Urinary tract infections in nephropathies
1. INTRODUCTION
Epidemiological studies demonstrate an
increasing number of patients suffering
from progressive deterioration of renal
function [1] (LoE 3), but it is not known
how many of these patients suffer from
urinary tract infections (UTI). Although
UTI can severely impair renal function,
this is rare in the absence of a major pre-
disposing factor such as obstruction, cal-
culus, reflux, abnormalities of the voiding
mechanism, or diabetes mellitus [2].
Chronic renal disease is rarely caused by
UTI, the rate is less than 1 per 5000 per-
sons per year [3] (LoE 3). In infants and
young children UTI might be expected
to damage the growing kidney. The inci-
dence is certainly higher than in adults
but the level is still modest, at about 1%
[4] (LoE 2a). Other kidney diseases are
responsible for the increasing burden of
end stage renal disease (ESRD) requiring
renal replacement therapy (RRT) reflect-
ing the rising world-wide prevalence of
chronic systemic degenerative vascular
disease and its association with diabetes
Table 1 Incidence rates of different kidney diseases causing end stage renal disease. Results of the German Dialysis Registry
for the years 2000 and 2004 [5].
Kidney diseases
diabetes mellitus type 2 and type 1
renal vascular diseases (due to hypertension and other causes)
glomerular nephropathies
tubulointerstitial nephritis3
polycystic kidneys (adult type dominant)
renal disease caused by systemic diseases (vasculitis, lupus erythem.)
hereditary disease
unknown causes
unclassified renal disease
1
based on 5641 patients
2
based on 6390 patients
3
includes pyelonephritis
428
mellitus and hypertension. Overall the
incidence of ESRD due to glomerular,
tubulointerstitial and toxic nephropathies
remains approximately stable [1, 5]. In
general, renal infectious diseases, such as
chronic pyelonephritis, are summarized
in the tubulointerstitial diseases without
specifying the kind of infection. For 2000
and 2004 the frequencies of ESRD in
Germany are listed in Table 1.
In patients with renal insufficiency
a wide variety of underlying predispos-
ing factors for UTI has to be considered,
such as age, gender, diabetes mellitus,
vesicoureteral reflux, urolithiasis, incon-
tinence, lower urinary tract dysfunction
as in neuropathic disorder, prior instru-
mentation of the urinary tract, polycystic
renal disease, and disturbances of spe-
cific and non specific immune reactions of
the host [3, 6] (LoE 2b). In patients with
ESRD due to obstructive uropathy, pyo-
cystis following urinary diversion, pyone-
phrosis or perinephric abscess, this may
cause recurrent infection, particularly in
the form of urosepsis, if the source cannot
be eliminated completely.
Incidence rate (%)
Year 20001 Year 20042
36 34
15 22
15 12
10 8
6 5
4 4
1 1
9 9
4 5
 Urinary tract infections in renal insufficiency and dialysis | 7.5 |

2. METHODS A total of 421 publications were found

A systematic literature search was per-
formed in the following data bases:
Medline and Medpilot (database of the
publishers Karger, Kluwer, Springer,
Thieme and Cochrane Database of
Systemic Reviews). The following key
words were used: urinary tract infec-
tion (UTI) AND renal diseases, kidney
diseases, renal insufficiency, kidney
insufficiency, dialysis (hemo-/peritoneal
dialysis); antibiotic treatment in renal
insufficiency; estimation of renal func-
tion. The following limitations were
used: humans (female, male); over 19
years old; clinical trials; randomised,
controlled trials; meta-analysis; only
publications with published abstracts.
All publications between 1998 and 2008
were considered and supplemented by a
few earlier key studies considered rel-
evant for this topic.
with these keywords and limitations:
for UTI AND renal/kidney insufficiency
271 in Medline and 13 in Medpilot; for
UTI AND dialysis (hemodialysis/perito-
neal dialysis) 119 in Medline and 18 in
Medpilot. The publications were screened
by title and abstract. Finally 32 publica-
tions were considered valid.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [7–8].
3. CLASSIFICATION AND DEFINITIONS
The typical sign of kidney damage is loss
of renal function. This is diagnosed by
morphological alterations and by altered
biomarkers characterizing kidney disease
(Table 2). All diagnostic steps to diagnose
UTI in renal insufficiency and decisions

Table 2 Biomarkers for kidney damage.

Routine clinical assesment Research assesment

Serum: Urine:
creatinine (and estimation of GFR) Tamm Horsefall protein (THP)
urea Secretory IgA
sodium α1-microglobulin
potassium IgG
acid-base-balance enzymuria, e.g. beta-NAG
glucose asymetric demethyl arginin (ADMA)*
uric acid IL-18*
C-reactiv Protein (CRP) proteomics*
gen polymorphisms of TNF-alpha*
Blood:
monocyte chemoattractant protein-1(MCP-1)*
ESR
leukocytes

Urine:
leukocytes
erythrocytes
proteinuria incl. microalbuminuria

*parameters more typical for glomerulonephritis, only few data available.

429
Chapter |7| Urinary tract infections in nephropathies
Table 3 K/DOQI Staging system for chronic kidney disease [6].
Stage Description
1 kidney damage with normal or increased GFR
2 mild decrease in GFR
3 moderate decrease in GFR
4 severe decrease in GFR
5 kidney failure
for drug administration depend on the
level of renal excretory function. The US
National Kidney Foundation has classi-
fied the degree of chronic kidney diseases
using the K/DOQI Staging System based
on the measurement of GFR [9] (Table 3).
In patients with mild and moderate
renal insufficiency and a normal urinary
tract lower UTI (cystitis) can be classi-
fied “uncomplicated”, because such an
infection has no adverse impact on renal
function. However, any kind of severe
infection, such as an acute episode of
pyelonephritis or uroseptic syndrome,
or UTI in patients with endstage renal
disease, undergoing dialysis and with
urinary tract abnormalities, such as
obstruction, reflux, polycystic disease,
urolithiasis, unstable metabolism e.g. due
to diabetes mellitus, should be classified
as “complicated”, because progression of
renal insufficiency may be promoted.
4. PATHOGENESIS
4.1 Uropathogens
There are only few studies evaluating
the uropathogens found in patients with
renal insufficiency or undergoing dialysis.
E. coli remains the most common infect-
ing organism. A wide variety of other
bacteriae, such as Proteus mirabilis,
Pseudomonas aeruginosa, Enterobacter
spp., staphylococci and enterococci may be
isolated in these patients [10–13] (LoE 3).
Nosocomial exposure, urological inter-
ventions and catheterizations in combi-
430
GFR/ml per minute per 1.73 m2
> = 90
60-89
30-59
15-29
<15 or dialysis
nation with repeated courses of antimi-
crobial therapy will increase the risk of
overgrowth of organisms with increased
antimicrobial resistance. There are no
studies characterizing the virulence
properties of uropathogens, comparing
patients with or without renal insuffi-
ciency or dialysis, respectively.
4.2 Host defence in renal
insufficiency
It is commonly accepted that the immune
status of patients with chronic renal dis-
ease and ESRF is compromised. One
measurable effect is of leucocyte dysfunc-
tion. This may favour infections in general
[6, 13–14], but has not been shown specifi-
cally to promote UTI. The activity of the
hexose monophosphate shunt pathway in
phagocytosis released respiratory burst is
disturbed [6, 15] (LoE 2b). Phagocytes not
only have the capacity to kill and destroy
bacteria but they also produce cytokines
and activate other components of the
immune system such as lymphocyte sub-
populations. Alteration of granulocyte
function, such as impairment of migra-
tion, chemotaxis, degranulation and block-
ade of glucose uptake will potentially
promote colonisation of the urinary tract
and host invasion. These factors also have
an inverse relationship with the degree of
renal insufficiency [13]. It is not known,
to what extent in chronic renal diseases
the virulence of uropathogens is influ-
enced by urinary variations of substances,
such as secretory IgA, Tamm-Horsfall
 Urinary tract infections in renal insufficiency and dialysis
protein (THP), β-defensine 1, which nor-
mally inhibit bacterial adherence.
5. DIAGNOSIS
The diagnosis of UTI is mainly based on
typical symptomatology and quantitation
of urinary bacteria and leucocytes (i.e.
pyuria) or surrogate parameters, such as
leucocyte esterase and nitrite reaction.
The criteria to diagnose UTI in patients
with renal insufficiency are similar to
those used in patients with normal renal
function, but it is necessary to point out
some peculiarities.
The typical clinical symptoms of UTI
can overlap with symptoms associated
with kidney related diseases. Pain of
cystitis or of pyelonephritis can be toned
down or intensified by complication of
uremic neuropathy (IV).
Guidelines in which pyuria is defined by
a white blood cell count of 10 per high field,
can generally be applied to the diagno-
sis of UTI in renal insufficiency. However,
31–53% of dialysis patients have pyuria
but no UTI [16–18] (LoE 3). Urinary leuco-
cyte count is broadly inversely proportional
to the urine volume [16–19] (LoE 2a).
This may be due to increased concentra-
tion of a constant number of leucocytes
secreted from the urothelial surfaces. On
the other hand dilution can also cause
misleading reduction in bacterial colony
counts and negative assessment of nitrites
on the “Multistix” dip test. Therefore in the
patient with symptoms suggestive of UTI it
is essential not to rely on stick testing but
always perform urinary culture and accept
that a count of <100,000 cfu/ml can be
pathological, particularly if a single organ-
ism is cultured and leucocytes are present.
Contamination can be suspected if
three or more microorganisms are found
simultaneously in the urine culture or
if numerous squamous epithelial cells
are detected on urinalysis [20] (LoE 3).
Lactobacilli, staphylococci (coagulase-neg-
ative), corynebacteria and streptococci are
| 7.5 |
microorganisms that are usually respon-
sible for contamination. In contamina-
tion, bacterial colony counts are usually
lower than if microorganisms are invasive
[17] (LoE 4). Colonization of the urinary
tract is defined as replication of microor-
ganisms in the urine, not accompanied by
invasion of the adjacent epithelial or sub-
epithelial tissue. These situations depend
on the host defence, which may be altered
in renal insufficiency, a possible reason
for the increased prevalence of asymp-
tomatic bacteriuria in these patients.
Bacteruria must be interpreted according
to the underlying clinical condition.
Some patients with renal insufficiency
and transient “significant” bacteriuria may
not have true infection [17, 19] (LoE 3), but
in others even a low bacterial colony count
with pyuria may represent true infection
[19, 21] (LoE 3). The clinical significance
of specific levels of bacteriuria and pyuria
in patients with decreasing renal function
and in dialysis patients may only be deter-
mined by prospective studies with long
term follow-up.
Recommendations for the diagnosis of
UTI in renal insufficiency are summa-
rized in Table 4. The standard clinical
and laboratory findings are usually suffi-
cient to characterize UTI including unde-
tected urological disease, e.g. urolithiasis,
upper and lower tract obstruction, poly-
cystic renal disease, and to estimate the
degree of renal insufficiency. Intravenous
urography has been mainly superseded
by high definition modern ultrasound,
ultrathin section CT and MRI but it is
probably contraindicated in patients with
CRF due to potential nephrotoxicity of IV
contrast [22] (LoE 2b).
6. TREATMENT
Effective treatment of UTI requires high
antimicrobial concentration in urine.
This is usually achieved as many antimi-
crobials are excreted mainly by glomeru-
lar filtration and tubular secretion [23]
431
Chapter |7| Urinary tract infections in nephropathies
Table 4 Recommendations for the diagnosis of UTI in renal insufficiency.
History
Clinical symptoms
Physical examination
Urological examination: e.g.
uroflowmetry, urodynamics
Imaging:
ultrasound, computer tomography, magnet resonance imaging, DMSA-scan, sometimes micturition
cystourethrography (MCUG)
(LoE 1a). The diseased kidney, however,
is insufficiently perfused, therefore lower
urinary antimicrobial concentrations are
achieved. This can apply irrespective
of the urine volume in stages 4 and 5 of
renal failure due to chronic renal disease
and in patients with acute renal failure.
6.1 Treatment strategies and
dosage adjustment
Generally the treatment strategies of
UTI in renal insufficiency are based on
the same principals as in patients with
normal renal function [24–25] (LoE 4).
UTI should respond rapidly, without
recurrence, nor emergence of resistant
pathogens.
Acute and chronic kidney diseases can
affect glomerular blood flow and filtra-
tion, tubular secretion and reabsorption,
as well as renal bioactivation and metab-
olism. Drug absorption, bioavailability,
protein binding, distribution volume, and
non-renal clearance (metabolism) can be
altered in renal insufficiency as well as
in hemo- and peritoneal dialysis [26–27].
Drug dosing errors are common in these
patients and can cause adverse effects
and poor outcome [28–29].
Most patients with early chronic renal
failure have normal or increased urine
volumes (stage 1 and 2/ K/DOQI-Staging
432
Routine laboratory measurements:
•  C-reactive protein (CRP)
•  erythrocyte sedimention rate 
•  leukocytes
•  Urine:
leucocyturia, bacteriuria
Research assessment:
THP, sIgA, NAG, ACB test,
Adhesion of uropathogens on uroepithelial cells
system). Oliguria only occurs terminally
on dialysis and in acute renal failure.
In this context oliguria however, is com-
bined with reduced ability to concen-
trate urine (stage 3,4,5/K/DOQI-Staging
system). This pathophysiology has also
direct implication for antibiotic therapy
(see below).
Dosage of drugs cleared renally should
be adjusted according to GFR as usually
determined by creatinine clearance [30]
(LoE 1a) The calculation of renal func-
tion is only valid in a stable situation and
with a constant serum creatinine con-
centration. The K/DOQI clinical practice
guidelines advocates using the traditional
Cockroft-Gault equation rather than the
Modification of Diet in Renal Disease
(MDRD) study equation for routine esti-
mation of GFR [9] (LoE 1a). However, In
patients with a GFR lower than 60 ml per
minute per 1.73 m2 and lower than 90 ml
per minute per 1.73 m2 in older patients,
the MDRD equation is superior to the
Cockroft-Gault equation [31] (LoE 1 a).
Many antimicrobial agents are elimi-
nated renally and require dosing adjust-
ment. Detailed publications, nomograms
and electronic calculators are available for
dose adjustments of antibiotics in patients
with chronic kidney disease and on long
term dialysis treatment. For some antibi-
otics depending on the pharmacological
 Urinary tract infections in renal insufficiency and dialysis | 7.5 |

properties a loading dose and maintenance
dosing are recommended [30, 32] (LoE
1a). Dosing adjustments in patients with
chronic renal failure for antibiotics gener-
ally used for treatment of UTI are shown
in Table 5. Dialysis treatment requires spe-
cial attention with regard to dose schedul-
ing and the possible need for supplemental
dosing for agents substantially cleared by
dialysis. The dialysability of drugs depends
on the molecular weight, water solubility
and degree of protein binding as well as
the kind of dialysis treatment.
For general information some exam-
ples for dialysability of antimicrobial sub-
stances undergoing hemodialysis are listed
in Table 6. The dialysability of drugs,
however, depends also on the techniques
of extracorporal treatment (hemodialysis,
hemofiltration, hemodiafiltration) and the
type of dialyzer (membrane type, hydraulic
permeability, biocompatibility profile). In
peritoneal dialysis the treatment modal-
ity (continuous technique, tidal dialysis,
nightly peritoneal dialysis) also influences
the drug levels. The effective antibiotic
dosage is dependent on the clinical state of
the patient and the dialysis strategy. Often
it is difficult to adjust the correct doses
except by carefully timed and interpreted
blood measurement. In general, antibiot-
ics eliminated by the dialysis procedure
have to be administered after the dialysis
process.

Table 5 Antimicrobial agents: Dosing requirements in patients with chronic renal failure.

Dosage adjustment in percentage of usual dosage

(based on GFR ml/min./1,73 m2)

Drug Usual dosage >50 50-10 <10

Ciprofloxacin 400 mg i.v. 100% 50-75% 50%

500 to 750 mg
orally every 12 hours

Levofloxacin 250 to 750 mg 100% 500 to 750 mg init. dose 500 mg init. dose
every 24 hours then 250 to 750 mg every than 250 to 500
24 hours every 48 hours

Gatifloxacin 400 mg every 24 hours 100% 400 mg initially, then 400 mg initially, then
200 mg dialy 200 mg

Amoxicillin 250 to 500 every 8 hours every 8 hours every 8 hours every 24 hours

Ampicillin/ 1 to 2 g ampicillin and 100% every 12 hours every 24 hours (GFR

Sulbactam 0,5 to 1 g Sulbactam every (GFR 15 to 29) 5 to 14)
(GFR >30)
6 to 8 hours

Cefaclor 250 to 500 mg every 8 hours 100% 50 to 100% 50%

Cefmandole 0,5 to 1 g every 4 to 8 hours every 6 hours every 6 to 8 hours every 8 to 12 hours

Cefazolidine 0,25 to 2 g every 6 hours every 8 hours every 12 hours 50% every 24 to 48
hours

Cefotaxime 1 to 2 g every 6 to 12 hours every 6 hours every 12 hours every 24 hours or

50%

Cefixime 200 mg every 12 hours 100% 75% 50%

Trimethoprim 100 mg every 12 hours every 12 hours every 12 hours (GFR >30%); every 24 hours
every 18 hours (GFR 10 to
30%)

(according to M.Y. Munar et al [23]).

433
Chapter |7| Urinary tract infections in nephropathies
Table 6 Dialysability of antimicrobial agents in patients undergoing haemodialysis treatment [32].
Cleared* Partially cleared*
Ampicillin Quinolones
Cephalosporin Cotrimoxazole
Aminoglycoside
Trimethoprim
*by dialysis procedure.
6.2 Choice of antibiotic
The choice of antibiotic depends on the
severity of the symptoms, the causative
microorganisms, the level of renal dis-
ease and whether complicating factors
are present.
Substances with nephrotoxic side
effects, e.g. aminoglycosides, should be
used with caution. Antibiotics without
cumulative effects and wide therapeutic
range index are preferred. Broad spec-
trum cephalosporins and fluoroquinolo-
nes may be effective and are the drugs
of choice in this setting [33–34] (LoE 4).
Nitrofurantoin should be avoided in
renal failure as the drug is not excreted
and toxic serum concentration may lead
to peripheral neuropathy [13]. Patients
with diminished renal function are also
susceptible to the nephrotoxic effects of
particular drug combinations e.g. cepha-
losporins with furosemide or ethacrynic
acid [35]. Some antibiotics cause eleva-
tion of the serum creatinine by mecha-
nisms other than direct nephrotoxicity.
Trimethoprim can inhibit tubular secre-
tion of creatinine. Tetracycline has an
antianabolic effect in renal failure and
is best avoided but doxycycline may be
used if there is a definite indication,
e.g. urethritis [36]. No other antimicro-
bials are specifically contraindicated in
renal insufficiency and in dialysis popu-
lations, although dosage adjustments
appropriate to the level of renal impair-
ment will usually be necessary [23]
(LoE 1a).
434
Not cleared*
Methicillin
Teicoplanin
6.3 Asymptomatic bacteriuria
High frequency of asymptomatic bacte-
riuria, ranging from 27–44% has been
reported in patients with chronic renal
failure with and without haemodialy-
sis [17]. It is difficult to determine its
specific cause because of the wide vari-
ety of underlying renal diseases, lack
of information on prior instrumenta-
tion of the urinary tract and/or poor
response to antimicrobial therapy.
Patients with progressive renal disease
for whom immunosuppressive agents
are part of the standard treatment pro-
tocol, e.g. nephrotic syndrome, some
types of glomerulonephritis, and oth-
ers whose immune responses are likely
to be severely impaired, asymptomatic
bacteriuria should probably be treated
[37–38] (LoE 4) (GoR B). Otherwise it
is not recommended (LoE 4) (GoR B).
However, there is no evidence that clear-
ance of bacteriuria is beneficial in terms
of slowing down the rate of progression
of deteriorating renal function.
6.4 Duration of therapy
There are no published data from ran-
domised trials determining the optimal
duration of treatment of UTI in renal
insufficiency and in dialysis patients.
It is customary to treat even uncompli-
cated cystitis for at least seven days and
continue for 21 days or more, accord-
ing to clinical severity and the pres-
ence or otherwise of a uropathy [14, 24]
 Urinary tract infections in renal insufficiency and dialysis
(LoE 4). However, the response to even
longer courses of antibiotics in higher
dosage may only be transitory. Even
when the concentration of antibiotic in
urine excreted from the diseased kidney
is adequate, infection may not be eradi-
cated leading to a relapse once antimi-
crobial treatment is discontinued. If
symptomatic relapses occur frequently,
extended courses of therapy of six to 12
weeks duration, or long term suppressive
therapy are recommended but may still
be ineffective [31] (LoE 4). Relapses pre-
sumably occur due to bacterial regrowth
from colonies of non-planktonic bacteria
residing in a protected biofilm environ-
ment which has developed deep within
damaged renal parenchymal or urothe-
lial tissue, or alternatively from intrac-
ellular communities of organisms living
temporarily as commensals and selected
by antibiotic therapy in the extracellular
milieu.
Ultimately the only available option
is surgical excision of diseased tissues.
Bilateral nephrectomy is still very occa-
sionally performed in patients with
incurable relapsing pyelonephritis and
end-stage renal failure due to a vari-
ety of uropathies, particularly terminal
stone disease, scarred kidneys associ-
ated with reflux, congenital obstruction
and adult polycystic disease. Very rarely,
in the context of chronic renal failure,
infection really does seem to be lateral-
ised and the response to antibiotics of
each recurring episode is substandard.
Because of the decreased perfusion of
the affected kidney, the urinary antimi-
crobial concentration is low unilaterally
and the beneficial effect is not sustained.
The concentration may seem adequate
in urine from the bladder but this
merely reflects excretion from the better
functioning kidney. However, just as in
patients with normal function and uni-
lateral renal disease, relapsing UTI does
not necessarily originate from a focus in
the affected kidney and therefore may
| 7.5 |
not be cured by nephrectomy. Sometimes
sampling and culture of urine specimens
obtained by retrograde catheterisation
can be helpful though the result is rarely
unequivocal.
7. FURTHER RESEARCH
The contemporary knowledge on many
aspects of UTI in patients with renal
insufficiency and/or on dialysis remains
incomplete. The populations are not
homogeneous and many factors influence
the deterioration of kidney function. The
specific properties of the infecting micro-
organisms, their geno- and phenotypical
clusters (e.g. presence of fimbriae, alpha
hemolysin, cytotoxic necrotizing factor)
as well as the efficacy of the systemic
and local host defence mechanisms (e.g.
phagocytosis and bacterial killing activ-
ity of granulocytes depending on uremic
situation, production of Tamm-Horsfall
glycoprotein, attachment capacity of
uroepithelial cells) are potentially signifi-
cant but their relative contributions to
the disease process need better clarifica-
tion. Also, any studies submitted for pub-
lication on patients with UTI and renal
insufficiency and/or on dialysis require
complete characterization of the popula-
tion under scrutiny for the complexity
of this multifactorial disease to be prop-
erly understood. Finally, the outcome and
management of UTI needs to be defined
separately for each category of renal
functional impairment (K/DOQI stag-
ing system), if improvements in recom-
mendations for diagnosis and treatment
of UTI in chronic renal failure are to be
effective.
8. CONCLUSIONS
There is no evidence that lesser degrees
of clinical UTI (e.g. cystitis in a mild or
moderate renal insufficiency and with a
435
Chapter |7| Urinary tract infections in nephropathies
normal urinary tract) or asymptomatic
bacteriuria increase the rate of neph-
ron loss. However, any kind of severe
infection, such as an acute episode of
pyelonephritis or urosepsis, or any UTI
in patients with ESRD, undergoing dialy-
sis and with urinary tract abnormalities,
such as obstruction, reflux, polycystic dis-
ease, urolithiasis, unstable metabolism
e.g. due to diabetes mellitus, should be
classified as “complicated”, because pro-
gression of renal insufficiency may be
promoted. Antibiotics excreted mainly by
the kidney require adjustment of the dose
depending on the degree of renal insuffi-
ciency. No prospective clinical trials are
available to determine the optimal man-
agement of UTI in patients with renal
insufficiency or in the dialysis population.
REFERENCES
1. Stengel B, Billon S, Van Dijk PC, Jager
KJ, Dekker FW, Simpson K, and Briggs
JD, Trends in the incidence of renal
replacement therapy for end-stage renal
disease in Europe, 1990–1999. Nephrol
Dial Transplant, 2003. 18(9): 1824–33.
2. Kunin CM, Does kidney infection cause
renal failure? Annu Rev Med, 1985. 36:
165–76.
3. Smith JW, Prognosis in pyelonephritis:
promise or progress? Am J Med Sci, 1989.
297(1): 53–62.
4. Sreenarasimhaiah S and Hellerstein
S, Urinary tract infections per se do not
cause end-stage kidney disease. Pediatr
Nephrol, 1998. 12(3): 210–3.
5. Frei U and Schober-Halstenberg H-J,
Nierenersatztherapie in Deutschland.
Bericht über Dialysebehandlung und
Nierentransplantation in Deutschland
2000 und 2004. Quasi-Niere GmbH. .
2001; 38 & 2006; 11.
6. Ringoir S and Vanholder R, Phagocytic
function in the uremic patient. Contrib
Nephrol, 1992. 100: 15–24.
7. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
436
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
9. K/DOQI clinical practice guidelines for
chronic kidney disease: evaluation, clas-
sification, and stratification. Am J Kidney
Dis, 2002. 39(2 Suppl 1): S1–266.
10. Vaziri ND, Cesarior T, Mootoo K, Zeien L,
Gordon S, and Byrne C, Bacterial infec-
tions in patients with chronic renal fail-
ure: occurrence with spinal cord injury.
Arch Intern Med, 1982. 142(7): 1273–6.
11. Kaminska W, Patzer J, and Dzierzanowska
D, Urinary tract infections caused by
endemic multi-resistant Enterobacter
cloacae in a dialysis and transplantation
unit. J Hosp Infect, 2002. 51(3): 215–20.
12. Szczepanska M, Szprynger K, and
Adamczyk P, [Effect of urinary tract infec-
tions in children with chronic renal fail-
ure on peritoneal dialysis]. Pol Merkur
Lekarski, 2004. 16(93): 223–7.
13. Stein G, Eichhorn T, and Fünfstück
R, Urinary tract infections in patients
with renal insufficiency. Nieren- and
Hochdruckkrankh, 2007. 36: 288–291.
14. Sobel JD, Pathogenesis of urinary tract
infection. Role of host defenses. Infect Dis
Clin North Am, 1997. 11(3): 531–49.
15. Vanholder R, Ringoir S, Dhondt A, and
Hakim R, Phagocytosis in uremic and
hemodialysis patients: a prospective and
cross sectional study. Kidney Int, 1991.
39(2): 320–7.
16. Saitoh H, Nakamura K, Hida M, and
Satoh T, Urinary tract infection in oligu-
ric patients with chronic renal failure.
J Urol, 1985. 133(6): 990–3.
17. Chaudhry A, Stone WJ, and Breyer JA,
Occurrence of pyuria and bacteriuria in
asymptomatic hemodialysis patients. Am
J Kidney Dis, 1993. 21(2): 180–3.
18. Eissinger RP, Asghar F, Kolasa C, and
Weinstein MP, Does pyuria indicate infec-
tion in asymptomatic dialysis patients?
Clin Neph 1997. 47: 50–51.
19. Hyodo T, Yoshida K, Sakai T, and Baba
S, Asymptomatic hyperleukocyturia in
hemodialysis patients analyzed by the
 Urinary tract infections in renal insufficiency and dialysis
automated urinary flow cytometer. Ther
Apher Dial, 2005. 9(5): 402–6.
20. Persson PB, Hansell P, and Liss P,
Pathophysiology of contrast medium-
induced nephropathy. Kidney Int, 2005.
68(1): 14–22.
21. Hellerstein S, Long-term consequences
of urinary tract infections. Curr Opin
Pediatr, 2000. 12(2): 125–8.
22. Marenzi G, Marana I, Lauri G, Assanelli
E, Grazi M, Campodonico J, Trabattoni D,
Fabbiocchi F, Montorsi P, and Bartorelli
AL, The prevention of radiocontrast-
agent-induced nephropathy by hemofil-
tration. N Engl J Med, 2003. 349(14):
1333–40.
23. Munar MY and Singh H, Drug dosing
adjustments in patients with chronic
kidney disease. Am Fam Physician, 2007.
75(10): 1487–96.
24. Nicolle L, Best pharmacological practice:
urinary tract infections. Expert Opin
Pharmacother, 2003. 4(5): 693–704.
25. Wagenlehner FM and Naber KG,
Treatment of bacterial urinary tract
infections: presence and future. Eur Urol,
2006. 49(2): 235–44.
26. Livornese LL, Jr., Benz RL, Ingerman
MJ, and Santoro J, Antibacterial agents
in renal failure. Infect Dis Clin North Am,
1995. 9(3): 591–614.
27. Burkhardt H, Hahn T, Gretz N, and
Gladisch R, Bedside estimation of the
glomerular filtration rate in hospitalized
elderly patients. Nephron Clin Pract,
2005. 101(1): c1–8.
28. Scheen AJ, Medications in the kidney.
Acta Clin Belg, 2008. 63(2): 76–80.
29. Bouvier d`Yvoire MJY and Maire PH,
Dosage regimens of antibacterials. Clin
Drug Invest, 1996. 11: 229–239.
| 7.5 |
30. Aronoff GR, Drug prescribing in renal
failure : dosing guidelines for adults. 4th
ed. 1999, Philadelphia, PA.: American
College of Physicians. 176 p.
31. Poggio ED, Wang X, Greene T, Van Lente
F, and Hall PM, Performance of the
modification of diet in renal disease and
Cockcroft-Gault equations in the estima-
tion of GFR in health and in chronic
kidney disease. J Am Soc Nephrol, 2005.
16(2): 459–66.
32. Swan SK and Bennett WM, Drug dosing
guidelines in patients with renal failure.
West J Med, 1992. 156(6): 633–8.
33. Williams DH and Schaeffer AJ, Current
concepts in urinary tract infections.
Minerva Urol Nefrol, 2004. 56(1): 15–31.
34. Naber KG, Experience with the new
guidelines on evaluation of new
anti-infective drugs for the treat-
ment of urinary tract infections. Int J
Antimicrob Agents, 1999. 11(3–4):
189–96; discussion 213–6.
35. Ammon HPT, Arzneimittelneben- und
-wechselwirkungen : ein Handbuch und
Tabellenwerk für Ärzte und Apotheker.
4., neu bearbeitet und erw. Aufl. ed.
2001, Stuttgart: Wissenschaftliche
Verlagsgesellschaft. xiii, 1738 p.
36. Levy J, Morgan J, and Brown EA, Oxford
handbook of dialysis. 2nd ed. Oxford
handbooks. 2004, Oxford; New York:
Oxford University Press. xxx, 903 p.
37. Chan TM, Preventing renal failure in
patients with severe lupus nephritis.
Kidney Int Suppl, 2005(94): S116–9.
38. Javaid B and Quigg RJ, Treatment
of glomerulonephritis: will we ever
have options other than steroids and
cytotoxics? Kidney Int, 2005. 67(5):
1692–703.
437
|7.6|
Urogenital infections in renal
transplant patients – causes and
consequences
Daniel A. Shoskes, Ismail R. Saad
Corresponding Author: Daniel Shoskes MD, Professor of Surgery, Cleveland Clinic Lerner College of Medicine, Director,
The Novick Center for Clinical and Translational Research, Glickman Urological and Kidney Institute, The Cleveland Clinic,
9500 Euclid Ave, Desk Q10-1, Cleveland, OH USA, 44195
ABSTRACT
Urinary tract infection (UTI) is the most
common infectious complication following
kidney transplantation. The incidence
in adults is about 20% in the first six
months and 50% in the first three years,
despite the common use of antibiotic
prophylaxis. Risk factors include more
intensive immunosuppression (especially
the use of depleting induction antibodies
and sirolimus), extremes of age, diabe-
tes, prolonged time on dialysis, abnormal
or reconstructed lower urinary tract and
prolonged use of urinary catheters and
stents. Diagnosis may be complicated by
other conditions causing urinary symp-
toms and fever in transplant recipients,
as well as immunosuppression mask-
ing the typical presentation and lack
of symptoms in a denervated kidney.
Infection may involve the graft or native
kidneys. Typical uropathogens are com-
monly involved but UTI’s may also be
caused by commensal and fastidious bac-
teria, fungus, mycobacteria and viruses.
Some studies suggest post transplant
UTI has a negative impact on graft sur-
vival and function, although causality
has not been established. There is a pau-
city of prospective controlled data that
can guide UTI prophylaxis or therapy in
terms of agent or duration although most
programs will routinely use prophylaxis
for at least six months.
Key words: kidney, transplant urinary
tract infection, bacteriuria
SUMMARY OF RECOMMENDATIONS
1. Antimicrobial prophylaxis following
renal transplantation reduces the
 Urogenital infections in renal transplant patients
incidence of urinary tract infection in
the first six months (GoR B)
2. While there are kidney and recipient
factors that increase the risk of UTI
post transplant, the value of more
intensive or greater duration prophy-
laxis is unproven (GoR C)
3. Post transplant UTI risk can be
reduced by early removal of urinary
foreign bodies (Foley catheter, ure-
teral stent) (GoR C)
4. Asymptomatic bacteriuria post kid-
ney transplant does not require
therapy beyond standard prophylaxis
(GoR C)
5. Therapy of post transplant UTI
should be guided by culture, sen-
sitivities and antibiotic charac-
teristics, favoring bacteriocidal
antibiotics with good tissue pene-
tration (e.g. sulfa drugs, quinolones)
rather than bacteriostatic antibi-
otics with poor tissue penetration
(e.g. nitrofurantoin) (GoR C)
1. INTRODUCTION
Kidney transplantation has witnessed
major advances in surgical techniques
and immunosuppression. Urinary tract
infection (UTI) is the most common infec-
tious complication following kidney trans-
plant [1]. UTI is a potential source of
severe systemic illness. However, its con-
tribution to permanent graft dysfunction
remains controversial.
This chapter aims at discussing the
classification, epidemiology and pathogen-
esis of UTI in renal transplant recipients.
Risk factors for UTI following transplan-
tation will be examined in terms of host,
graft, anatomical factors and timing. UTI
in the pediatric transplant patient will be
discussed considering that ESRD in this
age group is commonly related to ana-
tomical abnormalities and a history or
recurrent UTI.
| 7.6 |
2. METHODS
The consensus was reached after a
systematic Pubmed review of reports
published in last 20 years using the fol-
lowing keywords: kidney or renal, trans-
plantation, complications, (urinary tract
infection, or bacteriuria). This search
yielded 1343 articles of which 155 were
review articles. The studies were rated
according to the level of evidence (LoE)
and the grade of recommendation (GoR)
using ICUD standards (for details see
Preface) [2–3].
3. DEFINITIONS IN POST
TRANSPLANT UTI
The post transplant UTI literature has
contributions from many fields outside of
Urology and unfortunately the definition
of UTI can vary significantly. By strict
criteria, the presence of bacteria within
the urinary tract is bacteriuria. A uri-
nary tract infection requires pathological
invasion of the urothelium with microor-
ganisms resulting in tissue injury and an
inflammatory response. This inflamma-
tory response, which may be local and/or
systemic, produces the clinical syndrome
of infection. Common signs and symp-
toms of UTI may be mimicked by normal
post-transplant conditions (e.g. red and
white cells in the urine from a urinary
stent, urinary frequency from a small
defunctionalized bladder) or absent due
to therapy (e.g. fever suppressed by ster-
oids, minimal tenderness in a denervated
kidney). In reviewing the transplant lit-
erature, it is important to distinguish
articles that define UTI as bacteriuria,
symptoms alone or a combination.
Another issue is the diagnostic thresh-
old for a positive culture. Most labs will
report a positive urine culture with bac-
terial counts of at least 105 bacteria per
ml of fresh unspun midstream urine.
This definition is handed to us from stud-
ies in the 1970’s of college age females
439
Chapter |7| Urinary tract infections in nephropathies
which tried to find an appropriate cutoff
to diagnose pyelonephritis in the absence
of lower urinary tract symptoms. Clearly,
in a symptomatic patient, 102 bacteria
per ml is a sufficient threshold that does
not overly increase false positives, and in
transplant patients for whom the diagno-
sis of UTI may be equivocal the lab must
be asked to provide the actual numerical
bacterial count and not merely to report
“no significant growth” [4]. Conversely,
in a patient with a Foley catheter, urine
may have counts over 1010 and not be
infected.
Finally, the classification and defini-
tions of repeat UTI give important etio-
logic information in transplant recipients.
Repeat infections may be unresolved
(remain active during therapy), persist-
ent (resolve with therapy but recur soon
after with the same bacteria) or recur-
rent (resolve with therapy; recur a vari-
able time later with different bacteria).
Unresolved UTI’s usually indicate wrong
antibiotic choice or multiple organisms.
However, in immunosuppressed patients
consideration should also be given to
antibiotic action, since bacteriostatic
antibiotics may be insufficient to cure
the infection since the immune system
cannot eradicate the dormant bacteria.
Recurrent UTI’s often point to bacterial
re-introduction, often in women follow-
ing intercourse however in transplant
recipients it may point to over-immuno-
suppression. Persistent infections are
usually a clue to an unresolved bacterial
nidus and in transplant patients should
prompt a search for foreign bodies, inef-
ficient bladder emptying or a source from
the native kidneys (e.g. reflux, polycystic
kidney disease).
4. EPIDEMIOLOGY
4.1 Incidence
Thirty years ago, 60% of kidney trans-
plant recipients developed at least one
440
serious infection during the first year
post-transplant, with mortality rates
approaching 50% [5]. The current infec-
tion-related one-yr mortality has been
reduced to less than 5%. Nevertheless,
UTI’s are still common and while sel-
dom leading to death can produce signifi-
cant morbidity and possibly impact graft
survival.
Most articles addressing UTI incidence
after transplant are limited by being sin-
gle center with small numbers and mix
time of follow up, method of diagnosis
and hospitalized vs. outpatient records
(LoE 3). In studies of post transplant
infections, UTI was the most common at
about 45% [6]. In a study of 500 patients
from two centers, the incidence of UTI
was 43% within 42 months [7]. In the one
study that examined a large database
(USRDS with Medicare billing codes from
1996 to 2000), the cumulative incidence
of UTI during the first six months after
renal transplantation was 17% (equiva-
lent for men and women) [8]. At three
years the incidence was 60% for women
and 47% for men.
The rate of asymptomatic bacteriuria
post transplant shows great variation
between reports (4% to 60%) [9]. Early
studies report that up to 90% of post-
transplant UTIs were asymptomatic and
diagnosed only on the basis of culture
[10]. Graft and patient survival were
not found to be significantly affected by
asymptomatic bacteriuria in the absence
of other complications [11] (LoE 3).
Since it is standard practice to use
antimicrobial prophylaxis periopera-
tively for the wound (cephalosporins
in our program) and long term against
Pneumocystis pneumonia (Trimethoprim-
sulphamethoxazole [TMP-SMZ]), most
of the infections within 6 months were
almost certainly “breakthrough infec-
tions” with resistant strains. The inci-
dence of UTI post transplant without any
antibiotic use is unknown, although one
early study found 50% of patients with-
out prophylaxis developed a UTI during
 Urogenital infections in renal transplant patients
the hospital admission [10]. While we
presume that prophylaxis is of benefit, we
don’t know whether therapy in addition
to routine wound and lung prophylaxis,
especially in high risk patients reduces
UTI rates.
4.2 Timing
Historically, patients were at the high-
est risk for UTI in the first postoperative
month [12]. Recent literature indicates
fewer UTI’s in the early post transplant
period with one study finding 13% in the
first month, 75% between two and six
months and 32% after six months [13].
Late onset UTIs (occurring > 6months
post transplant) were believed to have a
benign outcome leading some transplant
centers to stop prophylaxis six months
after transplantation [14]. The previ-
ously mentioned USRDS study found late
onset UTI associated with increased inci-
dence of death and graft loss [8]. It was
not clear whether UTI were a cause of
this complications or whether they were
a marker for other comorbid conditions or
of over-immunosuppression.
5. ETIOLOGY AND RISK FACTORS
A combination of etiologies may account
for UTI following renal transplan-
tation. The pathogenesis is usually
multifactorial.
5.1 Patient factors
Age correlates with post transplant UTI’s
in a bimodal distribution, with the high-
est incidences in childhood and the eld-
erly. In the USRDS retrospective review
of Medicare claims of adult recipients,
age was found to be independently asso-
ciated with late UTIs (> six months fol-
lowing renal transplantation) in men
>55 years when compared with <55 years
[8]. Chuang et al reported that 55% of
the patients who were 65 years or older
at transplantation vs. 38% of patients
| 7.6 |
who were younger than 30 years at
transplantation developed post-trans-
plant UTIs [7]. Older patients may be at
higher risk due to inefficient voiding as
a result of poor bladder contractility (e.g.
diabetic cystopathy), outflow obstruc-
tion (e.g. prostatic hypertrophy) or over-
immunosuppression.
Pediatric renal allograft recipients
represent a special population with
respect to UTI. In this group, ESRD
is more likely to be the result of uri-
nary tract malformations or dysfunc-
tion. Abnormal lower urinary tracts are
present in up to 25% of children with
renal failure which is more common than
in adults. John et al, in their retrospec-
tive review of three centers found a UTI
rate of 36% (median time one year) and
28% of patients had recurrent UTI [15].
Even in pediatric patients with neph-
rological disease requiring renal trans-
plant there is a high incidence of lower
urinary tract symptoms and post trans-
plant UTI.
Gender is a UTI risk factor post trans-
plant and females are more likely to
develop graft pyelonephritis. In the
report by Chuang et al, 68% of the female
transplant patients vs. 30% of the male
transplant patients had at least one UTI
post-transplant with 71% of patients
with recurrent post-transplant UTI being
females [7]. In children however, boys are
more likely to develop post transplant
UTI [8] (LoE 3).
Comorbid conditions such as diabetes
mellitus (DM) may impact the frequency
of infections post transplant particularly
UTI [11] (LoE 3). DM recipients had
higher readmission rate due to infections
(45% vs. 32%) [16] and an increased risk
of fungal UTI [17].
Prolonged ESRD with dialysis pre-
transplant has also been correlated with
higher risk of UTI in renal transplant
recipients [8]. This might be related to a
higher incidence of complicated UTI in
recipients who had been anuric prior to
transplant [18].
441
Chapter |7| Urinary tract infections in nephropathies
Increased bacterial colonization and
bacteriuria are common in patients
transplanted into a reconstructed lower
urinary tract, but negative sequelae are
rare. In a recent case control study of
children with augmentation cystoplasty,
bacteriuria was more common than in
recipients with normal bladders (83%
vs. 17%) but graft survival and renal
function was the same [19]. Similarly,
in a study of patients transplanted into
an ileal conduit, symptomatic UTI’s
developed in 65% (their usual incidence
was not quoted) but there was no excess
graft loss or death as a result. Finally,
the use of clean intermittent catheteri-
zation following transplant is not asso-
ciated with excess UTI, graft loss or
patient death [20].
Summary Recipient-Related Risk
Factors
• UTI is the most common infec-
tious complication following renal
transplantation (LoE 3).
• Age extremes (children and elderly)
are associated with higher rates of
post transplant UTIs with up to a
third being recurrent. Abnormal
LUT and bladder outlet obstruction
account are likely culprits of UTI
in children and elderly respectively
(LoE 3).
• Patients with augmented LUT
present higher rates of asympto-
matic bacteriuria and UTI. Graft
survival is not affected by infection
episodes (LoE 3).
5.2 Transplant related factors
5.2.1 Donor type
Several studies have suggested that the
incidence of UTI is lower following living
donor transplant than cadaveric transplant
[6]. This is unlikely due to any issues of
donor contamination or ischemia but rather
due to shorter waiting times for a living
442
donor and less intensive immunosuppres-
sion (see below).
5.2.2 Immunosuppression
It is axiomatic that more intensive immu-
nosuppression increases the risk of infec-
tion. Unfortunately since there are no
reliable tests of degree of immune com-
promise, clinical management of trans-
plant recipients based upon drug levels
and weight based dosages will often lead
to over- and under-treatment, which won’t
be evident until acute rejection or infec-
tion develops. One study which looked at
infectious complications based on drug
selection found more bacterial infections
in patients receiving anti-thymocyte glob-
ulin (vs. basiliximab) and sirolimus (vs.
tacrolimus) [1]. In another study, acute
pyelonephritis was most strongly corre-
lated with prior therapy for acute rejec-
tion [21]. It is also possible, although not
directly studied, that patients with recur-
rent UTI may have their maintenance
immunosuppression reduced which might
lead to subsequent acute rejection.
5.2.3 Urinary catheters and stents
All patients following transplant require
bladder drainage, both to closely monitor
urine output and to allow the neo-urete-
rocystotomy to heal, however bacterial
colonization and biofilm formation are
inevitable over time. For patients with
otherwise normal bladders and unevent-
ful ureteral re-implant, Foley removal
as early as postoperative Day 2 appears
safe and can reduce the early UTI rate
[22]. For patients whose bladders do not
empty, intermittent self catheterization
is preferable to prolonged Foley drainage.
Suprapubic catheters may offer advan-
tages to those who cannot self catheterize
however the microbiologic implications of
their use has not been studied in trans-
plant patients.
A double J ureteral stent is often
placed at the time of renal transplant,
 Urogenital infections in renal transplant patients
either routinely or in patients consid-
ered at higher risk for urologic complica-
tions. Meta-analysis of published trials
confirms that stents reduce the incidence
of ureteral complications and simplify
their management. However, UTI’s are
more frequent in stented patients, espe-
cially when the stent is left in longer
than six weeks [23]. Removal of stents
between two and four weeks post trans-
plant appears to minimize UTI risk while
not compromising ureteral healing [24].
Percutaneous nephrostomy tubes are
also commonly used to manage urologic
complications after kidney transplant.
Prolonged use is associated with multi-
drug resistant bacteria [25] and fungal
infection.
Summary of Transplant Related UTI
Risk Factors
• Donor type (Living vs. deceased) has
conflicting evidence for UTI risk.
• ATG induction or sirolimus-based,
protocols are associated with higher
rates of UTI. Treatment of acute
rejection raises risk of post trans-
plant UTI (LoE 3).
• Early catheter removal reduces
early UTI rates (LoE 3).
• Routine ureteric stenting is\associ-
ated with higher rates of UTI. Early
stent removal (≤4 weeks) and cotri-
moxazole prophylaxis reduced infec-
tion rates (LoE 1).
6. MICROBIOLOGY OF UTI IN RENAL
TRANSPLANT RECIPIENTS
Bacteria, fungi, virus, parasites and
mycoplasma may all cause post trans-
plant UTI. Bacterial UTI pathogens in
renal transplant recipients are similar
to that in the non-transplantation popu-
lation. Gram-negative bacterial infec-
tions (Escherichia coli, Enterobacter,
Pseudomonas and Klebsiella) are most
common followed by Gram-positive
| 7.6 |
organisms (Enterococcus, staphylococcus
and streptococcus) and fungi [26] Due to
the routine use of post-transplant anti-
biotics and exposure to hospital acquired
organisms, infecting strains are often
multiply resistant to commonly used first
line antibiotics [13].
Fungal infections are more common in
immunosuppressed patients, especially
those with diabetes and urinary foreign
bodies [27]. Fungal UTI can lead to sys-
temic spread with significant mortality [1].
Locally, fungus may form into a ball lead-
ing to pelvic or ureteral obstruction [28].
The BK polyoma virus is an emerging
pathogen in transplant recipients and
may cause renal and ureteral injury [29].
BK virus is often found in immunocomp-
etant patients latently within urothelium
[30]. An early clue to infection and neph-
ropathy is the presence of “decoy cells” on
urinary cytology [31]. BK may be a cause
of hemorrhagic cystitis, although usually
only in bone marrow transplant recipi-
ents [32]. Low level injury within the
transplant ureter may contribute to stric-
ture or necrosis [33].
The parasite Schistosoma haematobium
is endemic in certain African countries.
Bacterial UTI, renal stones, and ureteric
complications were found to be greater
among kidney transplant recipients with
schistosomiasis than among controls.
However this did not impact patient or
graft outcome [34]. M. tuberculosis myco-
bacteria can be contracted by or reac-
tivated in immunosuppressed patients
leading in the urinary tract to UTI, epidi-
dymitis or prostatic abscess [35].
7. PRESENTATION AND EVALUATION
Symptomatic UTI after transplant has
a wide clinical spectrum including acute
cystitis, transplant pyelonephritis, and
pyelonephritis of native kidneys. Typical
signs and symptoms of UTI may be mim-
icked by other common post-transplant
conditions including catheter induced
443
Chapter |7| Urinary tract infections in nephropathies
bladder spasm, stent irritation, low vol-
ume defunctionalized bladder, polyuria
due to early loss of urinary concentrat-
ing ability, urinary retention and fever/
graft tenderness from acute rejection.
Furthermore, common UTI features may
not be evident. Immunosuppression can
suppress fever, primarily through block-
ade of IL-1 and tumour necrosis factor.
Blood WBC counts may not be elevated
due to bone marrow suppression. The
transplant kidney is denervated and
may not be tender even in the face of
pyelonephritis.
Given the high prevalence, uncom-
mon presentation and microbial diversity
in transplant UTI, lower urinary tract
symptoms, fever and unexplained leuko-
cytosis should prompt immediate urine
culture. If fungal infection is suspected,
microscopy and cytology may give a more
rapid result than culture. Blood cultures
should be included if fever or systemic
symptoms are present. Lower urinary
tract symptoms should be evaluated to
include assessment of the post void resid-
ual by ultrasound, especially in diabet-
ics, elderly men and in those with known
urologic abnormalities. Acute prostatitis
should be considered in febrile infections
in men and can be confirmed by pros-
tate exam without prostatic massage.
Particularly if the patient was trans-
planted elsewhere, consider a KUB to
ensure that a ureteric stent has not been
inadvertently overlooked.
8. PREVENTION AND THERAPY
Antimicrobial prophylaxis reduces the
incidence of post-transplant UTI and its
consequences. It is now standard practice
in most transplant centers [36]. TMP-
SMZ is the most commonly used due to
its activity against Pneumocystis cari-
nii. TMP-SMZ was found to significantly
reduce post-transplant UTI by 50% in
several prospective randomized trials
[37–39] (LoE 1b). A 40% reduction in cost
444
of diagnostic studies and systemic antibi-
otics was also noted but patient and graft
survival were not improved by prophy-
laxis [38]. Ciprofloxacin is effective but
has no prophylaxis against P. carnii,
Nocardia and Listeria species which
is otherwise provided by TMP-SMZ.
Grade-A recommendation can be drawn
for routine cost-effective prophylaxis with
TMP-SMX in renal transplant recipients
for at least one year.
Screening for asymptomatic bacteriuria
in renal transplant recipients has not been
fully evaluated. Moradi et al recommended
careful follow-up for asymptomatic bac-
teriuria with no therapy as it does not
decrease rate of UTI [40] (LoE 2b).
Therapy can range from oral outpa-
tient antibiotics to multidrug inpatient
intravenous therapy depending on the
clinical circumstance. Bacteriocidal
antibiotics are preferred since the com-
promised innate immune cells may not
be able to efficiently clear live bacte-
ria treated with bacteriostatic drugs.
Avoid drugs with primary urinary excre-
tion and low tissue penetration (e.g.
nitrofurantoin).
Predisposing factors should be cor-
rected if possible (e.g. optimal diabetic
control, removal or change of stents and
catheters, minimize immunosuppres-
sion based upon drug levels and clinical
course).
Interactions exist between antibiot-
ics used to treat post-transplant UTI and
immunosuppressant drugs. Ciprofloxacin
may raise calcineurin inhibitor (CNI)
levels, but levofloxacin and ofloxacin
usually do not [41]. Erthryomycin and
antifungal agents inhibit cytochrome
P450 and increase CNI levels. Rifampin,
imipenim and cephalosporins can reduce
CNI levels. Nephrotoxic antibiotics (e.g.
aminoglycosides, amphotericin) may have
synergistic effects with CNI’s, increasing
renal damage.
The ideal duration of antibiotic therapy
post transplant is not firmly established.
It is suggested that early (≤ six months)
 Urogenital infections in renal transplant patients
relapsing post-transplant UTI be treated
at least 6 weeks [36] (LoE 3). Lack of
rapid clinical response and relapsing UTI
should prompt the search for surgically
correctible causes such as abscess, stones,
urinary stenosis, reflux or leak and infec-
tion in a poorly functioning native kidney.
UTI can co-exist with common post-
transplant viral illnesses (e.g. cytomega-
lovirus). Transplant pyelonephritis may
cause elevated serum creatinine [15],
however reduced renal function should
not be simply attributed to the infec-
tion without ruling out other causes
(et. obstruction, rejection, drug toxic-
ity). Ultimately, lack of response should
prompt a biopsy to rule out rejection or
other renal conditions (e.g. primary dis-
ease recurrence).
9. IMPACT OF UTI ON GRAFT
SURVIVAL
Data on the long term impact of UTI
on transplant function and survival
is mixed, reflecting variations in defi-
nition (e.g. bacteriuria vs. cystitis vs.
pyelonephritis) and the difficulty of sep-
arating causality from association (i.e.
patients with UTI often have a history
of increased immunosuppression due
to acute rejection, which independently
would worsen graft survival). In adults,
the largest study of impact is the previ-
ously mentioned USRDS database review
[8] in which late UTI (>6 months) was
associated with increased risk of death,
even when adjusting for cardiac or other
infectious complications (LoE 3). The
authors did state that UTI might simply
be a clinical marker for serious underly-
ing illness. In a study of 177 transplant
patients from France, acute pyelonephri-
tis did not decrease graft or patient sur-
vival but did have a negative impact on
long term serum creatinine [21] (LoE 3).
In an analysis of the USRDS data for
pediatric recipients, risk for graft loss
was higher for early UTI but not late UTI
| 7.6 |
and neither impacted patient survival
[42] (LoE 3). In a study of 110 pediatric
recipients, serum creatinine returned to
baseline after therapy for UTI and there
was no impact on renal function at last
follow up [15] (LoE 3). It is likely that
pathogenic factors of the infecting bacte-
ria play a role in renal injury [43] (LoE
2a) which may also account for dispari-
ties in published studies.
REFERENCES
1. Alangaden GJ, Thyagarajan R, Gruber
SA, Morawski K, Garnick J, El-Amm JM,
West MS, Sillix DH, Chandrasekar PH,
and Haririan A, Infectious complications
after kidney transplantation: current
epidemiology and associated risk factors.
Clin Transplant, 2006. 20(4): 401–9.
2. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
3. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
4. Stamm WE, Protocol for diagnosis of uri-
nary tract infection: reconsidering the cri-
terion for significant bacteriuria. Urology,
1988. 32(2 Suppl): 6–12.
5. Simon DM and Levin S, Infectious com-
plications of solid organ transplantations.
Infect Dis Clin North Am, 2001. 15(2):
521–49.
6. Dantas SR, Kuboyama RH, Mazzali M,
and Moretti ML, Nosocomial infections in
renal transplant patients: risk factors and
treatment implications associated with
urinary tract and surgical site infections.
J Hosp Infect, 2006. 63(2): 117–23.
7. Chuang P, Parikh CR, and Langone A,
Urinary tract infections after renal trans-
plantation: a retrospective review at two
US transplant centers. Clin Transplant,
2005. 19(2): 230–5.
8. Abbott KC, Swanson SJ, Richter ER,
Bohen EM, Agodoa LY, Peters TG,
Barbour G, Lipnick R, and Cruess DF,
445
Chapter |7| Urinary tract infections in nephropathies
Late urinary tract infection after renal
transplantation in the United States. Am
J Kidney Dis, 2004. 44(2): 353–62.
9. Stein G and Funfstuck R, [Asymptomatic
bacteriuria]. Med Klin (Munich), 2000.
95(4): 195–200.
10. Bantar C, Fernandez Canigia L, Diaz C,
Ibanez C, Soto M, Smayevsky J, Rovegno
A, Fernandez H, and Bianchi H, [Clinical,
epidemiologic, and microbiologic study of
urinary infection in patients with renal
transplant at a specialized center in
Argentina]. Arch Esp Urol, 1993. 46(6):
473–7; discussion 477–8.
11. Goya N, Tanabe K, Iguchi Y, Oshima T,
Yagisawa T, Toma H, Agishi T, Ota K, and
Takahashi K, Prevalence of urinary tract
infection during outpatient follow-up after
renal transplantation. Infection, 1997.
25(2): 101–5.
12. Prat V, Horcickova M, Matousovic K,
Hatala M, and Liska M, Urinary tract
infection in renal transplant patients.
Infection, 1985. 13(5): 207–10.
13. Senger SS, Arslan H, Azap OK,
Timurkaynak F, Cagir U, and Haberal M,
Urinary tract infections in renal trans-
plant recipients. Transplant Proc, 2007.
39(4): 1016–7.
14. Brown PD, Urinary Tract Infections in
Renal Transplant Recipients. Curr Infect
Dis Rep, 2002. 4(6): 525–528.
15. John U, Everding AS, Kuwertz-Broking
E, Bulla M, Muller-Wiefel DE, Misselwitz
J, and Kemper MJ, High prevalence of
febrile urinary tract infections after paedi-
atric renal transplantation. Nephrol Dial
Transplant, 2006. 21(11): 3269–74.
16. Lansang MC, Ma L, Schold JD, Meier-
Kriesche HU, and Kaplan B, The rela-
tionship between diabetes and infectious
hospitalizations in renal transplant
recipients. Diabetes Care, 2006. 29(7):
1659–60.
17. Safdar N, Slattery WR, Knasinski V,
Gangnon RE, Li Z, Pirsch JD, and Andes
D, Predictors and outcomes of candiduria
in renal transplant recipients. Clin Infect
Dis, 2005. 40(10): 1413–21.
18. Wu YJ, Veale JL, and Gritsch HA,
Urological complications of renal trans-
plant in patients with prolonged anuria.
Transplantation, 2008. 86(9): 1196–8.
446
19. Pereira DA, Barroso U, Jr., Machado P,
Pestana JO, Rosito TE, Pires J, Almeida
C, Ortiz V, and Macedo A, Jr., Effects of
urinary tract infection in patients with
bladder augmentation and kidney trans-
plantation. J Urol, 2008. 180(6): 2607–10;
discussion 2610.
20. Hamdi M, Mohan P, Little DM, and
Hickey DP, Successful renal transplanta-
tion in children with spina bifida: long
term single center experience. Pediatr
Transplant, 2004. 8(2): 167–70.
21. Pelle G, Vimont S, Levy PP, Hertig A,
Ouali N, Chassin C, Arlet G, Rondeau
E, and Vandewalle A, Acute pyelone-
phritis represents a risk factor impair-
ing long-term kidney graft function.
Am J Transplant, 2007. 7(4):
899–907.
22. Rabkin DG, Stifelman MD, Birkhoff J,
Richardson KA, Cohen D, Nowygrod R,
Benvenisty AI, and Hardy MA, Early
catheter removal decreases incidence of
urinary tract infections in renal trans-
plant recipients. Transplant Proc, 1998.
30(8): 4314–6.
23. Wilson CH, Bhatti AA, Rix DA, and
Manas DM, Routine intraoperative
ureteric stenting for kidney transplant
recipients. Cochrane Database Syst Rev,
2005(4): CD004925.
24. Glazier DB, Jacobs MG, Lyman NW,
Whang MI, Manor E, and Mulgaonkar
SP, Urinary tract infection associated
with ureteral stents in renal transplan-
tation. Can J Urol, 1998. 5(1):
462–466.
25. Linares L, Cervera C, Cofan F, Ricart MJ,
Esforzado N, Torregrosa V, Oppenheimer
F, Campistol JM, Marco F, and Moreno A,
Epidemiology and outcomes of multiple
antibiotic-resistant bacterial infection in
renal transplantation. Transplant Proc,
2007. 39(7): 2222–4.
26. Valera B, Gentil MA, Cabello V,
Fijo J, Cordero E, and Cisneros JM,
Epidemiology of urinary infections in
renal transplant recipients. Transplant
Proc, 2006. 38(8): 2414–5.
27. Krcmery S, Dubrava M, and Krcmery
V, Jr., Fungal urinary tract infections in
patients at risk. Int J Antimicrob Agents,
1999. 11(3–4): 289–91.
 Urogenital infections in renal transplant patients
28. Sampol BJ, [Obstructive fungus ball in
kidney allografts]. Actas Urol Esp, 2008.
32(2): 267.
29. Bonvoisin C, Weekers L, Xhignesse P,
Grosch S, Milicevic M, and Krzesinski
JM, Polyomavirus in renal transplanta-
tion: a hot problem. Transplantation,
2008. 85(7 Suppl): S42–8.
30. Boldorini R, Veggiani C, Barco D, and
Monga G, Kidney and urinary tract
polyomavirus infection and distribution:
molecular biology investigation of 10 con-
secutive autopsies. Arch Pathol Lab Med,
2005. 129(1): 69–73.
31. Singh HK, Bubendorf L, Mihatsch MJ,
Drachenberg CB, and Nickeleit V, Urine
cytology findings of polyomavirus infec-
tions. Adv Exp Med Biol, 2006. 577:
201–12.
32. Paduch DA, Viral lower urinary tract
infections. Curr Urol Rep, 2007. 8(4):
324–35.
33. Karam G, Maillet F, Parant S, Soulillou
JP, and Giral-Classe M, Ureteral necrosis
after kidney transplantation: risk factors
and impact on graft and patient survival.
Transplantation, 2004. 78(5): 725–9.
34. Mahmoud KM, Sobh MA, El-Agroudy AE,
Mostafa FE, Baz ME, Shokeir AA, and
Ghoneim MA, Impact of schistosomiasis
on patient and graft outcome after renal
transplantation: 10 years’ follow-up.
Nephrol Dial Transplant, 2001. 16(11):
2214–21.
35. Cek M, Lenk S, Naber KG, Bishop MC,
Johansen TE, Botto H, Grabe M, Lobel
B, Redorta JP, and Tenke P, EAU guide-
lines for the management of genitouri-
nary tuberculosis. Eur Urol, 2005. 48(3):
353–62.
36. Munoz P, Management of urinary tract
infections and lymphocele in renal trans-
plant recipients. Clin Infect Dis, 2001. 33
Suppl 1: S53–7.
37. Khosroshahi HT, Mogaddam AN,
and Shoja MM, Efficacy of high-dose
| 7.6 |
trimethoprim-sulfamethoxazol prophy-
laxis on early urinary tract infection after
renal transplantation. Transplant Proc,
2006. 38(7): 2062–4.
38. Maki DG, Fox BC, Kuntz J, Sollinger
HW, and Belzer FO, A prospective,
randomized, double-blind study of
trimethoprim-sulfamethoxazole for
prophylaxis of infection in renal trans-
plantation. Side effects of trimethoprim-
sulfamethoxazole, interaction with
cyclosporine. J Lab Clin Med, 1992.
119(1): 11–24.
39. Fox BC, Sollinger HW, Belzer FO, and
Maki DG, A prospective, randomized,
double-blind study of trimethoprim-
sulfamethoxazole for prophylaxis of infec-
tion in renal transplantation: clinical
efficacy, absorption of trimethoprim-
sulfamethoxazole, effects on the micro-
flora, and the cost-benefit of prophylaxis.
Am J Med, 1990. 89(3): 255–74.
40. Moradi M, Abbasi M, Moradi A,
Boskabadi A, and Jalali A, Effect of anti-
biotic therapy on asymptomatic bacteriu-
ria in kidney transplant recipients. Urol
J, 2005. 2(1): 32–5.
41. Borras-Blasco J, Conesa-Garcia V,
Navarro-Ruiz A, Marin-Jimenez F,
Gonzalez-Delgado M, and Gomez-Corrons
A, Ciprofloxacin, but not levofloxacin,
affects cyclosporine blood levels in a
patient with pure red blood cell aplasia.
Am J Med Sci, 2005. 330(3): 144–6.
42. Dharnidharka VR, Agodoa LY, and Abbott
KC, Effects of urinary tract infection on
outcomes after renal transplantation in
children. Clin J Am Soc Nephrol, 2007.
2(1): 100–6.
43. Rice JC, Peng T, Kuo YF, Pendyala S,
Simmons L, Boughton J, Ishihara K,
Nowicki S, and Nowicki BJ, Renal allo-
graft injury is associated with urinary
tract infection caused by Escherichia
coli bearing adherence factors. Am J
Transplant, 2006. 6(10): 2375–83.
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 Chapter |8|

Urinary tract infections in

patients with underlying
urological abnormalities
Chair: Chris F. Heyns

CHAPTER OUTLINE
8.1 Introduction 450
8.2 Urinary tract infections in obstruction of the urinary tract 452
8.3 Urinary tract infections in patients with urolithiasis 481
8.4 Epidemiology, diagnosis and treatment of urinary tract
infections in patients with spina bifida 497
8.5 Urinary tract infections in patients with neurogenic bladder 507
|8.1|
Introduction
Chris F. Heyns
Professor and Head, Department of Urology, University of Stellenbosch and Tygerberg Hospital, South Africa
Address: Department of Urology, Faculty of Health Sciences, University of Stellenbosch
PO Box 19063, Tygerberg 7505, South Africa
Tel: +27 21 938 9282, Fax: +27 21 933 8010
This chapter deals with urinary tract
infection (UTI) associated with structural
or functional abnormalities of the urinary
tract. The first section focuses on UTI
associated with urinary tract obstruction
due to causes other than urolithiasis and
neuropathic bladder dysfunction, and
deals with conditions such as benign pro-
static hyperplasia (BPH), urethral stric-
ture, and urinary stasis associated with
diverticula of the urinary tract. The liter-
ature review by Chris Heyns analyses the
evidence which can be used to guide clini-
cally relevant recommendations about the
management of UTI associated with uri-
nary obstruction and stasis. The chapter
also discusses interesting new theories
that infection or inflammation may have
an etiological role in the pathogenesis of
BPH and prostate cancer.
Urolithiasis may be a cause as well as
a result of UTI. Stone obstruction leads
to urinary stasis, which enables bacteria
to adhere to the urothelium and multi-
ply, thus causing UTI. Urinary stasis pro-
motes the crystallization and precipitation
of solutes in the urine, while the cellular
debris of leucocytes and dead bacteria
provide a nidus for further nucleation and
stone formation. Primary UTI caused by
urea-splitting organisms may lead to stru-
vite stone formation, causing obstruction,
stasis and further infection. The clini-
cal consequences of this “vicious cycle” of
stones → obstruction → stasis → infec-
tion → stones are discussed in the chap-
ter on UTI in patients with urolithiasis by
Gianpaolo Zanetti and Alberto Trinchieri.
Neuropathic bladder dysfunction in
children is most often due to spina bifida
(myelomeningocele). The epidemiology,
diagnosis and treatment of UTI in chil-
dren with this condition are discussed by
Dan Wood and Christopher Woodhouse.
They review the significant advances
that have been made with regard to the
management of this disabling condition
in children, and also discuss the areas of
current controversy.
In adults, neuropathic bladder dys-
function may result from conditions such
as traumatic spinal cord or brain injuries,

stroke, cauda equina lesions or multiple
sclerosis. The neurogenic bladder remains
a common cause of UTI, presenting sev-
eral challenges in diagnosis and man-
agement. Due to improved management
of trauma patients as well as increasing
age of the overall population, the preva-
lence of neuropathic bladder dysfunction
as a cause of UTI has increased. James
Salerno and Diana Cardenas review the
management of UTI associated with neu-
rogenic bladder dysfunction and present
Introduction | 8.1 |
recommendations based on the best avail-
able evidence.
Despite the large body of literature on
these topics, numerous questions remain
to be answered and several controversies
need to be resolved, indicating the neces-
sity for well designed, prospective clini-
cal studies as well as basic laboratory
research to guide future evidence-based
recommendations on the management of
UTI in patients with underlying abnor-
malities of the urinary tract.
451
|8.2|
Urinary tract infections in
obstruction of the urinary tract
Chris F. Heyns
Professor and Head, Department of Urology, University of Stellenbosch and Tygerberg Hospital, South Africa
Department of Urology, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa
Tel: +27 21 938 9282, Fax: +27 21 933 8010
ABSTRACT
This chapter examines the association
between urinary tract infection (UTI)
and urinary tract obstruction, focusing
on conditions other than urolithiasis and
neuropathic bladder dysfunction, which
are dealt with in other chapters.
It is one of the axioms of urological
practice that urinary tract obstruction and
urinary stasis predispose to UTI. Clinical
studies confirm that most men with UTI
have an anatomical or functional abnor-
mality of the urinary tract. Experimental
studies indicate that, whereas transure-
thral inoculates of bacteria are rapidly
eliminated from the normal bladder, ure-
thral obstruction leads to cystitis, pyelone-
phritis and bacteremia.
Benign prostatic hyperplasia (BPH)
is, next to urolithiasis, the most common
cause of urinary tract obstruction pre-
disposing to UTI. It seems logical that
a large post-void residual (PVR) urine
volume should predispose to UTI, because
urinary stasis would allow more time for
bacterial adherence and multiplication.
However, there is scant evidence that
UTI in the aging male or female popu-
lation is associated with either PVR or
bladder outflow obstruction (BOO).
In men with symptomatic BPH treated
with placebo, the cumulative risk of UTI
at 4 years of follow up is less than 1%.
However, in men undergoing prostatec-
tomy, UTI is the indication for surgery
in 4% to 12% of cases. Bacteriuria prior
to prostatectomy for BPH is very com-
mon (up to 54% of cases), and bacteria
can often be cultured from prostatic tis-
sue, especially in those catheterized
before operation (up to 67% of cases).
Bacteriuria after prostatectomy despite
sterile urine at the time of the proce-
dure is also quite common (up to 40% of
patients).
An interesting theory is that inflam-
mation is an etiological factor in the
 Urinary tract infections in obstruction of the urinary tract
pathogenesis of BPH, although no causa-
tive bacterial or other antigen has been
identified. Elevated expression of pro-
inflammatory cytokines in BPH may
induce fibromuscular growth by an auto-
crine or paracrine loop or via induction of
cyclo-oxygenase-2 expression. Acute and/
or chronic intraprostatic inflammation
may be important in the pathogenesis
as well as progression of BPH, since the
risk of acute urinary retention (AUR) due
to BPH is greater in men with prostatitis
than in those without this condition.
In men with febrile UTI, the prostate
is frequently involved. Prostatitis causes
an increased total serum prostate specific
antigen (PSA) and decreased free/total
PSA ratio, which may be falsely inter-
preted as a sign of cancer. An interesting
theory is that bacterial colonization or
chronic inflammation of the prostate may
be a cause of prostate cancer. Proliferative
inflammatory atrophy is regarded as a
precursor to prostatic intraepithelial neo-
plasia (PIN) and prostate cancer.
Urethral stricture remains a com-
mon underlying abnormality in men
with UTI in many parts of the world,
and often presents with complications.
Diverticula of the bladder or urethra
may occur secondary to obstruction, and
urinary stasis in such diverticula pre-
disposes to UTI. Men with BPH plus a
bladder diverticulum have a higher risk
of UTI as well AUR, probably related to
the greater PVR and higher voiding pres-
sures. Diverticulectomy is recommended
for BPH-associated bladder diverticula.
Urethral diverticula in women present
with UTI in about 30% of cases. The
management is surgical, with excision of
the diverticulum and closure of the tract
communicating with the urethra.
Some studies from tropical countries
have indicated that Schistosoma haema-
tobium infestation predisposes to second-
ary bacterial UTI in up to 30% of cases.
This may be related to bladder wall
inflammation caused by Schistosomal
| 8.2 |
ova, leading to upper tract dilatation, uri-
nary stasis and bacterial superinfection.
Experimental studies have shown that
the kidney is relatively resistant to infec-
tion by organisms injected intravenously,
but if a ureter is ligated the obstructed
kidney becomes infected. Furthermore,
ureteric obstruction may cause renal dys-
function, so the kidney(s) may not be able
to concentrate antibiotics in the urine,
making eradication of bacteria difficult.
The most important determinants of UTI
caused by resistant strains are previ-
ous use of antibiotics and the presence of
underlying urological diseases.
In children prenatally diagnosed with
severe hydronephrosis and not on antibi-
otic prophylaxis, the overall incidence of
UTI during the first 12 months postna-
tally may be as high as 50%, especially in
those with obstruction at the ureterovesi-
cal junction. However, some studies have
shown a cumulative incidence of UTI
of only 4% to 8%. The use of antibiotic
prophylaxis in children with hydroneph-
rosis secondary to upper tract obstruction
remains controversial.
In some developing countries renal
infection associated with upper tract
obstruction remains a common reason for
nephrectomy, indicating the importance
of early diagnosis and proper treatment
of UTIs. Despite the lack of relevant clin-
ical studies, it is generally accepted prac-
tice that in patients with UTI and upper
urinary tract obstruction, empiric antibi-
otic treatment should be complemented
with urgent intervention to drain the
urinary tract (e.g. percutaneous neph-
rostomy or double-J ureteric stenting).
This should be followed with targeted
antibiotic treatment (according to urine
culture) and definitive surgery to remove
the cause of obstruction once infection is
under control.
Urinary tract abnormalities may pre-
dispose to infection with organisms other
than Escheria coli, and long-term antibiotic
therapy often leads to bacterial resistance
453
Chapter |8| Urinary tract infections in patients
or fungal superinfection. Urinary tract
obstruction may permit ascending infec-
tion of E. coli strains with lower adhesive
ability that would not be pathogenic in a
normal urinary tract.
In selected patients with UTI, imaging
of the urinary tract is indicated to detect
conditions that must be corrected to avoid
rapid deterioration of renal function or
systemic sepsis, and to prevent recur-
rent infections and long-term renal dam-
age. UTI in the presence of urinary tract
obstruction remains a serious, destructive
and potentially life-threatening process
that requires immediate antibiotic treat-
ment, supplemented with urgent inter-
vention to drain the obstructed system,
followed by surgery to correct the struc-
ture and function of the urinary tract.
Key words: Urinary tract; infection;
obstruction; prostate; urethra; stricture;
hydronephrosis; reflux; diverticulum
SUMMARY OF RECOMMENDATIONS
1. There is no clear evidence that a
large postvoid residual (PVR) urine
volume predisposes to bacteriuria or
urinary tract infection (UTI), there-
fore antibiotic prophylaxis is not
indicated in such patients (GoR B).
2. In men with lower urinary tract
symptoms (LUTS) due to benign
prostatic hyperplasia (BPH) the risk
of UTI is very small, therefore anti-
biotic prophylaxis is not indicated
(GoR A).
3. Recurrent or persistent UTI in men
with bladder outflow obstruction
(BOO) and BPH is an indication
for medical intervention, i.e. alpha
blocker and/or finasteride, or prosta-
tectomy (GoR A).
4. In patients undergoing prosta-
tectomy, UTI should be treated
according to urine culture, and peri-
operative antibiotic prophylaxis is
454
indicated in patients with negative
urine culture (GoR A).
5. Bladder diverticula do not always
require surgery, but those associated
with recurrent or persistent UTI
in the presence of BOO should be
treated with medical management or
prostatectomy; there is no clear evi-
dence that diverticulectomy in addi-
tion to prostatectomy is necessary
(GoR B).
6. Urethral diverticula associated
with UTI (in both men and women)
should be treated with surgical
diverticulectomy (GoR A).
7. Bladder calculi that are a result and/
or cause of UTI should be removed
(Grade A). Bladder calculi associated
with BPH are usually an indication
for prostatectomy as well as removal
of the stones; however, endoscopic
vesicolithotripsy and medical treat-
ment of BPH may be an option in
men with major anaesthetic risk
factors (GoR B).
8. Male urethral strictures increase the
risk of UTI and should be treated
with dilatation, internal urethrotomy
or urethroplasty (GoR A).
9. Urethrocutaneous fistulae usually
require suprapubic cystostomy and
subsequent urethroplasty (GoR A),
but may be treated with internal
urethrotomy alone (GoR B).
10. Female urethral stricture is
extremely uncommon, and there is
no evidence to support the use of
urethral dilatation as treatment of
LUTS or UTI in women (GoR B).
11. Schistosoma haematobium infesta-
tion may increase the risk for bacte-
rial UTI, but there is insufficient
evidence to recommend antibiotic
prophylaxis in patients with S
haematobium infestation (GoR C).
12. In infants and children with upper
urinary tract obstruction, antibiotic
 Urinary tract infections in obstruction of the urinary tract
prophylaxis to prevent UTI may
be advisable, but the role of antibi-
otic prophylaxis in adults remains
unclear (GoR C).
13. In patients with UTI and upper
urinary tract obstruction, empiric
broad-spectrum antibiotic therapy
should be complemented with urgent
intervention to drain the urinary
tract (e.g. percutaneous nephros-
tomy or double-J ureteric stenting)
and definitive surgery to remove the
cause of obstruction once infection is
under control (GoR A).
14. Renal calyceal diverticula usually do
not require treatment, but those asso-
ciated with recurrent UTI or stone
formation should be treated with
percutaneous, uretero-renoscopic,
laparoscopic or open nephrolithotomy
to remove stones and obliterate
or remove the diverticulum or to
improve its drainage (GoR A).
15. Emphysematous pyelonephritis with
gas in the renal collecting system
or parenchyma only, and those with
extension of gas into the perinephric
or pararenal spaces but no risk fac-
tors (thrombocytopenia, acute renal
function impairment, disturbance
of consciousness, or shock) can be
treated with antibiotics and percu-
taneous nephrostomy or ureteric
catheterization instead of urgent
nephrectomy (GoR C).
16. Xanthogranulomatous pyelonephritis
frequently requires nephrectomy
in addition to antibiotic treatment
(GoR A).
17. Urinary tract imaging is indicated
when complicated UTI due to an
underlying abnormality of the uri-
nary tract is suspected (GoR A).
18. Ultrasound with abdominal radiog-
raphy is equivalent to intravenous
urography (IVU) as screening study
in patients with complicated UTI,
and is the imaging study of first
| 8.2 |
choice, while computerised tomogra-
phy (CT) is indicated if more detailed
information is required (GoR B).
19. In patients with early recurrent or
persistent UTI, imaging and uro-
logical investigations should be
performed to identify underlying
abnormalities that may be surgically
correctable (GoR A).
20. In patients with complicated acute
pyelonephritis, blood cultures should
be reserved for those with an uncer-
tain diagnosis and those who do
not respond promptly to treatment
(GoR B).
21. In patients with bowel in the urinary
tract antibiotic prophylaxis is not
indicated for asymptomatic bacte-
riuria, but may be indicated in those
with recurrent symptomatic UTI
(GoR B).
1. INTRODUCTION
The prevalence and etiology of urinary
tract obstruction in patients with UTI
vary considerably in different reports
in the literature. In a study of men with
nonbacteremic UTI, identifiable compli-
cations included benign prostatic hyper-
plasia (BPH) in 27% of patients, prostatic
cancer in 8%, urethral stricture in 8% and
neuropathic bladder in 8% (LoE 3) [1].
In a review of patients admitted to a
urology department with complicated
UTI, the underlying abnormality was
urolithiasis in 49%, BPH in 45%, tran-
sitional cell carcinoma of the bladder or
ureter in 6% and renal tumours in 6%.
Mortality due to complicated UTI was
3.9% (LoE 3) [2].
In a study of adult men with proven
UTI, the diagnosis was bladder outflow
obstruction (BOO) in 36%, underactive
detrusor 7%, bladder diverticulum 7%,
chronic retention 4%, urethral stricture
3%, prostatitis 3%, renal stone 3%, ureteric
stone 2%, prostate cancer 2%, pelviureteric
455
Chapter |8| Urinary tract infections in patients
junction obstruction (PUJO) 2%, bladder
stone 1%, pelvic kidney 1%, and phimosis
1% (LoE 3) [3].
The aim of this review was to focus
on UTI associated with urinary tract
obstruction due to causes other than
urolithiasis and neuropathic bladder
dysfunction.
2. METHODS
An electronic literature search was per-
formed on PubMed using the key words
urinary tract infection (UTI) alone and
in combination with the following terms:
benign prostatic hyperplasia, BPH,
hydronephrosis, obstruction, reflux, diver-
ticulum, urethra and stricture. Abstracts
were reviewed, relevant articles were
studied in full-length version, and further
references were obtained from these arti-
cles. In total, 520 abstracts were reviewed,
210 articles were studied in detail, and
175 were included as references in this
chapter.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [4–5].
3. BENIGN PROSTATIC HYPERPLASIA
(BPH)
A review of more than 200 studies pub-
lished between 1954 and 1988 concluded
that most men with UTI have a func-
tional or anatomic abnormality of the
genitourinary tract. BPH and genitouri-
nary instrumentation were the major pre-
dispositions to UTI in men (LoE 3) [6].
An experimental animal model in mice
has shown that transurethral inoculation
with a strain of E. coli which is rapidly
eliminated from normal mice will cause
bacteriuria, bacteremia and pyelonephri-
tis after reversible urethral obstruction for
1 to 6 hours. Urethral obstruction enhances
the uropathogenicity of nonpathogenic
456
Figure 1 Cystogram shows trabeculation of bladder wall and
postvoid residual urine with midline filling defect due
to BPH.
E. coli and causes more severe renal lesions
in mice challenged with uropathogenic
E. coli (LoE 2b) [7].
In the presence of a large postvoid
residual (PVR), even a small bacterial
inoculum may lead to severe UTI that is
difficult to eradicate. The incidence of bac-
teriuria after urodynamic studies is higher
in men (36%) compared with women
(15%), probably due to larger PVR (LoE 3)
[8]. Mild episodes of UTI can become life-
threatening and may lead to systemic
sepsis when urinary tract obstruction is
present (LoE 3) (Figure 1) [9].
Although it seems logical that a large
PVR should predispose to UTI, because
urinary stasis would allow more time for
bacterial adherence and multiplication,
there is little evidence that the occur-
rence of UTI in the aging male population
is associated with either PVR or BOO
(LoE 3) [10]. In elderly men bacteriuria
does not appear to correlate with age,
PVR, or symptoms of BOO (LoE 3) [11].
In elderly women an increased PVR does
not appear to be associated with bacteriu-
ria (LoE 3) [12].
In older series, acute urinary reten-
tion (AUR) was the indication for surgery
in 25% to 30% of men who underwent
transurethral resection of the prostate
(TURP) and renal failure was present in a
mean of 14% of cases (range 0.3% to 30%)
 Urinary tract infections in obstruction of the urinary tract | 8.2 |

(Figure 2). In a more recent database of

patients who had upper tract imaging
prior to surgery, 7.6% had evidence of
hydronephrosis, of whom one third had
renal insufficiency (LoE 3) [13–15].
The natural history of untreated
BPH shows that it is not an invari-
ably progressive condition. In 5 studies
of men with lower urinary tract symp-
toms (LUTS) due to BPH followed for
3–6 years the PVR volume increased in
35%, decreased in 37%, and remained
unchanged in 28% of patients (LoE 3)
[10, 16]. In another study of men with
BPH randomized to watchful waiting
and followed for 5 years a PVR >150 ml
developed in only 7% and urinary reten-
tion in 3% (LoE 3) [17].
In older surgical series, UTI was the
indication for surgical intervention in
about 12% of men with BPH (LoE 3)
[18–19]. In a study of men with BPH Figure 2 Excretory urogram shows bilateral hydro-
ureteronephrosis with large post-void residual urine volume
treated at hospitals in Japan, UTI was due to bladder outflow obstruction.
the reason for presentation in 4% (LoE 3)
[20]. In a study of men with BPH in
Spain, the reported prevalence of UTI correlation between the incidence of pre-
was 5.2%, compared to incontinence in operative bacteriuria and the duration of
6.1%, acute retention in 5.1%, haema- catheterization as well as the volume of
turia in 2.5%, renal failure in 2.4%, and residual urine (LoE 3) [25–29].
bladder stones in 0.7% (LoE 3) [21]. In Bacteriuria after prostatectomy has
placebo-treated patients in the Medical been reported in 29% to 40% of patients
Therapy of Prostatic Symptoms (MTOPS) with sterile urine at the time of the pro-
study the cumulative incidence of UTI at cedure, and in 20% of preoperatively
4 years was <1% (95% confidence interval nonbacteriuric patients despite chemo-
0–1%), compared to AUR in 2% (1–4%) prophylaxis. One study reported postoper-
and incontinence <1% (0–1%) (LoE 3) ative bacteriuria in 32% of patients after
[22–23]. However, most of the clinical tri- TURP and in 51% after open prostatec-
als on BPH management have excluded tomy. There was an increased prevalence
subjects with high baseline PVR (>150 ml of Enterococcus and coagulase-negative
to >350 ml), so the natural history of men Staphylococcus isolates from postprosta-
with a high baseline PVR remains largely tectomy compared with preprostatectomy
unknown. Furthermore, it is well known bacteriuria. One study showed a signifi-
that PVR measurement is variable over cant correlation between postprostate-
short intervals of time (LoE 3) [24]. ctomy bacteriuria and meatal cultures,
Bacteriuria prior to prostatectomy in and another study showed an increased
men with BPH has been reported in 28% incidence of bacteriuria with increased
to 54% of cases. The incidence is higher in age (LoE 3) [20, 25, 30–32].
those catheterized before operation (44% Bacteria can be cultured from pros-
to 57%) than in those not catheterized tatic tissue obtained at prostatectomy in
(18%). Several studies have indicated a 21% to 44% of cases (67% in catheterized

457
Chapter |8| Urinary tract infections in patients
and 28% in uncatheterized patients)
(LoE 3) [33]. However, in one study only
34% of patients with preoperative cath-
eters had positive prostate cultures, and
of patients with positive prostate cul-
tures 82% had sterile urine cultures pre-
operatively (LoE 3) [34–35]. Histological
lesions indicating prostatitis associated
with BPH were found in 39% of patients,
regardless of the presence or absence of
bacteria in the prostate. Of the patients
with histologically demonstrated pro-
static inflammation, only 28% had a
positive prostatic culture. The microor-
ganisms most frequently isolated from
the prostate were coagulase negative
Staphylococci, E. coli and Enterococcus
faecalis (LoE 3) [36].
Bacteremia after TURP has been
reported in 23% to 29% of patients
despite antibiotic prophylaxis, in 54% of
patients with preoperative bacteriuria
and 8% without bacteriuria. In 70% to
81% of cases an identical species was iso-
lated from preoperative urine cultures,
and in 54% the organism causing bac-
teremia was identical to that cultured
from prostatic tissue. Bacteremia was
significantly more common in patients
with preoperative UTI, prostatitis on
histology, and positive prostatic cultures.
Staphylococcus epidermidis was the
most common organism isolated (LoE 3)
[31, 37].
It has been suggested that inflam-
mation is an etiological factor in the
pathogenesis of BPH, which may be an
immune-mediated inflammatory disease
(LoE 3) [38–43]. However, it is not clear if
infection is the primary event for a misdi-
rected immune response in the prostate.
No study has shown a single strain of
microorganisms present in all BPH sam-
ples, and viruses have been detected more
commonly in association with prostate
cancer than with BPH (LoE 3) [33, 44].
Data from the Medical Therapy of
Prostate Symptoms (MTOPS) study
showed that patients with BPH plus
chronic inflammation on biopsy who were
458
followed for 4.5 years had significantly
larger prostates, higher serum pros-
tate specific antigen (PSA) levels and a
greater risk of urinary retention. Other
studies have demonstrated elevated
expression of pro-inflammatory cytokines
in BPH. Interleukins 6, 8 and 17 may
perpetuate a chronic immune response
in BPH and induce fibromuscular growth
by an autocrine or paracrine loop or via
induction of cyclo-oxygenase-2 (cox-2)
expression (LoE 3) [45].
Histologically, almost all BPH speci-
mens show inflammatory infiltrates, but
correlation to bacterial or other anti-
gens has not been established. In BPH
compared with normal prostate, the
levels of interferon-gamma and inter-
leukin-2 (IL-2) are 10-fold increased,
and the levels of IL-2 and transform-
ing growth factor beta are 2-fold ele-
vated. As BPH nodules develop, IL-4
and IL-13 expression increases 2-fold.
Dysregulation of the immune response
in BPH may occur via elevated expres-
sion of IL-17, which stimulates produc-
tion of IL-6 and IL-8, thus inducing
stromal growth in BPH (LoE 3) [44].
However, chronic inflammatory pros-
tatitis does not appear to promote ang-
iogenesis or increase the microvessel
density in BPH cases (LoE 3) [46].
Some studies have suggested that pro-
static inflammation is associated with
UTI, prostatic infection, activated comple-
ment and downregulated mucosal immu-
nity in BPH (LoE 3) [47]. Acute and/or
chronic intraprostatic inflammation may
be important in the pathogenesis as well
as progression of BPH, since the risk of
urinary retention due to BPH is greater
in men with prostatitis than in those
without (LoE 3) [48]. It has been shown
that the use of a cox-2 inhibitor in combi-
nation with a 5-alpha reductase inhibitor
could increase the apoptotic index in BPH
tissue, but the value of cox-2 inhibitor
treatment in the prevention of BPH pro-
gression has not been evaluated in clini-
cal trials (LoE 3) [49].
 Urinary tract infections in obstruction of the urinary tract
4. PROSTATE CANCER AND
PROSTATITIS
In men with febrile UTI, the prostate is
frequently involved, causing PSA elevation
(LoE 3) [50]. Histological acute and chron-
ic-active prostatitis may induce high PSA
values via the leak phenomenon (LoE 3)
[51]. PSA elevation is not related to the
extent of inflammation, but to the aggres-
siveness of the inflammatory infiltrate, i.e.
disruption of epithelial integrity (LoE 3)
[52–55]. Acute as well as chronic prostati-
tis is associated with a decreased free/total
PSA ratio (LoE 3) [55–57]. The increased
total PSA and decreased free/total PSA
ratio in prostatitis may be falsely inter-
preted as a sign of cancer (LoE 3) [58–60].
The use of empiric antibiotic treatment to
decrease the PSA and avoid unnecessary
prostate biopsy remains controversial,
and well designed prospective studies are
required to determine the role of antibiotic
treatment (if any) in men with a slightly
elevated PSA and symptoms or signs of
prostatitis or UTI.
There appears to be a correlation
between bacterial colonization or chronic
inflammation of the prostate and the devel-
opment of prostate cancer. Genetic stud-
ies support the hypothesis that prostate
inflammation may be a cause of prostate
cancer development. Proliferative inflam-
matory atrophy is regarded as a precursor
to prostatic intraepithelial neoplasia (PIN)
and prostate cancer (LoE 3) [61].
It is postulated that during acute or
chronic inflammation in the prostate
various cells are activated by chemokines
via different chemotaxin receptors which
then trigger processes in angiogenesis,
cellular growth and neoplasia which may
lead to prostate cancer. Inflammation is
thought to incite carcinogenesis by caus-
ing cell and genome damage, and by pro-
moting cellular turnover (LoE 3) [49, 62].
A recent study suggested that the pres-
ence of Propionibacterium acnes in the
prostate was associated with prostate
cancer development (LoE 3) [63].
| 8.2 |
5. URETHRAL STRICTURES
In men with UTI in some countries
(especially in the developing world) the
second most frequent underlying abnor-
mality, after BPH, is urethral stricture
(LoE 3) [64]. A study of men with ure-
thral strictures treated in a hospital
in Spain reported that 89% presented
with complications, consisting of AUR
(57% of patients), bladder obstructive
uropathy (48%), UTI (36%) and vari-
ous degrees of renal failure (17%). In
the patients with UTI, 90% were single
microorganism infections, 44% being
caused by E. coli. Risk factors for the
development of complications were age
>70 years, history of sexually transmit-
ted infections, UTI, previous urethral
surgery for recurrent stenosis, and PVR
(LoE 3) [64–65].
Renal complications were noted in
21% of men with urethral stricture dis-
ease. The complications were renal fail-
ure (36%), hydroureteronephrosis (33%),
chronic pyelonephritis (16%) and vesico-
ureteric reflux (11%). UTI occurred in
76% of the men with renal complications
(LoE 3) [66]. A recent study from the USA
reported that men with urethral stricture
disease have a high rate of UTI (41%) and
incontinence (11%) (LoE 3) [67].
In a study of men with urethral stric-
tures in the Sudan, 63% had complica-
tions such as inflammatory periurethral
mass, “watering-can perineum” with dis-
charging sinuses and urethrocutaneous
fistulas, associated urethral calculi, periu-
rethral abscesses and urethral diverticula
(LoE 3) [68]. “Watering-can perineum”
results from long standing neglected
inflammatory urethral strictures, there-
fore prevention requires adequate treat-
ment of urethritis and urethral strictures
(LoE 3) [69]. Suprapubic cystostomy fol-
lowed by urethroplasty is the best treat-
ment. However, endoscopic treatment may
also be successful. In a Sudanese study of
men with a “watering-can perineum” the
fistulae healed completely after a single
459
Chapter |8| Urinary tract infections in patients
direct vision internal urethrotomy (DVIU)
in 64% of patients, and in the rest two
or more urethrotomies were required to
resolve the problem (LoE 3) [70].
6. DIVERTICULA
6.1 Bladder diverticula
Bladder diverticula are most often
acquired (also termed secondary) due
to BOO or neuropathic bladder dys-
function, but may also be iatrogenic.
They usually occur after the age of 60
years, are much more common in men
than women, and are most often associ-
ated with bladder trabeculation, BPH,
prostate cancer or urethral stricture,
although obstruction is not present in
all cases (Figs. 3,4). The reported preva-
lence of bladder diverticula in associa-
tion with LUTS is approximately 1% to
6% (LoE 3) [71–73].
Congenital bladder diverticula most
often present with UTI (LoE 3) [74].
Urinary stasis in a bladder diverticulum
Figure 3 Cystogram showing bladder diverticulum.
460
Figure 4 Ultrasound showing two large bladder diverticula.
may predispose to UTI and may impede
the eradication of established infection
(LoE 3) [75]. Relapsing or persistent UTI
unresponsive to antibiotic therapy may be
an indication for bladder diverticulectomy.
A study comparing patients with BPH
plus a bladder diverticulum and patients
with BPH only, found that the group with
BPH plus a diverticulum had a higher rate
of AUR (25% vs. 6% vs.) and UTI (22%
vs. 3%), a larger mean PVR (221 ml vs.
46 ml), a larger bladder capacity (351 ml
vs. 211 ml), more patients voided with
abdominal pressure (50% vs. 24%) and
they had greater urethral resistance. In
patients who underwent TURP with or
without diverticulectomy, urethral resist-
ance parameters and PVR decreased in
both groups. Diverticulectomy showed an
improvement of bladder contractility with
longer detrusor contraction duration, sup-
porting its use in cases of BPH-associated
diverticula (LoE 3) [76].
6.2 Urethral diverticula
Urethral diverticula in women are most
probably caused by infection of the per-
iurethral glands, possibly by Neisseria
gonorrhoeae, although the initial infec-
tion and especially subsequent rein-
fections may be caused by E. coli and
other coliform bacteria or vaginal flora.
 Urinary tract infections in obstruction of the urinary tract
Recurrent infection of the periurethral
glands leads to obstruction, suburethral
abscess formation and subsequent rup-
ture of the infected glands into the ure-
thral lumen. Reinfection, inflammation,
and recurrent obstruction of the neck of
the cavity result in enlargement of the
diverticulum. Some urethral divertic-
ula may be noncommunicating (LoE 3)
[77–78].
Urethral diverticula in women typi-
cally present with dysuria, dyspareunia
and post-micturition dribbling (LoE 3)
[79–80]. UTI is the mode of presentation
in about 30% of patients (LoE 3) [81–82].
E. coli is the most common organism iso-
lated in patients with urethral divertic-
ula, but other Gram-negative enteric flora
as well as N. gonorrhoeae, Chlamydia,
streptococci, and staphylococci are often
present. Calculi within urethral divertic-
ula occur in 4% to 10% of cases and are
most likely due to urinary stasis or infec-
tion (LoE 3) [83–84].
The management of female urethral
diverticulum is surgical, with excision
of the diverticulum and closure of the
tract communicating with the urethra. In
women with recurrent UTI and a large
PVR judged to be due to narrowing of
the urethra, dilatation of the urethra to
improve bladder emptying is often per-
formed, although there is no evidence to
support its efficacy (LoE 3) [85].
In the USA female urethral dilatation
is performed almost as much as treat-
ment for male urethral stricture disease,
despite the fact that true female ure-
thral stricture is an extremely uncommon
entity (LoE 3) [86]. The most common
etiologies of female urethral strictures
are traumatic or iatrogenic injury, and
inflammatory disease resulting in periu-
rethral fibrosis (LoE 3) [87].
Diverticula of the male penile urethra
are rare (LoE 3) [88]. Congenital urethral
diverticula usually occur in younger men
(mean age 25 years) whereas acquired
diverticula (due to trauma, urethral
| 8.2 |
Figure 5 Retrograde urethrogram shows strictures and diver-
ticula of male urethra after previous urethroplasty.
stricture disease or previous urethro-
plasty) occur in somewhat older men
(mean age 35 years) (Figure 5). Most male
urethral diverticula require open surgical
repair, although some can be left in situ
if they do not cause severe symptoms or
complications (LoE 3) [89].
7. BLADDER CALCULI
Up to 75% of bladder calculi may be
related to BOO, due to BPH, urethral
stricture, bladder neck contracture,
neuropathic bladder dysfunction and,
in women, urogenital prolapse (LoE 3)
(Figure 6) [90–91]. However, only 1% to
2% of men undergoing surgery for BPH
will have bladder calculi (LoE 3) [15].
A large PVR due to BOO predisposes
to UTI, and the combination of urinary
stasis and UTI promotes bladder stone
formation. Between 22% and 34% of
bladder calculi are associated with UTI,
most often Proteus, but other organ-
isms such as Pseudomonas, Ureaplasma
urealyticum, Providencia, Klebsiella,
Staphylococcus, and Mycoplasma species
are also capable of producing bacterial
urease (LoE 3) [90]. The enzyme urease
hydrolyzes urea, forming ammonium and
461
Chapter |8| Urinary tract infections in patients
Figure 6 Plain abdominal X-ray shows spina bifida, staghorn
calculus on right, and bladder stones; e figure xcretory uro-
gram shows hydronephrosis on right and neuropathic bladder
with filling defects (stones)
carbon dioxide, which increases urine pH.
Alkaline urine promotes supersaturation
and precipitation of crystals of magne-
sium ammonium phosphate and carbon-
ate apatite (LoE 3) [91].
In an older review, 92% of bladder cal-
culi occurred in men, 80% in patients
older than 50 years, and BPH was the
most frequent condition causing incom-
plete emptying (LoE 3) [92]. In a more
recent review 80% of bladder calculi
occurred in patients older than 60 years,
98% were male, and 88% had some form
of BOO (LoE 3) [93]. In one study the
disorders associated with bladder stones
were BPH and prostate cancer (48%),
neuropathic bladder (12%), and urethral
stricture (4%) in males, and neuropathic
bladder (48%), previous hysterectomy
(29%), and bladder cancer (6%) in females
(LoE 3) [94].
In an older study the major compo-
nents of vesical calculi were phosphate
(59%), oxalate (26%), and uric acid (5%)
(LoE 3) [92]. In a more recent study the
composition of bladder stones were mag-
nesium ammonium phosphate (MAP) in
50%, calcium (oxalate and/or phosphate)
in 40%, uric acid (urate) in 9%, and cys-
tine in 0.7%. UTI occurred as complica-
tion in 59% of patients with MAP stones,
in 41% with urate stones and in 20% with
calcium stones. The most often isolated
462
bacteria in the urine were Proteus species
(LoE 3) [94].
Bladder calculi associated with BPH
have historically been an absolute indi-
cation for TURP. In a recent report on
23 men with bladder stones secondary
to BPH, who had normal renal function,
no hydronephrosis, no history of AUR
or neuropathic bladder, the stones were
removed endoscopically and the patients
were treated with an alpha-receptor
blocker and/or finasteride. At a mean
follow-up of 30 months UTI developed in
22%, AUR in 17%, and recurrent calculi
in 17%. The authors concluded that men
with bladder stones can be successfully
and safely treated with transurethral
stone removal and medical manage-
ment of BPH (LoE 3) [95]. However,
it is debatable whether a stone recur-
rence rate of 17% within 30 months is
acceptable.
8. SCHISTOSOMIASIS
There is conflicting evidence on the rela-
tionship between Schistosoma haemato-
bium infestation and UTI (Figure 7). In
a study from Nigeria, urinary schisto-
somiasis combined with UTIs was found
in 22% of subjects. The most common bac-
teria were E. coli, Proteus, Pseudomonas
aeruginosa, Staphylococcus epidermidis
and Staphylococcus saprophyticus. The
authors stated that it is imperative to
incorporate the management of UTIs in
urinary schistosomiasis control programs
(LoE 3) [96].
In a study from a rural area in Nigeria
with prevalence rates of S. haemato-
bium infestation ranging from 64% in
children to 54% in adults, bacteriuria
occurred in 30% of study subjects with S
haematobium infection. The most com-
mon bacteria on urine culture were
Klebsiella species, Staphylococcus aureus,
E. coli and Candida albicans (LoE 3) [97].
However, in another study from Nigeria,
the prevalence of urinary schistosomiasis
 Urinary tract infections in obstruction of the urinary tract
Figure 7 Plain abdominal X-ray showing calcified bladder wall in patient with Schistosoma haema-
tobium infestation; post-void cystogram shows filling defects due to granulomata and blood clots
in patient with Bilharzia of the bladder.
was 51%, but significant bacteriuria was
found in only 0.9% of children with uri-
nary Bilharzia, compared to 1.8% in chil-
dren without urinary schistosomiasis
(LoE 3) [98].
In a study from a region in Kenya
where the prevalence of S. haematobium
infestation was 65%, subjects older
than 15 years had a greater frequency
of hydronephrosis. Among individu-
als with bladder calcification, 87% had
hydronephrosis or hydroureter, com-
pared to 40% in those without bladder
calcification (LoE 3) [99]. In a study from
Mali where the prevalence of S. haema-
tobium ranged from 77% in adolescents
to 51% in adults, bladder wall enlarge-
ment and irregularities, bladder masses,
pseudopolyps and dilatation of the upper
urinary tract were found ultrasono-
graphically in about one third of infected
individuals (LoE 3) [100].
In a study from Nigeria, ultrasound
imaging in volunteers infected with S.
haematobium showed bladder wall abnor-
malities in up to 70%, residual urine in
28%, hydroureter in 23% and hydrone-
phrosis in 19% (LoE 3) [101]. It is possi-
ble that urinary stasis may contribute to
a higher risk of UTI in subjects with S.
haematobium infestation. It seems pru-
dent to avoid invasive procedures such as
cystoscopy in these patients, because it
may introduce infection that may be dif-
ficult to eradicate.
| 8.2 |
9. UPPER TRACT OBSTRUCTION
It is generally accepted that urinary sta-
sis provides the time and opportunity
for bacteria to adhere to the urothelium,
multiply, and infect the host (LoE 3)
(Figure 8) [102]. A contributing factor
may be that ureteric obstruction causes
renal dysfunction, so the kidney(s) may
not be able to concentrate antibiotics in
the urine, making eradication of bacte-
ria difficult and potentially leading to
bacterial resistance. The most important
determinants of UTI caused by resistant
strains are previous use of antibiotics and
the presence of underlying urological dis-
eases (LoE 3) [85].
Hematogenous infection of the kidney
is rare in normal individuals, but it may
occur in patients with Staphylococcus
aureus bacteremia originating from cuta-
neous or oral sites. Experimental data
indicate that infection is enhanced when
the kidney is obstructed (LoE 2a) [103].
In an animal model of hematogenous
pyelonephritis, the kidney is relatively
resistant to infection by organisms injected
intravenously, but if a ureter is ligated,
the obstructed kidney becomes infected
(LoE 2a) [104].
In an experimental model in rats, tran-
sient ureteric obstruction (24 hours) with
inoculation of E. coli in the bladder after
release of ureteric obstruction predis-
poses to ascending pyelonephritis. It is
463
Chapter |8| Urinary tract infections in patients

UTI developed in 19% during 12 months

of follow up – in 84% of those cases
within the first 6 months. UTI devel-
oped in 39% of children with, and in 11%
without obstructive uropathy. High grade
hydronephrosis was associated with an
increased incidence of UTI: 40% in grade
IV hydronephrosis, 33% in grade III,
14% in grade II and 4% in grade I. UTI
occurred more frequently in patients
with, than in those without hydroureter
(47% vs. 13%). The authors recommended
antibiotic prophylaxis in neonates with
obstructive uropathy, severe hydroneph-
rosis or hydroureteronephrosis without
Figure 8 Ultrasound shows hydronephrosis.
VUR (LoE 3) [108].
However, another study of children with
antenatally diagnosed severe hydroneph-
postulated that acute ureteric obstruc- rosis secondary to obstructive megaureter
tion induces foci of medullary necrosis in or PUJO not maintained on prophylac-
the papillae, which may provide a nidus tic antibiotics reported an overall rate of
for bacterial invasion, while altered uro- UTI of only 4.3%. No statistically signifi-
dynamics after the release of ureteric cant difference in the infection rate was
obstruction may promote ascending infec- noted according to sex, obstruction level,
tion (LoE 2a) [105].
There are few clinical studies on the
risk of UTI associated with upper tract
obstruction. In children prenatally diag-
nosed with severe hydronephrosis and
not on antibiotic prophylaxis, the over-
all incidence of UTI during the first 12
months postnatally was 36%, and it was
more common with ureterovesical junc-
tion (UVJ) obstruction than with pel-
viureteric junction obstruction (PUJO)
(50% vs. 31%). Most cases of UTI (93%)
occurred in the first 6 months postnatally
(LoE 3) (Figure 9) [106].
In another study of children with pre-
natally detected renal pelvic dilata-
tion, the estimated cumulative incidence
of UTI was 8% at age 12 months, 13%
at 24 months and 21% at 36 months.
Independent predictors of UTI during fol-
low up were female gender and the pres-
ence of vesico-ureteric reflux (VUR) or
urinary tract obstruction (LoE 3) [107].
Figure 9 Excretory urogram shows right hydro-ureteronephrosis
In a study of children with prenatally due to congenital ureterovesical junction obstruction in a 4-year
diagnosed nonrefluxing hydronephrosis, old child.

464
 Urinary tract infections in obstruction of the urinary tract | 8.2 |

Despite a surprising lack of relevant

clinical studies, it is generally accepted
practice that in patients with UTI and
upper urinary tract obstruction, empiric
antibiotic treatment should be comple-
mented with urgent intervention to drain
the urinary tract (e.g. percutaneous neph-
rostomy or double-J ureteric stenting).
This should be followed with targeted
antibiotic treatment (according to urine
culture) and definitive surgery to remove
the cause of obstruction once infection is
under control (LoE 4).

9.1 Papillary necrosis

The role of UTI in the development and
progression of renal papillary necrosis
(RPN) is controversial (Figure 11). In
one study, 67% of patients with RPN had
acute or chronic UTI, but in only 15% was
pyelonephritis alone associated with RPN
(LoE 3) [113]. Although there are numer-
Figure 10 Retrograde ureteropyelogram shows pelvi-ureteric ous factors that on their own may cause
junction obstruction.
RPN, the coexistence of multiple factors
(e.g. diabetes mellitus or obstruction and
hydronephrosis grade, or circumcision UTI) increases the risk of developing
status. The authors concluded that antibi- RPN [85]. Therefore, in ureteric obstruc-
otic prophylaxis is unlikely to benefit most tion it is important to prevent UTI and,
children with hydronephrosis secondary if UTI is present, to drain the kidney by
to upper tract obstruction (LoE 3) (Figure ureteric catheter or percutaneous neph-
10) [109]. rostomy (LoE 4) [85, 114].
In some countries, renal infection is still
a common reason for nephrectomy. In a
study from Jordan, infection-related renal
conditions were the reason for nephrec-
tomy in 38% of cases (LoE 3) [110]. In a
report from Pakistan, 77% of nephrecto-
mies were for benign conditions, and in
this group the reason for nephrectomy
was renal stone in 53%, chronic pyelone-
phritis in 20%, neglected PUJO in 16%,
and renal tuberculosis in 8% (LoE 3) [111].
In a study from Nigeria, the indication for
nephrectomy was chronic pyelonephritis in
29% and hydronephrosis in 17% of cases.
The authors emphasised the importance (A) (B)
of early diagnosis and proper treatment of Figure 11 Excretory urogram shows (A) papillary necrosis
UTIs (LoE 3) [112]. and (B) medullary sponge kidney.

465
Chapter |8| Urinary tract infections in patients
9.2 Renal calyceal diverticula
Renal calyceal diverticula are often
asymptomatic, but may be associated
with UTI and stone formation in up to
39% of cases (LoE 3) (Figure 12) [115].
However, there appear to be no recent
studies reporting the incidence of UTI
in patients with calyceal diverticula.
The management is usually conserva-
tive, but indications for surgery include
persistent pain, UTI and nephrolithiasis
(LoE 3) [116]. Open surgery has been
largely replaced by percutaneous, urete-
ro-renoscopic or laparoscopic approaches
to remove stones and obliterate the
diverticulum, or to dilate the connection
between the collecting system and the
diverticulum to improve drainage (LoE 3)
[117–119].
9.3 Emphysematous pyelonephritis
In a study of patients with emphyse-
matous pyelonephritis (EPN), diabetes
mellitus was present in 96% and hydrone-
phrosis in 25% of cases. The most com-
mon pathogens were E. coli (69%) and
Klebsiella pneumoniae (29%). The mortal-
ity rate in patients who received antibiotic
treatment alone was 40%. The success rate
of management by percutaneous nephros-
tomy or ureteric catheter combined with
antibiotic treatment was 66% in the whole
group, 100% in those with gas in the renal
collecting system or parenchyma only, and
Figure 12 Intravenous pyelogram showing calyceal diverticulum containing a stone in the
right kidney (seen as a filling defect in the early pyelogram phase on the left).
466
85% in those with extension of gas into
the perinephric or pararenal spaces but
fewer than 2 risk factors (thrombocyto-
penia, acute renal function impairment,
disturbance of consciousness, or shock).
Patients with 2 or more risk factors had
a significantly higher failure rate (92%
vs. 15%), indicating that in such patients
immediate nephrectomy is the preferred
treatment (LoE 3) [120].
In another study of patients with EPN,
diabetes mellitus was present in all, but
ipsilateral hydronephrosis was found
in only one patient (6%). E. coli was the
commonest organism present in urine
cultures (52%), followed by Klebsiella
pneumoniae (24%) (LoE 3) [121].
Hydronephrosis, renal or perirenal
abscess, and even EPN are often first
treated percutaneously, with surgical
therapy later on, when the patient’s con-
dition has been stabilized (LoE 4) [122].
9.4 Xanthogranulomatous
pyelonephritis
In a study of patients who underwent
nephrectomy for xanthogranulomatous
pyelonephritis (XGP), all had renal cal-
culi, the ipsilateral kidney was non-
functioning but enlarged because of
hydronephrosis or pyonephrosis in all
cases and the contralateral kidney was
enlarged because of compensatory hyper-
trophy in 50% (LoE 3) [123].
 Urinary tract infections in obstruction of the urinary tract
In another study, patients with XGP
represented 19% of all nephrectomies
performed for pyelonephritis. CT findings
included hydronephrosis, kidney enlarge-
ment, poor excretion of contrast medium,
and air in the urinary tract. All patients
had renal calculi, 34% of which were stag-
horn calculi. The main organism isolated
was E. coli (LoE 3) [124]. Nephrectomy
and antibiotics are the treatment of choice
for XGP.
10. BOWEL IN THE URINARY TRACT
Bacteriuria is common in all patients
with bowel incorporated into the uri-
nary tract. Asymptomatic bacteriuria in
patients with a continent urinary diver-
sion is generally of no clinical impor-
tance, because the bacterial strains
growing in the reservoir represent colo-
nization rather than infection (LoE 3)
[125]. Intestine incorporated into the
genitourinary tract remains capable
of producing a local antibody response
against bacteria (as measured by uri-
nary IgA and IgG) (LoE 3).[126–127]
After ileocystoplasty, the incorporated
ileum may produce larger quantities
of IgA than the normal urinary tract,
thus preventing attachment of E. coli to
uroepithelial cells and subsequent tis-
sue invasion leading to clinical infection
(LoE 2b) [128–129].
Complete emptying seems to reduce
the bacterial burden, while clean inter-
mittent self-catheterization (CISC) and
residual urine seem to increase it. The
increased rate of bacteriuria indicates
a lack of antibacterial defenses, and the
symptom-free state of most patients sug-
gests that only a restricted host response
is triggered (LoE 3) [130–131]. Whereas
most (>70%) of the urine samples from
patients with neobladders showed
anaerobic or aerobic bacterial growth,
and uropathogens were identified in
about 45% of the samples, the local host
response (as measured by concentrations
| 8.2 |
of the inflammatory mediators inter-
leukin 6 and 8 in the urine) was markedly
induced only by uropathogenic strains in
the urine, but not by nonpathogenic or
anaerobic strains (LoE 3) [132].
In nonrefluxing enterocystoplasties
upper tract bacteriuria was demonstrated
after renal pelvic aspiration of urine
in 89% patients. Despite attempts to
maintain sterile urine with prophylactic
antimicrobial medications, ascending bac-
terial migration was the most plausible
cause for the bacteriuria (LoE 3) [133].
In a study of patients with an ortho-
topic neobladder after radical cystec-
tomy, the estimated 5-year probability of
UTI and urosepsis were 58% and 18%,
respectively. Urine culture with greater
than 100,000 bacteria and female gen-
der were the only factors predictive of
UTI on multivariate analysis. Urosepsis
occurred in 12% of patients overall, but
31% of those with a UTI went on to have
urosepsis. Recurrent UTI was the only
predictor for urosepsis. Hydronephrosis,
ureteric reflux and CISC did not increase
the risk of UTI or urosepsis. The authors
recommended prophylactic antibiotics for
patients with recurring UTIs, but not for
those with a positive urinary culture in
the absence of specific voiding symptoms
(LoE 3) [134].
In another study urine cultures from
67% of neobladder patients not on anti-
biotic therapy were culture positive, and
half of these contained uropathogenic
species, such as E. coli, Klebsiella pneu-
moniae, Pseudomonas aeruginosa, and
Enterococcus faecalis. Bacterial coloniza-
tion was strongly correlated with resid-
ual urine. Anaerobic strains were found
more frequently in urine from ileal than
colonic neobladders. Patients on prophy-
lactic antibiotics had bacteriuria in 80%
of the samples, the majority being anaer-
obic strains. The authors concluded that
antibiotic prophylaxis does not seem to
reduce the bacterial burden, but inter-
feres with the bacterial composition (LoE
3) [135].
467
Chapter |8| Urinary tract infections in patients
A study of patients with orthotopic ileal
neobladders not on antibiotic prophylaxis
found a steady decrease in the prevalence
of positive urine cultures, from 75% to
36% to 7% at 1, 6 and 18 months post-
operatively. Bacteriuria was found occa-
sionally in 68% and persistently in 15%,
while only 17% had no bacteriuria. E.
coli was the commonest organism (77%)
followed by Klebsiella pneumonia (16%).
The frequency of nocturnal enuresis (NE)
decreased with time, from 87% to 42%
to 28% at 1, 6 and 18 months postopera-
tively. There was a significant correlation
between the presence of bacteriuria and
NE during the first 6 months, but not
after that (LoE 3) [136].
In a study of patients with an ileal
neobladder 3–9 months after surgery,
recurrent bacteriuria was found in 57%,
while no bacteriuria occurred in 23%. E.
coli strains were cultured from 80% of
patients with persistently positive urine.
The concentration of leukocytes in the
urine was higher in those with sterile
urine than in those with asymptomatic
bacteriuria (LoE 3) [137].
There is an increased risk of adeno-
carcinoma of the colon after ureterosig-
moidostomy, possibly because bacteria
catalyse the formation and activation of
carcinogens such as N-nitrosamines (LoE
3) [138]. However, bacteriuria appears to
be less common in patients with a colonic
conduit (38%) than in those with an ileal
conduit (73%) (LoE 3) [138].
Bowel (ileum and colon) that is incor-
porated into the urinary tract predisposes
to stone formation because of bacterial
colonization with urea-splitting organ-
isms, urinary stasis, mucus production,
and the presence of foreign bodies (e.g.
metal staples). However, bladder augmen-
tation with a gastric segment has a lower
incidence of calculus formation, because
it produces minimal mucus and secretes
acid, thereby lowering urine pH and inhib-
iting bacterial growth (LoE 3) [139–140].
The incidence of urolithiasis in patients
with augmentation enterocystoplasty
468
varies from 0 to 53%, in ileal conduits
from 4% to 20%, and in colon conduits
from 3% to 11% (LoE 3) [141–142].
Continent diversions have higher stone
rates than freely draining conduits. The
Indiana pouch has a stone incidence of
3% to 13%, the Kock pouch 4% to 43%,
the Mainz pouch around 8% and the
cecal reservoir around 20% (LoE 3) [140,
143–144].
The stone recurrence rate in patients
with bowel urinary diversions can be as
high as 65% during 5 years of follow up
(LoE 3) [145]. Prophylactic measures
include high oral fluid intake, complete
evacuation of the reservoir, regular irri-
gation of the pouch with saline solution
or sterile water to remove mucus and
crystals, and eradication of urea-splitting
organisms (LoE 3) [140, 146].
There appears to be no statistically
significant difference in the incidence of
upper tract UTI and renal deterioration
between different types of urinary diver-
sion using ileum or colon, or between
antirefluxing versus freely refluxing ure-
terointestinal anastomotic techniques in
conduit diversions. However, wide con-
fidence intervals caused by the small
number of studied patients do not rule
out important differences (LoE 3) [131,
147–148].
11. BACTERIOLOGY
Urinary tract abnormalities may predis-
pose to infection with organisms other
than E. coli, and long-term antibiotic
therapy often leads to bacterial resistance
or fungal superinfection with Candida
albicans (LoE 3) [122]. The reported
prevalence rates of bacteria isolated
from serious UTI are: E. coli 21–54%,
Enterococci species 6–23%, miscellane-
ous Gram-negatives 4–20%, Pseudomonas
aeruginosa 2–19%, Providencia spe-
cies 18%, Klebsiella pneumoniae 2–17%,
Enterobacter species 2–10%, Proteus mira-
bilis 1–10%, Citrobacter species 5–6%,
 Urinary tract infections in obstruction of the urinary tract
coagulase negative Staphylococci 1–4%,
group B Streptococci 1–4%, Staphylococcus
aureus 1–2% (LoE 3) [149–150]. In infants
and children with UTI, there is a sig-
nificantly higher association of non-E.
coli disease with VUR, hydronephrosis,
younger age, and previous antibiotic treat-
ment (LoE 3) [151].
Urinary tract obstruction may permit
ascending infection of E. coli strains with
lower adhesive ability. P-fimbriae are
mannose-resistant adhesins of uropatho-
genic E. coli (UPEC) which cause acute
pyelonephritis (APN). The pap gene
cluster (PapGI, -II, and -III) encodes
the proteins required for P-fimbrial bio-
genesis [152]. E. coli strains lacking the
P-fimbriae phenotype are more com-
monly associated with APN in children
with urinary tract abnormalities (LoE 3)
[153]. There is a predominance of papG
Class II allele in infants with APN and
normal urinary tract anatomy (LoE 3)
[154]. In adults the incidence of the papG
class II allele in patients with hydrone-
phrosis is less than in those without uri-
nary tract abnormalities (69% versus
93%). These findings indicate that struc-
tural or functional abnormalities of the
urinary tract may permit infection with
E. coli strains that would not be patho-
genic in a normal urinary tract (LoE 3)
[155].
12. SPECIAL INVESTIGATIONS
The aim of imaging in UTI is to detect
conditions that must be corrected to avoid
rapid deterioration of renal function or
systemic sepsis, and to prevent recurrent
infections and long-term kidney dam-
age. Indications for imaging in patients
with UTI are shown in the Table [85, 122,
156–159].
Intravenous urography (IVU) and ultra-
sound (US) have traditionally been used
in the assessment of complicated UTI.
US with abdominal radiography (AXR/
KUB) is as accurate as IVU in detecting
| 8.2 |
Table Indications for imaging of patients with UTI.
•  Babies and children
•  Men (see text for exceptions)
•  Patients with history of:
o voiding difficulties
o urolithiasis
o previous renal disease
o previous urinary tract surgery
•  Neurological disease/neuropathic bladder
•  Poor response to appropriate antibiotic treatment
(after 3 to 6 days)
•  Recurrent or unusually severe symptoms
•  Diabetes mellitus or immunocompromised states
•  Renal failure
•  Haematuria (macroscopic, or microscopic >1 month
after UTI)
•  Acute urinary retention
•  Infection with urea-splitting bacteria
important urological abnormalities in
men presenting with UTI (LoE 2a) [5].
Computerised tomography (CT) has
become accepted as a more sensitive
modality. CT urography is increasingly
performed as a comprehensive urinary
tract imaging study. Magnetic resonance
(MR) imaging is particularly useful in
those with iodinated contrast allergies.
Nuclear medicine has a limited role but is
useful in the assessment of renal function
prior to surgery (LoE 3) [85, 158, 160–
161]. Imaging with microbubble ultra-
sonographic contrast agents (USCAs) can
overcome the limitations of conventional
B-mode imaging and may become the
modality of choice in the future (LoE 2a)
[162–164].
Imaging may not be necessary in all
men with febrile UTI. It has been sug-
gested that in men younger than 45
years with a first acute UTI no radio-
logic, endoscopic or urodynamic investi-
gation is required, provided a urethral
stricture has been excluded (LoE 3)
469
Chapter |8| Urinary tract infections in patients
[165]. Urological evaluation of men with
febrile UTI should primarily be focused
on the lower urinary tract, especially in
men with a history of voiding difficulties,
AUR, the presence of microscopic hae-
maturia at follow-up after one month, or
early recurrent symptomatic UTI (LoE
3) [157].
In women with early recurrent UTI,
imaging and cystoscopy are usually rec-
ommended, although the yield may be
quite low, with significant abnormalities
being detected in only 8%. The negative
predictive value of normal radiological
imaging is 99%, suggesting that women
with normal imaging do not need cystos-
copy (LoE 3) [166–167].
In patients with complicated acute
pyelonephritis (APN), urine cultures are
positive in 90–98% of cases and bacter-
emia may occur in 21–42%, but in only
a small minority (around 1%) the path-
ogens found in blood cultures are dif-
ferent from those in the urine (LoE 3)
[168–169]. Some authors have suggested
that blood cultures should be reserved
for patients with an uncertain diagno-
sis, those who are immunocompromised,
and those who do not respond promptly
to treatment (LoE 3) [170]. However,
others recommend that blood cultures
should be done in all patients with com-
plicated APN, because bacteremia indi-
cates severe disease, which is more likely
to recur within 6 months in patients with
non-E. coli bacteremia and those with
urolithiasis or hydronephrosis, especially
men (LoE 3) [169].
13. ANTIBIOTIC TREATMENT
The treatment of UTI in the presence of
urinary tract obstruction requires effec-
tive antibiotic therapy as well as appro-
priate Urological intervention to remove
predisposing factors and to restore as
far as possible the normal anatomy and
function of the urinary tract in order to
470
prevent septicemia and recurrent UTI
(LoE 3) [85].
In patients with mild to moderate UTI
(no nausea or vomiting) the recommended
empirical treatment is an oral fluoro-
quinolone used on an outpatient basis
(e.g. norfloxacin, ciprofloxacin, ofloxacin).
Severely ill patients with possible uro-
sepsis should be hospitalized and empiri-
cal treatment should include intravenous
ampicillin and gentamicin, or alternatives
such as ciprofloxacin, levofloxacin, ceftri-
axone, aztreonam, ticarcillin-clavulanate
or imipenem-cilastin. Every effort should
be made to correct any underlying urinary
tract abnormalities that may compromise
treatment efficacy. Therapy is usually
switched from parenteral to oral as soon
as possible (LoE 3) [85].
Empirical therapy of serious UTI
should usually include an intravenous
antipseudomonal agent. Targeted ther-
apy should be initiated once susceptibil-
ity data are known. Agents commonly
prescribed include aminoglycosides,
beta-lactamase inhibitor combinations,
imipenem, advanced-generation cepha-
losporins and fluoroquinolones. Several
pivotal clinical trials support the use
of fluoroquinolones for serious UTIs,
with ciprofloxacin the most frequently
studied drug (LoE 3) [149–150, 171].
Fluoroquinolones which are equivalent to
ciprofloxacin 500 mg twice daily, include
levofloxacin 500 mg once daily and gati-
floxacin 400 mg once daily (LoE 3) [172].
In a recent study from the USA, 92% of
bacterial isolates from patients with com-
plicated UTI or APN were susceptible to
levofloxacin and ciprofloxacin (LoE 3)
[173–174].
A 7-day course of therapy is recom-
mended for women with symptoms of 1
week or more, men (even those with appar-
ently uncomplicated cystitis), and indi-
viduals with possible complicating factors.
For patients with fever or more severe sys-
temic infection, therapy for 10 to 14 days
is recommended. Urine cultures should
 Urinary tract infections in obstruction of the urinary tract
be performed during antibiotic treatment
and 7–14 days after cessation of therapy
to determine whether treatment has been
effective (LoE 3) [6, 85, 165, 175].
14. FURTHER RESEARCH
Interesting preliminary data indicate
that acute and/or chronic intrapros-
tatic inflammation may be important
in the pathogenesis as well as pro-
gression of BPH. Further research is
required to substantiate or refute this
theory, and also to determine the possi-
ble role of anti-inflammatory medication
in the prevention of BPH as well as its
complications.
Most clinical trials of medical therapy
for BPH have excluded men with a large
PVR, bladder stones or recurrent UTI,
with the implication that prostatectomy
is indicated for all such patients. Recent
studies have suggested that bladder cal-
culi associated with BPH can be managed
with transurethral stone removal and
medical treatment of BPH. Prospective,
randomised clinical trials are required to
establish the role of medical treatment
in men with complications such as recur-
rent UTI or bladder calculi associated
with BPH.
The observation that prostatitis may
cause an increased total serum PSA and
decreased free/total PSA ratio, which may
be falsely interpreted as a sign of prostate
cancer, indicates the necessity for further
research to determine the role of empiric
antibiotic treatment in order to avoid
unnecessary prostate biopsy.
The theory that inflammation of the
prostate may be an etiological factor
in the development of prostate cancer
should be further investigated, especially
with regard to the potential use of anti-
inflammatory medication to decrease the
incidence of prostate cancer.
In view of the conflicting evidence in
the literature on the role of antibiotic
| 8.2 |
prophylaxis in children with antenatally
diagnosed hydronephrosis secondary to
upper tract obstruction, prospective, ran-
domized studies are required in order to
resolve the controversies.
15. CONCLUSIONS
The current enthusiasm for evidence
based medicine requires the ranking of
recommendations or guidelines on the
basis of levels of evidence, with the high-
est status assigned to prospective, rand-
omized clinical trials, and the lowest rank
assigned to “expert opinion”. However,
there are certain conditions where pro-
spective randomized trials have never
been done, largely due to the logic or
“common sense” of expert opinion.
A prime example of this is severe UTI
in the presence of urinary tract obstruc-
tion, e.g. pyocystis or pyonephrosis. Logic
dictates emergency drainage by means
of transurethral bladder catheterization,
ureteric stenting or percutaneous neph-
rostomy, and it is unlikely that a rand-
omized trial comparing drainage with
non-drainage will ever be performed. This
leads to the paradoxical phenomenon of a
high grade recommendation based on a
low level of evidence.
The increasing demands for evidence
based medical practice and exhaustive
treatment protocols based on consen-
sus guidelines should not blind us to the
imperatives of simple logic or plain com-
mon sense, or the value of expert opinion
based on clinical experience.
UTI in the presence of underlying uro-
logical abnormalities provides an excel-
lent model for studying the relationships
between anatomy, physiology, pathology,
microbiology and pharmacology. Although
major advances in the treatment of com-
plicated UTI have been made during the
past few decades, many questions remain
unanswered, and much investigative
work still needs to be done.
471
Chapter |8| Urinary tract infections in patients
REFERENCES
1. Corrado ML, Grad C, and Sabbaj J,
Norfloxacin in the treatment of urinary
tract infections in men with and without
identifiable urologic complications. Am
J Med, 1987. 82(6B): 70–4.
2. Chen SS, Chen KK, Lin AT, Chang YH,
Wu HH, Hsu TH, Chiu AW, and Chang
LS, Complicated urinary tract infection:
analysis of 179 patients. Zhonghua Yi Xue
Za Zhi (Taipei), 1998. 61(11): 651–6.
3. Andrews SJ, Brooks PT, Hanbury DC,
King CM, Prendergast CM, Boustead GB,
and McNicholas TA, Ultrasonography
and abdominal radiography versus
intravenous urography in investigation
of urinary tract infection in men: prospec-
tive incident cohort study. BMJ, 2002.
324(7335): 454–6.
4. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
5. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
6. Lipsky BA, Urinary tract infections in
men. Epidemiology, pathophysiology,
diagnosis, and treatment. Ann Intern
Med, 1989. 110(2): 138–50.
7. Johnson DE, Russell RG, Lockatell CV,
Zulty JC, and Warren JW, Urethral
obstruction of 6 hours or less causes bacte-
riuria, bacteremia, and pyelonephritis in
mice challenged with “nonuropathogenic”
Escherichia coli. Infect Immun, 1993.
61(8): 3422–8.
8. Payne SR, Timoney AG, McKenning ST,
den Hollander D, Pead LJ, and Maskell
RM, Microbiological look at urodynamic
studies. Lancet, 1988. 2(8620): 1123–6.
9. Ubhi SS and Cooke TJ, Infective arthritis
secondary to bladder outflow obstruction.
Postgrad Med J, 1990. 66(782): 1076–7.
10. Roehrborn CG and McConnell JD,
Benign prostatic hyperplasia: etiology,
pathophysiology and natural history, in
Campbell-Walsh urology, Campbell MF,
Wein AJ, and Kavoussi LR, Editors. 2007,
472
Saunders Elsevier: Philadelphia, PA.
p. 2727–2765.
11. Riehmann M, Goetzman B, Langer E,
Drinka PJ, Rhodes PR, and Bruskewitz
RC, Risk factors for bacteriuria in men.
Urology, 1994. 43(5): 617–20.
12. Barabas G and Molstad S, No association
between elevated post-void residual vol-
ume and bacteriuria in residents of nurs-
ing homes. Scand J Prim Health Care,
2005. 23(1): 52–6.
13. Powell PH, Smith PJ, and Feneley RC,
The identification of patients at risk from
acute retention. Br J Urol, 1980. 52(6):
520–2.
14. Stimson JB and Fihn SD, Benign pros-
tatic hyperplasia and its treatment. J Gen
Intern Med, 1990. 5(2): 153–65.
15. McConnell JD, Barry MJ, and Bruskewitz
RC, Benign prostatic hyperplasia: diagno-
sis and treatment. Agency for Health Care
Policy and Research. Clin Pract Guidel
Quick Ref Guide Clin, 1994(8): 1–17.
16. Kadow C, Feneley RC, and Abrams PH,
Prostatectomy or conservative manage-
ment in the treatment of benign prostatic
hypertrophy? Br J Urol, 1988. 61(5):
432–4.
17. Flanigan RC, Reda DJ, Wasson JH,
Anderson RJ, Abdellatif M, and
Bruskewitz RC, 5-year outcome of surgi-
cal resection and watchful waiting for
men with moderately symptomatic benign
prostatic hyperplasia: a Department of
Veterans Affairs cooperative study. J Urol,
1998. 160(1): 12–6;
discussion 16–7.
18. Holtgrewe HL, Mebust WK, Dowd JB,
Cockett AT, Peters PC, and Proctor C,
Transurethral prostatectomy: practice
aspects of the dominant operation in
American urology. J Urol, 1989. 141(2):
248–53.
19. Mebust WK, Holtgrewe HL, Cockett
AT, and Peters PC, Transurethral pros-
tatectomy: immediate and postoperative
complications. Cooperative study of 13
participating institutions evaluating
3,885 patients. J Urol, 141: 243–247,
1989. J Urol, 2002. 167(1): 5–9.
20. Fujita K, Murayama K, Ida T, Sumiyoshi
Y, Yoshida K, Takaha M, Kaji S, and
 Urinary tract infections in obstruction of the urinary tract
Kitagawa M, [A cooperative study on the
incidence of bacteriuria in patients with
benign prostatic hypertrophy]. Nippon
Hinyokika Gakkai Zasshi, 1994. 85(9):
1348–52.
21. Hunter DJ, Berra-Unamuno A, and
Martin-Gordo A, Prevalence of urinary
symptoms and other urological conditions
in Spanish men 50 years old or older.
J Urol, 1996. 155(6): 1965–70.
22. Bautista OM, Kusek JW, Nyberg LM,
McConnell JD, Bain RP, Miller G,
Crawford ED, Kaplan SA, Sihelnik SA,
Brawer MK, and Lepor H, Study design
of the Medical Therapy of Prostatic
Symptoms (MTOPS) trial. Control Clin
Trials, 2003. 24(2): 224–43.
23. McConnell JD, Roehrborn CG, Bautista
OM, Andriole GL, Jr., Dixon CM, Kusek
JW, Lepor H, McVary KT, Nyberg LM, Jr.,
Clarke HS, Crawford ED, Diokno A, Foley
JP, Foster HE, Jacobs SC, Kaplan SA,
Kreder KJ, Lieber MM, Lucia MS, Miller
GJ, Menon M, Milam DF, Ramsdell JW,
Schenkman NS, Slawin KM, and Smith
JA, The long-term effect of doxazosin,
finasteride, and combination therapy on
the clinical progression of benign prostatic
hyperplasia. N Engl J Med, 2003. 349(25):
2387–98.
24. Bruskewitz RC, Iversen P, and Madsen
PO, Value of postvoid residual urine deter-
mination in evaluation of prostatism.
Urology, 1982. 20(6): 602–4.
25. Williams M and Hole DJ, Bacteriuria in
patients undergoing prostatectomy. J Clin
Pathol, 1982. 35(11): 1185–9.
26. Okishio N, Hanai S, Ishiguro K, Yanaoka
M, Tamai H, and Naide Y, [Urinary tract
infection associated with benign prostatic
hypertrophy and related diseases and
transurethral surgery]. Hinyokika Kiyo,
1986. 32(11): 1610–6.
27. Pestalozzi DM, Boss HP, and Knonagel
H, [Infectious complications after tran-
surethral resection]. Helv Chir Acta, 1992.
59(3): 497–500.
28. te Slaa E, De Wildt MJ, Debruyne FM, De
Graaf R, and De La Rosette JJ, Urinary
tract infections following laser prostatec-
tomy: is there a need for antibiotic prophy-
laxis? Br J Urol, 1996. 77(2): 228–32.
| 8.2 |
29. Miller J, Ludwig M, Schroeder-Printzen
I, Schiefer HG, and Weidner W, Tran-
surethral laser therapy and urinary tract
infections. Ann Urol (Paris), 1996. 30(3):
131–8.
30. Ibrahim AI, Bilal NE, Shetty SD, Patil
KP, and Gommaa H, The source of organ-
isms in the post-prostatectomy bacteriuria
of patients with pre-operative sterile urine.
Br J Urol, 1993. 72(5 Pt 2): 770–4.
31. Ohkawa M, Shimamura M, Tokunaga S,
Nakashima T, and Orito M, Bacteremia
resulting from prostatic surgery in
patients with or without preoperative
bacteriuria under perioperative antibiotic
use. Chemotherapy, 1993. 39(2): 140–6.
32. Kiwamoto T, Endo T, and Sekizawa K, [A
case of septic pulmonary embolism induced
by urinary tract infection]. Nihon Kokyuki
Gakkai Zasshi, 2004. 42(1): 89–93.
33. Nickel JC, Downey J, Young I, and Boag
S, Asymptomatic inflammation and/or
infection in benign prostatic hyperplasia.
BJU Int, 1999. 84(9): 976–81.
34. Gorelick JI, Senterfit LB, and Vaughan
ED, Jr., Quantitative bacterial tissue cul-
tures from 209 prostatectomy specimens:
findings and implications. J Urol, 1988.
139(1): 57–60.
35. Mohanty NK and Jolly BB, Prevalence of
bacterial prostatitis in benign prostatic
hyperplasia. Indian J Pathol Microbiol,
1996. 39(2): 111–4.
36. Soler Soler JL, Hidalgo Dominguez MR,
Zuluaga Gomez A, Martinez Torres JL,
Lardelli Claret P, Liebana Urena J, and
Saharour G, [Bacterial content of the enu-
cleated prostate gland]. Arch Esp Urol,
1999. 52(8): 823–34.
37. Tokunaga S, Ohkawa M, Oshinoya Y,
Nakashima T, Hisazumi H, Nishikawa T,
Shimamura M, and Miyagi T, Bacteremia
from transurethral prostatic resection
under prophylactic use of antibiotics.
Kansenshogaku Zasshi, 1991. 65(6):
698–702.
38. Moore RA, Inflammation of the prostate
gland. J Urol, 1937. 38: 173–82.
39. Kohnen PW and Drach GW, Patterns of
inflammation in prostatic hyperplasia: a
histologic and bacteriologic study. J Urol,
1979. 121(6): 755–60.
473
Chapter |8| Urinary tract infections in patients
40. Schaeffer AJ, Wendel EF, Dunn JK, and
Grayhack JT, Prevalence and significance
of prostatic inflammation. J Urol, 1981.
125(2): 215–9.
41. Kramer G, Steiner GE, Handisurya A,
Stix U, Haitel A, Knerer B, Gessl A, Lee
C, and Marberger M, Increased expression
of lymphocyte-derived cytokines in benign
hyperplastic prostate tissue, identifica-
tion of the producing cell types, and effect
of differentially expressed cytokines on
stromal cell proliferation. Prostate, 2002.
52(1): 43–58.
42. Steiner GE, Stix U, Handisurya A,
Willheim M, Haitel A, Reithmayr F,
Paikl D, Ecker RC, Hrachowitz K,
Kramer G, Lee C, and Marberger M,
Cytokine expression pattern in benign
prostatic hyperplasia infiltrating T cells
and impact of lymphocytic infiltration on
cytokine mRNA profile in prostatic tissue.
Lab Invest, 2003. 83(8): 1131–46.
43. Steiner GE, Newman ME, Paikl D,
Stix U, Memaran-Dagda N, Lee C, and
Marberger MJ, Expression and function
of pro-inflammatory interleukin IL-17 and
IL-17 receptor in normal, benign hyper-
plastic, and malignant prostate. Prostate,
2003. 56(3): 171–82.
44. Kramer G, Mitteregger D, and Marberger
M, Is benign prostatic hyperplasia (BPH)
an immune inflammatory disease? Eur
Urol, 2007. 51(5): 1202–16.
45. Kramer G and Marberger M, Could
inflammation be a key component in the
progression of benign prostatic hyperpla-
sia? Curr Opin Urol, 2006. 16(1): 25–9.
46. Koseoglu RD, Erdemir F, Parlaktas BS,
Filiz NO, Uluocak N, and Etikan I, Effect
of chronic prostatitis on angiogenic activ-
ity and serum prostate specific antigen
level in benign prostatic hyperplasia.
Kaohsiung J Med Sci, 2007. 23(8): 387–94.
47. Yi FX, Wei Q, Li H, Li X, Shi M, Dong
Q, and Yang YR, Risk factors for pros-
tatic inflammation extent and infection
in benign prostatic hyperplasia. Asian J
Androl, 2006. 8(5): 621–7.
48. Mishra VC, Allen DJ, Nicolaou C, Sharif
H, Hudd C, Karim OM, Motiwala HG,
and Laniado ME, Does intraprostatic
inflammation have a role in the pathogen-
esis and progression of benign prostatic
474
hyperplasia? BJU Int, 2007. 100(2):
327–31.
49. Sciarra A, Mariotti G, Salciccia S, Gomez
AA, Monti S, Toscano V, and Di Silverio F,
Prostate growth and inflammation.
J Steroid Biochem Mol Biol, 2008.
108(3–5): 254–60.
50. Ulleryd P, Zackrisson B, Aus G, Bergdahl
S, Hugosson J, and Sandberg T, Prostatic
involvement in men with febrile urinary
tract infection as measured by serum
prostate-specific antigen and transrectal
ultrasonography. BJU Int, 1999. 84(4):
470–4.
51. Hasui Y, Marutsuka K, Asada Y, Ide
H, Nishi S, and Osada Y, Relationship
between serum prostate specific antigen
and histological prostatitis in patients
with benign prostatic hyperplasia.
Prostate, 1994. 25(2): 91–6.
52. Schatteman PH, Hoekx L, Wyndaele
JJ, Jeuris W, and Van Marck E,
Inflammation in prostate biopsies of men
without prostatic malignancy or clinical
prostatitis: correlation with total serum
PSA and PSA density. Eur Urol, 2000.
37(4): 404–12.
53. Yaman O, Gogus C, Tulunay O, Tokatli Z,
and Ozden E, Increased prostate-specific
antigen in subclinical prostatitis: the role
of aggressiveness and extension of inflam-
mation. Urol Int, 2003. 71(2): 160–4.
54. Ozden C, Ozdal OL, Guzel O, Han O,
Seckin S, and Memis A, The correlation
between serum prostate specific antigen
levels and asymptomatic inflammatory
prostatitis. Int Urol Nephrol, 2007. 39(3):
859–63.
55. Kandirali E, Boran C, Serin E, Semercioz
A, and Metin A, Association of extent
and aggressiveness of inflammation with
serum PSA levels and PSA density in
asymptomatic patients. Urology, 2007.
70(4): 743–7.
56. Jung K, Meyer A, Lein M, Rudolph B,
Schnorr D, and Loening SA, Ratio of free-
to-total prostate specific antigen in serum
cannot distinguish patients with prostate
cancer from those with chronic inflammation
of the prostate. J Urol, 1998. 159(5): 1595–8.
57. Lorente JA, Arango O, Bielsa O,
Cortadellas R, and Gelabert-Mas A, Effect
of antibiotic treatment on serum PSA and
 Urinary tract infections in obstruction of the urinary tract
percent free PSA levels in patients with
biochemical criteria for prostate biopsy and
previous lower urinary tract infections. Int
J Biol Markers, 2002. 17(2): 84–9.
58. Zackrisson B, Ulleryd P, Aus G, Lilja H,
Sandberg T, and Hugosson J, Evolution of
free, complexed, and total serum prostate-
specific antigen and their ratios during 1
year of follow-up of men with febrile urinary
tract infection. Urology, 2003. 62(2): 278–81.
59. Sindhwani P and Wilson CM, Prostatitis
and serum prostate-specific antigen. Curr
Urol Rep, 2005. 6(4): 307–12.
60. Hochreiter WW, The issue of prostate
cancer evaluation in men with elevated
prostate-specific antigen and chronic pros-
tatitis. Andrologia, 2008. 40(2): 130–3.
61. Sciarra A, Di Silverio F, Salciccia S,
Autran Gomez AM, Gentilucci A, and
Gentile V, Inflammation and chronic pro-
static diseases: evidence for a link? Eur
Urol, 2007. 52(4): 964–72.
62. Konig JE, Senge T, Allhoff EP, and Konig
W, Analysis of the inflammatory network
in benign prostate hyperplasia and pros-
tate cancer. Prostate, 2004. 58(2): 121–9.
63. Alexeyev O, Bergh J, Marklund I,
Thellenberg-Karlsson C, Wiklund F,
Gronberg H, Bergh A, and Elgh F,
Association between the presence of bacte-
rial 16S RNA in prostate specimens taken
during transurethral resection of prostate
and subsequent risk of prostate cancer
(Sweden). Cancer Causes Control, 2006.
17(9): 1127–33.
64. Yuyun MF, Angwafo IF, Koulla-Shiro S,
and Zoung-Kanyi J, Urinary tract infec-
tions and genitourinary abnormalities in
Cameroonian men. Trop Med Int Health,
2004. 9(4): 520–5.
65. Romero Perez P and Mira Llinares A,
[Male urethral stenosis: review of complica-
tions]. Arch Esp Urol, 2004. 57(5): 485–511.
66. Romero Perez P and Mira Llinares A,
[Renal and ureteral complications of
urethral stenosis]. Actas Urol Esp, 1995.
19(6): 432–40.
67. Santucci RA, Joyce GF, and Wise M, Male
urethral stricture disease. J Urol, 2007.
177(5): 1667–74.
68. Sharfi AR, Complicated male urethral
strictures: presentation and management.
Int Urol Nephrol, 1989. 21(5): 491–7.
| 8.2 |
69. Mungadi IA and Ntia IO, Management of
“watering-can” perineum. East Afr Med J,
2007. 84(6): 283–6.
70. Sharfi AR and Elarabi YE, The ‘watering-
can’ perineum: presentation and manage-
ment. Br J Urol, 1997. 80(6): 933–6.
71. Blacklock AR, Geddes JR, and Shaw RE,
The treatment of large bladder divertic-
ula. Br J Urol, 1983. 55(1): 17–20.
72. Gillon G, Nissenkorn I, and Servadio C,
Bladder diverticula in elderly females
with urgency, dysuria and incontinence.
Eur Urol, 1988. 14(1): 34–6.
73. Safir MH, Gousse AE, and Raz S, Bladder
diverticula causing urinary retention in
a woman without bladder outlet obstruc-
tion. J Urol, 1998. 160(6 Pt 1): 2146–7.
74. Pieretti RV and Pieretti-Vanmarcke RV,
Congenital bladder diverticula in chil-
dren. J Pediatr Surg, 1999. 34(3): 468–73.
75. Taylor WN, Alton D, Toguri A, Churchill
BM, and Schillinger JF, Bladder divertic-
ula causing posterior urethral obstruction
in children. J Urol, 1979. 122(3): 415.
76. Adot Zurbano JM, Salinas Casado J,
Dambros M, Virseda Chamorro M,
Ramirez Fernandez JC, Silmi Moyano A,
and Marcos Diaz J, [Urodynamics of the
bladder diverticulum in the adult male].
Arch Esp Urol, 2005. 58(7): 641–9.
77. Daneshgari F, Zimmern PE, and
Jacomides L, Magnetic resonance imaging
detection of symptomatic noncommuni-
cating intraurethral wall diverticula in
women. J Urol, 1999. 161(4): 1259–61;
discussion 1261–2.
78. Young GPH, Wahle GR, and Raz S,
Female urethral diverticulum, in Female
urology, Raz S, Editor. 1996, Saunders:
Philadelphia. p. 477–489.
79. Leach GE, Schmidbauer CP, Hadley
HR, Staskin DR, Zimmern P, and Raz S,
Surgical treatment of female urethral diver-
ticulum. Semin Urol, 1986. 4(1): 33–42.
80. Leach GE and Bavendam TG, Female
urethral diverticula. Urology, 1987. 30(5):
407–15.
81. Davis BL and Robinson DG, Diverticula
of the female urethra: assay of 120 cases.
J Urol, 1970. 104(6): 850–3.
82. Ganabathi K, Leach GE, Zimmern PE,
and Dmochowski R, Experience with the
management of urethral diverticulum
475
Chapter |8| Urinary tract infections in patients
in 63 women. J Urol, 1994. 152(5 Pt 1):
1445–52.
83. Hoffman MJ and Adams WE, Recognition
and Repair of Urethral Diverticula: A
Report of 60 Cases. Am J Obstet Gynecol,
1965. 92: 106–11.
84. Romanzi LJ, Groutz A, and Blaivas JG,
Urethral diverticulum in women: diverse
presentations resulting in diagnostic
delay and mismanagement. J Urol, 2000.
164(2): 428–33.
85. Schaeffer AJ and Schaeffer EM, Infections
of the urinary tract, in Campbell-Walsh
urology, Campbell MF, Wein AJ, and
Kavoussi LR, Editors. 2007, Saunders
Elsevier: Philadelphia, PA. p. 221–303.
86. Santucci RA, Payne CK, Anger JT, and
Saigal CS, Office dilation of the female
urethra: a quality of care problem in the
field of urology. J Urol, 2008. 180(5):
2068–75.
87. Keegan KA, Nanigian DK, and Stone AR,
Female urethral stricture disease. Curr
Urol Rep, 2008. 9(5): 419–23.
88. Parker WR, Wheat J, Montgomery JS,
and Latini JM, Urethral diverticulum
after endoscopic urethrotomy: case report.
Urology, 2007. 70(5): 1008 e5–7.
89. Allen D, Mishra V, Pepper W, Shah S, and
Motiwala H, A single-center experience of
symptomatic male urethral diverticula.
Urology, 2007. 70(4): 650–3.
90. Otnes B, Correlation between causes and
composition of urinary stones. Scand J
Urol Nephrol, 1983. 17(1): 93–8.
91. Drach GW, Urinary lithiasis: etiology,
diagnosis, and medical management,
in Campbell’s urology, Campbell MF
and Walsh PC, Editors. 1992, Saunders:
Philadelphia. p. 2085–2156.
92. Smith JM and O’Flynn JD, Vesical stone:
The clinical features of 652 cases. Ir Med
J, 1975. 68(4): 85–9.
93. Douenias R, Rich M, Badlani G, Mazor
D, and Smith A, Predisposing factors
in bladder calculi. Review of 100 cases.
Urology, 1991. 37(3): 240–3.
94. Takasaki E, Suzuki T, Honda M, Imai T,
Maeda S, and Hosoya Y, Chemical com-
positions of 300 lower urinary tract calculi
and associated disorders in the urinary
tract. Urol Int, 1995. 54(2): 89–94.
476
95. O’Connor RC, Laven BA, Bales GT, and
Gerber GS, Nonsurgical management of
benign prostatic hyperplasia in men with
bladder calculi. Urology, 2002. 60(2):
288–91.
96. Nmorsi O, Ukwandu N, Egwungenya O,
and Obhiemi N, Evaluation of CD4(+)/
CD8(+) status and urinary tract infec-
tions associated with urinary schisto-
somiasis among some rural Nigerians.
Afr Health Sci, 2005. 5(2): 126–30.
97. Nmorsi OP, Kwandu UN, and
Ebiaguanye LM, Schistosoma haemato-
bium and urinary tract pathogens
co-infections in a rural community of
Edo State, Nigeria. J Commun Dis,
2007. 39(2): 85–90.
98. Eyong ME, Ikepeme EE, and Ekanem
EE, Relationship between Schistosoma
haematobium infection and urinary
tract infection among children in South
Eastern, Nigeria. Niger Postgrad Med J,
2008. 15(2): 89–93.
99. King CH, Keating CE, Muruka JF,
Ouma JH, Houser H, Siongok TK, and
Mahmoud AA, Urinary tract morbidity
in schistosomiasis haematobia: associa-
tions with age and intensity of infection
in an endemic area of Coast Province,
Kenya. Am J Trop Med Hyg, 1988. 39(4):
361–8.
100. Vester U, Kardorff R, Traore M, Traore
HA, Fongoro S, Juchem C, Franke D,
Korte R, Gryseels B, Ehrich JH, and
Doehring E, Urinary tract morbidity due
to Schistosoma haematobium infection in
Mali. Kidney Int, 1997. 52(2): 478–81.
101. Nmorsi OP, Ukwandu NC, Ogoinja S,
Blackie HO, and Odike MA, Urinary
tract pathology in Schistosoma haemato-
bium infected rural Nigerians. Southeast
Asian J Trop Med Public Health, 2007.
38(1): 32–7.
102. Cox CE and Hinman F, Jr., Experiments
with induced bacteriuria, vesical empty-
ing and bacterial growth on the mecha-
nism of bladder defense to infection.
J Urol, 1961. 86: 739–48.
103. Smellie J, Edwards D, Hunter N,
Normand IC, and Prescod N, Vesico-
ureteric reflux and renal scarring.
Kidney Int Suppl, 1975. 4: S65–72.
 Urinary tract infections in obstruction of the urinary tract
104. Beeson PB and Guze LB, Experimental
pyelonephritis. I. Effect of ureteral liga-
tion on the course of bacterial infection in
the kidney of the rat. J Exp Med, 1956.
104(6): 803–15.
105. Bitz H, Darmon D, Goldfarb M, Shina
A, Block C, Rosen S, Brezis M, and
Heyman SN, Transient urethral obstruc-
tion predisposes to ascending pyelone-
phritis and tubulo-interstitial disease:
studies in rats. Urol Res, 2001. 29(1):
67–73.
106. Song SH, Lee SB, Park YS, and Kim KS,
Is antibiotic prophylaxis necessary in
infants with obstructive hydronephrosis?
J Urol, 2007. 177(3): 1098–101; discus-
sion 1101.
107. Coelho GM, Bouzada MC, Lemos GS,
Pereira AK, Lima BP, and Oliveira EA,
Risk factors for urinary tract infection in
children with prenatal renal pelvic dila-
tation. J Urol, 2008. 179(1): 284–9.
108. Lee JH, Choi HS, Kim JK, Won HS, Kim
KS, Moon DH, Cho KS, and Park YS,
Nonrefluxing neonatal hydronephrosis
and the risk of urinary tract infection. J
Urol, 2008. 179(4): 1524–8.
109. Roth CC, Hubanks JM, Bright BC,
Heinlen JE, Donovan BO, Kropp BP, and
Frimberger D, Occurrence of urinary
tract infection in children with signifi-
cant upper urinary tract obstruction.
Urology, 2009. 73(1): 74–8.
110. Ghalayini IF, Pathological spectrum
of nephrectomies in a general hospital.
Asian J Surg, 2002. 25(2): 163–9.
111. Rafique M, Nephrectomy: indications,
complications and mortality in 154 con-
secutive patients. J Pak Med Assoc, 2007.
57(6): 308–11.
112. Nggada HA, Eni UE, and Nwankwo EA,
Histopathological findings in nephrec-
tomy specimens – A review of 42 cases.
Niger Postgrad Med J, 2006. 13(3):
244–6.
113. Eknoyan G, Qunibi WY, Grissom RT,
Tuma SN, and Ayus JC, Renal papil-
lary necrosis: an update. Medicine
(Baltimore), 1982. 61(2): 55–73.
114. Jameson RM and Heal MR, The surgi-
cal management of acute renal papillary
necrosis. Br J Surg, 1973. 60(6): 428–30.
| 8.2 |
115. Timmons JW, Jr., Malek RS, Hattery
RR, and Deweerd JH, Caliceal diverticu-
lum. J Urol, 1975. 114(1): 6–9.
116. Krzeski T, Witeska A, Borowka A, and
Pypno W, Diverticula of renal calyces.
Int Urol Nephrol, 1981. 13(3): 231–5.
117. Chong TW, Bui MH, and Fuchs GJ,
Calyceal diverticula. Ureteroscopic man-
agement. Urol Clin North Am, 2000.
27(4): 647–54.
118. Canales B and Monga M, Surgical man-
agement of the calyceal diverticulum.
Curr Opin Urol, 2003. 13(3): 255–60.
119. Gross AJ and Herrmann TR,
Management of stones in calyceal diver-
ticulum. Curr Opin Urol, 2007. 17(2):
136–40.
120. Huang JJ and Tseng CC,
Emphysematous pyelonephritis: clinico-
radiological classification, management,
prognosis, and pathogenesis. Arch Intern
Med, 2000. 160(6): 797–805.
121. Soo Park B, Lee SJ, Wha Kim Y,
Sik Huh J, Il Kim J, and Chang SG,
Outcome of nephrectomy and kidney-
preserving procedures for the treatment
of emphysematous pyelonephritis. Scand
J Urol Nephrol, 2006. 40(4): 332–8.
122. Roberts JA, Management of pyelonephri-
tis and upper urinary tract infections.
Urol Clin North Am, 1999. 26(4): 753–63.
123. Dwivedi US, Goyal NK, Saxena V,
Acharya RL, Trivedi S, Singh PB,
Vyas N, Datta B, Kumar A, and Das S,
Xanthogranulomatous pyelonephritis:
our experience with review of published
reports. ANZ J Surg, 2006. 76(11): 1007–9.
124. Korkes F, Favoretto RL, Broglio M,
Silva CA, Castro MG, and Perez MD,
Xanthogranulomatous pyelonephri-
tis: clinical experience with 41 cases.
Urology, 2008. 71(2): 178–80.
125. Akerlund S, Campanello M, Kaijser B,
and Jonsson O, Bacteriuria in patients
with a continent ileal reservoir for uri-
nary diversion does not regularly require
antibiotic treatment. Br J Urol, 1994.
74(2): 177–81.
126. Woodside JR, Reed WP, and Borden TA,
Immunoglobulin in urine from ileal con-
duit and nephrostomy patients. Invest
Urol, 1979. 16(6): 473–5.
477
Chapter |8| Urinary tract infections in patients
127. Mansson W, Colleen S, Low K, Mardh
PA, and Lundblad A, Immunoglobulins
in urine from patients with ileal and
colonic conduits and reservoirs. J Urol,
1985. 133(4): 713–6.
128. Trinchieri A, Braceschi L, Tiranti D,
Dell’Acqua S, Mandressi A, and Pisani
E, Secretory immunoglobulin A and
inhibitory activity of bacterial adherence
to epithelial cells in urine from patients
with urinary tract infections. Urol Res,
1990. 18(5): 305–8.
129. Iwakiri J, Freiha FS, and Shortliffe
LM, Prospective study of urinary tract
infections and urinary antibodies after
radical prostatectomy and cystoprostate-
ctomy. Urol Clin North Am, 2002. 29(1):
251–8, xii.
130. Wullt B, Agace W, and Mansson W,
Bladder, bowel and bugs – bacteriuria in
patients with intestinal urinary diver-
sion. World J Urol, 2004. 22(3): 186–95.
131. Falagas ME and Vergidis PI, Urinary
tract infections in patients with urinary
diversion. Am J Kidney Dis, 2005. 46(6):
1030–7.
132. Wullt B, Bergsten G, Carstensen J,
Gustafsson E, Gebratsedik N, Holst
E, and Mansson W, Mucosal host
responses to bacteriuria in colonic and
ileal neobladders. Eur Urol, 2006. 50(5):
1065–71; discussion 1071–2.
133. Gonzalez R and Reinberg Y, Localization
of bacteriuria in patients with enterocys-
toplasty and nonrefluxing conduits.
J Urol, 1987. 138(4 Pt 2): 1104–5.
134. Wood DP, Jr., Bianco FJ, Jr., Pontes
JE, Heath MA, and DaJusta D,
Incidence and significance of posi-
tive urine cultures in patients with an
orthotopic neobladder. J Urol, 2003.
169(6): 2196–9.
135. Wullt B, Holst E, Steven K, Carstensen
J, Pedersen J, Gustafsson E, Colleen S,
and Mansson W, Microbial flora in ileal
and colonic neobladders. Eur Urol, 2004.
45(2): 233–9.
136. Abdel-Latif M, Mosbah A, El Bahnasawy
MS, Elsawy E, and Shaaban AA,
Asymptomatic bacteriuria in men with
orthotopic ileal neobladders: possible
relationship to nocturnal enuresis. BJU
Int, 2005. 96(3): 391–6.
478
137. Suriano F, Gallucci M, Flammia GP,
Musco S, Alcini A, Imbalzano G, and
Dicuonzo G, Bacteriuria in patients with
an orthotopic ileal neobladder: urinary
tract infection or asymptomatic bacteriu-
ria? BJU Int, 2008. 101(12): 1576–9.
138. Hill MJ, Hudson MJ, and Stewart M,
The urinary bacterial flora in patients
with three types of urinary tract diver-
sion. J Med Microbiol, 1983. 16(2):
221–6.
139. Kaefer M, Hendren WH, Bauer SB,
Goldenblatt P, Peters CA, Atala A, and
Retik AB, Reservoir calculi: a compari-
son of reservoirs constructed from stom-
ach and other enteric segments. J Urol,
1998. 160(6 Pt 1): 2187–90.
140. Kronner KM, Casale AJ, Cain MP, Zerin
MJ, Keating MA, and Rink RC, Bladder
calculi in the pediatric augmented blad-
der. J Urol, 1998. 160(3 Pt 2): 1096–8;
discussion 1103.
141. Fontaine E, Barthelemy Y, Houlgatte
A, Chartier E, and Beurton D, Twenty-
year experience with jejunal conduits.
Urology, 1997. 50(2): 207–13.
142. McDougal WS, Use of intestinal seg-
ments and urinary diversion, in
Campbell’s urology, Campbell MF and
Walsh PC, Editors. 1998, W.B. Saunders
Co.: Philadelphia. p. 3121–3161.
143. Turk TM, Koleski FC, and Albala DM,
Incidence of urolithiasis in cystectomy
patients after intestinal conduit or con-
tinent urinary diversion. World J Urol,
1999. 17(5): 305–7.
144. Benson MC and Olsson CA, Continent
urinary diversion, in Campbell’s urology,
Campbell MF and Walsh PC, Editors.
1998, W.B. Saunders Co.: Philadelphia.
p. 3190–3245.
145. Cohen TD, Streem SB, and Lammert G,
Long-term incidence and risks for recur-
rent stones following contemporary man-
agement of upper tract calculi in patients
with a urinary diversion. J Urol, 1996.
155(1): 62–5.
146. Palmer LS, Franco I, Kogan SJ, Reda
E, Gill B, and Levitt SB, Urolithiasis in
children following augmentation cysto-
plasty. J Urol, 1993. 150(2 Pt 2): 726–9.
147. Thoeny HC, Sonnenschein MJ,
Madersbacher S, Vock P, and Studer UE,
 Urinary tract infections in obstruction of the urinary tract
Is ileal orthotopic bladder substitution
with an afferent tubular segment detri-
mental to the upper urinary tract in the
long term? J Urol, 2002. 168(5): 2030–4;
discussion 2034.
148. Yong SM, Dublin N, Pickard R, Cody
DJ, Neal DE, and N’Dow J, Urinary
diversion and bladder reconstruction/
replacement using intestinal segments
for intractable incontinence or following
cystectomy. Cochrane Database Syst Rev,
2003(1): CD003306.
149. Carson C and Naber KG, Role of fluo-
roquinolones in the treatment of serious
bacterial urinary tract infections. Drugs,
2004. 64(12): 1359–73.
150. Wagenlehner FM and Naber KG,
Current challenges in the treatment of
complicated urinary tract infections and
prostatitis. Clin Microbiol Infect, 2006.
12 Suppl 3: 67–80.
151. Friedman S, Reif S, Assia A, Mishaal
R, and Levy I, Clinical and laboratory
characteristics of non-E. coli urinary
tract infections. Arch Dis Child, 2006.
91(10): 845–6.
152. Lane MC and Mobley HL, Role of
P-fimbrial-mediated adherence in pyelo-
nephritis and persistence of uropatho-
genic Escherichia coli (UPEC) in the
mammalian kidney. Kidney Int, 2007.
72(1): 19–25.
153. de Man P, Claeson I, Johanson IM, Jodal
U, and Svanborg Eden C, Bacterial
attachment as a predictor of renal abnor-
malities in boys with urinary tract infec-
tion. J Pediatr, 1989. 115(6): 915–22.
154. Jantunen ME, Siitonen A, Koskimies O,
Wikstrom S, Karkkainen U, Salo E, and
Saxen H, Predominance of class II papG
allele of Escherichia coli in pyelonephritis
in infants with normal urinary tract anat-
omy. J Infect Dis, 2000. 181(5): 1822–4.
155. Tseng CC, Huang JJ, Ko WC, Yan JJ,
and Wu JJ, Decreased predominance of
papG class II allele in Escherichia coli
strains isolated from adults with acute
pyelonephritis and urinary tract abnor-
malities. J Urol, 2001. 166(5): 1643–6.
156. Grossfeld GD and Coakley FV, Benign
prostatic hyperplasia: clinical overview
and value of diagnostic imaging. Radiol
Clin North Am, 2000. 38(1): 31–47.
| 8.2 |
157. Ulleryd P, Zackrisson B, Aus G,
Bergdahl S, Hugosson J, and Sandberg
T, Selective urological evaluation in men
with febrile urinary tract infection. BJU
Int, 2001. 88(1): 15–20.
158. Browne RF, Zwirewich C, and
Torreggiani WC, Imaging of urinary
tract infection in the adult. Eur Radiol,
2004. 14 Suppl 3: E168–83.
159. Johansen TE, The role of imaging in uri-
nary tract infections. World J Urol, 2004.
22(5): 392–8.
160. Kawashima A and LeRoy AJ, Radiologic
evaluation of patients with renal infec-
tions. Infect Dis Clin North Am, 2003.
17(2): 433–56.
161. Soler R, Pombo F, Gayol A, and
Rodriguez J, Focal xanthogranuloma-
tous pyelonephritis in a teenager: MR
and CT findings. Eur J Radiol, 1997.
24(1): 77–9.
162. Kim B, Lim HK, Choi MH, Woo JY,
Ryu J, Kim S, and Peck KR, Detection
of parenchymal abnormalities in acute
pyelonephritis by pulse inversion har-
monic imaging with or without microbub-
ble ultrasonographic contrast agent:
correlation with computed tomography.
J Ultrasound Med, 2001. 20(1): 5–14.
163. Correas JM, Claudon M, Tranquart F,
and Helenon AO, The kidney: imag-
ing with microbubble contrast agents.
Ultrasound Q, 2006. 22(1): 53–66.
164. Mitterberger M, Pinggera GM, Colleselli
D, Bartsch G, Strasser H, Steppan I,
Pallwein L, Friedrich A, Gradl J, and
Frauscher F, Acute pyelonephritis: com-
parison of diagnosis with computed
tomography and contrast-enhanced
ultrasonography. BJU Int, 2008. 101(3):
341–4.
165. Abarbanel J, Engelstein D, Lask D, and
Livne PM, Urinary tract infection in men
younger than 45 years of age: is there a
need for urologic investigation? Urology,
2003. 62(1): 27–9.
166. Nickel JC, Wilson J, Morales A, and
Heaton J, Value of urologic investigation
in a targeted group of women with recur-
rent urinary tract infections. Can J Surg,
1991. 34(6): 591–4.
167. Lawrentschuk N, Ooi J, Pang A, Naidu
KS, and Bolton DM, Cystoscopy in
479
Chapter |8| Urinary tract infections in patients
women with recurrent urinary tract
infection. Int J Urol, 2006. 13(4): 350–3.
168. Chen Y, Nitzan O, Saliba W, Chazan B,
Colodner R, and Raz R, Are blood cul-
tures necessary in the management of
women with complicated pyelonephritis?
J Infect, 2006. 53(4): 235–40.
169. Hsu CY, Fang HC, Chou KJ, Chen CL,
Lee PT, and Chung HM, The clinical
impact of bacteremia in complicated
acute pyelonephritis. Am J Med Sci,
2006. 332(4): 175–80.
170. Ramakrishnan K and Scheid DC,
Diagnosis and management of acute
pyelonephritis in adults. Am Fam
Physician, 2005. 71(5): 933–42.
171. Schaeffer AJ, Review of norfloxacin in
complicated and recurrent urinary tract
infections. Eur Urol, 1990. 17 Suppl 1:
19–23.
172. Naber KG, Which fluoroquinolones are
suitable for the treatment of urinary
480
tract infections? Int J Antimicrob Agents,
2001. 17(4): 331–41.
173. Peterson J, Kaul S, Khashab M, Fisher A,
and Kahn JB, Identification and pre-
therapy susceptibility of pathogens in
patients with complicated urinary tract
infection or acute pyelonephritis enrolled
in a clinical study in the United States
from November 2004 through April 2006.
Clin Ther, 2007. 29(10): 2215–21.
174. Peterson J, Kaul S, Khashab M, Fisher
AC, and Kahn JB, A double-blind, ran-
domized comparison of levofloxacin 750
mg once-daily for five days with ciproflox-
acin 400/500 mg twice-daily for 10 days
for the treatment of complicated urinary
tract infections and acute pyelonephritis.
Urology, 2008. 71(1): 17–22.
175. McMurdo ME and Gillespie ND, Urinary
tract infection in old age: over-diagnosed
and over-treated. Age Ageing, 2000.
29(4): 297–8.
|8.3|
Urinary tract infections in patients
with urolithiasis
Gianpaolo Zanetti1, Alberto Trinchieri2
1
Assistant Professor, Department of Urology, Fondazione IRCCS Ospedale Maggiore PO.MA.RE, Milan, Italy
2
Director, Urology Unit, Lecco Hospital, Lecco, Italy
ABSTRACT
Urease-producing micro-organisms can
be cultured from the stone in 48% of
patients with calculi containing magne-
sium ammonium phosphate. A negative
midstream urine (MSU) culture is not
sufficient to exclude the presence of uri-
nary tract infection (UTI) associated with
an obstructing stone. Only culture of the
stone (or of urine obtained from the renal
pelvis) is a good predictor of the risk of
post-treatment clinical sepsis.
Urinary stones containing struvite
or carbonate apatite result from UTI
by urease-producing micro-organisms.
Proteus, Klebsiella and Staphylococcus
species (spp) are the most commonly
encountered urease-producing micro-
organisms involved in stone formation.
Bacterial urease activity can also be
demonstrated in urine infected by other
micro-organisms not growing in common
culture media (Ureaplasma urealyticum,
Corynebacterium urealyticum).
Urease-producing bacteria grow as
biofilm adhering to stone surfaces where
struvite and calcium phosphate crystals
precipitate. Damage to the protective
layer of glycosaminoglycans (GAG) facili-
tates bacterial adherence and further tis-
sue invasion by bacteria. High urinary
calcium levels and low citrate levels pro-
mote urease-induced crystal precipita-
tion. Dissolution of infectious stones can
be accomplished by irrigation with acidi-
fying solutions, but they must be used
with caution because of the risk of severe
side-effects.
Percutaneous nephrolithotomy (PCNL)
should be the first treatment utilized for
removal of high burden infection stones.
Extracorporeal shock-wave lithotripsy
(ESWL) should be used only for residual
stones after PCNL, and as monotherapy
may be considered only in patients with
small volume staghorn stones with nor-
mal collecting system.
Antibiotic therapy is advisable in
patients affected by infection stones prior
Chapter |8| Urinary tract infections in patients
to and/or after treatment. Antibiotic proph-
ylaxis for ESWL and ureteroscopy for
uncomplicated stones in the distal ureter
should be reserved for high-risk patients.
Perioperative antibiotics should be rou-
tinely administered for ureteroscopy of
stones in the proximal ureter or impacted
stones, for PCNL or open stone surgery.
Residual stones and fragments cause
persistent infection and rapid stone
regrowth after surgical and ESWL treat-
ment of infected stones. The appropri-
ateness of chronic low-dosage antibiotic
suppression treatment and chronic uri-
nary acidification for the prophylaxis
of infection stones has not yet been suc-
cessfully demonstrated. Use of citrate as
a prophylactic agent for infection stones
could be an option. Urease enzyme inhibi-
tors are effective in limiting the change in
urinary pH caused by urease-producing
bacteria, but are associated with frequent
severe side-effects.
Key words: urinary tract infection,
urinary calculi, urolithiasis
SUMMARY OF RECOMMENDATIONS
1. In the presence of an obstructing
urinary tract stone, midstream urine
(MSU) culture should be obtained,
although it is not sufficient to
exclude the presence of urinary tract
infection (UTI) – only culture of the
stone, or of urine from the renal
pelvis, can predict the risk of post-
treatment clinical sepsis (GoR B).
2. Percutaneous nephrolithotomy
(PCNL) should be the first-line treat-
ment for removal of high burden
infection stones (GoR A).
3. Extracorporeal shock wave lithot-
ripsy (ESWL) should be used only for
residual stones after PCNL, and as
monotherapy may be considered only
in patients with small volume stag-
horn stones with a normal collecting
system (GoR B).
482
4. Dissolution of infection stones can
be accomplished by irrigation with
acidifying solutions, but they must
be used with caution, due to the risk
of severe side-effects (GoR B).
5. Eradication of all stones and frag-
ments is essential to prevent per-
sistent infection and recurrence of
infection stones (GoR B).
6. Antibiotic therapy is advisable in
patients affected by infection stones,
prior to and/or after treatment
(GoR B).
7. Antibiotic prophylaxis for ESWL
and ureteroscopy of uncomplicated
stones in the distal ureter should be
reserved for risk patients (GoR B).
8. Perioperative antibiotics should be
routinely administered for ureteros-
copy for stones in the proximal ure-
ter or impacted stones, for PCNL or
open stone surgery (GoR B).
9. Chronic low-dosage antibiotic sup-
pression treatment and chronic
urinary acidification for the prophy-
laxis of infection stones may be con-
sidered, but efficacy has not been
proven (GoR C).
10. The use of citrate as a prophylactic
agent for infection stones could be an
option (GoR C).
11. Urease enzyme inhibitors to limit
the change in urinary pH caused by
urease-producing bacteria can be
considered, but severe side-effects
may occur (GoR C).
1. INTRODUCTION
Urinary stone formation and UTI can
be associated under different conditions.
UTI can be present in urinary stone
patients as a consequence of obstructive
uropathy due to a pre-existing stone of
different origin, or UTI by itself can be
the primary cause of modifications of the
physicochemical composition of the urine,
 Urinary tract infections in patients with urolithiasis
promoting crystallization and stone for-
mation. The former condition is defined
as UTI “associated” with stone disease,
while the latter is “infectious stone
disease”.
Urinary stones are often associated
with persistent or recurrent UTIs that
can sometimes lead to bacteremia and
urosepsis after endourologic manipulation
or lithotripsy or persistent urinary tract
obstruction. “Infectious” or “infection”
stones are related to UTIs with urease-
producing organisms (Proteus, Klebsiella,
Providencia and Pseudomonas spp,
Staphylococcus aureus and Ureaplasma
urealyticum) that promote the formation
of struvite (magnesium ammonium phos-
phate) and apatite (calcium phosphate)
calculi.
2. METHODS
A systematic literature search was per-
formed in PubMed from October 1998
through September 2008, limited to stud-
ies in the English language. In total, 338
citations were extracted using the key
words “urinary calculi” AND “urinary
tract infection”. After screening the titles,
35 papers were selected, and after screen-
ing the abstracts only 10 studies were
included in the final analysis, supple-
mented by 74 publications cited in these
references and published before 1998, but
considered as “milestones” on this topic.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [1–2].
3. EPIDEMIOLOGY
The incidence of infection stones in dif-
ferent accounts and different countries
varies widely. In Western developed
countries, “infection” stones represent
approximately 10–15% of all urinary
stones (LoE 3) [3], but this rate tends to
| 8.3 |
decrease over time in relation to the pro-
gressive increase in the prevalence of cal-
cium oxalate stones of metabolic origin.
In less developed countries the preva-
lence is higher in relation to local health
conditions and to the lower prevalence of
other types of renal stones.
The presence of urinary calculi is a
risk factors for nosocomial acquired uri-
nary tract infections (NAUTIs) that were
found associated with urinary stones in
20% of patients in the PEP/PEAP study
(2003–2004) (LoE 3) [4].
In general infection stones tend to be
more common in female patients due to
the higher prevalence of recurrent UTIs
(LoE 3) [5]. Urease-producing microrgan-
isms could be cultured from the stone in
48% of patients with calculi containing mag-
nesium ammonium phosphate (LoE 3) [6].
Renal stones of metabolic origin are
more often associated with infection with
non-urease-producing micro-organisms.
Of patients with calcium oxalate or cal-
cium phosphate stones 32% had positive
stone cultures in comparison to only 8%
of patients with pure calcium oxalate
stones (LoE 3) [6]. Other authors found a
lower rate (5%) (LoE 3) [7].
On the other hand, this association
could be underestimated, because MSU
cultures often fail to detect stone infec-
tion. In a prospective study Mariappan
and Long suggested that in obstructive
uropathy secondary to stone, MSU cul-
ture is a poor predictor of infected urine
proximal to the obstruction and infected
stones (LoE 3) [8]. Among the patients
who developed urosepsis after stone
removal, stone culture was positive in
25% and pelvic urine culture was positive
in 66%, but MSU culture was negative in
all patients [8].
In a similar study in 54 patients under-
going PCNL, MSU culture was positive
only in 5.6% of the patients (LoE 3) [9].
Patients with infected stones and pelvic
urine carried a four-fold risk of develop-
ing urosepsis. Similarly, Margel et al.
have shown that MSU culture is a poor
483
Chapter |8| Urinary tract infections in patients

predictor of upper urinary tract colo-
nization, but stone culture is the only
parameter that may predict the risk of
developing post-treatment clinical sepsis
(LoE 3) [10].
formers who develop chronic renal failure
suffer from infectious stones (LoE 4) [15].
5. PATHOGENESIS

Infection urinary stones develop as a

4. CLINICAL EVALUATION/RISK result of persistent infections caused by
ASSESSMENT urease-producing bacteria and are often
associated with urinary tract obstruction
Infection stones present as casts of the (LoE 4) [16–17].
collecting system that can be partial or
complete with a “staghorn” configura- 5.1 Urea-splitting bacteria
tion. Bladder stones are commonly asso-
Urease splits urea into ammonia and car-
ciated with outlet obstruction and UTI.
bon dioxide, which are hydrolysed to ammo-
Struvite stones are characterised by
nium ions and bicarbonate, thus increasing
their exceptionally rapid growth (infec-
the pH. In the alkaline urine, phosphate
tion stones can form within 4–6 weeks)
is precipitated in the form of magnesium
(LoE 4) [11].
ammonium phosphate (struvite). Struvite
Cases of gas-containing renal stones
precipitation starts at a pH of 6.7–6.8,
associated with E. coli UTI have been
peaks at around pH 7.5 and then declines
reported (LoE 3) [12]. The gas-containing
markedly at higher pH (LoE 4) [18].
stones were visible on computed tomog-
Infection stones also consist of monoam-
raphy (CT) scans, ultrasound (US) and
monium urate and/or carbonate apatite
intravenous urography (IVU) and were
in relation to the urinary concentration of
radiolucent.
other available cations (LoE 4) [16].
Patients with struvite stones do not
Proteus, Klebsiella and Staphylococcus
typically present with colic, unless a
spp are the most commonly encoun-
stone fragment passes down the ure-
tered urease-producing micro-organisms
ter after prior manipulation. Infection
involved in stone formation (Table 1).
stones should be suspected as the source
Others such as Pseudomonas spp are less
of recurrent or persistent UTIs in the
likely to produce urease and are therefore
presence of mild recurrent flank pain.
less frequently connected with struvite
Assessing urinary pH is critical in help-
stone formation (LoE 3, LoE 4) [3, 18].
ing to determine the presence of struvite
Bacterial urease activity can be dem-
calculi that form in a urinary environ-
onstrated in the urine by a fast colori-
ment with a pH of at least 7.2, whereas
metric test (LoE 3) [3]. A recent study
normal urinary pH lies in the range of
further documented the pivotal role of
5.8–6.0. Persistently alkaline urine there-
urea-splitting bacteria in the formation of
fore suggests the presence of a struvite
struvite calculi: experimental instillation
calculus (LoE 4) [13].
of urease-negative Proteus into murine
Clinical sepsis can be seen following
bladders failed to produce encrustation,
stone surgery secondary to endotoxemia,
whereas wild-type Proteus spp rapidly
even without bacteremia. Some patients
formed encrustations containing bacteria
who develop clinical sepsis can have neg-
in the stone matrix (LoE 2b) [20].
ative cultures but exceedingly high lev-
els of endotoxin in the stone itself (LoE
5.2 Ureaplasma urealyticum
2b) [14].
Although end-stage renal disease is now U. urealyticum frequently colonizes the
rare in renal stone disease, most stone lower urinary tract in sexually active

484
 Urinary tract infections in patients with urolithiasis
Table 1 Frequency of urease-producing pathogens (modified from Bichler et al. [19] ).
Organism Total (N)
Proteus spp 54
Klebsiella spp 31
Staphylococcus spp 67
E. coli 142
Pseudomonas spp 20
Providencia spp 1 1
M. morganii 1 1
Total 423
individuals. It may also invade the upper
urinary tract and induce stone formation
in the kidneys by its urease activity.
Experimental studies demonstrated
that U. urealyticum is able to induce a
urinary pH increase and crystallization in
vitro (LoE 2b) [21] and to produce rapid
concretion formation after inoculation
into the rat bladder in vivo (LoE 2b) [22].
Its presence has been demonstrated as
the only urease-producing micro-organ-
ism in the urine of patients with infection
stones (LoE 3) [23–27]. U. urealyticum
can be overlooked by routine investiga-
tion, since it is not detected by stand-
ard urine cultures and its presence in
the stone is less well reflected by urine
culture.
5.3 Encrusted pyelitis and
corynebacteria
Encrusted pyelitis (EP) is an infectious
disease characterized by encrustation of
the collecting system. Corynebacterium
group D2 is the most common urea-
splitting micro-organism involved in the
pathogenesis of EP that can be treated
conservatively with intravenous vanco-
mycin and percutaneous acidification
of the renal collecting system (irriga-
tion with Thomas’ acid solution) (LoE 3)
[28]. Mortality directly associated with
infection by this organism is not fre-
quent, but encrusted pyelitis in kidney
| 8.3 |
Urease positive (N) Urease positive (%)
54 100
26 84
37 55
2 1.4
1 5
100
100
122 28.8
transplant recipients may cause graft
loss (LoE 3) [29].
5.4 Nanobacteria
The possible role of nanobacteria as the
initial nidus for stone formation has been
described by Kajander et al. (LoE 3) [30].
Nanobacteria are the smallest bacte-
ria with cell membranes, being 10–100
times smaller than bacteria known so far
(LoE 3) [31]. Kajander et al. demonstrated
that nanobacteria are able to excrete bio-
genic apatite (carbonate apatite) through
their cell cover, and found them in 90% of
human kidney stones examined, claim-
ing their important potential as nidus for
stone development.
However, other authors were not able
to confirm the presence of nanobacteria in
urinary stones, nor phosphate excretion
by these organisms (LoE 3) [32]. A recent
study investigating the presence of nano-
bacteria in stone patients with negative
conventional urinary cultures demon-
strated the presence of nanobacteria in
only 0.5% (LoE 3) [33].
The small organisms can be difficult to
identify, or the previously positive find-
ings published may have been caused by
contamination of the sample or of the cul-
ture media. In an in vitro study, inhibi-
tion of nanobacteria by tetracycline was
measured by a modified microdilution
method (LoE 2b) [34].
485
Chapter |8| Urinary tract infections in patients
5.5 Biofilm
The growth of bacteria on stones as biofilm
is a naturally occurring phenomenon that
has significant implications for antibiotic
resistance or minimum inhibitory con-
centrations of drugs required for effective
therapy (LoE 4) [35]. Urease-producing
bacteria adhere to stone surfaces where
struvite and calcium phosphate crystals
preferentially precipitate in the alkaline
urine environment and deposit on the bio-
film. As a consequence the calculi grow
rapidly with the addition of more bacte-
ria, matrix production and further deposi-
tion of crystals, and may eventually form
a staghorn calculus (LoE 2b) [36].
Antimicrobial agents are ineffective in
eradicating the infection, because bac-
teria are protected by bacterial extracel-
lular matrix. For this reason complete
stone clearance is mandatory to eradicate
UTI and to prevent rapid recurrence of
staghorn calculi.
5.6 Bacterial adherence
Ammonia damages the protective layer
of glycosaminoglycans (GAG) which acts
as a defence against bacterial adherence
and infection, so facilitating bacterial
adherence and further tissue invasion by
the bacteria (LoE 4) [37]. Experimental
damage of this protective layer increases
the adhesion of struvite crystal to the
rat bladder by five to six times compared
with an intact bladder (LoE 2b) [38–39].
Also other uropathogens could facilitate
stone formation by inducing an inflam-
matory reaction that can damage the pro-
tective GAG layer.
5.7 Other infection-related
mechanisms of calcium stone
formation
Non-urease-producing micro-organisms
can facilitate urine crystallization and
formation of calcium-containing stones,
acting as a nucleus for epitactic crystal-
lization (LoE 2b) [40].
486
Distal renal tubular acidosis (RTA I)
can result from chronic pyelonephri-
tis, which damages the distal tubular
cells, with acidification disturbances and
reduced excretion of citrate as well as
higher calcium excretion and partially
increased phosphate excretion [3] (LoE 3).
This condition predisposes to urinary
stone formation by pH changes and espe-
cially low citrate excretion.
E. coli infection depletes the urinary
content of citrate, a powerful inhibitor of
calcium stone formation (LoE 3) [41].
5.8 Urine composition
Several urine components, but most signif-
icantly citrate, have been shown to influ-
ence urease-induced precipitation (LoE
2b). [42–45] A low native urine pH and
high urinary phosphate (by its relevant
buffering effect of urine) reduce the risk of
alkalinisation of urine and consequent for-
mation of struvite crystals (LoE 3) [46].
On the other hand, high urinary cal-
cium levels promote urease-induced pre-
cipitation (LoE 3) [46]. High urine citrate
is associated with reduced concretion
production, owing to its inhibitory activ-
ity of nucleation and crystal aggregation,
although urine pH increases (LoE 2b)
[44–45, 47].
6. RISK FACTORS
Risk factors for the development of infec-
tion stones are urinary tract obstruction,
urinary diversion, presence of catheters
in the urinary tract, neurogenic bladder,
renal transplant, and medullary sponge
kidney (LoE 4) [3, 48].
7. TREATMENT
7.1 Medical treatment
Dissolution of infection stones could theo-
retically be accomplished by acidifying
the urine. Suby’s Solution G, consisting of
 Urinary tract infections in patients with urolithiasis | 8.3 |

citric acid, magnesium oxide and sodium
carbonate, can be used to dissolve kidney
stones containing carbonate-apatite and
struvite via nephrostomy or a ureteric
catheter (LoE 3) [49].
Other medications proposed for stone
dissolution are Renacidin (Hemiacidrin).
Renacidin is similar to Suby’s Solution
G, but contains additional magnesium
and D-gluconic acid (LoE 3) [50]. It has
proved effective to dissolve ureteral and
kidney stones with no side-effects (LoE 3)
[51–53]. On the other hand, side-effects
and even death after Renacidin treat-
ment have been reported (LoE 3) [54]. In
order to prevent the risk of side-effects,
Renacidin irrigation should be avoided in
the case of UTI or concomitant flank pain,
and magnesium serum levels must be
monitored to prevent hypermagnesemia.
7.2 Surgical treatment
Successful treatment of struvite infec-
tion stones requires complete clearance
of all stone material. Current treatment
options are PCNL and ESWL. Less inva-
sive methods are preferable and open
surgical procedures should be limited to
cases with giant stones or associated with
abnormalities of the urinary tract.
The treatment of high burden infec-
tion stones is best accomplished via the
percutaneous route. Single or multiple
percutaneous punctures with or without
adjuvant flexible endoscopy (nephroscopy
or ureteroscopy) allow for complete access
to the collecting system and the complete
removal of all stones. ESWL should be
used only for residual stones after PCNL,
and as monotherapy may be considered
only in patients with small volume stag-
horn stones with normal collecting sys-
tem (LoE 1a) [55].
7.3 Infection stone removal and
antibiotic treatment
Antibiotic therapy is advised in patients
affected by infection stones prior to and/or
after treatment. Antibiotic therapy signifi-
cantly reduces the bacterial load, although
urine does not always become sterile.
Besides decreasing the risk of sepsis, anti-
biotics prevent recurrence or re-growth of
stones after treatment.
In the literature, different schedules of
targeted antibiotic therapy are reported,
sometimes in association with urease
inhibitors (Table 2) (LoE 3) [10, 56–58].
According to the 2007 guidelines of the
European Association of Urology (EAU)
(LoE 4) [59], antibiotic therapy should be
combined with complete stone removal by
all possible treatments, including PCNL,
ESWL, and open surgery (Table 3).
7.4 Antibiotic prophylaxis for stone
procedures (all types)
There is controversy in the literature with
respect to the use of antibiotic prophylaxis
for stone procedures. Its role, expediency,
and duration in relation to the various

Table 2 Antibiotic treatment for infection stones.

Streem et al. [56] 1 or 2 weeks of pre-operative targeted antibiotic therapy + broad-spectrum IV therapy
intra- and post-operatively

Wang et al. [57] Targeted antibiotic therapy + urease inhibitors as completion of the PCNL + ESWL treatment

Margel et al. [10] 2 weeks of targeted antibiotic therapy prior to treatment (referring to the most recent positive
urine culture)

Sharifi Aghdas et al. [58] 1–2 days of antibiotic prophylaxis prior to treatment

487
Chapter |8| Urinary tract infections in patients

Table 3 Treatment of complete or partial staghorn stones.

Type of stone Procedure Grade of recommendation

Infection stones and stones with Antibiotics + PCNL A

infection
Antibiotics + PCNL + ESWL A
Antibiotics + ESWL + PCNL A
Antibiotics + ESWL + local chemolysis B
Antibiotics + open surgery

Table 4 Perioperative antibiotic prophylaxis for stone procedures (modified from EAU Guidelines).

Procedure Pathogens Prophylaxis Antibiotics Remarks

ESWL Enterobacteriacae No Cephalosporins 2nd-3rd generation Only in risk

patients
Enterococci TMP+/-SMX
Aminopenicillin/BLI

Ureteroscopy (uncomplicated Enterobacteriacae No Cephalosporins 2nd-3rd generation Only in risk

distal stones) patients
Enterococci TMP+/-SMX
Staphylococci Aminopenicillin/BLI
Fluoroquinolones

Ureteroscopy (proximal Enterobacteriacae All patients Cephalosporins 2nd-3rd generation Short course
stones or impacted stones)
Enterococci TMP+/-SMX
PCNL
Staphylococci Aminopenicillin/BLI
Fluoroquinolones

Open surgery Enterobacteriacae Recommended Cephalosporins 2nd-3rd generation Single pre-

operative
Enterococci TMP+/-SMX
dose
Staphylococci Aminopenicillin/B

surgical procedures are still debated.
Differences in the way infective complica-
tions are classified (fever, SIRS (Systemic
Inflammatory Response Syndrome),
symptomatic UTI, asymptomatic bacte-
riuria) makes it difficult to compare the
results of various studies.
The guidelines of the EAU for the
management of urinary and male geni-
tal tract infections strongly recommend
peri-operative prophylaxis for the pre-
vention of infection related to surgical
procedures[59] (LoE 4). These guide-
lines suggest antibiotic prophylaxis for
ESWL and ureteroscopy of uncomplicated
stones in the distal ureter only in high-
risk patients (e.g. when ureteric stent or
a nephrostomy is present). Perioperative
antibiotics should be routinely adminis-
tered for ureteroscopy of stones in the
proximal ureter or impacted stones, for
PCNL or open stone surgery (Table 4).
The EAU guidelines give no definite
indication as to the duration of antibi-
otic prophylaxis and whether prophy-
laxis must necessarily lead to continuous
therapy. For this reason endourology
centres often develop internal guidelines
according to their own clinical practice
(Table 5).

488
 Urinary tract infections in patients with urolithiasis | 8.3 |

Table 5 Antibiotic prophylaxis/treatment before and after different procedures for stone removal.

Authors Procedure Prophylaxis/Therapy Results

Charton et al. [62] PCNL No prophylaxis 35% UTI

Cadeddu et al. [61] PCNL Prophylaxis + Therapy 16% fever

(>38°C)
(Gentamicin + Ampicillin
or Cephalosporins)

Margel et al. [10] PCNL Prophylaxis 22% SIRS

(Cephalosporins 2 generation 1 g one shot)
nd

Sharifi Aghdas et al. [58] PCNL No prophylaxis 25.8% fever

(>38°C)

Mariappan et al. [64] PCNL Prophylaxis 3% SIRS

(Ciprofloxacin 500 mg x 2/day orally for 1 week)

Dogan et al .[65] PCNL Prophylaxis 20% fever

(Ofloxacin 200 mg IV one shot)

Dogan et al. [65] PCNL Therapy 21% fever

(Ofloxacin 400 mg/day orally)

Knopf et al. [67] ULL Prophylaxis 1.8% bacteriuria

(Levofloxacin 250 mg one shot)

Knopf et al. [67] ULL No prophylaxis 12.5%

bacteriuria

Tenke et al. [68] ULL Continuous therapy 12% UTI

(Levofloxacin 500 mg x 2/day for 18–21 days)

Tenke et al. [68] ULL Intermittent therapy 12% UTI

(Levofloxacin 500 mg x 2/day for 7+3 days)

Costantino et al. [69] ULL Prophylaxis + Therapy 14% UTI

(Levofloxacin 500 mg 4h pre-operatively
+ Levofloxacin 500 mg for 5 days)

Dincel et al. [71] SWL Prophylaxis 2–17% UTI

Petterson and Tiselius [74] SWL No prophylaxis (urine culture negative prior to treatment) 8–15% UTI

Bierkens et al. [73] SWL No prophylaxis (urine culture negative prior to treatment) 4–12% UTI

Zanetti et al. [75] SWL No prophylaxis (urine culture negative prior to treatment) 7.3% UTI

7.5 Percutaneous lithotripsy certainty that the urine is sterile. Several

Although the presence of turbid urine
by renal puncture is not predictive of
infected stone or urine, it is custom-
ary, when undertaking PCNL, to leave
a nephrostomy in place if there is evi-
dence of potentially infected urine, and
to postpone the procedure until there is
authors have shown an increase in septic
risk (including fatal risk) with the place-
ment of instruments in an infected cal-
iceal system (LoE 3) [9].
The incidence of urosepsis does not
increase with an increase in the number
of punctures of the pelvi-caliceal system

489
Chapter |8| Urinary tract infections in patients
during PCNL, nor does there seem to be a
close correlation between the duration of
the procedure and the occurrence of infec-
tive complications (LoE 3) [60–61].
In patients with negative pre-opera-
tive urine culture who did not undergo
any antibiotic prophylaxis, Charton et al.
observed a 35% incidence of UTI (LoE 3)
[62]. Several authors have shown how
prophylaxis, associated with antibiotic
therapy, markedly reduces the incidence
of UTIs and post-operative hyperpyrexia
(LoE 3) [61, 63].
In the presence of proven pre-operative
UTI, targeted antibiotic therapy should
be administered until the urine culture
is negative, or a cycle of broad-spectrum
antibiotic should be administered prior to
surgery (LoE 3) [10].
Recently, the use of fluoroquinolo-
nes has been proposed (LoE 3) (LoE 2a)
[64–65]. Antibiotic prophylaxis was
administered one week prior to sur-
gery for patients with staghorn stones
(>20 mm) and/or pyelocaliceal dilata-
tion. The results were compared with
those of a group of patients with the
same characteristics, but who did not
receive any prophylaxis (control group).
In the patients who had prophylaxis, a
3-fold lower risk of upper UTI and SIRS
was observed, and a considerably lower
number of positive pelvic and stone cul-
tures were found.
7.6 Ureterolitholapaxy (ULL)
During this procedure, the hydrostatic
pressure generated by the irrigation
fluid causes migration of bacteria and
endotoxins into the systemic circulation.
This process is apparently amplified in
the presence of urinary tract obstruc-
tion, because of the greater permeability
of the blood and lymphatic vessels of the
renal pelvis. Therefore, the incidence of
systemic infection can be reduced with
low-pressure irrigation or using a flexible
ureterorenoscope with a ureteral access
sheath (LoE 3) [66].
490
Knopf et al. compared two groups
of patients who underwent endoscopic
removal of ureteric stones: the first
group received prophylaxis with one-shot
levofloxacin 250 mg orally an hour prior
to treatment, while the second did not
receive any prophylaxis. No acute infec-
tive complication was observed in either
of the groups, but a relevant reduction in
bacteriuria was observed in patients who
had received prophylaxis. Levofloxacin
therefore proved useful in minimizing pos-
sible infective complications caused by the
surgical procedure (LoE 1b, 2b) [67–69].
7.7 Extracorporeal shock wave
lithotripsy (ESWL)
Renal and vascular trauma caused by
ESWL treatment can lead to the passage
of bacteria present in the urine into the
systemic circulation. Skolarikos et al.
found post-ESWL bacteriuria in 7–23%
of patients, bacteremia in 14% with evo-
lution toward urosepsis in less than 1%
of cases (but for infection stones this per-
centage rose to 2.7%). The risk of sepsis
increases in the presence of positive pre-
treatment urine culture and/or urinary
obstruction (LoE 4) [70].
Currently, the role of antibiotic prophy-
laxis for ESWL is controversial. Although
some authors support the usefulness
of routine prophylaxis (LoE 3) [71], the
most recent studies have not shown any
significant advantage in the prevention
of infection in the absence of pre-existing
UTIs or infected stones. There is, instead,
agreement on the use of prophylaxis or
antibiotic treatment in infection stones in
the presence of positive urine culture, in
patients with history of recurrent UTIs,
and in patients who undergo treatment
with stents or nephrostomies (LoE 3)
[70–75].
7.8 Prophylaxis
After treatment residual stone fragments
may settle in the dependent calices and
 Urinary tract infections in patients with urolithiasis
therefore lead to an increased recurrence
rate. Residual stones and fragments
cause persistent infection and rapid stone
regrowth in 61% of cases after surgical
therapy (LoE 3) [76] and in 65–78% after
ESWL (LoE 3) [77–78].
Antibiotics eliminate bacteriuria, but
the persistence of stones or residual frag-
ments compromises the possibility of
eradicating the infection. The presence of
persistent UTI increases the risk of stone
recurrence. In patients with infected
staghorn stones treated by Meretyk et al.,
stone recurrence was present in 33.3% of
cases post-ESWL and in 22% after PCNL
(LoE 1a) [79].
Complete eradication of the stones is a
pre-requisite for successful prophylaxis
of infection calculi. Similarly, the pres-
ence of concomitant obstruction of the
urinary tract should be addressed to pre-
vent persistence of infection and stone
recurrence. Despite broad-spectrum anti-
biotic use, little success can be obtained
with eradication of infection and recur-
rent stone formation in the presence of
residual stones or urinary stasis due
to obstruction related to urinary tract
abnormalities.
Patients should be strictly followed up
for recurrent UTI and stone recurrence.
Urine specimens for bacteriological cul-
ture should be routinely collected and
imaging of the urinary tract should be
obtained at each follow-up visit. In case of
newly arising infections, antibiotic ther-
apy based on results of sensitivity testing
should be given. Chronic low-dosage anti-
biotic suppression treatment for several
months has been recommended, but the
appropriateness of chronic treatment is
debated.
Alternative treatments have been
proposed, such as chronic urinary acidi-
fication or alkalisation of urine with cit-
rate. Chronic urinary acidification has
not yet been successfully demonstrated.
Ammonium chloride can be used only for
short-term treatment, whereas ammo-
nium sulphate can be used over longer
| 8.3 |
periods (LoE 4) [3]. Vitamin C admin-
istration only results in lowering the
urine pH to alkaline levels. Oral intake
of citrate has been suggested in order
to prevent struvite crystal formation and
aggregation by increasing urinary citrate
levels, although there has been a reluc-
tance in relation to the potential increase
in urinary pH. Successful use of citrate as
a prophylactic agent for infection stones
has been described by some authors
(LoE 1b) [80].
7.9 Urease enzyme inhibitors
Urease inhibition can limit the change in
urinary pH produced by urease-produc-
ing bacteria. Urease enzyme inhibitors
such as acetohydroxamic acid have been
developed (LoE 3) [81–83], but frequent
neurological, dermatological and haemo-
tological side-effects have limited long-
term efficacy (LoE 1b) [84].
Aceto-hydroxamic acid (AHA) causes a
complete non-reversible, non-competitive
inhibition of the enzyme urease. Other
urease inhibitors are hydroxyurea, bio-
suppressin (hydroxycarbamide), and furo-
semide. Other enzyme inhibitors with
fewer side-effects may be more useful in
the future.
8. FUTURE RESEARCH
In in order to expand further understand-
ing, future research is required:
• to find new methods of diagnosing and
quantifying biofilm infection
• to develop new strategies of antibiotic
treatment more effective against bac-
teria in the biofilm mode (higher doses,
longer duration of treatment, combina-
tion of antibiotics)
• to gain an understanding of the uri-
nary components involved in biofilm
formation and of the mechanism of
interaction between stone surface and
bacteria in order to engineer alterna-
tive non-antibiotic treatments aiming
491
Chapter |8| Urinary tract infections in patients
to interfere with microbial adherence
to stone surfaces
• to find new diagnostic tools to iden-
tify patients who require prolonged
antibiotic treatment prior to endouro-
logical procedures in order to prevent
sepsis.
9. CONCLUSIONS
The prevention and treatment of infec-
tion associated with urinary stones still
remain unresolved problems. Our knowl-
edge of bacterial biofilms is limited,
making treatment difficult and often
unsatisfactory. For treatment and preven-
tion of infection stone recurrence, com-
plete stone clearance by endourological
or surgical procedures still remains cru-
cial in order to obtain complete bacterial
eradication.
REFERENCES
1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
3. Bichler KH, Eipper E, Naber K, Braun V,
Zimmermann R, and Lahme S, Urinary
infection stones. Int J Antimicrob Agents,
2002. 19(6): 488–98.
4. Johansen TE, Cek M, Naber KG,
Stratchounski L, Svendsen MV, and
Tenke P, Hospital acquired urinary tract
infections in urology departments: patho-
gens, susceptibility and use of antibiotics.
Data from the PEP and PEAP-studies. Int
J Antimicrob Agents, 2006. 28 Suppl 1:
S91–107.
5. Daudon M, Dore JC, Jungers P,
and Lacour B, Changes in stone
composition according to age and
492
gender of patients: a multivariate epi-
demiological approach. Urol Res, 2004.
32(3): 241–7.
6. Hugosson J, Grenabo L, Hedelin H,
Pettersson S, and Seeberg S, Bacteriology
of upper urinary tract stones. J Urol,
1990. 143(5): 965–8.
7. Gault MH, Longerich LL, Crane G,
Cooper R, Dow D, Best L, Stockall E, and
Brown W, Bacteriology of urinary tract
stones. J Urol, 1995. 153(4): 1164–70.
8. Mariappan P and Loong CW, Midstream
urine culture and sensitivity test is a poor
predictor of infected urine proximal to
the obstructing ureteral stone or infected
stones: a prospective clinical study. J Urol,
2004. 171(6 Pt 1): 2142–5.
9. Mariappan P, Smith G, Bariol SV,
Moussa SA, and Tolley DA, Stone and
pelvic urine culture and sensitivity are
better than bladder urine as predictors of
urosepsis following percutaneous neph-
rolithotomy: a prospective clinical study.
J Urol, 2005. 173(5): 1610–4.
10. Margel D, Ehrlich Y, Brown N, Lask D,
Livne PM, and Lifshitz DA, Clinical
implication of routine stone culture in per-
cutaneous nephrolithotomy – a prospective
study. Urology, 2006. 67(1): 26–9.
11. Hinman F, Jr., Directional growth of renal
calculi. J Urol, 1979. 121(6): 700–5.
12. Nilsen FS, Karlsen SJ, and Gjertsen O,
Gas-containing renal stones treated with
percutaneous nephrolithotomy: case
report. J Endourol, 2001. 15(9): 915–7.
13. Abrahams HM and Stoller ML, Infection
and urinary stones. Curr Opin Urol, 2003.
13(1): 63–7.
14. McAleer IM, Kaplan GW, Bradley JS, and
Carroll SF, Staghorn calculus endotoxin
expression in sepsis. Urology, 2002. 59(4):
601.
15. Gambaro G, Favaro S, and D’Angelo A,
Risk for renal failure in nephrolithiasis.
Am J Kidney Dis, 2001. 37(2): 233–43.
16. Griffith DP and Osborne CA, Infection
(urease) stones. Miner Electrolyte Metab,
1987. 13(4): 278–85.
17. Schwartz BF and Stoller ML, Nonsurgical
management of infection-related renal
calculi. Urol Clin North Am, 1999. 26(4):
765–78, viii.
 Urinary tract infections in patients with urolithiasis
18. Hedelin H, Uropathogens and urinary
tract concretion formation and catheter
encrustations. Int J Antimicrob Agents,
2002. 19(6): 484–7.
19. Bichler KH, Behrendt WA, Haussmann A,
Schulze HS, and Harzmann R, [Detection
of ureolytic bacteria in the urine of stone
patients (author’s transl)]. Urol Int, 1980.
35(6): 421–6.
20. Li X, Zhao H, Lockatell CV,
Drachenberg CB, Johnson DE, and
Mobley HL, Visualization of Proteus
mirabilis within the matrix of urease-
induced bladder stones during experimen-
tal urinary tract infection. Infect Immun,
2002. 70(1): 389–94.
21. Grenabo L, Brorson JE, Hedelin H, and
Pettersson S, Ureaplasma urealyticum-
induced crystallization of magnesium
ammonium phosphate and calcium phos-
phates in synthetic urine. J Urol, 1984.
132(4): 795–9.
22. Grenabo L, Brorson JE, Hedelin H, and
Pettersson S, Concrement formation in
the urinary bladder in rats inoculated
with Ureaplasma urealyticum. Urol Res,
1985. 13(4): 195–8.
23. Hedelin H, Brorson JE, Grenabo L, and
Pettersson S, Ureaplasma urealyticum
and upper urinary tract stones. Br J Urol,
1984. 56(3): 244–9.
24. Becopoulos T, Tsagatakis E,
Constantinides C, Paniara O, Mouka N,
and Psaras L, Ureaplasma urealyticum
and infected renal calculi. J Chemother,
1991. 3(1): 39–41.
25. Dewan B, Sharma M, Nayak N, and
Sharma SK, Upper urinary tract stones &
Ureaplasma urealyticum. Indian J Med
Res, 1997. 105: 15–21.
26. Huang HS, Chen J, Teng LJ, and Lai MK,
Use of polymerase chain reaction to detect
Proteus mirabilis and Ureaplasma urea-
lyticum in urinary calculi. J Formos Med
Assoc, 1999. 98(12): 844–50.
27. Grenabo L, Claes G, Hedelin H, and
Pettersson S, Rapidly recurrent renal cal-
culi caused by Ureaplasma urealyticum: a
case report. J Urol, 1986. 135(5): 995–7.
28. Meria P, Desgrippes A, Fournier R, Arfi C,
Antoine C, Martinat L, Teillac P, and Le
Duc A, The conservative management
| 8.3 |
of corynebacterium group D2 encrusted
pyelitis. BJU Int, 1999. 84(3): 270–5.
29. Soriano F and Tauch A, Microbiological
and clinical features of Corynebacterium
urealyticum: urinary tract stones and
genomics as the Rosetta Stone. Clin
Microbiol Infect, 2008. 14(7): 632–43.
30. Kajander EO and Ciftcioglu N,
Nanobacteria: an alternative mecha-
nism for pathogenic intra- and extracel-
lular calcification and stone formation.
Proc Natl Acad Sci U S A, 1998. 95(14):
8274–9.
31. Kajander EO, Tahvanainen E, Kuronen I,
and Cíftçíoglu N, Comparison of
Staphylococci and novel bacteria-like par-
ticles from blood. Zentralblatt Bakteriol
1994. Suppl(26): 147–9.
32. Cisar JO, Xu DQ, Thompson J, Swaim W,
Hu L, and Kopecko DJ, An alternative inter-
pretation of nanobacteria-induced biomin-
eralization. Proc Natl Acad Sci U S A, 2000.
97(21): 11511–5.
33. Conte Visus A, Grases Freixedas F,
Costa-Bauza A, and Piza Reus P,
[Microinfections and kidney lithiasis].
Arch Esp Urol, 2001. 54(9): 855–60.
34. Ciftcioglu N, Miller-Hjelle MA, Hjelle JT,
and Kajander EO, Inhibition of nanobac-
teria by antimicrobial drugs as measured
by a modified microdilution method.
Antimicrob Agents Chemother, 2002.
46(7): 2077–86.
35. Tenke P, Kovacs B, Jackel M, and Nagy E,
The role of biofilm infection in urology.
World J Urol, 2006. 24(1): 13–20.
36. McLean RJ, Lawrence JR, Korber DR,
and Caldwell DE, Proteus mirabilis bio-
film protection against struvite crystal
dissolution and its implications in stru-
vite urolithiasis. J Urol, 1991. 146(4):
1138–42.
37. Parsons CL, Greenspan C, Moore SW, and
Mulholland SG, Role of surface mucin in
primary antibacterial defense of bladder.
Urology, 1977. 9(1): 48–52.
38. Grenabo L, Hedelin H, Hugosson J,
and Pettersson S, Adherence of urease-
induced crystals to rat bladder epithelium
following acute infection with different
uropathogenic microorganisms. J Urol,
1988. 140(2): 428–30.
493
Chapter |8| Urinary tract infections in patients
39. Holmang S, Grenabo L, Hedelin H,
Wang YH, and Pettersson S, Influence of
indomethacin on the adherence of urease-
induced crystals to rat bladder epithe-
lium. J Urol, 1991. 145(1): 176–8.
40. Edin-Liljegren A, Grenabo L, Hedelin H,
Larsson P, and Pettersson S, Influence of
Escherichia coli on urease-induced crys-
tallisation in human urine. Scand J Urol
Nephrol, 1993. 27(2): 163–7.
41. Edin-Liljegren A, Rodin L, Grenabo L,
and Hedelin H, The importance of glu-
cose for the Escherichia coli mediated
citrate depletion in synthetic and human
urine. Scand J Urol Nephrol, 2001. 35(2):
106–11.
42. Hugosson J, Grenabo L, Hedelin H,
Pettersson S, and Tarfusser I, How varia-
tions in the composition of urine influence
urease-induced crystallization. Urol Res,
1990. 18(6): 413–7.
43. Hugosson J, Grenabo L, Hedelin H, and
Pettersson S, Effects of serum, albumin
and immunoglobulins on urease-induced
crystallization in urine. Urol Res, 1990.
18(6): 407–11.
44. Wang YH, Grenabo L, Hedelin H,
McLean RJ, Nickel JC, and Pettersson S,
Citrate and urease-induced crystallization
in synthetic and human urine. Urol Res,
1993. 21(2): 109–15.
45. Wang YH, Grenabo L, Hedelin H, and
Pettersson S, The effects of sodium citrate
and oral potassium citrate on urease-
induced crystallization. Br J Urol, 1994.
74(4): 409–15.
46. Burr RG and Nuseibeh I, The blocking
urinary catheter: the role of variation in
urine flow. Br J Urol, 1995. 76(1): 61–5.
47. Edin-Liljegren A, Grenabo L, Hedelin H,
Jonsson O, Akerlund S, and Pettersson S,
Concrement formation and urease-
induced crystallization in urine from
patients with continent ileal reservoirs. Br
J Urol, 1996. 78(1): 57–63.
48. Siroky MB, Pathogenesis of bacteriuria
and infection in the spinal cord injured
patient. Am J Med, 2002. 113 Suppl 1A:
67S-79S.
49. Suby HI and Albright F, Dissolution
of phosphatic urinary calculi by the
494
retrograde introduction of a citrate solu-
tion containing magnesium. New Eng J
Med, 1943. 228: 81–91.
50. Mulvaney WP, The clinical use of renaci-
din in urinary calcifications. J Urol, 1960.
84: 206–12.
51. Shortliffe LM and Spigelman SS,
Infection stones. Evaluation and manage-
ment. Urol Clin North Am, 1986. 13(4):
717–26.
52. Mulvaney WP, A new solvent for certain
urinary calculi: a preliminary report. J
Urol, 1959. 82: 546–8.
53. Dretler SP and Pfister RC, Primary dis-
solution therapy of struvite calculi. J Urol,
1984. 131(5): 861–3.
54. Nemoy NJ and Staney TA, Surgical, bac-
teriological, and biochemical management
of “infection stones”. JAMA, 1971. 215(9):
1470–6.
55. Preminger GM, Assimos DG,
Lingeman JE, Nakada SY, Pearle MS, and
Wolf JS, Jr., Chapter 1: AUA guideline on
management of staghorn calculi: diagnosis
and treatment recommendations. J Urol,
2005. 173(6): 1991–2000.
56. Streem SB, Yost A, and Dolmatch B,
Combination “sandwich” therapy for
extensive renal calculi in 100 consecutive
patients: immediate, long-term and strati-
fied results from a 10-year experience. J
Urol, 1997. 158(2): 342–5.
57. Wang LP, Wong HY, and Griffith DP,
Treatment options in struvite stones. Urol
Clin North Am, 1997. 24(1): 149–62.
58. Sharifi Aghdas F, Akhavizadegan
H, Aryanpoor A, Inanloo H, and
Karbakhsh M, Fever after percutaneous
nephrolithotomy: contributing factors.
Surg Infect (Larchmt), 2006. 7(4): 367–71.
59. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H, Lobel B,
Jinenez Cruz F, and Selvaggi FP, EAU
guidelines for the management of urinary
and male genital tract infections. Urinary
Tract Infection (UTI) Working Group
of the Health Care Office (HCO) of the
European Association of Urology (EAU).
Eur Urol, 2001. 40(5): 576–88.
60. Matlaga BR, Hodges SJ, Shah OD,
Passmore L, Hart LJ, and Assimos DG,
 Urinary tract infections in patients with urolithiasis
Percutaneous nephrostolithotomy: predic-
tors of length of stay. J Urol, 2004.
172(4 Pt 1): 1351–4.
61. Cadeddu JA, Chen R, Bishoff J, Micali S,
Kumar A, Moore RG, and Kavoussi LR,
Clinical significance of fever after percu-
taneous nephrolithotomy. Urology, 1998.
52(1): 48–50.
62. Charton M, Vallancien G, Veillon B, and
Brisset JM, Urinary tract infection in
percutaneous surgery for renal calculi. J
Urol, 1986. 135(1): 15–7.
63. Inglis JA and Tolley DA, Antibiotic proph-
ylaxis at the time of percutaneous stone
surgery. J Endourol, 1988. 2: 59–62.
64. Mariappan P, Smith G, Moussa SA, and
Tolley DA, One week of ciprofloxacin
before percutaneous nephrolithotomy sig-
nificantly reduces upper tract infection
and urosepsis: a prospective controlled
study. BJU Int, 2006. 98(5): 1075–9.
65. Dogan HS, Sahin A, Cetinkaya Y,
Akdogan B, Ozden E, and Kendi S,
Antibiotic prophylaxis in percutaneous
nephrolithotomy: prospective study in 81
patients. J Endourol, 2002. 16(9): 649–53.
66. Auge BK, Pietrow PK, Lallas CD, Raj GV,
Santa-Cruz RW, and Preminger GM,
Ureteral access sheath provides protection
against elevated renal pressures during
routine flexible ureteroscopic stone manip-
ulation. J Endourol, 2004. 18(1): 33–6.
67. Knopf HJ, Graff HJ, and Schulze H,
Perioperative antibiotic prophylaxis in
ureteroscopic stone removal. Eur Urol,
2003. 44(1): 115–8.
68. Tenke P, Kovacs B, Benko R, Ashaber D,
and Nagy E, Continuous versus intermit-
tent levofloxacin treatment in complicated
urinary tract infections caused by urinary
obstruction temporarily relieved by foreign
body insertion. Int J Antimicrob Agents,
2006. 28 Suppl 1: S82–5.
69. Costantino G, Condorelli S, and
Costanzo V, The antibacterial chemoproph-
ylaxis in ureteroscopy: the employment of
the levofloxacin used as switch-therapy
versus oral treatment with a single 500mg
once a day. Gazz Med Ital – Arch Sci Med,
2005. 164: 43–6.
| 8.3 |
70. Skolarikos A, Alivizatos G, and de la
Rosette J, Extracorporeal shock wave
lithotripsy 25 years later: complications
and their prevention. Eur Urol, 2006.
50(5): 981–90; discussion 990.
71. Dincel C, Ozdiler E, Ozenci H, Tazici N,
and Kosar A, Incidence of urinary tract
infection in patients without bacteriuria
undergoing SWL: comparison of stone
types. J Endourol, 1998. 12(1): 1–3.
72. Moody FG, Lithotripsy in the treatment of
biliary stones. Am J Surg, 1993. 165(4):
479–82.
73. Bierkens AF, Hendrikx AJ, Ezz el Din
KE, de la Rosette JJ, Horrevorts A,
Doesburg W, and Debruyne FM, The value
of antibiotic prophylaxis during extracor-
poreal shock wave lithotripsy in the preven-
tion of urinary tract infections in patients
with urine proven sterile prior to treatment.
Eur Urol, 1997. 31(1): 30–5.
74. Pettersson B and Tiselius HG, Are pro-
phylactic antibiotics necessary during
extracorporeal shockwave lithotripsy?
Br J Urol, 1989. 63(5): 449–52.
75. Zanetti G, Montanari E, and Trinchieri A,
SWL and urinary infection in pretreat-
ment non-infected patients. Urology, ed.
Giuliani L and Puppo P 1992, Bologna:
Monduzzi Editore.
76. Martinez-Pineiro JA, de Iriarte EG, and
Armero AH, The problem of recurrences
and infection after surgical removal of
staghorn calculi. Eur Urol, 1982. 8(2):
94–101.
77. Beck EM and Riehle RA, Jr., The fate of
residual fragments after extracorporeal
shock wave lithotripsy monotherapy of
infection stones. J Urol, 1991. 145(1): 6–9;
discussion 9–10.
78. Zanetti G, Seveso M, Montanari E,
Guarneri A, Del Nero A, Nespoli R, and
Trinchieri A, Renal stone fragments fol-
lowing shock wave lithotripsy. J Urol,
1997. 158(2): 352–5.
79. Meretyk S, Gofrit ON, Gafni O, Pode D,
Shapiro A, Verstandig A, Sasson T,
Katz G, and Landau EH, Complete stag-
horn calculi: random prospective compari-
son between extracorporeal shock wave
lithotripsy monotherapy and combined
495
Chapter |8| Urinary tract infections in patients
with percutaneous nephrostolithotomy.
J Urol, 1997. 157(3): 780–6.
80. Cicerello E, Merlo F, Gambaro G,
Maccatrozzo L, Fandella A, Baggio B, and
Anselmo G, Effect of alkaline citrate ther-
apy on clearance of residual renal stone
fragments after extracorporeal shock wave
lithotripsy in sterile calcium and infection
nephrolithiasis patients. J Urol, 1994.
151(1): 5–9.
81. Kobashi K, Hase J, and Uehara K,
Specific inhibition of urease by
hydroxamic acids. Biochim Biophys Acta,
1962. 65: 380–3.
496
82. Kobashi K, Kumaki K, and Hase JI,
Effect of acyl residues of hydroxamic acids
on urease inhibition. Biochim Biophys
Acta, 1971. 227(2): 429–41.
83. Kobashi K, Takebe S, and Numata A,
Specific inhibition of urease by
N-acylphosphoric triamides. J Biochem,
1985. 98(6): 1681–8.
84. Griffith DP, Gleeson MJ, Lee H, Longuet R,
Deman E, and Earle N, Randomized,
double-blind trial of Lithostat (acetohy-
droxamic acid) in the palliative treatment
of infection-induced urinary calculi. Eur
Urol, 1991. 20(3): 243–7.
|8.4|

Epidemiology, diagnosis and

treatment of urinary tract
infections in patients with
spina bifida
Dan Wood1*, Christopher Woodhouse2
1
Consultant in Adolescent and Reconstructive Urology, University College London Hospitals.
2
Professor of Adolescent Urology, University College London Hospitals.
*Corresponding author: 1Mr Dan Wood PhD FRCS(Urol) Consultant in Adolescent and Reconstructive Urology, University
College London Hospitals.

ABSTRACT emphasised. The recognised complica-

This section examines the aetiology, diag-
nosis and treatment of urinary tract infec-
tions (UTIs) in patients with spina bifida.
The incidence of spina bifida has decreased
due to preconception administration of
folic acid and in some cases termination
of affected pregnancies. Aggressive early
management offers improved renal and
continence outcomes. Advanced reinnerva-
tion strategies may offer further hope for
an improved functional quality of life for
affected children.
The correct diagnosis of UTIs is impor-
tant in management of these patients,
particularly those who have been previ-
ously augmented. The importance of cor-
relating symptoms and investigations is
tions of cystoplasty are discussed.
There is little consensus about how to
manage asymptomatic bacteriuria and
little in the way of high level evidence
to guide strategies for prophylaxis. This
chapter aims to explain the potential
application of recognised strategies as
well as describing those that are less well
established in clinical practice.
Key words: myelomeningocele, spina
bifida, urinary tract infection, sepsis,
cystoplasty
SUMMARY OF RECOMMENDATIONS
1. There is no indication for antibiotic
prophylaxis in patients who are
Chapter |8| Urinary tract infections in patients
asymptomatic, have no vesico-ureteric
reflux and are able to self-catheterise
(GoR B).
2. In patients suffering with UTIs anti-
biotic prophylaxis strategies should
be discussed as an optional treatment
(GoR C).
3. Intravesical hyaluronic acid may
offer some benefit in recurrent UTIs
(GoR C).
4. We can make no recommendation
regarding perineal treatments, or
alternatives such as acupuncture or
cranberry juice (GoR C).
1. INTRODUCTION
Spina bifida and its association with dam-
age to the urinary tract create a lifelong
management problem for both physicians
and patients. Worldwide incidence of
spina bifida is 0.3–4.5 per 1000 live births.
In the last 60 years the medical profes-
sion has moved between extremes. Sixty
years ago before the description [1] and
popularisation of the ileal conduit [2]
or the use of clean intermittent self-
catheterisation (CISC) [3–4] the outcome
following a diagnosis of spina bifida in a
newborn infant was nearly always fatal.
Many would succumb to overwhelming
infection or progressive hydrocephalus
and death in early childhood.
Modern medicine has seen a dramatic
fall in the number of live births with
spina bifida – for two reasons:
1. The introduction of pre-conception
folic acid supplements for planned
pregnancies.
2. Improvements in antenatal diagnosis
and subsequent termination.
Better understanding and manage-
ment of spina bifida, such as early clo-
sure of the lesion and shunting, has lead
to increased survival and a reduction in
physical and intellectual problems of
498
those affected. However, improvements
are relative - with a survival at 35 years
of 50%. This has lead to greater empha-
sis on secondary problems such as those
within the urinary system.
If one could establish efficient, normal
voiding, all secondary urological manifes-
tations would be eliminated – including
UTI. The work of some groups in correct-
ing the anatomical deformity in utero
has shown some promise in dramati-
cally reducing neuromotor defects [5].
Carr’s 2007 review was extended with
further data at the American Academy
of Paediatrics 2008. Early data suggest
normal voiding behaviour in infants and
early childhood – the long-term success
of this treatment will take years to fully
understand.
Questions remain about the residual
neural dysplasia despite ‘anatomical’ clo-
sure. In functional terms the long-term
safety of the upper tracts will need careful
evaluation in order to accept such work
as the progress that it may represent.
The potential for re-innervation by anas-
tomosing somatic with autonomic nerves
[6] (LoE 3) and restoring voiding through
subsequent neurostimulation (a thigh
scratch) also offers hope for the future.
2. METHODS
The most up to date and relevant refer-
ences were identified using the keywords:
myelomeningocele, spina bifida, urinary
tract infection, sepsis, and cystoplasty with
the following limitations: peer reviewed
publications (abstract only publications
were excluded) and English language
papers were included and a manual review
of references was performed. This identified
357 papers. These were reviewed by title
and abstract, leaving a total of 47 papers
for analysis as described. A level of evi-
dence (LoE) was ascribed to each and key
points were distilled. Recommendations
were focused and chosen with relevance to
the remit of the chapter.
 Epidemiology, diagnosis and treatment of urinary
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [7–8].
3. EARLY MANAGEMENT
The major priorities in the first phase of
management are the reduction of risk to
the upper tracts and protection against
infection. In those patients who have an
acontractile pelvic floor and are there-
fore incontinent the upper tracts are safe.
Closure of the lesion may lead to conver-
sion to an overactive pelvic floor within
2–3 months[9] (LoE 4) creating detrusor
sphincter dyssynergia and consequently
high bladder pressures. Hence it is sen-
sible not to evaluate the urodynamics
until this has had a chance to develop.
Thus many patients have an aggressive
early regime to include an anticholiner-
gic, self-catheterisation and antibiotic
prophylaxis.
It has been argued that maximal
treatment of all patients will be over-
treatment for many (LoE 4)[10]. However,
there is evidence that aggressive manage-
ment yields high success – 92% kidneys
with normal imaging and 77% continence
rate (LoE 3) [9, 11]. The acknowledged
predictability of a call for a randomised
controlled trial becomes important in
establishing the correct balance for these
complex patients.
It is reflex behaviour for paediatric
urologists to prescribe antibiotic prophy-
laxis for all spina bifida patients. There is
little scientific evidence for this – however
it is regarded as safe practice to give
2 mg/kg trimethoprim antibiotic prophy-
laxis. The major objective is to prevent
renal scarring secondary to reflux and
infection. This is an important distinc-
tion. All patients with neuropathic void-
ing dysfunction at this age will enter a
programme of self-catheterisation, prob-
ably with anticholinergic medication to
be initiated once the spinal lesion has
| 8.4 |
been closed. Data have suggested it is
important to distinguish between asymp-
tomatic bacteriuria in the absence of
reflux, bacteriuria with reflux and those
suffering with periodic and systemic bac-
terial UTI (LoE 4) [12].
The literature indicates that there is
no indication for antibiotic prophylaxis
in bacteriuric patients who are asympto-
matic, do not have vesico-ureteric reflux,
and are on self-catheterisation (LoE 3).
4. CONSEQUENCES OF
AUGMENTATION
The indications to augment the blad-
der in a neuropathic bladder may have
changed slightly with the evidence to
support the use of botulinum toxin A in
paediatric patients. Data from short-term
cohort studies suggest a 65–73% improve-
ment in continence and improvements
in bladder capacity of 59% and a signifi-
cant reduction in mean detrusor pressure
(LoE 3) [13–14].
It remains common practice to aug-
ment the bladder of neurogenic patients
for two major indications:
1. Incontinence
2. Protection of the upper tracts
The controversies over who, how and
when patients should be augmented are
well rehearsed but beyond the scope of
this chapter. It may be that we shall see
less augmentation over coming years,
as selection criteria are refined (LoE 3)
[15]. It can be a successful treatment on
its own (LoE 4) [16]. However, it remains
a major decision to augment a bladder –
the consequences are discussed below.
4.1 Perforation
In their review Greenwell et al. show a
number of series with a range of perfora-
tion from 0–9% (LoE 3) [17]. This is the
most dangerous of all complications with
a mortality of up to 25% (LoE 3) [18–20].
499
Chapter |8| Urinary tract infections in patients
4.2 Stones
The rate of stone formation following aug-
mentation varies between urethral and
Mitrofanoff drainage, from 8% for ure-
thral drainage to 21–100% for Mitrofanoff
drainage (LoE 3) [21–25]. Other series
have suggested little difference between
the two (6% vs 10%) respectively. Hamid
et al. demonstrated that urinary citrate
and 24 hour urine volumes were both sig-
nificantly lower (173% and 41%) respec-
tively in those patients who formed
stone [26]. Stone formers also had signifi-
cantly higher urinary calcium excretion
(5.2 vs 2.78 mmol/l) – these factors cor-
related with a significantly higher risk of
both calcium oxalate and calcium phos-
phate stone formation in the stone form-
ing group (LoE 3) [26].
Whilst many authors have speculated
that UTI may be causative in stone for-
mation, it appears that urinary stasis is a
positive risk factor and bladder irrigation
protocols may reduce risk. Patients with
stones may present with an increased
incidence of UTI with organisms such
as Proteus mirabilis [22] (LoE 2b) or a
change in continence. There is little evi-
dence to support a direct link between
bacteriuria or urinary sepsis and stone
formation. With this evidence in mind it
is clear that a diagnosis of either upper
tract or reservoir stones must be consid-
ered in patients with enterocystoplasties
who present with a change in symptoms,
particularly an increase in UTIs.
The most important method of pre-
venting stone formation is probably to
increase daily fluid intake [26] (LoE 3).
Bladder irrigation is also an important
means of achieving this [22] (LoE 2b).
Other strategies may also be helpful –
including the addition of potassium
citrate.
4.3 Metabolic changes
All patients with enterocystoplasty will
have a degree of metabolic acidosis –
for the majority this is subclinical. This
500
arises as a result of absorption of ammo-
nia and net loss of bicarbonate. It proba-
bly has no direct association with UTI or
stone formation.
4.4 Malignant change
Opinions vary widely over the need for
surveillance of patients with cystoplasty.
The majority of centres appear to agree
on the need for follow-up in neuropathic
and other higher risk groups. It is true
that in patients with bacteriuria there
are higher N-nitrosamine levels. This
does not prove an association but may
suggest a possible link (LoE 3) [27].
5. PREGNANCY
There are very few data relating to the
care of patients with neuropathic blad-
ders, reconstruction and pregnancy.
Two series have sought to examine this
within the last few years (LoE 4) [22, 28].
Pregnancy must be established using a
serum hCG test as the urine test gives a
57% rate of false positive diagnosis (LoE
2b) [27].
These patients need to be carefully
monitored and shared care is impor-
tant through their pregnancy. The inci-
dence of UTI ranges from 53% to 91% in
pregnancy[28–30]. Therefore, they should
be on antibiotic prophylaxis (LoE 3). In
those who have had ileal conduits an
expanding uterus may compress the con-
duit, affecting emptying and therefore
increasing the risk of UTIs. In those that
have ureteric rerouting the possibility of
extrinsic compression by the uterus and
therefore hydronephrosis needs to be
considered.
Some expectant mothers with Mitrofanoff
channels will run into difficulty with cath-
eterisation and emptying as their preg-
nancy progresses. As this may represent an
additional risk for UTIs some will need an
indwelling catheter during their pregnancy.
This can be removed following delivery
 Epidemiology, diagnosis and treatment of urinary
and a normal CISC regime re-established
(LoE 4).
6. DEFINITION OF UTI WITH AN
AUGMENTED BLADDER
There is an unfortunate tendency for
patients and family doctors to ascribe a
wide range of symptoms to UTI, including
smelly urine, malaise, increased mucus
production and back pain. All of these
have other possible causes and are com-
mon in those with augmented bladders.
However, once the idea takes root that
UTI is the cause, courses of antibiotics are
requested by the patient and prescribed
by the doctor with little further thought.
Correlation of the symptoms with the
investigative findings is as important
as in any other clinical situation, even
though it may be difficult.
The history may be sufficient to exclude
infection as a cause – UTI does not give
intermittent symptoms and generally
they persist unless treated. Fever is a
common accompaniment. The smell of
urine from an augmented bladder is often
pungent. The subjective view of mucus
by a patient is very unreliable, especially
when there is no comparator other than
personal experience. Furthermore, mucus
will appear to be increased when urine is
concentrated.
Stick tests for ‘infection’ are commonly
positive as white cells and nitrites may
only be measures of inflammation or of
insignificant bacteriuria. Bacteria do not
carry enough protein to make a stick test
positive – the presence of protein is not
an indicator of infection.
It is essential that the symptoms are
correlated with urine culture. In doubtful
cases it may be necessary to culture the
urine monthly and compare the results
with a symptom diary. It is, in the long
term, a worthwhile, though often difficult,
exercise to establish the pattern of symp-
toms that are indicative of significant
infection for an individual patient. It will
| 8.4 |
then be possible to avoid unnecessary anti-
biotics for some and institute one of the
following schemes of treatment for others.
6.1 Management of UTIs
Any patient presenting with recurrent
UTIs to a urology clinic can appear as a
frustrating and clinically difficult prob-
lem to treat.
The first priority must be to establish
a definition and diagnosis. Treatment
should be reserved for patients who
present with symptomatic UTIs.
There is little clear consensus as to the
management and follow-up of asympto-
matic bacteriuria. In patients with neuro-
pathic bladders who are self-catheterising
76.8% have been demonstrated to have
bacteriuria, with E. coli being the most
common bacterial pathogen identified
(70%) (LoE 3) [31].
A survey of urological clinics suggested
follow-up with surveillance ultrasound
and urinalysis in 59% and urine culture
in 49%. Only 14% suggested that they
would perform baseline radio-isotope
evaluation of the kidneys. The authors
of this survey go on to suggest that age,
grade of vesico-ureteric reflux and abnor-
mal renal function do not appear to affect
treatment decisions. Most would wait
until a symptomatic presentation before
beginning treatment. In the presence of
fever 69% of clinics would begin empiri-
cal antibiotic treatment, 64% would treat
with flank pain (LoE 4) [32].
It is clear that patients need to be
watched closely since renal deterioration
is seen in 18% and 30% before and after
puberty, respectively, without diversion
(LoE 4) [33]. In those who have under-
gone cystoplasty and long term follow-up
around 20% will show deterioration in
renal function. It seems unlikely that renal
deterioration can be attributed solely to
cystoplasty. Therefore the management of
other factors including infection becomes
increasingly important (alongside stones
and non-compliance) (LoE 3) [34].
501
Chapter |8| Urinary tract infections in patients
7. AVOIDING INFECTION
The first principle with all those who
have spina bifida should be to avoid infec-
tion where possible – where achievable
this is a major victory. It is also vital to
have an overview of the whole patient.
This will include factors such as bowel
management. Faecal incontinence or con-
stipation may create major difficulties
with the control of UTIs. In patients who
do not respond to laxatives, the MACE
procedure can be used to improve con-
tinence (LoE 3) [35]. The association
between poor bowel function and UTIs is
well established and should be rigorously
applied in this group.
The need to establish regular and
complete bladder emptying has already
been discussed and is important in
these patients for a number of reasons.
Community based studies have looked at
colonisation with resistant organisms –
there was a lower level of colonisation
in those who were continent and self-
catheterising (LoE 3) [36].
Recent data have suggested that this
may be of fundamental importance. A study
from Game et al. suggests that in those neu-
rogenic patients who show a urodynamic
response to Botox A there is a significant
reduction in the number of UTIs. In this
study, prior to injection the mean number of
symptomatic UTIs over 6 months was 1.75
± 1.87. After injection, the mean was 0.2 ±
0.41 (p=0.003) (LoE 3) [37].
Editorial comment on the paper
acknowledged that detailed information
had been collected on the patients and
the differences appeared to be significant.
This is an original finding. However, it
was a small group and the findings could
not be widely accepted or used as jus-
tification to standardize this as a form
of treatment for this effect in isolation
(LoE 4) [38]. Since UTI is a common phe-
nomenon in these patients and many are
now undergoing Botox injections as a
treatment for bladder dysfunction, it may
be a fortuitous bystander effect.
502
7.1 Prophylaxis strategies
Many patients develop an established
pattern of proven UTIs. They can be dis-
tressing and uncomfortable for patients.
For those with ventricular shunts sys-
temic sepsis carries the risk of shunt
and CNS infection. There is little evi-
dence to support any significant change
in management. However, in a report of
3 patients who had UTIs all were shown
to have temporary dysfunction of their
shunt that settled with treatment of the
underlying UTI. There was no evidence of
shunt infection in any case. The authors
of this small case series emphasised the
need for close monitoring of patients in
this situation (LoE 4) [39].
Therefore management needs to cen-
tre on the degree and regularity of the
infection. Depending on the antibiotic
used, they may reduce the bacterial load
either directly within the urine or indi-
rectly within the gut, perineum or vagina
(LoE 3) [40]. The strategies that can be
adopted are the same as those used for
other patients with UTIs.
7.1.1 Expectant treatment on the
basis of symptoms and confirmed
microbiology
This involves a patient awaiting symptoms
of a UTI and presenting to a physician for
urinary culture and antibiotics – these
may be empirical initially and subse-
quently adjusted, as necessary, on the
basis of microbiological cultures.
7.1.2 Off the shelf treatment for
patients with an established
pattern of infection who are
able to recognise their own
symptoms
This enables patients to take their own
urine sample at home and initiate treat-
ment immediately – without the need
to wait and see a doctor before doing so.
This is useful in patients for whom an
established infection may result in either
prolonged treatment or severe sepsis and
 Epidemiology, diagnosis and treatment of urinary
hospital admission for treatment. The
more applied version of this relates to the
use of antibiotics around the time of trig-
gers such as intercourse.
7.1.3 Low dose daily antibiotic
strategies
Low dose daily antibiotic strategies are
employed in many patients and they
have a well established track record and
evidence basis with a significant reduc-
tion in comparison with placebo (LoE 2)
[41]. These can be used in cutting down
the number of infections but they do not
prevent all. Some patients suffer with
breakthrough infections which need to be
managed with urine culture and appropri-
ate treatment. Some will develop resist-
ant infection and therefore need to change
their form of prophylaxis. In undertaking
this strategy caution needs to be exercised
in the use of nitrofurantoin. The risks of
pulmonary and hepatic dysfunction are
numerically small but they exist and fol-
lowing recent successful litigation in the
UK, patients should certainly be warned
of this potential (LoE 4) [42].
There is no evidence that one of the
strategies is better than another and
their usage will come down to a combina-
tion of physician and patient preference
or motivation. It is our recommendation
that these treatment decisions be dis-
cussed with the parents/patient and the
strategy is adapted as best as possible
to the individual. There is little evidence
to support this but it is widely accepted
practice.
7.2 Intravesical treatments
Hyaluronic acid (Cystistat) has been
shown to reduce infections by 85% when
given in a protocol once per week for
4 weeks and then once per month for
5 months (LoE 3) [43]. Murine studies
have suggested that intraurethral instil-
lation of Lactobacillus casei is a potent
treatment for UTI [44]. In a trial with
spinal cord injured patients Hull et al.
| 8.4 |
prophylactically colonised patients’ blad-
ders with Escherichia coli 83972 – they
found a reduction from 3.1 symptomatic
infections per year to 0 infections over
18.4 patient years (LoE 3) [45]. Hyaluronic
acid may be applicable in patients with
difficult to treat recurrent UTIs.
7.3 Perineal treatments
Zarate et al. have suggested that the
use of Lactobacillus paracasei CRL1289
(a human vaginal strain) in pessary
form may be a means of reducing recur-
rent UTIs. This was tested in a murine
model (LoE 4) [46]. A phase 1 trial
using Lactobacillus crispatus has sug-
gested that this may be safe treatment
in humans but there are no data to sup-
port the suggestion that it may clinically
affect the number of UTIs (LoE 1) [47].
We make no recommendation for the use
of these treatments.
8. ALTERNATIVE TREATMENTS
The creation of vaccines for the treatment
of recurrent UTIs in young women may
create hope for groups of patients such
as those with significant reductions in
E. coli infections seen in a phase two trial
of vaginal mucosal vaccine (LoE 1) [48].
Acupuncture has been ventured as an
alternative treatment and when com-
pared to sham and control groups a
Scandinavian trial suggested a signifi-
cant effect (LoE 1) [49].
Whilst many people have talked about
the use of cranberry juice in preventing
UTIs, when its effect on bacteriuria was
assessed there was no significant effect
(LoE 3) [50]. We make no recommenda-
tion for the use of these treatments.
9. Future research
The outcome of phase II trials with
Lactobacillus is currently awaited and
will be important in establishing efficacy
503
Chapter |8| Urinary tract infections in patients
as well as safety. Vaccine research may
also offer opportunities to improve man-
agement for patients with recurrent
UTIs, which may be applicable to spina
bifida patients. It would be desirable, but
remains unlikely that resources would be
available to support credible trials of dif-
ferent prophylaxis strategies.
10. CONCLUSIONS
Our treatment recommendations are
based around aggressive early treatment
with CISC, anticholinergic treatment
and antibiotic prophylaxis. Urodynamic
assessment of the bladder will differen-
tiate the type of neurogenic dysfunction
and will dictate the management course.
Preservation of renal function remains
the priority. Some patients will still
require augmentation but with increas-
ing options this need may reduce. For
UTIs treatment is largely on the basis
of symptoms when the bladder has been
augmented. For those with recurrent or
persistent infection prophylactic strate-
gies are often necessary.
REFERENCES
1. Seiffert L, Die Darm-Siphonblase. Arch
Klin Chir 1935(183): 569–73.
2. Bricker EM, Bladder substitution after
pelvic evisceration. Surg Clin North Am,
1950. 30(5): 1511–21.
3. Guttmann L and Frankel H, The value of
intermittent catheterisation in the early
management of traumatic paraplegia and
tetraplegia. Paraplegia, 1966. 4(2): 63–84.
4. Lapides J, Diokno AC, Silber SJ, and
Lowe BS, Clean, intermittent self cathe-
terisation in the treatment of urinary tract
disease. J Urol, 1972. 108(1): 79–81.
5. Carr MC, Fetal myelomeningocele repair:
urologic aspects. Curr Opin Urol, 2007.
17(4): 257–62.
6. Xiao CG, Reinnervation for neurogenic
bladder: historic review and introduction
504
of a somatic-autonomic reflex pathway
procedure for patients with spinal cord
injury or spina bifida. Eur Urol, 2006.
49(1): 22–8; discussion 28–9.
7. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
9. de Jong TP, Chrzan R, Klijn AJ, and
Dik P, Treatment of the neurogenic
bladder in spina bifida. Pediatr Nephrol,
2008. 23(6): 889–96.
10. Woodhouse CR, Progress in the manage-
ment of children born with spina bifida.
Eur Urol, 2006. 49(5): 777–8.
11. Dik P, Klijn AJ, van Gool JD, de Jong-de
Vos van Steenwijk CC, and de Jong TP,
Early start to therapy preserves kidney
function in spina bifida patients. Eur
Urol, 2006. 49(5): 908–13.
12. Ottolini MC, Shaer CM, Rushton HG,
Majd M, Gonzales EC, and Patel KM,
Relationship of asymptomatic bacteriu-
ria and renal scarring in children with
neuropathic bladders who are practic-
ing clean intermittent catheterization.
J Pediatr, 1995. 127(3): 368–72.
13. Altaweel W, Jednack R, Bilodeau C, and
Corcos J, Repeated intradetrusor botuli-
num toxin type A in children with neuro-
genic bladder due to myelomeningocele.
J Urol, 2006. 175(3 Pt 1): 1102–5.
14. Kajbafzadeh AM, Moosavi S, Tajik P,
Arshadi H, Payabvash S, Salmasi AH,
Akbari HR, and Nejat F, Intravesical
injection of botulinum toxin type A:
management of neuropathic bladder
and bowel dysfunction in children with
myelomeningocele. Urology, 2006. 68(5):
1091–6; discussion 1096–7.
15. Snodgrass WT, Elmore J, and Adams R,
Bladder neck sling and appendicovesi-
costomy without augmentation for neu-
rogenic incontinence in children. J Urol,
2007. 177(4): 1510–4; discussion 1515.
16. Khoury AE, Dave S, Peralta-Del Valle
MH, Braga LH, Lorenzo AJ, and Bagli D,
 Epidemiology, diagnosis and treatment of urinary
Severe bladder trabeculation obviates the
need for bladder outlet procedures during
augmentation cystoplasty in incontinent
patients with neurogenic bladder. BJU
Int, 2008. 101(2): 223–6.
17. Greenwell TJ, Venn SN, and Mundy AR,
Augmentation cystoplasty. BJU Int, 2001.
88(6): 511–25.
18. Bauer SB, Hendren WH, Kozakewich H,
Maloney S, Colodny AH, Mandell J, and
Retik AB, Perforation of the augmented
bladder. J Urol, 1992. 148(2 Pt 2): 699–703.
19. Couillard DR, Vapnek JM, Rentzepis
MJ, and Stone AR, Fatal perforation of
augmentation cystoplasty in an adult.
Urology, 1993. 42(5): 585–8.
20. Elder JS, Snyder HM, Hulbert WC, and
Duckett JW, Perforation of the augmented
bladder in patients undergoing clean
intermittent catheterization. J Urol, 1988.
140(5 Pt 2): 1159–62.
21. Brough RJ, O’Flynn KJ, Fishwick J, and
Gough DC, Bladder washout and stone
formation in paediatric enterocystoplasty.
Eur Urol, 1998. 33(5): 500–2.
22. Hensle TW, Bingham J, Lam J, and
Shabsigh A, Preventing reservoir calculi
after augmentation cystoplasty and conti-
nent urinary diversion: the influence of an
irrigation protocol. BJU Int, 2004. 93(4):
585–7.
23. Kronner KM, Casale AJ, Cain MP, Zerin
MJ, Keating MA, and Rink RC, Bladder
calculi in the pediatric augmented blad-
der. J Urol, 1998. 160(3 Pt 2): 1096–8;
discussion 1103.
24. Nurse DE, McInerney PD, Thomas PJ,
and Mundy AR, Stones in enterocysto-
plasties. Br J Urol, 1996. 77(5): 684–7.
25. Woodhouse CR and Lennon GN,
Management and aetiology of stones in
intestinal urinary reservoirs in adoles-
cents. Eur Urol, 2001. 39(3): 253–9.
26. Hamid R, Robertson WG, and Woodhouse
CR, Comparison of biochemistry and diet
in patients with enterocystoplasty who do
and do not form stones. BJU Int, 2008.
101(11): 1427–32.
27. Woodhams SD, Greenwell TJ, Smalley T,
and Mundy AR, Factors causing variation
in urinary N-nitrosamine levels in entero-
cystoplasties. BJU Int, 2001. 88(3): 187–91.
| 8.4 |
28. Greenwell TJ, Venn SN, Creighton S,
Leaver RB, and Woodhouse CR,
Pregnancy after lower urinary tract recon-
struction for congenital abnormalities.
BJU Int, 2003. 92(7): 773–7.
29. Nethercliffe J, Trewick A, Samuell C,
Leaver R, and Woodhouse CR, False-
positive pregnancy tests in patients with
enterocystoplasties. BJU Int, 2001. 87(9):
780–2.
30. Hensle TW, Bingham JB, Reiley EA,
Cleary-Goldman JE, Malone FD, and
Robinson JN, The urological care and
outcome of pregnancy after urinary tract
reconstruction. BJU Int, 2004. 93(4):
588–90.
31. Szucs K, O’Neil KM, and Faden H,
Urinary findings in asymptomatic sub-
jects with spina bifida treated with inter-
mittent catheterization. Pediatr Infect Dis
J, 2001. 20(6): 638–9.
32. Elliott SP, Villar R, and Duncan B,
Bacteriuria management and urological
evaluation of patients with spina bifida
and neurogenic bladder: a multicenter
survey. J Urol, 2005. 173(1): 217–20.
33. Rickwood AMK, Hodgson J, and Lonton AP,
Medical and surgical complications in ado-
lescent and young adult patients with spina
bifida. Health Trends, 1984(16): 91–5.
34. Fontaine E, Leaver R, and Woodhouse
CR, The effect of intestinal urinary
reservoirs on renal function: a 10-year
follow-up. BJU Int, 2000. 86(3): 195–8.
35. Griffiths DM and Malone PS, The Malone
antegrade continence enema. J Pediatr
Surg, 1995. 30(1): 68–71.
36. Roghmann MC, Wallin MT, Gorman PH,
and Johnson JA, Prevalence and natural
history of colonization with fluoroqui-
nolone-resistant gram-negative bacilli in
community-dwelling people with spinal
cord dysfunction. Arch Phys Med Rehabil,
2006. 87(10): 1305–9.
37. Game X, Castel-Lacanal E, Bentaleb Y,
Thiry-Escudie I, De Boissezon X,
Malavaud B, Marque P, and Rischmann P,
Botulinum toxin A detrusor injections in
patients with neurogenic detrusor overac-
tivity significantly decrease the incidence
of symptomatic urinary tract infections.
Eur Urol, 2008. 53(3): 613–8.
505
Chapter |8| Urinary tract infections in patients
38. Novara G, Editorial comment on:
Botulinum toxin A detrusor injections in
patients with neurogenic detrusor overac-
tivity significantly decrease the incidence
of symptomatic urinary tract infections.
Eur Urol, 2008. 53(3): 618–9.
39. Tubbs RS, Wellons JC, 3rd, Blount JP,
and Oakes WJ, Transient ventricu-
loperitoneal shunt dysfunction in chil-
dren with myelodysplasia and urinary
bladder infection. Report of three cases.
J Neurosurg, 2005. 102(2 Suppl): 221–3.
40. Ludwig M, Hoyme U, and Weidner W,
[Recurrent urinary tract infection in
women. Long-term antibiotic prophy-
laxis]. Urologe A, 2006. 45(4): 436–42.
41. Nicolle LE and Ronald AR, Recurrent
urinary tract infection in adult women:
diagnosis and treatment. Infect Dis Clin
North Am, 1987. 1(4): 793–806.
42. Cetti RJ, Venn S, and Woodhouse CR, The
risks of long-term nitrofurantoin prophy-
laxis in patients with recurrent urinary
tract infection: a recent medico-legal case.
BJU Int, 2009. 103(5): 567–9.
43. Lipovac M, Kurz C, Reithmayr F,
Verhoeven HC, Huber JC, and Imhof M,
Prevention of recurrent bacterial urinary
tract infections by intravesical instillation
of hyaluronic acid. Int J Gynaecol Obstet,
2007. 96(3): 192–5.
44. Asahara T, Nomoto K, Watanuki M, and
Yokokura T, Antimicrobial activity of
intraurethrally administered probiotic
Lactobacillus casei in a murine model of
Escherichia coli urinary tract infection.
506
Antimicrob Agents Chemother, 2001.
45(6): 1751–60.
45. Hull R, Rudy D, Donovan W, Svanborg C,
Wieser I, Stewart C, and Darouiche R,
Urinary tract infection prophylaxis using
Escherichia coli 83972 in spinal cord injured
patients. J Urol, 2000. 163(3): 872–7.
46. Zarate G, Santos V, and Nader-Macias
ME, Protective Effect of Vaginal
Lactobacillus paracasei CRL 1289
against Urogenital Infection Produced by
Staphylococcus aureus in a Mouse Animal
Model. Infect Dis Obstet Gynecol, 2007.
2007: 48358.
47. Czaja CA, Stapleton AE, Yarova-Yarovaya
Y, and Stamm WE, Phase I trial of a
Lactobacillus crispatus vaginal supposi-
tory for prevention of recurrent urinary
tract infection in women. Infect Dis
Obstet Gynecol, 2007. 2007: 35387.
48. Hopkins WJ, Elkahwaji J, Beierle LM,
Leverson GE, and Uehling DT, Vaginal
mucosal vaccine for recurrent urinary
tract infections in women: results of
a phase 2 clinical trial. J Urol, 2007.
177(4): 1349–53; quiz 1591.
49. Aune A, Alraek T, LiHua H, and
Baerheim A, Acupuncture in the prophy-
laxis of recurrent lower urinary tract
infection in adult women. Scand J Prim
Health Care, 1998. 16(1): 37–9.
50. Schlager TA, Anderson S, Trudell J, and
Hendley JO, Effect of cranberry juice on
bacteriuria in children with neurogenic
bladder receiving intermittent catheteriza-
tion. J Pediatr, 1999. 135(6): 698–702.
|8.5|
Urinary tract infections in patients
with neurogenic bladder
James Salerno*, Diana D. Cardenas
University of Miami, Miami, Florida,
Corresponding author: James Salerno, MD,
*University of Miami Leonard M. Miller School of Medicine, Department of Rehabilitation Medicine, 1611 NW 12
Avenue, Bantle Rehabilitation Center, Basement, Room L105, Miami, FL 33136, (305) 585-1431 (o), (303) 585-1340 (f),
jsalerno@med.miami.edu
ABSTRACT
Proper management of urinary tract infec-
tion (UTI) in the neurogenic bladder popu-
lation involves a comprehensive approach.
This includes preventive measures coupled
with management of the underlying dys-
function. Understanding the dysfunction
and choosing the optimal management
technique, which varies from patient to
patient, are vital. If an infection develops,
one should use a recommended regimen
guided by laboratory data.
Key words: Neurogenic bladder, urinary
tract infection
SUMMARY OF RECOMMENDATIONS
1. Ensure bladder volumes do not exceed
500 mL (GoR A).
2. Clean intermittent catheterization
should be used, when possible, rather
than an indwelling catheter, to reduce
rates of UTI (GoR A).
3. Diagnosis of UTI should be supported
by appropriate laboratory data includ-
ing urinalysis and urine culture, as
symptoms may not coincide with
actual infection (GoR A).
4. Antimicrobial prophylaxis should not
be used in catheterized patients due to
risk of antimicrobial resistance (GoR A).
5. Treat UTI with appropriate antimicro-
bial regimen for seven days initially,
and for fourteen days if response is
delayed (GoR A).
1. INTRODUCTION
Traumatic spinal cord and brain inju-
ries, strokes, cauda equina lesions and
other diseases such as multiple sclerosis
are established risk factors for the devel-
opment of neurogenic bladder [1]. While
the location and severity of the injury
Chapter |8| Urinary tract infections in patients
determine the degree and duration of the
dysfunction, nearly all of these patients
will experience bladder dysfunction with
its resulting increased risk of urinary
tract infections (UTIs).
Due to improved techniques for man-
aging acute injuries at times of trauma
as well as increasing age of the overall
population, the prevalence of neurogenic
bladder has increased [1]. A concurrent
increase in UTIs has also been seen.
Overall prevalence in Europe has been
stated as 15.6% of men and 17.4% of
women. In Asia, women make up 53.1%
of those with neurogenic bladder. In the
United States, the prevalence has been
estimated at 16% for men and 16.9% for
women [2]. Incidence of UTIs in patients
with spinal cord injuries has been stated
at 2.5 episodes per patient per year [3–4].
2. METHODS
In examining the data on this subject,
PubMed was initially searched. A search
on Google Scholar was also performed.
The key words “neurogenic”, “bladder”,
and “urinary tract infection” were placed
into the search bar in different combina-
tions. All publications with a pertinent
title and available abstract were exam-
ined. No year or language restriction
was made, as long as an English trans-
lation was available. This produced 307
results on PubMed and approximately
7,500 results on Google Scholar. The
list of abstracts was filtered after read-
ing them, based on pertinence to the
chapter. In total, 72 papers were then
obtained and examined. Appropriate
ones were included. Other research
known to the authors from experience
was also included. The pertinent infor-
mation from Braddom’s textbook was
also examined.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [5–6].
508
3. ETIOLOGY
The various etiologies of a neurogenic
bladder are worth exploring in an effort
to help differentiate specific disease types
to guide overall treatment and discuss
prognosis with a patient. Prior to a brief
explanation of some of these etiologies,
discussion of the general classification of
upper motor versus lower motor neuro-
genic bladder is worthwhile.
An upper motor neuron neurogenic
bladder typically results from disrup-
tion of the sensory and motor bladder
pathways in the spinal cord above the
sacral segments. This will usually result
in detrusor overactivity. The majority of
these patients will also experience dys-
synergy of bladder function (concurrent
contraction of the sphincter and detru-
sor). Injuries involving sacral segments
can result in detrusor denervation and
an areflexic bladder. While catheteriza-
tion is used in both conditions, medica-
tions to reduce detrusor hyperactivity
can be useful in the upper motor neuron
patient.
Spinal cord injuries are commonly
related to traumatic events. However,
Pontine micturition
Supraspinal
center
Suprasacral
Conal S2, 3 and 4
Infrasacral Autonomic
neuropathy
Cauda equinal
Pelvic
Figure 1.

a spinal cord injury can also be due to
Schistosomiasis mansoni infection, which
is an endemic fluke in South America,
the Caribbean, and Africa. Infection of
the spinal cord, such as acute transverse
myelitis, is a well-recognized complica-
tion [7]. Along the line of acute transverse
myelitis, Human T-Lymphotrophic Virus
Type I (HTLV-I) as a causal organism is
also documented [8].
Of the subset of patients with spinal
cord injury, patients with black ethnic-
ity, poor personal hygiene, and less-than-
daily condom catheter changes have an
increased incidence of UTI, as do those
with complete functional dependence
and vesicoureteral reflux [3–4]. However,
bladder drainage method, age, years since
injury, income, education, sex, neurologic
level, and administration of prophylactic
antibiotics are reportedly not correlated
with increased risk of UTI [3].
Of note, it has been revealed that spi-
nal cord injury patients possess the same
neutrophil phagocytic and opsonic activity
as those without injury [9]. Therefore, the
data suggest that the bladder dysfunction
with compensatory catheterization is the
etiology of the increased incidence of UTI
in this population. The inability to clear
urine from the bladder creates a medium
for the growth of bacteria. Furthermore,
factors common to the neurogenic blad-
der population such as outlet obstruction,
high pressure voiding, and the presence
of stones in the urinary tract are gener-
ally accepted risk factors for UTI.
Other causes of neurogenic bladder
include chronic 3,4-methylenedioxymeth-
amphetamine (MDMA) use [10]. Post-
partum patients are subject to transient
urinary retention [11]. Aseptic and Listeria
meningitis have also been reported to
result in neurogenic bladder [12–13].
Overall, the importance of a neurogenic
bladder in the development of UTI has
been documented. The risk of UTI has
been reported to increase when only 2 or
more ultrasound PVR readings are more
than 150mL in the stroke rehabilitation
Urinary tract infections in patients | 8.5 |
population [14]. This has been supported
by evidence that restoring the normal
low-pressure reservoir function of the
bladder aids the prevention of UTI in
those with neurogenic bladder [15].
As a complication of UTI, certain
patients with neurogenic bladders, such
as those with multiple sclerosis, can
experience a decline in neurologic func-
tion [16].
4. MICROBIAL ORGANISMS
While a patient with neurogenic bladder
can suffer UTI due to the same organ-
isms as any other patient, the specific
incidence varies [15]. Posted rates are:
Escherichia coli 60% to 65%, Proteus
mirabilis 14%, Klebsiella pneumoniae
10%, Staphylococcus species 4%, and then
other enterobacteria [17–18]. Variation
between men and women has also been
reported with the predominant organ-
ism in women being E. coli and in men,
Gram-positive cocci [19].
Of note, it has been identified that E. coli
colonization does not confer an increased
risk of symptomatic disease or deterio-
ration of the upper urinary tract [20].
However, certain E. coli clones did confer
an increased risk of colonization [20].
5. MANAGEMENT
Clean intermittent catheterization (CIC)
is a preferred method for managing neu-
rogenic bladder in many patients. The
ability for a patient and/or family to per-
form the procedure is typically what pre-
cludes use of this technique. Data support
it as an excellent procedure for minimiz-
ing urinary tract complications, which
include UTI [19]. The volumes to target
are less than a maximum of 500mL [21–
22]. Volumes less than 100mL generally
do not require CIC [21].
Indwelling catheters are also used in
patients with neurogenic bladders to
509
Chapter |8| Urinary tract infections in patients
reduce bladder volumes. These are used
in the acute patients to closely monitor
fluid balances. Patients with chronic inju-
ries who cannot perform CIC, due to poor
skills, difficulty with fluid management,
failure of other methods, and limited
assistance may require use of an indwell-
ing catheter as well [22].
Regarding the method of indwelling
catheterization used, suprapubic cath-
eterization has lower rates of UTI when
compared to urethral catheterization in
select populations [23]. However, urethral
catheterization and suprapubic catheteri-
zation are both felt to be superior to other
forms of urinary management, excluding
CIC, especially compared to using vari-
ous methods at different times [24]. This
includes, but is not limited to, the use of
condom bag systems, diapers, and manu-
ally increasing bladder pressure.
Adoption of a closed catheter system
has been shown to reduce the rate of UTI
[25]. This has included the addition of a
urine sampling port in the drainage tub-
ing and the use of a preconnected cathe-
ter/collecting tube system [26–27].
Evaluation of sterile versus nonsterile
(or clean) urethral catheterization in an
observational study revealed a significant
cost variance. The rate of UTI was higher
in the nonsterile group (28.6% compared
to 42.4%) with an increased cost due to
antibiotic use at 43%. The increased base
cost of the sterile kits was 371% com-
pared to the nonsterile kits. The authors
estimated the overall increased cost of
the sterile kits was 277% compared to
nonsterile, after factoring in antibiotic
related costs [18].
Hydrophilic-coated catheters have been
shown to decrease the rate of UTI from
82% to 64% over a 12 month period [28].
Use of silver hydrogel urinary (SHU)
catheters has been recently explored.
Preliminary data suggest a positive effect
of using SHU in prevention of UTI [29].
Condom catheters have also been used
in patients who can reflex void or at
least micturate to some degree. However,
510
examination to verify effective emptying
of the bladder is necessary to lower the
risk of UTI [30].
Animal studies have started to point
towards the use of a micturition alert
device to compensate for a neurogenic
bladder [31]. These data suggested such a
device may be able to reduce bladder vol-
umes, reducing the risk of UTI [15].
Use of cranberry extract tablets in
reducing the rate of UTIs remains con-
troversial. Some data did not show a
benefit to its use [32–33]. However, it has
been suggested that cranberry extract
tablets may be beneficial, especially in
patients with a higher glomerular filtra-
tion rate (GFR) [34]. Similar conflicting
data surround the use of methenamine.
Evidence revealed methenamine can
reduce the rate of UTIs for the inpatient
population [35]. This does not necessar-
ily hold true for the outpatient popula-
tion [32].
Initial data were also not definitive
regarding use of antibiotic prophylaxis
[36]. Recent data have revealed that use
of a weekly oral cyclic antibiotic pro-
gram decreased the rate of symptomatic
UTIs from 9.4 per patient-year with 197
episodes of febrile UTIs and 45 hospi-
talizations to 1.8 per patient-year with
19 episodes of febrile UTIs [37]. Also, a
weekly regimen did not result in any new
cases of multi-drug resistant bacteria dur-
ing the two year follow-up in this study
[37]. However, it has been established
that antibiotic prophylaxis does result in
resistance in the general population, as
well as those with neurogenic bladders
[38]. Also, it has been shown that a sup-
pressive antibiotic regimen does not pre-
vent clinical UTI [39–41].
Conversely, inoculation with nonpatho-
genic Escherichia coli 83972 in patients
with a neurogenic bladder improved UTI
rates. The inoculated patients experi-
enced a 63-fold decrease in UTI rates
during colonization versus a prestudy
period of the same subjects and a 33-fold
decrease when compared to a population

not successfully colonized [42]. This
method of control has also been demon-
strated to be safe [42–43].
6. MODULATING THE UNDERLYING
DYSFUNCTION
In an effort to improve rates of UTI and
overall prognosis, new techniques have
been developed to return the patient to as
close to normal function as possible. This
has been approximated by modulating
risk factors common to patients with neu-
rogenic bladder.
To aid in the micturition process, pos-
terior tibial nerve stimulation has been
implemented with significant improve-
ment in volume reached prior to invol-
untary voiding and mean maximum
capacity [44].
Anterior root stimulation, placed intra-
durally, coupled with sacral deafferen-
tation resulted in a decline in UTI rate
from 6.3 per year to 1.2 per year [45]. The
procedure helped to restore the reservoir
function of the bladder and achieve con-
tinence, known to decrease UTI rates [15,
45]. Autonomic dysreflexia was reported
to have nearly disappeared in most cases
and accurate adjustment could result in
low resistance micturition [45].
In an effort to assess in which patient
sacral stimulation would be effective, a
detrusor contractility test was devised.
Electrostimulation of the sacral nerves
Table 1
Generally accepted risk factors
Over-distention of bladder
Vesicoureteral reflux
High pressure voiding
Large post-void residuals
Presence of stones in urinary tract
Outlet obstruction (detrusor-sphincter dyssynergia,
enlarged prostate)
Urinary tract infections in patients | 8.5 |
was performed with a lack of response
in either bladder or bowel pres-
sure indicating an irreversible blad-
der myopathy [46]. If no response, the
patient would be ruled out as a candi-
date. A successful response suggested
that the patient may respond to sacral
neurostimulation.
Surgeons have also tried to recon-
struct the reflex pathway by anastomos-
ing the spinal roots. This was performed
in patients with history of a traumatic
lesion of the conus medullaris. Functional
T11 ventral roots, being above the lesion,
were transected and anastomosed to
S2 ventral roots unilaterally by use of
a nerve graft. The T11 dorsal root was
left intact as the trigger for micturition
after axonal regeneration. Overall, 70%
of patients reported satisfactory bladder
control within 18–24 months. This 70%
did not experience any UTI during the
follow-up period [47].
Bladder augmentation can also aid
those patients with bladder dysfunc-
tion due to intractable involuntary blad-
der contractions causing incontinence.
The bladder is opened widely and then
a section of bowel is added to increase
the capacity and reduce pressure. This
is used in conjunction with intermit-
tent catheterization programs, typi-
cally through a stoma in the abdominal
wall [22]. In this population, pyuria
and bladder stones are common, but
symptomatic infections rare. Also, an
increased risk of bladder cancer has
been reported, but a causal relation-
ship has not yet been determined [22].
Of note, patients who undergo this pro-
cedure must be compliant with CIC to
avoid overdistention.
In male patients with detrusor-exter-
nal sphincter dyssynergia, sphincterot-
omy can be performed to permit effective
bladder drainage resulting in lower blad-
der volumes, thereby reducing UTI rates
[22]. A mesh wallstent has been shown
to be an acceptable long-term alterna-
tive to sphincterotomy with similar
511
Chapter |8| Urinary tract infections in patients
low bladder volumes and no significant
interference with erectile function [48].
However, stents should be avoided in
patients who cannot manage a condom
catheter, have urethral abnormalities,
and are female [22].
Recently, botulinum toxin serotype A
(BoNT-A) has been investigated to treat
neurogenic detrusor overactivity. Data
support its use in spinal cord injuries
and multiple sclerosis where there is
reported efficacy and improved quality
of life [49–52]. However, its use in neu-
rogenic detrusor overactivity for patients
with stroke damage, Parkinson’s disease,
and other central disorders has not been
fully delineated. Also, the available data
are limited, with the optimal dose not yet
proven [51].
Capsaicin and resiniferatoxin have
also been examined. Studies have overall
pointed to capsaicin as generally supe-
rior to placebo, with 3.8 less episodes of
urinary incontinence over 30 days [50].
Resiniferatoxin was felt to be comparable
to capsaicin [50] and effective in refrac-
tory patients [53–54].
Tolterodine 2mg taken twice a day
has been shown to improve catheteriza-
tion volumes and reduce incontinence
when compared to placebo [55]. Also,
this dosing of tolterodine has a reduced
side-effect profile when compared to oxy-
butynin [55].
As a result of the neurogenic bladder
and related repetitive infections, the uri-
nary tract itself can become mechanically
disturbed. This pathology is represented
by erosions, strictures, diverticula, ure-
throcutaneous fistulas, or combinations of
these processes. Surgical reconstruction
in patients with neurogenic bladders can
improve functional outcomes with limited
morbidity [56].
7. ASSESSMENT
In an effort to delineate which patients
have UTI, a history of presenting illness
512
is taken. However, it has been shown
that patients with a spinal cord injury
are not accurate in predicting when they
have a UTI based entirely on symptoms
[1, 57–58]. In an effort to further assess
for UTI, laboratory data are used. In a
spinal cord injury patient who complains
of typical UTI symptoms, lack of pyuria
reasonably predicts the absence of UTI
[57, 59].
Furthermore, while the symptoms of
a typical UTI may not correlate with an
actual infection in this population, the
complaints themselves may represent
psychological distress related to the use
of CIC [60]. Patients with spinal cord
injury due to HLTV-1 infection are par-
ticularly prone to having urinary symp-
tomatology without the presence of a true
UTI [8].
In treating patients with UTI, exam-
ining precipitating antibodies against
urinary tract pathogens (PAU) may be
an indicator of need for more aggressive
treatments [61]. While this practice is not
standard, it may represent an area for
future research. Also, it may have clinical
utility in the future.
In determining which patients do have
a UTI, urine culture, urine analysis, and
plasma white blood cell counts are reli-
able tests [62]. The presence of pyuria is
significantly associated with fever and
chills [3]. Of note, Gram-negative bac-
teria are relatively more pyogenic than
Gram-positive bacteria [3].
8. TREATMENT
The effective treatment of UTI is para-
mount to minimize long term complica-
tions. While use of urine cultures is vital
to directing antibiotic therapy, initial
treatment is still based on treatment
protocols.
Current guidelines recommend three
days of trimethoprim/sulfamethoxazole
as a first line agent in treating UTI.
Second line agents include three days

of a quinolone or seven days of nitro-
furantoin, amoxicillin, or a first genera-
tion cephalosporin [26]. However, these
guidelines are for uncomplicated UTIs,
and the presence of a neurogenic bladder
complicates the diagnosis.
For the neurogenic bladder popula-
tion, initial consideration can be made
to utilize trimethoprim/sulfamethoxazole
or quinolone therapy at longer courses
of treatment. Some sources recommend
courses of seven to fourteen days, depend-
ing on the clinical picture [63]. Courses
of treatment longer than twenty-eight
days have been shown to increase resist-
ance without improving clinical outcomes
[64]. If the patient has been recently
discharged from a long term care facil-
ity, is severely ill, or received quinolones
recently, consideration should be given to
using cefepime, ceftazidime, imipenem,
meropenem, or piperacillin-tazobactam
[63]. Also, if the culture reveals Gram-
positive cocci in a severely ill patient,
consideration should be given to initiat-
ing vancomycin therapy [63].
Also, some data point to the equiva-
lence of faropenem 300mg three times
daily and levofloxacin 100mg three times
daily in treating patients with neurogenic
bladder [65]. Use of newer generation
cephalosporins and carbapenems may
shorten the febrile period [66]. Antibiotic
therapy should be started without delay
in appropriate patients [67].
As this evidence reveals, clinical judg-
ment remains the current practice, with
most treating a complicated UTI between
seven to ten days. However, the Veterans’
Administration is currently enrolling
patients to determine if a five day course
of therapy is preferable. The preliminary
data are expected to become available in
mid-2009.
9. FURTHER RESEARCH
Management and modification of the
underlying dysfunction represent avenues
Urinary tract infections in patients | 8.5 |
for future research. Re-establishing
proper bladder function may lead to a
reduction in UTI rates. Also, research
into the relationship between asympto-
matic bacteriuria and UTI is required.
Further development of a first line as well
as definitive antibiotic regimen, including
agent and length of treatment, represents
another avenue open to investigators.
10. CONCLUSIONS
While the etiology of a neurogenic blad-
der and its management vary, UTI is a
common complication in this population.
Use of proven techniques as well as inves-
tigation into promising data are vital to
successful treatment of this condition,
thereby reducing UTI rates. When UTI
does occur, proper utilization of antibiot-
ics is vital in reducing acute and chronic
complications.
REFERENCES
1. Hampel C, Gillitzer R, Pahernik S,
Hohenfellner M, and Thuroff JW,
[Epidemiology and etiology of overactive
bladder]. Urologe A, 2003. 42(6):
776–86.
2. Stewart WF, Van Rooyen JB, Cundiff GW,
Abrams P, Herzog AR, Corey R, Hunt TL,
and Wein AJ, Prevalence and burden of
overactive bladder in the United States.
World J Urol, 2003. 20(6): 327–36.
3. Waites KB, Canupp KC, and DeVivo MJ,
Epidemiology and risk factors for uri-
nary tract infection following spinal cord
injury. Arch Phys Med Rehabil, 1993.
74(7): 691–5.
4. Esclarin De Ruz A, Garcia Leoni E, and
Herruzo Cabrera R, Epidemiology and
risk factors for urinary tract infection in
patients with spinal cord injury. J Urol,
2000. 164(4): 1285–9.
5. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
513
Chapter |8| Urinary tract infections in patients
6. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
7. Gomes CM, Trigo-Rocha F, Arap MA,
Gabriel AJ, Alaor de Figueiredo J, and
Arap S, Schistosomal myelopathy: uro-
logic manifestations and urodynamic
findings. Urology, 2002. 59(2): 195–200.
8. Rocha PN, Rehem AP, Santana JF, Castro
N, Muniz AL, Salgado K, Rocha H, and
Carvalho EM, The cause of urinary symp-
toms among Human T Lymphotropic
Virus Type I (HLTV-I) infected patients:
a cross sectional study. BMC Infect Dis,
2007. 7: 15.
9. Waites KB, Canupp KC, and DeVivo MJ,
Phagocytosis of urinary pathogens in per-
sons with spinal cord injury. Arch Phys
Med Rehabil, 1994. 75(1): 63–6.
10. Beuerle JR and Barrueto F, Jr.,
Neurogenic bladder and chronic urinary
retention associated with MDMA abuse.
J Med Toxicol, 2008. 4(2): 106–8.
11. Duenas-Garcia OF, Rico H, Gorbea-
Sanchez V, and Herrerias-Canedo T,
Bladder rupture caused by postpartum
urinary retention. Obstet Gynecol, 2008.
112(2 Pt 2): 481–2.
12. Urakawa M and Ueda Y, [A case of uri-
nary retention secondary to aseptic menin-
gitis]. No To Shinkei, 2001. 53(8): 742–6.
13. Fujita K, Tanaka T, Kono S, Narai H,
Omori N, Manabe Y, and Abe K, Urinary
retention secondary to Listeria meningitis.
Intern Med, 2008. 47(12): 1129–31.
14. Dromerick AW and Edwards DF, Relation
of postvoid residual to urinary tract infec-
tion during stroke rehabilitation. Arch
Phys Med Rehabil, 2003. 84(9): 1369–72.
15. Sauerwein D, Urinary tract infection in
patients with neurogenic bladder dysfunc-
tion. Int J Antimicrob Agents, 2002. 19(6):
592–7.
16. Hillman LJ, Burns SP, and Kraft GH,
Neurological worsening due to infection
from renal stones in a multiple sclerosis
patient. Mult Scler, 2000. 6(6): 403–6.
17. Hernandez Gonzalez E, Zamora Perez F,
Martinez Arroyo M, Valdez Fernandez M,
and Alberti Amador E, [Epidemiologic,
clinical and microbiological characteris-
tics of nosocomial urinary infection in the
514
spinal cord lesioned patient]. Actas Urol
Esp, 2007. 31(7): 764–70.
18. Prieto-Fingerhut T, Banovac K, and
Lynne CM, A study comparing sterile
and nonsterile urethral catheterization in
patients with spinal cord injury. Rehabil
Nurs, 1997. 22(6): 299–302.
19. Bakke A, Digranes A, and Hoisaeter PA,
Physical predictors of infection in patients
treated with clean intermittent catheteri-
zation: a prospective 7-year study. Br J
Urol, 1997. 79(1): 85–90.
20. Schlager TA, Johnson JR, Ouellette LM,
and Whittam TS, Escherichia coli coloniz-
ing the neurogenic bladder are similar
to widespread clones causing disease in
patients with normal bladder function.
Spinal Cord, 2008. 46(9): 633–8.
21. Fujimoto Y, Ueno K, Yamada S, Isogai
K, Komeda H, and Ban Y, [Clinical
investigation of clean intermittent cath-
eterization]. Hinyokika Kiyo, 1994. 40(4):
309–13.
22. Consortium for Spinal Cord Medicine,
Clinical Practice Guidelines – Bladder
Management in Adults with Spinal Cord
Injury. 2006(Aug): 21,32,33,37.
23. Nwadiaro HC, Nnamonu MI, Ramyil VM,
and Igun GO, Comparative analysis of
urethral catheterization versus suprapu-
bic cystostomy in management of neuro-
genic bladder in spinal injured patients.
Niger J Med, 2007. 16(4): 318–21.
24. Dahlberg A, Perttila I, Wuokko E, and
Ala-Opas M, Bladder management in per-
sons with spinal cord lesion. Spinal Cord,
2004. 42(12): 694–8.
25. National guideline clearinghouse,
Guideline for treatment of urinary tract
infections. http://www.guideline.gov.
26. DeMaoi J, Urinary Tract Infection,
Complicated (UTI). Antibiotic guide –
Johns Hopkins. http://prod.hopkins-
abxguide.org.
27. Platt R, Polk BF, Murdock B, and Rosner
B, Reduction of mortality associated
with nosocomial urinary tract infection.
Lancet, 1983. 1(8330): 893–7.
28. De Ridder DJ, Everaert K, Fernandez
LG, Valero JV, Duran AB, Abrisqueta ML,
Ventura MG, and Sotillo AR, Intermittent
catheterisation with hydrophilic-coated
catheters (SpeediCath) reduces the risk of

clinical urinary tract infection in spinal
cord injured patients: a prospective ran-
domised parallel comparative trial. Eur
Urol, 2005. 48(6): 991–5.
29. Estores IM, Olsen D, and Gomez-Marin
O, Silver hydrogel urinary catheters:
evaluation of safety and efficacy in single
patient with chronic spinal cord injury.
J Rehabil Res Dev, 2008. 45(1): 135–9.
30. Braddom RL and et al, Physical Medicine
& Rehabilitation. 2007: Saunders
Elsevier.
31. Wang J, Hou C, Zhang W, Zheng X, Xu Z,
Wang W, and Lin H, [Micturition alert
device dedicated to neurogenic bladders].
Zhongguo Xiu Fu Chong Jian Wai Ke Za
Zhi, 2008. 22(5): 597–601.
32. Lee BB, Haran MJ, Hunt LM, Simpson
JM, Marial O, Rutkowski SB, Middleton
JW, Kotsiou G, Tudehope M, and
Cameron ID, Spinal-injured neuropathic
bladder antisepsis (SINBA) trial. Spinal
Cord, 2007. 45(8): 542–50.
33. Linsenmeyer TA, Harrison B, Oakley A,
Kirshblum S, Stock JA, and Millis SR,
Evaluation of cranberry supplement for
reduction of urinary tract infections in
individuals with neurogenic bladders
secondary to spinal cord injury. A prospec-
tive, double-blinded, placebo-controlled,
crossover study. J Spinal Cord Med, 2004.
27(1): 29–34.
34. Hess MJ, Hess PE, Sullivan MR, Nee M,
and Yalla SV, Evaluation of cranberry
tablets for the prevention of urinary tract
infections in spinal cord injured patients
with neurogenic bladder. Spinal Cord,
2008. 46(9): 622–6.
35. Banovac K, Wade N, Gonzalez F, Walsh
B, and Rhamy RK, Decreased incidence
of urinary tract infections in patients
with spinal cord injury: effect of methen-
amine. J Am Paraplegia Soc, 1991. 14(2):
52–4.
36. Morton SC, Shekelle PG, Adams JL,
Bennett C, Dobkin BH, Montgomerie
J, and Vickrey BG, Antimicrobial
prophylaxis for urinary tract infection
in persons with spinal cord dysfunction.
Arch Phys Med Rehabil, 2002. 83(1):
129–38.
37. Salomon J, Denys P, Merle C, Chartier-
Kastler E, Perronne C, Gaillard JL, and
Urinary tract infections in patients | 8.5 |
Bernard L, Prevention of urinary tract
infection in spinal cord-injured patients:
safety and efficacy of a weekly oral cyclic
antibiotic (WOCA) programme with a 2
year follow-up – an observational prospec-
tive study. J Antimicrob Chemother, 2006.
57(4): 784–8.
38. Gribble MJ and Puterman ML,
Prophylaxis of urinary tract infection in
persons with recent spinal cord injury: a
prospective, randomized, double-blind,
placebo-controlled study of trimethoprim-
sulfamethoxazole. Am J Med, 1993. 95(2):
141–52.
39. Mohler JL, Cowen DL, and Flanigan RC,
Suppression and treatment of urinary
tract infection in patients with an inter-
mittently catheterized neurogenic bladder.
J Urol, 1987. 138(2): 336–40.
40. Maynard FM and Diokno AC, Urinary
infection and complications during clean
intermittent catheterization following
spinal cord injury. J Urol, 1984. 132(5):
943–6.
41. Lewis RI, Carrion HM, Lockhart JL, and
Politano VA, Significance of asymptomatic
bacteriuria in neurogenic bladder disease.
Urology, 1984. 23(4): 343–7.
42. Darouiche RO, Donovan WH, Del Terzo
M, Thornby JI, Rudy DC, and Hull RA,
Pilot trial of bacterial interference for pre-
venting urinary tract infection. Urology,
2001. 58(3): 339–44.
43. Darouiche RO and Hull RA, Bacterial
interference for prevention of urinary tract
infection: an overview. J Spinal Cord Med,
2000. 23(2): 136–41.
44. Kabay SC, Yucel M, and Kabay S, Acute
effect of posterior tibial nerve stimulation
on neurogenic detrusor overactivity in
patients with multiple sclerosis: urody-
namic study. Urology, 2008. 71(4): 641–5.
45. Kutzenberger J, Domurath B, and
Sauerwein D, Spastic bladder and spinal
cord injury: seventeen years of experience
with sacral deafferentation and implanta-
tion of an anterior root stimulator. Artif
Organs, 2005. 29(3): 239–41.
46. Bertapelle P, Bodo G, and Carone R,
Detrusor acontractility in urinary reten-
tion: detrusor contractility test as exclu-
sion criteria for sacral neurostimulation.
J Urol, 2008. 180(1): 215–6.
515
Chapter |8| Urinary tract infections in patients
47. Lin H, Hou CL, Zhong G, Xie Q, and
Wang S, Reconstruction of reflex pathways
to the atonic bladder after conus medulla-
ris injury: preliminary clinical results.
Microsurgery, 2008. 28(6): 429–35.
48. Hamid R, Arya M, Patel HR, and Shah
PJ, The mesh wallstent in the treatment
of detrusor external sphincter dyssynergia
in men with spinal cord injury: a 12-year
follow-up. BJU Int, 2003. 91(1): 51–3.
49. Giannantoni A, Mearini E, Del Zingaro M,
Santaniello F, and Porena M, Botulinum
A toxin in the treatment of neurogenic
detrusor overactivity: a consolidated field
of application. BJU Int, 2008. 102 Suppl
1: 2–6.
50. MacDonald R, Monga M, Fink HA, and
Wilt TJ, Neurotoxin treatments for uri-
nary incontinence in subjects with spinal
cord injury or multiple sclerosis: a system-
atic review of effectiveness and adverse
effects. J Spinal Cord Med, 2008. 31(2):
157–65.
51. MacDonald R, Fink HA, Huckabay C,
Monga M, and Wilt TJ, Botulinum toxin
for treatment of urinary incontinence
due to detrusor overactivity: a systematic
review of effectiveness and adverse effects.
Spinal Cord, 2007. 45(8): 535–41.
52. Schurch B, de Seze M, Denys P, Chartier-
Kastler E, Haab F, Everaert K, Plante P,
Perrouin-Verbe B, Kumar C, Fraczek S,
and Brin MF, Botulinum toxin type a is a
safe and effective treatment for neurogenic
urinary incontinence: results of a single
treatment, randomized, placebo control-
led 6-month study. J Urol, 2005. 174(1):
196–200.
53. Kim JH, Rivas DA, Shenot PJ, Green
B, Kennelly M, Erickson JR, O’Leary
M, Yoshimura N, and Chancellor MB,
Intravesical resiniferatoxin for refrac-
tory detrusor hyperreflexia: a multicenter,
blinded, randomized, placebo-controlled
trial. J Spinal Cord Med, 2003. 26(4):
358–63.
54. Lazzeri M, Spinelli M, Zanollo A, and
Turini D, Intravesical vanilloids and neu-
rogenic incontinence: ten years experience.
Urol Int, 2004. 72(2): 145–9.
55. Ethans KD, Nance PW, Bard RJ, Casey
AR, and Schryvers OI, Efficacy and safety
516
of tolterodine in people with neurogenic
detrusor overactivity. J Spinal Cord Med,
2004. 27(3): 214–8.
56. Casey JT, Erickson BA, Navai N, Zhao
LC, Meeks JJ, and Gonzalez CM,
Urethral reconstruction in patients with
neurogenic bladder dysfunction. J Urol,
2008. 180(1): 197–200.
57. Linsenmeyer TA and Oakley A, Accuracy
of individuals with spinal cord injury at
predicting urinary tract infections based
on their symptoms. J Spinal Cord Med,
2003. 26(4): 352–7.
58. Garcia Leoni ME and Esclarin De Ruz
A, Management of urinary tract infec-
tion in patients with spinal cord inju-
ries. Clin Microbiol Infect, 2003. 9(8):
780–5.
59. Cardenas DD and Hooton TM, Urinary
tract infection in persons with spinal cord
injury. Arch Phys Med Rehabil, 1995.
76(3): 272–80.
60. Bakke A and Malt UF, Psychological pre-
dictors of symptoms of urinary tract infec-
tion and bacteriuria in patients treated
with clean intermittent catheterization: a
prospective 7-year study. Eur Urol, 1998.
34(1): 30–6.
61. Moser C, Kriegbaum NJ, Larsen SO,
Hoiby N, and Biering-Sorensen F,
Antibodies to urinary tract pathogens in
patients with spinal cord lesions. Spinal
Cord, 1998. 36(9): 613–6.
62. Perkash I and Giroux J, Prevention,
treatment, and management of uri-
nary tract infections in neuropathic
bladders. J Am Paraplegia Soc, 1985.
8(1): 15–7.
63. Garibaldi RA, Burke JP, Dickman ML,
and Smith CB, Factors predisposing to
bacteriuria during indwelling urethral
catheterization. N Engl J Med, 1974.
291(5): 215–9.
64. Waites KB, Canupp KC, and DeVivo MJ,
Eradication of urinary tract infection
following spinal cord injury. Paraplegia,
1993. 31(10): 645–52.
65. Muratani T, Iihara K, Nishimura T,
Inatomi H, Fujimoto N, Kobayashi T,
Yamada Y, Takahashi K, and Matsumoto
T, [Faropenem 300 mg 3 times daily ver-
sus levofloxacin 100 mg 3 times daily

in the treatment of urinary tract infec-
tions in patients with neurogenic bladder
and/or benign prostatic hypertrophy].
Kansenshogaku Zasshi, 2002. 76(11):
928–38.
66. Matsumoto T, Takahashi K, Manabe N,
Iwatsubo E, and Kawakami Y, Urinary
Urinary tract infections in patients | 8.5 |
tract infection in neurogenic bladder.
Int J Antimicrob Agents, 2001. 17(4):
293–7.
67. Wong ES, Guideline for prevention of
catheter-associated urinary tract infec-
tions. Am J Infect Control, 1983. 11(1):
28–36.
517
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 Chapter |9|

Device associated urinary

tract infections
Chair: Peter Tenke

CHAPTER OUTLINE
9.1 Introduction 520
9.2 Urinary catheters and drainage systems: definition,
epidemiology and risk factors 522
9.3 Urinary catheters and drainage systems:
prevention and treatment of urinary tract infections 532
9.4 Evolution of catheter material for prevention of
catheter-associated urinary tract infections 541
9.5 Infections associated with the artificial urinary sphincter 549
9.6 Infections associated with penile prostheses 554
|9.1|
Introduction
Peter Tenke
Peter Tenke, MD, PhD, Head, Department of Urology, Jahn Ference Del-Pesti Korhaz,
Köves utca2-4, H-1204 Budapest, Hungary
Tel 0036-1-289.6200, tenkep@chello.hu; tenke.peter@jahndelpest.hu
The use of urological devices, especially
urinary catheters, forms the basis of the
daily praxis in urological departments,
and also has a great importance in every
medical discipline. Using a foreign body
always increases the risk of infectious
complications. Approximately 40% of
nosocomial infections originate in the uri-
nary tract, and most patients with nosoco-
mial urinary tract infections (UTIs) have
permanent urethral catheterisation or
other urinary foreign body. Catheter asso-
ciated urinary tract infections (CAUTI)
are the most common nosocomial infec-
tions worldwide. Although largely asymp-
tomatic, they are reservoirs for antibiotic
resistance and contribute to morbidity in
hospitals and long term care facilities.
When UTI occurs in a catheterized
patient it always requires special atten-
tion and knowledge. Due to biofilm for-
mation there are different causative
pathogens with different sensitivities
from what we see in the urinary tract
without foreign body. The present of a
CAUTI needs special evaluation of the
diagnostic results (e.g. urine cultures),
and the choice of antibiotic and also the
length of the therapy can differ from the
convectional ones.
Clinicians should always consider
alternatives to indwelling urethral cath-
eters that are less prone to causing symp-
tomatic infection. In appropriate patients
suprapubic catheters, condom drainage
systems and intermittent catheterisation
can be preferable to indwelling urethral
catheterization.
Urinary catheters are of varying
design and material. There are still great
efforts to develop catheter materials and
coatings witch can decrease or inhibit
CAUTIs.
In the first part of the section the
authors summarise the definition, epide-
miology and risk factors of catheter asso-
ciated urinary tract infections, present
evidence-based recommendations for the
prevention, diagnostic and treatment of
CAUTIs, and also compare the available
catheter materials and the different alter-
native methods of urine drainage.

With the design revisions, engineering
changes and improvements of surgical
techniques the non-infectious complication
rates of urological devices, such as artifi-
cial urinary sphincters and penile prosthe-
ses significantly decreased. As urological
devices are now expected to function for
many years post implantation, infection
has become a more significant problem.
Different conservative treatment modali-
ties, surgical techniques, and - in case
Introduction | 9.1 |
of penile prostheses - different coatings
have been developed to prevent or treat
infections.
In the second part of the section the
authors summarise the pathogenesis
and epidemiology of the infections of
artificial urinary sphincters and penile
prostheses, and present evidence-based
recommendations for the prevention
and treatment of device associated
infections.
521
|9.2|
Urinary catheters and
drainage systems: definition,
epidemiology and risk factors
Paul A. Tambyah1, Dariusz P. Olszyna1, Peter Tenke2, Bela Koves2
1
Department of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074
2
Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest, Hungary
Corresponding author: Paul Ananth Tambyah, MBBS, Dip ABIM (Inf Dis), Associate Professor, Consultant Infectious
Disease Physician, Department of Medicine, Yong Loo Lin School of Medicine, National University Hospital, 5 Lower Kent
Ridge Road, Singapore 119074
Tel.: 0065-6779.5555, Fax.: 0065-6779.4112, mdcpat@nus.edu.sg; ptambyah@pacific.net.sg

ABSTRACT catheterisation should be considered if

Catheter associated urinary tract infec-
tions (CAUTI) are the most common noso-
comial infections worldwide. Although
largely asymptomatic, they are reservoirs
for antibiotic resistance and contribute to
morbidity in hospitals and long term care
facillities. A recent European and Asian
guideline on CAUTI recommended a
threshold of 105 CFU/ml for the diagnosis
of CAUTI in asymptomatic patients and
102 CFU/ml in patients with symptoms
related to the urinary tract. The most
important risk factor for the development
of CAUTI is prolonged duration of cath-
eterisation, others include female gender,
insertion of the catheter outside the oper-
ating room, diabetes mellitus and other
patient factors. Alternatives to indwelling
possible including intermittent catheteri-
sation, use of condom catheters, suprapu-
bic catheterisation.
Key words: Urinary catheter Risk fac-
tor Epidemiology Nosocomial infection
SUMMARY OF RECOMMENDATIONS
1. The duration of indwelling cathterisa-
tion should be minimised (GoR A).
2. The use of nurse-based or electronic
reminder systems to remove unneces-
sary catheters can decrease the dura-
tion of catheterization and the risk of
CAUTI (GoR B).
3. Alternatives to indwelling catheteri-
sation should be considered where
 Urinary catheters and drainage systems
possible including condom catheters,
intermittent catheterisation and
supra-pubic catheterization (GoR B).
4. There is insufficient evidence of cost
effectiveness at this time to recom-
mend antiseptic or antimicrobial
coated catheters (GoR C).
1. INTRODUCTION
Urinary catheters are among the most
commonly used devices in nursing homes
and hospitals especially in peri-operative
and intensive care unit patients. Recent
data show that more than 80% of patients
undergoing major surgery receive peri-
operative indwelling urinary catheters
[1]. Overall, up to 25% of all patients
admitted to hospital can expect a urinary
catheterization performed at some time
during their stay for a variety of indica-
tions [2]. The most common complication
associated with indwelling urinary cath-
eters is urinary tract infection (UTI).
Hospital acquired UTIs amount to
approximately 500,000 cases a year
in the United States alone [3] and are
responsible for 42% of all hospital –
acquired infections [4]. They result in
extension of hospital stay on average of
one day and are a major reservoir for
antibiotic-resistant pathogens [5].
Urinary catheters have long been
recognized as the major risk factor for
developing healthcare associated UTIs.
The presence of a urinary catheter has
been associated with up to 80% of noso-
comial UTIs [3]. In more recent studies
conducted hospital-wide [6] or in urology
departments [7], the association of cath-
eters with nosocomial UTIs remains high
with at least two thirds of nosocomial
UTIs associated with indwelling urinary
catheters. Every additional day of cath-
eterization is associated with a further
3–10 % risk of developing bacteriuria [8].
Bacteria can be introduced to the
urinary tract at the time of catheter
| 9.2 |
insertion due to inadequate preparation
of the meatus or perineum. Up to 20%
of individuals will be colonised immedi-
ately after catheterisation [9] (LoE 2a-3).
Subsequently, more bacteria can enter the
bladder through the lumen of the cathe-
ter by reflux of urine from contaminated
drainage bags or ascend from the urethra
along the extraluminal catheter-urethral
surface [10]. In males the predominant
route of invasion is the intraluminal, sug-
gesting an exogenous source. It is dem-
onstrated that the intraluminal ascent
of bacteria is faster (32–48 h) than the
extraluminal route (72–168 h) [11]. The
normal host defence mechanisms that
result in rapid clearance of introduced
microorganisms with voiding in non-
catheterized individuals are bypassed by
the presence of the indwelling urinary
catheter.
In addition, the presence of a biofilm
on the surfaces of the catheter provides
a favourable environment for bacterial
invasion and proliferation via the extra-
luminal route; thereby it is a major con-
tributor to the pathogenesis of UTI in
catheterized patients. Biofilm is defined
as an accumulation of microorgan-
isms and their extracellular products
that form a structured community on
a solid surface. Biofilms are ubiquitous
and have been demonstrated on cath-
eters, drainage bags and other foreign
bodies and prostheses [12]. Biofilm is
composed of three layers: (i) the linking
film, attached to the surface tissue or
biomaterial; (ii) the basal layer; and (iii)
the surface film adjacent to the lumen,
from which planktonic organisms can be
released. Organisms within the biofilm
are well protected from mechanical flush-
ing by urine flow, other host defences and
antibiotics or antiseptics. Conventional
microbiologic laboratory testing can eas-
ily detect planktonic free-floating bacte-
ria within the urine or occasionally in the
tissue. However, sessile pathogens from
the biofilm will not be detected with rou-
tine methods [12].
523
Chapter |9| Device associated urinary tract infections
2. METHODS
We surveyed the extensive literature
regarding the definition and epidemiol-
ogy of catheter-associated UTIs using the
following key words “urine” “catheter”
and “infection” and the following limita-
tions “English language”, “Human” and
“review”. We systematically searched for
meta-analyses of randomised controlled
trials available in Medline by giving pref-
erence to the Cochrane Central Register
of Controlled Trials and also considered
other relevant publications until March
2008. Studies were identified through a
PubMed search. More than 600 publica-
tions were found, which were screened
by title and abstracts and finally 51 were
included into the analysis.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[13–14].
3. DEFINITIONS OF CATHETER
ASSOCIATED UTI
The presence of an indwelling urethral
catheter inevitably leads to bacteriuria.
However, bacteriuria leads to bacter-
emia in less than 5% of the catheterized
patients [15]. Symptoms of dysuria in
combination with pyuria help clinicians
in diagnosing a UTI in patients without a
urinary catheter. Traditionally, these clin-
ical tools have also been used to help dis-
tinguish between bacterial colonization of
the catheterized urinary tract or asymp-
tomatic bacteriuria and symptomatic UTI
in catheterized patients. However, the
roles of dysuria, pyuria and even fever in
patients with suspected catheter-related
UTI have been questioned. A prospective
study of 1497 newly catheterized patients
showed that fewer than 10% of patients
who developed bacteriuria reported
symptoms normally associated with UTI,
a number not different from catheterized
524
patients without bacterial colonisation
[15]. Further analysis showed that such
symptoms have low predictive value of
UTI in catheterized patients as the pres-
ence of catheter alone can result in com-
plaints resembling dysuria. The study
also showed that the presence of periph-
eral leucocytosis is also not predictive of
UTI in this group. It has been proposed
that the presence of urinary catheter
actually limits the symptoms of dysuria
in the presence of bacteriuria [13]. There
is also no convincing evidence that fever
is a reliable symptom of catheter-related
UTI, especially in elderly patients [16].
It is thus very difficult to distinguish
asymptomatic catheter-associated bacte-
riuria from symptomatic catheter associ-
ated urinary tract infections.
What is clear, is that it is not possible
to have a symptomatic catheter associated
UTI without significant bacteriuria. The
degree of bacteriuria that is considered
significant is also controversial. A recent
European and Asian guideline on cath-
eter associated urinary tract infections
determined that a qualitative count ≥105
cfu/ml with one or more uropathogens
isolated in urine specimen should be used
to define significant catheter-associated
bacteriuria in asymptomatic patients
with indwelling urethral, suprapubic or
intermittent catheterisation, and a quali-
tative count ≥102 cfu/ml in the presence
of symptoms traditionally associated
with UTI. To define significant catheter-
associated bacteriuria in case of condom
catheter a qualitative count ≥105 cfu/ml
should be used in asymptomatic patients,
and a qualitative count ≥103 cfu/ml in
symptomatic patients [17].
4. RISK FACTORS OF CATHETER
ASSOCIATED UTI
4.1 Duration of catheterization
The length of catheterization is an
established risk factor for developing
 Urinary catheters and drainage systems
bacteriuria and a subsequent UTI
[18–19]. Every day of continuing cathe-
terization is associated with an increased
risk of approximately 3–10% of develop-
ing bacteriuria [18] and long term cath-
eterized patients will inevitably have the
presence of bacteria in the urine by day
30 of catheterization [1, 20]. Wald et.al.
performed a large retrospective cohort
study of 35,904 patients undergoing a
major surgery which showed that the
risk of developing a documented physi-
cian treated UTI was doubled after two
days of catheterization [1]. The same
study showed that as many as 50% of
patients who underwent a major surgery
stayed catheterized for longer than two
days. In another, randomized study of
patients undergoing an abdominal sur-
gery catheterization duration of longer
than seven days was found to carry an
increased risk of developing UTI (rela-
tive risk of 3.4) [16]. These observations,
however, are not limited to surgical
patients. A study in neurological patients
without previous infection who received
a urinary catheter for at least one week
showed that the length of catheterization
was the major risk factor for developing
a UTI [17].
The evidence shows clearly that the
duration of catheterization is the major
risk factor for developing a catheter
associated UTI (LoE 2a-3) and the con-
tinuing indication for keeping a cath-
eter should be reassessed by clinicians
regularly.
Although there is extensive literature
on the type, maintenance and techniques
for the insertion of urinary catheters, lit-
tle attention is paid to their removal. The
importance of urethral catheter manage-
ment is recognised; however, there is no
consensus about the optimal time and
method for removal of indwelling ure-
thral catheters.
According to the Cochrane database
[18], there is not sufficient evidence of the
benefit of using a catheter for a period
after operation (such as 24 h) compared
| 9.2 |
with immediate removal after operation,
but there is some evidence that there is
less need for re-catheterisation following
hysterectomy if there is a short period of
continuous drainage. Eleven trials con-
sidering the duration of catheterisation
after surgery showed considerable heter-
ogeneity and did not prove that any one
policy was better than another. In gen-
eral, fewer UTIs occurred when the cath-
eter was removed as soon as possible.
Removal of the indwelling urinary
catheter before midnight may be bene-
ficial (GoR C). There are some resource
implications but their magnitude is
not defined. Patients stay in hospital
for a shorter period of time after early,
rather than delayed catheter removal,
but the effects on other outcomes are
unclear [18].
Physicians are often unaware that their
patients have a urinary catheter. The use
of nurse-based or electronic reminder sys-
tems to remove unnecessary catheters
can decrease the duration of catheteriza-
tion and the risk of CAUTI [19–21] (LoE
2a, GoR B).
Other risk factors identified have
included [22–25] (IIa): (i) colonisation of
the drainage bag, catheter and periure-
thral segment; (ii) diabetes mellitus; (iii)
female gender; (iv) older age; (v) renal
function impairment; (vi) poor quality of
catheter care including insertion outside
of an operating room; and (vii) lack of
antimicrobial therapy.
4.2 Type of catheterization
4.2.1 One-time single (straight)
catheterisation
After single (straight) catheterisation,
bacteriuria develops in less than 5% of
cases [22–23] (LoE 3). The risk of infec-
tion is increased in female patients,
patients with urinary retention, in peri-
partum catheterisation, in men with pro-
static obstruction, in diabetes mellitus
and in debilitated and elderly patients
[18] (LoE 3).
525
Chapter |9| Device associated urinary tract infections
4.2.2 Short-term catheterisation
Short-term catheterization is usually
defined as having a catheter in place for
less than seven days [26]. Indications
for short-term bladder catheterisation
are to monitor urine output (i) in acutely
ill patients, (ii) for urinary obstruction
and (iii) in the perioperative period. The
majority of studies have been done on
short term catheterization in identifying
the risk factors described above.
Most episodes of short-term catheter-
associated bacteriuria are asymptomatic
and are caused by single organisms; up
to 15% may be polymicrobial [5] (LoE
3), reflecting the prevailing flora in hos-
pital or community environments. The
most common organism causing UTIs
in patients with short term urinary
catheters is Escheria coli. Other organ-
isms that are increasingly identified
include Klebsiella spp, Pseudomonas
spp, Acinetobacter spp, Enterobacter spp,
Candida spp and enterococci [22, 24].
4.3.3 Long-term catheterisation
When indwelling catheterisation lasts
for more than 28 days it is defined as
‘long-term’ or ‘chronic’. Unfortunately,
there is no consensus on the classifica-
tion or nomenclature for indwelling cath-
eters in place for 8–29 days. The risk of
bacteriuria with at least one strain is
universal in patients with a long-term
indwelling catheters, whilst most patients
are infected with two or more strains of
bacteria [27–28] (LoE 2b). The common-
est infecting organism is E. coli, followed
by Providentia stuartii, Pseudomonas,
Proteus, Morganella and Acinetobacter,
Enterococcus and Candida spp. Bacte-
riuria is polymicrobial in up to 95% of
urine specimens from long-term catheter-
ised patients [29–31] (LoE 2b-3). One-
quarter of organisms in catheter urine
are not present in urine simultaneously
obtained by suprapubic bladder puncture,
suggesting that some organisms colonise
the catheter only [32] (LoE 2b).
526
Despite the high level of bacteriuria in
patients with long-term indwelling cath-
eters, symptomatic manifestations, either
through ascending infection or through
bacteraemia, are uncommon. Studies in
a long-term facility identified UTIs as
a source of febrile episodes in less than
10% of patients [27] despite near uni-
versal bacteriuria (LoE 3). It is therefore
extremely important to rule out other
sources of fever (GoR A).
Although, asymptomatic bacteriuria is
common during initial catheter insertion
or during catheter exchange in chroni-
cally catheterised patients [33], the risk of
bacteraemia during catheter exchange is
low [34]. Chronic catheterisation can lead
to obstruction of the lower urinary tract
owing to catheter blockage as well as to
urinary tract stones, epididymitis, pros-
tatitis and scrotal abscess [35–37] (LoE
2a-3). Up to 50% of patients undergoing
catheterisation for more than 28 days
experience recurrent encrustation and
catheter blockage (LoE 2a). Intermittent
urinary retention can also lead to vesi-
coureteral reflux and ascending compli-
cated infection. Infecting organisms often
include P. mirabilis, a potent urease pro-
ducer, which promotes the development
of struvite stones by hydrolysis of urea to
ammonium (LoE 2b-3).
As indwelling urethral catheters are
prone to cause symptomatic infection, cli-
nicians should always consider alterna-
tives. In appropriate patients, suprapubic
catheters, condom drainage systems or
intermittent catheterisation are prefera-
ble to indwelling urethral catheterisation
(GoR B).
4.3.4 Transurethral versus suprapubic
catheters
Transurethral indwelling catheters are
the most commonly used catheters in both
hospitals and nursing homes. Suprapubic
catheters have long been an alternative
to the transurethral indwelling cath-
eterisation. The issue whether they are
 Urinary catheters and drainage systems
associated with fewer UTIs than tradi-
tional catheters has not been resolved
until today. A number of studies have
been performed, mainly in patients under-
going surgical procedures to compare the
risks of developing a UTI between the two
methods of catheterisation.
A meta-analysis of six randomized con-
trolled trials in patients after abdominal
surgery found that transurethral cath-
eterisation was associated with more sig-
nificant bacteriurias than suprapubic
catheterisation [38]. A Cochrane analy-
sis by Niël-Weise of studies comparing
suprapubic and transurethral catheters in
surgical patients also found that the lat-
ter were associated with higher rates of
bacteriuria [39]. In another meta-analysis
which included patients undergoing a uro-
genital surgery, four randomized trials
were analyzed [40]. The data were incon-
clusive. It has been noted that patient
comfort is higher with supra-pubic cath-
eterisation than with urethral catheterisa-
tion (LoE 3).
Most of the studies that were included
in the meta-analyses defined a catheter-
associated UTI as a presence of bac-
teriuria only. In contrast, a study by
Baan et al. compared suprapubic and
transurethral catheters after an abdom-
inal surgery and found no difference in
incidence of symptomatic urinary tract
infections [41].
In summary, despite a number of ran-
domized trials and at least three meta-
analyses, we cannot conclusively state
that suprapubic catheterization is supe-
rior to urethral catheterization in reduc-
ing the incidence of UTIs.
4.3.5 Urethral stents
Urethral stents/prostheses are often
inserted into the prostatic urethra for
a variety of indications, including neu-
rogenic bladder dysfunction, preven-
tion of strictures, treatment of urinary
retention. Bacteriuria, which is usu-
ally asymptomatic, occurs in 10–35% of
| 9.2 |
patients [42–43] (LoE 3). There are no
well-designed studies investigating the
significance of bacteriuria or symptomatic
UTI in correlation with various urethral
inserts and stents in comparison with
other drainage methods.
4.3.6 Coated catheters
A meta-analysis of 11 trials comparing
antiseptic impregnated urinary catheters
to standard catheters suggested that sil-
ver alloy coated catheters may carry a
lower risk for UTI. The beneficial effect of
combination of minocycline and rifampin
was less clear [44].
A more recently published Cochrane
analysis also suggested that silver alloy
catheters or antibiotic – impregnated
catheters may be beneficial in preventing
bacteriuria in selected groups of adults
with short term indwelling catheters.
However, a cost-benefit analysis of such
devices has yet to be performed [45].
4.3.7 Condom catheters
Condom catheters are usually used for
reliable monitoring of urine when there
is no urinary tract obstruction or urine
retention or when patient has problems
reaching the toilet or other urine col-
lection device. Although they are less
reliable than indwelling catheters in
measuring urine output due to leakage,
condom catheters cause less discomfort
to the patients. However, condom drain-
age may be unsatisfactory in confused or
uncooperative patients or where there is
obesity and/or a short penis. Skin mac-
eration and ulceration can occur. Daily
changing of the condom catheter is rec-
ommended, although changes every other
day are not associated with increased
infection rates [46]. Data on UTIs asso-
ciated with condom catheters are scarce.
Small studies have suggested that they
are associated with lower rates of UTI
provided manipulation of the catheter by
staff or the patient was kept to minimum
[47–48] (LoE 3).
527
Chapter |9| Device associated urinary tract infections
4.3.8 Intermittent catheterisation
Clean intermittent catheterisation is pop-
ular in the management of voiding dys-
function due to a wide variety of causes,
including a neuropathic bladder, women
with incontinence caused by uncontrolled
reflex detrusor contraction, women and
men with urinary retention due to inef-
fective or absent detrusor contraction and
males with bladder outlet obstruction who
are not fit for surgery [49]. Bacteriuria
is acquired at the rate of approximately
1–3% per catheterisation, however, this
might be transient and not cumulative
[48–51]. Complications include bleeding,
urethral inflammation, stricture, false
passage, epididymitis, bladder stone and
hydronephrosis.
Three trials compared indwelling ure-
thral catheterisation with intermittent
catheterisation. In two trials there were
more cases of bacteriuria in the indwelling
catheterisation group (relative ratio 2.90,
95% confidence interval 1.44–5.84). Cost
analyses of these trials however, favoured
the indwelling catheter. A randomised
study showed no difference in sympto-
matic UTIs between clean and sterile
intermittent catheterisation, although
obviously the former was associated with
reduced costs [52] (LoE 1b). There was
limited evidence that post-operative inter-
mittent catheterisation reduced the risk
of bacteriuria (asymptomatic and symp-
tomatic) in patients with hip or knee
surgery compared with indwelling cath-
eterisation, therefore no recommendation
can be made (GoR C).
5. FURTHER RESEARCH
Although urinary catheters have been
used for several hundred years, there are
still a number of unanswered questions
about how to prevent the most common
complication associated with catheter
use – infection. Due to the large scale of
the problem, this is clearly an important
field for good clinical research.
528
6. CONCLUSIONS
Catheter associated urinary tract infec-
tions are a major problem in hospitals
and nursing homes worldwide. The defi-
nition of these infections is complicated
as the symptoms of urinary tract infec-
tion are protean in patients with ind-
welling catheters and bacteruria is very
common in patients with prolonged cath-
eterization. The most important risk fac-
tor for catheter associated urinary tract
infection is the duration of catheteriza-
tion and strategies are being developed
to reduce catheterization using elec-
tronic and other reminders. Alternatives
to indwelling urethral catheteriza-
tion should also be considered where
possible.
REFERENCES
1. Wald HL, Ma A, Bratzler DW, and
Kramer AM, Indwelling urinary catheter
use in the postoperative period: analysis
of the national surgical infection preven-
tion project data. Arch Surg, 2008. 143(6):
551–7.
2. Haley RW, Hooton TM, Culver DH,
Stanley RC, Emori TG, Hardison CD,
Quade D, Shachtman RH, Schaberg DR,
Shah BV, and Schatz GD, Nosocomial
infections in U.S. hospitals, 1975–1976:
estimated frequency by selected character-
istics of patients. Am J Med, 1981. 70(4):
947–59.
3. Stamm WE, Martin SM, and Bennett JV,
Epidemiology of nosocomial infection due
to Gram-negative bacilli: aspects relevant
to development and use of vaccines.
J Infect Dis, 1977. 136 Suppl: S151–60.
4. Haley RW, Culver DH, White JW, Morgan
WM, and Emori TG, The nationwide noso-
comial infection rate. A new need for vital
statistics. Am J Epidemiol, 1985. 121(2):
159–67.
5. Tambyah PA, Knasinski V, and Maki DG,
The direct costs of nosocomial catheter-
associated urinary tract infection in the
era of managed care. Infect Control Hosp
Epidemiol, 2002. 23(1): 27–31.
 Urinary catheters and drainage systems
6. Bonza E, San Juan R, Muñoz P, Voss A,
and Kluytmans J, Co-operative Group of
the European Study Group on Nosocomial
Infections. A European perspective on
nosocomial urinary tract infections II.
Report on incidence, clinical character-
istics and outcome (ESGNI-004 study).
European Study Group on Nosocomial
Infection. Clin Microbiol Infect 2001.
7: 532–42.
7. Bjerklund Johansen TE, Cek M, Naber K,
Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
8. Warren JW, Platt R, Thomas RJ,
Rosner B, and Kass EH, Antibiotic irriga-
tion and catheter-associated urinary-tract
infections. N Engl J Med, 1978. 299(11):
570–3.
9. Garibaldi RA, Burke JP, Britt MR, Miller
MA, and Smith CB, Meatal colonization
and catheter-associated bacteriuria.
N Engl J Med, 1980. 303(6): 316–8.
10. Tambyah PA, Halvorson KT, and Maki
DG, A prospective study of pathogen-
esis of catheter-associated urinary tract
infections. Mayo Clin Proc, 1999. 74(2):
131–6.
11. Warren JW, Tenney JH, Hoopes JM,
Muncie HL, and Anthony WC, A prospec-
tive microbiologic study of bacteriuria in
patients with chronic indwelling urethral
catheters. J Infect Dis, 1982. 146(6):
719–23.
12. Costerton JW, Introduction to biofilm.
Int J Antimicrob Agents, 1999. 11(3–4):
217–21; discussion 237–9.
13. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
14. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
15. Tambyah PA and Maki DG, Catheter-
associated urinary tract infection is rarely
symptomatic: a prospective study of 1,497
catheterized patients. Arch Intern Med,
2000. 160(5): 678–82.
| 9.2 |
16. Kunin CM, Chin QF, and Chambers S,
Morbidity and mortality associated with
indwelling urinary catheters in elderly
patients in a nursing home – confounding
due to the presence of associated diseases.
J Am Geriatr Soc, 1987. 35(11): 1001–6.
17. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008.
31 Suppl 1: S68–78.
18. Griffiths R and Fernandez R, Policies for
the removal of short-term indwelling ure-
thral catheters. Cochrane Database Syst
Rev, 2005(1): CD004011.
19. Apisarnthanarak A, Thongphubeth K,
Sirinvaravong S, Kitkangvan D, Yuekyen
C, Warachan B, Warren DK, and Fraser
VJ, Effectiveness of multifaceted hospi-
talwide quality improvement programs
featuring an intervention to remove unnec-
essary urinary catheters at a tertiary care
center in Thailand. Infect Control Hosp
Epidemiol, 2007. 28(7): 791–8.
20. Saint S, Kaufman SR, Thompson M,
Rogers MA, and Chenoweth CE, A
reminder reduces urinary catheterization
in hospitalized patients. Jt Comm J Qual
Patient Saf, 2005. 31(8): 455–62.
21. Topal J, Conklin S, Camp K, Morris V,
Balcezak T, and Herbert P, Prevention of
nosocomial catheter-associated urinary
tract infections through computerized
feedback to physicians and a nurse-
directed protocol. Am J Med Qual, 2005.
20(3): 121–6.
22. Warren JW, Catheter-associated urinary
tract infections. Int J Antimicrob Agents,
2001. 17(4): 299–303.
23. Platt R, Polk BF, Murdock B, and
Rosner B, Risk factors for nosocomial
urinary tract infection. Am J Epidemiol,
1986. 124(6): 977–85.
24. Stamm WE, Hooton TM, Johnson JR,
Johnson C, Stapleton A, Roberts PL,
Moseley SL, and Fihn SD, Urinary tract
infections: from pathogenesis to treatment.
J Infect Dis, 1989. 159(3): 400–6.
25. Maki DG and Tambyah PA, Engineering
out the risk for infection with urinary cath-
eters. Emerg Infect Dis, 2001. 7(2): 342–7.
529
Chapter |9| Device associated urinary tract infections
26. Warren J, Bakke A, and Desgranchamps
F, Catheter-associated bacteriuria and
the role of biomaterial in prevention,
in Nosocomial and health care associ-
ated infections in urology, Naber KG,
Pechere JC, Kumazawa J, Khoury
S, Gerberding IL, and Schaeffer AJ,
Editors. 2001, Health Publication Ltd:
Plymouth. p. 207 p.
27. Warren JW, Damron D, Tenney JH,
Hoopes JM, Deforge B, and Muncie HL,
Jr., Fever, bacteremia, and death as com-
plications of bacteriuria in women with
long-term urethral catheters. J Infect Dis,
1987. 155(6): 1151–8.
28. Steward DK, Wood GL, Cohen RL, Smith
JW, and Mackowiak PA, Failure of the
urinalysis and quantitative urine culture
in diagnosing symptomatic urinary tract
infections in patients with long-term uri-
nary catheters. Am J Infect Control, 1985.
13(4): 154–60.
29. Warren JW, Providencia stuartii: a com-
mon cause of antibiotic-resistant bacteriu-
ria in patients with long-term indwelling
catheters. Rev Infect Dis, 1986. 8(1): 61–7.
30. Tenney JH and Warren JW, Bacteriuria
in women with long-term catheters: paired
comparison of indwelling and replace-
ment catheters. J Infect Dis, 1988. 157(1):
199–202.
31. Rahav G, Pinco E, Silbaq F, and
Bercovier H, Molecular epidemiology of
catheter-associated bacteriuria in nurs-
ing home patients. J Clin Microbiol, 1994.
32(4): 1031–4.
32. Bergqvist D, Bronnestam R, Hedelin H,
and Stahl A, The relevance of urinary
sampling methods in patients with ind-
welling Foley catheters. Br J Urol, 1980.
52(2): 92–5.
33. Jewes LA, Gillespie WA, Leadbetter A,
Myers B, Simpson RA, Stower MJ, and
Viant AC, Bacteriuria and bacteraemia
in patients with long-term indwelling
catheters – a domiciliary study. J Med
Microbiol, 1988. 26(1): 61–5.
34. Bregenzer T, Frei R, Widmer AF, Seiler
W, Probst W, Mattarelli G, and Zimmerli
W, Low risk of bacteremia during catheter
replacement in patients with long-term
urinary catheters. Arch Intern Med, 1997.
157(5): 521–5.
530
35. Kunin CM, Chin QF, and Chambers S,
Formation of encrustations on indwell-
ing urinary catheters in the elderly: a
comparison of different types of catheter
materials in “blockers” and “nonblockers”.
J Urol, 1987. 138(4): 899–902.
36. Stickler DJ, Evans A, Morris N, and
Hughes G, Strategies for the control of
catheter encrustation. Int J Antimicrob
Agents, 2002. 19(6): 499–506.
37. Choong S, Wood S, Fry C, and Whitfield
H, Catheter associated urinary tract infec-
tion and encrustation. Int J Antimicrob
Agents, 2001. 17(4): 305–10.
38. McPhail MJ, Abu-Hilal M, and Johnson
CD, A meta-analysis comparing suprapu-
bic and transurethral catheterization for
bladder drainage after abdominal sur-
gery. Br J Surg, 2006. 93(9): 1038–44.
39. Niel-Weise BS and van den Broek PJ,
Urinary catheter policies for long-term
bladder drainage. Cochrane Database
Syst Rev, 2005(1): CD004201.
40. Phipps S, Lim YN, McClinton S, Barry C,
Rane A, and N’Dow J, Short term urinary
catheter policies following urogenital sur-
gery in adults. Cochrane Database Syst
Rev, 2006(2): CD004374.
41. Baan AH, Vermeulen H, van der Meulen
J, Bossuyt P, Olszyna D, and Gouma DJ,
The effect of suprapubic catheterization
versus transurethral catheterization after
abdominal surgery on urinary tract infec-
tion: a randomized controlled trial. Dig
Surg, 2003. 20(4): 290–5.
42. Petas A, Talja M, Tammela TL, Taari K,
Valimaa T, and Tormala P, The biodegrad-
able self-reinforced poly-DL-lactic acid
spiral stent compared with a suprapubic
catheter in the treatment of post-operative
urinary retention after visual laser abla-
tion of the prostate. Br J Urol, 1997. 80(3):
439–43.
43. Nissenkorn I and Slutzker D, The intrau-
rethral catheter: long-term follow-up in
patients with urinary retention due to
infravesical obstruction. Br J Urol, 1991.
68(3): 277–9.
44. Brosnahan J, Jull A, and Tracy C, Types
of urethral catheters for management of
short-term voiding problems in hospital-
ised adults. Cochrane Database Syst Rev,
2004(1): CD004013.
 Urinary catheters and drainage systems
45. Schumm K and Lam TB, Types of ure-
thral catheters for management of short-
term voiding problems in hospitalised
adults. Cochrane Database Syst Rev,
2008(2): CD004013.
46. Ouslander JG, Greengold B, and Chen S,
External catheter use and urinary tract
infections among incontinent male nurs-
ing home patients. J Am Geriatr Soc,
1987. 35(12): 1063–70.
47. Hirsh DD, Fainstein V, and Musher DM,
Do condom catheter collecting systems
cause urinary tract infection? JAMA,
1979. 242(4): 340–1.
48. Bakke A, Irgens LM, Malt UF, and
Hoisaeter PA, Clean intermittent cathe-
terisation-performing abilities, aversive
experiences and distress. Paraplegia,
1993. 31(5): 288–97.
| 9.2 |
49. Pearman JW, Urological follow-up of 99
spinal cord injured patients initially
managed by intermittent catheterisation.
Br J Urol, 1976. 48(5): 297–310.
50. Wyndaele JJ and Maes D, Clean inter-
mittent self-catheterization: a 12-year
followup. J Urol, 1990. 143(5): 906–8.
51. Diokno AC, Sonda LP, Hollander JB,
and Lapides J, Fate of patients started
on clean intermittent self-catheterization
therapy 10 years ago. J Urol, 1983. 129(6):
1120–2.
52. Duffy LM, Cleary J, Ahern S,
Kuskowski MA, West M, Wheeler L,
and Mortimer JA, Clean intermittent
catheterization: safe, cost-effective blad-
der management for male residents of
VA nursing homes. J Am Geriatr Soc,
1995. 43(8): 865–70.
531
|9.3|

Urinary catheters and

drainage systems: prevention
and treatment of urinary tract
infections
Peter Tenke, Bela Koves, Karoly Nagy
Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest, Hungary
Corresponding author: Peter Tenke, MD, PhD, Head, Department of Urology, Jahn Ference Del-Pesti Korhaz,
Köves utca2-4, H-1204 Budapest, Hungary
Tel 0036-1-289.6200, tenkep@chello.hu; tenke.peter@jahndelpest.hu

ABSTRACT Healthcare workers should be constantly

We surveyed the extensive literature
regarding the prevention and treatment
of catheter-associated urinary tract infec-
tions (CAUTIs). The clinician should be
aware of two priorities: the catheter sys-
tem should remain closed and the duration
of catheterisation should be minimal. In
case of short-term catheterisation routine
prophylaxis with systemic antibiotics is
not recommended. There are sparse data
about antibiotic prophylaxis in patients
on long-term catheterisation, therefore
no recommendation can be made. For
patients using intermittent catheterisa-
tion routine antibiotic prophylaxis is not
recommended. Antibiotic irrigation of the
catheter and bladder is of no advantage.
aware of the risk of cross-infection between
catheterised patients. They should observe
protocols on hand washing and the need
to use disposable gloves. While a catheter
is in place, systemic antimicrobial treat-
ment of asymptomatic catheter-associated
bacteriuria is not recommended, except
for some special cases. Routine urine cul-
ture in an asymptomatic catheterised
patient is also not recommended because
treatment is in general not necessary.
Antibiotic treatment is recommended only
for symptomatic infection. After initia-
tion of empirical treatment usually with
broad-spectrum antibiotics based on local
susceptibility patterns, the choice of anti-
biotics may need to be adjusted accord-
ing to urine culture results. Long-term
 Urinary catheters and drainage systems
antibiotic supportive therapy is not effec-
tive. In case of asymptomatic candiduria,
neither systemic nor local antifungal
therapy is indicated, but removal of the
catheter or stent could be considered. In
case of candiduria associated with urinary
symptoms or if candiduria is the sign of a
systemic infection, systemic therapy with
antifungals is indicated.
Key words: urinary, infection, catheter,
UTI, CAUTI, prevention, prophylaxis,
treatment, bacteriuria, candiduria
SUMMARY OF RECOMMENDATIONS
General aspects
1. Health care workers should observe
protocols on hand hygiene and the
need to use disposable gloves between
catheterised patients (GoR A).
Catheter insertion and choice of
catheter
2. An indwelling catheter should be
introduced under antiseptic conditions
(GoR B).
3. Urethral trauma should be minimised
by the use of adequate lubricant and
the smallest possible catheter caliber
(GoR B).
Prevention and prophylaxis
4. The catheter system should remain
closed (GoR A).
5. The duration of catheterisation should
be minimal (GoR A).
6. Topical antiseptics or antibiotics
applied to the catheter, drainage bag,
urethra or meatus are not recom-
mended (GoR A).
7. In case of short-term catheterisation
routine antibiotic prophylaxis is not
recommended (GoR A).
8. The data comparing antibiotic prophy-
laxis to giving antibiotics when
| 9.3 |
clinically indicated in patients on
long-term catheterisation are sparse.
Therefore no recommendation can be
made (GoR D).
9. There is little evidence suggest-
ing that antibiotic prophylaxis
decreases bacteriuria in patients
using intermittent catheterisation,
therefore it is not recommended
(GoR B).
10. Long-term indwelling catheters
should be changed in intervals
adapted to the individual patient,
but must be changed before blockage
is likely to occur, however there is
no evidence for the exact intervals of
changing catheters (GoR B).
Diagnostics
11. Routine urine culture in asympto-
matic catheterised patients is not
recommended (GoR B).
12. Urine, and in septic patients also
blood for culture must be taken
before any antimicrobial therapy is
started (GoR A).
13. Febrile episodes are only found in
less than 10% of catheterised patients
living in a long-term facility. It is
therefore extremely important to rule
out other sources of fever (GoR A).
Treatment
14. Whilst the catheter is in place, sys-
temic antimicrobial treatment of
asymptomatic catheter-associated
bacteriuria is not recommended,
except in certain circumstances:
especially prior to traumatic urinary
tract interventions (GoR A).
15. Antimicrobial treatment is recom-
mended only for symptomatic infec-
tion (GoR B).
16. Elderly female patients may need
treatment if asymptomatic bacteriu-
ria does not resolve spontaneously
after catheter removal (GoR B).
533
Chapter |9| Device associated urinary tract infections
17. Chronic antibiotic suppressive ther-
apy is generally not recommended
(GoR A).
18. In case of symptomatic CAUTI it
may be reasonable to replace or
remove the catheter before starting
antimicrobial therapy if the indwell-
ing catheter has been in place for
more than 7 days (GoR B).
19. For empiric therapy broad-spectrum
antibiotics must be given based on
local susceptibility patterns (GoR A).
20. After culture results are available
antibiotic therapy has to be adjusted
according to sensitivities of the path-
ogens (GoR A).
21. In case of asymptomatic candiduria,
neither systemic nor local antifungal
therapy is indicated (GoR A).
22. In case of asymptomatic candiduria
removal of the catheter or stent could
be considered (GoR C).
23. In case of candiduria associated with
urinary symptoms or if candiduria
is the sign of a systemic infection,
systemic therapy with antifungals is
indicated (GoR B).
1. INTRODUCTION
Approximately 40% of nosocomial infec-
tions originate in the urinary tract.
Most patients with nosocomial urinary
tract infections (UTIs) have either had
genitourinary or urological manipula-
tion (ca. 10–20%) or permanent urethral
catheterisation (ca. 80%), or both [1–5]
(LoE 3).
The aim of this chapter is to give evi-
dence based recommendations for the
prevention and treatment of catheter-
associated bacteriuria and urinary
tract infection (UTI) for all medical
disciplines, with special emphasis on
urology where catheter care is an impor-
tant issue, and to assist and to encour-
age urological departments to establish
534
written guidance on catheter care on
evidence-based grounds.
2. METHODS
We surveyed the extensive literature
regarding the prevention and therapy
of catheter-associated UTIs through a
PubMed search using the following key
words in different combinations: catheter,
infection, urinary, UTI, CAUTI, preven-
tion, treatment, bacteriuria. We system-
atically searched for meta-analyses of
randomised controlled trials available
in Medline by giving preference to the
Cochrane Central Register of Controlled
Trials and also considered other rele-
vant publications until March 2008. The
publications were screened by title and
abstracts and after exclusion of duplicates
a total of 50 publication were included
into the analysis.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [6–7].
3. PREVENTION OF BACTERIURIA
AND PROPHYLAXIS
3.1 Prevention of bacteriuria
The following recommendations are com-
monly used [8–10] (LoE 3). A closed-
catheter system with ports in the distal
catheter for needle aspiration of urine
should be used (GoR B). An indwell-
ing catheter should be introduced under
antiseptic conditions (GoR B). Urethral
trauma should be minimised by the use
of adequate lubricant and the smallest
possible catheter (GoR B). A limited study
indicates that the risk of bacteriuria is
equally high if a sterile or clean tech-
nique or an antiseptic gel is used [11–12]
(LoE 2a). The drainage bag should be
always kept below the level of the blad-
der and the connecting tube [13] (GoR B).
 Urinary catheters and drainage systems
The clinician should be aware of two pri-
orities: the catheter system must remain
closed (GoR A) and the duration of cath-
eterisation has to be minimal (GoR A).
There is a resurgence of interest in
the use of the convenient flip valve as a
replacement for the daytime catheter
bag. It is expected that the risk of coloni-
sation of such a device will be a problem,
although a randomised controlled study of
100 patients comparing the use of cathe-
ter valve with standard drainage systems
showed no difference in the incidence of
UTIs [14]. Adequate urine flow must be
ensured. The patient should receive suf-
ficient fluids given orally to maintain
an output of more than 50–100 mL/h.
Bacteraemia is not prevented by topical
antiseptics or antibiotics applied to the
catheter, urethra or meatus.
There is no consensus as to the time
in which routine catheter changes have
to be made. This may be dictated by the
manufacturer’s instructions and condi-
tions for indemnity. Shorter periods may
be necessary if there is catheter malfunc-
tion or leakage. In general, long-term ind-
welling catheters must be changed before
blockage occurs or is likely to occur. The
time differs very much from one patient
to another. Some patients form deposit in
the catheter lumen very quickly [10, 15].
These individuals (‘blockers’) need to have
catheter changes more frequently than
‘non-blockers’, i.e. weekly or even twice
weekly [16–17]. Some authors advise
leaving the catheter out for at least one
hour, but no longer than two hours,
when a long-term indwelling catheter is
changed, to allow the urethral glands to
drain [10]. However, this method has no
evidence-based support.
3.2 Prophylaxis with systemic
antibiotics
In a recent Cochrane review of anti-
biotic policies for short-term catheter
bladder drainage in adults the authors
concluded that there was weak evidence
| 9.3 |
that antibiotic prophylaxis compared to
giving antibiotics when clinically indi-
cated reduced the rate of symptomatic
UTIs in female patients with abdominal
surgery and a urethral catheter for 24
hours. There was limited evidence that
prophylactic antibiotics reduced bacteriu-
ria in non-surgical patients [18] (LoE 1a).
Therefore in case of short-term catheteri-
sation routine prophylaxis is not recom-
mended (GoR A).
According to the Cochrane database
the data comparing antibiotic prophylaxis
to giving antibiotics when clinically indi-
cated in patients on long-term catheteri-
sation are sparse [19] (LoE 1a). Therefore
no recommendation can be made (GoR D).
For patients using intermittent catheteri-
sation, there is limited evidence suggest-
ing that antibiotic prophylaxis decreases
the rate of bacteriuria (asymptomatic and
symptomatic) [19]. Therefore it is not rec-
ommended (GoR B). Possible benefits of
prophylaxis must be balanced against cost
and adverse effects, such as development
of antimicrobial resistance. Cycling of
antibiotics on a weekly basis can be pos-
sible way to reduce the risk of resistance,
but further research is needed before a
recommendation can be made [20].
3.3 Additional methods of
prevention
According to a recent Cochrane review of
randomised controlled trials cranberry
products (juice or tablets) did not reduce
significantly the incidence of catheter-
associated bacteriuria or CAUTI in
patients with neurogenic bladder requir-
ing intermittent or indwelling cath-
eterisation [21]. Therefore they are not
recommended (GoR A). There is no avail-
able data on the use of cranberry prod-
ucts for prevention of catheter-associated
bacteriuria or CAUTI in patients without
neurogenic bladder, therefore no recom-
mendation can be made (GoR D).
Methenamin salts (methenamine man-
delate or methenamine hippurate) reduced
535
Chapter |9| Device associated urinary tract infections
the incidence of asymptomatic bacteriuria
and symptomatic UTIs in post-surgical
patients without renal tract abnormali-
ties with an indwelling catheter for no
more than one week [22–23] (LoE 1b).
Benefits from antiseptic substances, such
as oral methenamine have never been
established in patients with intermittent
catheterisation.
Catheter irrigation with antiseptics
(povidone–iodine or chlorhexidine) or
antibiotics are not effective in prevent-
ing catheter associated bacteriuria in
patients with indwelling catheterisation
[24–25], therefore they are not recom-
mended (GoR A) There is some evidence
that catheter irrigation with antisep-
tics may prevent bacteriuria in surgical
patients undergoing short-term catheteri-
sation [26–27] (LoE 1b). Administration
of antimicrobials in the drainage bag is
not recommended [28] (GoR A).
3.4 Prevention of cross-infection
Healthcare workers should be constantly
aware of the risk of cross-infection
between catheterised patients. They
should observe protocols on hand wash-
ing and the need to use disposable gloves
(GoR A). The periurethral bacterial flora,
surfaces of the catheter system and the
persistent, huge reservoir of contami-
nated urine as well as the skin of the
patient are sources for contamination
of the hands of medical personnel who
may carry the bacteria to other patients
[29–32] (LoE 2b-3). This may be reduced
by treating the catheterised urinary tract
as an open wound. It is therefore essen-
tial to use gloves after hand washing in
antiseptic solutions [33–35] (LoE 2a-3).
4. TREATMENT
4.1 Treatment of asymptomatic
bacteriuria
Generally, asymptomatic bacteriuria
should not be treated (GoR A) because
536
bacteriuria will either not be eradicated
or will return rapidly. However, antimi-
crobial therapy may contribute to the
selection of resistant organisms and to
adverse reactions. There is no evidence
that antimicrobial therapy decreases
morbidity or mortality from UTI in cath-
eterised patients [18], therefore systemic
antimicrobial treatment of asymptomatic
catheter-associated bacteriuria is only
recommended in the following circum-
stances [8–9, 29–30, 36–37]: (i) patients
undergoing urological surgery or implan-
tation of prostheses (GoR A); (ii) treat-
ment may be part of a plan to control
nosocomial infection due to a particularly
virulent organism prevailing in a treat-
ment unit (GoR B); (iii) patients who have
a high risk of serious infectious complica-
tions, e.g. patients who are immunosup-
pressed (GoR C); (iv) in case of pregnancy
(GoR B); and (v) infections caused by
strains causing a high incidence of bacter-
aemia, e.g. Serratia marcescens (GoR B).
If the catheter drains properly, routine
urine cultures in asymptomatic catheter-
ised patients are also not recommended
(GoR B) because treatment generally is
not necessary. Also, it has not been shown
that a uropathogen cultured from an
asymptomatic patient will be the causa-
tive organism when a symptomatic episode
occurs. Following catheter removal in ca.
one-third to one-half of cases, the urinary
tract will clear bacteria spontaneously [10,
30] (LoE 3). Spontaneous clearance occurs
more commonly in women under 65 years
of age or when S. epidermidis is the infect-
ing organism [10]. However, one study
shows that elderly females may need
treatment if bacteriuria does not resolve
spontaneously [38] (LoE 2a) or if sympto-
matic infection occurs.
4.2 Treatment of symptomatic UTI
The most frequent clinical manifestation
of symptomatic UTI in catheterised resi-
dents is fever. Some patients may also
become septic with at least two of the
 Urinary catheters and drainage systems
followings symptoms: hypothermia, tach-
ycardia (> 90/min), tachypnoea (>20/min
and/or pCO2 <33 Hgmm), leucocytosis
(>12/nl) or leucopenia (<4/nl). Since
patients with long-term indwelling cath-
eters always have positive urine cultures,
a definite diagnosis of the source of infec-
tion remains problematic in a febrile or
septic catheterized patient without local-
ising genitourinary symptoms and if not
bacteraemic due to the same urinary
pathogen. UTI may be the source of fever;
if there are no localising features such as
obstruction, haematuria or costovertebral
angle tenderness, alternative diagnoses
must be considered (GoR A). Observation,
rather than immediate antimicrobial
therapy, should be considered when the
patient is clinically stable and the fever
is of low grade [39].
Antibiotic treatment is recommended
only in symptomatic infection (bacter-
aemia, pyelonephritis, epididymitis,
prostatitis) (GoR B). In catheterized
patients the presence or the degree of
pyuria should not be used to differenti-
ate catheter-associated bacteriuria from
CAUTI [40–41] (GoR B), and it is not an
indication for antimicrobial treatment.
Systemic antibiotics should be used for
catheterised patients who are febrile and
appear to be ill, because of the possibility
of UTI-related bacteraemia or pyelone-
phritis (GoR B). Owing to the likelihood
of bacteria sequestered in a biofilm on the
catheter surface, it may be reasonable
to replace or remove the catheter (if the
indwelling catheter has been in place for
more than 7 days) before the therapy of
symptomatic catheter-associated bacte-
riuria [10, 33, 42–43] (GoR B). After ini-
tiation of empirical treatment usually
with broad-spectrum antibiotics based on
local susceptibility patterns, the choice
of antibiotics may need to be adjusted
according to urine culture results
(GoR A). Therefore, urine, and in septic
patients also blood for culture, must be
taken before any antibacterial therapy is
started (GoR A).
| 9.3 |
Although there are no adequate clini-
cal studies to guide the length of therapy
for catheter-related symptomatic UTI,
antimicrobial treatment usually var-
ies from 5 days to 21 days depending on
the organism, co-morbid conditions and
patient response [33, 38, 44] (LoE 1-3).
In patients with CAUTI, who are not
severely ill, a 5-day regimen of a fluoro-
quinolone should be considered [45–46]
(GoR B). Chronic antibiotic suppressive
therapy is not effective and generally
not recommended (GoR A). Catheterised
urine cannot be permanently sterilised
[8–9, 31, 33, 39, 47] (LoE 2a-3). For
women age 65 or younger who develop
CAUTI without upper tract symptoms
after the catheter has been removed, a
3-day antimicrobial regimen is recom-
mended (GoR C).
Occasionally, the culture shows candi-
duria, which is usually asymptomatic and
often resolves without treatment. In this
case neither systemic nor local (bladder
irrigation) antifungal therapy is indicated
[48–49] (LoE 1b, GoR A), but removal of
the catheter or stent could be considered
(GoR C). If the infection is associated
with urinary symptoms or candiduria is
the sign of a systemic infection, systemic
therapy with antifungals is indicated
[50–52] (LoE 2a, GoR B).
5. FURTHER RESEARCH
However there are prospective, ran-
domised studies regarding the most
aspects of the prevention and treatment
of CAUTIs, there are still some unan-
swered questions, such as the need of
antibiotic prophylaxis in patients on
long-term catheterisation, the length of
therapy for catheter-related symptomatic
UTIs, or the time in which routine cathe-
ter changes have to be made. Prospective
studies and long-term follow up are
needed to answer these questions and to
make evidence-based recommendations
about them.
537
Chapter |9| Device associated urinary tract infections
6. CONCLUSIONS
The urinary tract is the commonest
source of nosocomial infections, and one
of the leading risk factors is urethral
catheterisation. Therefore the evidence-
based prevention and treatment of cath-
eter associated UTIs are very important
in the daily practice. Written catheter
care protocols are necessary to decrease
the number of nosocomial infections, with
special emphasis on urology departments.
REFERENCES
1. Haley RW, Culver DH, White JW, Morgan
WM, and Emori TG, The nationwide noso-
comial infection rate. A new need for vital
statistics. Am J Epidemiol, 1985. 121(2):
159–67.
2. Stamm WE, Martin SM, and Bennett JV,
Epidemiology of nosocomial infection due
to Gram-negative bacilli: aspects relevant
to development and use of vaccines.
J Infect Dis, 1977. 136 Suppl: S151–60.
3. Haley RW, Hooton TM, Culver DH,
Stanley RC, Emori TG, Hardison CD,
Quade D, Shachtman RH, Schaberg DR,
Shah BV, and Schatz GD, Nosocomial
infections in U.S. hospitals, 1975–1976:
estimated frequency by selected character-
istics of patients. Am J Med, 1981. 70(4):
947–59.
4. Krieger JN, Kaiser DL, and Wenzel RP,
Urinary tract etiology of bloodstream
infections in hospitalized patients.
J Infect Dis, 1983. 148(1): 57–62.
5. Asher EF, Oliver BG, and Fry DE,
Urinary tract infections in the surgical
patient. Am Surg, 1988. 54(7): 466–9.
6. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
7. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. Warren JW, Tenney JH, Hoopes JM,
Muncie HL, and Anthony WC,
538
A prospective microbiologic study of bac-
teriuria in patients with chronic indwell-
ing urethral catheters. J Infect Dis, 1982.
146(6): 719–23.
9. Warren JW, Catheter-associated urinary
tract infections. Int J Antimicrob Agents,
2001. 17(4): 299–303.
10. West DA, Cummings JM, Longo WE,
Virgo KS, Johnson FE, and Parra RO,
Role of chronic catheterization in the
development of bladder cancer in patients
with spinal cord injury. Urology, 1999.
53(2): 292–7.
11. Carapeti EA, Andrews SM, and
Bentley PG, Randomized study of sterile
versus non-sterile urethral catheterization.
Ann R Coll Surg Engl 1994. 78: 59–60.
12. Schiotz HA, Antiseptic catheter gel and
urinary tract infection after short-term
postoperative catheterization in women.
Arch Gynecol Obstet, 1996. 258(2):
97–100.
13. Maki DG and Tambyah PA, Engineering
out the risk for infection with urinary
catheters. Emerg Infect Dis, 2001.
7(2): 342–7.
14. Wilson C, Sandhu SS, and Kaisary AV, A
prospective randomized study comparing
a catheter-valve with a standard drainage
system. Br J Urol, 1997. 80(6): 915–7.
15. Kunin CM, Kunin CMDp, and manage-
ment of urinary tract i, Urinary tract
infections : detection, prevention, and
management. 5th ed. ed. 1997, Baltimore;
London: Williams & Wilkins. ix, 419p.
16. Platt R, Polk BF, Murdock B, and Rosner
B, Mortality associated with nosocomial
urinary-tract infection. N Engl J Med,
1982. 307(11): 637–42.
17. Stickler DJ, Evans A, Morris N, and
Hughes G, Strategies for the control of
catheter encrustation. Int J Antimicrob
Agents, 2002. 19(6): 499–506.
18. Niel-Weise BS and van den Broek PJ,
Antibiotic policies for short-term catheter
bladder drainage in adults. Cochrane
Database Syst Rev, 2005(3): CD005428.
19. Niel-Weise BS and van den Broek PJ,
Urinary catheter policies for long-term
bladder drainage. Cochrane Database
Syst Rev, 2005(1): CD004201.
20. Salomon J, Denys P, Merle C, Chartier-
Kastler E, Perronne C, Gaillard JL, and
 Urinary catheters and drainage systems
Bernard L, Prevention of urinary tract
infection in spinal cord-injured patients:
safety and efficacy of a weekly oral cyclic
antibiotic (WOCA) programme with a 2
year follow-up – an observational prospec-
tive study. J Antimicrob Chemother, 2006.
57(4): 784–8.
21. Jepson RG and Craig JC, Cranberries
for preventing urinary tract infections.
Cochrane Database Syst Rev, 2008(1):
CD001321.
22. Lee BB, Simpson JM, Craig JC, and
Bhuta T, Methenamine hippurate for
preventing urinary tract infections.
Cochrane Database Syst Rev, 2007(4):
CD003265.
23. Schiotz HA and Guttu K, Value of urinary
prophylaxis with methenamine in gyneco-
logic surgery. Acta Obstet Gynecol Scand,
2002. 81(8): 743–6.
24. Warren JW, Platt R, Thomas RJ, Rosner
B, and Kass EH, Antibiotic irrigation
and catheter-associated urinary-tract
infections. N Engl J Med, 1978. 299(11):
570–3.
25. Davies AJ, Desai HN, Turton S, and
Dyas A, Does instillation of chlorhexidine
into the bladder of catheterized geriatric
patients help reduce bacteriuria? J Hosp
Infect, 1987. 9(1): 72–5.
26. Ball AJ, Carr TW, Gillespie WA, Kelly M,
Simpson RA, and Smith PJ, Bladder
irrigation with chlorhexidine for the
prevention of urinary infection after
transurethral operations: a prospective
controlled study. J Urol, 1987. 138(3):
491–4.
27. Richter S, Kotliroff O, and Nissenkorn I,
Single preoperative bladder instillation
of povidone-iodine for the prevention of
postprostatectomy bacteriuria and wound
infection. Infect Control Hosp Epidemiol,
1991. 12(10): 579–82.
28. Thompson RL, Haley CE, Searcy MA,
Guenthner SM, Kaiser DL, Groschel DH,
Gillenwater JY, and Wenzel RP, Catheter-
associated bacteriuria. Failure to reduce
attack rates using periodic instillations of
a disinfectant into urinary drainage
systems. JAMA, 1984. 251(6): 747–51.
29. Rutala WA, Kennedy VA, Loflin HB, and
Sarubbi FA, Jr., Serratia marcescens
nosocomial infections of the urinary tract
| 9.3 |
associated with urine measuring contain-
ers and urinometers. Am J Med, 1981.
70(3): 659–63.
30. Schaberg DR, Weinstein RA, and Stamm
WE, Epidemics of nosocomial urinary
tract infection caused by multiply resist-
ant gram-negative bacilli: epidemiology
and control. J Infect Dis, 1976. 133(3):
363–6.
31. Warren JW, Anthony WC, Hoopes JM,
and Muncie HL, Jr., Cephalexin for
susceptible bacteriuria in afebrile, long-
term catheterized patients. JAMA, 1982.
248(4): 454–8.
32. Bjork DT, Pelletier LL, and Tight RR,
Urinary tract infections with antibiotic
resistant organisms in catheterized nurs-
ing home patients. Infect Control, 1984.
5(4): 173–6.
33. Zimakoff JD, Pontoppidan B, Larsen SO,
Poulsen KB, and Stickler DJ, The man-
agement of urinary catheters: compliance
of practice in Danish hospitals, nursing
homes and home care to national guide-
lines. Scand J Urol Nephrol, 1995. 29(3):
299–309.
34. Ehrenkranz NJ and Alfonso BC, Failure
of bland soap handwash to prevent hand
transfer of patient bacteria to urethral
catheters. Infect Control Hosp Epidemiol,
1991. 12(11): 654–62.
35. Casewell M and Phillips I, Hands as route
of transmission for Klebsiella species.
Br Med J, 1977. 2(6098): 1315–7.
36. Kumon H, Management of biofilm infec-
tions in the urinary tract. World J Surg,
2000. 24(10): 1193–6.
37. Maki DG, Hennekens CG, Phillips CW,
Shaw WV, and Bennett JV, Nosocomial
urinary tract infection with Serratia
marcescens: an epidemiologic study.
J Infect Dis, 1973. 128(5): 579–87.
38. Harding GK, Nicolle LE, Ronald AR,
Preiksaitis JK, Forward KR, Low
DE, and Cheang M, How long should
catheter-acquired urinary tract infec-
tion in women be treated? A randomized
controlled study. Ann Intern Med, 1991.
114(9): 713–9.
39. Sedor J and Mulholland SG, Hospital-
acquired urinary tract infections associ-
ated with the indwelling catheter. Urol
Clin North Am, 1999. 26(4): 821–8.
539
Chapter |9| Device associated urinary tract infections
40. Tambyah PA and Maki DG, The rela-
tionship between pyuria and infection in
patients with indwelling urinary cath-
eters: a prospective study of 761 patients.
Arch Intern Med, 2000. 160(5): 673–7.
41. Steward DK, Wood GL, Cohen RL, Smith
JW, and Mackowiak PA, Failure of the
urinalysis and quantitative urine culture
in diagnosing symptomatic urinary tract
infections in patients with long-term
urinary catheters. Am J Infect Control,
1985. 13(4): 154–60.
42. Raz P, Urinary tract infection in elderly
women. Int J Antimicrob Agents, 1998.
10(3): 177–9.
43. Nicolle LE, The chronic indwelling catheter
and urinary infection in long-term-care
facility residents. Infect Control Hosp
Epidemiol, 2001. 22(5): 316–21.
44. Nicolle LE, Catheter-related urinary
tract infection. Drugs Aging, 2005. 22(8):
627–39.
45. Nicolle LE, A practical guide to antimi-
crobial management of complicated uri-
nary tract infection. Drugs Aging, 2001.
18(4): 243–54.
46. Peterson J, Kaul S, Khashab M, Fisher
AC, and Kahn JB, A double-blind, rand-
omized comparison of levofloxacin 750 mg
once-daily for five days with ciprofloxacin
400/500 mg twice-daily for 10 days for
the treatment of complicated urinary
540
tract infections and acute pyelonephritis.
Urology, 2008. 71(1): 17–22.
47. Peloquin CA, Cumbo TJ, and Schentag
JJ, Kinetics and dynamics of tobramy-
cin action in patients with bacteriuria
given single doses. Antimicrob Agents
Chemother, 1991. 35(6): 1191–5.
48. Sobel JD, Kauffman CA, McKinsey D,
Zervos M, Vazquez JA, Karchmer AW, Lee
J, Thomas C, Panzer H, and Dismukes
WE, Candiduria: a randomized, double-
blind study of treatment with fluconazole
and placebo. The National Institute of
Allergy and Infectious Diseases (NIAID)
Mycoses Study Group. Clin Infect Dis,
2000. 30(1): 19–24.
49. Jacobs LG, Skidmore EA, Freeman K,
Lipschultz D, and Fox N, Oral fluconazole
compared with bladder irrigation with
amphotericin B for treatment of fungal
urinary tract infections in elderly patients.
Clin Infect Dis, 1996. 22(1): 30–5.
50. Sobel JD and Lundstrom T, Management
of candiduria. Curr Urol Rep, 2001. 2(4):
321–5.
51. Jacobs LG, Fungal urinary tract infec-
tions in the elderly: treatment guidelines.
Drugs Aging, 1996. 8(2): 89–96.
52. Hamory BH and Wenzel RP, Hospital-
associated candiduria: predisposing fac-
tors and review of the literature. J Urol,
1978. 120(4): 444–8.
|9.4|
Evolution of catheter material for
prevention of catheter-associated
urinary tract infections
U-Syn Ha, Yong-Hyun Cho
Department of Urology, Catholic University of Korea, Medical College, Seoul, South Korea
Corresponding author: Yong-Hyun Cho, Department of Urology, Catholic University of Korea,
Medical College, Seoul, South Korea
Tel: 82-2-3779-1024, Fax: 82-2-761-1626, cyh0831@catholic.ac.kr
ABSTRACT
Nosocomial urinary tract infection is
the most common infection acquired in
both hospitals and nursing homes and is
usually associated with catheterization.
These catheter-associated urinary tract
infections (CAUTIs) have been reported
to increase the mortality rate and consid-
erable economic impact. Currently, there
are many types of catheters available,
which try to alter the catheter material
in order to inhibit CAUTIs. Many sub-
stances are being challenged for their
potential as catheter material or coat-
ings. There are still no trials and con-
sensus which provide sufficient evidence
to suggest whether or not any of the
standard catheters results in a decreased
rate of bacteriuria compared to another
standard catheter. However, among these
catheters, recently developed antiseptic
and antibiotic-coated catheters may pro-
vide promise for the control of CAUTIs.
Silver alloy coated catheter significantly
prevent asymptomatic bacteriuria in the
short-term (at both less and more than
one week of catheterization) catheter-
ized patient in comparison with standard
catheter. Antibiotic-impregnated cathe-
ters reduce the asymptomatic bacteriuria
in hospitalized adults who are catheter-
ized up to one week in comparison with
standard catheter. For more than one
week there was no significant effect.
There is no trial in comparison between
antiseptic impregnated catheters or
between antibiotic impregnated cathe-
ters. More basic research at the level of
pathogenesis and catheter substance is
needed to design novel strategies.
Key words: catheter material, catheter,
evolution, urinary tract infection
Chapter |9| Device associated urinary tract infections
SUMMARY OF RECOMMENDATIONS
1. There are still no trials and consen-
sus which provided sufficient evi-
dence to suggest whether or not any
of the standard catheters results in
a decreased rate of bacteriuria com-
pared to another standard catheter.
Therefore no recommendation con-
cerning any preference can be made
(GoR D).
2. Silver alloy coated catheter signifi-
cantly prevent asymptomatic bac-
teriuria in the short-term (at both
less and more than one week of cath-
eterization) catheterized patient in
comparison with standard catheter.
Therefore, this kind of catheter could
be useful, if short-term prevention of
asymptomatic bacteriuria is impor-
tant, e.g. before a urological interven-
tion (GoR C).
3. Antibiotic-impregnated catheters
reduce the asymptomatic bacte-
riuria in hospitalized adults who
are catheterized up to one week in
comparison with standard catheter.
For more than one week there was
no significant effect. Therefore, this
kind of catheter could be useful, if
short-term prevention of asympto-
matic bacteriuria is important, e.g.
before an urological intervention
(GoR C).
4. There is no trial in comparison
between antiseptic impregnated cathe-
ters or between antibiotic impregnated
catheters. Therefore, no recommen-
dation concerning preference can be
made (GoR D).
1. INTRODUCTION
Indwelling urinary catheters are of
varying design and material. The most
common standard catheters include poly-
vinyl chloride, latex, teflon and silicone.
Latex catheters are relatively cheap but
542
irritation and allergic reaction may occur
[1] (LoE 2a). Silicone catheters are more
biocompatible and obstruct less than
normal latex ones and therefore are bet-
ter choices for long-term usage. However
teflon- or silicone-coated latex catheters
in patients are prone to catheter encrus-
tation which is thick and condensed bio-
film, occluding the inner or outer surface
of the catheter [2–3] (LoE 2a). Polyvinyl
chloride is a strong material that often
composes the three-way catheters used
for bladder irrigation and wash-out. On
the other hand, there is not enough evi-
dence to define whether any standard
catheter was better than another in terms
of reducing the risk of UTI in adults hos-
pitalized short-term, although silicone
catheters may be less likely to cause ure-
thral side effects in men. There are still
no trials and consensus which provide
sufficient evidence to suggest whether or
not any of the standard catheters result
in a decreased rate of bacteriuria com-
pared to another standard catheters [4].
Many innovations have been tried in
clinical settings to prevent CAUTI. These
have included the use of antiseptic lubri-
cating gel at catheter insertion [5], the
use of a tape seal applied to the catheter
drainage tubing junction [6], anti-reflux
valves, anti-infective irrigation of the
bladder or instillation of antiseptics in
the collection bag [7–8]. However, com-
pared with the closed drainage system,
all of these have failed to show significant
benefits.
Biofilm formation on the urinary cath-
eter may play a key role in the pathogen-
esis of CAUTIs and in the resistance of
CAUTIs to management. Renewed inter-
est has therefore arisen in altering and
coating the catheter surface to inhibit
biofilm formation. A recent approach to
solve some of the problems associated
with CAUTI has been the application of
a range of different coatings to the sur-
face of the catheter. The results have
been varied but the problems remain
unsolved.
 Evolution of catheter material for prevention
2. METHODS
2.1 Systematic literature search
We surveyed the extensive literature
regarding the development and mate-
rial of catheter-associated UTIs. We sys-
tematically searched all randomized and
quasi-randomized controlled trials com-
paring types of indwelling urinary cath-
eters available in Medline via Pubmed by
giving preference to the Cochrane Central
Register of Controlled Trials and also con-
sidered other relevant publications until
October 2008. The search strategy used
terms: catheter, catheterization, urethra,
urinary tract, combined with the terms:
infection or bacteriuria. For the purpose
of this review a total of 111 possibly eligi-
ble publications were found, which were
screened by title and abstracts and finally
22 publications [9–30] were included into
the analysis. The limitations for this lit-
erature search were language problems
(among 22 trials, four eligible trials
[10, 23, 29–30] were not fully reviewed
because just only abstracts were written
in English). Short-term catheterization is
defined as catheter in place up to 14 days
and long-term was defined as more than
30 days. There were no eligible trials that
provided data concerning indwelling cath-
eters in place for 15–29 days.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [31–32].
2.2 Analysis
We compared the effect of the type of the
urinary catheter on the risk of urinary
tract infection in hospitalized adults as
follows:
1. Antiseptic impregnated urethral
catheters versus standard indwelling
urethral catheters;
2. Antibiotic impregnated urethral
catheters versus standard indwelling
urethral catheters;
| 9.4 |
3. Antibiotic impregnated urethral cath-
eters versus antiseptic impregnated
indwelling urethral catheters;
4. One type of antiseptic impregnated
urethral catheter versus another type
of antiseptic impregnated indwelling
urethral catheter;
5. One type of antibiotic urethral cath-
eter versus another type of antibiotic
impregnated urethral catheter.
3. ANTISEPTIC IMPREGNATED
URETHRAL CATHETERS VERSUS
STANDARD URETHRAL CATHETERS
There were two types of antiseptic cath-
eters compared with a standard catheter:
silver oxide and silver alloy.
3.1 Short-time catheterization
3.1.1 Silver oxide
Three trials compared silver oxide coated
catheters with a standard catheter [12,
21, 23].
Johnson et al reported that silver-coated
catheters reduced the incidence of UTI
only among women not receiving antimi-
crobial agents in a prospective clinical
trial involving 482 hospitalised patients
[12] (LoE 2a). In a clinical trial involving
1309 hospitalised patients, Riley et al. [21]
not only failed to demonstrate the efficacy
of silver-coated catheters in the prevention
of CAUTI, as suggested in prior studies,
but also showed a significantly increased
incidence of bacteriuria in male patients
(LoE 2a). This study found that silver-ox-
ide impregnated urinary catheters were
not effective in preventing CAUTI. Until
now, the use of more expensive silver-
coated catheters to prevent CAUTI has
not been supported by quality data, and
resistance to silver was likely to become a
problem with widespread use.
Pooling the results of all three tri-
als using a fixed effects model by The
543
Chapter |9| Device associated urinary tract infections
Cochrane Review did not provide enough
evidence to show whether or not there
was a reduction in risk of developing bac-
teriuria (Relative Risk (RR) 0.89, 95%
Confidence Interval (CI) 0.68 to 1.15) [4]
(LoE 1a). There was no statistically sig-
nificant difference in the number with
bacteriuria between groups.
3.1.2 Silver alloy
Six trials have compared silver alloy cath-
eters with a standard catheter [15–18,
25, 27, 33] (LoE 2a). All the trials defined
infection as bacteriuria greater than 105
CFU/ml. The timing of the outcome meas-
urement varied considerably between tri-
als so results were analyzed as outcomes
in two time periods (less than one week
and greater than one week). Pooling the
results of all three trials using a fixed
effects model by The Cochrane Review
indicated that at less than one week of
catheterization the risk of asymptomatic
bacteriuria was statistically significantly
reduced in the silver alloy group (RR
0.54, 95% CI 0.43 to 0.67) [4] (LoE 1a).
Beyond one week the estimated effect was
smaller but the risk of asymptomatic bac-
teriuria was still less in the silver alloy
group (RR 0.64, 95% CI 0.51 to 0.80). In
summary, these studies provide the evi-
dence that a catheter coated with silver
alloy significantly decreased the risk of
infection during short term period (within
two weeks). For those catheterized for
less than one week the estimated risk of
asymptomatic bacteriuria was at least a
half of that with a standard catheter.
3.2 Long-term catheterization
3.2.1 Silver oxide
No trials were found that addressed this
comparison.
3.2.2 Silver alloy
Only one very small trial, in which 12
participants were enrolled, compared a
type of silver alloyed Foley catheter with
544
a standard silicone coated catheter [29].
This trial defined infection as patients
with catheters in situ > 30 days had bac-
teriuria greater than 105 CFU/ml. There
were no significant differences between
the different types of catheters in terms
of urinary tract infections because all the
participants had UTIs.
4. ANTIBIOTIC IMPREGNATED
URETHRAL CATHETERS VERSUS
STANDARD URETHRAL CATHETERS
4.1 Short-term catheterization
Reid et al. [34] reported that pre-
treatment of urinary silicone latex
catheters in vitro with ciprofloxacin sig-
nificantly reduced the adhesion and sur-
vival of the clinical isolate Pseudomonas
aeruginosa. Results of these in vitro stud-
ies suggest that there could be a clinical
role for antibiotics in preventing CAUTI
associated with bacterial adherence to
prosthetic devices. Further research
has continued into the use of various
antibiotics, including gentamicin, nor-
floxacin, nitrofurazone and minocycline
with rifampicin for impregnated mate-
rial. Among these trials, there were two
types of antibiotic coated catheters exam-
ined by randomized controlled trials.
The trials for each were analysed in two
subgroups depending on the type of inter-
vention catheter and grouped into sepa-
rate outcomes dependent upon duration
of catheterisation.
4.1.1 Minocycline and rifampicin
There was only one trial (n=124) that
compared a minocycline and rifampicin
impregnated catheter with a standard
catheter [11]. Outcome measures included
bacteriuria (greater than 104 cfu/ml) at day
three, day seven and day 14, and sympto-
matic UTI (timing not stated) as defined
by the health care provider. Patients who
received the antimicrobial-impregnated
catheters had significantly lower rates of
 Evolution of catheter material for prevention
bacteriuria than those in the control group
both at day seven (15.2% versus 39.7%)
and at day 14 (58.5% versus 83.5%) after
catheter insertion. Patients who received
the antimicrobial-impregnated catheters
had significantly lower rates of gram-
positive bacteriuria than the control group
(7.1% versus 38.2%; P<0.001) but similar
rates of gram-negative bacteriuria (46.4%
versus 47.1%) and candiduria (3.6% ver-
sus 2.9%). Catheters impregnated with
minocycline and rifampin significantly
reduced the rate of gram-positive catheter-
associated bacteriuria up to two weeks.
4.1.2 Nitrofurazone
Three trials compared nitrofurazone-
impregnated catheters with standard
catheters [9, 14, 22]. Al Habdan used a
latex catheter as the standard catheter
whilst Lee and Stensballe both used sili-
cone catheters as the comparison.
All outcome measures included bacte-
riuria (defined as greater than 103 cfu/ml)
and, in one trial, associated funguria [22].
Lee et al reported that the inci-
dence rate of CAUTI was lower in the
nitrofurazone-coated catheter group
compared with the control group [14].
When the catheters were maintained
for >5 days but <7 days, the incidence
rate of CAUTI was statistically signifi-
cantly lower in the experimental group
compared with that in the control group.
Considering that the incidence rate of
CAUTI is very low within five days of
catheter insertion, provided the cath-
eter was inserted aseptically and a
closed drainage system was maintained
[35], this result is clinically important
since the effect of inhibiting CAUTI was
proven during the clinically important
period of CAUTI expression between
five and seven days of catheterization
[14]. In other study, 1190 urine cultures
were obtained over 1001 catheter-days.
Catheter-associated bacteriuria and fun-
guria occurred less frequently in the
nitrofurazone catheter group than in the
| 9.4 |
silicone catheter group (seven of 77 [9.1%]
vs. 19 of 77 [24.7%]; incidence per 1000
catheter-days, 13.8 vs. 38.6 (adjusted
risk 0.31, 95% CI 0.14 to 0.70). Onset of
CAUTI was also delayed in the nitrofura-
zone group and nitrofurazone catheters
led to fewer instances of new or changed
antimicrobial therapy (adjusted risk 0.27,
95% CI 0.10 to 0.69) [22].
Pooling the results of all three tri-
als using a fixed effects model by The
Cochrane Review indicated that at less
than one week of catheterisation the risk
of asymptomatic bacteriuria was statis-
tically significantly reduced in the nitro-
furazone impregnated catheter group (RR
0.52, 95% CI 0.34 to 0.78) [4]. As with
minocycline and rifampicin impregnated
catheters, at greater than one week the
benefit from nitrofurazone impregnated
catheters in preventing bacteriuria was
inconclusive, but the numbers were small
(RR 0.31, 95% CI 0.06 to 1.66).
In addition to above results, the
Cochrane Review reported the overall
effect for antibiotic impregnated cath-
eters (irrespective of antibiotic type)
compared to a standard control was a sig-
nificant reduction in the risk of asympto-
matic bacteriuria at less than one week of
catheterisation (RR 0.47, 95% CI 0.33 to
0.67). However, for more than one week,
there was no statistically significant dif-
ference in the incidence of asymptomatic
bacteriuria (RR 0.85 95% CI 0.76 to 0.96).
4.2 Long-term catheterization
No trials were found that addressed this
comparison.
5. ANTIBIOTIC IMPREGNATED
URETHRAL CATHETERS VERSUS
ANTISEPTIC IMPREGNATED
URETHRAL CATHETERS
No trials were found either for short- or
long-term catheterization that addressed
this comparison.
545
Chapter |9| Device associated urinary tract infections
6. ONE TYPE OF ANTISEPTIC
IMPREGNATED URETHRAL
CATHETER VERSUS ANOTHER TYPE
OF ANTISEPTIC IMPREGNATED
URETHRAL CATHETER
No trials were found either for short- or
long-term catheterization that addressed
this comparison.
7. ONE TYPE OF ANTIBIOTIC
IMPREGNATED URETHRAL
CATHETER VERSUS ANOTHER TYPE
OF ANTIBIOTIC IMPREGNATED
URETHRAL CATHETER
No trials were found either for short- or
long-term catheterization that addressed
this comparison.
8. FURTHER RESEARCH
Bacterial adherence and its colonializa-
tion on catheter surfaces as biofilm are
naturally occurring phenomena and bio-
film formation plays a key role in CAUTI.
Understanding the pathogenesis of bio-
film formation, which includes identify-
ing molecular targets of biofilm bacteria
as well as the urinary components that
take part in biofilm formation, may lead
to development of an ideal device surface
that resists CAUTI.
9. CONCLUSIONS
Numerous strategies have been tried to
reduce the incidence of CAUTI, but there
are only a few results which have proven
effective. Silver alloy coated catheter and
antibiotic-impregnated catheters could
prevent or delay the onset of CAUTI dur-
ing short-term catheterisation. This out-
come may implicate the possibility of
suppression of CAUTI. However, more
well-designed basic research at the level
of pathogenesis and catheter substance is
546
needed to produce ideal urinary catheters
for control of CAUTI.
REFERENCES
1. Platt R, Polk BF, Murdock B, and Rosner
B, Mortality associated with nosocomial
urinary-tract infection. N Engl J Med,
1982. 307(11): 637–42.
2. Sofer M and Denstedt JD, Encrustation
of biomaterials in the urinary tract. Curr
Opin Urol, 2000. 10(6): 563–9.
3. Schierholz JM, Konig DP, Beuth J, and
Pulverer G, The myth of encrustation
inhibiting materials. J Hosp Infect, 1999.
42(2): 162–3.
4. Schumm K and Lam TB, Types of ure-
thral catheters for management of short-
term voiding problems in hospitalised
adults. Cochrane Database Syst Rev,
2008(2): CD004013.
5. Schiotz HA, Antiseptic catheter gel and
urinary tract infection after short-term
postoperative catheterization in women.
Arch Gynecol Obstet, 1996. 258(2):
97–100.
6. Huth TS, Burke JP, Larsen RA, Classen
DC, and Stevens LE, Clinical trial of
junction seals for the prevention of
urinary catheter-associated bacteriuria.
Arch Intern Med, 1992. 152(4): 807–12.
7. Gillespie WA, Simpson RA, Jones JE,
Nashef L, Teasdale C, and Speller DC,
Does the addition of disinfectant to urine
drainage bags prevent infection in cath-
eterised patients? Lancet, 1983. 1(8332):
1037–9.
8. Thompson RL, Haley CE, Searcy MA,
Guenthner SM, Kaiser DL, Groschel DH,
Gillenwater JY, and Wenzel RP, Catheter-
associated bacteriuria. Failure to reduce
attack rates using periodic instillations of
a disinfectant into urinary drainage sys-
tems. JAMA, 1984. 251(6): 747–51.
9. Al-Habdan I, Sadat-Ali M, Corea JR,
Al-Othman A, Kamal BA, and Shriyan
DS, Assessment of nosocomial urinary
tract infections in orthopaedic patients: a
prospective and comparative study using
two different catheters. Int Surg, 2003.
88(3): 152–4.
 Evolution of catheter material for prevention
10. Chene G, Boulard G, and Gachie JP,
[A controlled trial of a new material for
coating urinary catheters]. Agressologie,
1990. 31(8 Spec No): 499–501.
11. Darouiche RO, Smith JA, Jr., Hanna H,
Dhabuwala CB, Steiner MS, Babaian
RJ, Boone TB, Scardino PT, Thornby JI,
and Raad, II, Efficacy of antimicrobial-
impregnated bladder catheters in reduc-
ing catheter-associated bacteriuria: a
prospective, randomized, multicenter
clinical trial. Urology, 1999. 54(6): 976–81.
12. Johnson JR, Roberts PL, Olsen RJ,
Moyer KA, and Stamm WE, Prevention of
catheter-associated urinary tract infection
with a silver oxide-coated urinary cath-
eter: clinical and microbiologic correlates.
J Infect Dis, 1990. 162(5): 1145–50.
13. Kalambaheti K, Siliconized Foley cath-
eters. Am J Surg, 1965. 110(6): 935–6.
14. Lee SJ, Kim SW, Cho YH, Shin WS, Lee
SE, Kim CS, Hong SJ, Chung BH, Kim
JJ, and Yoon MS, A comparative multi-
centre study on the incidence of catheter-
associated urinary tract infection between
nitrofurazone-coated and silicone cath-
eters. Int J Antimicrob Agents, 2004.
24 Suppl 1: S65–9.
15. Liedberg H and Lundeberg T, Silver
alloy coated catheters reduce catheter-
associated bacteriuria. Br J Urol, 1990.
65(4): 379–81.
16. Liedberg H, Lundeberg T, and Ekman P,
Refinements in the coating of urethral
catheters reduces the incidence of catheter-
associated bacteriuria. An experimental
and clinical study. Eur Urol, 1990. 17(3):
236–40.
17. Lundeberg T, Prevention of catheter-
associated urinary-tract infections by use
of silver-impregnated catheters. Lancet,
1986. 2(8514): 1031.
18. Maki DG, Knasinski V, Halvorson K,
and Tambyah PA, A novel silver-
hydrogel-impregnated indwelling urinary
catheter reduces CAUTIs: A prospective
double-blind trial. Infection Control &
Hospital Epidemiology 1998. 1992(19): 682.
19. Nacey JN, Tulloch AG, and Ferguson AF,
Catheter-induced urethritis: a comparison
between latex and silicone catheters in a
prospective clinical trial. Br J Urol, 1985.
57(3): 325–8.
| 9.4 |
20. Nickel JC, Feero P, Costerton JW, and
Wilson E, Incidence and importance of
bacteriuria in postoperative, short-term
urinary catheterization. Can J Surg, 1989.
32(2): 131–2.
21. Riley DK, Classen DC, Stevens LE, and
Burke JP, A large randomized clinical
trial of a silver-impregnated urinary cath-
eter: lack of efficacy and staphylococcal
superinfection. Am J Med, 1995. 98(4):
349–56.
22. Stensballe J, Tvede M, Looms D, Lippert
FK, Dahl B, Tonnesen E, and Rasmussen
LS, Infection risk with nitrofurazone-
impregnated urinary catheters in trauma
patients: a randomized trial. Ann Intern
Med, 2007. 147(5): 285–93.
23. Takeuchi H, Hida S, Yoshida O, and
Ueda T, [Clinical study on efficacy of a
Foley catheter coated with silver-protein
in prevention of urinary tract infections].
Hinyokika Kiyo, 1993. 39(3): 293–8.
24. Talja M, Korpela A, and Jarvi K,
Comparison of urethral reaction to full
silicone, hydrogen-coated and siliconised
latex catheters. Br J Urol, 1990. 66(6):
652–7.
25. Thibon P, Le Coutour X, Leroyer R, and
Fabry J, Randomized multi-centre trial of
the effects of a catheter coated with hydro-
gel and silver salts on the incidence of
hospital-acquired urinary tract infections.
J Hosp Infect, 2000. 45(2): 117–24.
26. Tidd MJ, Gow JG, Pennington JH,
Shelton J, and Scott MR, Comparison
of hydrophilic polymer-coated latex,
uncoated latex and PVC indwelling
balloon catheters in the prevention of
urinary infection. Br J Urol, 1976. 48(4):
285–91.
27. Verleyen P, De Ridder D, Van Poppel H,
and Baert L, Clinical application of the
Bardex IC Foley catheter. Eur Urol, 1999.
36(3): 240–6.
28. Bull E, Chilton CP, Gould CA, and Sutton
TM, Single-blind, randomised, parallel
group study of the Bard Biocath catheter
and a silicone elastomer coated catheter.
Br J Urol, 1991. 68(4): 394–9.
29. Nakada J, Kawahara M, Onodera S,
and Oishi Y, [Clinical study of Silver
Lubricath Foley catheter]. Hinyokika
Kiyo, 1996. 42(6): 433–8.
547
Chapter |9| Device associated urinary tract infections
30. Bergqvist D, Hedelin H, Stenstrom G,
and Stahl A, [Clinical evaluation of Foley
catheters]. Lakartidningen, 1979. 76(15):
1416–8.
31. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
32. Abrams P, Khoury S, and Grant A,
Evidence–based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
33. Karchmer TB, Giannetta ET, Muto CA,
Strain BA, and Farr BM, A randomized
548
crossover study of silver-coated urinary
catheters in hospitalized patients. Arch
Intern Med, 2000. 160(21): 3294–8.
34. Reid G, Sharma S, Advikolanu K, Tieszer
C, Martin RA, and Bruce AW, Effects of
ciprofloxacin, norfloxacin, and ofloxacin
on in vitro adhesion and survival of
Pseudomonas aeruginosa AK1 on urinary
catheters. Antimicrob Agents Chemother,
1994. 38(7): 1490–5.
35. Sedor J and Mulholland SG,
Hospital-acquired urinary tract infec-
tions associated with the indwelling
catheter. Urol Clin North Am, 1999. 26(4):
821–8.
|9.5|
Infections associated with the
artificial urinary sphincter
Alexander von Bargen1, Margit Fisch2
1
Department of Urology, Asklepios Hospital Harburg, Eißendorfer Pferdeweg 52, 21075 Hamburg, Germany
2
Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D – 20246 Hamburg, Germany
Corresponding author: Dr. med. Alexander von Bargen, M.B.A., Asklepios Hospital Harburg, Eißendorfer Pferdeweg 52,
21075 Hamburg, Germany, a.bargen@asklepios.com
ABSTRACT
The artificial urinary sphincter (AUS)
AMS 800 is still the most effective ther-
apy in patients with severe urinary stress
incontinence. Continence rates and satis-
faction of patients are high. Despite the
fact that the artificial sphincter is well
accepted by physicians and patients,
there are significant number of com-
plications and reoperations associated
with the device. A remarkable number of
infections – also known from other inter-
ventions using alloplastic material – are
noted with the AUS (up to 12%). To avoid
infections several important points have
to be considered. First, a strict antimicro-
biotic intra- and perioperative manage-
ment is needed. Furthermore, intensive
education of the patient but also physi-
cian involved in patients care is manda-
tory to prevent iatrogen damage of the
AUS subsequently leading to an infection
of the device. Additionally, a special
passport handed out to the patient gives
information on the device in emergency
situations. If an infection of the AUS
occurs, removal of all components of
the device is required. A systemic ther-
apy with a broad spectrum antibiotic
drug including the usual gram-positive
skin flora and the predominant patho-
gens of the urogenital tract should be
started immediately and frequent clini-
cal checks should be performed. In case
of simultaneous erosion into the urethra
a transurethral or suprapubic catheter is
essential to ensure an optimal healing of
the urethra. A reimplantation of an AUS
should not be performed before three
months after explantation.
Key words: Infection, arrosion, com-
plication, artificial sphincter, artificial
urinary sphincter, ams 800, prosthesis,
implant, urogenital
Chapter |9| Device associated urinary tract infections
SUMMARY OF RECOMMENDATIONS
1. To avoid the infection of an AUS a
strict antimicrobiotic intra- and periop-
erative management is needed (GoR B)
2. To prevent iatrogen damage of the
AUS an intensive education of
patients and physicians is important
(GoR B)
3. The patient should store a special
passport and x-rays of the device in the
purse in case of emergency (GoR C)
4. In case of infection of the AUS imme-
diate removal of all components of the
device is necessary (GoR B)
5. In case of simultaneous arrosion of the
urethra a transurethral or suprapubic
catheter is essential (GoR B)
6. A broad systemic antibiotic therapy
including the usual gram-positive
skin flora and the predominant patho-
gens of the urogenital tract must be
started immediately in case of infec-
tion (GoR B)
7. A reimplantation of an AUS should
not be performed within three months
after explantation (GoR C)
1. INTRODUCTION
Urinary stress incontinence is more com-
mon than expected. Besides medical prob-
lems it presents a severe social handicap,
which can lead to total social isolation of
the respective person [1].
In cases of severe urinary stress incon-
tinence or failure of less invasive thera-
peutic options the artificial urinary
sphincter (AUS) still represents the gold
standard especially in men. The main
indication in men is post-prostatectomy
incontinence. Postoperative urinary
incontinence affects 5–30% of patients
undergoing radical prostatectomy, with
a significant effect on their quality of life
[2]. Success rates related to social conti-
nence (range 61–96%) and to patient’s
550
satisfaction (more than 95%) are high.
Since the introduction of the narrow back
cuff in 1987, mechanical durability has
significantly improved. Nevertheless, a
significant number of complications can
occur [3]. A reoperation rate up to 35%
has been reported due to mechanical and
non-mechanical failure [4]. The typical
reason for mechanical failure is leakage
of one of the parts of the device, most
common leakage of the cuff. An impor-
tant non-mechanical reason is the atro-
phy of the urethral tissue below the cuff
which leads to recurrent incontinence.
Recurrent incontinence can have different
mechanical or non-mechanical reasons. A
rare but severe complication is the infec-
tion of the device. It is known from many
other alloplastic implants that the risk
of infection is high. Precautions must be
taken to keep the rate of infections low
and in case of an infection of the device
a strict management is necessary to pre-
vent further damage to the patient.
This guideline should help to avoid
infections of an artificial urinary sphinc-
ter and present a concept to handle this
complication if it occurs.
2. METHODS
A literature search was done by PubMed.
The time horizon was defined with 30
years, but the focus was laid on the last 15
years. The search was performed by using
the following key words in different com-
binations: infection, arrosion, complica-
tion, artificial sphincter, artificial urinary
sphincter, ams 800, prosthesis, implant.
Within the last 15 years more than 200
publications were identified which were
screened by the two authors by title and
abstract. Finally 22 publications were eval-
uated, but eight of them had to be excluded
because the infection of the device as a
special complication was not worked out
clearly enough in these studies.
The studies were rated according to the
level of evidence (LoE) and the grade of
 Infections associated with the artificial urinary sphincter
recommendation (GoR) using ICUD
standards (for details see Preface) [5–6].
Within the 14 relevant publications
there was however no prospective com-
parative study on this subject (LoE 1)
nor any level 2 studies. Most of the stud-
ies were level 3 studies (12 of 14 studies).
The remaining two studies are expert
opinions (LoE 4). Additionally the expe-
riences, results and studies of our own
department were included.
3. DEFINITION OF THE DISEASE
Infection of the device is a rare but severe
non-mechanical complication and is
defined as the bacterial colonisation of
the device. There are two main reasons
for an infection of an artificial sphincter.
During surgery bacterial contamination
may occur. Symptoms usually present
within the first days or weeks after
implantation. These infections may be
induced by atmospheric pathogens, unrec-
ognized urinary tract infections and skin
pathogens [3]. In rare cases an unnoticed
intraoperative arrosion of the urethra or
vagina is responsible for the infection of
the device. In contrast to this early infec-
tion late infection may occur. They are
mainly caused by iatrogenic manipula-
tion, for example traumatic catheteriza-
tion or surgery (e.g. internal urethrotomy,
herniotomy) in the area of the device. The
rate of infections ranges between 2–12%
in the literature [3, 7–12]. However, com-
parability between all these studies is
limited because of different follow-up, dif-
ferent cuff locations, different number of
study attendees, different indications and
complexity of patient histories.
4. CLINICAL EVALUATION/RISK
ASSESSMENT
Clinical symptoms of infection are: scro-
tal, perineal or abdominal pain, reddening,
tumescence, dysuria, fever. Ultrasonography
| 9.5 |
may show accumulation of fluid around the
infected parts of the device. In severe cases
an abscess can be found. Blood leucocytes
and c-reactive protein can be elevated. In
the case of erosion a urethroscopy confirms
the diagnosis. A retrograde urethrogramm
may also be helpful.
Risk factors for a higher rate of infec-
tion are diabetes [13], a complex history
and irradiation [11, 14].
During any type of revisional sur-
gery with complete or partial change
of the device smears of the balloon, the
tubes, the cuff and the pump should be
taken. If the microbiologic investigation
reveals any bacterial contamination a
specific targeted antibiotic therapy is
initiated.
5. TREATMENT
To avoid the infection of an artificial
sphincter a strict antimicrobiotic periop-
erative management should be followed:
The clinical investigation should
exclude any infection of the skin e.g. myco-
sis. The urine culture must be sterile. One
day prior to surgery the patient himself
disinfects the area of the lower abdomen
and external genitalia with an antiseptic
spray. Parenteral broad spectrum antibi-
otic treatment is started one day before
the operation and continued until the fifth
postoperative day. Immediately before
surgery the lower abdomen and external
genitalia is washed for 10 minutes with
an antiseptic soap, followed by routine
disinfection. The components of the device
are stored in an antibiotic solution before
implantation (not required for coated
devices) (LoE 4, GoR B).
To avoid postoperative erosion with
subsequent infection, an intensive edu-
cation of patients and physicians is
important (LoE 4, GoR B). Furthermore
the patient has to be able to handle the
sphincter mechanism and should be
able to deactivate the system. He has to
be informed that the system has to be
551
Chapter |9| Device associated urinary tract infections
deactivated before any transurethral
manipulation (catheterisation, urethros-
copy) is performed. For emergencies a
special passport with x-rays of the device
filled with contrast medium is handed
over to the patient. Patient should carry
this passport all the time with him
(LoE 4, GoR C).
If erosion or infection occurs immediate
removal of all components of the device is
required (LoE 3, GoR B). Reimplantation
should be performed at a later stage
[3–4], preferably after three months
(LoE 4, GoR C). During explantation, rec-
ommendations for septic surgery must
be followed. Antibiotic lavage, wound
debridement, sufficient drainage of the
whole area and keeping the wound open
may be indicated. In patients with ero-
sion of the device into the urethra urinary
diversion with suprapubic cystostomy
or transurethral catheter is required [4]
(LoE 3, GoR B). Time of urinary diversion
depends on the extent of the defect and
should be continued for a minimum of two
weeks. Before voiding is initiated com-
plete closure of the defect should be docu-
mented by voiding cystogram.
When infection is suspected or con-
firmed, systemic antibiotic therapy must
be started immediately. As the pathogenic
organism initially is unknown, antibiotic
drugs given should be effective against
the usual Gram-positive skin flora but
also against the typical predominant
organisms of the urogenital tract (LoE
3, GoR B). Bryan et. al [15] described
these two origins of bacteria for infec-
tions found during salvage procedures
for non eroded artificial urinary sphinc-
ters. An older study on periprosthetic
infections [13] investigated the respon-
sible agents for infections in 15 artificial
urinary sphincters and inflatable penile
prostheses out of a total of 556 implanta-
tions. Eight patients had infections with
Gram-positive organisms (five S. epider-
midis, one S. aureus, one Staphylococcus
species, one Enterococcus species) and
three had Gram-negative infections
552
(one Klebsiella, one Enterobacter, one
Pseudomonas species). Cultures of the
periprosthetic fluid were not available
in two patients and they were sterile in
two patients. These data support the
need for a broad antibiotic therapy if
the pathogen is unknown (e.g. a cepha-
losporin of the second or third generation
combined with gentamycin). The course
of healing is monitored by clinical exami-
nations, investigation of infection param-
eters in the blood and ultrasonography.
A reimplantation of the AUS should not
be performed within three months after
infection or erosion [16] (LoE 4, GoR C).
6. FURTHER RESEARCH
Attention should be paid to the reasons
for the large varieties of infections in dif-
ferent studies after the implantation of
an artificial urinary sphincter. For early
infections particularly, it could be possible
to detect the causes within the different
perioperative managements. Determining
and respecting the important parts of this
management should lead to a reduction
in the rate of infection.
Further technical developments in
antimicrobial surface coating will hope-
fully decrease the rate of infections.
7. CONCLUSIONS
Infections of the artificial urinary sphinc-
ter after implantation still occur in a
significant number, varying in different
studies. Early infections can be reduced
by strictly following a broad antimicro-
bial protocol. Late infections after sev-
eral months or years are mostly caused
by iatrogenic manipulation. Intensive
education of all participants is impor-
tant to avoid these complications. In
the case of an infection, an immediate
explantation of the system is necessary.
A re-implantation is possible with a time
interval of several months.
 Infections associated with the artificial urinary sphincter
REFERENCES
1. Welz-Barth A, [Incontinence in old age: a
social and economic problem]. Urologe A,
2007. 46(4): 363–4, 366–7.
2. Peyromaure M, Ravery V, and Boccon-
Gibod L, The management of stress
urinary incontinence after radical
prostatectomy. BJU Int, 2002. 90(2):
155–61.
3. Hussain M, Greenwell TJ, Venn SN, and
Mundy AR, The current role of the artifi-
cial urinary sphincter for the treatment
of urinary incontinence. J Urol, 2005.
174(2): 418–24.
4. Raj GV, Peterson AC, and Webster GD,
Outcomes following erosions of the arti-
ficial urinary sphincter. J Urol, 2006.
175(6): 2186–90; discussion 2190.
5. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
6. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
7. Raj GV, Peterson AC, Toh KL, and
Webster GD, Outcomes following revi-
sions and secondary implantation of the
artificial urinary sphincter. J Urol, 2005.
173(4): 1242–5.
8. Guralnick ML, Miller E, Toh KL, and
Webster GD, Transcorporal artificial
urinary sphincter cuff placement in cases
requiring revision for erosion and urethral
| 9.5 |
atrophy. J Urol, 2002. 167(5): 2075–8;
discussion 2079.
9. Kowalczyk JJ, Spicer DL, and
Mulcahy JJ, Long-term experience with
the double-cuff AMS 800 artificial urinary
sphincter. Urology, 1996. 47(6): 895–7.
10. O’Connor RC, Gerber GS, Avila D, Chen
AA, and Bales GT, Comparison of out-
comes after single or DOUBLE-CUFF
artificial urinary sphincter insertion.
Urology, 2003. 62(4): 723–6.
11. Walsh IK, Williams SG, Mahendra V,
Nambirajan T, and Stone AR, Artificial
urinary sphincter implantation in the
irradiated patient: safety, efficacy and
satisfaction. BJU Int, 2002. 89(4): 364–8.
12. Dalkin BL, Wessells H, and Cui H, A
national survey of urinary and health
related quality of life outcomes in men
with an artificial urinary sphincter for
post-radical prostatectomy incontinence.
J Urol, 2003. 169(1): 237–9.
13. Montague DK, Periprosthetic infections.
J Urol, 1987. 138(1): 68–9.
14. Gomha MA and Boone TB, Artificial
urinary sphincter for post-prostatectomy
incontinence in men who had prior radio-
therapy: a risk and outcome analysis.
J Urol, 2002. 167(2 Pt 1): 591–6.
15. Bryan DE, Mulcahy JJ, and Simmons
GR, Salvage procedure for infected non-
eroded artificial urinary sphincters.
J Urol, 2002. 168(6): 2464–6.
16. Webster GD and Sherman ND,
Management of male incontinence follow-
ing artificial urinary sphincter failure.
Curr Opin Urol, 2005. 15(6): 386–90.
553
|9.6|
Infections associated with
penile prostheses
Bela Koves, Peter Tenke, Karoly Nagy
Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest, Hungary
Corresponding author: Bela Koves, MD, Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest,
Hungary, bkoves@gmail.com
ABSTRACT
Inflatable penile prostheses have been
available since the 1970s. Designs revi-
sions and engineering changes have
reduced the mechanical malfunctions
associated with these prostheses to less
than 5%. As penile prostheses are now
expected to function for an average of
eight to 12 years post implantation, infec-
tion has become a more significant prob-
lem. The majority of prosthesis infections
occur secondary to bacterial seeding at
the time of surgery, Staphylococcus spe-
cies, especially Staphylococcus epider-
midis are the most common pathogens
found in penile prostheses infection.
Known risk factors are urinary tract
infection, infections elsewhere in the body
and hematogenous spread. The role of
diabetes mellitus and spinal chord injury
as risk factors of penile prosthesis infec-
tion are contradictory. Because in most
cases bacterial contamination occurs at
the time of surgery, it is essential to use
appropriate preoperative preparations.
Antibiotics should be administered one
to two hours prior to surgery and con-
tinued for 36–48 hours postoperative. To
decrease the infectious complications of
penile prosthesis implantations, the use
of antibiotic impregnated penile pros-
theses can be recommended. Although
preliminary data using hydrophilic coat-
ing device shows promise, long-term fol-
low-up and prospective studies are not
yet available, therefore no recommenda-
tion can be made. In case of subclinical
infection initial trial of oral antibiotic
therapy using long-term antibiotics can
be recommended. If pain fails to resolve
or rapidly returns after antibiotics, sur-
gical intervention is appropriate. In case
of clinically apparent infection surgical
intervention along with antibiotics is of
critical importance. The traditional treat-
ment is the immediate removal of all the
components followed by delayed reim-
plantation two to 12 months later. To
avoid complications of late reinsertion the
 Infections associated with penile prostheses
salvage protocol is a treatment alterna-
tive of traditional delayed reimplantation.
In patients with life-threatening systemic
conditions such as septicemia, or dia-
betic ketoacidosis, or in whom necrotizing
infections of penile skin is occurring sal-
vage procedure is not recommended.
Key words: penile prosthesis, infection,
complication, antibiotic impregnation,
salvage
SUMMARY OF RECOMMENDATIONS
Prevention
1. Washing the genital region with
strong soap in the days before the
procedure, preoperative shaving and
an aggressive scrub of the operat-
ing area with povidone-iodine in the
operating room should be performed
(GoR C).
2. Prophylactic antibiotics should be
administered 1–2 hours prior to sur-
gery and continued for 36–48 hours
postoperative (GoR B)
3. To decrease the infectious com-
plications of penile prosthesis
implantations the use of antibiotic
impregnated penile prostheses can be
recommended (GoR A)
4. Although preliminary data using
hydrophilic coating device shows
promise, long-term follow-up and
prospective studies are not yet avail-
able, therefore no recommendation
can be made (GoR D)
Treatment
5. In case of subclinical infection initial
trial of oral antibiotic therapy using
long-term antibiotics (ciprofloxacin
500mg twice daily) can be recom-
mended. Following initiation of
antibiotics, pain suppression should
suggest continuing antibiotics for
10–12 weeks (GoR C).
| 9.6 |
6. If pain fails to resolve or rapidly
returns after antibiotics, surgical
intervention is appropriate (GoR A).
7. In case of clinically apparent infec-
tion surgical intervention along with
antibiotics is of critical importance
(GoR A).
8. To avoid complications of late rein-
sertion the salvage protocol is a
treatment alternative of traditional
delayed reimplantation (GoR B).
9. In patients with life-threatening sys-
temic conditions such as septicemia,
or diabetic ketoacidosis, or in whom
necrotizing infections of penile skin
is occurring salvage procedure is not
recommended (GoR B).
10. There is no significant benefit of
delayed salvage procedure compared
to immediate salvage protocol, there-
fore it is not recommended (GoR B).
1. INTRODUCTION
Phosphodiesterase type 5 (PDE-5)
inhibitors have achieved widespread
acceptance in the treatment of erectile
dysfunction. However, penile implants
are still a popular choice, especially in
patients who have failed to successfully
achieve erections by chemical enhance-
ment or in those who have considerable
scar tissue in the penis resulting in erec-
tion deformalities [1].
The types of prosthesis most commonly
implanted are the three-piece inflatable
device, the two-piece inflatable device,
and the soft and malleable prosthesis. In
the last few years the three-piece inflat-
able device has been used for prefer-
ence, as it improves the erection with the
most acceptable cosmetic and functional
results [2–3].
Inflatable penis prostheses have been
available since the 1970s. Designs revi-
sions and engineering changes have
reduced the mechanical malfunctions
555
Chapter |9| Device associated urinary tract infections
associated with these prostheses to less
than 5% [4–5]. As penile prostheses are
now expected to function for an average
of eight to 12 years post implantation,
infection has become a more significant
problem. The incidence of infection has
been reported to range from 0.5–17.7%
[6–7] usually about 1–3% in case of pri-
mary implantation, and about 10–13% in
case of revision or reimplantation [8].
Penile prosthesis infection is tradition-
ally treated by systematic and local anti-
biotics application with the removal of
the device followed by reinsertion within
two to 12 months. However, removal of
the device along with inflammation from
the infectious process leads to corpo-
real fibrosis and scarring, which almost
always results in penile shortening and
may make dilation of the corporeal bod-
ies very difficult, resulting reinsertion of
a new device more complicated and some-
times impossible [1, 9].
To reduce the risk of device associ-
ated infections and to avoid the difficul-
ties associated with late reinsertions
many modifications have been developed
such as antibiotic or hydrophilic coated
devices and immediate replacement of the
infected prosthesis (salvage techniques).
The aim of this chapter is to summa-
rize the different methods of preven-
tion and treatment of penile prosthesis
infections.
2. METHODS
We surveyed the extensive literature
regarding the prevention and treatment
of penile prosthesis infections. We sys-
tematically searched for meta-analyses
of randomised controlled trials available
in Medline by giving preference to the
Cochrane Central Register of Controlled
Trials and also considered other rel-
evant publications until February
2009. Studies were identified through
a PubMed search. The search was per-
formed by using the following items in
556
different combinations: penile prosthesis,
infection, complication, bacteriuria, coat-
ing, salvage. The identified publications
were screened by title and abstract,
after exclusion of duplicates a total of
33 publications were included into the
analysis. The studies were rated accord-
ing to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[10–11].
3. PATHOGENESIS/EPIDEMIOLOGY
Staphylococcus species, especially
Staphylococcus epidermidis are the most
common pathogens found in penile pros-
theses infection, isolated from 35–56% of
infected penile prostheses patients [12].
Gram-negative enteric bacteria including
Proteus mirabilis, Pseudomonas aerugi-
nosa, Escherichia coli and Serratia mar-
censes may also be pathogens, accounting
for 20% of infections [8]. In severe infec-
tions Gram-negative bacteria can com-
bine with anaerobic organisms, such
as Bacteroides species, and lead to gan-
grene of the penis. Fungi, mycobacteria
and Neisseria gonorrhea have also been
reported as etiological agents in penile
prosthesis infections [8, 13].
The majority of prosthesis infections
occur secondary to bacterial seeding at
the time of surgery. Prosthetic materials
attract bacteria and support subsequent
biofilm formation. In a multicenter study
culture positive bacteria were found in
70% of patients with clinically uninfected
penile prostheses during revision surgery
for mechanical malfunction, with 90%
growing Saphylococcus species [14], which
have an enhanced ability to produce gly-
cocalyx biofilm.
Penile prosthesis infections can be
divided into clinically apparent and sub-
clinical infections. Most of the infections
occur within the first 12 months follow-
ing implantation [15]. Clinical infec-
tions present with fever, penile pain,
 Infections associated with penile prostheses
erythema, induration, purulent drain-
age from the wound and extrusion while
subclinical infections most often mani-
fest by chronic prosthesis-associated
pain.
4. RISK FACTORS
Known risk factors for penile prosthesis
infection include urinary tract infection,
infections elsewhere in the body and
hematogenous spread [16–17] (LoE 3).
There is an increased incidence of infec-
tion among patients undergoing primary
implantation with penile reconstruction
or secondary prosthesis revision com-
pared to primary implantation alone,
probably due to the increased dura-
tion of surgery [7, 18] (LoE 3). The role
of diabetes mellitus and spinal chord
injury as risk factors of penile prosthe-
sis infection are contradictory [18–19]
(LoE 3).
5. PREVENTION
5.1 General aspects
Because in most cases bacterial contam-
ination occurs at the time of surgery, it
is essential to use appropriate preopera-
tive preparations. Short preoperative
hospital stays have been documented to
maintain low virulence [12]. It is impor-
tant to eliminate skin infections and
to have sterile urine prior to surgery.
Washing the genital region with strong
soap in the days before the procedure,
preoperative shaving and an aggres-
sive scrub of the operating area with
povidone-iodine in the operating room
should be performed [1, 20] (LoE 3–4,
GoR C).
During surgery adequate sterile tech-
nique, short operating time, minimal tis-
sue devitalization along with effective
wound closure can all decrease the rate of
perioperative infections [21] (LoE 3–4).
| 9.6 |
5.2 Perioperative antibiotic
prophylaxis
Athough the effectiveness of prophylactic
perioperative antibiotics for implanta-
tion of penile prosthesis has never been
proven in prospective series their use
has become established and favored by
most urologists. Antibiotics should be
administered one to two hours prior to
surgery and continued for 36–48 hours
postoperative (LoE 3, GoR B). Most com-
mon pathogenic organisms most likely
to produce infections must be targeted
when choosing prophylactic antibiotics.
Therefore traditional prophylaxis include
a parenteral aminoglycoside for Gram-
negative and a first- or second generation
cephalosporin or vancomycin for Gram-
positive organisms coverage [22–23].
Schwarz et al found in a randomized
prospective trial of 20 patients that oral
fluoroquinolone (ofloxacin) administered
2 hours before surgery achieved signifi-
cantly higher intracavernosal levels and
was more cost-effective than the combi-
nation of gentamicin and cefazolin [22]
(LoE 1a). To estimate the safety and effi-
cacy of this prophylaxis modality, further
studies with similar settings, but bigger
sample size should be performed.
5.3 Antibiotic impregnation
Early efforts in device impregnation
focused on coating catheters with anti-
biotics. In 1995 Raad et al reported that
in in vitro studies catheters coated with
a combination of rifampin and minocy-
cline provided significantly better inhibi-
tory activities against S. epidermidis,
S. aureus and E. faecalis than catheters
coated with either drug alone or vanco-
mycin [24]. After additional in vitro and
in vivo studies in 2001 the US Food and
Drug Administration approved the use of
penile prosthesis coated with a combina-
tion of rifampin and minocycline called
InhibiZone. The concentrations of the
antibiotics, while adequate for decreas-
ing colonization, provided only minimal
557
Chapter |9| Device associated urinary tract infections
serum levels of the agents [5]. Coated
inflatable penile prostheses are implanted
in a fashion similar to those without anti-
biotic treatment except that the devices
are not soaked prior to implantation [5].
In a retrospective study of more than
4,000 prostheses, Carson et al reported
61.7% decrease in perioperative infection
with InhibiZone compared to controls [25]
(LoE 3). In 2007 Wilson et al. began a
prospective randomized study comparing
the infection rate of rifampin and mino-
cycline coated implants with implants
without impregnation [26] (LoE 1b). After
it became evident that the infection rate
was less with the impregnated group
they abandoned the other arm because of
ethical considerations and compared they
results with the previously published
series of the same surgical team with
noncoated implants [6, 27]. The use of
antibiotic coated inflatable penile prosthe-
sis resulted in a statistically significant
reduction in the infection rates compared
with the historical data in nondiabetic
virgin implant patients (p=0,0024), dia-
betic virgin implant patients (p=0,0141)
and in revision patients in whom wash-
out with antiseptic solutions was used
(p= 0,0095). Revision without washout
had the same infection rate (10%) as
with noncoated implants. To decrease the
infectious complications of penile pros-
thesis implantations the use of antibiotic
impregnated penile prostheses can be rec-
ommended (GoR A).
5.4 Hydrophilic coating
In 2002 a hydrophilic penile prosthesis
coating was developed which has been
shown to decrease bacterial adherence in
vitro and in animal models [28]. Further,
this coating absorbs surgeon chosen
intraoperative antibiotics that can elute
into surrounding tissues over 24–72 h to
further decrease infection [29] (LoE 2b).
Clinical data on the hydrophilic coated
inflatable penile prosthesis is limited.
Wolter et al. presented their one-year
558
experience with the device [30], the infec-
tion rate for 2357 coated penile prosthe-
ses was 1,06 % compared to 2,07 % in 482
uncoated penile prostheses implanted
over the same time period (LoE 3).
Although preliminary data using this
device shows promise, long-term fol-
low-up and prospective studies are not
yet available; therefore no recommenda-
tion can be made (GoR D).
6. TREATMENT
Subclinical infections may be more com-
mon than clinically apparent infections
[31]. These infection which most often
manifest by chronic prosthesis-associated
pain, are difficult to diagnose and even
more challenging to treat. Parsons et al.
recommend initial trial of oral antibiotic
therapy using long-term antibiotics (cip-
rofloxacin 500mg twice daily) [31] (LoE
4, GoR C). Following initiation of antibi-
otics, pain suppression should suggest
continuing antibiotics for 10–12 weeks.
The authors reported a 60% success rate
with conservative treatment of subclini-
cal penile prosthesis infections. The use
of oral cephalosporins (cefalexin and
cephradine) has also been suggested for
10–12 weeks, although success rates are
lower at 25–30% [12, 32] (LoE 4). If pain
fails to resolve or rapidly returns after
antibiotics, however, surgical interven-
tion is appropriate (GoR A). Parsons et al.
have reported 90% success rate in treat-
ing these prostheses with an exchange
protocol including systemic antibiotics for
24–48 h using vancomycin. The suspected
infected prosthesis is then removed and
a combination of vancomycin and pro-
tamine was used for antibiotic irrigation
prior to reimplantation of a new prosthe-
sis. Patients are maintained on vancomy-
cin and parental antibiotics for one week
[12, 31].
In case of clinically apparent infection
surgical intervention along with antibiot-
ics is of critical importance (GoR A). The
 Infections associated with penile prostheses
traditional treatment is the immediate
removal of all the components followed by
delayed reimplantation 2–12 months later
[20, 33]. The advantage of this solution is
that the new implant is scheduled only
when the infection has completely cleared.
However, removal of the device along with
inflammation from the infectious process
leads to corporeal fibrosis and scarring,
which almost always results in penile
shortening and may make dilation of the
corporeal bodies very difficult, resulting
reinsertion of a new device more compli-
cated and sometimes impossible [1, 9].
To avoid difficult reinsertion and main-
tain as much penile length as possible, a
salvage protocol was instituted in 1991.
The salvage procedure involves remov-
ing all parts of the infected prosthesis,
washing the wound, and replacing the
device at the same procedure. Mulcahy
et al. recommend a sequence of irrigating
solutions including kanamycin (80 mg/l)
and bacitracin (1 g/l) in normal saline
followed by half-strength hydrogen per-
oxide, half-strength povidone/iodine solu-
tion, 5 l of pressurized normal saline
containing vancomycin (1 g) and gen-
tamicin (80 mg), half-strength povidone/
iodine, half-strength hydrogen peroxide,
and finally another kanamycin/bacitracin
solution [34]. Gloves, instruments, gowns,
and drapes are changed and a new inflat-
able penile prosthesis is immediately
implanted. Postoperatively, patients are
treated with antibiotics (2×500 mg cipro-
floxacin) for 4–6 weeks. Antibiotics can be
modified based on culture and sensitiv-
ity results. The reported success rate of
the salvage procedure is 84–91% [9, 33]
(LoE 3). To avoid complications of late
reinsertion the salvage protocol is a treat-
ment alternative of traditional delayed
reimplantation (GoR B).
In patients with life-threatening sys-
temic conditions such as septicemia, or
diabetic ketoacidosis, or in whom necro-
tizing infections with death of penile skin
is occurring salvage procedure is not rec-
ommended [1, 9] (LoE 4, GoR B).
| 9.6 |
The delayed salvage procedure con-
sists of placement of a drainage tube after
removal of the prosthesis; antibiotic solu-
tion is irrigated through the drain and a
new prosthesis is placed about 3 days later.
In a retrospective review of 41 patients
reported by Knoll there was no statistically
significant difference between immediate
and delayed salvage procedure [35] (LoE 3),
therefore it is not recommended (GoR B).
7. FURTHER RESEARCH
Prospective studies and long-term follow
up are needed to make stronger recom-
mendations about the different methods
in the prevention or treatment of penile
prostheses infections, especially about the
hydrophilic coated penile prosthesis.
8. CONCLUSIONS
The efforts to apply more effective meth-
ods of prevention and the new develop-
ments of prosthesis coatings resulted a
significant reduction of the infectious
complications of penile prosthesis implan-
tation. Further improvements of surgical
procedures and prosthesis materials and
coatings can lead to further decrease of
the infection rates in the future.
REFERENCES
1. Mulcahy JJ, Management of the infected
penile implant – concepts on salvage tech-
niques. Int J Impot Res, 1999. 11 Suppl
1: S58–9.
2. Bettocchi C, Ditonno P, Palumbo F,
Lucarelli G, Garaffa G, Giammusso B,
and Battaglia M, Penile Prosthesis: What
Should We Do about Complications? Adv
Urol, 2008: 573560.
3. Minervini A, Ralph DJ, and Pryor JP,
Outcome of penile prosthesis implantation
for treating erectile dysfunction: experi-
ence with 504 procedures. BJU Int, 2006.
97(1): 129–33.
559
Chapter |9| Device associated urinary tract infections
4. Carson CC, Mulcahy JJ, and Govier FE,
Efficacy, safety and patient satisfaction
outcomes of the AMS 700CX inflatable
penile prosthesis: results of a long-term
multicenter study. AMS 700CX Study
Group. J Urol, 2000. 164(2): 376–80.
5. Carson C, Antibiotic impregnation of
inflatable penile prostheses: effect on
perioperative infection. Expert Rev Med
Devices, 2004. 1(2): 165–7.
6. Wilson SK and Delk JR, 2nd, Inflatable
penile implant infection: predisposing
factors and treatment suggestions. J Urol,
1995. 153(3 Pt 1): 659–61.
7. Quesada ET and Light JK, The AMS 700
inflatable penile prosthesis: long-term
experience with the controlled expansion
cylinders. J Urol, 1993. 149(1): 46–8.
8. Abouassaly R, Montague DK, and
Angermeier KW, Antibiotic-coated medi-
cal devices: with an emphasis on inflat-
able penile prosthesis. Asian J Androl,
2004. 6(3): 249–57.
9. Brant MD, Ludlow JK, and Mulcahy JJ,
The prosthesis salvage operation: immedi-
ate replacement of the infected penile pros-
thesis. J Urol, 1996. 155(1): 155–7.
10. US Department of Health and Human
Services, Public Health Service, Agency
for Health Care Policy and Research.
1992: pp. 115–127.
11. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
12. Carson CC, Diagnosis, treatment and
prevention of penile prosthesis infec-
tion. Int J Impot Res, 2003. 15 Suppl 5:
S139–46.
13. Carson CC, Infections in genitourinary
prostheses. Urol Clin North Am, 1989.
16(1): 139–47.
14. Henry GD, Wilson SK, Delk JR, 2nd,
Carson CC, Silverstein A, Cleves MA, and
Donatucci CF, Penile prosthesis cultures
during revision surgery: a multicenter
study. J Urol, 2004. 172(1): 153–6.
15. Silverstein A and Donatucci CF, Bacterial
biofilms and implantable prosthetic
devices. Int J Impot Res, 2003.
15 Suppl 5: S150–4.
560
16. Carson CC and Robertson CN, Late
hematogenous infection of penile prosthe-
ses. J Urol, 1988. 139(1): 50–2.
17. Little JW and Rhodus NL, The need for
antibiotic prophylaxis of patients with
penile implants during invasive dental
procedures: a national survey of urolo-
gists. J Urol, 1992. 148(6): 1801–4.
18. Jarow JP, Risk factors for penile pros-
thetic infection. J Urol, 1996. 156(2 Pt 1):
402–4.
19. Cakan M, Demirel F, Karabacak O,
Yalcinkaya F, and Altug U, Risk factors
for penile prosthetic infection. Int Urol
Nephrol, 2003. 35(2): 209–13.
20. Gomelsky A and Dmochowski RR,
Antibiotic prophylaxis in urologic pros-
thetic surgery. Curr Pharm Des, 2003.
9(12): 989–96.
21. Scott FB, Prosthetic infections. J Urol,
1987. 138(1): 113.
22. Schwartz BF, Swanzy S, and Thrasher
JB, A randomized prospective comparison
of antibiotic tissue levels in the corpora
cavernosa of patients undergoing penile
prosthesis implantation using gentamicin
plus cefazolin versus an oral fluoroqui-
nolone for prophylaxis. J Urol, 1996.
156(3): 991–4.
23. Naber KG, Hofstetter AG, Bruhl P,
Bichler K, and Lebert C, Guidelines for
the perioperative prophylaxis in urologi-
cal interventions of the urinary and male
genital tract. Int J Antimicrob Agents,
2001. 17(4): 321–6.
24. Raad I, Darouiche R, Hachem R,
Sacilowski M, and Bodey GP, Antibiotics
and prevention of microbial coloniza-
tion of catheters. Antimicrob Agents
Chemother, 1995. 39(11): 2397–400.
25. Carson CC, 3rd, Efficacy of antibiotic
impregnation of inflatable penile
prostheses in decreasing infection in
original implants. J Urol, 2004. 171(4):
1611–4.
26. Wilson SK, Zumbe J, Henry GD, Salem
EA, Delk JR, and Cleves MA, Infection
reduction using antibiotic-coated inflata-
ble penile prosthesis. Urology, 2007. 70(2):
337–40.
27. Wilson SK, Carson CC, Cleves MA, and
Delk JR, 2nd, Quantifying risk of penile
 Infections associated with penile prostheses
prosthesis infection with elevated glyco-
sylated hemoglobin. J Urol, 1998. 159(5):
1537–9; discussion 1539–40.
28. Rajpurkar A, Fairfax M, Li H, and
Dhabuwala CB, Antibiotic soaked
hydrophilic coated bioflex: a new strat-
egy in the prevention of penile prosthesis
infection. J Sex Med, 2004. 1(2): 215–20.
29. Hellstrom WJ, Hyun JS, Human L,
Sanabria JA, Bivalacqua TJ, and
Leungwattanakij S, Antimicrobial activ-
ity of antibiotic-soaked, Resist-coated
Bioflex. Int J Impot Res, 2003. 15(1):
18–21.
30. Wolter CE and Hellstrom WJ, The
hydrophilic-coated inflatable penile pros-
thesis: 1-year experience. J Sex Med, 2004.
1(2): 221–4.
| 9.6 |
31. Parsons CL, Stein PC, Dobke MK,
Virden CP, and Frank DH, Diagnosis and
therapy of subclinically infected prosthe-
ses. Surg Gynecol Obstet, 1993. 177(5):
504–6.
32. Choong S and Whitfield H, Biofilms and
their role in infections in urology. BJU
Int., 2000. 86((8)): 935–41.
33. Mulcahy JJ, Treatment alternatives for
the infected penile implant. Int J Impot
Res, 2003. 15 Suppl 5: S147–9.
34. Mulcahy JJ, Brant MD, and Ludlow JK,
Management of infected penile implants.
Tech Urol, 1995. 1(3): 115–9.
35. Knoll LD, Penile prosthetic infection:
management by delayed and immediate
salvage techniques. Urology, 1998. 52(2):
287–90.
561
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 Chapter |10|

Healthcare associated
urinary tract infections
Chair: Truls E. Bjerklund Johansen

CHAPTER OUTLINE
10.1 Introduction 564
10.2 Criteria for health care associated urinary tract
infections: an update on current definitions 567
10.3 Epidemiology, treatment and prevention of
healthcare-associated urinary tract infections 575
10.4 Urinary tract infections in long term care patients 589
|10.1|
Introduction
Truls E. Bjerklund Johansen
Urology Department of Urology, Århus University Hospital, Skejby, Aarhus University, Århus, Denmark
Corresponding author: Truls E. Bjerklund Johansen, MD, PhD, Chairman and Professor, Urology Department,
Århus University Hospital, Skejby, Aarhus University, Brendstrupgårdvej 100, DK-8200 Århus N, Denmark
Tel office: (45) 89 49 59 00, tebj@ki.au.dk
Without effective antimicrobial treatment
urinary tract infection (UTI) can create
big problems in urology. Without effective
antimicrobial prophylaxis most of mod-
ern urological surgery would be high risk
surgery. Even today with effective anti-
biotics available in most countries, the
prevalence of healthcare associated UTI
(HAUTI) in urology departments is on
average about 10% [1] and UTI accounts
for more than 40% of all health care asso-
ciated infections [2].
In this section several important
aspects are discussed:
1. Healthcare associated urinary tract
infection (HAUTI) means an infection
caused by a healthcare event, whether
during hospital admission, accommo-
dation in nursing homes or during an
outpatient visit. To diagnose HAUTI
there must be no evidence that the
infection was present or incubating
at the time of admission [3]. In case
of a negative culture and no sympto-
matic UTI at admission the situation
is clear. In asymptomatic bacteriuria
(ASB), and when patients cannot
communicate about symptoms, the
situation is more complex. Because of
outpatient procedures and sometimes
very short hospitalisation, observa-
tion time to define HAUTI (usually 48
hours in the past) has to be revisited
(see chapter 10.2).
2. There are very few situations when
screening for and treating ASB is evi-
dence based, such as in pregnancy and
before invasive urological procedures
[4]. In most other situations detection
of ASB may lead to administration
of antibiotics that are not indicated.
Considering ASB an infection creates
a dilemma when the prevalence of
HAUTI is used as a quality indica-
tor. For these reasons ASB should be
regarded as colonisation, probably as
a risk factor under certain circum-
stances, but no longer as an infection,
which unfortunately is not so clearly
stated in the CDC criteria [3].

3. In many developing countries there
is poor availability of antibiotics,
and in some regions even in Europe
today there are countries where
available antibiotics are no longer
effective. Modern urological surgery
has to rely on effective antimicro-
bial prophylaxis otherwise UTI
will become a severe problem. Most
HAUTIs are complicated infections,
although the group is not very homo-
geneous. Furthermore, HAUTIs are
frequently caused by other patho-
gens than those found in community
acquired UTI, and these pathogens
often show reduced antimicrobial
susceptilibility.
4. It is suggested that ASB should no
longer be recognised as infection but
only as a risk factor under certain
circumstances. Several years of regis-
tration of NAUTI and HAUTI in the
GPIU-studies have shown that ASB is
the most common type of UTI reported
(>30%) [5]. We also know that in
hospitals urinary pathogens are fre-
quently transferred between patients
[6]. ASB is thus still important, but
probably more as a source of informa-
tion about the bacterial environment
in urology departments and intensive
care units, than as a basis for treat-
ment. Monitoring ASB is probably
important for learning how to tailor
antimicrobial prophylaxis in each
urology department.
5. Because the prevalence of HAUTI
has become an important quality
parameter, hospitals and clinical
departments are often compared. The
prevalence of HAUTI depends on the
type of surgery, the hygienic meas-
ures and the antimicrobial prophy-
laxis. For this reason key urological
interventions should be established
for comparison and the prevalence
of HAUTI should be related to the
types of surgery being undertaken
in a department, the extent of
Introduction | 10.1 |
antimicrobial prophylaxis as well as
the number of blood and urine cul-
tures taken.
6. HAUTI should be prevented with
all measures available. Basic hygi-
enic and surgical principles must be
adhered to. Antimicrobial prophylaxis
can never compensate for poor surgi-
cal technique. Risk factors for HAUTI
must be analysed and avoided.
Urinary catheters are the most impor-
tant factor, and biofilm is a key issue
[7]. Antimicrobial treatment of HAUTI
in urology departments should be
based on close collaboration between
urologists, microbiologists and infec-
tious disease specialists as well as
knowledge on pharmacological proper-
ties of antibiotics.
Because of the importance especially
in urology an international prevalence
study on HAUTI in urology departments
has been run on an annual basis since
2003 by the European Association of
Urology/European Section on Infections
in Urology in collaboration with many
other national and international scientific
societies. This global prevalence study on
infection in urology (GPIU) is fully spon-
sored by EAU. A research group of more
than 100 hospitals is established. More
than 20 000 patients have been screened
and a database with detailed informa-
tion from more than 2000 patients with
HA-UTI has been built. An extensive
evaluation is ongoing.
REFERENCES
1. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
2. Gastmeier P, Kampf G, Wischnewski N,
Hauer T, Schulgen G, Schumacher M,
Daschner F, and Ruden H, Prevalence of
nosocomial infections in representative
565
Chapter | 10 | Healthcare associated urinary tract infections
German hospitals. J Hosp Infect, 1998.
38(1): 37–49.
3. Horan TC, Andrus M, and Dudeck MA,
CDC/NHSN surveillance definition of
health care-associated infection and cri-
teria for specific types of infections in the
acute care setting. Am J Infect Control,
2008. 36(5): 309–32.
4. Nicolle LE, Asymptomatic bacteriuria:
review and discussion of the IDSA guide-
lines. Int J Antimicrob Agents, 2006. 28
Suppl 1: S42–8.
5. Bjerklund-Johansen TE, Cek M, Naber KG,
Stratchounski L, Svenden MV, and
P T, Hospital acquired urinary tract infec-
tions in urology departments: pathogens,
susceptibility and use of antibiotics. Data
566
from PEP and PEAP-studies. Int J Antimicr
Agents, 2006. 28(Suppl): S91-S107.
6. Wagenlehner FM, Krcmery S, Held
C, Klare I, Witte W, Bauernfeind
A, Schneider I, and Naber KG,
Epidemiological analysis of the spread of
pathogens from a urological ward using
genotypic, phenotypic and clinical param-
eters. Int J Antimicrob Agents, 2002.
19(6): 583–91.
7. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008. 31
Suppl 1: S68–78.
|10.2|

Criteria for healthcare associated

urinary tract infections: an EAU/
ESIU update on current definitions
Truls E. Bjerklund Johansen1, Henry Botto2, Mete Cek3, Magnus Grabe4, Peter Tenke5, Florian M.E.
Wagenlehner6, Kurt G. Naber7
1
Urology Department of Urology, Århus University Hospital, Skejby, Århus University, Århus, Denmark
2
Department of Urology, Hopital Foch, Suresnes Cedex, France
3
Department of Urology, Taksim Teaching Hospital Istanbul, Istanbul, Turkey
4
Department of Urology, Malmö General Hospital, University of Lund, Malmö, Sweden
5
Department of Urology, Jahn Ference Del-Pesti Korhaz, Budapest, Hungary
6
Department of Urology, University of Giessen-Marburg, Giessen, Germany
7
Technical University of Munich, Munich, Germany
Corresponding Author: Truls E. Bjerklund Johansen, MD, PhD, Chairman and Professor, Urology Department,
Århus University Hospital, Skejby, Aarhus University, Brendstrupgårdvej 100, DK-8200 Århus N, Denmark
Tel office: (45) 89 49 59 00, tebj@ki.au.dk

ABSTRACT infections in urology, because the same

Healthcare associated infections (HAI)
have a high impact not only on the indi-
vidual patient but also on the total
healthcare system. Healthcare associated
urinary tract infections (HAUTI) are the
most frequent HAI in a general hospital.
The EAU/ESIU recommends in general
the CDC/NHSN criteria for HAI and espe-
cially HAUTI. However, the ESIU has
adapted and modified the CDC/NHSN
criteria for special usage in urology and
especially when urologists are taking part
in the annual global prevalence study on
criteria have to be used if data of differ-
ent institutions are collected/compared
and if the efficacy of any intervention has
to be tested.
Key words: healthcare associated infec-
tions, nosocomial infections, urinary tract
infections, asymptomatic bacteriuria
SUMMARY OF RECOMMENDATIONS
The EAU/ESIU recommends in general
the CDC/NHSN criteria for HAI and espe-
cially HAUTI [1]. The ESIU has adapted

Received 03 Febr 2010-CorrTi-05–02–10-Na-05–02–05

Chapter | 10 | Healthcare associated urinary tract infections
and modified the CDC/NHSN criteria for
usage in urology, especially when urolo-
gists are taking part in the annual GPIU
study.
In the following only recommendations
are mentioned which are either clarifica-
tions or modifications of the CDC/NHSN
criteria for HAUTI [1], which are com-
pletely listed in Table 1.
1. The time interval is no longer a cri-
terion for the definition of a HAUTI.
It should be replaced by a negative
urine culture on admission and a
careful clinical evaluation that there
was no UTI present on admission
(GoR B).
2. During the study time (month) all
patients should have at least one
(in case of ASB without indwelling
catheter urine two) culture(s) follow-
ing any urological intervention to
improve the diagnosis of HASUTI/
HAASB, not depending too often on
surrogate parameters only (GoR B).
3. An exacerbation from ASB to a
symptomatic UTI after any interven-
tion has to be considered healthcare
associated caused by an endogenous
source (GoR A).
4. Any extension of infection already
present at admission with a change
in pathogen, including emergence
of resistance, has to be considered
healthcare associated (GoR A).
5. Screening for HAASB may not be
necessary routinely because treat-
ment is not indicated in general
(GoR C). Since HAASB can con-
tribute to the environmental flora
by cross contamination/infection in
certain time intervals screening for
HAASB should be included into the
surveillance of HAI (GoR B). This
is also necessary during the GPIU
study period (GoR A).
6. Screening for ASB is always nec-
essary before all the mucosa
568
traumatizing urological interventions
of the urinary tract, because treat-
ment of ASB has to be initiated before
any such interventions (GoR A).
7. Health care associated asympto-
matic bacteriuria (HAASB) should
be considered as colonisation, prob-
ably as risk factor under certain
circumstances, but not as infection
(GoR B).
8. If differentiation between sympto-
matic HAUTI (SHAUTI) and HAASB
is difficut, e.g. intensive care medi-
cine, the diagnosis should be based
on clinical judgment by experienced
specialists (GoR B).
9. For routine surveillance we rec-
ommend that the time interval
for diagnosing HAUTI or HAASB
should be seven days after the
intervention, or in case of ongoing
antibiotic therapy seven days after
the end of antibiotic therapy, or in
case of an indwelling urinary cath-
eter seven days after removal of the
catheter (GoR B).
10. Continuous surveillance of regular
urine cultures results should be the
rational basis for tailoring antimicro-
bial prophylaxis (GoR B).
11. Key urological interventions should
be established for comparison and
the prevalence of HAUTI should be
related to the types of surgery being
undertaken in the department as
well as the extent of the antimicro-
bial prophylaxis (GoR B).
12. Physicians/institutions responsible
for the interventions have to inform
not only the patient, but also the
following treating physician about
the specific risk of HAI in a specific
patient and the following treating
physician has to inform the physi-
cian/institution responsible for the
intervention about any occurrence of
HAI in this specific patient (GoR A).
 Criteria for healthcare associated urinary tract infections | 10.2 |

Table 1 Summary of CDC/NHSN criteria of healthcare associated urinary tract infection (HAUTI)
according to Horan et al 2008 [1].

General criteria of healthcare associated infection (HAI) and HAUTI

1. (For the diagnosis of an HAI) “there must be no evidence that the infection was present or incubating at the time of
admission to the acute care setting”.
2. HAIs may be caused by infectious agents from endogenous or exogenous sources.
3. Infections are not considered HAI if associated with complications or extensions of infections already present on admis-
sion, unless a change in pathogen or symptoms strongly suggests the acquisition of a new infection.
4. The following conditions are not infections:
4.1 Colonization, which means the presence of microorganisms on skin, on mucous membranes, in open wounds, or in
excretions or secretions but are not causing adverse clinical signs or symptoms; and
4.2 Inflammation that results from tissue response to injury or stimulation by non-infectious agents,
such as chemicals
5. HAUTI comprises healthcare associated symptomatic UTI (HASUTI), asymptomatic bacteriuria (HAASB), and other infec-
tions of the urinary tract (HA-OUTI), such as kidney, ureter, bladder, urethra, or tissue surrounding the retroperitoneal or
perinephric space.

I. Symptomatic urinary tract infection (HASUTI)

A symptomatic urinary tract infection must meet at least 1 of the following criteria:
1. Patient has at least 1 of the following signs or symptoms with no other recognized cause: fever (>38°C), urgency, fre-
quency, dysuria, or suprapubic tenderness (in patient <1 year of age signs and symptoms with no other recognized
cause: fever (>38°C), hypothermia (37°C), apnea, bradycardia, dysuria, lethargy, or vomiting)
and
patient has a positive urine culture, that is, >105 microorganisms per cc of urine with no more than 2 species of
microorganisms.
2. Patient has at least two (in patient <1 year of age one) of the following signs or symptoms with no other recognized
cause: fever (>38°C), urgency, frequency, dysuria, or suprapubic tenderness (in patient <1 year of age signs and
symptoms with no other recognized cause: fever (>38°C), hypothermia (37°C), apnea, bradycardia, dysuria, lethargy, or
vomiting)
and
at least 1 of the following
a. positive dipstick for leukocyte esterase and/ or nitrate
b. pyuria (urine specimen with >10 white blood cell [WBC]/mm3 or >3 WBC/highpower field [HPF] of unspun urine)
c . organisms seen on Gram’s stain of unspun urine
d. at least 2 urine cultures with repeated isolation of the same uropathogen (gramnegative bacteria or Staphylococcus
saprophyticus) with >102 colonies/mL in non-voided specimens
e. >105 colonies/mL of a single uropathogen (gram-negative bacteria or S. saprophyticus) in a patient being treated with
an effective antimicrobial agent for a urinary tract infection
f. physician diagnosis of a UTI
g. physician institutes appropriate therapy for a UTI

II Asymptomatic bacteriuria (HAASB)

An asymptomatic bacteriuria must meet at least 1 of the following criteria:
1. Patient has had an indwelling urinary catheter within 7 days before the culture
and
patient has a positive urine culture, that is, >105 microorganisms per cc of urine with no more than 2 species of
microorganisms
and
patient has no fever (<38oC), urgency, frequency, dysuria, or suprapubic tenderness.
2. Patient has not had an indwelling urinary catheter within 7 days before the first positive culture
and
patient has had at least 2 positive urine cultures, that is, >105 microorganisms per cc of urine with repeated isolation of
the same microorganism and no more than 2 species of microorganisms
and
patient has no fever (<38oC), urgency, frequency, dysuria, or suprapubic tenderness.

continued

569
Chapter | 10 | Healthcare associated urinary tract infections

Table 1 Summary of CDC/NHSN criteria of healthcare associated urinary tract infection (HAUTI)
according to Horan et al 2008 [1] – cont’d

III. Other infections of the urinary tract (HA-OUTI)

(kidney, ureter, bladder, urethra, or tissue surrounding the retroperitoneal or perinephric space)
Other infections of the urinary tract must meet at least 1 of the following criteria:
1. Patient has organisms isolated from culture of fluid (other than urine) or tissue from affected site.
2. Patient has an abscess or other evidence of infection seen on direct examination, during a surgical operation, or
during a histopathologic examination.
3. Patient has at least two (in patient <1 year of age one) of the following signs or symptoms with no other recognized cause:
fever (>38oC), localized pain, or localized tenderness at the involved site (in patient <1 year of age signs and symptoms with
no other recognized cause: fever (>38oC), hypothermia (37oC), apnea, bradycardia, dysuria, lethargy, or vomiting)
and
at least 1 of the following:
a. purulent drainage from affected site
b. organisms cultured from blood that are compatible with suspected site of infection
c. radiographic evidence of infection (eg, abnormal ultrasound, computerized tomography [CT] scan, magnetic
resonance imaging [MRI], or radiolabel scan [gallium, technetium], etc)
d. physician diagnosis of infection of the kidney, ureter, bladder, urethra, or tissues surrounding the retroperitoneal or
perinephric space
e. physician institutes appropriate therapy for an infection of the kidney, ureter, bladder, urethra, or tissues surrounding
the retroperitoneal or perinephric space.

Comments
A positive culture of a urinary catheter tip is not an acceptable laboratory test to diagnose a UTI
a

Urine cultures must be obtained using appropriate technique, such as clean catch collection or catheterization.
b

In infants, a urine culture should be obtained by bladder catheterization or suprapubic aspiration; a positive urine culture
from a bag specimen is unreliable and should be confirmed by a specimen aseptically obtained by catheterization or
suprapubic aspiration.

1. INTRODUCTION (LoE 3). For daily practise and especially

for this study it is important to use the
Healthcare associated infections (HAI) commonly accepted criteria. Otherwise
have a high impact not only on the indi- data of different institutions cannot be
vidual patient but also on the total collected/compared and interventions
healthcare system. At 42.1% health- cannot be tested for effectiveness.
care associated urinary tract infections
(HAUTI) are the most frequent HAI in
general German hospitals [2] (LoE 2a). 2. AIM AND METHODS
Urologists have become more and more
concerned about minimizing the rate of For surveillance of healthcare associated
HAI in their institutions. Since 2003 the infections (HAI) the EAU/ESIU recom-
EAU/ESIU in collaboration with many mends in general the CDC/NHSN defini-
scientific societies has performed every tions for HAUTI as updated in 2008 [1]
year a worldwide (global) prevalence (LoE 4). The results are summarized in
study on infections in urology (GPIU) Table 1. However, some clarifications or
with special emphasis on HAUTI. In this modifications will be discussed and rec-
study it was found that the prevalence ommended for special usage in urology,
of HAUTI in urological departments is especially when urologists are taking part
about 10% but with very wide variations in the annual global prevalence study on
between countries and institutions [3–4] infections in urology.

570
 Criteria for healthcare associated urinary tract infections
3. DISCUSSION
In the CDC/NHSN document the term “noso-
comial” was replaced by “healthcare associ-
ated” to indicate that all infections have to
be considered as HAI whether acquired in
an outpatient or in an institutional (hospi-
tal) acute care setting. HAIs may be caused
by an infectious agent(s) or its toxin(s)
from endogenous or exogenous sources.
Unfortunately it is not mentioned whether
infections acquired by patients living in
long-term facilities, e.g. nursing homes,
should also be considered as HAI. The
reason for that may have been that these
infections were not in the scope of the sur-
veillance recommended by the CDC/NHSN.
Under the diagnosis of healthcare
associated UTI (HAUTI) the CDC/NHSN
incorporates three different entities:
i) symptomatic UTI; ii) asymptomatic bac-
teriuria; iii) other infections of the urinary
tract (kidney, ureter, bladder, urethra, or
tissue surrounding the retroperitoneal or
perinephric space). To comply with these
guidelines, the following problems have to
be considered or clarified, respectively.
3.1 Rule out UTI at admission
To diagnose HAUTI “there must be no
evidence that the infection was present
or incubating at the time of admission”
according to the CDC/NHSN definitions
for HAUTI as updated in 2008 [1] (LoE 4).
It is not difficult to achieve this require-
ment in an otherwise healthy patient
undergoing an elective urological opera-
tion/intervention, who has no signs and
symptoms of UTI, was not treated with
antibiotics during the last week and
whose urine culture shows no growth.
However, the guidelines do not provide
any recommendations on what minimal
investigations are required to exclude the
presence of UTI/bacteriuria at admission.
Often a 48 hour delay from admission to
start of symptoms is thought to be required
to qualify for a HAI, including HAUTI.
With an average period of hospitalisation
| 10.2 |
close to two days in many departments,
this definition makes no sense any more.
The time interval is no longer a criterion
for the definition of a HAUTI. It should
be replaced by a negative urine culture on
admission and a careful clinical evaluation
that there was no UTI present on admis-
sion (GoR B, LoE 4).
3.2 Infections not considered HAUTI
The CDC/NHSN document states that
infections associated with complications
or extensions already present on admis-
sion are not considered healthcare asso-
ciated, unless a change in pathogen or
symptoms strongly suggest the acquisi-
tion of a new infection [1].
How should a patient with asympto-
matic bacteriuria (ASB) or presumed
ASB, e.g. in case of an infection stone or
indwelling urinary catheter, at the time of
admission followed by an exacerbation of
infection with the same pathogen in asso-
ciation with any kind of healthcare provi-
sion, e.g. change of catheter, be classified?
In this situation we strongly suggest that
HAUTI has to be diagnosed as caused by
an infectious agent from an endogenous
source (GoR A, LoE 4) .
How should a patient admitted with an
acute pyelonephritis due to an obstruc-
tive urinary stone and incomplete stone
removal, who experience extension of infec-
tion leading to prolonged antibiotic therapy
and emergence of resistance of the same
pathogen be classified? In this situation we
also strongly suggest that HAUTI has to be
diagnosed as caused by a resistant patho-
gen, although the pathogen may belong to
the same type/species, but emergence of
resistance was associated with antibacterial
therapy (GoR A, LoE 4).
3.3 Diagnosis of healthcare
associated symptomatic
UTI (HASUTI)
The diagnosis of symptomatic HAUTI is
based on two principles: i) symptoms and
ii) the presence of bacteriuria
571
Chapter | 10 | Healthcare associated urinary tract infections
There is no problem if in association
with any healthcare provision the patient
has experienced (suddenly) at least one
typical urinary symptoms of the upper or
lower urinary tract and a positive urine
culture with a high bacterial load (cfu
>105/ml) with no more than 2 species of
(uropathogenic) microorganisms can be
documented.
However in case no urine culture was
taken or the culture only showed a low
bacterial load (cfu <104/ml) according
to the CDC/NHSN document surrogate
parameters have to be taken to diagnose
HAUTI, such as pyuria, leukocyte este-
rase, nitrite test, repeated urine cultures,
effective antimicrobial therapy, physi-
cian’s diagnosis and/or antibiotic therapy
for UTI. Whether the requirement of two
urinary symptoms (instead of one urinary
symptom as above) in conjunction with
one surrogate parameter will improve the
diagnosis, remains questionable, espe-
cially since after many urological inter-
ventions patients will experience urinary
symptoms, like dysuria, frequency and
urgency, and for example, pyuria may
only reflect an inflammatory and not
necessarily an infectious process of the
urinary tract. Unfortunately in such a
situation many urologists nevertheless
diagnose HAUTI and recommend antibi-
otic therapy “just to be on the safe side”.
According to the CDC/NHSN criteria a
physician’s diagnosis and appropriate
therapy for UTI are also accepted as cri-
teria for HAUTI, which also can be con-
sidered as surrogate parameters.
3.4 Diagnosis of healthcare
associated asymptomatic
bacteriuria (HAASB)
According to the CDC/NHSN document
HAASB is diagnosed in an asymptomatic
patient i) who had an indwelling urinary
catheter within seven days before the
culture (one culture with >105/ml with
no more than two uropathogenic species
is sufficient) or ii) who had no indwelling
572
urinary catheter within seven days before
the first urine culture (two cultures with
>105/ml with no more than two uropatho-
genic species are required).
It is appreciated that in the defini-
tion of HAASB the term “infection” is not
used. However, in the document ASB is
subclassified to HAUTI and it is not men-
tioned as one of the conditions which are
not an infection. This is misleading and
not in line with the most recent IDSA
guidelines [5–6] (LoE 1a) which strongly
advise not to consider ASB as infection
and therefore not to treat ASB except in
two situations (because of risk factors):
i) during pregnancy and ii) before the
mucosa traumatizing interventions of the
urinary tract (GoR A). Therefore, HAASB
should be considered as colonisation,
probably as risk factor under certain cir-
cumstances, but not as infection (GoR B,
LoE 1a). There is probably no difference
whether a mucous membrane is colonized
after intubation or the bladder mucous
membrane after catheter insertion. This
change of paradigm will have therapeutic
and probably also legal implications.
The IDSA guidelines [5–6] (LoE 1a)
imply that in general screening for ASB
is not indicated, because treatment is
not necessary. In the context of HAASB
we face the problem that if screening for
HAASB is not recommended, HAASB will
not be diagnosed. However we know that
uropathogens, especially from patients
with indwelling urinary catheter, can cause
cross contamination/infection in other
patients [7–8] (LoE 2a). Therefore surveil-
lance of HAASB may also be an important
issue and quality parameter. The CDC/
NHSN document does not give any advice,
how this dilemma could be solved.
We recommend that at least in certain
time intervals a screening for HAASB
should be performed in each institution
(GoR B, LoE 4). The results should, how-
ever, be analysed separately from the
HASUTI. The data will supplement the
assessment of the bacterial spectrum and
the susceptibility pattern in a certain
 Criteria for healthcare associated urinary tract infections
environment (ward), which may have
implications for antibiotic usage for treat-
ment and prophylaxis.
There are situations, in which SUTI
and ASB cannot easily be differentiated
especially when systemic symptoms, like
fever etc, are missing. This is always the
case in unconscious patients, e.g. inten-
sive care medicine, but it is also often
difficult in patients with indwelling cath-
eter, whether the “urinary symptoms” are
caused by the foreign body or by a UTI,
and in patients with atypical urinary
symptoms, e.g. neurogenic bladder distur-
bances. In such situations the diagnosis
should be based on clinical judgment by
experienced specialists (GoR B, LoE 4).
3.5 Diagnosis of other healthcare
associated infections of the
urinary tract (HAOUTI)
The EAU/ESIU definitions of HAOUTI fol-
low the CDC/NHSN definitions of surgical
site infections, that a physician diagno-
sis of infection can be derived from direct
observation during surgical operation,
endoscopic examination, or other diagnos-
tic studies or from clinical judgment.
3.6 Diagnosis of urosepsis
The GPIU studies have shown an increas-
ing proportion of urosepsis reported as
HAUTI (LoE 3). Diagnosing urosepsis in
urology departments represents a diag-
nostic dilemma because many patients
will have SIRS after undergoing urologi-
cal surgery, and transient bacteriaemia
is common, especially after transurethral
resection of the prostate [9] (LoE 3). Thus
there is a risk for overdiagnosis which
will increase with the number of blood
cultures taken.
3.7 Comparison of departments
and hospitals
Because the prevalence of HAUTI has
become an important quality parame-
ter, hospitals and departments are often
| 10.2 |
compared. The prevalence of HAUTI
depends on the type of surgery, the hygiene
measurements and the antimicrobial
prophylaxis. For this reason key urologi-
cal interventions should be established
for comparison and the prevalence of
HAUTI should be related to the types of
surgery being undertaken in the depart-
ment as well as the extent of the antimi-
crobial prophylaxis (GoR B, LoE 4). The
effect of prophylaxis depends on the local
environment. Continuous surveillance of
regular urine cultures results should be
the rational basis for tailoring antimicro-
bial prophylaxis (GoR B, LoE 4).
3.8 Observation period to diagnose
HAUTI/HAASB
Because of the short hospitalisation period
nowadays and the increased number of
outpatient procedures many patients will
be discharged from the institution (hospi-
tal or outpatient clinic) before any HAUTI/
HAASB can be diagnosed. Therefore a
minimal observation time needs to be
defined when an infection should still be
considered healthcare associated. For
practical reasons we recommend that this
time should be seven days after the inter-
vention, or in case of ongoing antibiotic
therapy seven days after the end of anti-
biotic therapy, or in case of an indwelling
urinary catheter seven days after removal
of the catheter (GoR B, LoE 4).
Physicians/institutions responsible for
the interventions have to inform not only
the patient, but also the following treat-
ing physician about the specific risk of
HAI in a specific patient and the follow-
ing treating physician has to inform the
physician/institution responsible for the
intervention about any occurrence of HAI
in this specific patient (GoR A, GCP).
4. FURTHER RESEARCH
Especially in patients in whom symptoms
cannot be registered, e.g. intensive care
medicine, or with atypical symptoms, e.g.
573
Chapter | 10 | Healthcare associated urinary tract infections
young children, elderly, patients with spi-
nal cord injury, differentiation between
symptomatic UTI and ASB is almost
always impossible. Determination of bac-
terial virulence factors could probably
help to differentiate between an invasive
infection and colonisation.
5. CONCLUSIONS
Since HAUTI is common in urology, urol-
ogists have a high responsibility to care
about this kind of infection and minimise
it as much as possible. Widely accepted
criteria like the CDC/NHSN criteria
should be applied when data from differ-
ent institutions are collected and com-
pared. However, some modifications are
necessary to adapt them specifically to
urological needs.
REFERENCES
1. Horan TC, Andrus M, and Dudeck MA,
CDC/NHSN surveillance definition of
health care-associated infection and cri-
teria for specific types of infections in the
acute care setting. Am J Infect Control,
2008. 36(5): 309–32.
2. Gastmeier P, Kampf G, Wischnewski N,
Hauer T, Schulgen G, Schumacher M,
Daschner F, and Ruden H, Prevalence of
nosocomial infections in representative
German hospitals. J Hosp Infect, 1998.
38(1): 37–49.
3. Bjerklund-Johansen TE, Cek M, Naber
KG, Stratchounski L, Svenden MV, and
574
P T, Hospital acquired urinary tract infec-
tions in urology departments: pathogens,
susceptibility and use of antibiotics.
Data from PEP and PEAP-studies.
Int J Antimicr Agents, 2006. 28(Suppl):
S91-S107.
4. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
5. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
6. Nicolle LE, Asymptomatic bacteriuria:
review and discussion of the IDSA
guidelines. Int J Antimicrob Agents,
2006. 28 Suppl 1: S42–8.
7. Wagenlehner FM, Krcmery S, Held
C, Klare I, Witte W, Bauernfeind
A, Schneider I, and Naber KG,
Epidemiological analysis of the spread of
pathogens from a urological ward using
genotypic, phenotypic and clinical param-
eters. Int J Antimicrob Agents, 2002.
19(6): 583–91.
8. Naber KG, Witte W, Bauernfeind A,
Wiedemann B, Wagenlehner F, Klare I,
and Heisig P, Clinical significance and
spread of fluoroquinolone resistant
uropathogens in hospitalised urological
patients. Infection, 1994. 22 Suppl 2:
S122–7.
9. Grabe M, Antimicrobial agents in
transurethral prostatic resection.
J Urol, 1987. 138(2): 245–52.
|10.3|

Epidemiology, treatment and

prevention of healthcare-associated
urinary tract infections
Florian M.E. Wagenlehner1, Mete Cek2, Hiroshi Kiyota3, Truls E. Bjerklund-Johansen4
1
Department of Urology, University Giessen, Germany
2
Department of Urology, Taksim Teaching Hospital, Istanbul, Turkey
3
Department of Urology, Jikei University Affiliated Aoto Hospital, Tokyo, Japan
4
Urology Department, Århus University Hospital, Skejby, Århus University, Århus, Denmark
Corresponding author: F.M.E. Wagenlehner, Clinic of Urology, Pediatric Urology and Andrology, Justus-Liebig-University,
Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany.
Tel: +49/ 641-99 44518; Fax : +49/ 641-99 44509 ; E-mail: Wagenlehner@AOL.com

ABSTRACT of HA-uropathogens are provided. The

Healthcare associated (HA) urinary tract
infections (UTI) are the most frequent
healthcare associated infections (HAI)
in a general hospital. They are almost
exclusively complicated UTIs, although
the complicating factors are very heter-
ogenous. HAUTIs are mainly catheter
associated. Most of them are asympto-
matic and do not need antimicrobial ther-
apy. However, cross-contamination and
cross-infection may contribute to the
distribution of resistant uropathogens.
The bacterial spectrum of HAUTI is
broad and antibiotic resistance is com-
mon. The results of international and
national surveillance studies on the bac-
terial spectrum and antibiotic resistance
treatment of HAUTI encompasses treat-
ment of the complicating factors as well
as the antimicrobial chemotherapy. At
least in serious UTI adequate initial anti-
biotic therapy results in lower mortality.
Therefore the initial antibiotic regimen
must provide sufficient antibiotic cov-
erage. This can only be achieved if the
bacterial spectrum and antibiotic resist-
ance patterns of uropathogens in the
own institution is followed continuously.
Provisional microbiological findings, such
as reports on Gram-stain or certain bio-
chemical results can lead to early strati-
fication of pathogens and allow a more
taylored empiric antibiotic therapy.
Antibiotic therapy of HAUTI has to con-
sider two different aspects: i) therapeutic
Chapter | 10 | Healthcare associated urinary tract infections
success in the individual patient, and ii)
prevention of emergence of antibiotic resist-
ant mutants. For both aspects adequate
drug selection and dosing are paramount.
Since most of the HAUTI are catheter asso-
ciated UTI (CAUTI), prudent catheter man-
agement and prevention of CAUTI should
be considered high priority in urology.
Key words: Healthcare associated UTI,
Nosocomial UTI; antibiotic treatment of
UTI; emergence of antibiotic resistant
uropathogens
SUMMARY OF RECOMMENDATIONS
1. All urinary tract infections (UTI)
acquired in an outpatient or in an
institutional care setting, should be
considered as healthcare-associated
UTI (HAUTI) (GoR B).
2. Healthcare associated asymptomatic
bacteriuria (HAASB) should not be
treated with antimicrobials, except
before the mucosa traumatizing
interventions of the urinary tract
and in pregnant women (GoR A).
3. In HAUTIs a wide spectrum of fre-
quently also multiresistant uropath-
ogenic bacteria has to be considered
(GoR B).
4. For rational empiric therapy the
local susceptibility pattern of the
uropathogens must be continuously
followed and considered (GoR A).
5. A urine specimen and in case of
urosepsis also a blood specimen for
culture must be obtained before initia-
tion of any antibiotic therapy (GoR A).
6. Antibiotic treatment should be initi-
ated after the results of the suscepti-
bility testing are available, whenever
possible (GoR B).
7. If empiric antibiotic treatment is
warranted, it should be tailored after
the results of the susceptibility test-
ing are available (GoR B).
576
8. Antibiotics with best performance in
biofilm infection should be selected
and the dosage should be sufficiently
high when treating HAUTI (GoR B).
9. Prevention of catheter associated
UTI (CAUTI) is the gold standard for
prevention of HAUTI (GoR A).
10. For prevention of HAUTI in short-
term catheterization the following
recommendations are to be consid-
ered: i) staff education about catheter
management; ii) catheterization only
when indicated and prompt removal
of indwelling catheters; iii) hand-
washing; iv) catheter insertion with
aseptic technique and sterile equip-
ment, and v) maintenance of a closed
urinary drainage system (GoR A).
11. For prevention of HAUTI in long-
term catheterization the following
recommendations should be consid-
ered: i) hydration; ii) appropriate
catheter exchange; iii) no antimicro-
bial prophylaxis (GoR B).
12. For avoidance of long-term bladder
catheterization the following meth-
ods should be considered:
12.1. in case of incomplete emptying
of the bladder: i) medications
for complete emptying the
urinary bladder, such as
cholinergic drugs and/or
alpha-1 adrenergic inhibitors;
ii) operative deobstruction for
benign prostatic hypertrophy
(BPH); iii) clean intermittent
catheterization (GoR B).
12.2. in case of incontinence: i.)
medications for incontinence;
ii) operative treatment of
incontinence (GoR B).
1. INTRODUCTION
A healthcare associated infection (HAI) is
defined as a localised or systemic condi-
tion that results from an adverse reaction
 Epidemiology, treatment and prevention
to the presence of an infectious agent or
its toxin, and was not present or incubat-
ing prior to the initiation of a healthcare
encounter [1–2]. The term “healthcare
associated infection” incorporates the
term “nosocomial” or “hospital acquired”,
which refers to infections that occur as
a result of hospital care, but also any
infection occurring in an institutional
(long-term facilities, nursing home) or
outpatient care settings. Healthcare asso-
ciated urinary tract infections (UTI) are
the most frequent healthcare associated
infections (HAI) and account for more
than 40% of all HAI in a general hospital
[3–5] (LoE 2b). They are mainly catheter-
associated [3–4, 6] (LoE 2b). Bacteriuria
develops in up to 25% of patients who
require a urinary catheter for seven days
or more, with a daily risk of 5% [6] (LoE
3). Most of the catheter associated bac-
teriuria are asymptomatic (CAASB) [7]
(LoE 3) and therefore do not need antibi-
otic therapy. However, the pathogens are
fully exposed to the healthcare setting
(nosocomial) environment, including the
selective pressure of antibiotic or antisep-
tic substances. HAUTIs comprise perhaps
the largest institutional reservoir of anti-
biotic-resistant pathogens [6] (LoE 3).
2. METHODS
This review is based on a systematic liter-
ature search for the last 10 years (2000–
2009) in PubMed. Two searches were
performed: i) surveillance AND suscepti-
bility AND nosocomial urinary tract infec-
tion (for search the term “nosocomial”
was used instead of “healthcare associ-
ated”); and ii) randomized clinical trials
AND nosocomial urinary tract infection
AND antibiotic therapy. The first search
revealed 55 publications. There were sev-
eral local or national surveillance stud-
ies, but only three multinational studies
were found and used for this review. The
second search revealed 15 publications.
No prospective controlled, randomized
| 10.3 |
therapeutic study was found, in which
only patients with nosocomial UTI were
treated or such patients were substrati-
fied. Only one study investigated the
effect of antibiotic prophylaxis at urinary
catheter removal, which was included
into this review and one study investi-
gated the effect of an antibiotic coated
urinary catheter on prophylaxis of noso-
comial UTI, which was included into this
review. These publications were aug-
mented with publications known by the
authors.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [8–9].
3. EPIDEMIOLOGY
The incidence of HAIs has stayed more
or less stable over the last one to two dec-
ades. However, certain aspects of patient
care have changed during this period. As
minimally invasive techniques develop
and patient care improves, patients are
being treated either on an outpatient
basis or they stay in hospitals for shorter
periods. Particularly in urology there is a
wide range of operations which allow the
patient to be discharged within 48 hours
of operations. This has two important
implications on the incidence of HAIs: 1)
More elderly patients with comorbidities
are hospitalised [10–11]. Shorter hospital
stays make it difficult to assess the true
frequency of healthcare associated infec-
tions. The incubation periods of certain
infections (e.g. surgical site infections)
are sometimes longer than the hospital
stay of patients. It is thus more prefer-
able to calculate the incidence of HAIs
on the basis of patient days, rather than
actual number of admissions [12]. The
denominator can also be the number of
patients at risk, or days of indwelling
catheterisation [13]. The rate of nosoco-
mial infections per 1000 patients’ days
in the United States of America was
577
Chapter | 10 | Healthcare associated urinary tract infections
calculated to be 9.8 in 1995 [12–13]. More
recent estimates (for 2002) for all infec-
tions combined are not comparable to pre-
vious overall estimates [5]. On the other
hand, the incidence of nosocomial urinary
infections in European countries was
found to be 3.55 episodes/1000 patient-
days and the prevalence was estimated to
be 10.65/1000 [14].
The prevalence of HAUTI in urologi-
cal departments was 10% in the Pan
European Prevalence (PEP) study,
14% in the Pan Euro-Asian Prevalence
(PEAP) study, and 11% in the combined
analysis [15]. The largest group was
asymptomatic bacteriuria (29%) followed
by cystitis (26%), pyelonephritis (21%),
and urosepsis (12%). The prevalence of
HAUTIs was found to be 14.7% in the
Global Prevalence Study on Infections
in Urology (GPIU) 2008 (unpublished
data). Another finding which raises con-
cern is the rising percentage of urosep-
sis from 9.3% in 2006 to 21.8% in 2008
while the prevalence of HAUTI stayed
more or less stable around 14% in the
same period. This suggests that pro-
phylactic measures in various urology
clinics may not be appropriate and the
choice of prophylactic antibiotics is still
not optimal [16].
4. RISK FACTORS
Several characteristics related to the
healthcare provider, the patient and the
procedures are known to increase the risk
of NAUTI. The most important risk fac-
tors for HAUTI are an indwelling catheter
and the duration of catheterisation [17].
Other significant risk factors are i) UTI
during the previous 12 months; ii) urinary
tract obstruction; iii) urinary stones; iv)
previous antibiotic usage within the last 3
months and v) hospitalisation within the
last six months due to any reason [17].
The study also showed that for patients
having more than three risk factors,
578
there was a significantly increased risk
of having a Candida sp., Klebsiella sp.,
or Pseudomonas sp. as a causative path-
ogen, when compared to those patients
with three or less risk factors.
Another recent study also found strong
evidence between HAUTI and prolonged
length of stay, urinary catheter and
female sex [18]. Other factors found sig-
nificant in this study were e.g. spinal
injury or fracture/dislocation, transfer to
another hospital, underlying neurologic
disease, some assistance required prior
to admission, and previous stroke sug-
gesting chronic health problems and
reduced health status which needs to be
further elucidated. Studies suggested
also the severity score of hospitalised
patients as an important risk factor
for the development of HAUTI [11, 19].
On the other hand, immmunosupressant
therapy within 14 days, history of malig-
nancy, cigarette smoking in the past and
male sex, are shown to be risk factors for
nosocomially urinary tract related bacter-
emia [20].
5. BACTERIAL SPECTRUM
Whereas community acquired UTI are
often uncomplicated, almost all HAUTIs
are complicated infections with structural
or functional abnormalities within the
urinary tract, such as indwelling cath-
eters or some kind of urinary obstruc-
tion. The bacterial etiology of UTI differs
markedly between uncomplicated and
complicated UTIs.
5.1 Bacterial spectrum in
complicated HAUTI
The bacterial spectrum of complicated
HAUTIs comprises a wide range of Gram-
negative and Gram-positive species. The
bacterial spectrum can vary geographically,
over the time and between distinct special-
ities at the same institution [21] (LoE 3).
 Epidemiology, treatment and prevention
5.1.1 Bacterial spectrum of HAUTI in
North-America (SENTRY study)
The SENTRY antimicrobial surveillance
program, initiated in 1997, has chrono-
logically examined urinary pathogens
collected from hospitalized patients
from different hospital departments
across North America and thus provides
insight into pathogen frequency and
resistance rates [22] (LoE 3). A surveil-
lance study based on 1998 data encom-
passed 31 North American institutions
which examined 1,510 urinary isolates
from hospitalized patients from differ-
ent departments. Approximately 25% of
these isolates were HA-strains, of which
20% were isolated from intensive care
units [23].
For Gram-negative organisms, E. coli
was responsible for 47% of UTIs, followed
by Klebsiella spp. (11%), Pseudomonas
spp. (8%), Proteus spp. (5%), Enterobacter
spp. (4%), and Citrobacter spp. (3%)
(Table 1). The most commonly isolated
Gram-positive uropathogens from this
cohort of hospitalized patients were
Enterococcus spp. (13%), coagulase-
negative staphylococcus (3%), and S.
aureus (3%) (Table 1).
5.1.2 Bacterial spectrum of HAUTI in
Europe (ESGNI-003 study)
A European multi-center one-day preva-
lence study on HAUTI of patients from
different hospital departments tested 607
uropathogens from 228 hospitals through-
out Europe [24] (LoE 2b). Patients from
different departments throughout the
hospital were evaluated. E. coli was
responsible for 36% of UTIs, followed by
Klebsiella spp. (8%), Proteus spp. (8%),
Pseudomonas spp. (7%), Enterobacter
spp. (4%), and Citrobacter spp. (2%). With
Gram-positive uropathogens Enterococcus
spp. was isolated in 13%, coagulase-
negative staphylococcus in 2% and S.
aureus in 2%. Candida spp. was isolated
in 9% (Table 1).
| 10.3 |
5.1.3 Bacterial spectrum of HAUTI
in urological patients in Europe
(PEP-study)
A European multi-center one-day preva-
lence study on HAUTI in urology tested
320 uropathogens from 232 urological
departments throughout Europe [17] LoE
3). E. coli was responsible for 35% of UTIs,
followed by Pseudomonas spp. (13%),
Klebsiella spp. (10%), Proteus spp. (7%)
and Enterobacter spp. (3%). With Gram-
positive uropathogens Enterococcus spp.
was isolated in 9% and Staphylococcus
spp. in 4%. Candida spp. was isolated in
3% (Table 1).
6. ANTIBIOTIC RESISTANCE
Since antibiotics have been introduced
into clinical medicine, antibiotic resistant
bacteria have evolved. The epidemiology
of antibiotic resistant bacteria, however,
varies from region to region, from speci-
ality to speciality, from infection type to
infection type and from time to time.
6.1 Antibiotic resistance in
complicated HAUTI
HA-uropathogens are frequently subject
to antibiotic pressure and cross-infec-
tion [25] (LoE 2b). The influence of these
parameters can vary between regions and
specialities [21] (LoE 3). Different species
of uropathogens show distinct abilities to
develop antibiotic resistance.
6.1.1 Antibiotic resistance in HAUTI in
North America, Latin America and
Europe (SENTRY study)
In the SENTRY study a central refer-
ence laboratory was employed using
NCCLS (National Committee for Clinical
Laboratory Standards) criteria [23]
(LoE 3). Strains were sent from the local
microbiology laboratories. Global resist-
ance rates (combined resistance of E. coli,
Klebsiella spp., P. aeruginosa, and ente-
rococci) in North America for Ampicillin,
579
Table 1 Bacterial spectrum of nosocomial uropathogens (≥ 2%) from distinct surveillance studies.

Name of study SENTRY [29] SENTRY [29] SENTRY [29] ESGNI-003 [24] PEP-study [17]
Regions of the world North America Latin America Europe Europe Europe
Year of surveillance 2000 2000 2000 2000 2003
Type of surveillance longitudinal longitudinal longitudinal Cross section Cross section
Origin of samples Microbiology laboratories Microbiology laboratories Microbiology laboratories Different departments in the hospital Urology departments
Number of pathogens n=1,466 n=531 n=783 n=607 n=320
Species %
E. coli 43% 60% 46% 36% 35%
Klebsiella spp. 12% 12% 9% 8% 10%
Pseudomonas spp. 7% 6% 9% 7% 13%
Proteus spp. 6% 7% 10% 8% 7%
Enterobacter spp. 3% 4% 4% 4% 3%
Citrobacter spp. 4% 2% 2% 2% n.r.
Enterococcus spp. 16% 4% 13% 16% 9%
Staphylococcus spp. 6% 3% 3% 4% 4%
Resistance rates of antibiotics %
Ampicillin 59%e 62%e 65%e 66%a 51%
e e e a
Ampicillin + BLI 31% 36% 36% 29% 30%
e e e a
TMP/SMZ 43% 38% 48% 32% 45%
Ciprofloxacin 29%e 32%e 29%e 17%b 34%
Gentamicin n.r. n.r. n.r. 18% 34%
c
Ceftazidime n.r. n.r. n.r. 13% 17%
Amikacin n.r. n.r. n.r. 19%c 14%
Piperacillin/Tazobactam n.r. n.r. n.r. n.r. 15%
Imipenem n.r. n.r. n.r. 14%c 7%
d
Vancomycin n.r. n.r. n.r. 1% n.r.
a b c d e
n.r. – not reported; – Gram-negative bacteria excluding P. aeruginosa; - Gram-negative bacteria; – P. aeruginosa; – enteroccoci.; – E. coli, Klebsiella spp., P. aeruginosa, enterococci.
 Epidemiology, treatment and prevention
Amoxicillin/ clavulanate, Trimethoprim/
Sulfamethoxazole and Ciprofloxacin were
59%, 31%, 43% and 29%, respectively.
Global resistance rates in Latin America
for Ampicillin, Amoxicillin/ clavulanate,
Trimethoprim/ Sulfamethoxazole and
Ciprofloxacin were 62%, 36%, 38% and
32%, respectively. Global resistance rates
in Europe for Ampicillin, Amoxicillin/ cla-
vulanate, Trimethoprim/ Sulfamethoxazole
and Ciprofloxacin were 62%, 36%, 38%
and 32%, respectively (Table 1).
6.1.2 Antibiotic resistance in HAUTI
in Europe (ESGNI-003 study)
The European Study Group on Nos-
ocomial Infections (29 countries) also
evaluated antimicrobial susceptibility
against hospital-acquired urinary isolates
[24] (LoE 2b). Sensitivity assays were not
performed in a central laboratory and
local results of susceptibility testing were
taken at face-value. During 1999, 607
organisms from 522 patients with HAUTI
were tested. Resistance rates were for E.
coli comparable to those observed from
the North American SENTRY experience
(Table 1): TMP/SMX (28%), ampicillin
(55%), ciprofloxacin (9%), and gentamicin
(6%). However, it is worth noting that
non-European Union countries tended
to have higher rates of E. coli resistance
than European union countries.
In particular, amikacin, ceftazidime,
and cefepime were the most active
agents (>90% susceptible), imipenem
and tobramycin were moderately active
(>85% susceptible), and ciprofloxacin
and gentamicin were the least active
(~75% susceptible). In contrast, P. aeru-
ginosa isolates from non-European Union
countries (e.g. Estonia, Serbia) showed
resistance rates of over 50% for fluoro-
quinolones and non-amikacin aminogly-
cosides. The authors speculated that this
high rate of resistance to pseudomonal
strains might be explained by the lack of
strict antimicrobial policies in hospitals
within non-European Union countries.
| 10.3 |
6.1.3 Antibiotic resistance in HAUTI
in urological patients in Europe
(PEP-study)
The PEP-study also evaluated resistance
rates of uropathogens causing HAUTI in
urological patients [17] (LoE 3). However,
there was no reference laboratory and dif-
ferent standards were employed for test-
ing of the strains (178 hospitals employed
NCCLS criteria, 34 DIN (Deutsches
Institut für Normung) criteria, and 20
other criteria) and not all hospitals have
tested all antibiotics. Global resistance
rates for the total bacterial spectrum were
as follows (Table 1): Ampicillin 51%, amp-
icillin + beta-lactamase-inhibitor 30%,
piperacillin 21%, piperacillin/ tazobactam
15%, cefazolin 44%, cefuroxime 25%,
ceftazidime 17%, cefepime 21%, imipenem
7%, gentamicin 34%, amikacin 14%, cipro-
floxacin 34% and TMP/SMZ 45%.
In all these studies increasing resist-
ance rates were found for some species
like E. coli, but not for all uropathogens.
However, resistance rates may vary sub-
stantially between regions. Therefore
local, hospital based surveillance of the
bacterial spectrum and antibiotic sensi-
tivity is paramount for a rational empiric
therapy.
7. TREATMENT OF HAUTI
As mentioned earlier, HAUTI are mainly
catheter associated. Most of them are
asymptomatic and do not need antibiotic
therapy according to the current guide-
lines, except before an traumatizing
intervention of the urinary tract and in
pregnant women [26] (LoE 1a). However,
by cross-contamination and cross-infec-
tion healthcare associated asymptomatic
bacteriuria (HAASB) may also contrib-
ute very much to the distribution of
resistant uropathogens throughout the
institution (nursing home, hospital) [25]
(LoE 2b) and also throughout the com-
munity in case of an outpatient care
setting. Therefore, HAASB may be an
581
Chapter | 10 | Healthcare associated urinary tract infections
important factor for the spread of resist-
ant uropathogens and should therefore
be included into a systematic (not rou-
tine) surveillance. But in general, anti-
biotic therapy should only be considered
for symptomatic HAUTI. In some situa-
tions, however, the distinction between
HAASB and symptomatic HAUTI may
be difficult, e.g. intensive care medi-
cine, patients with spinal cord injury,
physically and mentally handicapped
(geriatric) patients or children in young
age. Careful consideration of all clinical
parameters is necessary before antibiotic
therapy is initiated.
7.1 General aspects of antibiotic
therapy of UTI
In the antimicrobial treatment of uncom-
plicated UTIs the rapid elimination of the
pathogen is most important. In compli-
cated HAUTIs, the primary goal of anti-
biotic therapy is to contain the spread of
infection and prevent the emergence of
resistant mutants.
Drusano and Craig determined four
parameters for the rational dosing of an
antibiotic in a population [27]:
1. the minimal inhibitory concentration
(MIC) of the clinical isolates.
2. the pharmacokinetic (PK) profile.
3. the pharmacodynamic (PD) profile.
4. the protein binding of the applied
antibiotic.
The distribution of the MIC values of
nosocomial clinical isolates is the great-
est variable parameter and the MICs
vary geographically and by time [28–29]
(LoE 2b). The other three parameters are
usually determined from Phase I to III
studies. There is, however, a surprisingly
high interindividual variation. Certain
subgroups, however, are not studied and
recommendations for antibiotic therapy
must be extrapolated from the results of
other related groups.
An additional 5th parameter is extremely
important for the treatment of HAUTI. In
582
many cases of complicated UTIs biofilm
infection is predominant. In a biofilm, the
pathogens adhere to anatomical structures
of the urinary tract - stones, foreign materi-
als or necrotic tissue - and are embedded in
organic (exopolysaccharide) and anorganic
(phosphate) material [30–31] (LoE 3). This
leads to reduced susceptibility of the patho-
gens and therefore it is necessary to elevate
antibiotic concentrations by 10- to 100 fold
in order to inhibit or kill the pathogens [32]
(LoE 2b). Such increased antibiotic con-
centrations are often not clinically achiev-
able. Fluoroquinolones and macrolides
(only effective against Gram-positive bacte-
ria) exhibit a specific effect on the biofilm
formation, which, however, is usually not
sufficient to eradicate the pathogens [33]
(LoE 3). Therefore, antimicrobial therapy
in complicated UTIs may only kill the bac-
teria dissolved from the biofilm (planctonic
form) and thus inhibit spread of the infec-
tious process. An accompanying urological
therapy must aim to remove the biofilm.
In any case, antibiotics with best perform-
ance in biofilm infection should be selected
and the dosage should generally be high
when treating complicated HAUTIs [34].
The dosage should even be sufficiently
high enough to eradicate also the first step
resistant mutants [35] (LoE 3).
At least in severe UTIs, adequate
initial antibiotic therapy results in
lower mortality compared with inad-
equate antibiotic treatment [36] (LoE 3).
Susceptibility testing should be carried
out in any case of HAUTI, and if possi-
ble the results should be awaited before
treatment. However, in severe infections
an initial empiric therapy must be insti-
gated immediately after microbiologi-
cal sampling. Susceptibility testing can
serve in these cases to narrow the antibi-
otic coverage. Provisional microbiological
findings, such as reports on Gram-stain
or certain biochemical results, such as
oxidase, coagulase, catalase, can lead
to early stratification of pathogens and
allow a more taylored empiric antibi-
otic therapy [37] (LoE 3). Prudent use of
 Epidemiology, treatment and prevention
antimicrobials may also help to reduce
the selection of resistant pathogens to a
minimum (see chapter 4.7)
7.2 Antibiotic selection for
therapy of complicated
HAUTI and urosepsis
Antibiotics with an enlarged antibac-
terial spectrum are necessary for ini-
tial empiric treatment [38] (LoE 4). The
empiric parenteral treatment could start
with a cephalosporin group 3a, a fluo-
roquinolone with good renal excretion or
with an aminopenicilline in combination
with a betalactamase-inhibitor (recom-
mended dosages see Table 2). If clinical
improvement fails after two to three days,
treatment should be switched to a pseu-
domonas active acylaminopenicilline/
betalactamase-inhibitor, a group 3b cepha-
losporin or a group 1 carbapenem. Other
reasons for treatment failure, such as per-
sistent complicating factors, other infec-
tions or noninfectious sources, should also
be taken into account and be re-evaluated.
Regional variations in resistance must be
also considered for empiric treatment.
The use of parenteral antibiotics is
determined by the general condition of
the patient (e.g., nausea, vomiting) and
the severity of the infection; oral anti-
biotics can be continued as soon as the
clinical situtation has improved. After the
results of the susceptibility testing have
arrived, the antibiotic treatment should
be aligned accordingly. Treatment dura-
tion should continue for at least three to
five days beyond defervescence, depend-
ent on the removal of the complicating
factor. However, this recommendation
does not hold true for the treatment of
pyelonephritis with abscess formation or
chronic bacterial prostatitis, which should
usually continue for several weeks.
8. PREVENTION OF HAUTI
The best treatment is prevention; this
is also true for HAUTI. Since most of
| 10.3 |
HAUTI are CAUTI, optimal management
of any indwelling catheter and prevention
of CAUTI should be of highest priority in
urology. Some principles are listed here,
but for more details see Section 11.
8.1 Prevention of HAUTI in short-
term indwelling catheterization
According to CDC guidelines prevention
of catheter-associated urinary tract infec-
tions (CAUTI) is the gold standard for
prevention of HAUTI [39]. The following
have to be considered:
i. staff education about catheter
management,
ii. catheterization only when indicated
and prompt removal of indwelling
catheters,
iii. handwashing,
iv. catheter insertion with aseptic tech-
nique and sterile equipment, and
v. maintenance of a closed urinary
drainage system,
vi. silver- or antibiotic coated uri-
nary catheter may reduce the risk
for CAUTI [40–41] (LoE 1b), but
whether this also holds true for epi-
sodes of symptomatic CAUTI, needs
to be shown,
vii. a short term antibiotic prophylaxis
at urinary catheter removal may
prevent UTI after short-term ind-
welling catheterization [42] (LoE 1b),
however may increase the total anti-
biotic selection pressure.
8.2 Prevention of HAUTI in long-term
indwelling catheterization
The CDC guidelines mentioned earlier have
been developed only for the patients with
short-term indwelling urethral catheteriza-
tion. Catheter-associated bacteriuria (CA-B)
is ultimately not avoidable in patients with
long-term indwelling catheterization. Since
most CA-Bs with long-term indwelling
catheterization are asymptomatic [43] (LoE
3), prevention of symptomatic episodes is
583
Chapter | 10 | Healthcare associated urinary tract infections

Table 2 Bacterial spectrum of nosocomial uropathogens (≥ 2%) from distinct surveillance studies.

Antibiotic group Substance Dosage

oral IV

Aminopenicillin + BLI Ampicillin/Sulbactam 0.750g bid 0.75–3g tid

Amoxicillin/Clavulanic acid 1g bid or 0.625g tid 1.2–2.2g tid

Acylureidopenicillin + BLI Piperacillin/Tazobactam - 2.5–4.5g tid

Piperacillin/Combactam - 5g tid

Cephalosporine Gr. 1 Cephalexin Prophylaxis only -

Cephalosporine Gr. 2 Cefuroxime axetil 500mg bid -

Cefuroxime - 0.75–1.5g tid

Cefotiam - 1–2g b/tid

Cephalosporine Gr. 3 Cefpodoxime proxetil 200mg bid -

Ceftibuten 200–400mg qd -

Cephalosporine Gr. 3a Cefotaxime - 1–2g b/tid

Cetriaxone - 1–2g qd

Cephalosporine Gr. 3b Ceftazidime - 1–2g b/tid

Cephalosporine Gr. 4 Cefepime - 2g bid

Carbapenem Gr. 1 Imipenem - 0.5–1g q6–8h

Meropenem - 0.5–1g tid

Doripenem 0.5g tid

Carbapenem Gr. 2 Ertapenem - 1g qd

Fluoroquinolone Gr. 2 Ciprofloxacin 500–750mg bid 400mg bid

Ciprofloxacin XR 1000mg qd -

Fluoroquinolone Gr. 3 Levofloxacin 500–750mg qd 500mg qd

the aim to look for. The following practical
points are recommended, but the level of
evidence is low (LoE 4).
i. Hydration - the increase of urine
volume by hydration results in
wash-out of bacteria from the
urinary bladder and thus inhibiting
bacterial growth in the urinary
bladder. Hydration also prevents
obstruction of the urethral catheter
due to encrustation.
ii. Catheter exchange - routine catheter
exchange is usually performed every
4 to 6 weeks. However, the optimal
frequency of catheter exchange
depends on the individual patient,
because the catheter encrustation
sometimes happens in shorter
periods. In these cases, catheter
exchange should be performed more
frequently.
iii. No antimicrobial prophylaxis (AMP)
- AMP can delay the occurrence
of CAB. However, the incidence of
drug-resistant bacteria increases in
the presence of AMP. Therefore AMP
should be avoided
[6] (LoE 4).

584
 Epidemiology, treatment and prevention
8.3 Avoidance of long-term
indwelling catheterization
To prevent CAUTI long-term indwell-
ing catheterization should be avoided
at the first place. There are two fre-
quent indications for long-term bladder
catheterization:
– incomplete emptying of the bladder
and
– non-obstructive incontinence.
In both indications attempts, such as
i) medications for complete emptying the
urinary bladder, ii) operative techniques
such as deobstruction in case of pros-
tatic obstruction in males, or pelvic floor
reconstruction in case of pelvic floor dis-
orders, such as cystocele formation, iii)
clean intermittent catheterization (CIC)
or iv) urethral stent for benign pros-
tatic enlargement (BPE) [44–45] (LoE
3), [46–47] (LoE 3) may be considered.
There is little evidence whether CIC pre-
vents symptomatic UTIs [48] (LoE 4).
The frequency of CIC may be important
for the prevention of UTIs, because resid-
ual urine is a rich medium for bacterial
growth.
9. FURTHER RESEARCH
In the past most studies did not distin-
guish between HASUTI and HAASB.
There is now agreement, that HAASB
should not be treated with antimicrobials,
therefore routine screening for HAASB
seems to be not indicated. However, its
impact to induce infections when spread
to other patients is not well understood.
Prospective studies are needed to clar-
ify, whether systematic surveillance of
HAASB is recommended and if so, at
what time intervals.
10. CONCLUSIONS
HAUTIs are almost exclusively compli-
cated UTIs and mainly catheter associated.
| 10.3 |
HAASB should not be treated with anti-
microbials except before traumatizing
interventions of the urinary tract and in
pregnant women. Besides of an adequate
antibiotic therapy the complicating factors
need to be treated effectively. For initial
empiric therapy the regional susceptibility
profile of common uropathogens such as
E. coli must be known to choose the most
appropriate antibiotic. In case of severe,
bacteremic UTIs it has been shown that
an inadequate initial antibiotic regimen
has an elevated mortality. Before initia-
tion of antibiotic therapy a urine speci-
men for culture must be obtained to be
able to adapt the antibiotic regimen to the
susceptibility profile. Increasing antibiotic
resistance requires a more prudent use of
antimicrobial drugs also in the treatment
of HAUTIs.
REFERENCES
1. Hooton TM, Carlet, J.M., Duse,
A.G., Krieger, J.N., Steele, L., Sunakawa,
K., Definitions and epidemiology, in
Nosocomial and Health Care Associated
Infections in Urology, Naber KG,
Pechere, J.C., Kumazawa, J., Khoury,
S., Gerberding, J.L., Schaeffer, A.J.,
Editor. 2001, Health Publication Ltd.:
Plymouth, UK.
2. Horan TC, Andrus M, and Dudeck MA,
CDC/NHSN surveillance definition of
health care-associated infection and cri-
teria for specific types of infections in the
acute care setting. Am J Infect Control,
2008. 36(5): 309–32.
3. Gastmeier P, Kampf G, Wischnewski
N, Hauer T, Schulgen G, Schumacher
M, Daschner F, and Ruden H, Prevalence
of nosocomial infections in representative
German hospitals. J Hosp Infect, 1998.
38(1): 37–49.
4. Ruden H, Gastmeier P, Daschner
FD, and Schumacher M, Nosocomial
and community-acquired infections in
Germany. Summary of the results of the
First National Prevalence Study (NIDEP).
Infection, 1997. 25(4): 199–202.
585
Chapter | 10 | Healthcare associated urinary tract infections
5. [cited 2010 08.01.2010]; Available from:
http://www.cdc.gov/ncidod/dhqp/hai.html.
6. Maki DG and Tambyah PA, Engineering
out the risk for infection with urinary
catheters. Emerg Infect Dis, 2001. 7(2):
342–7.
7. Tambyah PA, Knasinski V, and Maki DG,
The direct costs of nosocomial catheter-
associated urinary tract infection in the
era of managed care. Infect Control Hosp
Epidemiol, 2002. 23(1): 27–31.
8. US Department of Health and Human
Services, Public Health Service, Agency
for Health Care Policy and Research.
1992: 115–127.
9. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. Levy SB and Marshall B, Antibacterial
resistance worldwide: causes, challenges
and responses. Nat Med, 2004. 10(12
Suppl): S122–9.
11. Safdar N and Maki DG, The commonality
of risk factors for nosocomial colonization
and infection with antimicrobial-resistant
Staphylococcus aureus, enterococcus,
gram-negative bacilli, Clostridium diffi-
cile, and Candida. Ann Intern Med, 2002.
136(11): 834–44.
12. Weinstein RA, Nosocomial infection
update. Emerg Infect Dis, 1998. 4(3):
416–20.
13. National Nosocomial Infections
Surveillance (NNIS) System Report, data
summary from January 1992 through
June 2004, issued October 2004. Am J
Infect Control, 2004. 32(8): 470–85.
14. Bouza E, San Juan R, Munoz P, Voss A,
and Kluytmans J, A European perspective
on nosocomial urinary tract infections II.
Report on incidence, clinical character-
istics and outcome (ESGNI-004 study).
European Study Group on Nosocomial
Infection. Clin Microbiol Infect, 2001.
7(10): 532–42.
15. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology
departments. Eur Urol, 2007. 51(4):
1100–12.
586
16. Naber KG, Urogenital infections: The piv-
otal role of the urologist. Eur Urol, 2006.
50(4): 657–9.
17. Johansen TE, Cek M, Naber KG,
Stratchounski L, Svendsen MV, and
Tenke P, Hospital acquired urinary tract
infections in urology departments: patho-
gens, susceptibility and use of antibiotics.
Data from the PEP and PEAP-studies. Int
J Antimicrob Agents, 2006. 28 Suppl 1:
S91–107.
18. Graves N, Tong E, Morton AP, Halton
K, Curtis M, Lairson D, and Whitby M,
Factors associated with health care-
acquired urinary tract infection. Am J
Infect Control, 2007. 35(6): 387–92.
19. Leone M, Albanese J, Garnier F, Sapin C,
Barrau K, Bimar MC, and Martin C, Risk
factors of nosocomial catheter-associated
urinary tract infection in a polyvalent
intensive care unit. Intensive Care Med,
2003. 29(7): 1077–80.
20. Saint S, Kaufman SR, Rogers MA, Baker
PD, Boyko EJ, and Lipsky BA, Risk fac-
tors for nosocomial urinary tract-related
bacteremia: a case-control study. Am J
Infect Control, 2006. 34(7): 401–7.
21. Tambić A, Tambić, T., Kuˇcišec-Tepeš, N.,
Prevalence and antibiotic sensitivity pat-
tern variations of bacterial isolates in
different settings and different periods of
time. Acta med Croatica, 1996. 50: 5–10.
22. Jones RN, Kugler KC, Pfaller MA, and
Winokur PL, Characteristics of patho-
gens causing urinary tract infections in
hospitals in North America: results from
the SENTRY Antimicrobial Surveillance
Program, 1997. Diagn Microbiol Infect
Dis, 1999. 35(1): 55–63.
23. Mathai D, Jones RN, and Pfaller MA,
Epidemiology and frequency of resistance
among pathogens causing urinary tract infec-
tions in 1,510 hospitalized patients: a report
from the SENTRY Antimicrobial Surveillance
Program (North America). Diagn Microbiol
Infect Dis, 2001. 40(3): 129–36.
24. Bouza E, San Juan R, Munoz P, Voss
A, and Kluytmans J, A European per-
spective on nosocomial urinary tract
infections I. Report on the microbiology
workload, etiology and antimicrobial sus-
ceptibility (ESGNI-003 study). European
Study Group on Nosocomial Infections.
 Epidemiology, treatment and prevention
Clin Microbiol Infect, 2001. 7(10):
523–31.
25. Wagenlehner FM, Krcmery S, Held C,
Klare I, Witte W, Bauernfeind A,
Schneider I, and Naber KG,
Epidemiological analysis of the spread of
pathogens from a urological ward using
genotypic, phenotypic and clinical param-
eters. Int J Antimicrob Agents, 2002.
19(6): 583–91.
26. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
27. Drusano GL, Preston SL, Hardalo C,
Hare R, Banfield C, Andes D, Vesga O,
and Craig WA, Use of preclinical data for
selection of a phase II/III dose for evern-
imicin and identification of a preclini-
cal MIC breakpoint. Antimicrob Agents
Chemother, 2001. 45(1): 13–22.
28. Kahlmeter G, An international survey
of the antimicrobial susceptibility of
pathogens from uncomplicated urinary
tract infections: the ECO.SENS Project.
J Antimicrob Chemother, 2003. 51(1):
69–76.
29. Gordon KA and Jones RN, Susceptibility
patterns of orally administered antimi-
crobials among urinary tract infection
pathogens from hospitalized patients
in North America: comparison report to
Europe and Latin America. Results from
the SENTRY Antimicrobial Surveillance
Program (2000). Diagn Microbiol Infect
Dis, 2003. 45(4): 295–301.
30. Costerton JW, Introduction to biofilm.
Int J Antimicrob Agents, 1999. 11(3–4):
217–21; discussion 237–9.
31. Reid G, Biofilms in infectious disease and
on medical devices. Int J Antimicrob Agents,
1999. 11(3–4): 223–6; discussion 237–9.
32. Goto T, Nakame Y, Nishida M, and Ohi
Y, Bacterial biofilms and catheters in
experimental urinary tract infection.
Int J Antimicrob Agents, 1999. 11(3–4):
227–31; discussion 237–9.
33. Tsukamoto T, Matsukawa M, Sano M,
Takahashi S, Hotta H, Itoh N, Hirose T,
and Kumamoto Y, Biofilm in complicated
urinary tract infection. Int J Antimicrob
| 10.3 |
Agents, 1999. 11(3–4): 233–6; discussion
237–9.
34. Pea F, Pavan F, Di Qual E, Brollo L,
Nascimben E, Baldassarre M, and
Furlanut M, Urinary pharmacokinetics
and theoretical pharmacodynamics of
intravenous levofloxacin in intensive care
unit patients treated with 500 mg b.i.d.
for ventilator-associated pneumonia. J
Chemother, 2003. 15(6): 563–7.
35. Zhao X and Drlica K, A unified anti-
mutant dosing strategy. J Antimicrob
Chemother, 2008. 62(3): 434–6.
36. Elhanan G, Sarhat M, and Raz R,
Empiric antibiotic treatment and the
misuse of culture results and antibiotic
sensitivities in patients with community-
acquired bacteraemia due to urinary tract
infection. J Infect, 1997. 35(3): 283–8.
37. Wagenlehner E, Niemetz A, and Naber G,
[Spectrum of pathogens and resistance to
antibiotics in urinary tract infections and
the consequences for antibiotic treatment:
study of urology inpatients with urinary
tract infections (1994–2001)]. Urologe A,
2003. 42(1): 13–25.
38. Grabe M (chairman) BM, Bjerklund-
Johansen TE, Botto H, Cek M, Lobel
B, Naber KG, Palou J, Tenke P,
Wagenlehner F, Guidelines on urological
infections., in European Association of
Urology Guidelines, Urology EAo, Editor.
2009, European Association of Urology
Arnhem, The Netherlands. p. 1–110.
39. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008. 31
Suppl 1: S68–78.
40. Karchmer TB, Giannetta ET, Muto CA,
Strain BA, and Farr BM, A randomized
crossover study of silver-coated urinary
catheters in hospitalized patients. Arch
Intern Med, 2000. 160(21): 3294–8.
41. Al-Habdan I, Sadat-Ali M, Corea JR,
Al-Othman A, Kamal BA, and Shriyan
DS, Assessment of nosocomial urinary
tract infections in orthopaedic patients: a
prospective and comparative study using
two different catheters. Int Surg, 2003.
88(3): 152–4.
587
Chapter | 10 | Healthcare associated urinary tract infections
42. Pfefferkorn U, Lea S, Moldenhauer J,
Peterli R, von Flue M, and Ackermann C,
Antibiotic prophylaxis at urinary catheter
removal prevents urinary tract infections:
a prospective randomized trial. Ann Surg,
2009. 249(4): 573–5.
43. Tambyah PA and Maki DG, Catheter-
associated urinary tract infection is rarely
symptomatic: a prospective study of 1,497
catheterized patients. Arch Intern Med,
2000. 160(5): 678–82.
44. Oesterling JE, A permanent, epithelial-
izing stent for the treatment of benign pro-
static hyperplasia. Preliminary results. J
Androl, 1991. 12(6): 423–8.
45. Gottfried HW, Schlmers HP, Gschwend J,
Brandle E, and Hautmann RE,
588
Thermosensitive stent (Memotherm)
for the treatment of benign prostatic
hyperplasia. Arch Esp Urol, 1994. 47(9):
933–43; discussion 943–6.
46. Ala-Opas M, Talja M, Tiitinen J, Hellstrom
P, Heikkinen A, and Nurmi M, Prostakath
in urinary outflow obstruction. Ann Chir
Gynaecol Suppl, 1993. 206: 14–8.
47. Poulsen AL, Schou J, Ovesen H, and
Nordling J, Memokath: a second genera-
tion of intraprostatic spirals. Br J Urol,
1993. 72(3): 331–4.
48. Moore KN, Fader M, and Getliffe K,
Long-term bladder management by inter-
mittent catheterisation in adults and
children. Cochrane Database Syst Rev,
2007(4): CD006008.
|10.4|
Urinary tract infections in
long term care patients
Lindsay E. Nicolle
Professor, Department of Internal Medicine and Medical Microbiology, University of Manitoba, Health Sciences Centre,
Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9
Tel: (204) 787-7029, Fax: (204) 787-4826, e-mail: lnicolle@hsc.mb.ca
ABSTRACT
Urinary tract infection is one of the
most common problems encountered in
residents of long term care facilities.
Asymptomatic bacteriuria is present in
25–50% of women and 15–40% of men
without a chronic indwelling catheter, and
is associated with incontinence of blad-
der and bowel and increasing functional
impairment. Asymptomatic bacteriuria
appears to be benign, and antimicrobial
treatment does not improve outcomes.
Symptomatic urinary tract infection in
the resident without a chronic indwell-
ing catheter is diagnosed when localiz-
ing genitourinary signs or symptoms are
present and a urine culture is positive.
Impaired communication, chronic comor-
bid symptoms, and the high prevalence
of bacteriuria interfere with diagnostic
precision. Non-specific decline in resident
function or nonlocalizing signs and symp-
toms, even with a positive urine culture,
should not be interpreted as urinary tract
infection. Pyuria is expected with both
symptomatic and asymptomatic infec-
tion, and is not an indication for anti-
microbial therapy. For residents with
long term indwelling catheters, the most
common presentation is fever by itself
without localizing genitourinary find-
ings. Prophylactic antimicrobial therapy
should be given prior to invasive geni-
tourinary procedures likely to be associ-
ated with mucosal bleeding, to prevent
post procedure sepsis. Removal of a long
term indwelling catheter whenever feasi-
ble, avoiding catheter trauma, and early
identification of obstruction will likely
prevent symptomatic urinary infection.
Other strategies effective to limit asymp-
tomatic or symptomatic urinary tract
infection have not yet been identified.
Key words: elderly, nursing home, long
term care, bacteriuria, urinary infection,
chronic urinary catheter
Chapter | 10 | Health care associated urinary tract infections
SUMMARY OF RECOMMENDATIONS
Diagnosis
Clinical diagnosis
1. The diagnosis of symptomatic uri-
nary infection for residents of long
term care facilities without a chronic
indwelling catheter should be made
only when acute localizing genitouri-
nary signs or symptoms are present
(GoR B) [1–2].
2. For residents with a chronic indwell-
ing catheter, a diagnosis of sympto-
matic urinary infection requires the
presence of fever, acute confusion,
rigors, or costovertebral angle pain
or tenderness without an alternate
source, with or without other localiz-
ing genitourinary signs or symptoms
(GoR B) [1–2].
Laboratory diagnosis
3. Screening of asymptomatic residents
for bacteriuria, with or without an
indwelling catheter, is not recom-
mended (GoR A) [1, 3].
4. A quantitative count of ≥ 105 cfu/ml
is appropriate for the microbiologic
diagnosis of urinary infection in resi-
dents with or without an indwelling
catheter (GoR B).
5. For individuals with localizing geni-
tourinary symptoms, lower quantita-
tive counts may also be consistent
with symptomatic infection (GoR C).
6. For urine specimens collected from
external condom catheters in men,
the appropriate quantitative count is
≥105 cfu/ml (GoR B) [4–5].
7. For specimens obtained by in and
out catheter, ≥ 103 cfu/ml is the
quantitative criteria for bacteriuria
(GoR C) [3].
8. The presence of pyuria with bac-
teriuria without localizing clinical
signs or symptoms is not sufficient
590
to diagnose symptomatic urinary
tract infection, and is not an indi-
cation for antimicrobial therapy
(GoR B) [1, 3].
9. Urine specimens for culture should
be collected, wherever possible, by a
clean catch technique (GoR B).
10. For women who cannot cooperate for
specimen collection, a urine speci-
men should be obtained by in and
out catheter (GoR C).
11. For men with voiding managed by
external condom catheters, a urine
specimen can be obtained following
cleaning of the glans and meatus and
after application of a freshly applied
clean condom catheter and drainage
bag (GoR B) [4–5].
12. For residents with chronic indwell-
ing catheters, the indwelling cath-
eter should be removed and replaced
with a urine specimen for culture
obtained through the newly inserted
catheter prior to institution of anti-
microbial therapy (GoR A) [2, 6].
Treatment
13. Asymptomatic bacteriuria should
not be treated in residents of long
term care facilities whether or not
a chronic indwelling catheter is
present (GoR A) [1, 3].
14. Antimicrobial therapy is selected
considering the known or suspected
infecting organism, patient toler-
ance, prevalence of antimicrobial
resistance in the institution, and doc-
umented effectiveness of the agent in
urinary tract infection (GoR C)
15. Parenteral antimicrobial therapy
should be initiated for patients
with hemodynamic instability, who
are unable to tolerate or absorb
oral medication, or with known or
suspected resistant organisms for
which oral therapy is not available
(GoR C).
 Urinary tract infections in long term care patients
16. For symptomatic infection in men or
suspected renal infection in women
the treatment course should be 7–10
days (GoR B).
17. Women with symptoms of acute cys-
titis should be treated with a short
course of antimicrobial therapy
appropriate for the antimicrobial
used (GoR A) [7].
18. For men with suspected chronic
bacterial prostatitis manifesting as
recurrent acute cystitis, retreatment
with 6–12 weeks antimicrobial ther-
apy may be considered (GoR B) [8].
19. For residents with chronic indwell-
ing catheters, duration of therapy
should not exceed 7 days when there
has been a prompt clinical response
following institution of antimicrobial
therapy (GoR C).
Prevention
20. Residents with asymptomatic bacte-
riuria should receive antimicrobial
prophylaxis prior to genitourinary
interventions where mucosal bleed-
ing is anticipated (GoR A) [3].
21. Use of cranberry juice is not recom-
mended for the prevention of symp-
tomatic urinary infection (GoR A) [9].
22. Topical estrogen is not recommended
for the prevention of asymptomatic
or symptomatic urinary tract infec-
tion (GoR B) [10–11].
23. Indwelling urethral catheters should
be used only with clear indications
(GoR C).
24. The need for an indwelling urethral
catheter should be reviewed on a
continuing basis, and the catheter
discontinued as soon as feasible
(GoR C)
25. For men, an external condom cath-
eter should be used when possible
rather than an indwelling urethral
catheter (GoR B) [12].
| 10.4 |
26. Intermittent catheterization should
be used rather than chronic ind-
welling catheters where possible
(GoR B).
27. Intermittent catheterization should
use a clean technique (GoR A) [13].
28. For residents with chronic indwell-
ing catheters, catheter care must
minimize mucosal trauma and iden-
tify catheter obstruction promptly
(GoR C).
29. Routine catheter changes are not rec-
ommended to prevent symptomatic
urinary tract infection (GoR C).
30. Antimicrobial therapy at the time of
catheter change is not recommended
(GoR B) [14–15].
31. Routine use of antimicrobial or silver
coated catheters is not recommended
(GoR B) [1].
1. INTRODUCTION
Urinary tract infection is the most com-
mon infection which occurs in long term
care facilities [16]. The majority of these
infections are asymptomatic, and benign
(3). However, symptomatic infection does
occur, and urinary infection is a frequent
indication for antimicrobial therapy in
these settings [2]. Clinical ascertain-
ment of symptomatic infection may be
problematic given chronic genitourinary
symptoms, difficulties in communica-
tion and atypical presentations [2, 17].
This uncertainty, together with the high
prevalence of bacteriuria, leads to anti-
microbial overuse and the accompanying
problems of adverse effects from anti-
microbials and increased antimicrobial
resistance.
This guideline provides recommen-
dations for the management of urinary
infection in residents of long term care
facilities. It addresses both asymptomatic
and symptomatic urinary tract infection,
and includes patients with and without
591
Chapter | 10 | Health care associated urinary tract infections
long term indwelling catheters. The dis-
cussion is relevant to residents without
a chronic indwelling catheter unless spe-
cifically noted to address the catheterized
individual.
2. METHODS
This document incorporated and updated
the 2005 Infectious Diseases Society of
America Guideline for the management
of asymptomatic bacteriuria [3] and the
2001 SHEA Guideline for urinary tract
infections in long term care facilities
[1]. These were updated using a sys-
tematic literature search performed in
MEDLINE, Cochrane, and Embase. The
key words used included urinary infec-
tion, bacteriuria, nursing homes, and
long term care facility. The limitations
included adult clinical studies, English,
and peer reviewed. A total of 145 pub-
lications were identified, and screened
by title and abstract. After exclusion
of duplicates, a total of 8 were included
in the review. The information identi-
fied through the literature review was
supplemented by citations in published
reports as well as other papers identified
by the author.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [18–19].
3. DEFINITION OF THE DISEASE
Urinary tract infection is the isolation of
bacteria or yeast from the urine in counts
meeting accepted quantitative criteria.
Asymptomatic urinary infection, or bac-
teriuria, is present when microbiologic
criteria are met but there are no acute
signs or symptoms referable to the uri-
nary tract. Symptomatic infection may be
restricted to the bladder (cystitis), affect
the kidneys (pyelonephritis) or, in men,
the prostate.
592
4. EPIDEMIOLOGY
4.1 Prevalence of bacteriuria
Studies consistently report a prevalence
of asymptomatic bacteriuria in women in
long term care facilities of 25–50%, and
in men from 15–40% [3, 16, 20]. A recent
study of residents of long term care facili-
ties in three municipal areas of Sweden is
consistent with earlier reports. The preva-
lence of bacteriuria was 43% in women and
30% in men, with 23% and 16% remaining
bacteriuric on a second consecutive urine
specimen [20]. The mean age of these resi-
dents was 84.6 years, and 47% of residents
in these facilities were excluded because of
severe incontinence or dementia. As incon-
tinence and dementia is strongly associ-
ated with bacteriuria, the prevalence in
the full population would have been even
higher than reported [1, 16].
Bacteriuria in long term care facility
residents is dynamic [21]. Repeated prev-
alence surveys report that individuals
who are initially not bacteriuric become
positive, and residents with bacteriuria
may become negative, often following
antimicrobial therapy. Some residents
have persistent infection with the same
organism for months or years, while oth-
ers have repeated reinfections with new
organisms [22–23].
4.2 Incidence of symptomatic
urinary infection
Symptomatic urinary infection occurs
infrequently relative to the high preva-
lence of bacteriuria. Rates of sympto-
matic urinary infection vary from 0.1 to
2.4/1,000 resident days [16]. This varia-
tion reflects underlying differences in the
populations studied, as well as different
definitions used for case ascertainment
[16, 24]. A mean of 0.6 symptomatic uri-
nary infections/1,000 residents’ days was
reported in a group of facilities in one US
state when uniform surveillance meth-
odology, including consistent definitions,
was used [24].
 Urinary tract infections in long term care patients
4.3 Risk factors
The prevalence of asymptomatic bacteri-
uria increases with increasing functional
disability [16, 21]. Long term care facil-
ity residents with incontinence of bladder
or bowel, dementia, and who score poorly
in measures of functional ability have an
increased prevalence. Voiding abnormal-
ity which accompanies the chronic neu-
rologic diseases which often precipitate
institutional care likely explains the high
prevalence observed. Oral [10] or topical
[11] estrogen therapy does not influence
the frequency of bacteriuria or symp-
tomatic urinary infection in women. In
men, an additional contributing factor is
prostatic hypertrophy and chronic pros-
tatitis [8]. Men with continence managed
using external condom catheters have a
higher incidence and prevalence of bac-
teriuria, with the highest risk observed
when there is obstruction or manipula-
tion of the condom or drainage tubing
[12]. Cross-sectional [25] and prospective
[26] studies have not reported any associ-
ation of bacteriuria or symptomatic infec-
tion with increased post-void residual
urine volume in men or women. Other
risk factors for development of sympto-
matic urinary infection, other than the
presence of a chronic indwelling catheter,
are not well defined.
4.4 Microbiology
A wide variety of organisms are isolated
from both asymptomatic and sympto-
matic urinary tract infection [16, 21].
For women, Escherichia coli remains
the most common organism, although
this species is proportionally lower than
observed in noninstitutionalized older
populations. For men, Enterococcus
spp and Proteus mirabilis have been
reported to be the most frequent organ-
isms isolated, but the spectrum of infect-
ing organisms varies among institutions.
From 10 to 25% of residents with bacte-
riuria will have more than one organism
| 10.4 |
isolated. Repeated prior antimicrobial
exposure and opportunities for transmis-
sion of organisms within the long term
care setting promote isolation of organ-
isms of increased antimicrobial resist-
ance [27–28].
4.5 Chronic indwelling urethral
catheter
From 4–7% of residents of long term care
facilities have voiding managed with a
chronic indwelling catheter [29]. The
limited indications for use of long term
catheters include obstruction, to assist
with healing of a pressure ulcer and,
uncommonly, in managing incontinence
for patient comfort or end of life care.
Individuals with a chronic indwelling
catheter are always bacteriuric, usually
with 2–5 organisms isolated at any time
[30]. There are a wide variety of organ-
isms isolated, with urease producing
organisms such as Proteus mirabilis and
Providencia stuartii over-represented.
Bacteria produce and grow on the inter-
nal and external catheter surfaces within
a biofilm which incorporates protein and
metal ions from the urine. This provides
a protected environment which limits
exposure to host defenses as well as anti-
microbials in the urine [31].
The presence of a chronic indwelling
catheter is associated with excess mor-
bidity from urinary infection [29–30].
Residents with a chronic indwelling
catheter, compared with bacteriuric
residents without catheters, have been
reported to have three times more epi-
sodes of fever of presumed urinary
source [29], from three to 39 times the
frequency of bacteremia from a uri-
nary source [16], and seven times more
frequent histologic evidence of acute
pyelonephritis at autopsy [29]. Residents
with an indwelling catheter also have
increased mortality, but this is attrib-
uted to increased functional and medical
impairment in these individuals, rather
than urinary infection [32].
593
Chapter | 10 | Health care associated urinary tract infections
5. CLINICAL EVALUATION
5.1 Symptomatic urinary infection
The diagnosis of lower urinary tract infec-
tion (cystitis) is made when acute local-
izing genitourinary findings are present
including dysuria, new or increased
incontinence, urgency, frequency, and
hematuria. For pyelonephritis, costover-
tebral angle pain or tenderness with or
without fever are the usual localizing
symptoms. Chronic genitourinary symp-
toms are common in these individuals
including incontinence, nocturia, and fre-
quency. These chronic symptoms are not
improved with treatment of bacteriuria,
and should not be interpreted as sympto-
matic infection (LoE 2a) [1]. In addition,
a presentation of nonspecific, nonlocaliz-
ing symptoms, such as decline in general
clinical status, is not symptomatic uri-
nary infection, even with a positive urine
culture (LoE 2b) [1].
Fever without localizing findings is the
most common presentation for residents
with chronic indwelling catheters [29].
Costovertebral angle pain or tenderness
may be present. Severe systemic infection
attributable to urosepsis may present as
an acute confusional state in residents
with or without a catheter, similar to any
other serious infections in this population.
5.2 Microbiologic diagnosis
A urine specimen for culture should be
obtained prior to initiating antimicrobial
therapy for any resident with presumed
urinary tract infection. A clean catch
voided method is preferred to collect the
urine specimen from residents without
chronic indwelling catheters. For women
with severe incontinence or who are oth-
erwise unable to cooperate, it may not be
possible to obtain a clean catch specimen.
In these cases, where a urine specimen is
necessary for patient management, the
specimen should be collected by using an
in and out catheter (LoE 4) [1]. For men
594
with voiding managed with an external
condom catheter, a specimen may be col-
lected using a freshly applied clean con-
dom and leg bag (LoE 2a) [4–5].
A urine specimen obtained from an ind-
welling catheter in place for several days
will sample the biofilm on the interior of
the catheter as well as bladder urine [6,
29]. To obtain a more reliable urine speci-
men for microbiology by sampling only
bladder urine, the chronic indwelling cath-
eter should be replaced and a specimen
obtained from the new catheter prior to ini-
tiating antimicrobial therapy (LoE 2a) [6].
5.3 Pyuria
Pyuria is universally present with symp-
tomatic urinary tract infection [33].
However, it is also present in virtually all
residents with asymptomatic bacteriuria,
and as many as 30% of residents without
bacteriuria [16, 21]. Thus, the presence of
pyuria identified either on urinalysis or
with leukocyte esterase screening is not
useful to differentiate symptomatic from
asymptomatic infection, and is not an indi-
cation for antimicrobial therapy (LoE 2a).
The absence of pyuria, however, has a high
negative predictive value and is reliable to
exclude a diagnosis of urinary infection [2].
6. TREATMENT
6.1 Asymptomatic bacteriuria
Clinical trials have consistently docu-
mented no benefits with antimicrobial
treatment of asymptomatic bacteriuria in
long term care facility residents (LoE 1a)
[1, 3]. Specifically, treatment of asympto-
matic bacteriuria does not improve chronic
genitourinary symptoms, prevent sub-
sequent symptomatic episodes, improve
survival, or decrease the overall preva-
lence of bacteriuria. On the other hand
treatment is associated with increased
adverse effects attributed to the medica-
tion, increased reinfection with organisms
of increased resistance, and cost.
 Urinary tract infections in long term care patients
6.2 Symptomatic infection
When symptoms are mild or uncertain,
it is preferable to delay initiation of anti-
microbial therapy until the results of a
urine culture are available. This allows
use of optimal, targeted antimicrobial
therapy and, in some cases, symptoms
may resolve spontaneously so antimicro-
bial therapy is not required.
Ascertainment of symptoms may be
difficult because of impaired communica-
tion and chronic genitourinary symptoms
[1–2]. A consensus guideline has provided
recommendations for criteria to be met
prior to initiating antimicrobial ther-
apy for presumed symptomatic urinary
tract infection [34]. For residents with-
out indwelling catheters, these criteria
are either acute dysuria by itself, or one
of fever, acute mental deterioration, or
chills together with at least one localizing
genitourinary symptom (new or worsen-
ing urgency, frequency, suprapubic pain,
gross hematuria, costovertebral angle
tenderness, or urinary incontinence).
Thus, genitourinary signs or symptoms
must be present. Cloudy or foul smelling
urine are not, by themselves, sufficient to
diagnose symptomatic infection [17]. For
residents with a chronic indwelling cath-
eter, the consensus recommendations for
institution of antimicrobial therapy for
urinary infection include at least one of
fever, new costovertebral angle tender-
ness, rigors or new onset delirium with no
alternate source. These consensus guide-
lines have been validated in a prospective
randomized trial which document that
application of the guidelines is safe and
associated with a decreased overall use
of antimicrobial therapy for urinary tract
infection (LoE 1b) [35].
For residents with a chronic indwell-
ing catheter, the catheter should be
replaced and a urine specimen for culture
obtained immediately prior to institut-
ing antimicrobial therapy (LoE 1b) [30]. A
prospective, randomized trial of catheter
replacement or no catheter replacement
| 10.4 |
prior to antimicrobial treatment for
symptomatic urinary infection reported a
shorter time to defervescence of fever, and
decreased frequency of recurrent symp-
tomatic urinary infection post-therapy
with catheter replacement, in addition
to obtaining a more reliable urine speci-
men for microbiology [6]. The clinical
benefits are assumed to reflect removal of
the biofilm on the catheter where organ-
isms may persist despite antimicrobial
therapy.
6.3 Medication/drug therapy
The choice of antimicrobial agent and
duration of therapy do not differ for insti-
tutionalized or non-institutionalized
older individuals. Antimicrobial selection
is determined by severity of presenta-
tion, site of infection, known or predicted
infecting organism, and patient tolerance.
The selection of empiric antimicrobial
therapy should consider the prevalence
of resistant organisms in the institution.
Few clinical trials directly compare differ-
ent regimens for management of urinary
tract infection in long term care facility
residents. One study compared a cipro-
floxacin suspension with trimethoprim/
sulfamethoxazole (TMP/SMX) in women
with cystitis and reported improved short
term cure rates with the ciprofloxacin.
This was largely attributable to higher
baseline TMP/SMX resistance [36].
6.4 Duration of therapy
A double-blind randomized controlled
trial compared 3 to 7 days ciprofloxacin
therapy for symptomatic cystitis in
older women, including some residents
of long term care facilities. The shorter
course of therapy had similar efficacy
and a lower frequency of side-effects
(LoE 1b) [7]. A more prolonged course
of therapy of 7–10 days should be con-
sidered for pyelonephritis or if there is
an early symptomatic recurrence after
short course therapy. For men the rec-
ommended duration of treatment is 7–14
595
Chapter | 10 | Health care associated urinary tract infections
days, but there are no clinical trials
defining optimal duration. If recurrent
cystitis in men is attributed to chronic
bacterial prostatitis, retreatment with
a more prolonged course of 6–12 weeks
is recommended [8], but this more pro-
longed course has not been evaluated in
long term care facility residents (LoE 1b).
The optimal duration of therapy for indi-
viduals with chronic indwelling catheters
has not been addressed in clinical trials.
If there is a prompt response to antimi-
crobial therapy, a duration of only 7 days
is recommended to limit emergence of
resistant organisms [17].
7. PREVENTION
For residents without indwelling urethral
catheters, clinical trials have not identi-
fied specific interventions to decrease the
prevalence of asymptomatic bacteriuria
in long term care facility residents. Risk
factors associated with development of
symptomatic infection are also not well
characterized, and no interventions have
been documented to be effective in pre-
venting symptomatic infection specifi-
cally in this population. Trials evaluating
estrogen use for women [10] or daily cran-
berry juice [9] did not report a decrease in
symptomatic infection (LoE 1b). Low dose
prophylactic antimicrobial therapy may
prevent symptomatic cystitis in older
women, as in younger, but this would not
usually be recommended for women resi-
dent in long term care facilities because
of concerns with increased antimicrobial
resistance and transmission of organisms
among residents. When persons with
asymptomatic bacteriuria undergo trau-
matic genitourinary interventions (e.g.
transurethral resection of the prostate)
antimicrobial therapy should be initiated
immediately prior to the intervention to
prevent bacteremia or sepsis (LoE 1b) [3].
The most effective means to prevent
symptomatic infection or bacteriuria
in residents with a chronic indwelling
596
catheter is to avoid use of the catheter or
to limit duration of use, if possible. For
men with incontinence, an external con-
dom catheter may be used (LoE 3) [12].
For some residents, intermittent cath-
eterization to assist with voiding rather
than an indwelling catheter is an option
(LoE 3). A prospective randomized trial
reported that clean and sterile technique
for intermittent catheterization have sim-
ilar risks of bacteriuria and symptomatic
infection but clean technique is less costly
(LoE 1b) [13]. Thus, use of the clean tech-
nique is preferred. When an indwelling
catheter must be used, symptomatic epi-
sodes can likely be minimized by avoid-
ing catheter trauma to the mucosa, and
prompt identification and management
of catheter obstruction. Prophylactic
antimicrobial therapy does not prevent
symptomatic infection in residents with
chronic indwelling catheters, but is asso-
ciated with infection with organisms
of increased resistance (LoE 1b) [37].
When catheters are changed there is a
risk of bacteremia, but limited morbid-
ity has been reported, so antimicrobial
therapy with catheter change is not rec-
ommended (LoE 3) [14–15]. There are no
studies to suggest routine changing of
chronic indwelling catheters is beneficial.
Catheters should be changed only if they
are obstructed, otherwise not function-
ing, or prior to treatment of symptomatic
infection. Antimicrobial coated catheters
have not been evaluated for patients with
chronic catheters, but would not be antic-
ipated to have a benefit as any impact on
bacteriuria with these devices appears to
be short-term (LoE 4).
8. GUIDELINES
Consensus guidelines have been pub-
lished to address urinary tract infection
in long term care facilities. The Society
for Healthcare Epidemiology of America
(SHEA) guidelines specifically address
management of urinary infection in
 Urinary tract infections in long term care patients
long term care [1]. There are also guide-
lines identifying diagnostic criteria
for surveillance of urinary infection
[38] and when to initiate antimicrobial
therapy for urinary tract infection [34].
The management of asymptomatic bac-
teriuria is addressed in the Infectious
Diseases Society of America (IDSA)
guidelines on this topic [3]. Other IDSA
guidelines for evaluation of fever and
infection in long term care facilities pro-
vide recommendations for clinical and
microbiologic diagnosis of urinary tract
infection [2].
9. FURTHER RESEARCH
Further studies to clarify symptoms con-
sistent with urinary infection in this pop-
ulation are necessary. Exploration of the
utility of laboratory investigations such
as urinary cytokines and other urinary
markers may also improve diagnostic pre-
cision. Prospective, randomized clinical
trials which identify appropriate dura-
tions of therapy for both men and women,
including those with chronic indwelling
catheters, are necessary. Finally, a resid-
ual important question with respect to
prevention of complications with chronic
indwelling catheters is whether there
are any benefits with routine catheter
change.
10. CONCLUSIONS
Urinary tract infection is common in
the long term care facility popula-
tion. Infection is usually asymptomatic.
However, the identification of sympto-
matic infection is problematic because
of difficulties in assessment of signs and
symptoms, and the high prevalence of
bacteriuria. Individuals with a long term
indwelling catheter have increased mor-
bidity from urinary infection. Efforts to
prevent infection should focus on limiting
the use of chronic indwelling catheters
| 10.4 |
as well as limiting inappropriate use of
antimicrobials for bacteriuric individuals
without an indwelling catheter and with
non localizing symptoms.
REFERENCES
1. Nicolle LE, Urinary tract infections in
long-term-care facilities. Infect Control
Hosp Epidemiol, 2001. 22(3): 167–75.
2. High KP, Bradley SF, Gravenstein S,
Mehr DR, Quagliarello VJ, Richards
C, and Yoshikawa TT, Clinical practice
guideline for the evaluation of fever and
infection in older adult residents
of long-term care facilities: 2008 update
by the Infectious Diseases Society of
America. Clin Infect Dis, 2009.
48(2): 149–71.
3. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines for
the diagnosis and treatment of asympto-
matic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
4. Ouslander JG, Greengold BA, Silverblatt
FJ, and Garcia JP, An accurate method
to obtain urine for culture in men with
external catheters. Arch Intern Med, 1987.
147(2): 286–8.
5. Nicolle LE, Harding GK, Kennedy J,
McIntyre M, Aoki F, and Murray D, Urine
specimen collection with external devices
for diagnosis of bacteriuria in elderly
incontinent men. J Clin Microbiol, 1988.
26(6): 1115–9.
6. Raz R, Schiller D, and Nicolle LE,
Chronic indwelling catheter replacement
before antimicrobial therapy for symp-
tomatic urinary tract infection. J Urol,
2000. 164(4): 1254–8.
7. Vogel T, Verreault R, Gourdeau M, Morin
M, Grenier-Gosselin L, and Rochette L,
Optimal duration of antibiotic therapy for
uncomplicated urinary tract infection in
older women: a double-blind randomized
controlled trial. CMAJ, 2004. 170(4):
469–73.
8. Schaeffer AJ, Clinical practice. Chronic
prostatitis and the chronic pelvic pain
syndrome. N Engl J Med, 2006. 355(16):
1690–8.
597
Chapter | 10 | Health care associated urinary tract infections
9. Avorn J, Monane M, Gurwitz JH, Glynn
RJ, Choodnovskiy I, and Lipsitz LA,
Reduction of bacteriuria and pyuria after
ingestion of cranberry juice. JAMA, 1994.
271(10): 751–4.
10. Ouslander JG, Greendale GA, Uman G, Lee
C, Paul W, and Schnelle J, Effects of oral
estrogen and progestin on the lower urinary
tract among female nursing home residents.
J Am Geriatr Soc, 2001. 49(6): 803–7.
11. Maloney C and Oliver ML, Effect of local
conjugated estrogens on vaginal pH in
elderly women. J Am Med Dir Assoc,
2001. 2(2): 51–5.
12. Ouslander JG, Greengold B, and Chen S,
External catheter use and urinary tract
infections among incontinent male nurs-
ing home patients. J Am Geriatr Soc,
1987. 35(12): 1063–70.
13. Duffy LM, Cleary J, Ahern S, Kuskowski
MA, West M, Wheeler L, and Mortimer
JA, Clean intermittent catheterization:
safe, cost-effective bladder management
for male residents of VA nursing homes. J
Am Geriatr Soc, 1995. 43(8): 865–70.
14. Jewes LA, Gillespie WA, Leadbetter A,
Myers B, Simpson RA, Stower MJ, and
Viant AC, Bacteriuria and bacteraemia
in patients with long-term indwelling
catheters – a domiciliary study. J Med
Microbiol, 1988. 26(1): 61–5.
15. Bregenzer T, Frei R, Widmer AF, Seiler
W, Probst W, Mattarelli G, and Zimmerli
W, Low risk of bacteremia during catheter
replacement in patients with long-term
urinary catheters. Arch Intern Med, 1997.
157(5): 521–5.
16. Nicolle LE, Strausbaugh LJ, and
Garibaldi RA, Infections and antibi-
otic resistance in nursing homes. Clin
Microbiol Rev, 1996. 9(1): 1–17.
17. Nicolle LE, Consequences of asympto-
matic bacteriuria in the elderly. Int J
Antimicrob Agents, 1994. 4(2): 107–11.
18. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
19. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
598
20. Hedin K, Petersson C, Wideback
K, Kahlmeter G, and Molstad S,
Asymptomatic bacteriuria in a population
of elderly in municipal institutional care.
Scand J Prim Health Care, 2002. 20(3):
166–8.
21. Nicolle LE, Asymptomatic bacteriuria
in the elderly. Infect Dis Clin North Am,
1997. 11(3): 647–62.
22. LiPuma JJ, Stull TL, Dasen SE, Pidcock
KA, Kaye D, and Korzeniowski OM, DNA
polymorphisms among Escherichia coli
isolated from bacteriuric women. J Infect
Dis, 1989. 159(3): 526–32.
23. Rahav G, Pinco E, Bachrach G, and
Bercovier H, Molecular epidemiology of
asymptomatic bacteriuria in the elderly.
Age Ageing, 2003. 32(6): 670–3.
24. Stevenson KB, Moore J, Colwell H, and
Sleeper B, Standardized infection sur-
veillance in long-term care: interfacility
comparisons from a regional cohort of
facilities. Infect Control Hosp Epidemiol,
2005. 26(3): 231–8.
25. Barabas G and Molstad S, No association
between elevated post-void residual vol-
ume and bacteriuria in residents of nurs-
ing homes. Scand J Prim Health Care,
2005. 23(1): 52–6.
26. Omli R, Skotnes LH, Mykletun A, Bakke
AM, and Kuhry E, Residual urine as a risk
factor for lower urinary tract infection: a
1-year follow-up study in nursing homes.
J Am Geriatr Soc, 2008. 56(5): 871–4.
27. Muder RR, Brennen C, Drenning SD,
Stout JE, and Wagener MM, Multiply
antibiotic-resistant gram-negative bacilli
in a long-term-care facility: a case-
control study of patient risk factors and
prior antibiotic use. Infect Control Hosp
Epidemiol, 1997. 18(12): 809–13.
28. Viray M, Linkin D, Maslow JN, Stieritz
DD, Carson LS, Bilker WB, and
Lautenbach E, Longitudinal trends in
antimicrobial susceptibilities across long-
term-care facilities: emergence of fluoro-
quinolone resistance. Infect Control Hosp
Epidemiol, 2005. 26(1): 56–62.
29. Warren JW, Catheter-associated urinary
tract infections. Int J Antimicrob Agents,
2001. 17(4): 299–303.
30. Nicolle LE, The chronic indwelling cath-
eter and urinary infection in long-term-
 Urinary tract infections in long term care patients
care facility residents. Infect Control Hosp
Epidemiol, 2001. 22(5): 316–21.
31. Saint S and Chenoweth CE, Biofilm and
catheter-associated urinary tract infec-
tions. Infect Dis Clin North Am, 2003. 17:
411–432.
32. Kunin CM, Douthitt S, Dancing J,
Anderson J, and Moeschberger M, The
association between the use of urinary
catheters and morbidity and mortal-
ity among elderly patients in nursing
homes. Am J Epidemiol, 1992. 135(3):
291–301.
33. Juthani-Mehta M, Tinetti M, Perrelli E,
Towle V, and Quagliarello V, Role of dip-
stick testing in the evaluation of urinary
tract infection in nursing home residents.
Infect Control Hosp Epidemiol, 2007.
28(7): 889–91.
34. Loeb M, Bentley DW, Bradley S, Crossley
K, Garibaldi R, Gantz N, McGeer A, Muder
RR, Mylotte J, Nicolle LE, Nurse B, Paton
S, Simor AE, Smith P, and Strausbaugh L,
Development of minimum criteria for the
initiation of antibiotics in residents of long-
term-care facilities: results of a consensus
conference. Infect Control Hosp Epidemiol,
2001. 22(2): 120–4.
| 10.4 |
35. Loeb M, Brazil K, Lohfeld L, McGeer A,
Simor A, Stevenson K, Zoutman D, Smith
S, Liu X, and Walter SD, Effect of a multi-
faceted intervention on number of antimi-
crobial prescriptions for suspected urinary
tract infections in residents of nursing
homes: cluster randomised controlled
trial. BMJ, 2005. 331(7518): 669.
36. Gomolin IH, Siami PF, Reuning-Scherer
J, Haverstock DC, and Heyd A, Efficacy
and safety of ciprofloxacin oral suspen-
sion versus trimethoprim-sulfamethox-
azole oral suspension for treatment of
older women with acute urinary tract
infection. J Am Geriatr Soc, 2001. 49(12):
1606–13.
37. Warren JW, Anthony WC, Hoopes JM,
and Muncie HL, Jr., Cephalexin for
susceptible bacteriuria in afebrile, long-
term catheterized patients. JAMA, 1982.
248(4): 454–8.
38. McGeer A, Campbell B, Emori TG,
Hierholzer WJ, Jackson MM, Nicolle
LE, Peppler C, Rivera A, Schollenberger
DG, Simor AE, and et al., Definitions of
infection for surveillance in long-term
care facilities. Am J Infect Control, 1991.
19(1): 1–7.
599
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 Chapter |11|

Urosepsis
Chair: Bernhard Lobel

CHAPTER OUTLINE
11.1 Introduction 602
11.2 Pathogenesis of sepsis as related to novel
therapeutic concepts 604
11.3 Urosepsis – from the view of the intensivist 615
11.4 Urosepsis – from the view of the urologist 630
|11.1|
Introduction
Pierre Tattevin, Matthieu Revest, Bernhard Lobel
Université de Rennes 1, Hôpital Pontchaillou, Rennes, France
Corresponding author: Professeur Bernard Lobel, Service d’ Urologie, Hopital Pontchaillou, Rue Henri le Guilloux
F-35033 Rennes Cedex, France
Tel 0033-2-9924.4269, Fax 0033-2-9928.4113, bernard.lobel@chu-rennes.fr
Sepsis is defined as a combination of
pathologic infection and physiological
changes known collectively as the sys-
temic inflammatory response syndrome
[1]. Sepsis is often lethal, killing 20–50%
of severely affected patients; epidemio-
logic data from the United States showed
that between 1979 and 2000, there was
an annualized increase in the incidence
of sepsis of 8.7%, from 164,000 cases
(82.7 per 1000,000 population) to 660,000
cases (240.4 per 1000,000 population) [2].
Urinary tract infections (UTI) are among
the most common causes of sepsis, total-
ling as much as 20–30% of all sepsis cat-
egories in one large multicentric study
performed in a French ICU [3], the higher
prevalence of UTI (30%) being encoun-
tered among patients presenting with
the most severe forms of sepsis (i.e. sep-
tic shock). Thus, urosepsis, now widely
accepted as the preferred term for any
degree of systemic inflammatory response
related to UTI, is not uncommon and may
be associated with severe consequences,
including long-term disabilities and even
death. Given this dreadful combination
of high incidence and potential for severe
consequences, urosepsis deserves signifi-
cant consideration from the urology and
the intensive care communities.
On this issue, three up-to-date pap-
ers present an overview of urosepsis.
Firstly, Evangelos Giamarellos-Bourboulis
describes what is currently known about
sepsis pathogenesis; initially, sepsis may
be characterized by increases in inflamma-
tory mediators, but as sepsis persists, there
is a shift toward an anti-inflammatory
state which may adversely affect outcome
[1]. Indeed, patients with sepsis have fea-
tures consistent with immunosuppression,
including a loss of delayed hypersensitiv-
ity, an inability to clear infection, and a
predisposition to nosocomial infections
[4]. The main mechanisms of immune
suppression demonstrated thus far are:
i) a shift to anti-inflammatory cytokines;
ii) anergy; and iii) death of immune cells
[1]. Significant progress has been accom-
plished over the last two decades, the
most famous finding being the discovery of

toll-like receptors (TLR), and the complex
interactions between pathogen-associated
molecular patterns (PAMPs) and pattern-
recognition receptors (PRRs). The manage-
ment of patients with severe sepsis and
septic shock has been somewhat improved
through large-scale, double-blind, control-
led randomized studies, although some of
them brought more confusion than clarity.
Issues such as the use of adrenal hormone
replacement therapy (hydrocortisone),
blood glucose control, and interventions
against excess coagulopathy (drotrecogin-
alpha) have probably been pushed too far,
following a few convincing clinical studies;
their values are now being re-evaluated
throughout selected clinical studies trying
to better define the patients who would
clearly benefit from these interventions.
Undoubtedly, the paper by Evangelos
Giamarellos-Bourboulis on this topic will
be an invaluable guide for those of us who
are not aware of the latest developments
in sepsis pathogenesis and novel thera-
peutic concepts.
In the second paper dealing with uro-
sepsis in this section, Florian Wagenlehner
et al. present the ‘view of the urologist’.
This paper is an executive summary of
the authors’ findings about the manage-
ment of urosepsis, based on a literature
review and on the authors’ experience.
Indeed, given that randomized controlled
studies have not addressed all of the spe-
cific issues relating to this topic, Florian
Wagenlehner’s own expertise in antimi-
crobial treatment of UTI was required to
fill the numerous gaps. This up-to-date
review provides us with important and
practical ‘take home messages’.
Last but not least, Lifen Li et al. per-
formed an extensive analysis of the
standard-of-care for patients with urosep-
sis. Although this paper focuses mainly
on therapeutics usually administered in
intensive care units, recent studies have
shown that early management of severe
Introduction | 11.1 |
sepsis and septic shock is one of the major
prognostic factors for this condition, with
a well-documented impact on morbidity
as well as mortality. Consequently, every
physician who may be confronted with
patients with urosepsis, whatever the sit-
uation (urology department, emergency
ward, outpatient clinic), must acquire
or preserve standard knowledge about
the key points for the management of
patients with urosepsis.
Only with this effort will our patients’
prognosis significantly improve, as one
hour too late may be too late in rapidly
evolving diseases such as septic shock.
Lifen Li et al. carefully present an easy-
to-read, concise, up-to-date review of uro-
sepsis management from the view of the
intensivist.
Do not forget that any obstruction in
the urinary tract must be treated surgi-
cally in an emergency with the support
of intensive care. Mostly in these cases,
drainage by itself cures most patients. We
hope our readers enjoy these papers, and
their patients benefit.
REFERENCES
1. Hotchkiss RS and Karl IE, The patho-
physiology and treatment of sepsis.
N Engl J Med, 2003. 348(2): 138–50.
2. Martin GS, Mannino DM, Eaton S, and
Moss M, The epidemiology of sepsis in the
United States from 1979 through 2000.
N Engl J Med, 2003. 348(16): 1546–54.
3. Alberti C, Brun-Buisson C, Burchardi
H, Martin C, Goodman S, Artigas A,
Sicignano A, Palazzo M, Moreno R,
Boulme R, Lepage E, and Le Gall R,
Epidemiology of sepsis and infection
in ICU patients from an international
multicentre cohort study. Intensive Care
Med, 2002. 28(2): 108–21.
4. Annane D, Bellissant E, and Cavaillon
JM, Septic shock. Lancet, 2005.
365(9453): 63–78.
603
|11.2|
Pathogenesis of sepsis as related
to novel therapeutic concepts
Evangelos J. Giamarellos-Bourboulis
4th Department of Internal Medicine, University of Athens, Medical School, Greece
Correspondence: 4th Department of Internal Medicine, ATTIKON University Hospital, 1 Rimin Str., 124 62 Athens, Greece
Tel: 0030 210 58 31 994, Fax: 0030 210 53 26 446, e-mail: giamarel@ath.forthnet.gr
ABSTRACT
The complex pathogenesis of sepsis is ini-
tiated when damage-associated molecular
patterns are recognized by the pattern rec-
ognition receptors of the cells of the innate
immune system of the host. This leads
to the generation of pro-inflammatory
cytokines which promote intense inflam-
matory phenomena. This reaction is per-
petuated with transition from the innate
to the adaptive immune system. As the
disease progresses, the TH2 anti-inflam-
matory response predominate, leading
to immunosuppression. In parallel, the
coagulation cascade is triggered by tis-
sue factors expressed on the damaged
vascular bed and on the cell membrane
of monocytes. Coagulopathy is further
intensified when protein C levels secreted
by the endothelium are decreased. In an
attempt to decrease mortality from sep-
sis, several trials have been conducted
with compounds aiming to decrease excess
inflammation or excess coagulation. Meta-
analysis of randomized trials disclosed
survival benefit from the administration
of intravenous immunoglobulins particu-
larly when using preparations enriched
in IgM and IgA. Administration of hydro-
cortisone 50mg intravenously every six
hours is accompanied by earlier reversal
of shock. Results of three trials about the
benefit of intensive insulin therapy aim-
ing to achieve capillary blood glucose
levels between 80 and 110 mg/dl are con-
troversial. Considerable reduction of risk
of death from septic shock and multiple
organ dysfunctions (MODS) was found
from one randomized trial by the intra-
venous administration of clarithromycin.
Results of four trials suggest the admin-
istration of recombinant human activated
protein C (rhAPC) in patients with pres-
entation of signs of MODS within less
than 24 hours and an APACHE II score
greater than 25. It should not be given in
children and in patients with a history of

recent bleeding or a bleeding predisposi-
tion. Therapeutic options aiming to inter-
vene in the inflammatory cascade of the
septic host have been evaluated by the
“Surviving Sepsis Campaign” (SSC) panel
of experts, who have also developed a
grading system for recommendations.
Key words: sepsis; inflammation; coag-
ulopathy; immunointervention
SUMMARY OF RECOMMENDATIONS
1. It is suggested that hydrocortisone
should be administered in patients with
septic shock at a dose of 50 mg every
six hours. This leads to earlier reversal
of shock (LoE 1b, GoR A, SSC 2c)
2. It is suggested that capillary glucose
should be maintained below 150 mg/dl
in patients with severe sepsis (LoE 1b,
GoR A, SSC 2c)
3. Recombinant human activated protein
C (drotrecogin-alpha) is suggested
for patients with severe sepsis and
two or more failing organs or with an
APACHE II score greater than 25.
It is not given in children. Contra-
indications are signs of active bleed-
ing, recent hemorrhagic stroke, recent
surgical operation, multiple traumas
with an increased risk for bleeding
and a predisposition for hemorrhage
i.e. thrombocytopenia, increased INR
or prolongation of aPTT. Drotrecogin-
alpha is administered at a dose of
24 µg/kg/h for 94 continuing hours
(LoE 1b, GoR A, SSC 2b)
1. INTRODUCTION
Severe sepsis and septic shock are recog-
nized as the tenth greatest cause of death
in the United States [1]. It is estimated
that almost 1.5 million people develop sep-
tic syndrome annually in North America
and another 1.5 million in Northern
Europe. The case-fatality ranges among
Pathogenesis of sepsis | 11.2 |
30–35% for severe sepsis and 40–50% for
septic shock [2]. A registry for sepsis was
started in January 2007 in Greece (www.
sepsis.gr). Mortality from septic shock is
almost 50% for patients hospitalized in
an Intensive Care Unit (ICU) and almost
65% for those hospitalized on a general
ward. It is estimated that almost 82,000
cases of severe sepsis and septic shock
occur annually in Greece, a country with
10 million inhabitants.
The great lethality of septic syn-
drome has lead to the creation of world-
recognized efforts attempting to decrease
overall mortality. This effort is known as
the “Surviving Sepsis Campaign” (SSC)
which published international guide-
lines in 2004 and 2008 [3–4]. A common
denominator of these guidelines is that
patient support should comprise all of the
following: a) fluid and oxygen resuscita-
tion; b) administration of vasopressors if
necessary; c) early-directed antimicrobial
therapy; d) eradication of the infection
source; e) immunomodulatory therapies;
f) conditions of mechanical ventilation;
and g) transfusion of blood and blood
products.
Part of the above therapies is attempt-
ing to modulate the inflammatory
response of the host. This creates the
need to understand the complex patho-
genesis of sepsis. The present review
aims to provide the current schema of
pathogenesis of sepsis and to analyze cur-
rent therapeutic options of intervention
in the mechanisms of pathogenesis.
2. METHODS
For the presentation of the basic scheme
of pathogenesis of sepsis, 13 review arti-
cles published in major journals in 2008
were included. The articles were retrieved
by a PubMed search using the following
limits: 2008; English; pathogenesis; sepsis;
reviews. Well-cited peer-reviewed research
articles of major interest published the
last five years were also applied.
605
Chapter | 11 | Urosepsis

For the treatment recommendations, pneumonia, intrabdominal infections, pri-

20 published major clinical trials were
used. These were retrieved from the
PubMed database using the following
key-words: clinical trials; anti-endotoxin
antibodies; anti-TNF antibodies; drot-
recogin-alpha; tifacogin; hydrocortisone;
insulin; immunoglobulins; clarithromy-
cin. The following limits were used in the
literature search: English; clinical trials.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[5–6]. Since therapeutic options aiming
to intervene in the inflammatory cascade
of the septic host have been evaluated by
the “Surviving Sepsis Campaign” (SSC)
panel of experts according to the GRADE
system [3–4], grading according to that
system is also provided in the present
chapter. This system is given in Table 1.
3. PATHOGENESIS
The occurrence of sepsis requires the exist-
ence of a well-defined source of infection.
The most common sources of infection are
acute pyelonephritis, community-acquired
mary bacteremia and ventilator-associated
pneumonia (VAP). The most common
microbial causes are Gram-negative
bacteria and Gram-positive cocci. Their
frequency differs from country to coun-
try. Since 1987, Gram-positive cocci pre-
dominate in the Northern countries [7];
in other countries like Greece, Gram-
negative bacteria predominate.
3.1 Stimulation of the inflammatory
cascade
Despite the need for an underlying infec-
tious focus, it is considered that the host
creates the disease. Current belief on the
pathogenesis of sepsis relies on a complex
interaction between pathogen-associated
molecular patterns (PAMPs) residing on
the bacterial cell and pattern-recognition
receptors (PRRs) on cell membranes
of the cells of the innate and adaptive
immune system of the host. Several mol-
ecules released from cells of the host
following necrosis are able to stimu-
late PRRs. These are called “alarmins”.
Both alarmins and PAMPs are known as
damage-associated molecular patterns
(DAMPs) [8].

Table 1 The GRADE system of recommendations adapted by the expert committee of the “Surviving Sepsis Campaign”
guidelines. RCT = Randomised controlled trial.

Grade Benefit/risk Level of evidence Grading

1A Benefit >>> risk RCTs without any methodological problem/ Strongly recommended for all
limitation or high-powered observational studies patients

1B Benefit >>> risk RCTs with several methodological problems/ Recommended for all patients
limitations or strong observational studies

1C Benefit >>> risk Observational studies Recommendation that may change

2A Benefit ≥ risk RCTs without any methodological problem/ Suggested

limitation or high-powered observational studies

2B Benefit ≥ risk RCTs with several methodological problems/ limita- Weak suggestion
tions or strong observational studies

2C Unknown Observational studies Very weak suggestion

606

The best studied PRRs are toll-like
receptors (TLRs) that are transmem-
brane receptors of blood monocytes
and tissue macrophages. Ten TLRs are
described so far of which the most impor-
tant are TLR2, TLR4, TLR5 and TLR9.
Endotoxins (LPS) of the outer membrane
of Gram-negative bacteria and heat-
shock protein 90 (HSP90) are agonists
of TLR4; lipoteichoic acid (LTA) of the
cell wall of Gram-positive cocci is an ago-
nist of TLR2; bacterial flaggelin of TLR5;
and CpG DNA of TLR9 [9]. Binding of
LPS to TLR4 triggers the adaptor mol-
ecule myeloid-differentiation factor-88
(MyD88). Intracellular signaling requires
bridging of MyD88 with the MyD88-
adapter like /TIR-associated protein (Mal/
TIRAP). This leads to activation of inter-
leukin (IL)-1 receptor-associated kinase
(IRAK)-4 which phosphorylates IRAK-1.
The latter is activated and recruits TRAF
(TNF-receptor associated factor)-6 which
activates the mitogen activated p38
(MAP) kinase. The latter phosphorylates
IkB into nuclear factor-kB (NF-kB). In
parallel, activator-protein 1 (AP-1) is
generated. Both NF-kB and AP-1 initiate
the transcription of genes of pro-inflam-
matory and anti-inflammatory cytokines
[10]. Among these pro-inflammatory
cytokines, IL-1β is generated as a pro-
peptide, namely pro-IL-1β. This requires
cleavage to IL-1β through the cas-
pase-1 IL-1β converting enzyme (ICE).
Activation of ICE is regulated though the
NALP-3 inflammasome. Constituents of
the cell wall of Gram-positive cocci like
muramyl dipeptide are agonists of the
inflammasome [11].
There are growing numbers of mol-
ecules reported to inhibit the TLR4 sig-
naling pathway. The best known are
radioprotective 105 (RP105) and a splice
variant of MyD88 known as sMyD88 [12].
The best studied pro-inflammatory
cytokines are tumour necrosis factor-alpha
(TNFα), IL-1β, IL-6 and IL-8. TNFα and
IL-1β induce fever responses, endothe-
lial leaking, chemotaxis of neuthrophils,
Pathogenesis of sepsis | 11.2 |
tissue cell apoptosis and kidney damage.
IL-6 induces the production of acute phase
reactants from liver. IL-8 is a potent che-
moattractant for neutrophils. The latter
once recruited in the inflammatory site
release reactive oxygen species (ROS)
which further augment tissue injury.
The deterioration of vascular endothe-
lium promotes a leak of cytokines in the
systemic circulation leading to multiple
organ dysfunction (MODS) [12]. IL-10 is
a well known anti-inflammatory cytokine
attempting to eliminate systemic inflam-
mation. As the septic response progresses,
the innate immune response generat-
ing the first cytokine storm gives its
place to an adaptive immune response of
T-helper cells (TH). Depending on the type
of released cytokines from TH cells, the
TH-response is divided into TH1 charac-
terized by the release of TNFα, IL-2 and
interferon-gamma (IFNγ) and into TH2
characterized by the release of IL-4, IL-5,
IL-6 and IL-10. The TH1 response is pro-
inflammatory and the TH2 response is anti-
inflammatory. As time progresses, the TH2
response predominates which is equivalent
with immunosuppression of the host [8].
A novel subset of TH cells has been recog-
nized releasing IL-17. They are known as
T17 cells. Released IL-17 is a strong che-
moattractant of neutrophils. The latter
invade tissue and lead to MODS.
A receptor that has been recently recog-
nized is a triggering receptor expressed on
myeloid cells (TREM-1) embedded on the
cell membranes of neutrophils and mono-
cytes. Its ligand is yet unknown though
Staphylococcus aureus, Pseudomonas
aeruginosa and Aspergillus fumigatus are
potential agonists. TREM-1 is stimulated
in the event of septic shock. Its adaptor
molecule is DAP12 (DNAX activation pro-
tein of 12 KDa). Stimulation leads to the
rise of intracellular Ca2+ accompanied by
the release of TNFα and IL-8 [13–14]. A
soluble form of TREM-1 has been recog-
nized, namely sTREM-1. Though its con-
centrations are considerably increased
in serum in the event of septic shock, it
607
Chapter | 11 | Urosepsis
is thought that sTREM-1 behaves as
an anti-inflammatory mediator prob-
ably binding to the unknown ligand of
TREM-1 [15].
Necrosis of cells due to tissue inflam-
mation leads to the release of high-
mobility group box-1 (HMGB1). This is
a non-histonic protein bound to nuclear
DNA and behaves as a late cytokine pro-
moting pro-inflammatory phenomena
and progression to MODS. HMGB1 also
stimulates TLR4 and leads to a second
cytokine storm [8].
Recent data have shown that early
apoptosis of monocytes may be a major
determinant of the final outcome of the
septic host. Apoptosis of circulating
monocytes at a level greater than 50% is
connected with favorable outcome in the
event of septic shock; in the contrary a
level of apoptosis lower than 50% is con-
nected with increased chance for death.
This is probably related to lower biosyn-
thesis of pro-inflammatory cytokines by
the apoptotic monocytes [16].
3.2 Coagulopathy
Sepsis is characterized by excess genera-
tion of thrombin and impaired fibrinolysis.
Thrombin on its own is able to stimu-
late the production of TNFα and IL-6 by
monocytes. It also behaves as a C3 conver-
tase cleaving C5 compound of the comple-
ment into C5a which recruits neutrophils
in the inflammatory site [8]. Protein C
is secreted by the endothelium; once
interacting with the thrombomodulin-
thrombin complex it is activated (APC).
Formation of APC is 20-fold enhanced
in the presence of the endothelial pro-
tein receptor (EPCR). APC inactivates
coagulation factors Va and VIIIa with
protein S as a co-factor. APC has also anti-
inflammatory and anti-apoptotic effects
on both monocytes and endothelial cells
by inhibiting NF-kB and the subse-
quent production of pro-inflammatory
cytokines. Damage of the endothelium
in sepsis reduces production of APC;
608
levels of protein S are also decreased
in sepsis [17]. HMGB1 also inhibits the
APC pathway by interfering with the
thrombin-thrombomodulin complex [8].
As a consequence, a hyper-coagulable and
hyper-inflammatory state supervenes.
Damage of the endothelium in sepsis
leads to release of tissue factor (TF), an
effect promoted by HMGB1. TF is also
released on the surface of monocytes. TF is
acting as an agonist of cytokine receptors
and it is an initiator of the extrinsic coag-
ulation pathway. TF-pathway inhibitor
(TFPI) is a serine protease inhibiting acti-
vated factor Xa and the TF/VIIa complex.
Concentrations of TFPI are decreased in
patients with sepsis. The above combina-
tion of events promotes further hyper-
coagulation and inflammation [18].
A summary of the above mentioned
mechanisms of pathogenesis in sepsis is
shown in Figure 1.
4. THERAPEUTIC OPTIONS BASED
ON THE MECHANISMS OF
PATHOGENESIS
The understanding that antimicrobial
therapy and source control solely may not
reduce the high mortality of sepsis led to
the development of therapeutic strategies
targeting the mechanisms of pathogen-
esis as analyzed above. These strategies
may be divided into two categories: a)
anti-inflammatory therapies; and b) mod-
ulation of the coagulation cascade.
4.1 Anti-inflammatory therapies
These therapies aim to restrain the
excess inflammatory state of the host.
They comprise antibodies targeting LPS
and TNFα; soluble receptors of TNFα;
antagonists of TLR4; intravenous immu-
noglobulins; low dose hydrocortisone;
intensive insulin therapy; and intrave-
nous clarithromycin.
Eleven randomized trials have been pub-
lished in patients with severe sepsis where
 Pathogenesis of sepsis | 11.2 |

Figure 1 A schematic representation of the interplay between monocytes and endothelium in the pathogenesis of sepsis.
Activation of TLR4 by bacterial endotoxins (LPS) or by the late cytokine HMGB1 leads, through the activation of a series of
adaptor proteins, to formation of NF-kB. NF-kB acts as a transcription factor for the genes of pro- and anti-inflammatory
cytokines. The latter disrupt the integrity of vascular endothelium leading to expression of tissue factor (TF) and reduced
production of activated protein C (APC). These result in generation of thrombin and in a hyper-coagulable state. Thrombin
stimulates further production of cytokines.

anti-LPS [19] and anti-TNFα [20–22] anti-
bodies and soluble TNFα receptors were
applied [23–24]. All these trials failed and
so these therapeutic strategies were aban-
doned. Several TLR4 antagonists have
been developed and they are at the stage
of clinical evaluation [25].
Benefit arising from the application of
intravenous immunoglobulins (IVIG) is
connected with improved opsonization
of the offending pathogens and blockade
of LPS. Published trials have given con-
flicting results. A recent meta-analysis
comprised 27 randomized trials; 15 in
adults and 12 in pre-term and on-term
neonates all suffering from severe sep-
sis or septic shock. Statistical results
revealed a significant reduction of 28-day
mortality (21% in adults and of 44% in
neonates) by the application of IVIG. The
greatest benefit arises with the applica-
tion of preparations enriched in IgM and
IgA compared with preparations con-
taining only IgG. The proposed dose for
preparations enriched in IgM and IgA is
0.03–0.21 g/kg; and for those enriched in
IgG 0.18–1.33 g/kg [26]. This therapeutic
approach has not however been graded by
the SSC expert panel [3–4].
It is considered that almost 60% of
patients with septic shock suffer from rel-
ative adrenal insufficiency. These patients
may benefit from the infusion of a low
dose of hydrocortisone. Two randomized
clinical trials have been published. The
first enrolled 299 patients who were allo-
cated either to placebo or to hormone
replacement. Replacement consisted of

609
Chapter | 11 | Urosepsis
50mg intravenous bolus hydrocortisone
every six hours and 50 µg fluodrocorti-
sone orally once daily. Results revealed a
significantly lower hazard risk for death
after 28 days among treated patients with
relative adrenal insufficiency compared
with placebo. This was accompanied by
earlier withdrawal from vasopressors
(median time of withdrawal 10 days in
placebo versus seven days in treated
patients) [27]. The CORTICUS trial pub-
lished in 2008 enrolled 499 patients with
septic shock allocated either to placebo
or to 50mg bolus intravenous hydrocor-
tisone every six hours [28]. The total
duration of treatment was five days with
gradual dose tapering. Results failed to
disclose any survival benefit. However,
the time for reversal of shock was con-
siderably diminished with hydrocorti-
sone treatment. Results of these trials led
to a recommendation of hydrocortisone
administration at the dose mentioned
above only for patients with septic shock
with the goal of earlier reversal of shock
[29] (LoE 1b, GoR A, SSC 2c).
Administration of insulin seems to
control hyperglycemia and uncontrolled
inflammation. Three randomized clini-
cal trials have been published. A total
of 1548 patients hospitalized in surgi-
cal ICUs were enrolled in the first study.
They were allocated either to conven-
tional insulin therapy aiming to maintain
blood glucose below 200 mg/dl or to inten-
sive insulin therapy aiming to maintain
blood glucose between 80 and 110 mg/dl.
Insulin was infused via a pump. The sur-
vival benefit of the second strategy was
pronounced [30]. A similar study design
was repeated later in 1200 patients hos-
pitalized in medical ICUs. No effect of
intensive insulin therapy could be found
on mortality. A significant benefit was
however denoted in terms of earlier wean-
ing from mechanical ventilation, earlier
discharge from the ICU and earlier dis-
charge from hospital [31]. A third trial
attempted to repeat the same design in
610
a mixed ICU population of 537 patients.
The trial was prematurely stopped after
the first safety analysis due to the high
frequency of hypoglycemia in the inten-
sive-insulin group (12.1% versus 2.1%
in the conventional therapy group) [32].
The controversial findings of these trials
have created a dilemma about the role of
intensive insulin therapy in severe sepsis
or septic shock [4]. The current sugges-
tion is to achieve euglycemia after stabili-
zation of the patient, aiming to maintain
capillary glucose levels below 150 mg/dl
(LoE 1b, GoR A, SSC 2c).
Clarithromycin is a macrolide that
can inhibit the in vitro formation of
NF-kB in monocytes following stimula-
tion by LPS and the subsequent biosyn-
thesis of IL-8 [33]. A randomized clinical
trial has been recently published in 200
patients with sepsis arising in the field
of VAP [2]. Patients were allocated to
either placebo or to clarithromycin.
The latter was administered once daily
at a dose of 1000 mg at one-hour infu-
sion time through a central catheter.
Administration lasted for three consecu-
tive days. Odds ratio for death due to
septic shock and MODS was 3.78 among
clarithromycin-treated patients com-
pared with 19.00 of the placebo group
(p: 0.048). Median time to resolution of
VAP was 15.5 days in the placebo group;
it was reduced to 10.0 days in the clari-
thromycin group (p: 0.011). Respective
time to withdrawal from mechanical ven-
tilation was 22.5 and 16.0 days (p: 0.049).
Median time to progression to MODS
was 3.38 days in the placebo group and
5.78 days in the clarithromycin group
(p: 0.006). Administration of clarithro-
mycin was not accompanied by serious
adverse events. Although results of that
trial point towards a favorable response
of clarithromycin treatment in the final
outcome of patients with septic shock
and MODS along with earlier withdrawal
from mechanical ventilation, they should
be repeated in a second clinical trial.

Clarithromycin has not been evaluated
as a therapeutic option by the SSC expert
panel.
4.2 Intervention against excess
coagulopathy
There have been two main attempts; the
development of recombinant human APC
(rhAPC, drotrecogin-alpha) and the devel-
opment of recombinant TFPI (tifacogin).
The administration of rhAPC aimed
to harness its anti-inflammatory, anti-
apoptotic and anti-coagulant properties.
Four randomized clinical trials have been
published. In the PROWESS trial, 1690
patients were enrolled and therapy was
started within 24 hours of presentation
with one or more organ failures. The study
was prematurely stopped due to the ben-
efit from the allocated treatment. A reduc-
tion of the absolute risk of death of 6.1%
was identified which was proved by sur-
vival analysis for 28 days. This was greater
for patients with an APACHE II score >25.
Administration of rhAPC increased the risk
of serious bleeding (3.5% versus 2% in pla-
cebo) [34]. rhAPC was administered in the
prospective, open-label, non-randomized
ENHANCE trial within <48 hours of pres-
entation with signs of one or more failing
organs in 2378 patients. Survival character-
istics were similar to those of the treatment
arm of the PROWESS trial [35]. No sur-
vival benefit was disclosed by the adminis-
tration of rhAPC in the ADDRESS trial. A
total of 2640 patients were enrolled, all with
an APACHE II score <25. Treatment was
started within <48 hours of presentation
with signs of one or more failing organs.
Results revealed a significant risk of serious
bleeding events amongst treated patients
[36]. Due to the high risk of bleeding events
by rhAPC the XPRESS trial was conducted
where 1194 patients were enrolled. All
received rhAPC either with placebo, low
molecular weight heparin or unfractionated
heparin. No harmful interaction between
rhAPC and heparin was found [37].
Pathogenesis of sepsis | 11.2 |
Based on the analysis of the above four
trials, rhAPC is licensed in the European
Union for patients with severe sepsis
and two or more failing organs and in
the USA for patients with severe sepsis
and an APACHE II score more than 25.
It is not given in children. Other contra-
indications are signs of active bleeding,
recent hemorrhagic stroke, recent surgi-
cal operation, multiple traumas with an
increased risk of bleeding and a predispo-
sition towards hemorrhage i.e. thrombo-
cytopenia, increased INR or prolongation
of aPTT. rhAPC is administered at a dose
of 24 µg/kg/h for 94 continuing hours
(LoE 1b, GoR A, SSC 2b).
Tifacogin was administered in a single
randomized trial of 1987 patients. In the
OPTIMIST trial treated patients were
enrolled within <24 hours of presentation
with signs of two or more failing organs;
1781 patients had INR ≥ 1.2 and 206 had
INR <1.2. Tifacogin was administered at
a dose of 0.025 mg/kg/h for 96 consecutive
hours. The trial failed to demonstrate
any 28-day survival benefit. However,
when considering patients with INR <1.2
mortality was 22.9% among placebo com-
pared with 12.0% among those treated
with tifacogin (p: 0.051) [38]. Tifacogin
has not been evaluated by the SSC panel
of experts.
5. CONCLUSIONS
Despite numerous efforts attempting to
modulate the intense inflammatory reac-
tion, it is evident that none of the availa-
ble therapies is sine qua non for the septic
host. This may be attributed to the complex
pathogenesis of sepsis and to the advent of
immunoparalysis with disease progression
at a time when the administration of any
immunomodulator may be worthless. In
any case, interference in the mechanisms
of pathogenesis seems to constitute the
only promising pathway for decreasing the
mortality of septic syndrome.
611
Chapter | 11 | Urosepsis
REFERENCES
1. Heron M, Deaths: leading causes for 2004.
Natl Vital Stat Rep, 2007. 56(5): 1–95.
2. Giamarellos-Bourboulis EJ, Pechere
JC, Routsi C, Plachouras D, Kollias S,
Raftogiannis M, Zervakis D, Baziaka F,
Koronaios A, Antonopoulou A, Markaki V,
Koutoukas P, Papadomichelakis E, Tsaganos
T, Armaganidis A, Koussoulas V, Kotanidou
A, Roussos C, and Giamarellou H, Effect of
clarithromycin in patients with sepsis and
ventilator-associated pneumonia. Clin Infect
Dis, 2008. 46(8): 1157–64.
3. Dellinger RP, Carlet JM, Masur H,
Gerlach H, Calandra T, Cohen J, Gea-
Banacloche J, Keh D, Marshall JC,
Parker MM, Ramsay G, Zimmerman JL,
Vincent JL, and Levy MM, Surviving
Sepsis Campaign guidelines for manage-
ment of severe sepsis and septic shock.
Intensive Care Med, 2004. 30(4): 536–55.
4. Dellinger RP, Levy MM, Carlet JM, Bion
J, Parker MM, Jaeschke R, Reinhart K,
Angus DC, Brun-Buisson C, Beale R,
Calandra T, Dhainaut JF, Gerlach H,
Harvey M, Marini JJ, Marshall J, Ranieri
M, Ramsay G, Sevransky J, Thompson
BT, Townsend S, Vender JS, Zimmerman
JL, and Vincent JL, Surviving Sepsis
Campaign: international guidelines for
management of severe sepsis and septic
shock: 2008. Crit Care Med, 2008. 36(1):
296–327.
5. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
6. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
7. Hodgin KE and Moss M, The epidemiol-
ogy of sepsis. Curr Pharm Des, 2008.
14(19): 1833–9.
8. Rittirsch D, Flierl MA, and Ward PA,
Harmful molecular mechanisms in sepsis.
Nat Rev Immunol, 2008. 8(10): 776–87.
9. Tsujimoto H, Ono S, Efron PA, Scumpia
PO, Moldawer LL, and Mochizuki H, Role
of Toll-like receptors in the development of
sepsis. Shock, 2008. 29(3): 315–21.
612
10. Weighart H and Holzmann B, Role of
Toll-like receptor response for sepsis
pathogenesis. Immunobiology, 2008. 212:
715–722.
11. Drenth JP and van der Meer JW, The
inflammasome – a linebacker of innate
defense. N Engl J Med, 2006. 355(7):
730–2.
12. Wang H and Ma S, The cytokine storm
and factors determining the sequence and
severity of organ dysfunction in multiple
organ dysfunction syndrome. Am J Emerg
Med, 2008. 26(6): 711–5.
13. Tessarz AS and Cerwenka A, The
TREM-1/DAP12 pathway. Immunol Lett,
2008. 116(2): 111–6.
14. Bouchon A, Facchetti F, Weigand MA,
and Colonna M, TREM-1 amplifies
inflammation and is a crucial mediator
of septic shock. Nature, 2001. 410(6832):
1103–7.
15. Giamarellos-Bourboulis EJ, Zakynthinos
S, Baziaka F, Papadomichelakis E,
Virtzili S, Koutoukas P, Armaganidis A,
Giamarellou H, and Roussos C, Soluble
triggering receptor expressed on myeloid
cells 1 as an anti-inflammatory media-
tor in sepsis. Intensive Care Med, 2006.
32(2): 237–43.
16. Giamarellos-Bourboulis EJ, Routsi C,
Plachouras D, Markaki V, Raftogiannis
M, Zervakis D, Koussoulas V, Orfanos S,
Kotanidou A, Armaganidis A, Roussos C,
and Giamarellou H, Early apoptosis of
blood monocytes in the septic host: is it a
mechanism of protection in the event of
septic shock? Crit Care, 2006. 10(3): R76.
17. Levi M and van der Poll T, Recombinant
human activated protein C: current
insights into its mechanism of action. Crit
Care, 2007. 11 Suppl 5: S3.
18. Diehl JL and Borgel D, Sepsis and coagu-
lation. Curr Opin Crit Care, 2005. 11(5):
454–60.
19. Bone RC, Balk RA, Fein AM, Perl TM,
Wenzel RP, Reines HD, Quenzer RW,
Iberti TJ, Macintyre N, and Schein RM,
A second large controlled clinical study of
E5, a monoclonal antibody to endotoxin:
results of a prospective, multicenter, ran-
domized, controlled trial. The E5 Sepsis
Study Group. Crit Care Med, 1995. 23(6):
994–1006.

20. Rice TW, Wheeler AP, Morris PE, Paz HL,
Russell JA, Edens TR, and Bernard GR,
Safety and efficacy of affinity-purified,
anti-tumor necrosis factor-alpha, ovine
fab for injection (CytoFab) in severe
sepsis. Crit Care Med, 2006. 34(9):
2271–81.
21. Reinhart K, Wiegand-Lohnert C,
Grimminger F, Kaul M, Withington S,
Treacher D, Eckart J, Willatts S, Bouza
C, Krausch D, Stockenhuber F, Eiselstein
J, Daum L, and Kempeni J, Assessment of
the safety and efficacy of the monoclonal
anti-tumor necrosis factor antibody-
fragment, MAK 195F, in patients with
sepsis and septic shock: a multicenter,
randomized, placebo-controlled, dose-
ranging study. Crit Care Med, 1996.
24(5): 733–42.
22. Cohen J and Carlet J, INTERSEPT:
an international, multicenter, placebo-
controlled trial of monoclonal antibody
to human tumor necrosis factor-alpha in
patients with sepsis. International Sepsis
Trial Study Group. Crit Care Med, 1996.
24(9): 1431–40.
23. Abraham E, Laterre PF, Garbino J,
Pingleton S, Butler T, Dugernier T,
Margolis B, Kudsk K, Zimmerli W,
Anderson P, Reynaert M, Lew D,
Lesslauer W, Passe S, Cooper P, Burdeska
A, Modi M, Leighton A, Salgo M, and
Van der Auwera P, Lenercept (p55 tumor
necrosis factor receptor fusion protein) in
severe sepsis and early septic shock: a ran-
domized, double-blind, placebo-controlled,
multicenter phase III trial with 1,342
patients. Crit Care Med, 2001. 29(3):
503–10.
24. Abraham E, Glauser MP, Butler T,
Garbino J, Gelmont D, Laterre PF,
Kudsk K, Bruining HA, Otto C, Tobin
E, Zwingelstein C, Lesslauer W, and
Leighton A, p55 Tumor necrosis factor
receptor fusion protein in the treatment
of patients with severe sepsis and septic
shock. A randomized controlled multi-
center trial. Ro 45-2081 Study Group.
JAMA, 1997. 277(19): 1531–8.
25. Leon CG, Tory R, Jia J, Sivak O, and
Wasan KM, Discovery and development
of toll-like receptor 4 (TLR4) antagonists:
a new paradigm for treating sepsis and
Pathogenesis of sepsis | 11.2 |
other diseases. Pharm Res, 2008. 25(8):
1751–61.
26. Kreymann KG, de Heer G, Nierhaus A,
and Kluge S, Use of polyclonal immu-
noglobulins as adjunctive therapy for sep-
sis or septic shock. Crit Care Med, 2007.
35(12): 2677–85.
27. Annane D, Sebille V, Charpentier C,
Bollaert PE, Francois B, Korach JM,
Capellier G, Cohen Y, Azoulay E, Troche
G, Chaumet-Riffaud P, and Bellissant
E, Effect of treatment with low doses of
hydrocortisone and fludrocortisone on
mortality in patients with septic shock.
JAMA, 2002. 288(7): 862–71.
28. Sprung CL, Annane D, Keh D, Moreno
R, Singer M, Freivogel K, Weiss YG,
Benbenishty J, Kalenka A, Forst H,
Laterre PF, Reinhart K, Cuthbertson BH,
Payen D, and Briegel J, Hydrocortisone
therapy for patients with septic shock.
N Engl J Med, 2008. 358(2): 111–24.
29. Marik PE, Pastores SM, Annane D,
Meduri GU, Sprung CL, Arlt W, Keh D,
Briegel J, Beishuizen A, Dimopoulou I,
Tsagarakis S, Singer M, Chrousos GP,
Zaloga G, Bokhari F, and Vogeser M,
Recommendations for the diagnosis and
management of corticosteroid insufficiency
in critically ill adult patients: consensus
statements from an international task
force by the American College of Critical
Care Medicine. Crit Care Med, 2008.
36(6): 1937–49.
30. van den Berghe G, Wouters P, Weekers
F, Verwaest C, Bruyninckx F, Schetz M,
Vlasselaers D, Ferdinande P, Lauwers P,
and Bouillon R, Intensive insulin therapy
in the critically ill patients. N Engl J Med,
2001. 345(19): 1359–67.
31. Van den Berghe G, Wilmer A, Hermans
G, Meersseman W, Wouters PJ, Milants I,
Van Wijngaerden E, Bobbaers H, and
Bouillon R, Intensive insulin therapy in
the medical ICU. N Engl J Med, 2006.
354(5): 449–61.
32. Brunkhorst FM, Engel C, Bloos F, Meier-
Hellmann A, Ragaller M, Weiler N,
Moerer O, Gruendling M, Oppert M,
Grond S, Olthoff D, Jaschinski U, John
S, Rossaint R, Welte T, Schaefer M,
Kern P, Kuhnt E, Kiehntopf M, Hartog C,
Natanson C, Loeffler M, and Reinhart K,
613
Chapter | 11 | Urosepsis
Intensive insulin therapy and pentastarch
resuscitation in severe sepsis. N Engl J
Med, 2008. 358(2): 125–39.
33. Kikuchi T, Hagiwara K, Honda Y,
Gomi K, Kobayashi T, Takahashi H,
Tokue Y, Watanabe A, and Nukiwa T,
Clarithromycin suppresses lipopolysac-
charide-induced interleukin-8 produc-
tion by human monocytes through AP-1
and NF-kappa B transcription factors.
J Antimicrob Chemother, 2002. 49(5):
745–55.
34. Bernard GR, Vincent JL, Laterre PF,
LaRosa SP, Dhainaut JF, Lopez-Rodriguez
A, Steingrub JS, Garber GE, Helterbrand
JD, Ely EW, and Fisher CJ, Jr., Efficacy
and safety of recombinant human acti-
vated protein C for severe sepsis. N Engl J
Med, 2001. 344(10): 699–709.
35. Vincent JL, Bernard GR, Beale R, Doig
C, Putensen C, Dhainaut JF, Artigas A,
Fumagalli R, Macias W, Wright T, Wong
K, Sundin DP, Turlo MA, and Janes J,
Drotrecogin alfa (activated) treatment in
severe sepsis from the global open-label
trial ENHANCE: further evidence for sur-
vival and safety and implications for early
treatment. Crit Care Med, 2005. 33(10):
2266–77.
614
36. Abraham E, Laterre PF, Garg R, Levy H,
Talwar D, Trzaskoma BL, Francois B,
Guy JS, Bruckmann M, Rea-Neto A,
Rossaint R, Perrotin D, Sablotzki A,
Arkins N, Utterback BG, and Macias
WL, Drotrecogin alfa (activated) for
adults with severe sepsis and a low risk
of death. N Engl J Med, 2005. 353(13):
1332–41.
37. Levi M, Levy M, Williams MD, Douglas I,
Artigas A, Antonelli M, Wyncoll D,
Janes J, Booth FV, Wang D, Sundin DP,
and Macias WL, Prophylactic heparin
in patients with severe sepsis treated
with drotrecogin alfa (activated). Am
J Respir Crit Care Med, 2007. 176(5):
483–90.
38. Abraham E, Reinhart K, Opal S,
Demeyer I, Doig C, Rodriguez AL, Beale
R, Svoboda P, Laterre PF, Simon S,
Light B, Spapen H, Stone J, Seibert A,
Peckelsen C, De Deyne C, Postier R,
Pettila V, Artigas A, Percell SR, Shu
V, Zwingelstein C, Tobias J, Poole L,
Stolzenbach JC, and Creasey AA, Efficacy
and safety of tifacogin (recombinant tissue
factor pathway inhibitor) in severe sepsis:
a randomized controlled trial. JAMA,
2003. 290(2): 238–47.
|11.3|

Urosepsis – from the view

of the intensivist
Lifen Li 1, Bin Ouyang 1,*, Weide Zhong 2, Xiangdong Guan 1
1
Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
2
Department of Urology, Guangzhou First Municipal People’s Hospital, Guangzhou, China
*Corresponding author: Surgical Intensive Care Unit (SICU), The First Affiliated Hospital of Sun Yat-sen University,
58# Zhongshan Road 2, 510080 Guangzhou, China
Tel: 86 20 8775 5766-8454, Fax: 86 20 8775 5766-8800, e-mail: binouyang@yahoo.com

ABSTRACT tissue and organ perfusion in severe

Sepsis has drawn much attention because
of its high morbidity, mortality and enor-
mous medical cost. Urosepsis is defined
as sepsis caused by urinary tract infection
(UTI). It occurs in approximately 25% of
all sepsis cases. Urosepsis in critically ill
adult patients is associated with increased
morbidity, prolonged hospitalization, and
greater healthcare expenditure, and a
high mortality rate of 25–60% in some
critical patients. Early rapid diagnosis
is crucial in permitting timely treatment
of urosepsis. The therapeutic strategy of
urosepsis consists of hemodynamic resus-
citation, treatment of infection, and spe-
cific supportive and adjunctive therapy.
Early goal-directed therapy is crucial for
restoring intravascular volume, correct-
ing the septic shock and maintaining
urosepsis and septic shock. Source con-
trol and initial broad-spectrum antimi-
crobial therapy is important for early
and effective control of the infection.
Other adjunctive therapies in urosep-
sis include intensive insulin therapy
for controlling blood glucose <150mg/dl,
low-dose hydrocortisone for patients with
septic shock, activated protein C (APC)
for patients with high risk for death,
lung protective ventilation strategy for
patients with mechanical ventilation, and
prophylactic therapy of deep vein throm-
bosis/stress ulcer.
Key words: urosepsis; sepsis; severe
sepsis; septic shock; diagnosis; treatment
of urosepsis; antimicrobial therapy;
EGDT; fluid resuscitation; intensive insu-
lin therapy; rhAPC
Chapter | 11 | Urosepsis
SUMMARY OF RECOMMENDATIONS
Diagnosis
1. Urine and blood cultures must be
implemented in the initial routine
laboratory tests before antimicrobial
therapy (GoR A).
2. Bedside ultrasound is useful for
some critical patients to confirm the
source of infection (GoR B).
Management
Hemodynamic resuscitation
3. Resuscitation has to be started
immediately as soon as patients are
recognized as having hypotension or
serum lactate >4mmol/l (GoR A).
4. The initial six-hour resuscitation must
meet the following goals (GoR A):
a. central venous pressure (CVP)
8–12 mmHg, or higher target
CVP of 12–15 mmHg in patients
with mechanical ventilation.
b. mean arterial pressure
(MAP)≥65mm Hg.
c. urine output≥0.5mL.kg–1.hr –1.
d. central venous oxygen
saturation(ScvO2)≥70%, or
mixed venous oxygen saturation
(SvO2)≥65%.
5. Fluids for resuscitation must be
either crystalloids or colloids in
patients with normal renal function
and the cumulative dose of colloids
has to be limited to avoid acute renal
failure in patients with pre-existing
kidney disease (GoR A).
6. Either norepinephrine or dopamine
must be the first choice of vaso-
pressor to correct the hypotension
in septic shock (GoR A). Low-dose
dopamine should not be used for the
purpose of renal protection (GoR A).
Epinephrine should be the first cho-
sen alternative agent if septic shock
616
is poorly responsive to dopamine or
norepinephrine (GoR B).
7. Dobutamine must be used to
increase cardiac output in patients
with low cardiac output despite ade-
quate fluid resuscitation (GoR A).
8. Packed red blood cell transfusion has
to be used to increase oxygen delivery
when hemoglobin is <70g/L to target a
hemoglobin of 70–90g/L in the absence
of coronary artery disease, acute hem-
orrhage, or lactic acidosis (GoR A).
Source control
9. Source control must be implemented
as soon as possible following success-
ful initial resuscitation (GoR A).
Antibiotic therapy
10. Intravenous antibiotic therapy must
be started as soon as possible and
within the first hour of recognition of
septic shock (GoR A).
11. The initial empirical anti-infective
therapy in patients with severe sep-
sis or septic shock must be broad-
spectrum and include one or more
antimicrobials, to cover all likely
pathogens (GoR A).
12. De-escalation to an appropriate anti-
microbial can be performed when the
causative organism and its antibiotic
susceptibilities are defined (GoR C).
Corticosteroids
13. Intravenous hydrocortisone should
been given only to adult septic shock
patients who require vasopressor
therapy despite adequate fluid resus-
citation (GoR B).
14. The dose of corticosteroids must be
≤300 mg hydrocortisone daily or com-
parable for other steroids (GoR A).
15. Steroid therapy should be weaned
once vasopressors are no longer
required (GoR B).
 Urosepsis – from the view of the intensivist
Intensive glucose control
16. IV insulin has to be used to con-
trol hyperglycemia in patients with
severe sepsis in the ICU (GoR A).
17. The target glucose level in severe
sepsis should be adjusted to the
range < 150 mg/dl instead of the
range < 110 mg/dl. A safe and vali-
dated protocol should be applied to
guarantee the glucose target and
also avoid the occurrence of hypogly-
cemia (GoR B).
Recombinant human activated
protein C (rhAPC)
18. Activated protein C (APC) should be
used only in patients with high risk
for death (typically an APACHE II
score ≥ 25 or multiple organ failure)
(GoR B).
1. INTRODUCTION
Sepsis has drawn much attention because
of its high morbidity, mortality and enor-
mous medical cost. Sepsis develops in
750,000 people annually in the United
States, and more than 210,000 die. An
almost 18–29% mortality was reported in
sepsis. A higher mortality of 30–52% was
reported in severe sepsis and septic shock
despite advances in critical care. A $16.7
billion annual healthcare cost for sepsis
was reported [1–6].
Urosepsis is defined as sepsis caused
by urinary tract infection (UTI). It occurs
in approximately 25% of all sepsis cases
[7]. The incidence of urosepsis was about
15.8–16 % in different ICUs [8–9]. Most
cases of urosepsis in ICUs developed from
nosocomial urinary tract infection (UTI)
and more than 90% of nosocomial UTIs
were associated with urinary catheters
[10–11]. Critically ill patients are immu-
no-deficient and easily develop nosoco-
mial infection and sepsis. The risk factors
| 11.3 |
in ICUs associated with the development
of sepsis include: age, diabetes mellitus,
immuno-suppression (such as transplant
recipients), chemotherapy or corticoster-
oids treatment, mechanical ventilation,
increased duration of urinary catheteri-
zation, length of ICU stay, and preceding
systemic antimicrobial therapy [10–12].
On the other hand, some patients with
underlying severe urological infection,
who develop severe sepsis or septic shock,
need to be transferred to the ICU for
intensive medical therapy.
Urosepsis in critically ill adult patients
is associated with increased morbidity,
prolonged hospitalization, and greater
healthcare expenditures, but not mortal-
ity. Patients with a designated urinary
source of sepsis had a significantly lower
risk of death than patients with gastroin-
testinal, respiratory, or other sources of
sepsis [13]. However, urosepsis still has
a high mortality rate of 25–60% in some
special critical patients [9]. When severe
sepsis or septic shock is present, mortal-
ity is unbelievably high. Therefore, early
intensive therapy used for urosepsis is
important and necessary.
2. METHODS
To understand the epidemiology, the
diagnosis and the treatment of urosep-
sis, we searched the PubMed database
using the following key-words: urosep-
sis, sepsis, sever sepsis, septic shock, uro-
sepsis AND ICU, urinary tract infection,
urinary tract infection AND ICU, EGDT,
fluid resuscitation, corticosteroid AND
septic shock, intensive insulin therapy,
Drotrecogin alfa OR rhAPC, procalci-
tonin OR PCT AND sepsis, antimicrobial
therapy AND sepsis. The following limits
were added to the searching: published –
last 10 years; added to Pubmed – last 10
years; humans; languages – English; type
of article – clinical trial; editorial; meta-
analysis; practice guideline; randomized
controlled trial; review; classical article;
617
Chapter | 11 | Urosepsis
clinical conference; clinical trial phase
I to IV; comparative study; consensus
development conference; NIH controlled
clinical trial; NIH guideline; NIH multi-
center study; abstract available. A total
of 14793 publications (published from
1999–2008) were found and screened by
title and abstract, and 318 suitable arti-
cles were selected, analyzed and included
in this review.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [14–15].
3. DEFINITION
Urosepsis is sepsis caused by urinary
tract infection. Sepsis, severe sepsis and
septic shock are often defined according to
the American College of Chest Physicians/
Society of Critical Care Medicine (ACCP/
SCCM) Consensus Conference of 1991 as
follows [16].
• Sepsis is the systemic inflammatory
response to infection. The manifesta-
tions of the systemic inflammatory
response syndrome (SIRS) include,
but are not limited to, more than one
of the following: (1) a temperature
greater than 38º or less than 36º; (2)
an elevated heart rate greater than
90 beats per minute; (3) tachypnea,
manifested by a respiratory rate
greater than 20 breaths per minute
or hyperventilation, as indicated by a
PaCO2 of less than 32 mm Hg; and (4)
an alteration in the white blood cell
count, such as a count greater than
12,000/cu mm, a count less than 4,000/
cu mm; or the presence of more than
10% immature neutrophils. It should
be identified whether these manifesta-
tions are a part of the direct systemic
response to the presence of an infec-
tious process or, in the absence of
infection, to other known causes for
such abnormalities.
618
• Severe sepsis is defined as sepsis
associated with organ dysfunction,
hypoperfusion abnormality, or sepsis-
induced hypotension. Hypoperfusion
abnormalities include lactic acidosis,
oliguria, and acute alteration of mental
status.
• Sepsis-induced hypotension is defined
by the presence of a systolic blood
pressure of less than 90 mmHg or its
reduction by 40 mm Hg or more from
baseline in the absence of other causes
for hypotension (e.g. cardiogenic shock).
• Septic shock is a subset of severe sep-
sis and is defined as sepsis-induced
hypotension, persisting despite ade-
quate fluid resuscitation, along with
the presence of hypoperfusion abnor-
malities or organ dysfunction. Patients
receiving inotropic or vasopressor
agents may no longer be hypotensive
by the time they manifest hypoper-
fusion abnormalities or organ dysfunc-
tion, yet they would still be considered
to have septic shock.
Sepsis and its related syndromes rep-
resent a continuum of clinical and patho-
physiologic severity. The degree of severity
may affect prognosis independently.
4. DIAGNOSIS OF UROSEPSIS
The diagnosis of urosepsis should con-
firm the presence of both UTI and sepsis.
Primary urological infection can be identi-
fied with exclusive local features such as
f lank pain, renal colic pain, costoverte-
bral angle tenderness, micturition, hae-
maturia, or urinary retention. However,
special attention needs to be paid to
critically ill patients who have poor con-
sciousness or are under sedation and
analgesia since they are incapable of stat-
ing that they are uncomfortable. Besides,
many ICU-acquired urinary tract infec-
tions are catheter-related UTI which are
rarely symptomatic [17]. Therefore, the
definite diagnosis of urosepsis in critical
 Urosepsis – from the view of the intensivist
ill patients becomes difficult. Moreover,
patients with long-term indwelling cath-
eters may have bacteriuria, and thus con-
firmation of the urinary tract as the only
source of infection remains problematic.
Sonography or further radiographic inves-
tigations (such as CT-scan) of the urogeni-
tal organ should be performed promptly in
an attempt to confirm the source of infec-
tion, if safe to do so [18–19]. Ultrasound
should be useful for bedside studies in
some critical patients who are unstable
and difficult to transport outside of the
ICU [20] (LoE 3, GoR B). Urine and blood
cultures must be carried out in initial rou-
tine laboratory tests before antimicrobial
therapy, if this is not associated with a sig-
nificant delay in antibiotic administration
[20] (LoE 3, GoR A). Cultures from other
sites, such as respiratory secretions, celiac
f luid, wounds, or other body fluids that
may be the source of infection, should also
be obtained before antibiotic therapy in
order to exclude other causes of infection.
Sepsis is diagnosed according to the
criteria of ACCP/SCCM Consensus
Conference of 1991. However, the symp-
toms and signs of SIRS, which include
changes in body temperature, tachycar-
dia, tachypnea, and leukocytosis are nei-
ther sensitive nor specific enough for the
diagnosis of sepsis. These parameters
can also be misleading because critically
ill patients with trauma, or after major
surgery, often present with systemic
inf lammatory response syndrome but
no infection [21–23]. In the 2001 SCCM/
ESICM/ACCP/ATS/SIS conference par-
ticipants added several new diagnostic
criteria for sepsis, in particular includ-
ing the biomarkers procalcitonin (PCT)
and C-reactive Protein (CRP), despite
the overall conclusion that it was prema-
ture to use biomarkers for sepsis diag-
nosis [24]. Many prospective researches
demonstrated that PCT is a reliable and
promising marker of sepsis in critically
ill patients. It may complement clinical
signs and routine laboratory parameters,
suggest severe infection and distinguish
| 11.3 |
infection from other inflammatory dis-
eases. PCT is also an indicator of sever-
ity and prognosis of sepsis in critically
ill patients [25–30]. However we should
still continue to search for rapid diagnos-
tic methods to identify sepsis precisely.
A swift diagnosis is crucial in permitting
timely treatment for a life threatening
condition and then improving outcomes
of sepsis [31].
5. MANAGEMENT OF UROSEPSIS
The management of urosepsis includes
treatment of urinary infection and treat-
ment of sepsis. Once severe sepsis and
septic shock appear, the treatment strat-
egy is similar with sepsis from other
sources. It is necessary to follow the
Surviving Sepsis Campaign guidelines
of 2008, which consist of hemodynamic
resuscitation, treatment of infection
(including source control and early anti-
microbial therapy), specific supportive
and adjunctive therapy [20].
5.1 Hemodynamic resuscitation
The crucial aspect of the management of
the patient with severe sepsis or septic
shock is optimal hemodynamic resuscita-
tion, essentially involving administration
of sufficient fluids and vasoactive agents
when required.
5.1.1 Initial resuscitation
General hemodynamic assessment on the
basis of heart rate, blood pressure, central
venous pressure (CVP), and urinary out-
put is very useful but not enough in guid-
ing the resuscitation of hypoperfusion
in shock or occult shock. Hypoperfusion
in shock leads to global tissue hypoxia
because of the imbalance between sys-
temic oxygen delivery and oxygen
demand. The parameters indicating the
balance of tissue oxygen metabolism
(such as mixed venous oxygen saturation
(SvO2), arterial lactate concentration, and
619
Chapter | 11 | Urosepsis
base deficit) are important hemodynamic
variables as resuscitation end points
[31–32]. However, in patients with renal
insufficiency, base deficit is not a reliable
parameter for tissue oxygen metabolism.
The invasive procedure of central ven-
ous catheterization or pulmonary artery
catheterization (PAC) for hemodynamic
monitoring is necessary for critically ill
patients with severe sepsis and septic
shock although many debates about the
usage of PAC are continuing. Indwelling
PAC is the best hemodynamic manipula-
tion in critically ill patients not only for
measurement of SvO2 but also for meas-
urement of cardiac output and pulmo-
nary arterial wedge pressure [33]. Central
venous oxygen saturation (ScvO2) is an
attractive alternative to SvO2 because it is
easier and less risky to perform. Recently,
studies indicated that SvO2 is 5–7% lower
than central venous oxygen saturation
(ScvO2) in septic shock [34].
Many recent studies support the claim
that early goal directed therapy (EGDT)
in patients with severe sepsis and sep-
tic shock provides a good outcome and
reduces mortality [31, 35–37]. It is recom-
mended that resuscitation begin as soon
as patients are recognized with hypo-
tension or an elevated serum lactate
>4mmol/l and this must not be delayed
pending ICU admission [20] (LoE 3,
GoR A). During the first six hours of
resuscitation, the following goals must be
achieved:
i. Central venous pressure (CVP)
8–12mm Hg, higher target CVP of
12–15 mmHg in the patients with
mechanical ventilation.
ii. Mean arterial pressure
(MAP)≥65mm Hg.
iii. Urine output≥0.5mL.kg–1.hr –1.
iv. Central venous (superior vena
cava) oxygen saturation (ScvO2)
≥70% or mixed venous oxygen
saturation (SvO2) ≥65% [20] (LoE 3,
GoR A).
620
Fluid challenge is required firstly for
restoration of intravascular volume sta-
tus to meet the initial target of a CVP
of 8–12mm Hg (even higher CVP of
12–15mmHg if mechanically ventilated).
The types of fluid for resuscitation (col-
loids or crystalloids, natural or artificial
colloids) remain in discussion with regard
to clinical relevance. The Saline versus
Albumin Fluid Evaluation (SAFE) study
indicated 4% albumin administration was
as safe and equally effective as normal
saline for fluid resuscitation [38]. This
study demonstrated the safe application
of albumin as well as crystalloids to differ-
ent groups of critically ill patients, except
patients with brain injury. The disadvan-
tage of crystalloids for fluid resuscitation
is that more fluid is required to achieve
the same end points and results in more
edema, because the volume of distribu-
tion is much larger for crystalloids than
for colloids, while vascular permeability
is increased. However albumin is expen-
sive and theoretically risks transmission
of infectious agents [39], so the study
promoted the more widespread use of
semisynthetic colloids for septic patients
such as Gelatins and hydroxyethyl starch
(HES). For patients with urosepsis, the
risk of renal function impairment is con-
sidered especially. Various crystalloid
and colloid solutions are available to cor-
rect hypovolemia but some of them have
been implicated in impairment of renal
function. Gelatins and HES are preferred
colloids in patients with normal kidney
function, although there is some evidence
that the latter is associated with impaired
renal function in patients with pre-exist-
ing kidney disease. Moreover any hyper-
oncotic colloid given in large amounts may
decrease glomerular filtration and should
therefore be combined with crystalloids
[40]. Several studies showed the admin-
istration of hydroxyethyl starch for vol-
ume resuscitation in patients with septic
shock was significantly faster in normal-
izing CVP than Ringer’s lactate ( RL), and
had the same effect on 28-day mortality
 Urosepsis – from the view of the intensivist
as RL, but the risk of acute renal failure
increased, associated with the cumula-
tive dose of hydroxyethyl starch [41–42].
However, recently a large multicentre
observational European study showed
that the administration of normal dose
HES had no influence on renal function
or the need for renal replacement therapy
(RRT) in the ICU [43]. Therefore fluids
for resuscitation have to be either crystal-
loids or colloids in patients with normal
kidney function and the cumulative dose
of colloids must be limited to avoid acute
renal failure in patients with pre-exist-
ing kidney disease [20] (LoE 2, GoR A).
Therefore maybe the safest options for
fluid resuscitation in sepsis for EGDT are
combination colloids with crystalloids or
crystalloids alone. The rate of fluid chal-
lenge in patients with suspected hypo-
volemia has to be started with at least
1000mL of crystalloids or 300–500mL of
colloids over 30 minutes. More rapid and
larger volumes are required in sepsis-
induced tissue hypoperfusion [20] (LoE 4,
GoR A). The degree of intravascular vol-
ume depletion in patients with severe
sepsis varies. With peripheral vasodilata-
tion and ongoing capillary leak, most sep-
tic patients require further fluid therapy
during not only the first six hours but
also 24 hours of management. The rate
of fluid administration must be reduced
substantially if cardiac filling pressures
increase without concurrent hemody-
namic improvement [20] (LoE 4, GoR A).
5.1.2 Vasopressors
The presence of perfusion abnormalities
may persist despite adequate fluid resus-
citation in some patients with refractory
hypotensions. Therefore vasopressor ther-
apy may be required to achieve a minimal
perfusion pressure and maintain ade-
quate flow in these patients. The goal of
mean arterial pressure (MAP) ≥65 mm Hg
must be maintained [20] (LoE 3, GoR A).
The choice of vasopressors has also
been the subject of considerable debate
with conflicting opinions, in particular
| 11.3 |
regarding the supremacy of dopamine
or norepinephrine [44–45]. There is no
high-quality primary evidence to recom-
mend one catecholamine over another.
Either norepinephrine or dopamine has
to be recommended as the first choice
vasopressor agent to correct hypoten-
sion in septic shock [20] (LoE 3, GoR A).
Norepinephrine may be more effective
and reliable at reversing hypotension due
to its vasoconstrictive effects in patients
with septic shock. Moreover norepine-
phrine was able to increase mean per-
fusion pressure without apparent adverse
effect on peripheral blood flow or on renal
blood f low. Because norepinephrine has a
greater effect on efferent than on afferent
arteriolar resistance and increases the
filtration fraction in hyperdynamic sep-
tic shock, normalization of renal vascular
resistance could effectively reestablish
urine flow [46]. On the other hand, nore-
pinephrine has a potential risk of myo-
cardial ischemia due to the contraction
of the coronary artery and impairment
of tissue oxygenation due to excessive
vasoconstriction [47]. To avoid such a del-
eterious effect, the rational use of nore-
pinephrine should be based not only on
the reversal of hypotension, but also on
the achievement of appropriate physi-
ologic end-points on SvO2 [48]. Dopamine
may be particularly useful in patients
with compromised systolic function, pri-
marily due to an increase in stroke vol-
ume and heart rate. A placebo-controlled
randomized trial and a meta-analysis
found no difference in either renal protec-
tion or survival by comparing low-dose
dopamine to placebo [49–50]. Low dose
dopamine should not be used solely for
renal protection [20] (LoE 1, GoR A). In
some studies, epinephrine showed some
disadvantages with potential for causing
tachycardia, hyperlactemia, and worse
circulation, but without showing worse
outcomes over dopamine and norepine-
phrine [51–53]. Epinephrine should be
the first chosen alternative agent if septic
shock is poorly responsive to dopamine
621
Chapter | 11 | Urosepsis
or norepinephrine [20] (LoE 2, GoR
B). Vasopressin at a dose of 0.01–0.04
units/min may be a considered alterna-
tive because of its effectiveness in rais-
ing blood pressure in patients refractory
to other vasopressors [54]. However, we
should be cognizant of the disadvantage
that higher doses of vasopressin have
been associated with cardiac, digital, and
splanchnic ischemia. Vasopressin should
not be administered as the initial vaso-
pressor in septic shock [55].
5.1.3 Inotropic therapy
Septic patients with myocardial depres-
sion present with low cardiac output and
elevate cardiac filling pressures, and
have poor tolerance for further fluid chal-
lenge. Dobutamine is the first choice for
inotropic therapy. Dobutamine is used to
increase cardiac output and oxygen deliv-
ery, and thereby elevate ScvO2 or SvO2 in
order to achieve the resuscitation goal of
a ScvO2 ≥70% or SvO2 ≥65% respectively.
If septic patients maintain a low ScvO2
or SvO2 during the first six hours of fluid
resuscitation and vasopressors or ino-
tropic therapy are used, then a red blood
cell transfusion to a target hematocrit of
30% is recommended to increase oxygen
delivery. It recommend that red blood
cell transfusion occurs when hemoglobin
decreases to < 7.0 g/dL (< 70 g/L) to target
a hemoglobin of 7.0–9.0 g/dL (70–90 g/L)
in adults in the absence of myocardial
ischemia, severe hypoxemia, acute hem-
orrhage, cyanotic heart disease, or lactic
acidosis [20] (LoE 2, GoR A).
5.2 Treatment of infection
5.2.1 Source control
Source control is crucial in the manage-
ment of urosepsis. The source of infec-
tion should be eliminated by proper
surgical intervention, such as drainage
and removal. In principle, source control
includes identification of the source of
infection and elimination of the infected
622
focus [56]. Source control has to be imple-
mented as soon as possible following
successful initial resuscitation (LoE 3,
GoR A) and should be chosen with maxi-
mum efficacy and minimal physiologic
upset [20] (LoE 4, GoR A). In urosepsis,
when obstruction of the urinary tract is
identified as the source of infection, a low-
level invasive procedure (e.g. insertion of
an indwelling bladder catheter, percu-
taneous nephrostomy or drainage of an
abscess) usually needs to be performed,
and a urological operation should even
be considered. In addition, most urosep-
sis in critically ill patients is caused by
catheter-associated urinary tract infec-
tions, therefore the first reasonable inter-
vention may be to replace or remove the
catheter [57].
5.2.2 Antibiotic therapy
Undoubtedly, antimicrobial therapy is the
most essential treatment for critically ill
patients with severe infections. The prin-
ciple of antibiotic therapy in severe sepsis
may be summarized in three words: early,
appropriate and adequate.
A large retrospective study demon-
strated that initial, prompt antibiotic ther-
apy within the first hour of sepsis-induced
hypotension improved outcomes in septic
shock [58]. It showed that 79.9% of septic
patients survived owing to early antimi-
crobial therapy and survival descended to
5% with delay of therapy. Therefore intra-
venous antibiotic therapy must be started
as early as possible and within the first
hour of recognition of septic shock (LoE
2, GoR A) or severe sepsis without sep-
tic shock [20] (LoE 4, GoR A). Critically
ill patients associated with elderly, bad
underlying disease, severe clinical mani-
festation, and acquired immuno-suppres-
sion have the greatest susceptibility to a
wide range of potential pathogens (bacte-
rial and/or fungal). However, there is little
margin for error in the choices of antimi-
crobial therapy for patients with severe
sepsis or septic shock. The inappropriate
 Urosepsis – from the view of the intensivist
use of antimicrobials may cause thera-
peutic failure and accordingly increase
morbidity and mortality [59]. The initial
selection of empirical anti-infective ther-
apy in patients with severe sepsis or sep-
tic shock must be broad-spectrum therapy
that includes one or more antimicrobials
to cover all likely pathogens [20] (LoE 2,
GoR A). All patients must receive a full
loading dose of each antimicrobial to pen-
etrate adequate concentrations into the
presumed source of sepsis [20] (LoE 2,
GoR A). De-escalation to an appropriate
antimicrobial should be performed while
the causative organism and its antibiotic
susceptibilities are defined [20] (LoE 4,
GoR B). More importantly, this strategy
can also reduce the development of super-
infection and antimicrobial resistance [60].
Especially in the antibiotic treatment
of urosepsis, it is important to achieve
optimal exposure to antibacterials both
in plasma and in the urinary tract [61].
Since bacteriuria is usual in any urinary
tract infection, the role of antibiotics with
high renal excretion rates is required
to achieve high urinary concentrations.
Furthermore, the bacterial spectrum in
urosepsis may also be considered for the
selection of antimicrobials. Thus anti-
microbials that have a high intrinsic
potency (low MIC) against the common
uropathogens with modest elimination
by renal mechanisms are suitable for the
treatment of urosepsis [62].
5.3 Specific supportive and
adjunctive therapy
5.3.1 Corticosteroids
The prevalence of adrenal insufficiency
in septic shock is about 50% [63]. Septic
shock may be associated with relative
adrenal insufficiency. However, the use
of corticosteroid therapy in patients with
sepsis and septic shock has been contro-
versial. Initial studies with short courses
of high dose corticosteroid in sepsis and
septic shock showed no benefit in outcome
| 11.3 |
[64]. Currently, one French multi-center,
randomized, controlled trial (RCT) using
low-dose hydrocortisone therapy in
patients with vasopressor-unresponsive
septic shock and relative adrenal insuffi-
ciency shows a significantly faster shock
reversal and significant mortality reduc-
tion [65]. A recent large, European mul-
ticenter controlled trial (CORTICUS)
showed that hydrocortisone did speed up
shock reversal but did not improve sur-
vival or resolve shock either in patients
with septic shock or in patients who did
not have a response to corticotrophin [66].
It also showed that the use of the ACTH
test (responders and nonresponders)
did not predict the resolution of shock.
Therefore, intravenous hydrocortisone
should be given only to adult septic shock
patients with blood pressure identified
to be poorly responsive to fluid resuscita-
tion and vasopressor therapy [20] (LoE 3,
GoR B). It is best not to administer corti-
costeroids for the treatment of sepsis in
the absence of shock. Corticosteroid dose
must be comparable to ≤300 mg hydro-
cortisone daily (LoE 1, GoR A). Steroid
therapy should be weaned once vasopres-
sors are no longer required [20] (LoE 4,
GoR B).
5.3.2 Intensive glucose control
Hyperglycaemia associated with insu-
lin resistance is common in critically ill
patients. We recommend that IV insulin
should be used to control hyperglycemia
in patients with severe sepsis in the ICU
(LoE 2, GoR A). A well-known prospective,
randomized, controlled study performed
by van den Berghe in 2001 demonstrated
intensive insulin therapy (maintenance
of blood glucose at a level between 80 and
110 mg/dL) reduced ICU mortality to 4.6%
from 8.0% with conventional treatment
among critically ill patients in the surgical
ICU [67]. In this study, intensive insulin
therapy also showed a reduction of overall
in-hospital mortality, bloodstream infec-
tions, acute renal failure and requirement
623
Chapter | 11 | Urosepsis
of mechanical ventilation. Later in 2006,
Van den Berghe performed an intensive
insulin therapy trial in the medical ICU
[68]. It was found that intensive insu-
lin therapy did not significantly reduce
in-hospital mortality among critically ill
patients in MICU (40.0% in conventional
treatment versus 37.3% in intensive glu-
cose control) but carried a high risk of
hypoglycemia at 17.9%. However, the
morbidity of newly-acquired kidney injury
was reduced significantly, length of venti-
lation decreased, and length of ICU and
hospital stay decreased significantly. The
multi-center VISEP trial on glucose con-
trol in Germany was discontinued prema-
turely because of a high incidence (12.1%)
of hypoglycemia but without an identical
mortality benefit in the glucose control
group [69]. Therefore, the target glucose
levels in severe sepsis should be adjusted
to the range < 150 mg/dl instead of the
range < 110 mg/dl by use of a safe and val-
idated protocol for insulin dose [20] (LoE
3, GoR B). Further studies are needed to
confirm the safe and effective target glu-
cose levels for intensive insulin therapy.
5.3.3 Recombinant Human Activated
Protein C (rhAPC)
Drotrecogin alfa (activated protein C), or
recombinant human activated protein C,
has antithrombotic, antiinflammatory,
and profibrinolytic properties. Reduced
levels of protein C are found in the major-
ity of patients with sepsis and are associ-
ated with an increased risk of death. The
Recombinant Human Activated Protein C
Worldwide Evaluation in Severe Sepsis
(PROWESS) trial, involving 1690 patients
with severe sepsis from 164 centers in 11
countries, showed activated protein C
(APC) reduced mortality from 30.8% in the
placebo group to 24.7% in the treatment
group [70]. The incidence of serious bleed-
ing was insignificantly higher in the acti-
vated protein C (APC) group than in the
placebo group (3.5% vs. 2.0%). The recent
Administration of activated protein C
624
(APC) in Early Severe Sepsis (ADDRESS)
study involved 2,613 patients with severe
sepsis judged to have a low risk of death
(APACHE II score less than 25) at the
time of enrollment. This study showed no
benefit in the 28-day mortality with APC
administration (18.5% in the APC group
versus 17% in the placebo group) [71]. The
rate of serious bleeding was greater in
the APC group (2.4%) than in the placebo
group (1.2%). Therefore, rhAPC should be
considered in adult patients with sepsis-
induced organ dysfunction with clinical
assessment of high risk of death (typically
APACHE II ≥25 or multiple organ fail-
ure) if there are no contraindications [20]
(LoE 2, GoR B). Because of the absence of
a beneficial treatment effect coupled with
an increased incidence of serious bleed-
ing complications, adult patients with
severe sepsis and low risk of death (most
of whom will have an APACHE II score <
20 or one organ failure) must not receive
rhAPC [20] (LoE 1, GoR A).
5.3.4 Other supportive therapy
In patients with sepsis-induced acute
lung injury/acute respiratory distress
syndrome (ALI/ARDS), lung protective
strategies coupled with plateau pres-
sures ≤30 cm H2O with limited tidal
volume 6 ml/kg predicted body weight
for mechanical ventilation, has demon-
strated a mortality benefit and has been
widely accepted [72]. In septic patients
with acute renal failure, continuous ven-
ovenous haemodiafiltration (CVHD) is
able to offer easier management of fluid
balance than using intermittent haemo-
dialysis (IHD) when hemodynamics
are unstable [73]. For all patients with
severe sepsis, it is necessary to prevent
deep vein thrombosis (DVT) by using
pharmacologic and/or mechanical therapy
unless contraindicated [74]. Stress ulcer
prophylaxis is also necessary for patients
with severe sepsis and septic shock. H2
blocker or proton pump inhibitor may be
used [75].
 Urosepsis – from the view of the intensivist
6. FURTHER RESEARCH
Statins, inhibitors of 3-hydroxy-3-meth-
ylglutaryl coenzyme A reductase, have
anti-inflammatory and immunomodula-
tory pleiotropic effects and may provide a
new approach for adjuvant therapy in the
patients with sepsis. Large prospective
and randomize controlled clinical trials
need to be done to test the efficacy and
safety of statin therapy [76–77].
7. CONCLUSIONS
Urosepsis is still associated with high
mortality in critically ill patients. The
optimum treatment for urosepsis is a
dynamic and evolving process. Early diag-
nosis is important in improving outcomes
because it allows treatment as early
as possible in the sepsis process. After
obtaining causative samples we should
initiate broad-spectrum antimicrobials
within one hour and surgically intervene
to remove the infection source. Early goal-
directed therapy (EGDT) should be imple-
mented to stabilize circulation in patients
with hypoperfusion. Corticosteroids ther-
apy is suggested in septic shock patients
poorly responsive to fluid resuscitation.
Drotrecogin alfa activated (rhAPC) should
be considered in patients with sepsis
induced multiple organ dysfunction asso-
ciated with a clinical assessment of high
risk of death (APACHE II≥25) if there are
no contraindications. Supportive therapy
of organ function is important when sep-
sis has developed due to multiple organ
dysfunction.
REFERENCES
1. Hotchkiss RS and Karl IE, The patho-
physiology and treatment of sepsis.
N Engl J Med, 2003. 348(2): 138–50.
2. Angus DC, Linde-Zwirble WT, Lidicker J,
Clermont G, Carcillo J, and Pinsky MR,
Epidemiology of severe sepsis in the
| 11.3 |
United States: analysis of incidence, out-
come, and associated costs of care. Crit
Care Med, 2001. 29(7): 1303–10.
3. Martin GS, Mannino DM, Eaton S, and
Moss M, The epidemiology of sepsis in the
United States from 1979 through 2000. N
Engl J Med, 2003. 348(16): 1546–54.
4. Angus DC and Wax RS, Epidemiology of
sepsis: an update. Crit Care Med, 2001.
29(7 Suppl): S109–16.
5. Brunkhorst FM, [Epidemiology, economy
and practice – results of the German study
on prevalence by the competence network
sepsis (SepNet)]. Anasthesiol Intensivmed
Notfallmed Schmerzther, 2006. 41(1):
43–4.
6. Moerer O, Schmid A, Hofmann M,
Herklotz A, Reinhart K, Werdan K,
Schneider H, and Burchardi H, Direct
costs of severe sepsis in three German
intensive care units based on retrospec-
tive electronic patient record analysis of
resource use. Intensive Care Med, 2002.
28(10): 1440–6.
7. Book M, Lehmann LE, Schewe JC, Weber
S, and Stuber F, [Urosepsis. Current
therapy and diagnosis]. Urologe A, 2005.
44(4): 413–22; quiz 423–4.
8. Ortiz R and Lee K, Nosocomial infec-
tions in neurocritical care. Curr Neurol
Neurosci Rep, 2006. 6(6): 525–30.
9. Rosser CJ, Bare RL, and Meredith JW,
Urinary tract infections in the critically
ill patient with a urinary catheter. Am J
Surg, 1999. 177(4): 287–90.
10. Bagshaw SM and Laupland KB,
Epidemiology of intensive care unit-
acquired urinary tract infections. Curr
Opin Infect Dis, 2006. 19(1): 67–71.
11. Richards MJ, Edwards JR, Culver DH,
and Gaynes RP, Nosocomial infections in
medical intensive care units in the United
States. National Nosocomial Infections
Surveillance System. Crit Care Med,
1999. 27(5): 887–92.
12. Vincent JL, Bihari DJ, Suter PM,
Bruining HA, White J, Nicolas-Chanoin
MH, Wolff M, Spencer RC, and Hemmer
M, The prevalence of nosocomial infection
in intensive care units in Europe. Results
of the European Prevalence of Infection
in Intensive Care (EPIC) Study. EPIC
625
Chapter | 11 | Urosepsis
International Advisory Committee. JAMA,
1995. 274(8): 639–44.
13. Knaus WA, Sun X, Nystrom O, and
Wagner DP, Evaluation of definitions for
sepsis. Chest, 1992. 101(6): 1656–62.
14. Department of Health and Human
Services, Public Health Service, 1992,
Agency for Health Care Policy and
Research. p. 115–127.
15. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
16. Bone RC, Balk RA, Cerra FB, Dellinger
RP, Fein AM, Knaus WA, Schein RM,
and Sibbald WJ, Definitions for sepsis and
organ failure and guidelines for the use of
innovative therapies in sepsis. The ACCP/
SCCM Consensus Conference Committee.
American College of Chest Physicians/
Society of Critical Care Medicine. Chest,
1992. 101(6): 1644–55.
17. Tambyah PA and Maki DG, Catheter-
associated urinary tract infection is rarely
symptomatic: a prospective study of 1,497
catheterized patients. Arch Intern Med,
2000. 160(5): 678–82.
18. Hoddick W, Jeffrey RB, Goldberg HI,
Federle MP, and Laing FC, CT and sonog-
raphy of severe renal and perirenal infec-
tions. AJR Am J Roentgenol, 1983. 140(3):
517–20.
19. Soulen MC, Fishman EK, Goldman SM,
and Gatewood OM, Bacterial renal infec-
tion: role of CT. Radiology, 1989. 171(3):
703–7.
20. Dellinger RP, Levy MM, Carlet JM,
Bion J, Parker MM, Jaeschke R,
Reinhart K, Angus DC, Brun-Buisson C,
Beale R, Calandra T, Dhainaut JF,
Gerlach H, Harvey M, Marini JJ,
Marshall J, Ranieri M, Ramsay
G, Sevransky J, Thompson BT,
Townsend S, Vender JS, Zimmerman
JL, and Vincent JL, Surviving Sepsis
Campaign: international guidelines for
management of severe sepsis and septic
shock: 2008. Intensive Care Med, 2008.
34(1): 17–60.
21. Reinhart K, Diagnosis of sepsis. Novel
and conventional parameters. Minerva
Anestesiol, 2001. 67(10): 675–82.
626
22. Rangel-Frausto MS, Pittet D, Costigan M,
Hwang T, Davis CS, and Wenzel RP, The
natural history of the systemic inflamma-
tory response syndrome (SIRS). A prospec-
tive study. JAMA, 1995. 273(2): 117–23.
23. Brun-Buisson C, The epidemiology of the
systemic inflammatory response. Intensive
Care Med, 2000. 26 Suppl 1: S64–74.
24. Levy MM, Fink MP, Marshall JC,
Abraham E, Angus D, Cook D, Cohen
J, Opal SM, Vincent JL, and Ramsay
G, 2001 SCCM/ESICM/ACCP/ATS/
SIS International Sepsis Definitions
Conference. Intensive Care Med, 2003.
29(4): 530–8.
25. Assicot M, Gendrel D, Carsin H,
Raymond J, Guilbaud J, and Bohuon C,
High serum procalcitonin concentrations
in patients with sepsis and infection.
Lancet, 1993. 341(8844): 515–8.
26. Vincent JL, Procalcitonin: THE marker
of sepsis? Crit Care Med, 2000. 28(4):
1226–8.
27. Brunkhorst FM, Wegscheider K, Forycki
ZF, and Brunkhorst R, Procalcitonin
for early diagnosis and differentiation
of SIRS, sepsis, severe sepsis, and sep-
tic shock. Intensive Care Med, 2000. 26
Suppl 2: S148–52.
28. Harbarth S, Holeckova K, Froidevaux C,
Pittet D, Ricou B, Grau GE, Vadas L, and
Pugin J, Diagnostic value of procalci-
tonin, interleukin-6, and interleukin-8 in
critically ill patients admitted with sus-
pected sepsis. Am J Respir Crit Care Med,
2001. 164(3): 396–402.
29. Muller B, Becker KL, Schachinger H,
Rickenbacher PR, Huber PR, Zimmerli W,
and Ritz R, Calcitonin precursors are reli-
able markers of sepsis in a medical inten-
sive care unit. Crit Care Med, 2000. 28(4):
977–83.
30. Schroder J, Staubach KH, Zabel P,
Stuber F, and Kremer B, Procalcitonin
as a marker of severity in septic shock.
Langenbecks Arch Surg, 1999. 384(1):
33–8.
31. Rivers E, Nguyen B, Havstad S, Ressler
J, Muzzin A, Knoblich B, Peterson E,
and Tomlanovich M, Early goal-directed
therapy in the treatment of severe sepsis
and septic shock. N Engl J Med, 2001.
345(19): 1368–77.
 Urosepsis – from the view of the intensivist
32. Rady MY, Rivers EP, and Nowak RM,
Resuscitation of the critically ill in the
ED: responses of blood pressure, heart
rate, shock index, central venous oxygen
saturation, and lactate. Am J Emerg Med,
1996. 14(2): 218–25.
33. Sakr Y, Vincent JL, Reinhart K, Payen
D, Wiedermann CJ, Zandstra DF, and
Sprung CL, Use of the pulmonary artery
catheter is not associated with worse
outcome in the ICU. Chest, 2005. 128(4):
2722–31.
34. Reinhart K, Kuhn HJ, Hartog C, and
Bredle DL, Continuous central venous
and pulmonary artery oxygen saturation
monitoring in the critically ill. Intensive
Care Med, 2004. 30(8): 1572–8.
35. Sebat F, Johnson D, Musthafa AA,
Watnik M, Moore S, Henry K, and Saari
M, A multidisciplinary community hos-
pital program for early and rapid resus-
citation of shock in nontrauma patients.
Chest, 2005. 127(5): 1729–43.
36. Nguyen HB, Corbett SW, Steele R,
Banta J, Clark RT, Hayes SR, Edwards J,
Cho TW, and Wittlake WA, Implementation
of a bundle of quality indicators for the
early management of severe sepsis and sep-
tic shock is associated with decreased mor-
tality. Crit Care Med, 2007. 35(4): 1105–12.
37. Trzeciak S, Dellinger RP, Abate NL,
Cowan RM, Stauss M, Kilgannon JH,
Zanotti S, and Parrillo JE, Translating
research to clinical practice: a 1-year
experience with implementing early
goal-directed therapy for septic shock in
the emergency department. Chest, 2006.
129(2): 225–32.
38. Finfer S, Bellomo R, Boyce N, French J,
Myburgh J, and Norton R, A comparison
of albumin and saline for fluid resuscita-
tion in the intensive care unit. N Engl J
Med, 2004. 350(22): 2247–56.
39. Grocott MP, Mythen MG, and Gan TJ,
Perioperative fluid management and clini-
cal outcomes in adults. Anesth Analg,
2005. 100(4): 1093–106.
40. Jakob SM, Prevention of acute renal
failure–fluid repletion and colloids. Int J
Artif Organs, 2004. 27(12): 1043–8.
41. Schortgen F, Lacherade JC, Bruneel F,
Cattaneo I, Hemery F, Lemaire F, and
Brochard L, Effects of hydroxyethylstarch
| 11.3 |
and gelatin on renal function in severe
sepsis: a multicentre randomised study.
Lancet, 2001. 357(9260): 911–6.
42. Hankeln K, Radel C, Beez M, Laniewski
P, and Bohmert F, Comparison of hydrox-
yethyl starch and lactated Ringer’s
solution on hemodynamics and oxygen
transport of critically ill patients in pro-
spective crossover studies. Crit Care Med,
1989. 17(2): 133–5.
43. Sakr Y, Payen D, Reinhart K, Sipmann
FS, Zavala E, Bewley J, Marx G, and
Vincent JL, Effects of hydroxyethyl starch
administration on renal function in
critically ill patients. Br J Anaesth, 2007.
98(2): 216–24.
44. Vincent JL and de Backer D, The
International Sepsis Forum’s controver-
sies in sepsis: my initial vasopressor agent
in septic shock is dopamine rather than
norepinephrine. Crit Care, 2003. 7(1):
6–8.
45. Sharma VK and Dellinger RP, The
International Sepsis Forum’s controversies
in sepsis: my initial vasopressor agent in
septic shock is norepinephrine rather than
dopamine. Crit Care, 2003. 7(1): 3–5.
46. Martin C, Papazian L, Perrin G, Saux P,
and Gouin F, Norepinephrine or dopamine
for the treatment of hyperdynamic septic
shock? Chest, 1993. 103(6): 1826–31.
47. Domsky MF and Wilson RF,
Hemodynamic resuscitation. Crit Care
Clin, 1993. 9(4): 715–26.
48. Martin C, Saux P, Eon B, Aknin P, and
Gouin F, Septic shock: a goal-directed
therapy using volume loading, dob-
utamine and/or norepinephrine. Acta
Anaesthesiol Scand, 1990. 34(5): 413–7.
49. Bellomo R, Chapman M, Finfer S,
Hickling K, and Myburgh J, Low-dose
dopamine in patients with early renal dys-
function: a placebo-controlled randomised
trial. Australian and New Zealand
Intensive Care Society (ANZICS) Clinical
Trials Group. Lancet, 2000. 356(9248):
2139–43.
50. Kellum JA and J MD, Use of dopamine in
acute renal failure: a meta-analysis. Crit
Care Med, 2001. 29(8): 1526–31.
51. De Backer D, Creteur J, Silva E, and
Vincent JL, Effects of dopamine, norepine-
phrine, and epinephrine on the splanchnic
627
Chapter | 11 | Urosepsis
circulation in septic shock: which is best?
Crit Care Med, 2003. 31(6): 1659–67.
52. Levy B, Bollaert PE, Charpentier C, Nace
L, Audibert G, Bauer P, Nabet P, and
Larcan A, Comparison of norepinephrine
and dobutamine to epinephrine for hemo-
dynamics, lactate metabolism, and gastric
tonometric variables in septic shock: a
prospective, randomized study. Intensive
Care Med, 1997. 23(3): 282–7.
53. Annane D, Vignon P, Renault A,
Bollaert PE, Charpentier C, Martin
C, Troche G, Ricard JD, Nitenberg G,
Papazian L, Azoulay E, and Bellissant E,
Norepinephrine plus dobutamine versus
epinephrine alone for management of
septic shock: a randomised trial. Lancet,
2007. 370(9588): 676–84.
54. Lauzier F, Levy B, Lamarre P, and Lesur
O, Vasopressin or norepinephrine in early
hyperdynamic septic shock: a randomized
clinical trial. Intensive Care Med, 2006.
32(11): 1782–9.
55. Dunser MW, Mayr AJ, Tur A, Pajk W,
Barbara F, Knotzer H, Ulmer H, and
Hasibeder WR, Ischemic skin lesions as
a complication of continuous vasopressin
infusion in catecholamine-resistant
vasodilatory shock: incidence and risk
factors. Crit Care Med, 2003. 31(5): 1394–8.
56. Jimenez MF and Marshall JC, Source
control in the management of sepsis.
Intensive Care Med, 2001. 27 Suppl 1:
S49–62.
57. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008. 31
Suppl 1: S68–78.
58. Kumar A, Roberts D, Wood KE, Light
B, Parrillo JE, Sharma S, Suppes R,
Feinstein D, Zanotti S, Taiberg L, Gurka
D, and Cheang M, Duration of hypoten-
sion before initiation of effective antimi-
crobial therapy is the critical determinant
of survival in human septic shock. Crit
Care Med, 2006. 34(6): 1589–96.
59. Ibrahim EH, Sherman G, Ward S, Fraser
VJ, and Kollef MH, The influence of inad-
equate antimicrobial treatment of blood-
stream infections on patient outcomes
628
in the ICU setting. Chest, 2000. 118(1):
146–55.
60. Roberts JA, Kruger P, Paterson DL, and
Lipman J, Antibiotic resistance–what’s
dosing got to do with it? Crit Care Med,
2008. 36(8): 2433–40.
61. Wagenlehner FM, Weidner W, and Naber
KG, Pharmacokinetic characteristics of
antimicrobials and optimal treatment
of urosepsis. Clin Pharmacokinet, 2007.
46(4): 291–305.
62. Naber KG, Which fluoroquinolones are
suitable for the treatment of urinary tract
infections? Int J Antimicrob Agents, 2001.
17(4): 331–41.
63. Annane D, Bellissant E, Bollaert
PE, Briegel J, Keh D, and Kupfer Y,
Corticosteroids for severe sepsis and septic
shock: a systematic review and meta-anal-
ysis. BMJ, 2004. 329(7464): 480.
64. Cronin L, Cook DJ, Carlet J, Heyland DK,
King D, Lansang MA, and Fisher CJ, Jr.,
Corticosteroid treatment for sepsis: a criti-
cal appraisal and meta-analysis of the liter-
ature. Crit Care Med, 1995. 23(8): 1430–9.
65. Annane D, Sebille V, Charpentier C,
Bollaert PE, Francois B, Korach JM,
Capellier G, Cohen Y, Azoulay E,
Troche G, Chaumet-Riffaud P, and
Bellissant E, Effect of treatment with
low doses of hydrocortisone and fludro-
cortisone on mortality in patients with
septic shock. JAMA, 2002. 288(7):
862–71.
66. Sprung CL, Annane D, Keh D, Moreno R,
Singer M, Freivogel K, Weiss YG,
Benbenishty J, Kalenka A, Forst H,
Laterre PF, Reinhart K, Cuthbertson BH,
Payen D, and Briegel J, Hydrocortisone
therapy for patients with septic shock. N
Engl J Med, 2008. 358(2): 111–24.
67. van den Berghe G, Wouters P, Weekers
F, Verwaest C, Bruyninckx F, Schetz M,
Vlasselaers D, Ferdinande P, Lauwers P,
and Bouillon R, Intensive insulin therapy
in the critically ill patients. N Engl J Med,
2001. 345(19): 1359–67.
68. Van den Berghe G, Wilmer A, Hermans G,
Meersseman W, Wouters PJ, Milants I,
Van Wijngaerden E, Bobbaers H, and
Bouillon R, Intensive insulin therapy in
the medical ICU. N Engl J Med, 2006.
354(5): 449–61.
 Urosepsis – from the view of the intensivist
69. Brunkhorst FM, Kuhnt E, Engel C,
Meier-Hellmann A, Raggaler M,
Quintel M, Weiler N, Grundling M,
Oppert M, and Deufel T, Intensive insulin
in patients with severe sepsis and septic
shock is associated with an increased
rate of hypoglycemia – results from a
randomized multicenter study (VISEP).
Infection, 2005. 33: 19–20.
70. Bernard GR, Vincent JL, Laterre PF,
LaRosa SP, Dhainaut JF, Lopez-Rodriguez
A, Steingrub JS, Garber GE, Helterbrand
JD, Ely EW, and Fisher CJ, Jr., Efficacy
and safety of recombinant human acti-
vated protein C for severe sepsis. N Engl J
Med, 2001. 344(10): 699–709.
71. Abraham E, Laterre PF, Garg R, Levy
H, Talwar D, Trzaskoma BL, Francois
B, Guy JS, Bruckmann M, Rea-Neto
A, Rossaint R, Perrotin D, Sablotzki A,
Arkins N, Utterback BG, and Macias WL,
Drotrecogin alfa (activated) for adults
with severe sepsis and a low risk of death.
N Engl J Med, 2005. 353(13): 1332–41.
72. Ventilation with lower tidal volumes as
compared with traditional tidal volumes
for acute lung injury and the acute res-
piratory distress syndrome. The Acute
| 11.3 |
Respiratory Distress Syndrome Network.
N Engl J Med, 2000. 342(18): 1301–8.
73. Vinsonneau C, Camus C, Combes A,
Costa de Beauregard MA, Klouche K,
Boulain T, Pallot JL, Chiche JD,
Taupin P, Landais P, and Dhainaut JF,
Continuous venovenous haemodiafiltra-
tion versus intermittent haemodialysis
for acute renal failure in patients with
multiple-organ dysfunction syndrome:
a multicentre randomised trial. Lancet,
2006. 368(9533): 379–85.
74. Geerts W, Cook D, Selby R, and
Etchells E, Venous thromboembolism
and its prevention in critical care.
J Crit Care, 2002. 17(2): 95–104.
75. Cook DJ, Witt LG, Cook RJ, and Guyatt
GH, Stress ulcer prophylaxis in the
critically ill: a meta-analysis. Am J Med,
1991. 91(5): 519–27.
76. Falagas ME, Makris GC, Matthaiou DK,
and Rafailidis PI, Statins for infection
and sepsis: a systematic review of the clin-
ical evidence. J Antimicrob Chemother,
2008. 61(4): 774–85.
77. Gao F, Linhartova L, Johnston AM, and
Thickett DR, Statins and sepsis. Br J
Anaesth, 2008. 100(3): 288–98.
629
|11.4|
Urosepsis – from the view
of the urologist
Florian M.E. Wagenlehner, Adrian Pilatz, Wolfgang Weidner
Urologic Clinic, Justus-Liebig-University Gießen, Germany
Corresponding author: Florian M.E. Wagenlehner, MD, PhD, Department of Urology, Pediatric Urology and Andrology
University Hospital Giessen, Rudolf-Buchheim-Str. 23, D-35392 Giessen, Germany
Tel: +49-641/ 9944518, Fax: +49-641/ 9944509, Wagenlehner@aol.com
ABSTRACT
Urosepsis accounts for approximately 25%
of all sepsis cases and may develop from
a community or nosocomial acquired uri-
nary tract infection (UTI). The underlying
UTI is almost exclusively a complicated
one with involvement of parenchymatous
urogenital organs (e.g. kidneys, prostate).
In urosepsis, as in other types of sepsis,
the severity of sepsis depends mostly
upon the host response. The urological
management of urosepsis comprises early
diagnosis, early fluid-and oxygen treat-
ment, early antibiotic therapy and early
control of the complicating factor in the
urinary tract.
Time from admission to therapy is
critical. The shorter the time to effective
treatment, the higher is the success rate.
This aspect has to become incorporated
into the organisational process, including
urologists, radiologists and intensive care
specialists amongst others.
Adequate initial antibiotic therapy has
to be insured. This goal implies however
a wide array of measures over time to
ensure a rational antibiotic policy, includ-
ing microbiologists and clinical pharma-
cologists. Dosage of an antibiotic in the
septic patient generally has to be high to
ensure adequate pharmacological expo-
sure in the individual patient.
Key words: Urinary tract infections;
urosepsis; SIRS; obstructive pyelonephri-
tis; sepsis treatment; antibiotic policy.
SUMMARY OF RECOMMENDATIONS
1. Broad-spectrum beta-lactam antibiot-
ics are the first choice for systemic
treatment of urosepsis (GoR A).
2. In case of high local rates of entero-
bacteria producing extended-spectrum
beta-lactamases and patients with
severe urosepsis, carbapenems should
 Urosepsis – from the view of the urologist
be used for initial systemic treatment
(GoR B).
3. The patient population warrant-
ing carbapenem treatment as first
line agents must however be defined
strictly in order to keep the antibiotic
pressure of these reserve antibotics as
low as possible (GoR A).
4. The most important urological feature
in urosepsis is obstructive pyelone-
phritis. Obstruction in urosepsis
therefore must be diagnosed or ruled
out and treated accordingly (GoR A).
5. Deobstruction in the uroseptic patient
should be performed by the least inva-
sive way (GoR B).
1. INTRODUCTION
In 20–30% of all septic patients the infec-
tious focus is localised in the urogenital
tract [1]. The prevalence of urosepsis in
urological patients with nosocomial UTI
is high and was in one study on average
about 12% [2], whereas in patients with
nosocomial UTI treated in other speci-
alities the prevalence for severe sepsis
was 2% and for septic shock 0.3% [3]. In
recent years, the incidence of sepsis and
urosepsis has even increased [4–5], but
the associated mortality has decreased
suggesting improved management of
patients [4–5]. This review deals with
the question about the optimal manage-
ment of urosepsis. This question was
divided into several issues, such as choice
of antimicrobial drug for empiric therapy;
development of bacterial resistance; most
important urological feature; and prob-
lems of antibiotic therapy.
2. METHODS
A systematic literature search was per-
formed the PubMed database with the fol-
lowing search terms: “urosepsis”, “sepsis
AND urinary tract infection”, “sepsis AND
| 11.4 |
ESBL”, urinary tract infection AND ESBL”,
“urinary tract infections AND MRSA”,
“urinary tract infections AND VRE”, and
using the following limits: published and
added to PubMed within the last 10 years;
English and German language; and only
the following types of articles: clinical trial;
meta-analysis; practice guideline; rand-
omized controlled trial; clinical conference;
clinical trial phase I to IV; comparative
study; consensus development conference;
NIH controlled clinical trial; NIH guide-
line; NIH multicenter study. Papers pub-
lished in non-reviewed supplements were
not included.
The search identified a total of 205
articles published from 1999–2008.
The included articles were rated
according levels of evidence following
ICUD standard [6–7] based on: 1) the
hierarchy of study types and, 2) how well
the study was designed and carried out.
The hierarchy of study types was: sys-
tematic reviews and meta-analysis of
randomized controlled trials, randomized
controlled clinical trials, non-randomized
cohort studies, case-control studies, case
series, and expert opinion as the lowest
level.
Of the 205 identified articles, a total of
45 articles met the criteria for detailed
analysis and rating. These 45 articles
were reviewed in detail for how well each
study was designed and carried out using
a standard checklist adopted from the
CONSORT statement (available at http:
//www.consort-statement.org). Of these
a total of 35 articles met the criteria for
rating (Table 1). According to the hierar-
chy of study types these papers included:
two systemic reviews or meta-analyses,
four randomized clinical trials, three non-
randomized cohort studies, seven case-
control studies, nine case series, three
articles incorporating expert opinion,
no cost-effectiveness studies, and seven
in vitro, laboratory or animal model stud-
ies (Table 1).
According to the level of evidence,
one study was identified as a Level 1
631
Chapter | 11 | Urosepsis

study [8]; nine as Level 2 studies includ- 3. EPIDEMIOLOGY OF UROSEPSIS

ing: one systematic review [9], three ran-
domized clinical trials [10–12] and two
non-randomized cohort studies [13–14]
and three case control studies [15–17]
(Table 1); 14 as Level 3 studies includ-
ing: one randomized clinical trial [18], one
non-randomized cohort study [19], four
case-control studies [20–23], eight case
series [24–31] (Table 1); and 10 as Level
4 studies including: three articles based
on expert opinion [32–34], and seven in
vitro, laboratory, or animal model studies
[35–41] (Table 1). The results of the indi-
vidual studies and their level of evidence
are summarized in Table 1.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [6–7].
Severe sepsis is a critical situation with
a reported mortality rate ranging from
20–42% [5]. Most severe sepsis cases reported
in the literature are related to pulmonary
(50%) or abdominal infections (24%), with
urinary tract infections (UTIs) accounting for
approximately 5% [42] to 7% [43]. Sepsis is
more common in men than in women [5].
The leading cause for developing uro-
septic shock in urological patients was
urinary obstruction in 78% and uropathies
with significant impact on urodynam-
ics in 22% [44]. 17% of patients develop
urosepsis after urological interventions.
Obstructive diseases of the urinary tract
leading to obstructive pyelonephritis
are caused by ureteral stones in 65%,
by tumors in 21%, by pregnancy in 5%,

Table 1 Evidence Table: Studies on management of urosepsis that include Original Data, Systematic Review or Meta-analysis,
Expert Opinion, or Other Data (1999–2008).

Study Type First author, Subjects Design Aspects Critical Findings Rating of
year, Evidence
reference

Systematic
reviews and
Meta-analyses

Vidal L et al., 503 Efficacy and safety Aminoglycoside 2, positive

2007 [9] patients with of aminoglycoside monotherapy
end-point monotherapy equally effective as
mortality comparators. Paucity of
patients
with sepsis.

Schwaber MJ 16 studies Mortality and delay in Bacteremia due to 1, positive

et al., 2007 [8] effective therapy asso- enterobacteria
ciated with ESBL pro- producing ESBL
ducing enterobacteria results in increased
bacteremia mortality (RR 1,85) and
delay in effective therapy
(RR 5,56)

Randomized
clinical trials

McKinnon PS 76 Comparative trial of No differences in 2, positive

et al., 2008 cefepime vs ceftazidime outcomes between both
[12] in patients with sepsis antibiotics. Significant
of different origins PK/PD differences in
(cUTI) parameters in both
antibiotics (AUIC ≥
250 and T>MIC = 100%)

632
 Urosepsis – from the view of the urologist
Byl B et al., 27/ 5 UTI Comparative trial
2001 [10] of imipenem vs
ceftazidime in patients
with Gram-negative
infections (7 bacteremia)
Luchi M et al., 33 Comparative trial of
2000 [11] imipenem vs ceftazidime
in urosepsis with
Gram-negative bacilli
Kuo BI et al., 50 Comparative trial of
2000 [18] meropenem and
imipenem in patients
with sepsis (pneumonia
and UTI)
Non-
randomized
cohort studies
Bin C et al., 22 Comparative consecuti-
2006 [19] ve trial of ceftazidime vs
imipenem vs cefopera-
zone/ sulbactam in
patients with
bacteremia due to
ESBL (MIC
ceftazidime ≤ 8 mg/L
Magill SS et al., 182 Association between
2006 [13] anatomic site of
candida colonization,
invasive candidiasis and
mortality in critically ill
surgical patients
Van Dissel JT Chills, bacteremia and
et al., 2005 endotoxemia in patients
[14] with sepsis and
in-hospital mortality
and 5–10 years survival
Case-control
studies
Nguyen LH et Retrospective,
al., 2008 [21] comparing 2 time
periods (2001–02 vs
2005–06), reducing
empirical
fluoroquinolone use for
P. aeruginosa
Venier AG et Clinical and bacterial
al., 2007 [23] determinants in E. coli
UTI bacteremia vs no
bacteremia
| 11.4 |
No differences in 2, positive
endotoxine, IL-6 or
TNF-alpha release
No differences in plasma 2, positive
endotoxin, IL-6, TNF-alpha,
and urine endotoxine,
IL-6, 8
No differences in 3, positive
clinical or
microbiological response
Not significantly different 3, positive
treatment success ratio
(ceftazidime 85.7%, imipe-
nem 87.5%, cefoperazone/
sulbactam 71.4%)
Patients with 2, positive
candiduria significantly
more frequently
invasive candidiasis (p=0.2).
Candiduria at any time in
the ICU higher mortality
(OR, 2,86)
Decreased mortality risk at 2, positive
long-term follow up (OR,
0,644) for patients with
chills at presentation of
sepsis
Study patients were elderly, 3, positive
median 3
comorbidities, median
APACHE II score of 13,
75% had pneumonia or
urosepsis.
Empirical use of
fluoroquinolones was redu-
ced by 30% in 2005–06,
piperacillin/ tazobactam
usse was increased 39%
Being female and having a 3, negative
catheter significantly less
prevalent among patients
with bacteremia. Virulence
factors not different.
(Continued)
633
Chapter | 11 | Urosepsis

Study Type First author, Subjects Design Aspects Critical Findings Rating of
year, Evidence
reference

Binelli CA et 115 Association between Significant association of 2, positive

al., 2006 [15] candiduria and candiduria and candidemia.
candidemia Isolates from urine and
blood different in 52%

Mariappan P et 115 Comparing 2 time Ciprofloxacin 3, positive

al., 2006 [20] periods. 1st period no pretreatment
treatment, 2nd period significantly reduced upper
1 week ciprofloxacin UTI and SIRS
250 mg/bid p.o. before
PCNL in patients with
stones ≥ 20 mm or dila-
ted pelvicalyceal system

Guidet B et al., 5,675 with 1 Incidence and severity Patients with ≥2 organ 2, positive
2005 [16] organ dys- of organ dysfunction dysfunctions have less UTI
function vs associated with sepsis
12,598 with
≥2 organ
dysfunctions

Ho PL et al., Risk factors and Risk factors for E. coli ESBL 2, positive
2002 [17] outcome of were: severe underlying
bacteremia due to E. diseases (OR 31.2), nosoco-
coli producing ESBL mial origin (OR 16.5),
urinary origin (OR 7.8).
Mortality in ESBL E. coli
patients twice as high as
controls.

Olszyna DP et 33 Production of CXC CXC chemokines are pre- 3, positive

al., 2000 [22] chemokines in urosepsis dominantly produced
within the urinary tract

Case-series

Chou YY et al., 12 Clinical features UTI 8.3%. E. faecium 3, positive

2008 [25] and outcome of higher 60-days
patients with mortality than
vancomycin- E. faecalis (63%)
resistant enterococcal
bacteremia

Lee, CC et al., 890 Outcome of UTI main source for blood- 3, positive
2007 [28] community- stream infections among
acquired bloodstream patients >65 years. Patients
infections >65 years fewer signs and
symptoms of BSI, but wor-
se prognosis

Hsu CY et al., 128 Clinical impact of Bacteremia present in 42% 3, positive

2006 [27] bacteremia in and indicated a more seve-
complicated re disease. Blood cultures
pyelonephritis in cases with complicated
APN

Bjerklund 6033, One day prevalence Urosepsis 12% of 3, positive

Johansen TE et including 727 study on nosocomial UTI nosocomial UTI
al., 2007 [24] with nosoco-
mial UTI

634
 Urosepsis – from the view of the urologist | 11.4 |

Mariappan P et 54 Correlation between Patients with infected 3, positive

al., 2005 [29] different sites of stones significantly higher
microbiological sam- rate of urosepsis
pling and the predictive
value for urosepsis.

Christoph F et 189, 50 Clinical course of in- 7.9% with 3, positive

al., 2005 [26] positive renal fected hydronephrosis
pelvis urine hydronephrosis, developed SIRS/
cultures, 15 predictive parameters sepsis. Initial fever and
patients SIRS/ elevated BMI indicated
sepsis higher risk for SIRS/sepsis

Efstathiou SP 225 Retrospective A score consisting of: 3, positive

et al., 2003 investigation to shock, bedridden status,
[31] predict mortality and age > 65 years, previous
failure of treatment in antibiotic treatment,
acute pyelonephritis in immunosuppression predic-
adults ted mortality in men and
women.

McAleer IM et 34 renal Endotoxin content in Significantly higher levels 3, positive

al., 2003 [30] calculi renal calculi of endotoxin found in renal
calculi of infection stones
compared to non-infection
calculi

Expert opinion

Calandra T et n.a. Definitions of Standardized 4, positive

al., 2005 [32] infections associated definitions for clinical trials
with sepsis

Dhainaut JF et 1,690 Blinded, critical Drotrecogin alfa 4, positive

al., 2003 [33] severe integrated review of beneficial also in urosepsis
sepsis data on PROWESS trial
patients

Naber KG et n.a. Guidelines for Classification, 4, positive

al., 2001 [34] management of diagnosis, treatment,
urinary tract infections follow-up of sepsis
syndrome, urosepsis

Cost-
effectiveness
Studies

none

In vitro,
laboratory, or
animal model
studies

Van Zoelen MA 10 Group box 1 Delayed HMGB1 4, positive

et al., 2007 concentrations in diffe- response in urosepsis.
[41] rent origins of sepsis HMGB1 release at site of
infection.

Moreno E et 150 strains Virulence Similar virulence scores. 4, negative

al., 2005 [38] determinants of Differences in
E. coli in strains phylogenetic groups with
causing UTI regard to
bacteremia vs compromised hosts.
pyelonephritis vs other
sources of bacteremia

(Continued)

635
Chapter | 11 | Urosepsis

Study Type First author, Subjects Design Aspects Critical Findings Rating of
year, Evidence
reference

Kizirgil A et al., 75 ESBL pro- In vitro activity of In vitro susceptibility of 4, positive

2005 [37] ducing stra- meropenem, cipro- ESBL producing E. coli and
ins of blood floxacin, amikacin K. pneumoniae was 100%
isolates against ESBL-producing for meropenem, 33 and
and non-producing 26% for ciprofloxacin,
strains of E. coli and and 95% and 83% for
K. pneumoniae amikacin

Alhambra A et 482 strains In vitro susceptibility of Ertapenem was the most 4, positive
al., 2004 [35] of UTI ertapenem, active drug tested
ampicillin, cefazolin,
cefuroxime, cefotaxime,
co-amoxiclav,
piperacillin/tazobactam,
imipenem, gentamicin,
amikacin, fosfomycin,
ciprofloxacin,
co-trimoxazole in
uropathogens

Rosenthal EJ, 9,555 Epidemiology of 77.2% enterobacteriaceae 4, positive

2002 [40] isolates septicemia pathogens in urosepsis. Increase in
resistance to beta-
lactams and ciprofloxacin

Jantunen ME, 10 Chromosomal In 8/10 infants 4, positive

et al., 2001 genotypes of E. coli iso- genetically identical
[36] lates from blood, urine E. coli isolates in blood, uri-
and faeces of infants ne and faeces. Reservoir of
with urosepsis pyelonephritogenic
E. coli in infants is colon.

Otto G et al., 81 IL-6 and disease Serum and urine 4, positive

1999 [39] severity in patients with IL-6 higher in
and without bacteremic bacteremic patients vs non-
febrile UTI bacteremic and pyelonep-
hritis vs
non-pyelonephritis

by anomalies of the urinary tract in 5% The patients are affected by microor-

and following operations in 4% [45]. In
another study, from 205 analyzed case
histories of urosepsis, 43% resulted from
urolithiasis, 25% from prostatic adenoma,
18% from urologic cancer and 14% suf-
fered other urologic diseases complicated
by urosepsis [46].
4. DEFINITION OF UROSEPSIS
Urosepsis is defined as sepsis caused
by infection of the urinary tract and/or
male genital organs (e.g. prostate) [47].
ganisms capable of inducing inflamma-
tion within the urinary and male genital
tract.
In urosepsis, as in other types of
sepsis, the severity of sepsis depends
mostly upon the host response. Patients
who are more likely to develop urosep-
sis include: elderly patients, diabetics,
immunosuppressed patients such as
transplant recipients, patients receiving
cancer chemotherapy or corticosteroids,
and patients with acquired immunode-
ficiency syndrome. Sepsis is a systemic
inflammatory response to infection.

636

The signs and symptoms of SIRS (sys-
temic inflammatory response syndrome)
which were initially considered to be
‘mandatory’ for the diagnosis of sepsis
[48–49], are now considered to be alerting
Criterium I: Proof of bacteremia or clinical suspicion of sepsis.
Criterium II: Systemic Inflammatory Response Syndrome (SIRS)
Body temperature
Tachycardia
Tachypnea
Respiratory alcalosis
Leucocytes
Criterium III: Multiple Organ Dysfunction Syndrome (MODS)
Heart, circulation
Kidney
Lung
Platelets
Metabolic Acidosis
Encephalopathy
Following these criteria the sepsis syn-
drome is classified into three levels:
Sepsis: Criterium I + ≥2 criteria II.
Associated letality: 2 criteria II – 7 %;
3 criteria II – 10 %; 4 criteria II – 17 %.
Severe sepsis: Criterium I + ≥2 criteria II
+ ≥1 criterium III.
Associated letality: For each affected
organ: + 15 – 20 %.
Septic shock: Criterium I + ≥2 criteria II
+ refractory arterial hypo-
tension ≤90 mm Hg.
Associated letality: 50 – 80 %.
For therapeutic purposes, the diag-
nostic criteria of sepsis should identify
patients at an early stage of the syn-
drome. The clinical evidence of urosepsis
is based upon symptoms, physical exam-
ination, sonographic and radiological
Urosepsis – from the view of the urologist | 11.4 |
symptoms [50]. Many other clinical or
biological symptoms must be considered.
The classification of the sepsis syndrome
follows different levels of criteria:
≥38°C oder ≤36°C
≥90 beats/min
≥20 breaths/min
PaCO2 ≤32 mm Hg
≥12,000/µl or ≤4,000/µl or band forms >10%
arterial systolic blood pressure ≤90 mm Hg or mean arterial blood pres-
sure ≤70 mm Hg, ≥1 hour despite adequate fluid- or vasopressure agents
resuscitation.
Production of urine <0.5 ml/kg body weight/ hour despite adequate fluid
resuscitation.
PaO2 ≤75 mm Hg (breathing room air) or PaO2/FiO2 ≤250 (assissted respira-
tion) ((PaO2, arterial O2-partial pressure; FiO2, inspiratory O2-concentration)).
Platelets <80,000/µl or decrease ≥50% in 3 days.
Blood-pH ≤7.30 or base excess ≥5 mmol/l; plasma-lactate ≥1.5fold of
normal.
Somnolence, agitation, confusion, coma.
features and laboratory data, such as
bacteriuria and leucocyturia.
5. DIAGNOSIS OF UROSEPSIS
A rapid diagnosis is critical to meet
the requirements of early goal directed
therapy [51].
The initial patient aspect is often
directive. The clinical picture of a sep-
tic patient frequently, but not always,
involves warm skin, bounding pulses and
hyperdynamic circulation. Flank pain,
costovertebral tenderness, renal colic,
pain at micturition, urinary retention,
prostatic or scrotal pain point to the uro-
genital tract. A digital rectal examina-
tion of the prostate is mandatory to rule
out acute prostatitis. Urinary analysis
637
Chapter | 11 | Urosepsis
as well as urine and blood cultures must
be included into the first routine labora-
tory tests. Sonographic examination of
the urogenital organs should be followed,
including sonographic examination of
the prostate to rule out prostatic abscess.
Further radiographic investigations (e.g.
CT-scan) of the urinary tract are now gen-
erally applied to specify the complicating
factor. Computer tomography is nowadays
almost generally available and offers the
possibility to quickly detect urolithiasis
and especially renal abscesses as a source
of urosepsis with a high sensitivity [52].
The presence of hydronephrosis and/or
urinary stones [20, 26, 29] together with
systemic signs of infection are suspicious
of urosepsis. If a complicating factor war-
ranting treatment is identified, control
and/or removal of the complicating fac-
tor should follow immediately. This pro-
cedure frequently is performed at two
stages: Low level invasive treatment for
control of the complicating factor (e.g.
emergency drainage) and thereafter
definitive elimination of the complicat-
ing factor. Clinically there seems to be no
significant difference between ureteral
stent and percutaneous nephrostomy for
the control of ureteral calculi [53–54]. In
parallel with the urological control of the
septic focus adequate antimicrobial treat-
ment has to be initiated.
6. TREATMENT
6.1 Antimicrobial therapy
Immediately after microbiological sam-
pling of urine and blood, empirical broad
spectrum antibiotic therapy should be
started parenterally. An adequate initial
(e.g. in the first hour) antibiotic ther-
apy ensures improved outcome in septic
shock [55–56]. Administration of an effec-
tive antimicrobial within the first hour of
documented hypotension was associated
with a survival rate of 80% in a retrospec-
tive cohort study [57]. Each hour of delay
638
in antimicrobial administration over the
ensuing six hours was associated with an
average decrease in survival of 8% [57].
Inappropriate antimicrobial therapy in
severe UTI is linked to a higher mortality
rate [58] as it has been shown with other
infections as well [59–60]. Empirical
antibiotic therapy therefore needs to fol-
low certain rules [61], which are based
upon the expected bacterial spectrum,
the institutional specific resistance rates,
specific pharmacokinetic and pharmaco-
dynamic factors in UTI, and the individ-
ual patient’s requirements.
The bacterial spectrum in urosepsis
predominantly consists of enterobacteria,
such as E. coli, Proteus spp., Enterobacter
and Klebsiella spp., non-fermenting
organisms such as P. aeruginosa and
also Gram-positive organisms [40, 62].
Candida spp. and Pseudomonas spp.
occur as causative agents in urosepsis
mainly if host defence is impaired [63].
Patients with candiduria also frequently
show invasive candidiasis and candi-
demia [13, 15]. Candiduria at any time
in an intensive care unit is associated
with higher mortality rates (OR, 2,86)
[13]. Viruses are not common causes of
urosepsis.
Although urosepsis is a systemic dis-
ease the activity of an antibiotic sub-
stance at the site of the infection is
critical. A variety of studies could show
that inflammatory mediators such as
IL-6, CXC chemokines, endotoxin or
HMGB1 are produced and released in the
urinary tract [22, 30, 39, 41]. Therefore
predominantly antimicrobial substances
with a high activity in the urogenital
tract are recommended.
The increasing antibiotic resistance
rates of pathogens causing urosepsis sig-
nificantly diminish the choice of antibiotic
substances available for adequate empiri-
cal initial treatment in urosepsis. The
increasing rates of enterobacteriaceae pro-
ducing extended spectrum β-lactamases
(ESBL) especially pose clinically relevant
problems [8, 17, 37] (LE 1, positive). Other
 Urosepsis – from the view of the urologist
developments comprise the increased
rates of fluoroquinolone resistant entero-
bacteria and vancomycin resistant ente-
rococci [21, 25]. Dosing of the antibiotic
generally has to be high. There are
no specific pharmacokinetic/pharmacody-
namic parameters yet available for the
treatment of uroseptic patients.
Correct dosing in urosepsis has to
consider the altered systemic and espe-
cially renal pathophysiology in patients
with urosepsis. Sepsis and the treatment
thereof result in higher clearances of anti-
bacterial drugs [64]. The increased vol-
ume of distribution as a result of edema
in sepsis will lead to underexposure espe-
cially of hydrophilic antimicrobials such
as β-lactams and aminoglycosides, which
exhibit a volume of distribution mainly
restricted to the extracellular space [65].
Sepsis may also cause increased clear-
ance of antibacterial drugs and increased
dosing is therefore necessary. Only in the
case of multiple organ dysfunctions, such
as hepatic or renal dysfunction, result-
ing in decreased clearance of antibacte-
rial drugs, is a dose reduction necessary.
As β-lactams are time-dependent anti-
bacterials, the best administration is
via continuous infusion. In one study an
area under the antibiotic concentration
time curve (AUIC) ≥ 250 and time over
the minimal inhibitory concentration
(T>MIC) = 100% has been associated with
treatment success [12]. Fluoroquinolones
on the other hand display largely concen-
tration dependent activity. The volume of
distribution of fluoroquinolones in sepsis
is not much influenced by fluid shifts and
therefore no alterations of standard doses
are necessary, unless renal dysfunction
occurs [64].
Depending on the local susceptibil-
ity patterns a third generation cepha-
losporin, piperacillin in combination
with a β-lactamase inhibitor (BLI) or
carbapenem may be appropriate for
empiric treatment [10–12, 18–19] (LoE 2,
GoR B). In areas with a high (> 10%) rate
of enterobacteriaceae producing ESBL
| 11.4 |
initial treatment with a carbapenem
might be advisory [10–11, 18–19, 35]
(LoE 2; GoR B). Aminoglycosides as mon-
otherapy might be an alternative, how-
ever the data supporting monotherapy in
uroseptic patients are not sufficient [9]
(LoE 2, GoR B). In case of candiduria and
signs of sepsis antifungal treatment is
recommended [13, 15] (LoE 3, GoR B).
Biofilm infection plays a considerable
role in urosepsis, in association with uri-
nary catheters, scar tissue, stones, pros-
tatitis and in any obstructed urinary
tract [66–69]. The MICs in biofilm are
increased several 10 to 100-folds, there-
fore generally high dosages of antimicro-
bials need to be applied in conjunction
with the attempt to eliminate the biofilm
and the biofilm causing complicating fac-
tor [70].
6.2 Other issues related to clinical
assessment
Further intensive medical treatment
encompassing adjunctive sepsis therapy
such as cardiovascular support, mechani-
cal ventilation, organ substitution, or man-
agement of endocrine insufficiency should
be instigated if warranted [71–72]. In con-
trast to earlier reports Drotrecogin alpha
(activated protein C) seems also to be ben-
eficial in urosepsis [33] (LoE 4, GoR C).
7. FURTHER RESEARCH
The widespread current management of
urosepsis by urologists is rather good and
successful, although organizational proc-
esses always can be improved. Urosepsis
nowadays has a much more benign clini-
cal course than any other sepsis entity.
Therefore urosepsis should serve as a
gold-standard control group to which
other sepsis entities should be compared.
In this way important mechanisms might
perhaps be discovered which regulate the
complex sepsis pathways for the worse or
for the better.
639
Chapter | 11 | Urosepsis
Adequate initial antibiotic treatment
is still one of the most important aspects
in sepsis management. Pharmacokinetics
in septic patients, however are not ade-
quately investigated, which frequently
leads to underdosing and perhaps treat-
ment failure. Therefore studies in
this specific patient group should be
undertaken.
The prevention of sepsis is especially
important in urosepsis, because a signifi-
cant portion of urosepsis is caused by uro-
logical procedures. Therefore risk factors
for urosepsis should be evaluated in more
detail in the future.
8. CONCLUSIONS
Urosepsis is one of the most frequent sep-
sis entities. The lethality rate is however
much lower, which might be attributable
to a good current management of uro-
sepsis patients. The increasing antibiotic
resistance, however, and especially the
increasing rates of extended-spectrum
β-lactamase producing enterobacteria,
pose a significant threat for a favourable
outcome in those patients. Currently car-
bapenems can still fill the gap. However
increased use of carbapenems will inevi-
tably lead to an increase in carbapenem
resistant strains. Therefore a prudent
antibiotic policy is nowadays more impor-
tant than ever.
REFERENCES
1. Brun-Buisson C, The epidemiology of the
systemic inflammatory response. Intensive
Care Med, 2000. 26 Suppl 1: S64–74.
2. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–12.
3. Bouza E, San Juan R, Munoz P, Voss A,
and Kluytmans J, A European perspec-
tive on nosocomial urinary tract infections
I. Report on the microbiology workload,
640
etiology and antimicrobial susceptibil-
ity (ESGNI-003 study). European Study
Group on Nosocomial Infections. Clin
Microbiol Infect, 2001. 7(10): 523–31.
4. Brun-Buisson C, Meshaka P, Pinton P,
and Vallet B, EPISEPSIS: a reappraisal
of the epidemiology and outcome of severe
sepsis in French intensive care units.
Intensive Care Med, 2004. 30(4): 580–8.
5. Martin GS, Mannino DM, Eaton S, and
Moss M, The epidemiology of sepsis in the
United States from 1979 through 2000. N
Engl J Med, 2003. 348(16): 1546–54.
6. US Department of Health and Human
Services, Public Health Service, Agency
for Health Care Policy and Research.
1992: 115–127.
7. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. Schwaber MJ and Carmeli Y, Mortality
and delay in effective therapy associated
with extended-spectrum beta-lactamase
production in Enterobacteriaceae bacter-
aemia: a systematic review and meta-
analysis. J Antimicrob Chemother, 2007.
60(5): 913–20.
9. Vidal L, Gafter-Gvili A, Borok S, Fraser
A, Leibovici L, and Paul M, Efficacy
and safety of aminoglycoside mono-
therapy: systematic review and meta-
analysis of randomized controlled trials.
J Antimicrob Chemother, 2007. 60(2):
247–57.
10. Byl B, Clevenbergh P, Kentos A, Jacobs
F, Marchant A, Vincent JL, and Thys JP,
Ceftazidime- and imipenem-induced endo-
toxin release during treatment of gram-
negative infections. Eur J Clin Microbiol
Infect Dis, 2001. 20(11): 804–7.
11. Luchi M, Morrison DC, Opal S, Yoneda
K, Slotman G, Chambers H, Wiesenfeld
H, Lemke J, Ryan JL, and Horn D, A
comparative trial of imipenem versus
ceftazidime in the release of endotoxin
and cytokine generation in patients with
gram-negative urosepsis. Urosepsis Study
Group. J Endotoxin Res, 2000. 6(1):
25–31.
12. McKinnon PS, Paladino JA, and
Schentag JJ, Evaluation of area under
 Urosepsis – from the view of the urologist
the inhibitory curve (AUIC) and time
above the minimum inhibitory concentra-
tion (T>MIC) as predictors of outcome for
cefepime and ceftazidime in serious bacte-
rial infections. Int J Antimicrob Agents,
2008. 31(4): 345–51.
13. Magill SS, Swoboda SM, Johnson EA,
Merz WG, Pelz RK, Lipsett PA, and
Hendrix CW, The association between
anatomic site of Candida colonization,
invasive candidiasis, and mortality in
critically ill surgical patients. Diagn
Microbiol Infect Dis, 2006. 55(4): 293–301.
14. Van Dissel JT, Numan SC, and Van’t
Wout JW, Chills in ‘early sepsis’: good for
you? J Intern Med, 2005. 257(5): 469–72.
15. Binelli CA, Moretti ML, Assis RS, Sauaia
N, Menezes PR, Ribeiro E, Geiger DC,
Mikami Y, Miyaji M, Oliveira MS, Barone
AA, and Levin AS, Investigation of the
possible association between nosoco-
mial candiduria and candidaemia. Clin
Microbiol Infect, 2006. 12(6): 538–43.
16. Guidet B, Aegerter P, Gauzit R, Meshaka
P, and Dreyfuss D, Incidence and impact
of organ dysfunctions associated with
sepsis. Chest, 2005. 127(3): 942–51.
17. Ho PL, Chan WM, Tsang KW, Wong
SS, and Young K, Bacteremia caused
by Escherichia coli producing extended-
spectrum beta-lactamase: a case-control
study of risk factors and outcomes. Scand
J Infect Dis, 2002. 34(8): 567–73.
18. Kuo BI, Fung CP, and Liu CY, Meropenem
versus imipenem/cilastatin in the treat-
ment of sepsis in Chinese patients.
Zhonghua Yi Xue Za Zhi (Taipei), 2000.
63(5): 361–7.
19. Bin C, Hui W, Renyuan Z, Yongzhong
N, Xiuli X, Yingchun X, Yuanjue Z, and
Minjun C, Outcome of cephalosporin
treatment of bacteremia due to CTX-M-
type extended-spectrum beta-lactamase-
producing Escherichia coli. Diagn
Microbiol Infect Dis, 2006. 56(4): 351–7.
20. Mariappan P, Smith G, Moussa SA, and
Tolley DA, One week of ciprofloxacin
before percutaneous nephrolithotomy sig-
nificantly reduces upper tract infection
and urosepsis: a prospective controlled
study. BJU Int, 2006. 98(5): 1075–9.
21. Nguyen LH, Hsu DI, Ganapathy V,
Shriner K, and Wong-Beringer A,
| 11.4 |
Reducing empirical use of fluoroquinolo-
nes for Pseudomonas aeruginosa infec-
tions improves outcome. J Antimicrob
Chemother, 2008. 61(3): 714–20.
22. Olszyna DP, Opal SM, Prins JM, Horn
DL, Speelman P, van Deventer SJ, and
van der Poll T, Chemotactic activity of
CXC chemokines interleukin-8, growth-re-
lated oncogene-alpha, and epithelial cell-
derived neutrophil-activating protein-78
in urine of patients with urosepsis. J
Infect Dis, 2000. 182(6): 1731–7.
23. Venier AG, Talon D, Patry I, Mercier-
Girard D, and Bertrand X, Patient and
bacterial determinants involved in symp-
tomatic urinary tract infection caused by
Escherichia coli with and without bacter-
aemia. Clin Microbiol Infect, 2007. 13(2):
205–8.
24. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
25. Chou YY, Lin TY, Lin JC, Wang NC, Peng
MY, and Chang FY, Vancomycin-resistant
enterococcal bacteremia: comparison of
clinical features and outcome between
Enterococcus faecium and Enterococcus
faecalis. J Microbiol Immunol Infect,
2008. 41(2): 124–9.
26. Christoph F, Weikert S, Muller M, Miller
K, and Schrader M, How septic is urosep-
sis? Clinical course of infected hydroneph-
rosis and therapeutic strategies. World J
Urol, 2005. 23(4): 243–7.
27. Hsu CY, Fang HC, Chou KJ, Chen CL,
Lee PT, and Chung HM, The clinical
impact of bacteremia in complicated
acute pyelonephritis. Am J Med Sci, 2006.
332(4): 175–80.
28. Lee CC, Chen SY, Chang IJ, Chen SC,
and Wu SC, Comparison of clinical mani-
festations and outcome of community-
acquired bloodstream infections among
the oldest old, elderly, and adult patients.
Medicine (Baltimore), 2007. 86(3):
138–44.
29. Mariappan P, Smith G, Bariol SV, Moussa
SA, and Tolley DA, Stone and pelvic urine
culture and sensitivity are better than
bladder urine as predictors of urosepsis
641
Chapter | 11 | Urosepsis
following percutaneous nephrolithotomy:
a prospective clinical study. J Urol, 2005.
173(5): 1610–4.
30. McAleer IM, Kaplan GW, Bradley JS,
Carroll SF, and Griffith DP, Endotoxin
content in renal calculi. J Urol, 2003.
169(5): 1813–4.
31. Efstathiou SP, Pefanis AV, Tsioulos DI,
Zacharos ID, Tsiakou AG, Mitromaras
AG, Mastorantonakis SE, Kanavaki SN,
and Mountokalakis TD, Acute pyelone-
phritis in adults: prediction of mortality
and failure of treatment. Arch Intern
Med, 2003. 163(10): 1206–12.
32. Calandra T and Cohen J, The interna-
tional sepsis forum consensus conference
on definitions of infection in the intensive
care unit. Crit Care Med, 2005. 33(7):
1538–48.
33. Dhainaut JF, Laterre PF, LaRosa SP,
Levy H, Garber GE, Heiselman D,
Kinasewitz GT, Light RB, Morris P,
Schein R, Sollet JP, Bates BM, Utterback
BG, and Maki D, The clinical evaluation
committee in a large multicenter phase
3 trial of drotrecogin alfa (activated) in
patients with severe sepsis (PROWESS):
role, methodology, and results. Crit Care
Med, 2003. 31(9): 2291–301.
34. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H, Lobel
B, Jinenez Cruz F, and Selvaggi FP, EAU
guidelines for the management of urinary
and male genital tract infections. Urinary
Tract Infection (UTI) Working Group
of the Health Care Office (HCO) of the
European Association of Urology (EAU).
Eur Urol, 2001. 40(5): 576–88.
35. Alhambra A, Cuadros JA, Cacho J,
Gomez-Garces JL, and Alos JI, In vitro
susceptibility of recent antibiotic-resist-
ant urinary pathogens to ertapenem
and 12 other antibiotics. J Antimicrob
Chemother, 2004. 53(6): 1090–4.
36. Jantunen ME, Saxen H, Lukinmaa S,
Ala-Houhala M, and Siitonen A, Genomic
identity of pyelonephritogenic Escherichia
coli isolated from blood, urine and fae-
ces of children with urosepsis. J Med
Microbiol, 2001. 50(7): 650–2.
37. Kizirgil A, Demirdag K, Ozden M,
Bulut Y, Yakupogullari Y, and Toraman
ZA, In vitro activity of three different
642
antimicrobial agents against ESBL pro-
ducing Escherichia coli and Klebsiella
pneumoniae blood isolates. Microbiol Res,
2005. 160(2): 135–40.
38. Moreno E, Planells I, Prats G, Planes AM,
Moreno G, and Andreu A, Comparative
study of Escherichia coli virulence deter-
minants in strains causing urinary
tract bacteremia versus strains causing
pyelonephritis and other sources of bac-
teremia. Diagn Microbiol Infect Dis, 2005.
53(2): 93–9.
39. Otto G, Braconier J, Andreasson A, and
Svanborg C, Interleukin-6 and disease
severity in patients with bacteremic and
nonbacteremic febrile urinary tract infec-
tion. J Infect Dis, 1999. 179(1): 172–9.
40. Rosenthal EJ, [Epidemiology of septicae-
mia pathogens]. Dtsch Med Wochenschr,
2002. 127(46): 2435–40.
41. van Zoelen MA, Laterre PF, van Veen
SQ, van Till JW, Wittebole X, Bresser
P, Tanck MW, Dugernier T, Ishizaka A,
Boermeester MA, and van der Poll T,
Systemic and local high mobility group box
1 concentrations during severe infection.
Crit Care Med, 2007. 35(12): 2799–804.
42. Hotchkiss RS and Karl IE, The patho-
physiology and treatment of sepsis. N
Engl J Med, 2003. 348(2): 138–50.
43. Meisner M, Brunkhorst FM, Reith HB,
Schmidt J, Lestin HG, and Reinhart K,
Clinical experiences with a new semi-
quantitative solid phase immunoassay for
rapid measurement of procalcitonin. Clin
Chem Lab Med, 2000. 38(10): 989–95.
44. Hofmann W, [Urosepsis and uroseptic
shock]. Z Urol Nephrol, 1990. 83(6):
317–24.
45. Vahlensieck W, Infizierte
Harnstauungsniere und Pyonephrose, in
Facharztwissen Urologie, Schmelz HU,
Sparwasser, C., Weidner, W., Editor. 2006,
Springer: Heidelberg. p. 24.
46. Serniak PS, Denisov VK, Guba GB,
Zakharov VV, Chernobrivtsev PA, Berko
EM, Luneva AG, Oleshenko ND, and
Aziukovskaia IS, [The diagnosis of uro-
sepsis]. Urol Nefrol (Mosk), 1990(4): 9–13.
47. Wagenlehner FM, Pilatz A, Naber KG,
and Weidner W, Therapeutic challenges
of urosepsis. Eur J Clin Invest, 2008. 38
Suppl 2: 45–9.
 Urosepsis – from the view of the urologist
48. Bone RC, Balk RA, Cerra FB, Dellinger
RP, Fein AM, Knaus WA, Schein RM, and
Sibbald WJ, Definitions for sepsis and
organ failure and guidelines for the use of
innovative therapies in sepsis. The ACCP/
SCCM Consensus Conference Committee.
American College of Chest Physicians/
Society of Critical Care Medicine. Chest,
1992. 101(6): 1644–55.
49. Bone RC, Sprung CL, and Sibbald WJ,
Definitions for sepsis and organ failure.
Crit Care Med, 1992. 20(6): 724–6.
50. Levy MM, Fink MP, Marshall JC, Abraham
E, Angus D, Cook D, Cohen J, Opal SM,
Vincent JL, and Ramsay G, 2001 SCCM/
ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference. Crit Care
Med, 2003. 31(4): 1250–6.
51. Rivers E, Nguyen B, Havstad S, Ressler
J, Muzzin A, Knoblich B, Peterson E,
and Tomlanovich M, Early goal-directed
therapy in the treatment of severe sepsis
and septic shock. N Engl J Med, 2001.
345(19): 1368–77.
52. Hoddick W, Jeffrey RB, Goldberg HI,
Federle MP, and Laing FC, CT and sonog-
raphy of severe renal and perirenal infec-
tions. AJR Am J Roentgenol, 1983. 140(3):
517–20.
53. Gorelov S, Zedan F, and Startsev V, The
choice of urinary drainage in patients
with ureteral calculi of solitary kidneys.
Arch Ital Urol Androl, 2004. 76(2): 56–8.
54. Hsu JM, Chen M, Lin WC, Chang HK,
and Yang S, Ureteroscopic management
of sepsis associated with ureteral stone
impaction: is it still contraindicated? Urol
Int, 2005. 74(4): 319–22.
55. Kreger BE, Craven DE, and McCabe
WR, Gram-negative bacteremia. IV.
Re-evaluation of clinical features and
treatment in 612 patients. Am J Med,
1980. 68(3): 344–55.
56. Kreger BE, Craven DE, Carling PC, and
McCabe WR, Gram-negative bacteremia.
III. Reassessment of etiology, epidemiology
and ecology in 612 patients. Am J Med,
1980. 68(3): 332–43.
57. Kumar A, Roberts D, Wood KE, Light
B, Parrillo JE, Sharma S, Suppes R,
Feinstein D, Zanotti S, Taiberg L,
Gurka D, and Cheang M, Duration of
hypotension before initiation of effective
| 11.4 |
antimicrobial therapy is the critical deter-
minant of survival in human septic shock.
Crit Care Med, 2006. 34(6): 1589–96.
58. Elhanan G, Sarhat M, and Raz R,
Empiric antibiotic treatment and the
misuse of culture results and antibiotic
sensitivities in patients with community-
acquired bacteraemia due to urinary tract
infection. J Infect, 1997. 35(3): 283–8.
59. Kollef MH and Ward S, The influence of
mini-BAL cultures on patient outcomes:
implications for the antibiotic manage-
ment of ventilator-associated pneumonia.
Chest, 1998. 113(2): 412–20.
60. Luna CM, Vujacich P, Niederman MS,
Vay C, Gherardi C, Matera J, and Jolly
EC, Impact of BAL data on the therapy
and outcome of ventilator-associated
pneumonia. Chest, 1997. 111(3): 676–85.
61. Singh N and Yu VL, Rational empiric
antibiotic prescription in the ICU. Chest,
2000. 117(5): 1496–9.
62. Menninger M, Urosepsis, Klinik,
Diagnostik und Therapie, in Urogenitale
Infektionen, Hofstetter A, Editor. 1998,
Springer: Berlin Heidelberg New York. p.
521–528.
63. Johansen TE, Cek M, Naber KG,
Stratchounski L, Svendsen MV, and
Tenke P, Hospital acquired urinary tract
infections in urology departments: patho-
gens, susceptibility and use of antibiotics.
Data from the PEP and PEAP-studies. Int
J Antimicrob Agents, 2006. 28 Suppl 1:
S91–107.
64. Roberts JA and Lipman J, Antibacterial
dosing in intensive care: pharmacokinet-
ics, degree of disease and pharmacody-
namics of sepsis. Clin Pharmacokinet,
2006. 45(8): 755–73.
65. Pea F, Viale P, and Furlanut M,
Antimicrobial therapy in critically ill
patients: a review of pathophysiological
conditions responsible for altered disposi-
tion and pharmacokinetic variability. Clin
Pharmacokinet, 2005. 44(10): 1009–34.
66. Anderson GG, Martin SM, and Hultgren
SJ, Host subversion by formation of intra-
cellular bacterial communities in the uri-
nary tract. Microbes Infect, 2004. 6(12):
1094–101.
67. Justice SS, Hung C, Theriot JA, Fletcher
DA, Anderson GG, Footer MJ, and
643
Chapter | 11 | Urosepsis
Hultgren SJ, Differentiation and devel-
opmental pathways of uropathogenic
Escherichia coli in urinary tract patho-
genesis. Proc Natl Acad Sci U S A, 2004.
101(5): 1333–8.
68. Kumon H, Management of biofilm infec-
tions in the urinary tract. World J Surg,
2000. 24(10): 1193–6.
69. Nickel JC, Olson ME, and Costerton
JW, Rat model of experimental bacterial
prostatitis. Infection, 1991. 19 Suppl 3:
S126–30.
70. Goto T, Nakame Y, Nishida M, and Ohi
Y, Bacterial biofilms and catheters in
experimental urinary tract infection.
Int J Antimicrob Agents, 1999. 11(3–4):
227–31; discussion 237–9.
71. Dellinger RP, Levy MM, Carlet JM, Bion
J, Parker MM, Jaeschke R, Reinhart K,
Angus DC, Brun-Buisson C, Beale R,
Calandra T, Dhainaut JF, Gerlach H,
644
Harvey M, Marini JJ, Marshall J, Ranieri
M, Ramsay G, Sevransky J, Thompson
BT, Townsend S, Vender JS, Zimmerman
JL, and Vincent JL, Surviving Sepsis
Campaign: international guidelines for
management of severe sepsis and septic
shock: 2008. Intensive Care Med, 2008.
34(1): 17–60.
72. Dellinger RP, Levy MM, Carlet JM, Bion
J, Parker MM, Jaeschke R, Reinhart K,
Angus DC, Brun-Buisson C, Beale R,
Calandra T, Dhainaut JF, Gerlach H,
Harvey M, Marini JJ, Marshall J, Ranieri
M, Ramsay G, Sevransky J, Thompson
BT, Townsend S, Vender JS, Zimmerman
JL, and Vincent JL, Surviving Sepsis
Campaign: international guidelines for
management of severe sepsis and septic
shock: 2008. Crit Care Med, 2008. 36(1):
296–327.
 Chapter |12|

Prevention of infections
associated with urological
surgery
Chair: Magnus Grabe

CHAPTER OUTLINE
12.1 Introduction 646
12.2 Hygiene and education 649
12.3 Sterilisation and disinfection of urological instruments
for endoscopy and for prostate biopsy 660
12.4 Preoperative assessment of the patient,
risk factors identification and tentative
classification of surgical field contamination
in urologic surgery 667
12.5 Antibiotic prophylaxis in urological surgery,
a European viewpoint 686
12.6 Antibiotic prophylaxis in urological surgery:
a USA viewpoint of best practice 699
|12.1|
Introduction
Magnus Grabe
Department of Urology, Malmö University Hospital, University of Lund, Malmö, Sweden
Corresponding Author: Magnus Grabe, MD, Associate Professor, Department of Urology, Malmö University Hospital
University of Lund, S-20502 Malmö, Sweden
Tel 0046-40-33 18 25, Fax 0046-40-33 70 49, magnus.grabe@skane.se
“There are rather a large number of cases in
which the gravest accidents, and even death
itself, have supervened upon catheterism
without our being able to find upon exami-
nation after death anything but some simple
affection of the urethra”.
Velpeau, 1841
Healthcare associated infections (HAI)
are a global phenomenon and have been
a hot topic for decades. Their prevalence
appears to be about 8% in high-income
countries, with national values ranging
from 6–12% (1). Urinary tract infections
represent some 30–40% of those, mainly
related to indwelling catheter treatment
[1]. HAI are also common in urological
care. In a series of prevalence studies car-
ried out in a large number of urological
centres worldwide, as many as 10–12%
of the hospitalized patients presented
with a healthcare associated infection. Of
these, approximately one in ten had clini-
cal signs of septicaemia [2]. Prevention
of infection is, consequently, of primary
important for the security of the patients.
Table 1 shows the different types of infec-
tious complications encountered in urolog-
ical wards and associated with surgery.
Infections associated with the care of
the patients were formerly often called
Nosocomial infections from the old Greek
words nosos (disease) and komiál (care):
nosokomeíon or disease acquired in the
care of the patient in a hospital and
transferred from one patient to another.
More recently, the terms healthcare
acquired or healthcare associated infec-
tions (HAI) have been introduced to bet-
ter cover modern aspects of health care.
The exact frame of healthcare associated
infections is still under debate. Surgical
Site Infections (SSI) are traditionally
used as a parameter of infection rates
and infection control. The criteria for SSI
are defined as either incisional/wound
related or confined to an organ or space
[3]. By extension, the urinary tract can
be regarded as an organ and/or space.
A HAI in urological care can be related
to a transmission within the patient’s

Table 1 Different types of infectious complications associated with urological interventions.
Site of infection
Surgical wound or incisional
infection (SSI)
Organ/Space SSI
Urinary tract (UTI)
Other urogenital site
Blood stream
Other site/organs
group (nosocomial) or being introduced
into the patient during the care or dur-
ing a diagnostic or therapeutic procedure
(iatrogenic ) or even, in a wider sense, be
caused by an undetected infection har-
boured by the patient. The shares of these
infection routes are not known.
Infectious complications can be related
to the host, the environment and the
procedure. The present chapter explores
the current knowledge in the field. The
chapter is divided into four sections and
six reports. The two first approaches
the key questions of a secure and clean
environment both in the ward and in
the operation theatre. It is of para-
mount importance that the introduction
of virulent, more or less resistant bacte-
rial strains in the patient in conjunction
with health care and any procedure is
avoided. These two first topics are cov-
ered by Bong-Suk Shim who reviews the
importance of hygiene and education
and Shingo Yamamoto who describes the
basic principles of sterilization and dis-
infection of standard instruments used
on a daily basis in urological praxis.
The conclusions are that 1) the environ-
ment must be clean, 2) that hand wash-
ing and disinfection between all patients
contact and appropriate hospital clothing
are of paramount importance to limit the
Introduction | 12.1 |
Minor events Major events
Superficial wound infection Deep wound infection
Wound abscess
Deep wound rupture
Asymptomatic Bacteriuria Pyelonephritis
Colonization Febrile UTI
Symptomatic lower UTI Renal scaring
Epididymitis Acute bacterial Prostatitis (NIH
type I)
Bacteriemia Septicaemia/sepsis
Pneumonia
Septic emboli
transmission of pathogens and 3) that
careful cleaning, washing, drying and
sterilisation of instruments by appropri-
ate means is necessary. The basic meth-
ods of choice are described.
The role of the host and the procedure
are discussed in the third sections, focus-
ing on the identification and preoperative
control of the patients’ risk factors and
the relative risk associated with different
types of interventions. A comprehensive
assessment of each patient is as impor-
tant as good hygiene and sterilization.
The bacterial burden has to be estimated
in each individual case. All similar proce-
dures and all patients are not the same.
Figure 1 in the chapter on assessment of
the patient (see chapter 10.4) illustrates
the complexity and interactions between
the host and the different procedures,
passing through a similar environment.
This detailed assessment in each individ-
ual case will determine the level of meas-
ures to be taken to keep the infectious
complication rates as low as possible.
Antibiotic prophylaxis is one of several
measures to keep the rates of infectious
complication as low as possible. Antibiotic
prophylaxis has been controversial for
decades. In a recent systematic review
on the topic, Bootsma and co-workers [4]
came to the conclusion that “Except for
647
Chapter | 12 | Prevention of infections associated with urological surgery
the TURP and prostate biopsy, there is
a lack of well performed studies investi-
gating the need for antibiotic prophylaxis
in urologic interventions”. Consequently,
assumption and extrapolation from com-
plication rates in surgery in general and
surveillance programmes in particular is
necessary. As opinions are diverging, the
policy has to be based on data from the
literature in association with a consen-
sus of expert opinions and local routines.
Dissimilarity in guidelines is explained
by difference in the interpretation of the
results of studies and the weight given
to risk factors. This appears in the dif-
ference presented between the European
and American viewpoints in for instance
antibiotic prophylaxis.
Another reason for a global strategy
and a behavioural change is that anti-
biotic prophylaxis is contributing to the
total antibiotic load and, thus, to the
development of antibiotic resistance, a
worldwide on-going threat [5]. Surgeons
thus face the paradox of having to both
secure a low infectious rate and to limit
the use of antibiotics, in other words to be
rational.
Not all infections can be avoided.
The ambition must nonetheless be to
648
eliminate the preventable infections
that might follow in the track of a lack
of preparation of the patient, an unclean
environment, inappropriate antibiotic
prophylaxis and poor clinical praxis.
The present chapter aims at assisting the
urologist to act in that direction.
REFERENCES
1. Marcel, J.P., et al., Healthcare-associated
infections: think globally, act locally. Clin
Microbiol Infect, 2008. 14(10): p. 895–907.
2. Bjerklund Johansen, T.E., et al.,
Prevalence of hospital-acquired urinary
tract infections in urology departments.
Eur Urol, 2007. 51(4): p. 1100–11; discus-
sion 1112.
3. Mangram, A.J., et al., Guideline for pre-
vention of surgical site infection, 1999.
Hospital Infection Control Practices
Advisory Committee. Infect Control Hosp
Epidemiol, 1999. 20(4): p. 250–78; quiz
279–80.
4. Bootsma, A.M., et al., Antibiotic prophy-
laxis in urologic procedures: a systematic
review. Eur Urol, 2008. 54(6): p. 1270–86.
5. Cars, O., et al., Meeting the challenge of
antibiotic resistance. BMJ, 2008. 337: p.
a1438.
|12.2|
Hygiene and education
Bong-Suk Shim
Bong-Suk Shim, M.D., Ph.D., Professor, Department of Urology, School of Medicine,
Ewha Womans University Hospital, 911-1, Mok-6-Dong, Yangchoen-ku, Seoul, 158-710, Korea
Tel: +82-2-2650-2863, Fax: +82-2-2654-3682, e-mail: bonstone@ewha.ac.kr
ABSTRACT
The safety of the patient depends upon a
clean environment in the wards and oper-
ating theatre. Good hospital hygiene is
an integral and important component of a
strategy for preventing hospital acquired
infections. The hospital environment
must be visibly clean, free from dust and
spoilage, acceptable to the patients, their
family and visitors and to the staff. Each
hospital should have rules and recom-
mendations for maintaining a clean envi-
ronment with scheduled routines. All staff
must maintain good personal hygiene.
Appropriate hospital clothing is recom-
mended in conjunction with all patient
contact in the wards, the out-patient
departments and operating area. Careful
hand washing and disinfection and appro-
priate clothing are key measures to limit
cross-contamination and each hospital
must have written policies and proce-
dures for these matters. Regular teaching
and training of staff in infection control
is required to reach the aims of reducing
health acquired infections.
Key words: Hospital environment, Per-
sonal hygiene, Hand washing, Education,
Infection control
SUMMARY OF RECOMMENDATIONS
Note that most recommendations are of
grade (GoR) B or C based on available lit-
erature. Nonetheless, they merit a strong
recommendation grade A, because no
weaknesses in the maintenance of clean-
ness and hygiene are acceptable for a safe
environment.
Hospital environment hygiene
1. The hospital environment must be
visibly clean, free from dust and
spoilage, and acceptable to patients,
their visitors and staff (GoR C)
Operating room hygiene
• Cleaning
2. All surfaces kept clean, free from
dust and spoilage (GoR B).
Chapter | 12 | Prevention of infections associated with urological surgery
3. Regular schedule for cleaning and disin-
fection of the operating theatre (GoR B):
• Every morning before any inter-
vention: cleaning of all horizontal
surfaces
• Between procedures: cleaning and
disinfection of horizontal surfaces
and all surgical items (e.g. tables,
buckets)
• At the end of the working day:
complete cleaning of the operating
theatre using a recommended dis-
infectant cleaner
• Once a week: complete cleaning of
the operating room area, includ-
ing all annexes such as dressing
rooms, technical rooms, cupboards.
4. Perform routine cleaning of these sur-
faces to re-establish a clean environ-
ment after each operation (GoR B).
5. Wet vacuum the operating room
floor after the last operation of the
day or night with an Environmental
Protection Agency-approved hospital
disinfectant (GoR B).
• Ventilation
6. Maintain positive-pressure ventilation
in the operating room with respect to
the corridors and adjacent areas (GoR B).
7. Maintain a minimum of 15 air
changes per hour, of which at least 3
should be fresh air (GoR B).
8. Filter all air, re-circulated and fresh,
through the appropriate filters per
the American Institute of Architects’
recommendations (GoR B).
9. Introduce all air at the ceiling, and
exhaust near the floor (GoR B).
10. Limit the number of personnel enter-
ing the operating room to necessary
personnel (GoR C).
• Surgical attire
11. All persons entering the surgical
theatre must wear surgical attire
restricted to being worn only within
the surgical area (GoR C).
650
12. Wear a cap or hood to fully cover
hair on the head and face when
entering the operating room (GoR B).
13. Wear a surgical mask that fully cov-
ers the mouth and nose when enter-
ing the operating room if an operation
is about to begin or is already under
way, or if sterile instruments are
exposed. Wear the mask throughout
the operation (GoR B).
14. Full body, fluid repellent gowns
should be worn where there is a risk
of extensive splashing of blood, body
fluids, secretions and excretions,
with the exception of sweat, onto
the skin of health care practitioners
(GoR B).
15. Do not wear shoe covers for the
prevention of SSI (GoR B).
16. Gloves must be worn for invasive
procedures, contact with sterile
sites, and non-intact skin, mucous
membranes, and all activities that
have been assessed as carrying a
risk of exposure to blood, body fluids,
secretions and excretions; and when
handling sharp or contaminated
instruments. (GoR B).
17. Gloves should be worn as single use
items. Put gloves on immediately
before an episode of patient contact
or treatment and remove them as
soon as the activity is completed.
Change gloves between caring for
different patients, or between differ-
ent care/treatment activities for the
same patient (GoR B).
18. Powdered and polythene gloves
should not be used in health care
activities (GoR B)
• Sampling
19. Do not perform routine environmen-
tal sampling of the operating room.
Perform microbiologic sampling
of operating room environmental
surfaces or air only as part of an
epidemiologic investigation (GoR B).

Personal Hygiene
20. All staff must maintain good personal
hygiene. Nails must be clean and kept
short. False nails should not be worn.
Hair must be worn short or pinned up.
Beard and moustaches must be kept
trimmed short and clean (GoR C).
Hand hygiene
21. Hands must be decontaminated
immediately before each and every
episode of direct patient contact and
care and after any activity or contact
that potentially results in hands
becoming contaminated (GoR B)
22. Hands that are visibly soiled or poten-
tially grossly contaminated with dirt
or organic material must be washed
with liquid soap and water (GoR B).
23. Apply an alcohol-based hand rub
or wash hands with liquid soap
and water to decontaminate hands
between caring for different patients,
or between different caring activities
for the same patient (GoR B).
24. Remove all wrist and ideally hand
jewellery at the beginning of each
clinical shift before regular hand
decontamination begins. Cuts and
abrasions must be covered with
waterproof dressings (GoR C).
25. Effective hand washing technique
involves three stages: preparation,
washing and rinsing, and drying.
Preparation requires wetting hands
under tepid running water before
applying liquid soap or an antimicro-
bial preparation. The hand wash solu-
tion must come into contact with all
the surfaces of the hand. The hands
must be rubbed together vigorously
for a minimum of 10–15 seconds, pay-
ing particular attention to the tips of
the fingers, the thumbs and the areas
between the fingers. Hands should be
rinsed thoroughly prior to drying with
good quality paper towels (GoR C).
Hygiene and education | 12.2 |
Disposal of sharps
26. Sharps must not be passed directly
from hand to hand and handling
should be kept to a minimum (GoR C).
27. Used sharps must be discarded into
a sharps container at the point of
use. These must not be filled above
the mark indicating that they are
full. Containers in public areas must
not be placed on the floor and should
be located in a safe position (GoR C).
Education
28. All staff involved in hospital hygiene
activities must be included in educa-
tion and training related to the pre-
vention of hospital-acquired infection
(GoR C).
1. INTRODUCTION
The aim of prophylaxis in urological
intervention is to prevent infectious com-
plications resulting from diagnostic and
therapeutic procedures, as defined in
the introduction to the chapter. A clean,
hygienic environment is one of the essen-
tial pillars of surgical practice. A clean
environment aims at reducing bacterial
burden and risk of contamination in the
clinical and surgical environment. For
urological intervention, the same rules
are applied as in hygiene for preven-
tion of nosocomial infections. Risk factors
for perioperative infections are related,
among others, to the patient, the health-
care workers and the environment in the
wards and operating rooms [1–4]. Patient
related risk factors such as advanced age,
malnutrition, diabetes, smoking, obesity,
infections at sites other than the surgi-
cal sites, deficiency of the immune status
and a long preoperative hospital stay, are
reviewed in this chapter in the section on
“preparation of the patient”. Healthcare
worker factors are contaminated hands
and poor hygiene of personal protective
equipment such as working clothes, shoes,
651
Chapter | 12 | Prevention of infections associated with urological surgery
caps, masks and gloves. Environmental
risk factors are inappropriate skin prepa-
ration, preoperative hair removal, pro-
longed operation time, inappropriate
antimicrobial prophylaxis, poor controlled
operating room ventilation system, inade-
quate sterilization of surgical instruments,
foreign body use in operation, inappropri-
ate drain use, and inappropriate surgical
techniques. Good hospital hygiene is thus
an integral and important component of a
strategy for preventing hospital-acquired
infections. The environment should be
maintained in accordance with the hospi-
tal hygiene team’s recommendations.
2. METHODS
A standard search of the literature includ-
ing available guidelines and expert opin-
ions was performed with the following
key words: infection, hygiene, hospital,
environment, and education one by one,
using only English language papers with
the abstract available. A total number of
600 publications were found, which were
screened and reviewed by title and abstract
and finally 60 publications were included
into this review. No randomised control-
led trials were found which are usually
not appropriate for the present topic. The
present review is based on available litera-
ture, established praxis and recommenda-
tions by manufacturers. Case reports or
oral presentations are not included. The
studies were rated according to the level
of evidence (LoE) and the grade of recom-
mendation (GoR) using ICUD standards
(for details see Preface) [5–6].
3. HOSPITAL HYGIENE
3.1 Hospital environmental hygiene
Good hospital hygiene is an integral and
important component of a strategy for
preventing hospital-acquired infections
[7]. Hospital environmental hygiene
encompasses a wide range of routine
652
activities that are generally considered to
be central to the prevention of hospital-
acquired infection (LoE 3) [8–9]. Routine
cleaning is necessary to ensure a hospital
environment which is visibly clean, and
free from dust and soil. 90% of microor-
ganisms are present within visible dirt,
and the purpose of routine cleaning is
to eliminate this dirt. Neither soap nor
detergents have antimicrobial activity,
and the cleaning process depends essen-
tially on mechanical action. There must
be a hospital policy and recommenda-
tions specifying the frequency of cleaning
and cleaning agents used for walls, floors,
windows, beds, curtains, screens, fixtures,
furniture, baths and toilets, and all reused
medical devices. Bacteriological testing
of the environment is not recommended
except in selected circumstances such as
1) epidemic investigation where there is a
suspected environmental source, 2) dialy-
sis water monitoring for bacterial counts,
as required by standards, 3) quality con-
trol when changing cleaning practices
(LoE 1b) [9].
4. OPERATION ROOM HYGIENE
4.1 Operating room environment
In the operating room environment, air-
borne bacteria must be minimized, and
surfaces kept clean (LoE 1b). A recom-
mended schedule for cleaning and disin-
fection of the operating theatre is [9]:
• every morning before any intervention:
cleaning of all horizontal surfaces
• between procedures: cleaning and dis-
infection of horizontal surfaces and all
surgical items (e.g. tables, buckets)
• at the end of the working day: complete
cleaning of the operating theatre using
a recommended disinfectant cleaner
• once a week: complete cleaning of the
operating room area, including all
annexes such as dressing rooms, tech-
nical rooms, cupboards.

4.2 Ventilation
Operating rooms should be maintained at
positive pressure with respect to corridors
and adjacent areas [10]. Positive pressure
prevents airflow from less clean areas into
cleaner ones. All ventilation or air condi-
tioning systems in hospitals, including
those in operating rooms, should have two
filter beds in series, with the efficiency of
the first filter bed being >30% and that
of the second filter bed being >90% [11].
Operating room ventilation systems pro-
duce a minimum of about 15 air changes
of filtered air per hour, three (20%) of
which must be fresh air. Air should be
introduced at the ceiling and exhausted
near the floor [12–13]. Laminar airflow
has been suggested as additional meas-
ures to reduce surgical site infections
(SSI) risk for certain operations. Laminar
airflow is designed to move particle-free
air (called ultraclean air) over the asep-
tic operating field at a uniform velocity
(0.3 to 0.5 µm/sec), sweeping away parti-
cles in its path. Laminar airflow can be
directed vertically or horizontally, and re-
circulated air is usually passed through a
high efficiency particulate air (HEPA) fil-
ter [14–15]. HEPA filters remove particles
>0.3µm in diameter with an efficiency of
99.97% (LoE 1b) [12, 14, 16].
4.3 Environmental surfaces
Environmental surfaces in operating
rooms such as tables, floors, walls, ceil-
ings, lights, are rarely implicated as an
important source of pathogens in the
development of SSIs. Nevertheless, it is
important to perform routine cleaning of
the surfaces to restore a clean environ-
ment after each operation [12, 14]. There
are no data to support routine disinfecting
of environmental surfaces or equipment
between operations in the absence of con-
tamination or visible soiling (LoE 3–4).
Wet-vacuuming of the floor with a hos-
pital disinfectant should be performed
routinely after the last operation of the
day or night. Care should be taken to
Hygiene and education | 12.2 |
ensure that medical equipment left in
the operating room be covered so that
solutions used during cleaning and dis-
infecting do not contact sterile devices or
equipment [17].
4.4 Microbiologic sampling
Because there are no standardized
parameters by which to compare micro-
bial levels obtained from cultures of
ambient air or environmental surfaces
in the operating room, routine microbio-
logic sampling cannot be justified. Such
environmental sampling should only be
performed as part of an epidemiologic
investigation LoE 2b) [1].
4.5 Operating room activities
Operating room air may contain microbial-
laden dust, lint, skin squamae, or res-
piratory droplets. The microbial level in
operating room air is directly proportional
to the number of people moving about
in the room [18]. Therefore the number
of persons entering the theatre during
an operation should be minimized. And
unnecessary movement or conversation
should be avoided (LoE 3).
5. PERSONAL HYGIENE
Staff can normally wear a personal uniform
or street clothes covered by a white coat in
hospital. However, in view of the increas-
ing number of resistant bacterial strains,
most hospitals nowadays recommend
wearing only short sleeved working clothes
and disposable aprons in all contact with
the patients. The working outfit must be
made of a material which is easy to wash
and decontaminate. If possible, a clean out-
fit should be worn each day. An outfit must
be changed after exposure to blood or if it
becomes wet through excessive sweating or
other fluid exposure (LoE 3) [9].
All staff must maintain strict personal
hygiene. Nails must be clean and kept
short. False nails should not be worn.
653
Chapter | 12 | Prevention of infections associated with urological surgery
Hair must be worn short or pinned up.
Beards and moustaches must be kept
trimmed short and clean (LoE 4).
6. HAND HYGIENE
There must be written policies and pro-
cedures for hand washing. There are sev-
eral levels of hand cleaning according to
the needs. In summary (LoE 2b):
• Routine care and contact: Hand wash-
ing with non-antiseptic soap or hygi-
enic hand disinfection with alcoholic
based solution;
• Antiseptic hand cleaning in the care of
infected patients: hygienic hand wash-
ing with antiseptic soap following the
manufacturer’s instructions or, as a
minimum, hand disinfection as above;
• Surgical hand and forearm
preparation:
❍ Surgical hand and forearm washing
with antiseptic soap for sufficient
time and duration of contact, usu-
ally 3–5 minutes (manufacturer’s
instruction)
❍ Surgical hand and forearm washing
with standard soap for same period
of time, followed by drying and two
applications of a hand disinfectant
until dryness or according to the
product’s recommendations
6.1 Patient contact
Hand hygiene is considered the primary
measure to reduce the transmission of
nosocomial pathogens (LoE 2b) [19–20].
The importance of hands in the transmis-
sion of hospital infections has been well
demonstrated, and can be minimized with
appropriate hand hygiene. The consist-
ent practice of adequate hand hygiene,
either by washing the hands with soap
and water or disinfecting them with an
antiseptic solution [21], is considered to
be the single most important intervention
to prevent nosocomial infections [20].
654
Patients are put at potential risk of
developing a hospital-acquired infection
when a health care practitioner caring
for them has contaminated hands. Hands
must be decontaminated before every epi-
sode of care that involves direct contact
with patients’ skin, their food, invasive
devices or dressings. Hands need to be
decontaminated after completing an epi-
sode of patient care to minimize cross con-
tamination of the environment [21–23].
The preparations for the decontami-
nation of hands include washing with
plain soap and water, antimicrobial hand
wash, and alcohol hand rub. In general,
effective hand washing with a liquid soap
will remove transient microorganisms
and render the hands socially clean. This
level of decontamination is sufficient for
general social contact and most clinical
care activities. The use of an antimicro-
bial liquid soap preparation will reduce
transient microorganisms and resident
flora, and result in hand antisepsis [21–
22, 24]. The effective use of alcohol-based
hand rubs on contaminated hands will
also result in substantial reductions of
transient microorganisms, although alco-
hol is not effective at removing dirt and
organic material [24]. However, alcohol
hand rubs offer a practical and accept-
able alternative to hand washing when
the hands are not grossly soiled and are
increasingly being recommended for rou-
tine use [22, 24].
The duration of hand decontamination,
the exposure of all aspects of the hands
and wrists to the preparation being used,
the use of vigorous rubbing to create fric-
tion, thorough rinsing in the case of hand
washing, and ensuring that hands are
completely dry are key factors in effec-
tive hand hygiene and the maintenance
of skin integrity [21–22].
6.2 Hand washing before surgery
The preparation of hand asepsis before sur-
gery is well established and each hospital
has to have clear rules. It includes washing

of the hands and wrists and forearms for
a defined period of time, clean short cut
nails, rubbing with soap or antiseptic soap,
thorough rinsing, drying and application
of a disinfectant solution. Procedures will
vary with the patient risk assessment [9].
6.3 Jewells
Jewellery must be removed before washing.
7. SURGICAL ATTIRE
The term surgical attire refers to scrub
suits, caps/hoods, shoe covers, masks,
gloves, and gowns. All persons entering
the surgical theatre must wear surgical
attire restricted to being worn only within
the surgical area. The design and compo-
sition of surgical attire should minimize
bacterial shedding into the environment.
The use of surgical attires seems prudent
to minimize a patient’s exposure to the
skin, mucous membranes, or hair of sur-
gical team members, as well as to protect
surgical team members from exposure to
blood and blood borne pathogens [25–27].
All personnel entering in the operating
suite must remove any jewellery; nail
polish or artificial nails must not be worn.
7.1 Surgical caps or hoods
Surgical caps/hoods reduce contamination
of the surgical field by organisms shed from
the hair and scalp. SSI outbreaks have
occasionally been traced to organisms iso-
lated from the hair or scalp (S.aureus and
group A Streptococcus), even when caps
were worn by personnel during the opera-
tion and in the operating suites [28–29]. All
head and facial hair, including sideburns,
and neckline, must be covered [9].
7.2 Masks
The wearing of surgical masks during
operations to prevent potential micro-
bial contamination of incisions is a long-
standing surgical tradition [30]. The
Hygiene and education | 12.2 |
efficacy and cost-benefit of surgical masks
in reducing SSI risk are inconclusive.
Nevertheless, wearing a mask can be ben-
eficial since it protects the wearer’s nose
and mouth from inadvertent exposures
(i.e. splashes) to blood and other body
fluids. There should be full coverage of
the mouth and nose area with a surgical
mask for everyone entering the operating
suite [31].
Masks of cotton wool, gauze, or paper
are ineffective. Paper masks with syn-
thetic material for filtration are an effec-
tive barrier against microorganisms [8].
• Masks are used in various situations;
mask requirements differ for different
purposes.
• Patient protection: staff must wear
masks to work in the operating room,
to care for immuno-compromised
patients, and to puncture body cavi-
ties. A surgical mask is sufficient.
• Staff protection: staff must wear
masks when caring for patients with
airborne infections, or when per-
forming bronchoscopies or similar
examination. A high-efficiency mask is
recommended. Masks with additional
transparent face and eyes shields are
used in case of patients with blood
borne infectious diseases.
• Patients with infections which may
be transmitted by the airborne route
must use surgical masks when outside
their isolation room.
7.3 Grown and apron
Protective clothing should be worn by
all health care practitioners when blood,
body fluids, secretions, and excretions
(with the exception of sweat), or close
contact with the patient, materials or
equipment may lead to contamination of
the clothing with microorganisms [24].
Plastic aprons are recommended for
general use [15]. Full body gowns need
only be used where there is the possibil-
ity of extensive splashing of blood, body
655
Chapter | 12 | Prevention of infections associated with urological surgery
fluids, secretions or excretions, and these
should be fluid repellent [32].
7.4 Shoe cover
The use of shoe covers has never been
shown to decrease SSI risk or to decrease
bacteria counts on the operating room
floor [33–34]. Shoe covers may, however,
protect surgical team members from
exposure to blood and other body fluids
during an operation.
7.5 Surgical gloves
Operating staff must wear sterile gloves.
The use of gloves protect hands from
contamination with organic matter and
microorganisms and reduce the risks of
transmission of microorganisms to both
patients and staff [30]. The reported occur-
rence of glove punctures ranges from 11.5%
to 53% of procedures [35], and double glov-
ing is recommended when operating on
patients known to be infected with blood
borne pathogens such as the human immu-
nodeficiency virus (HIV), hepatitis B, or
hepatitis C [36]. Gloves should be changed
immediately after any accidental puncture.
Gloves must be discarded after each
care activity for which they were worn
in order to prevent the transmission of
microorganisms to other sites in that
individual or to other patients [35, 37].
Cornstarch powder, used to assist in
the donning of gloves, is harmful and is
associated with adhesions, latex allergy,
and increasing risks of infection associ-
ated with invasive devices contaminated
with cornstarch powder [38]. As a conse-
quence, powdered gloves should not be
used in healthcare [39].
8. DISPOSAL OF SHARP ITEMS
The safe handling and disposal of nee-
dles and other sharp instruments should
form part of an overall strategy of clinical
waste disposal to protect staff, patients
and visitors from exposure to blood borne
pathogens. In general clinical settings,
656
sharps injuries are predominantly caused
by needle devices and associated with
blood vessel puncture, administration of
medication via intravascular lines and
recapping of needles during the disassem-
bly of equipment [40–42].
9. EDUCATION
Infection prevention and control personnel
must be specifically trained in methods of
SSI surveillance. They must have knowl-
edge of and the ability to prospectively
apply the Centre for Disease Control and
Prevention definitions of SSI. Also, they
should possess basic computer and math-
ematical skills, and be adept at providing
feedback and education to healthcare per-
sonnel when appropriate [1].
It is essential to regularly provide
education to the surgeons and operat-
ing room staff through continuing educa-
tional activities focusing on minimizing
the SSI risk through implementation of
recommended process measures. Several
educational components can be com-
bined into concise, efficient, and effec-
tive recommendations that are easily
understood and remembered [43]. This
also includes feedback on the outcome of
implemented preventive measures from
patients [14] families, surgeons, and
associated staff.
10. FURTHER RESEARCH
The evidence concerning the control of
perioperative infections in the urologi-
cal field are limited. Hygiene refers to
practices associated with ensuring good
health and cleanliness. Existing study
designs for hygiene are inherently weak.
Unfortunately, appropriate prospective
randomised studies are missing for most
urological procedures. At present, most
studies are poorly designed. Further stud-
ies for additional evidence, particularly
specific to urological intervention, are

necessary to make these guidelines more
appropriate. Alternative precautions for
high risk procedures are also required.
Education is one of the cornerstones for
improvement within hygiene practices.
Hygiene education must be promoted at
all levels of experience to maintain good
hygiene and aseptic techniques.
11. CONCLUSIONS
Good hospital hygiene is an integral
and important component of a strategy for
preventing hospital-acquired infections,
therefore hygiene for both environment
and personnel should be carried out. This
includes hospital environment hygiene,
hand hygiene and the use of personal
protective equipment. Education should
regularly be provided to physicians and
perioperative personnel through continu-
ing educational activities.
REFERENCES
1. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline for
Prevention of Surgical Site Infection,
1999. Centers for Disease Control and
Prevention (CDC) Hospital Infection
Control Practices Advisory Committee.
Am J Infect Control, 1999. 27(2): 97–132;
quiz 133–4; discussion 96.
2. Cruse PJ and Foord R, The epidemiology
of wound infection. A 10-year prospective
study of 62,939 wounds. Surg Clin North
Am, 1980. 60(1): 27–40.
3. Pittet D and Ducel G, Infectious risk factors
related to operating rooms. Infect Control
Hosp Epidemiol, 1994. 15(7): 456–62.
4. Garibaldi RA, Skolnick D, Lerer T, Poirot
A, Graham J, Krisuinas E, and Lyons R,
The impact of preoperative skin disinfec-
tion on preventing intraoperative wound
contamination. Infect Control Hosp
Epidemiol, 1988. 9(3): 109–13.
5. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
Hygiene and education | 12.2 |
6. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
7. Dancer SJ, Mopping up hospital infection.
J Hosp Infect, 1999. 43(2): 85–100.
8. Pratt RJ, Pellowe C, Loveday HP,
Robinson N, Smith GW, Barrett
S, Davey P, Harper P, Loveday C,
McDougall C, Mulhall A, Privett S,
Smales C, Taylor L, Weller B, and
Wilcox M, The epic project: developing
national evidence-based guidelines for
preventing healthcare associated infec-
tions. Phase I: Guidelines for preventing
hospital-acquired infections. Department
of Health (England). J Hosp Infect,
2001. 47 Suppl: S3–82.
9. Ducel G, Fabry J, Nicolle LE, and World
Health Organization, Prevention of hospi-
tal-acquired infections: a practical guide.
2nd ed. 2002, Geneva: World Health
Organization. vi, 64 p.
10. Lidwell OM, Clean air at operation and
subsequent sepsis in the joint. Clin Orthop
Relat Res, 1986(211): 91–102.
11. AIA Academy of Architecture for Health.
and United States. Dept. of Health
and Human Services., Guidelines for
design and construction of hospital and
health care facilities. 1996–97. ed. 1996,
Washington, D.C.: American Institute of
Architects Press. xi, 143 p.
12. Nichols RL, The operating room, in
Hospital infections, Bennett JV and
Brachman PS, Editors. 1992, Little,
Brown: Boston. p. 461–73.
13. Laufman H, The operating room, in
Hospital infections, Bennett JV and
Brachman PS, Editors. 1986, Little,
Brown: Boston. p. 315–23.
14. Sessler DI, McGuire J, Hynson J, Moayeri
A, and Heier T, Thermoregulatory vaso-
constriction during isoflurane anesthesia
minimally decreases cutaneous heat loss.
Anesthesiology, 1992. 76(5): 670–5.
15. Hambraeus A, Aerobiology in the operat-
ing room – a review. J Hosp Infect, 1988.
11 Suppl A: 68–76.
16. Babb JR, Lynam P, and Ayliffe GA, Risk
of airborne transmission in an operat-
ing theatre containing four ultraclean
657
Chapter | 12 | Prevention of infections associated with urological surgery
air units. J Hosp Infect, 1995. 31(3):
159–68.
17. Rudnick JR, Beck-Sague CM, Anderson
RL, Schable B, Miller JM, and Jarvis
WR, Gram-negative bacteremia in open-
heart-surgery patients traced to probable
tap-water contamination of pressure-mon-
itoring equipment. Infect Control Hosp
Epidemiol, 1996. 17(5): 281–5.
18. Ayliffe GA, Role of the environment of the
operating suite in surgical wound infec-
tion. Rev Infect Dis, 1991. 13 Suppl 10:
S800–4.
19. Pittet D, Mourouga P, and Perneger TV,
Compliance with handwashing in a teach-
ing hospital. Infection Control Program.
Ann Intern Med, 1999. 130(2): 126–30.
20. Boyce JM and Pittet D, Guideline for
Hand Hygiene in Health-Care Settings.
Recommendations of the Healthcare
Infection Control Practices Advisory
Committee and the HICPAC/SHEA/
APIC/IDSA Hand Hygiene Task Force.
Society for Healthcare Epidemiology of
America/Association for Professionals
in Infection Control/Infectious Diseases
Society of America. MMWR Recomm Rep,
2002. 51(RR-16): 1–45, quiz CE1–4.
21. Larson EL, APIC guideline for handwash-
ing and hand antisepsis in health care
settings. Am J Infect Control, 1995. 23(4):
251–69.
22. Garner JS and Favero MS, CDC
Guideline for Handwashing and Hospital
Environmental Control, 1985. Infect
Control, 1986. 7(4): 231–43.
23. Teare EL, Cookson B, French GL,
Jenner EA, Scott G, Pallett A, Gould D,
Schweiger M, Wilson J, and Stone S, UK
handwashing initiative. J Hosp Infect,
1999. 43(1): 1–3.
24. Ward V and Great Britain. Public Health
Laboratory Service., Preventing hospital-
acquired infection: clinical guidelines.
1997, [London]: Public Health Laboratory
Service. 42 p.
25. Dineen P, The role of impervious drapes
and gowns preventing surgical infection.
Clin Orthop Relat Res, 1973(96): 210–2.
26. Ha’eri GB and Wiley AM, The efficacy
of standard surgical face masks: an
investigation using “tracer particles”.
658
Clin Orthop Relat Res, 1980(148):
160–2.
27. Moylan JA, Fitzpatrick KT, and
Davenport KE, Reducing wound
infections. Improved gown and drape
barrier performance. Arch Surg, 1987.
122(2): 152–7.
28. Dineen P and Drusin L, Epidemics of
postoperative wound infections associated
with hair carriers. Lancet, 1973. 2(7839):
1157–9.
29. Mastro TD, Farley TA, Elliott JA,
Facklam RR, Perks JR, Hadler JL,
Good RC, and Spika JS, An outbreak of
surgical-wound infections due to group A
streptococcus carried on the scalp. N Engl
J Med, 1990. 323(14): 968–72.
30. Garner JS, Guideline for isolation precau-
tions in hospitals. The Hospital Infection
Control Practices Advisory Committee.
Infect Control Hosp Epidemiol, 1996.
17(1): 53–80.
31. Orr NW, Is a mask necessary in the oper-
ating theatre? Ann R Coll Surg Engl,
1981. 63(6): 390–2.
32. Great Britain. Expert Advisory Group on
AIDS., Guidance for clinical health care
workers: protection against infection with
HIV and hepatitis viruses: recommenda-
tions of the Expert Advisory Group on
AIDS. 1990, London: HMSO. 52 p.
33. Humphreys H, Marshall RJ, Ricketts
VE, Russell AJ, and Reeves DS, Theatre
over-shoes do not reduce operating theatre
floor bacterial counts. J Hosp Infect, 1991.
17(2): 117–23.
34. Weightman NC and Banfield KR,
Protective over-shoes are unnecessary in
a day surgery unit. J Hosp Infect, 1994.
28(1): 1–3.
35. Dodds RD, Guy PJ, Peacock AM, Duffy
SR, Barker SG, and Thomas MH,
Surgical glove perforation. Br J Surg,
1988. 75(10): 966–8.
36. Caillot JL, Cote C, Abidi H, and Fabry
J, Electronic evaluation of the value of
double gloving. Br J Surg, 1999. 86(11):
1387–90.
37. Whyte W, Hambraeus A, Laurell G, and
Hoborn J, The relative importance of
routes and sources of wound contamina-
tion during general surgery.

I. Non-airborne. J Hosp Infect, 1991.
18(2): 93–107.
38. Korniewicz DM, Laughon BE, Butz A, and
Larson E, Integrity of vinyl and latex proce-
dure gloves. Nurs Res, 1989. 38(3): 144–6.
39. Medical Devices Agency, Latex medical
gloves (surgeons and examination) pow-
dered latex medical gloves (surgeons and
examination). SN(98)25 1998, London:
HMSO.
40. Henry K and Campbell S, Needlestick/
sharps injuries and HIV exposure among
health care workers. National estimates
based on a survey of U.S. hospitals. Minn
Med, 1995. 78(11): 41–4.
41. Jagger J, Hunt EH, Brand-Elnaggar J,
and Pearson RD, Rates of needlestick
Hygiene and education | 12.2 |
injury caused by various devices in a
university hospital. N Engl J Med, 1988.
319: 284–8.
42. McCormick RD, Meisch MG, Ircink
FG, and Maki DG, Epidemiology of
hospital sharps injuries: a 14-year
prospective study in the pre-AIDS and
AIDS eras. Am J Med, 1991. 91(3B):
301S-307S.
43. van Kasteren ME, Mannien J, Kullberg
BJ, de Boer AS, Nagelkerke NJ,
Ridderhof M, Wille JC, and Gyssens IC,
Quality improvement of surgical prophy-
laxis in Dutch hospitals: evaluation of
a multi-site intervention by time series
analysis. J Antimicrob Chemother, 2005.
56(6): 1094–102.
659
|12.3|
Sterilisation and disinfection
of urological instruments for
endoscopy and for prostate biopsy
Shingo Yamamoto, Ryoichi Hamasuna
Corresponding author: Shingo Yamamoto, M.D., Ph.D., Professor and Chairman, The Department of Urology,
Hyogo College of Medicine, 1-1 Mukogawacho, Nisinomiya, Hyogo, 663-8501, Japan
Tel: +81-798-45-6366, Fax: +81-798-45-6368, E-mail: shingoy@hyo-med.ac.jp
ABSTRACT
The Spaulding Classification System
determines the level of sterilisation
required. Endoscopic equipment entering
sterile body cavities, such as the urinary
tract, must be sterilised. Several modes
predominate for cleansing of urologic
instruments: pressurized steam sterili-
zation, ethylene oxide gas, liquid chemi-
cal germicides, and hydrogen peroxide
gas plasma sterilization, and each mode
has its advantages and drawbacks. Some
rigid and semi–rigid endoscopes may
be sterilized using a pressurized steam
autoclave. Ethylene oxide gas is the most
common effective method of sterilization
for medical instruments that cannot be
autoclaved, although the entire process
can take up to 14 hours. Glutaraldehyde,
orthophthalaldehyde solution (OPA), and
peroxyacetic acid are the liquid chemical
sterilants used most commonly as high-
level disinfectants. However, OPA is now
contraindicated for the disinfection of
urologic endoscopes because of its ana-
phylactic toxicity. Peroxyacetic acid may
cause corrosion of metallic materials.
Transrectal ultrasound (TRUS) guided
prostate biopsy is a potential cause of cross
infection, unless strict disinfection and
sterilization protocols are followed between
patients. Outbreaks of cross-contamination
have been reported after core prostate
biopsy and endoscopy. A significant rate
of perforation of condoms following TRUS
guided prostate biopsies has also been dem-
onstrated. The probe and the needle guide
have to be separately disinfected in a high-
level disinfectant.
Key words: Sterilisation, disinfection,
urological endoscopes, transrectal ultra-
sound guided prostate biopsy
 Sterilisation and disinfection of urological instruments
SUMMARY OF RECOMMENDATIONS
Note that most recommendations are
of grade B or C based on available lit-
erature according to level of evidence.
Nonetheless, they merit rather a strong
recommendation (GoR A), because no
weaknesses in the maintenance of clean-
ness and hygiene are acceptable for a safe
environment.
Cleaning of urological instruments
for endoscopy
1. Avoid drying (GoR C).
2. Disassemble all instruments and
detachable parts before pre-cleaning
(GoR B).
3. Clean immediately after use to
remove debris which may cause
insufficient sterilisation (GoR B).
4. Brush clean the exterior of the
device and all channels and internal
ports with an enzymatic detergent.
Channels that are too small to brush
manually, should be flushed with an
enzymatic solution (GoR C).
5. Rinse with tap water and flush all
channels with clean water (GoR C).
6. Dry with a disposable cloth and
purge channels with air. Dry
condition both outside and inside the
endoscopes is required to achieve
effective sterilisation using ethylene
oxide gas or hydrogen peroxide gas
plasma (GoR B).
7. Visual inspection to ensure that the
devices are clean and dry (GoR C).
Sterilisation and high-level
disinfection
8. Steam sterilise all heat-stable
reusable components (Many
manufactures may recommend
low-temperature sterilisation of
autoclavable instruments to prolong
the life if the devices/optics) (GoR C).
9. Sterilisation with ethylene oxide
or hydrogen peroxide gas plasma.
| 12.3 |
Ethylene oxide gas is the most com-
mon effective method for sterilisation
of medical instruments that cannot
be autoclaved (GoR B).
10. Hydrogen peroxide gas plasma steri-
lisation is safe for the environment
and staff (GoR B).
11. High-level disinfection is achieved
with liquid chemicals such as glu-
taraldehyde and peroxyacetic acid.
Disinfectants must be used only in
well-ventilated areas, and be com-
pletely rinsed by sterilised distilled
water before clinical use (GoR B).
12. It is recommended to use automatic
endoscope washer-disinfectors when-
ever possible (GoR C).
13. Store appropriately to ensure
that the instruments are not
re-contaminated (GoR B).
14. It is essential to inspect the instru-
ments for damage at all stages of
handling (GoR C).
15. Users should be familiar with the
manufacturer’s recommendations
(GoR C).
16. Formaldehyde and orthophthalalde-
hyde (OPA) are contraindicated for
disinfection of urologic instruments
(GoR B)
17. Pressurised steam sterilisation is
deleterious for heat-labile instru-
ments such as flexible endoscopes
(GoR B)
Transrectal ultrasound guided
core biopsy of the prostate
18. After TRUS-guided prostate biopsy,
the rectal probe as well as the nee-
dle guide must be cleaned and dis-
infected to prevent cross infection
between patients (GoR B).
19. The process requires disassembling
the device and immersing the probe
and the needle guide separately in
a high-level disinfectant such as
glutaraldehyde (GoR B).
661
Chapter | 12 | Prevention of infections associated with urological surgery
1. INTRODUCTION
It is important to sterilise and disinfect
instruments after urological instrumen-
tation to avoid infectious complicati-
ons. Studies have reported outbreaks of
P. aeruginosa via biopsy-needle guides,
endoscopes and contaminated cystoscopy
rooms, which indicates that inadequate
sterilization of instruments for endos-
copy and biopsy can be environmental risk
factors for infections after urologic inter-
ventions [1–3] (LoE 3). Guidelines for gas-
trointestinal endoscopy have been published
and have achieved widespread adoption
[4–5]. Guidelines for the care and steriliza-
tion of urologic endoscopes and ultrasound
probes are much less widespread.
The aim of the present report is to
present the methods for decontamination
of instruments and risk factors for infec-
tions after endoscopy and TRUS prostate
biopsy, which are the two most common
urologic procedures.
2. METHODS
A standard search of the literature in
PubMed and of available guidelines and
expert opinions was performed using the
following key words: sterilization, disin-
fection, infection, endoscope, and prostate
biopsy. Approximately 200 of 1,600 articles
were identified to be appropriate for the
present topic, and were screened by title
and abstract. In regard to sterilisation of
urologic instruments, randomised con-
trolled trials were not found. Therefore,
the present review is mainly based on
available guidelines, literatures and case
reports, established practice and recom-
mendation by manufactures. The level
of evidence (LoE) is consequently mostly
Level 3 and 4 and the grade of recommen-
dation (GoR) B and C and only suggestive.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD stand-
ards (for details see Preface) [6–7].
662
3. STERILISATION PROCESS OF
UROLOGIC INSTRUMENTS
3.1 Urologic endoscopes
In 1968, Earle H. Spaulding developed a
classification system categorizing medical
instruments by their use and the risk of
infection associated with their use [8]. In
the Spaulding Classification System, med-
ical instruments are classified into three
categories as critical, semi–critical or non–
critical, and the cleaning levels required to
prevent infection have been determined.
According to this classification, laparo-
scopes, arthroscopes and some endoscopic
accessories, such as biopsy forceps, are
categorized as critical equipment, and all
microbes, including bacterial endospores,
must be inactivated during the steriliza-
tion/disinfection process (LoE 4). Thus
sterilization or high-level disinfection is
required for processing endoscopic equip-
ment in urologic departments and oper-
ating rooms, since these are used under
sterile conditions, i.e., in the urinary sys-
tem (LoE 4). New thinner and flexible uro-
logic endoscopes have been designed for
smoother use in the urinary tract. These
instruments are more delicate and frag-
ile than those for other procedures, and
the slightest damage can leave the instru-
ment useless. Poor care should therefore
be avoided to avoid breakage and ruin the
fine instruments during the sterilization
process [9] (LoE 4).
Previously, steam–formaldehyde was
used widely for disinfection of endoscopic
instruments. However, this chemical can
remain in the disinfected material, and
should be avoided because of its toxicity,
including carcinogenicity, to humans [10]
and unreliability for disinfection [11–12]
(LoE3, GoR B). Today, several modes
predominate for cleansing of urologic
endoscopes: pressurized steam steriliza-
tion, ethylene oxide gas, liquid chemical
germicides, and hydrogen peroxide gas
plasma sterilization, and each mode has
its advantages and drawbacks.
 Sterilisation and disinfection of urological instruments
Pre-cleaning before sterilization is
an important step to remove the debris,
which causes insufficient sterilization
(GoR B). All instruments and detach-
able parts must be disconnected (GoR B).
After soaking in a detergent enzymatic
solution, the exterior of the endoscopes,
as well as all channels and internal ports,
should be cleaned with appropriately
sized brushes. Channels that are too
small to be manually brushed should be
flushed with an enzymatic solution. Next,
the entire endoscope should be immersed
in clean rinse water, and all channels
should be flushed with clean water and
then purged with air to remove water
from the channels. Completely dry condi-
tions outside and inside the endoscopes is
required to achieve effective sterilization
using ethylene oxide gas or hydrogen per-
oxide gas plasma (GoR B). For this pur-
pose, flushing with alcohol followed by air
purging may be recommended (GoR C).
3.2 Pressurized steam sterilization
Pressurized steam autoclaving is non-
toxic, inexpensive, and easy to control and
monitor (LoE3, GoR B). Its rapid cycle
time and microbicidal effect are also rea-
sons for it being the most popular mode of
sterilization of medical equipment in hos-
pitals. Furthermore, pressurized steam
sterilization can penetrate medical packing
and device lumens, and is little affected
by organic/inorganic soils. However, this
mode is deleterious for heat-labile instru-
ments such as flexible endoscopes. Some
rigid and semi–rigid endoscopes may be
sterilized using pressurized steam steri-
lization, while many manufacturers rec-
ommend low-temperature sterilization
whenever possible to prolong the life of the
lens even if the instruments can be auto-
claved (LoE4, GoR C).
3.3 Ethylene oxide gas
Ethylene oxide gas is the most com-
mon effective method of sterilization
for medical instruments that cannot
| 12.3 |
be autoclaved, since the gas penetrates
medical packaging and plastics, and it
is compatible with most medical materi-
als that must be stored in a sterile con-
dition and be ready for use (LoE3, GoR
B). Although the operating and monitor-
ing processes are easy, the time required
to process through an entire sterilization
cycle can be up to 14 hours. For this rea-
son, instruments that must be sterilized
using the ethylene oxide method can
only be used once in a 24-hour period.
This is impractical when doing more
than a single procedure per day; e.g.,
cystoscopy in an outpatient clinic. The
potential hazard to patients and staff
must also be noted, since ethylene oxide
gas is a severe local irritant and has
been implicated as a carcinogen, and its
use requires satisfactory aeration [9, 12]
(LoE 3, GoR B).
3.4 Liquid chemical germicides
Glutaraldehyde, orthophthalaldehyde
(OPA) and peroxyacetic acid are the
most commonly used sterilants for high-
level disinfectants of endoscopes, since
the process of sterilization using these
liquid chemicals is easy and requires a
shorter time than other methods (LoE 3).
However, the safety of patients and staff
is not always ensured because the chemi-
cals are irritating to the skin, therefore,
the instruments need to be completely
rinsed by sterilized distilled water before
clinical use (LoE 3, GoR B). Furthermore,
since the vapour may cause irritation of
the eyes and nasal mucosa, the chemi-
cals must be used only in well-ventilated
areas, and if possible, use of automatic
endoscope washer–disinfectors is recom-
mended (GoR C). Some cases of anaphy-
lactic reactions after using cystoscopes
disinfected with OPA have even been
reported [13–14] (LoE 3) and OPA is
now contraindicated for the disinfec-
tion of urologic endoscopes [15] (GoR B).
Peroxyacetic acid may cause corrosion of
metallic materials (LoE 4).
663
Chapter | 12 | Prevention of infections associated with urological surgery
3.5 Hydrogen peroxide gas plasma
Hydrogen peroxide gas plasma steriliza-
tion is a new technology for sterilization
of medical devices. This method is safe
for the environment and staff, because
it leaves no toxic residues and requires
no ventilation (LoE 3, GoR B). The cycle
time of the procedure is as short as
60 minutes, and the process temperature
is up to 45°C. The method is compatible
with most heat-labile medical devices and
convenient for instruments used several
times per day. Since some endoscopes are
not effectively sterilized because of their
lumen internal diameters and lengths,
their manufacturer’s recommendation
should be consulted before use. The cost
of the hydrogen peroxide gas plasma ster-
ilizing machine is still expensive.
4. TRANSRECTAL ULTRASOUND-
GUIDED CORE PROSTATE BIOPSY
Transrectal ultrasound (TRUS) guided
biopsy of the prostate is a standard uro-
logic procedure for detecting prostate
cancer. Although infections following
this procedure are generally believed to
be infrequent when prophylactic oral or
intravenous antibiotics are administered
[16–19] (LoE 1b), in some cases, infec-
tive complications are potentially fatal
[20–21] (LoE 3). Furthermore, TRUS
guided prostate biopsy potentially causes
cross infection, particularly with blood-
borne communicable diseases such as
hepatitis and HIV infection, unless strict
disinfection and sterilization protocols
are followed between patients (LoE 4).
In TRUS guided prostate biopsy, to pro-
tect patients from cross infection, the rectal
probe as well as the needle guide must be
cleaned and disinfected between patients
(GoR B). One study has reported an out-
break including four cases of P. aeruginosa
infection after TRUS guided prostate biop-
sies, in which contamination of the TRUS
equipment was the likely source. All four
664
patients were hospitalized, and three were
admitted with a diagnosis of septicemia.
A likely origin for these infections was tap
water contamination of the probe and nee-
dle guide during inadequate rinsing and
drying; i.e., by means of an alcohol rinse
following the tap water rinse and forced-
air drying [2] (LoE 3). Another report has
demonstrated a significant rate of condom
perforation (9%; 10/107) following TRUS-
guided prostate biopsies [22] (LoE 3).
Probe swab samples after condom perfo-
ration have also been shown to be positive
for bacterial growth in patients undergoing
transvaginal sonography [23] (LoE 3).
An in vitro study of P. aeruginosa has
demonstrated that disinfection can be
achieved if the needle guide is removed
from the probe when the equipment
is immersed in 2% glutaraldehyde for
20 minutes. However, disinfection is not
achieved when the needle guide is left in
the probe channel during immersion in
glutaraldehyde, which indicates that the
process requires disassembling the device
and immersing the probe and the needle
guide separately in a high-level disinfect-
ant [24] (LoE 2b).
5. FURTHER RESEARCH
Although sterilization or high-level dis-
infection is required for processing endo-
scopic equipment, most urologic flexible
endoscopes are too delicate and fragile.
Disinfection using liquid chemical steri-
lants is convenient and inexpensive,
but these germicides are more or less
toxic for patients and staff. To overcome
these drawbacks and establish a safe
and economical procedure of sterilization
or high-level disinfection, more effort on
industrial development will be needed.
6. CONCLUSIONS
According to the Spaulding Classification
System, endoscopic equipment entering
 Sterilisation and disinfection of urological instruments
sterile body cavities, such as the urinary
tract, must be sterilised by pressurized
steam sterilization, ethylene oxide gas,
liquid chemical germicides, or hydro-
gen peroxide gas plasma sterilization.
Steam–formaldehyde as well as orthoph-
thalaldehyde solution (OPA) is now
contraindicated for the disinfection of
urologic endoscopes because of their tox-
icity. The probe and the needle guide for
TRUS guided prostate biopsies have to
be separately disinfected in a high-level
disinfectant.
REFERENCES
1. Pena C, Dominguez MA, Pujol M,
Verdaguer R, Gudiol F, and Ariza J,
An outbreak of carbapenem-resistant
Pseudomonas aeruginosa in a urology
ward. Clin Microbiol Infect, 2003. 9(9):
938–43.
2. Gillespie JL, Arnold KE, Noble-Wang J,
Jensen B, Arduino M, Hageman J, and
Srinivasan A, Outbreak of Pseudomonas
aeruginosa infections after transrec-
tal ultrasound-guided prostate biopsy.
Urology, 2007. 69(5): 912–4.
3. Kayabas U, Bayraktar M, Otlu B, Ugras
M, Ersoy Y, Bayindir Y, and Durmaz R,
An outbreak of Pseudomonas aeruginosa
because of inadequate disinfection pro-
cedures in a urology unit: a pulsed-field
gel electrophoresis-based epidemiologic
study. Am J Infect Control, 2008. 36(1):
33–8.
4. Guideline for the use of high-level disin-
fectants and sterilants for reprocessing
of flexible gastrointestinal endoscopes.
Society of Gastroenterology Nurses and
Associates, Inc. Gastroenterol Nurs, 1999.
22(3): 127–34.
5. Nelson DB, Jarvis WR, Rutala WA, Foxx-
Orenstein AE, Isenberg G, Dash GR,
Alvarado CJ, Ball M, Griffin-Sobel J,
Petersen C, Ball KA, Henderson J, and
Stricof RL, Multi-society guideline for
reprocessing flexible gastrointestinal
endoscopes. Society for Healthcare
Epidemiology of America. Infect Control
Hosp Epidemiol, 2003. 24(7): 532–7.
| 12.3 |
6. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
7. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
8. Spaulding EH, Chemical disinfection
of medical and surgical materials, in
Disinfection, sterilization, and preserva-
tion, Lawrence CA and Block SS, Editors.
1968, Lea & Febiger: Philadelphia,.
p. viii, 808 p.
9. Gregory E, Simmons D, and Weinberg
JJ, Care and sterilization of endourologic
instruments. Urol Clin North Am, 1988.
15: 541–546.
10. International Agency for Reasearch on
Cancer (IARC). IARC classifies formalde-
hyde as carcinogenic to humans. Available
from: http://www.iarc.fr/en/Media-
Centre/IARC-Press-Releases/Archives-
2006–2004/2004/IARC-classifies-
formaldehyde-as-carcinogenic-to-humans.
11. Vink P, Residual formaldehyde in steam-
formaldehyde sterilized materials.
Biomaterials, 1986. 7(3): 221–4.
12. Ayliffe GA, The use of ethylene oxide and
low temperature steam/formaldehyde in
hospitals. Infection, 1989. 17(2): 109–10.
13. Sokol WN, Nine episodes of anaphylaxis
following cystoscopy caused by Cidex
OPA (ortho-phthalaldehyde) high-level
disinfectant in 4 patients after cytoscopy.
J Allergy Clin Immunol, 2004. 114(2):
392–7.
14. Cooper DE, White AA, Werkema AN, and
Auge BK, Anaphylaxis following cystos-
copy with equipment sterilized with Cidex
OPA (ortho-phthalaldehyde): a review
of two cases. J Endourol, 2008. 22(9):
2181–4.
15. Hamasuna R, Nose K, Osada Y, and
Muscarella LF, Correction: high-level
disinfection of cystoscopic equipment with
ortho-phthalaldehyde solution. J Hosp
Infect, 2005. 61(4): 363–4.
16. Shandera KC, Thibault GP, and Deshon
GE, Jr., Efficacy of one dose fluoroqui-
nolone before prostate biopsy. Urology,
1998. 52(4): 641–3.
665
Chapter | 12 | Prevention of infections associated with urological surgery
17. Griffith BC, Morey AF, Ali-Khan MM,
Canby-Hagino E, Foley JP, and Rozanski
TA, Single dose levofloxacin prophylaxis
for prostate biopsy in patients at low risk.
J Urol, 2002. 168(3): 1021–3.
18. Cormio L, Berardi B, Callea A, Fiorentino
N, Sblendorio D, Zizzi V, and Traficante A,
Antimicrobial prophylaxis for transrectal
prostatic biopsy: a prospective study of
ciprofloxacin vs piperacillin/tazobactam.
BJU Int, 2002. 90(7): 700–2.
19. Yamamoto S, Ishitoya S, Segawa T,
Kamoto T, Okumura K, and Ogawa O,
Antibiotic prophylaxis for transrectal
prostate biopsy: a prospective randomized
study of tosufloxacin versus levofloxacin.
Int J Urol, 2008. 15(7): 604–6.
20. Gilad J, Borer A, Maimon N, Riesenberg
K, Klein M, and Schlaeffer F, Failure of
ciprofloxacin prophylaxis for ultrasound
guided transrectal prostatic biopsy in the
era of multiresistant enterobacteriaceae.
J Urol, 1999. 161(1): 222.
666
21. Binsaleh S, Al-Assiri M, Aronson S, and
Steinberg A, Septic shock after transrectal
ultrasound guided prostate biopsy. Is cip-
rofloxacin prophylaxis always protecting?
Can J Urol, 2004. 11(4): 2352–3.
22. Masood J, Voulgaris S, Awogu O, Younis
C, Ball AJ, and Carr TW, Condom per-
foration during transrectal ultrasound
guided (TRUS) prostate biopsies: a poten-
tial infection risk. Int Urol Nephrol, 2007.
39(4): 1121–4.
23. Amis S, Ruddy M, Kibbler CC,
Economides DL, and MacLean AB,
Assessment of condoms as probe cov-
ers for transvaginal sonography. J Clin
Ultrasound, 2000. 28(6): 295–8.
24. Rutala WA, Gergen MF, and Weber DJ,
Disinfection of a probe used in ultrasound-
guided prostate biopsy. Infect Control
Hosp Epidemiol, 2007. 28(8): 916–9.
|12.4|

Preoperative assessment of the

patient, risk factors identification
and tentative classification of
surgical field contamination in
urologic surgery
Magnus Grabe1, Henry Botto2, Mete Cek3, Peter Tenke4, Florian M.E. Wagenlehner5,
Kurt G. Naber6, Truls E. Bjerklund Johansen7
1
Department of Urology, Skåne University Hospital, Malmö, University of Lund, Sweden
2
Department of Urology, Hôpital Foch, Suresnes Cedex, France
3
Department of Urology, Taksim Teaching Hospital Istanbul, Istambul, Turkey
4
Department of Urology, Jahn Ference Del-Pesti Korhaz, Budapest, Hungary
5
Department of Urology, University if Giessen, Giessen, Germany
6
Technical University of Munich, Munich, Germany
7
Department of Urology, Århus University Hospital, Skejby, Århus University, Århus, Denmark
Corresponding author: Magnus Grabe, MD, PhD, Associate Professor, Department of Urology,
Skåne University Hospital, University of Lund, S-20502 Malmö, Sweden
Tel 0046-40-33 18 25, Fax 0046-40-33 70 49, magnus.grabe@skane.se

ABSTRACT patient and type of surgery is suggested

Identifying and controlling risk factors
for infectious complications minimises the
patient’s risk of being subjected to such
a complication. Risk factors are bound
to the patient and to the procedure itself
and are associated with the environ-
ment where the healthcare is provided.
Assuming a clean environment, a five
level assessment ladder related to the
considering: 1) the ASA score, 2) the gen-
eral risk factors, 3) the individual endog-
enous and exogenous risk factors, 4) the
class of surgery and the potential bac-
terial contamination burden and 5) the
level of severity of the surgical interven-
tion. A cumulative approach will identify
the level of risk for the individual patient
and define the preventive measures such
as the type of antibiotic prophylaxis or
Chapter | 12 | Prevention of infections associated with urological surgery
therapeutic measures before surgery.
There are data suggesting that the higher
the ASA score, the higher the risk of
infectious complication. Dysfunction of the
immune system, hypoalbuminemia/malnu-
trition or extreme weight, and uncontrolled
blood glucose are independent general risk
factors whilst bacteriuria, indwelling cath-
eter treatment, urinary tract stone disease,
urinary tract obstruction and a history of
genitourinary infection are urological spe-
cific risk factors. There is inconclusive evi-
dence for most other reported risk factors.
The level of contamination of the surgical
field is of the utmost importance and has
to be reflected by the subsequent antibiotic
prophylaxis strategy.
Key words: Urologic surgery, endourol-
ogy, risk factors, infectious complications,
urinary tract infection, surgical classes,
surgical field contamination.
SUMMARY OF RECOMMENDATIONS
1. It is recommended to assess all
patients before surgery for: (GoR B)
a. the ASA score P1–P5
b. the presence of general risk factors
for complications
c. the presence of particular endog-
enous and exogenous risk factors
d. the class of surgery and potential
bacterial contamination or burden
e. the expected level of surgical inva-
siveness and degree of difficulty
2. Special concern is given to general
risk factors and specific risk factors as
stated in Tables 1–7 (GoR B).
3. Infectious complications should be reg-
istered. Infection control is a valuable
method for monitoring a department’s
quality output and for feedback to sur-
geons (GoR B).
4. Quality registries and risk factor reg-
istration should be developed (GoR C).
668
1. INTRODUCTION
Preparing the patient for urologic instru-
mentation or surgery involves the assess-
ment of the patient’s vulnerability for a
complication in general and an infectious
complication in particular and aims at
identifying risk factors for such compli-
cations. The control of risk factors aims
at minimising the complications. This
section describes the factors shown or
assumed to put a patient at a particular
risk of infectious complication in conjunc-
tion with an urological intervention, with-
out, though, pretending to be complete as
the independent contribution of the dif-
ferent risk factors has not been assessed
after the control of confounding factors
and only a few risk factors have been well
defined.
2. METHODS
A review of the topic risk factors for infec-
tious complications was undertaken
for the International Consultations on
Nosocomial and Health Care Associated
Infections in Urology in Paris 2000 [1].
An updated search on Medline from the
year 2000 related to risk factors in uro-
logic surgery by procedure was under-
taken using the following keywords:
endourological surgery, endourology, gen-
itourinary surgery, risk factors, infectious
complications, urinary tract infection.
A variety of unspecific articles on urology
were displayed in large numbers but only
very few of them appeared at screening to
address the issues of patient preparation
and risk factor evaluation. All presump-
tive or generally accepted risk factors
could not be reviewed, i.e. diabetes mel-
litus, smoking, overweight, individually
or cumulatively, as each merits an inde-
pendent systematic review. The list of
references thus includes, whenever possi-
ble, review articles. Furthermore, all arti-
cles reviewed for the section on antibiotic
prophylaxis were specifically scrutinised
 Preoperative assessment of the patient
by the first author for reported risk fac-
tors. As there are no international stand-
ards for scoring risk factors, each of them
were weighted and reported as evidence
for if there was consistency in the findings
or inconclusive evidence for if there were
conflicting data on their role (Table 7).
A tentative classification of the urologi-
cal procedures in relation to the present
accepted surgical classes is suggested.
The studies were rated according to
the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[2–3]. The data presented in this section
and references lists are a linked to the
ones presented in the two sections on
antibiotic prophylaxis (European and
US view).
3. RISK FACTORS FOR INFECTIOUS
COMPLICATIONS
3.1 Defining a risk factor
There is a baseline risk of infection asso-
ciated with each type of intervention. This
level is not always known and can only be
assumed studying the natural history –
the expected natural development of a
process after intervention – using cohorts
or placebo controlled studies. A risk fac-
tor is a factor that further increases the
risk of an infection, beyond the baseline
level of a given procedure. To measure the
relative role of a risk factor or its interac-
tive cumulative impact in modifying the
course of the natural history requires
very large sized studies.
Identifying the risk factor is defining
the relative risk. Measuring the relative
risk is assessing the independent value of
different variables for the occurrence of a
certain event. The term risk factor has a
particular meaning in epidemiology and
expresses the probability that an event
occurs in an exposed group as compared
with an unexposed group. It is a ratio
that assesses the strength of association
| 12.4 |
between a variable and an event or dis-
ease. In the context of surgical site infec-
tion (SSI) for instance, a risk factor strictly
refers to a variable that has a significant
independent association with the develop-
ment of SSI after a specific operation. The
same is true for urinary tract infections
(UTI).
Risk factors are identified by multivar-
iate analysis. However, commonly, uni-
variate analysis is also used. Thus, both
analytical methods have to be considered
in accepting predictors for increased risk
for infection in conjunction with health-
care [4–5].
Risk factors are related to the patient,
the environment and to the procedure
itself.
3.2 Risk factors related to the host
Risk factors related to the patient can
be built in a stepwise level. A key ques-
tion is whether the source of bacteria in
urological infections is exogenous, that
is brought into the patient in conjunc-
tion with instrumentation, or whether
the infection is endogenous, that is har-
boured, undetected by standard cultures,
in the patient and exacerbated during the
procedure.
Figure 1 gives a synoptic image of the
different groups of risk factors to be con-
sidered in the preparation of the patient.
3.2.1 General physical status
The first step in the assessment of a
patient’s risk is to determine the general
health state of the patient as defined by
associations of anaesthesiology such as
the American Society of Anaesthesiology.
The risk groups are given by the classes
P1–P5 related to the general health of the
patient (Table 1) [6].
Opinions diverge on the relationship
between the classes P1–P5 and SSI. There
are, however, studies that identify an
increased risk of infectious complications
in patients with reduced general health
669
Chapter | 12 | Prevention of infections associated with urological surgery

Figure 1 Stepwise assessment of the patient’s risk factors and procedure, given a fully controlled
surgical environment (modified from 1).

Table 1 General physical status defined by the American Society of Anaesthesiology [6].

Category Clinical evaluation

P1 A normal healthy patient

P2 A patient with a mild systemic disease

P3 A patient with a severe systemic disease

P4 A patient with a severe systemic disease that is a constant threat of life

P5 A moribund patient who is not expected to survive with or without the operation

status [7], especially P3 and above. Those
patients are usually older with more
advanced disease and co-morbidity [8].
3.2.2 General risk factors
The second step is to identify risk fac-
tors for complications. These factors have
principally been identified for the risk of
a SSI [4]. Several of these remain contro-
versial because the independent contribu-
tion has usually not been assessed after
controls for confounding factors [4]. Very
little work has been done so far as uro-
logical surgery is concerned. Most stud-
ies are related to cardiac and orthopaedic
surgery. It is, however, assumed that
the characteristics presented in Table 2
mean an increased risk for infectious
complication.
3.2.3 Diabetes mellitus
The independent role of diabetes for SSI is
still controversial [4]. In a recent prospec-
tive study from Japan, poor postoperative
blood glucose control was directly cor-
related to an increased rate of SSI [9]. A
stable and correct blood sugar level is con-
sidered important before, during and after
surgery [10–11]. It is also recognised that
bacteriuria is more often present in indi-
viduals with diabetes, is more severe and
lasts longer [12–13]. As bacteriuria is a well
defined risk factor for post-operative infec-
tious complications, patients with diabetes

670
 Preoperative assessment of the patient
Table 2 General patient related risk factors that may
influence the risk for SSI [4].
General Risk factors
High age
Deficient nutritional status
Diabetes mellitus
Smoking
Extreme weight
Coexisting infection at a remote site
Colonization with micro-organisms
Altered immune response
Long preoperative hospital stay
Lack of elimination or control of risk factors
must be considered at risk and their treat-
ment optimised. As diabetes mellitus is
increasing in most societies, we can assume
that there will be an increased number of
patients at risk of infectious complications.
Obviously, more studies are necessary to
better understand the role of diabetes in the
healing process and as a risk factor of infec-
tious complications (LoE 2a).
3.2.4 Other characteristics
Nicotine use delays primary healing and
may increase the risk of SSI [14] (LoE 3).
The same is valid for steroid use and
malnutrition. Malnutrition, measured
by the nutritional risk index, was found
to be an independent factor associated
with nosocomial infections [15]. Low
level of albumin is one marker of mal-
nutrition. In a review of 10,253 general
(non urological) surgical procedures,
Haridas and Malangoni [8] found that
316 (3.1%) developed SSI, mainly super-
ficial wound infections (84%) (LoE 2a).
In a matched control study using mul-
tivariate analysis, they found that pre-
vious operation, hypoalbuminaemia
and or low haemoglobin levels, and a
history of chronic obstructive lung dis-
ease were independent risk factors for
SSI. Also excessive use of alcohol was
| 12.4 |
deleterious and increased the risk of SSI.
Only hypoalbuminaemia and previous
surgery were associated with deep wound
infections. It is, however, worth under-
lining that the benefits of preoperative
nutritional repletion in reducing the SSI
risk are unproven [4] (LoE 2a).
3.3 Particular risk factors
The third step is the identification of par-
ticular risk factors. These can be divided
into two major sub-groups, endogenous
and exogenous risk factors (Table 3).
3.3.1 Endogenous risk factors
The endogenous risk factors are those
prevailing in the individual patient. They
are secondary to an anatomical abnor-
mality, an organic dysfunction or one or
several concomitant disease(s). The most
frequently reported risk factors are listed
in Table 3a. In urological prevalence stud-
ies, catheterisation, previous hospitali-
sation, antibiotic treatment and urinary
tract stones were found to be the key risk
factors for nosocomial UTI [16]. The fact
that previous antibiotic treatment and
hospitalisation go with increased risk
may be interpreted to the fact that those
patients have a known focus, have a more
severe disease or have a weaker status.
3.3.1.1 Bacterial colonization
The periurethral zone and the distal
urethra are naturally colonized by both
Gram-negative and Gram-positive bacte-
ria [17] that can enter the bladder either
by own migration, via an indwelling cath-
eter or during instrumentation (LoE 3).
Bacterial presence naturally increases
with age, especially in women [18] (LoE 3).
Also in men subjected to TURP and hav-
ing no indwelling catheter, preoperative
bacteriuria is observed in more than 10%
[19]. Bacteriuria at the time of TURP
increases the risk of a febrile infection
by 5–10 times [20] (LoE 2b). Regrettably,
baseline data do not exist for most uro-
logical interventions but there are no
671
Chapter | 12 | Prevention of infections associated with urological surgery

Table 3 List of the most important endogenous and exogenous risk factors (modified from [1]).

Endogenous risk factors (3a) Exogenous risk factors (3b)

High age Introduction of micro-organisms

Colonization Increased burden

Faecal – intestinal flora Increased virulence factors

Periurethral Susceptibility to antibiotics

Increased microbial burden Instrumentation

Immunity (native or altered) Endoscopic diagnosis

Age related Surgical intervention

Compromised host defence mechanisms Catheterization

HIV/AIDS Indwelling catheter

Haematological Nephrostomy tubes

Related to a concomitant disease Stents (double J-stent)

Associated with burns Metallic stents

Genetic determinants Central vein catheters

Gender Perfusion

Familial

Genitourinary (GU) anatomical factors Implantation of prosthetic devices

Prepuce

Vesico-ureteral reflux

Bladder dysfunction

Residual urine

Augmentation related

Poor vascularisation

Poor emptying of the GU system

Hydronephrosis

Urinary tract stones

Inflammatory disease of the prostate

Particular physiological status

Pregnancy Sexual activity

Postmenopausal hormonal deficiency

Concomitant diseases

Diabetes mellitus

Renal insufficiency

Cardiovascular diseases with poor circulation

Obstructive pulmonary diseases

Anatomic area subjected to radiotherapy

672
 Preoperative assessment of the patient
reasons to believe the situation would
be different than for TURP. Bacteria can
be “hidden” in the ducts of the prostatic
gland [21], in the bladder, in dilated cal-
ices or diverticulae or other sites and
adhere to biofilms of urinary tract stones
or implanted devices [22] that would not
always be detected by standard cultures
and might produce a clinical infection at
the time of surgery and lesion of the pro-
tective mucosa layer.
3.3.1.2 Renal stones
Urease-producing bacteria such as
Proteus spp are well known in infectious
calculi and staghorn stones. However, it
has also been clearly shown by consecu-
tive stone culture that pathogens adhere
to stones in 30–70 % of the stones [23].
Although a urine culture is recommended
before an intervention, it is not necessar-
ily a good predictor of a microbial pres-
ence [24]. Thus, all stone situations with
a major kidney stones or stones of the
proximal ureter, especially in the pres-
ence of an obstruction of the system, have
a potentially increased microbial burden
even in the absence of growth on a stand-
ard urine culture [24–25] (LoE 2b).
3.3.1.3 Inflammatory disease of the
prostate
Little is known about the role of asymp-
tomatic prostatitis and the risk of infec-
tious complications at endoscopic surgery.
However, a history of urogenital infection
or prostatitis is shown to be a risk factor
for infectious complication after core pros-
tate biopsy [26], TURP [20, 27] and prob-
ably other surgery [16] which confirms
the clinical empirical experience (LoE 3).
3.3.2 Exogenous risk factors
The exogenous risk factors are those
introduced for one or another reason into
the patient and that contribute directly
to increase the risk of infection. The most
frequently reported risk factors are given
in Table 3b.
| 12.4 |
3.3.2.1 Indwelling catheter
The urinary tract is the commonest source
of HAI, particularly when the bladder is
catheterised, representing some 40% of
health care associated infections, origi-
nating from either urological manipu-
lation (10–20%) or permanent urethral
catheterisation (approx 80%) [28] (LoE 3).
Most UTIs are derived from the patient’s
own colonic flora. All type of catheters,
i.e. bladder catheter, nephrostomy tube
or double-J stents, predispose to UTI.
Duration of catheterisation is the most
important risk factor. Most episodes of
short-term catheter-associated bacteriu-
ria are asymptomatic and caused by a sin-
gle organism. When the catheterisation is
long-lasting, there is a tendency for multi-
ple strain colonisation (LoE 2a). Biofilms
and encrustations are formed on the
catheter creating a secondary limitation
of the inner tube and finally obstruction.
Stone formation in the bladder is seen in
conjunction with long-term catheterisa-
tion. While a catheter is in place, routine
urine culture and antibiotic treatment is
not recommended in asymptomatic cases.
However, a urine culture is mandatory
prior to surgery in order to direct the
treatment and sterilise the urine before
the intervention [28] (LoE 2b).
3.4 Surgical field classification
in urology
3.4.1 Surgical class
The fourth step in the planning of sur-
gery is defining the category of surgery or
surgical class, in other words the level of
contamination of the procedure. The cur-
rent classes of surgery/surgical field con-
tamination were developed during World
War II and adapted to war surgery. They
were subsequently updated for open sur-
gery and determining the relative risk of
surgical wound infection [29]. Urological
interventions have not been classified
and the current definitions do not include
endoscopic surgery, ESWL or core pros-
tate biopsy. It is, however, understood
673
Chapter | 12 | Prevention of infections associated with urological surgery

that opening the urinary tract, even in
the presence of a negative urine culture,
should automatically classify the inter-
vention as a clean-contaminated infection
[4, 29] (LoE 3). It is also suggested here
that the opening of the gastro-intestinal
tract would theoretically implies a heav-
ier bacterial load, clean-contaminated or
contaminated class. Therefore, for prac-
tical reasons in urology, clean-contam-
inated operations are in this proposal
divided into two sub-groups. Table 4a
shows a tentative classification of open
and laparoscopic procedures. In an exten-
sion, this classification could theoretically
be widened to also cover endoscopic uro-
logical procedures, the surgical site being
the urinary tract and the SSI being UTI.
This suggestion is also presented in Table
4a and the extended criteria of classifica-
tion for common urological procedures are
given in Table 4b.

Table 4a Surgical Wound Classes (based on [4, 29]) and risk of wound infection [29] and suggested ESIU classification of
urological instrumentation and procedures in the different classes. The risk of wound infection is that of classical wound
infection and not bacteriuria or UTI in urological surgery.

Category of Open or laparoscopic Endoscopic urological

intervention (risk of urological surgery instrumentation and
wound infection) Description (Examples) surgery (examples)

Clean (1–4%) Urogenital tract not entered Simple nephrectomy Cystoscopy

No evidence of inflammation Planned scrotal Urodynamic study
surgery
No break in technique TURB (minor, fulguration)*
Vasectomy
Blunt trauma ESWL*
Varicocele surgery

Clean-contaminated Urogenital tract entered with
(4–10%) no or little (controlled) spillage
No major break in technique
Pelvio-ureteric junction TURB (major, necrotic)*
repair
TURP*
Nephron-sparing tumour
Diagnostic URS*
resection
Uncomplicated URS* and
Total/radical prostatectomy
PCNL stone management
Bladder surgery and partial
ESWL*
cystectomy
Incl. Vaginal surgery

Gastrointestinal tract Urine diversion (orthotopic

entered with no or little bladder replacement; ileal
(controlled) spillage conduit)
No break in technique

Contaminated (10–15%)
Spillage of Gastrointestinal
content
Inflammatory tissue
Major break in technique
Open, fresh accidental wounds
Urine deviation (colon) and
small intestine/spillage
Trauma surgery
Concomitant gastrointestinal
disease
Core prostate biopsy*
TURP*
Impacted proximal stone
management
Complicated PCNL

Dirty (15–40%) Pre-existing infection Drainage of abscess Infectious stone surgery

Perforated viscera at surgery Large dirty trauma surgery
Old traumatic wound

*Detailed description in table 4b.

674
 Preoperative assessment of the patient | 12.4 |

Table 4b Tentative list of essential criteria for assessment of surgical class/surgical field contamination level of common
urological procedures: The estimated risk of infectious complication is related to the surgical class or category.

Operation/ Endoscopy Prostate

Category TURB TURP Stone ESWL biopsy

Clean Small tumours - Distal ureteral stone Standard ureteral -

or kidney stone
No history UTI Not impacted
No history UTI
Sterile urine Sterile urine
(similar Sterile urine
No or minor obstruction
cystoscopy)
No or mild
No other RF
obstruction

Clean- Large tumours No history All ureteral stone Standard ureteral Transperineal
contaminated UTI/UGI or kidney stone
History UTI History UTI Sterile urine
Sterile urine History UTI
Sterile urine Sterile urine No history UTI/UGI
No catheter Sterile urine
Minor/moderate
obstruction Moderate
obstruction
No stent
Other RF
Other RF

Contamin- Large tumours History UTI/UGI Proximal impacted Complex stone Transperineal
ated stone
Necrosis Catheter prior History UTI Sterile urine
to surgery History UTI
Bacteriuria Obstruction History UTI/UGI
controlled Bacteriuria Sterile urine or
Bacteriuria Transrectal
controlled controlled bacteriuria
controlled
No- or history UTI/
Moderate obstruction
Stent or UGI
Stent/catheter nephrostomy
Sterile urine
tube

Dirty Clinical infected Clinical infected Clinical infected Clinical infected Transrectal
Emergency Emergency Drainage only Drainage only Presence of
catheter or
bacteriuria

*UTI = urinary tract infection. UGI = urogenital infection (i.e. prostatitis). RF = risk factor.

The criteria for assessment of contami- Criteria for assessment of contamina-

nation categories in open surgery are the tion in endoscopic urological surgery and
same as for other types of open surgery: ESWL are mainly:
• Type of incision (primary, secondary, • History of UTI or other urogenital
tertiary) infection
• Opening of a tract • History of infection in relation to stone
• Spillage from tract (renal obstructed disease
cavity, small bowel, colon) • Knowledge of contamination level
• Evidence of infection or inflammation • Result of the urine examination before
in the surgical field surgery

675
Chapter | 12 | Prevention of infections associated with urological surgery

• Catheter in place at the start of
surgery
• Site of entry of surgery (urethra,
nephrostomy channel, pouch, vagina)
• Perforation of the urinary tract
• Evidence of infected urine found dur-
ing surgery (obstructed area, cavity)
In essence, these characteristics deal
with the contamination due to the proce-
dure per se, and the contamination of the
surgical field, whenever present before
surgery. Thus, an operation within the
urinary tract in the presence of a positive
culture is either contaminated or in some
situations dirty.
For transrectal core biopsy of the pros-
tate the circumstances are particular as
one initially sterile needle is used for sev-
eral core biopsies in the same patient,
passing the rectal contaminated field and
not renewed or disinfected between each
the biopsies.
3.5 Risk of infectious complication
associated with urological
surgery
Table 5 gives baseline data without
antibiotics on the range of infectious
complications as reported in the litera-
ture for a limited number of urological
procedures. Most data are older but are
usually the only ones that present a
natural history perspective to the differ-
ent procedures.

Table 5 Approximate rates of infectious complications after a selected number of urological instrumentations, in patients
assumed free from infection within the genitourinary tract at time of the procedure and receiving no antibiotic prophylaxis.

Febrile or
Procedure Bacteriuria symptomatic UTI Sepsis References

Cystoscopy 1–9% 1–5% No data [37–45]

Urodynamic studies 13% (average; 2–3% No data [46–48]

range 4–30%)

Transrectal core prostate 5–26% 3–10% <5% [49–53]

biopsy

TURB 4–6% No data No data [42, 54–55]

TURP 6–70% 5–10% 0–4% [19, 56–59]

ESWL 0–28% 5,7% (median 1% but limited [60–68]

probability) data

Ureteroscopy (standard) Up to 13% No data No data [25, 69–71]

Percutaneous stone extraction Up to 35% 4–25% 15% [24–25,

and difficult ureterorenoscopy 72–73]

Open/Lap Nephrectomy Skin SSI < 5% No data [31, 34, 74]

Catheter Higher reported
associated

Open/Lap/robotic Total Dito SSI <5% No data, [75–78]

prostatectomy no RCT

Cystectomy and bladder Dito SSI 10–15% Limited data [79–81]

substitution

Scrotal surgery Skin SSI 3–9% No data [82–83]

Implantation of prosthetic Skin 1–16,7% No data [84–85]

devices

676
 Preoperative assessment of the patient
Table 6 General operative and environmental risk factors associated with an increased risk of infectious complications [1, 4].
Preoperative and operative characteristics
(patient and procedure related)
Preoperative preparation of the patient
Long preoperative hospitalisation
Insufficient cleaning of surgical site
Inappropriate antibiotic prophylaxis
Operation characteristics
Length of operation
Surgical technique
Tissue damage
Bleeding
Experience of the surgeon
Implantation of prosthetic devices
Drainage
Perioperative oxygen tension
3.5.1 Risk factors associated with
the surgical environment
and managemant
The fifth step is to estimate the complex-
ity of the procedure in terms of severity,
difficulty and size of the intervention
(i.e. size of prostate, bladder tumour,
stone localisation), time of operation,
risk of bleeding and tissue trauma, sur-
geon’s experience; all factors that have
been linked to complications [4] Table 6.
Obviously, these parameters may change
during the procedure. For instance, a
large prostate resection in an older man
cannot be compared with a smaller resec-
tion in a healthy man; a large impacted,
ESWL resistant proximal stone is dif-
ferent from a distal 6–8 millimetre dis-
tal stone in an otherwise normal ureter
[30]. Such factors are rarely considered in
| 12.4 |
Surgical environment (related to theatre, staff,
microbial environment)
Staff related
Hygiene and aseptic environment
Elimination of transmission between staff and patients
Operation theatre
Clean environment
Ventilation
Number of staff
Order of surgery
Sterilisation of instruments
Microorganisms
Burden
Virulence
Sensitivity to antibiotics
Special strains
Specific pathogens
Viruses (HIV, Hepatitis, Herpes)
studies but must eventually be reported
in a standardised way (LoE 4).
Has the introduction of laparoscopic
and robotic surgery changed the risk of
infectious complications? No RCT cov-
ers the subject in urology. Montgomery
showed a lower rate of wound infections
in hand-assisted laparoscopic urologic
surgery compared with open surgery, but
more often than with standard laparos-
copy [31]. We have to refer to informa-
tion from other abdominal surgery. In one
meta-analysis about laparoscopic versus
open surgery for peptic ulcer, there was
a significant lower frequency of surgical
site wound infections in the laparoscopic
group, 2.5% versus 6.9% [32]. Similar
results have been shown for other laparo-
scopic digestive surgery [33]. The NNIS
database supports this trend [34] (LoE 3).
677
Chapter | 12 | Prevention of infections associated with urological surgery
3.5.1.1 Prolonged preoperative hospital stay
A long preoperative hospitalisation is
often claimed as a risk factor for increased
SSI risk. Indeed, the risk of colonisa-
tion by resistant strains is increased.
However, a long hospital stay may also
be the indicator for the severity of illness
and co-morbidity, influencing both the
preoperative diagnostic and therapeutic
procedures [4, 8] (LoE 2b).
3.5.1.2 Prolonged operation time
As for preoperative hospital stay, this fac-
tor may be related to more advanced dis-
ease and more complicated surgery [8, 34]
(LoE 2b).
3.5.1.3 Surgical technique
Tissue traumas, poor haemostasis, fail-
ure to obliterate dead spaces, and the
experience of the surgeon have all been
Table 7 Risk factors and level of evidence for infectious complications in some urological procedures.
Type of intervention
Aspiration biopsy/cytology
of the prostate
Transrectal Core biopsy
of the prostate
Cystoscopy (diagnostic)
Transurethral resection
of the prostate (TURP)
Other endoscopic surgery
678
mentioned as risk factors for SSI. Con-
versely, meticulous surgery performed as
quickly as is safe, with as little blood loss
as possible followed by scrupulous post-
operative care are obviously key factors
that may keep the infection rate as low
as possible. This may also be extended to
endoscopic surgery [4] (LoE 2a). Also the
perioperative administration of supple-
mentary oxygen reduces the rates of sur-
gical wound infection [35].
3.5.2 Evidence of risk factors for
different type of procedures
Table 7 shows the risk factors by level of
evidence for a certain number of proce-
dures. Bacteriuria and any type of cathe-
ter (urethral catheter, nephrostomy tubes,
JJ-stents) and a recent history of UTI or
Evidence for Inconclusive evidence for
Connective tissue disease Prostatitis
Bacteriuria Diabetes mellitus
Indwelling catheter Steroids
History of UTI or Prostatitis Pre-biopsy enema
Absence of antibiotic prophylaxis
Bacteriuria Bladder dysfunction
Indwelling catheter Impaired immune status
History of associated UTI Foreign body
Preoperative indwelling catheter High age
Renal failure Bladder dysfunction
Rupture of closed drainage Surgeons experience
Bleeding
Duration of surgery
Bacteriuria High age
Urethral stent Renal failure
Nephrostomy tubes Duration of surgery
Diabetes mellitus
Absence of antibiotic prophylaxis
 Preoperative assessment of the patient | 12.4 |

Type of intervention Evidence for Inconclusive evidence for

ESWL Bacteriuria High age

Urethral stent Renal failure
Nephrostomy tubes Diabetes
Staghorn stones

Open adenoma enucleation Bacteriuria High age

of the prostate
Indwelling catheter Renal failure
Rupture of closed drainage Duration of surgery
Diabetes mellitus
Absence of antibiotic prophylaxis

Nephrectomy Increasing number of risk factors

Total prostatectomy

Other operations with open Bacteriuria Absence of antibiotic prophylaxis

urinary tract
Indwelling catheter

Surgery and urinary diversion Absence of antibiotic prophylaxis Length of surgery

with open bowel

Implantation of prosthetic Concomitant procedures Diabetes mellitus

devices
Remote site infection
Previous radiotherapy
Transplanted and immune system
deficiency
Repeated implantation
Spinal cord injury

prostatitis are reckoned to be risk factors
with a high level of evidence, whilst other
risk factors are reported inconclusively
in the literature. Diabetes mellitus for
instance was shown in prostate biopsy to
be a risk factor in one study on core pros-
tate biopsy [36], but most other studies
have not been broken down into subgroups,
making a conclusion impossible. For most
urological studies, there are no prospective
or case controlled studies looking specifi-
cally at risk factors, leaving many ques-
tions to be answered in the forthcoming
years. The only approach to identify risk
factors is probably very large prospective
quality control studies including key risk
factor parameters in the reporting [26].
4. DISCUSSION
The present review shows the relative
lack of systematic knowledge regarding
the factors that might influence the devel-
opment of infectious complications in con-
junction with urological surgery. There
are no international standards for a com-
prehensive assessment of patients before
surgery. The ASA score is related to the
risk of anesthesia but reflect also the
health state of the patient. The general
risk factors are based on large registry of
infectious complications in mainly general
and digestive surgery, cardiovascular and
orthopedic intervention, rarely on uro-
logical procedures. Data are not always
consistent and most studies reporting on
infectious complications have not spe-
cifically addressed the role of specific risk
factors. For this reason, we advocate that
contamination classes should be assessed
according to the basic surgical principles
and criteria, especially when new proce-
dures or approaches are being introduced.
Frequently, what was expected to be a
clean or a clean-contaminated operation

679
Chapter | 12 | Prevention of infections associated with urological surgery
has to be upgraded during the procedure
due to intraoperative findings or infec-
tious foci.
We know of a few key risk factors such
as the presence of bacteriuria, with or
without an attachment to an indwelling
catheter, kidney stones, a history of former
genitourinary infection. However, the
knowledge of the underlying mechanism,
the exact source of the germs, the relative
role of the host, the parasite and the envi-
ronment are still poorly understood.
A key question is whether the patient
harbours a virulent pathogen that is
not detected by standard pre-operative
means, as for instance in stone surgery
[24] and prostate biopsy. There is a lack
of tools to identify “hidden” infections. A
urine culture is important if showing bac-
terial growth, but in a substantial number
of cases it would turn out negative, even
in the presence of bacterial growth in
some location of the urinary tract. Thus,
new methods have to be developed.
In the abscence of large databases on
infective complications after urological pro-
cedures, we are confined to assume criteria
and categorise procedures on a reasonable
ground in order to asses the patient’s risk
for complications and to give recommenda-
tions on antimicrobial prophylaxis.
5. FURTHER RESEARCH
Registration of infectious complications
and relating them to risk factors would
eventually improve our knowledge on how
to minimize postoperative complications
in general and infectious complications
in particular. This can preferably be done
via large multicentre, national and inter-
national quality registries comprising
thousands of patients. An international
standard and scoring system for preop-
erative risk assessment has long been
awaited, and that is why the European
Section of Infections in Urology (ESIU),
a section of the European Association
of Urology (EAU), is suggesting this
680
categorization of patients undergoing
urological surgery. However, as all new
score systems, it has to be tested in large
scale through quality registries. It is the
ambition of the ESIU to develop the well
established Global Prevalence Study on
Infections in Urology [16] into an impor-
tant instrument in this direction.
The mechanism of infectious complica-
tions, molecular basis and bacterial viru-
lence are areas for further research. There
is also a need to develop better diagnostic
tools to detect “hidden” infections.
6. CONCLUSIONS
It is essential to carefully asses a patient
before undergoing urological surgery to
reduce postoperative morbidity and mor-
tality. A stepwise assessment ladder is
proposed including a risk factor analy-
sis. We know of a few general key risk
factors such as high age, nutritional and
immunological deficiencies, high body
mass index and prolonged preoperative
hospital stay. It can be stated that the
presence of bacteriuria, with or without
an attachment to an indwelling catheter,
kidney stones, a history of former uro-
genital infection are specific risk factors.
However, there is a lack of evidence for a
large number of factors that eventually
have to be assessed. For this, large cohort
studies and quality registries includ-
ing infectious complication controls have
to be set up. We suggest a new frame of
categorization of urological patients to
undergo surgery into the classical surgi-
cal field contamination classes.
REFERENCES
1. Grabe M, Shortliffe L, Arakawa S,
Kitamura T, and et al., Risk Factors, in
Nosocomial and Health Care Associated
Infections in Urology. 1st International
Consultations on Nosocomial and Health
Care Associated Infections in Urology 2000,
Paris. Naber K, Pechère J.C, Kumazawa
 Preoperative assessment of the patient
J, Khoury S, and et al., Editors. 2001:
Plymbridge Distributors Ltd
2. Department of Health and Human
Services, Public Health Service,1992,
Agency for Health Care Policy and
Research. p. 115–127.
3. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of
the main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
4. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline
for prevention of surgical site infection,
1999. Hospital Infection Control Practices
Advisory Committee. Infect Control Hosp
Epidemiol, 1999. 20(4): 250–78; quiz
279–80.
5. Pagano M and Gauvreau K, Principles
of biostatistics. 2nd ed. 2000, Australia ;
Pacific Grove, CA: Duxbury. 1 v. (various
pagings).
6. American Society of Anesthesiologists.
ASA physical Status Classification
System. Available from: http://asahq.org/
clinical/physicalstatus.htm.
7. Woodfield JC, Beshay NM, Pettigrew RA,
Plank LD, and van Rij AM, American
Society of Anesthesiologists classifica-
tion of physical status as a predictor of
wound infection. ANZ J Surg, 2007. 77(9):
738–41.
8. Haridas M and Malangoni MA, Predictive
factors for surgical site infection in gen-
eral surgery. Surgery, 2008. 144(4): 496–
501; discussion 501–3.
9. Ambiru S, Kato A, Kimura F, Shimizu H,
Yoshidome H, Otsuka M, and Miyazaki
M, Poor postoperative blood glucose con-
trol increases surgical site infections after
surgery for hepato-biliary-pancreatic can-
cer: a prospective study in a high-volume
institute in Japan. J Hosp Infect, 2008.
68(3): 230–3.
10. Dronge AS, Perkal MF, Kancir S, Concato
J, Aslan M, and Rosenthal RA, Long-term
glycemic control and postoperative infec-
tious complications. Arch Surg, 2006.
141(4): 375–80; discussion 380.
11. Shilling AM and Raphael J, Diabetes,
hyperglycemia, and infections. Best
Pract Res Clin Anaesthesiol, 2008. 22(3):
519–35.
| 12.4 |
12. Geerlings SE, Urinary tract infections in
patients with diabetes mellitus: epidemi-
ology, pathogenesis and treatment. Int J
Antimicrob Agents, 2008. 31 Suppl 1:
S54–7.
13. Stapleton A, Urinary tract infections in
patients with diabetes. Am J Med, 2002.
113 Suppl 1A: 80S–84S.
14. Cheadle WG, Risk factors for surgical site
infection. Surg Infect (Larchmt), 2006.
7 Suppl 1: S7–11.
15. Schneider SM, Veyres P, Pivot X,
Soummer AM, Jambou P, Filippi J,
van Obberghen E, and Hebuterne X,
Malnutrition is an independent factor
associated with nosocomial infections.
Br J Nutr, 2004. 92(1): 105–11.
16. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
17. Helmholz HF, Sr., Determination of the
bacterial content of the urethra: a new
method, with results of a study of 82 men.
J Urol, 1950. 64(1): 158–66.
18. Foxman B, Epidemiology of urinary tract
infections: incidence, morbidity, and eco-
nomic costs. Am J Med, 2002. 113 Suppl
1A: 5S–13S.
19. Grabe M, Antimicrobial agents in
transurethral prostatic resection. J Urol,
1987. 138(2): 245–52.
20. Grabe M and Hellsten S, Bacteriuria a
risk factor in men with bladder outlet
obstruction, in Host Parasite interac-
tions in urinary tract infection, Kass EH
and Svanborg Eden C, Editors. 1986,
University of Chicago Press Chicago.
p. 303–306.
21. Evans JP, Smart JG, and Bagshaw PF,
Bacterial content of enucleated prostate
glands. Urology, 1981. 17(4): 328–31.
22. Soto SM, Smithson A, Martinez JA,
Horcajada JP, Mensa J, and Vila J,
Biofilm formation in uropathogenic
Escherichia coli strains: relationship with
prostatitis, urovirulence factors and anti-
microbial resistance. J Urol, 2007. 177(1):
365–8.
23. Hugosson J, Grenabo L, Hedelin H,
Pettersson S, and Seeberg S, Bacteriology
681
Chapter | 12 | Prevention of infections associated with urological surgery
of upper urinary tract stones. J Urol,
1990. 143(5): 965–8.
24. Mariappan P, Smith G, Bariol SV, Moussa
SA, and Tolley DA, Stone and pelvic urine
culture and sensitivity are better than
bladder urine as predictors of urosepsis
following percutaneous nephrolithotomy:
a prospective clinical study. J Urol, 2005.
173(5): 1610–4.
25. Rao PN, Dube DA, Weightman NC,
Oppenheim BA, and Morris J, Prediction
of septicemia following endourological
manipulation for stones in the upper uri-
nary tract. J Urol, 1991. 146(4): 955–60.
26. Lindstedt S, Lindstrom U, Ljunggren
E, Wullt B, and Grabe M, Single-dose
antibiotic prophylaxis in core prostate
biopsy: Impact of timing and identifica-
tion of risk factors. Eur Urol, 2006. 50(4):
832–7.
27. Robinson MR, Arudpragasam ST, Sahgal
SM, Cross RJ, Akdas A, Fittal B, and
Sibbald R, Bacteraemia resulting from
prostatic surgery: the source of bacteria.
Br J Urol, 1982. 54(5): 542–6.
28. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008.
31 Suppl 1: S68–78.
29. Culver DH, Horan TC, Gaynes RP,
Martone WJ, Jarvis WR, Emori TG,
Banerjee SN, Edwards JR, Tolson JS,
Henderson TS, and et al., Surgical
wound infection rates by wound class,
operative procedure, and patient risk
index. National Nosocomial Infections
Surveillance System. Am J Med, 1991.
91(3B): 152S–157S.
30. Grabe M, Controversies in antibiotic
prophylaxis in urology. Int J Antimicrob
Agents, 2004. 23 Suppl 1: S17–23.
31. Montgomery JS, Johnston WK, 3rd, and
Wolf JS, Jr., Wound complications after
hand assisted laparoscopic surgery.
J Urol, 2005. 174(6): 2226–30.
32. Lunevicius R and Morkevicius M,
Systematic review comparing laparo-
scopic and open repair for perforated
peptic ulcer. Br J Surg, 2005. 92(10):
1195–207.
682
33. de Oliveira AC, Ciosak SI, Ferraz EM,
and Grinbaum RS, Surgical site infection
in patients submitted to digestive sur-
gery: risk prediction and the NNIS risk
index. Am J Infect Control, 2006. 34(4):
201–7.
34. National Nosocomial Infections
Surveillance (NNIS) System Report, data
summary from January 1992 through
June 2004, issued October 2004. Am J
Infect Control, 2004. 32(8): 470–85.
35. Greif R, Akca O, Horn EP, Kurz A, and
Sessler DI, Supplemental perioperative
oxygen to reduce the incidence of surgical-
wound infection. Outcomes Research
Group. N Engl J Med, 2000. 342(3):
161–7.
36. Aus G, Ahlgren G, Bergdahl S, and
Hugosson J, Infection after transrectal
core biopsies of the prostate--risk factors
and antibiotic prophylaxis. Br J Urol,
1996. 77(6): 851–5.
37. Clark KR and Higgs MJ, Urinary
infection following out-patient flexible
cystoscopy. Br J Urol, 1990. 66(5):
503–5.
38. Almallah YZ, Rennie CD, Stone J, and
Lancashire MJ, Urinary tract infection
and patient satisfaction after flexible
cystoscopy and urodynamic evaluation.
Urology, 2000. 56(1): 37–9.
39. Burke DM, Shackley DC, and O’Reilly
PH, The community-based morbidity of
flexible cystoscopy. BJU Int, 2002. 89(4):
347–9.
40. Johnson MI, Merrilees D, Robson WA,
Lennon T, Masters J, Orr KE, Matthews
JN, and Neal DE, Oral ciprofloxacin or
trimethoprim reduces bacteriuria after
flexible cystoscopy. BJU Int, 2007. 100(4):
826–9.
41. Jimenez Cruz JF, Sanz Chinesta S, Otero
G, Diaz Gonzalez R, Alvarez Ruiz F,
Flores N, Virseda J, Rioja LA, Zuluaga
A, Tallada M, and et al., [Antimicrobial
prophylaxis in urethrocystoscopy.
Comparative study]. Actas Urol Esp,
1993. 17(3): 172–5.
42. MacDermott JP, Ewing RE, Somerville
JF, and Gray BK, Cephradine prophylaxis
in transurethral procedures for carcinoma
of the bladder. Br J Urol, 1988. 62(2):
136–9.
 Preoperative assessment of the patient
43. Rane A, Cahill D, Saleemi A, Montgomery
B, and Palfrey E, The issue of prophylac-
tic antibiotics prior to flexible cystoscopy.
Eur Urol, 2001. 39(2): 212–4.
44. Manson AL, Is antibiotic administration
indicated after outpatient cystoscopy.
J Urol, 1988. 140(2): 316–7.
45. Wilson L, Ryan J, Thelning C, Masters
J, and Tuckey J, Is antibiotic prophylaxis
required for flexible cystoscopy? A trun-
cated randomized double-blind controlled
trial. J Endourol, 2005. 19(8): 1006–8.
46. Latthe PM, Foon R, and Toozs-Hobson P,
Prophylactic antibiotics in urodynamics:
a systematic review of effectiveness and
safety. Neurourol Urodyn, 2008. 27(3):
167–73.
47. Cundiff GW, McLennan MT, and Bent AE,
Randomized trial of antibiotic prophy-
laxis for combined urodynamics and
cystourethroscopy. Obstet Gynecol, 1999.
93(5 Pt 1): 749–52.
48. Logadottir Y, Dahlstrand C, Fall M,
Knutson T, and Peeker R, Invasive uro-
dynamic studies are well tolerated by the
patients and associated with a low risk
of urinary tract infection. Scand J Urol
Nephrol, 2001. 35(6): 459–62.
49. Enlund AL and Varenhorst E, Morbidity
of ultrasound-guided transrectal core
biopsy of the prostate without prophylactic
antibiotic therapy. A prospective study in
415 cases. Br J Urol, 1997. 79(5): 777–80.
50. Larsson P, Norming U, Tornblom M, and
Gustafsson O, Antibiotic prophylaxis
for prostate biopsy: benefits and costs.
Prostate Cancer Prostatic Dis, 1999. 2(2):
88–90.
51. Puig J, Darnell A, Bermudez P, Malet
A, Serrate G, Bare M, and Prats J,
Transrectal ultrasound-guided prostate
biopsy: is antibiotic prophylaxis neces-
sary? Eur Radiol, 2006. 16(4): 939–43.
52. Kapoor DA, Klimberg IW, Malek GH,
Wegenke JD, Cox CE, Patterson AL,
Graham E, Echols RM, Whalen E, and
Kowalsky SF, Single-dose oral cipro-
floxacin versus placebo for prophylaxis
during transrectal prostate biopsy.
Urology, 1998. 52(4): 552–8.
53. Aron M, Rajeev TP, and Gupta NP,
Antibiotic prophylaxis for transrectal
needle biopsy of the prostate: a
| 12.4 |
randomized controlled study. BJU Int,
2000. 85(6): 682–5.
54. Upton JD and Das S, Prophylactic antibi-
otics in transurethral resection of bladder
tumors: are they necessary? Urology, 1986.
27(5): 421–3.
55. Delavierre D, Huiban B, Fournier G,
Le Gall G, Tande D, and Mangin P,
[The value of antibiotic prophylaxis in
transurethral resection of bladder tumors.
Apropos of 61 cases]. Prog Urol, 1993.
3(4): 577–82.
56. Berry A and Barratt A, Prophylactic
antibiotic use in transurethral prostatic
resection: a meta-analysis. J Urol, 2002.
167(2 Pt 1): 571–7.
57. Qiang W, Jianchen W, MacDonald R,
Monga M, and Wilt TJ, Antibiotic prophy-
laxis for transurethral prostatic resection
in men with preoperative urine containing
less than 100,000 bacteria per ml:
a systematic review. J Urol, 2005. 173(4):
1175–81.
58. Wagenlehner FM, Wagenlehner C,
Schinzel S, and Naber KG, Prospective,
randomized, multicentric, open, compara-
tive study on the efficacy of a prophylactic
single dose of 500 mg levofloxacin versus
1920 mg trimethoprim/sulfamethoxazole
versus a control group in patients under-
going TUR of the prostate. Eur Urol,
2005. 47(4): 549–56.
59. Colau A, Lucet JC, Rufat P, Botto H,
Benoit G, and Jardin A, Incidence and
risk factors of bacteriuria after transure-
thral resection of the prostate. Eur Urol,
2001. 39(3): 272–6.
60. Charton M, Vallancien G, Veillon B,
Prapotnich D, Mombet A, and Brisset JM,
Use of antibiotics in the conjunction with
extracorporeal lithotripsy. Eur Urol, 1990.
17(2): 134–8.
61. Deliveliotis C, Giftopoulos A,
Koutsokalis G, Raptidis G, and
Kostakopoulos A, The necessity of pro-
phylactic antibiotics during extracor-
poreal shock wave lithotripsy. Int Urol
Nephrol, 1997. 29(5): 517–21.
62. Dincel C, Ozdiler E, Ozenci H, Tazici N,
and Kosar A, Incidence of urinary tract
infection in patients without bacteriuria
undergoing SWL: comparison of stone
types. J Endourol, 1998. 12(1): 1–3.
683
Chapter | 12 | Prevention of infections associated with urological surgery
63. Gattegno B, Sicard F, Alcaidinho
D, Arnaud E, and Thibault P,
[Extracorporeal lithotripsy and prophylac-
tic antibiotic therapy]. Ann Urol (Paris),
1988. 22(2): 101–2.
64. Pettersson B and Tiselius HG, Are pro-
phylactic antibiotics necessary during
extracorporeal shockwave lithotripsy?
Br J Urol, 1989. 63(5): 449–52.
65. Claes H, Vandeursen R, and Baert L,
Amoxycillin/clavulanate prophylaxis for
extracorporeal shock wave lithotripsy –
a comparative study. J Antimicrob
Chemother, 1989. 24 Suppl B: 217–20.
66. Knipper A, Bohle A, Pensel J, and
Hofstetter AG, [Antibiotic prophylaxis
with enoxacin in extracorporeal shock-
wave lithotripsy]. Infection, 1989. 17
Suppl 1: S37–8.
67. Bierkens AF, Hendrikx AJ, Ezz el Din KE,
de la Rosette JJ, Horrevorts A, Doesburg
W, and Debruyne FM, The value of anti-
biotic prophylaxis during extracorporeal
shock wave lithotripsy in the prevention
of urinary tract infections in patients with
urine proven sterile prior to treatment.
Eur Urol, 1997. 31(1): 30–5.
68. Pearle MS and Roehrborn CG,
Antimicrobial prophylaxis prior to shock
wave lithotripsy in patients with sterile
urine before treatment: a meta-analysis
and cost-effectiveness analysis. Urology,
1997. 49(5): 679–86.
69. Fourcade RO, Antibiotic prophylaxis with
cefotaxime in endoscopic extraction of
upper urinary tract stones: a randomized
study. The Cefotaxime Cooperative Group.
J Antimicrob Chemother, 1990. 26 Suppl
A: 77–83.
70. Knopf HJ, Graff HJ, and Schulze H,
Perioperative antibiotic prophylaxis in
ureteroscopic stone removal. Eur Urol,
2003. 44(1): 115–8.
71. Hendrikx AJ, Strijbos WE, de Knijff DW,
Kums JJ, Doesburg WH, and Lemmens
WA, Treatment for extended-mid and dis-
tal ureteral stones: SWL or ureteroscopy?
Results of a multicenter study.
J Endourol, 1999. 13(10): 727–33.
72. Charton M, Vallancien G, Veillon B, and
Brisset JM, Urinary tract infection in per-
cutaneous surgery for renal calculi.
J Urol, 1986. 135(1): 15–7.
684
73. Osman M, Wendt-Nordahl G, Heger
K, Michel MS, Alken P, and Knoll T,
Percutaneous nephrolithotomy with
ultrasonography-guided renal access:
experience from over 300 cases. BJU Int,
2005. 96(6): 875–8.
74. Steiner T, Traue C, and Schubert J,
[Perioperative antibiotic prophylaxis in
transperitoneal tumor nephrectomy: does
it lower the rate of clinically significant
postoperative infections?]. Urologe A,
2003. 42(1): 34–7.
75. Stranne J, Aus G, Hansson C, Lodding P,
Pileblad E, and Hugosson J, Single-dose
orally administered quinolone appears
to be sufficient antibiotic prophylaxis for
radical retropubic prostatectomy. Scand
J Urol Nephrol, 2004. 38(2): 143–7.
76. Terai A, Ichioka K, Kohei N, Ueda N,
Utsunomiya N, and Inoue K, Antibiotic
prophylaxis in radical prostatectomy:
1-day versus 4-day treatments. Int J Urol,
2006. 13(12): 1488–93.
77. Takeyama K, Takahashi S, Maeda T,
Mutoh M, Kunishima Y, Matsukawa M,
and Takagi Y, Comparison of 1-day, 2-day,
and 3-day administration of antimicro-
bial prophylaxis in radical prostatectomy.
J Infect Chemother, 2007. 13(5): 320–3.
78. Sakura M, Kawakami S, Yoshida S,
Masuda H, Kobayashi T, and Kihara K,
Prospective comparative study of single
dose versus 3-day administration of anti-
microbial prophylaxis in minimum inci-
sion endoscopic radical prostatectomy. Int
J Urol, 2008. 15(4): 328–31.
79. Takeyama K, Matsukawa M, Kunishima
Y, Takahashi S, Hotta H, Nishiyama
N, and Tsukamoto T, Incidence of and
risk factors for surgical site infection in
patients with radical cystectomy with uri-
nary diversion. J Infect Chemother, 2005.
11(4): 177–81.
80. Hara N, Kitamura Y, Saito T,
Komatsubara S, Nishiyama T, and
Takahashi K, Perioperative antibiotics in
radical cystectomy with ileal conduit uri-
nary diversion: efficacy and risk of anti-
microbial prophylaxis on the operation
day alone. Int J Urol, 2008. 15(6): 511–5.
81. Studer UE, Danuser H, Merz VW,
Springer JP, and Zingg EJ, Experience in
100 patients with an ileal low pressure
 Preoperative assessment of the patient
bladder substitute combined with an
afferent tubular isoperistaltic segment.
J Urol, 1995. 154(1): 49–56.
82. Kiddoo DA, Wollin TA, and Mador DR, A
population based assessment of complica-
tions following outpatient hydrocelectomy
and spermatocelectomy. J Urol, 2004.
171(2 Pt 1): 746–8.
83. Swartz MA, Morgan TM, and Krieger
JN, Complications of scrotal surgery for
| 12.4 |
benign conditions. Urology, 2007. 69(4):
616–9.
84. Mould JW and Carson CC, Infectious
complications of penile prostheses.
Infections in Urology, 1989. 139: 50–52.
85. Carson CC, Diagnosis, treatment and
prevention of penile prosthesis infec-
tion. Int J Impot Res, 2003. 15 Suppl 5:
S139–46.
685
|12.5|
Antibiotic prophylaxis in urological
surgery, a European viewpoint
Magnus Grabe
Associate Professor, Department of Urology, Skåne University Hospital, University of Lund, S-20502 Malmö, Sweden
Tel 0046-40-33.37.55/4, Fax 0046-40-33.70.49, magnus.grabe@skane.se
ABSTRACT
Surgical site infections (SSI) including
urinary tract infections (UTI) cause a
significant morbidity in urological sur-
gery. Antibiotic prophylaxis is one of sev-
eral factors impacting on infection rates.
Antibiotic prophylaxis is relevant only for
clean and clean-contaminated operations
and in the absence of bacterial growth in
the urine. Strict classification is lacking,
but a proposal is presented in the previ-
ous section. Only TURP and transrectal
core prostate biopsy are well documented.
The present review confirms that there is
a lack of hard data, insufficient consist-
ency in classification and definitions, and
that new well-powered RCT and large
multicentre quality cohort studies includ-
ing risk factor analysis are necessary to
improve recommendations for antibiotic
prophylaxis in urologic surgery.
Key words: Surgical site infection,
wound infection, urinary tract infection,
antibiotic prophylaxis
SUMMARY OF RECOMMENDATIONS
The reader will find a paradox in the level
of evidence and the policy recommended.
The reasons are therefore explained for
each procedure in its respective section.
1. INTRODUCTION
The use of antibiotics in urologic sur-
gery has been controversial for decades
[1–2]. Over the same period of time, sur-
gical procedures and interventions have
evolved remarkably from high-invasive
open to low-invasive surgery due to a fas-
cinating improvement of technologies and
instruments. Also, medical treatment has
replaced surgery in a substantial number
of situations and in this way modified the
profile of patients undergoing surgery.
The basic principle of antibiotic proph-
ylaxis is to protect the patient undergoing
surgery against undesirable infectious
complications by lowering the bacterial
 Antibiotic prophylaxis in urological surgery, a European viewpoint | 12.5 |

Table 1 Summary of recommendation for antibiotic prophylaxis (ABP) per type of procedure.

Type of procedure Level of recommendation Remarks

Diagnostic procedures

Cystoscopy No systematic ABP (GoR A) Low frequency of infections

Contradictory findings

Urodynamic study No systematic ABP (GoR A) Low frequency of infections

Contradictory findings

Core prostate biopsy To all patients (GoR A) Single dose to all low risk patients (GoR A)
Prolonged in high risk patients (GoR C)

URS diagnostic No systematic ABP (GoR C) No available studies

Therapeutic procedures

TURB As for cystoscopy in standard small No concern of tumour burden in studies

TURB (GoR C)
Consider in large tumours (GoR C)

TURP All patients (GoR A) Well documented

Show-wave lithotripsy (ESWL) No systematic ABP (GoR A) Low frequency of infections

Contradictory findings

Ureteroscopic stone To all patients (GoR B) Simple mid and distal stones
management
Complex, proximal stones as for PCNL

Percutaneous stone To all patients (GoR B) Single dose to simple stones (GoR C)
management
Consider prolongation in complex stones
(GoR C)

Open/Lap nephrectomy No systematic ABP (GoR C) Catheter related BU/UTI

Open/lap nephroureterectomy To all patients (GoR C) No available studies

Defined as clean-contaminated – single dose

PUJ repair To all patients (GoR C) Defined as clean-contaminated – single dose

Open/lap bladder resection, To all patients (GoR C) Defined as clean-contaminated – single dose
ureteral repair

Open/lap prostatectomy To all patients (GoR B) Defined as clean-contaminated – single dose

Cystectomy with urine To all patients (GoR B) Defined as clean-contaminated – single dose
deviation
Prolongation of ABP on individual basis

Surgery for hydrocele and No systematic ABP (GoR B) Review studies contradictory
spermatocoele

Prosthetic procedures To all patients (GoR B) Regimen not defined

burden. Antibiotic prophylaxis is appli- of detectable bacterial growth in urine

cable for clean and clean-contaminated (<104 cfu/ml). In clean operations, the
operations. For the urinary tract, anti- urinary tract is not opened. In clean-
biotic prophylaxis implies the absence contaminated operations, the urinary

687
Chapter | 12 | Prevention of infections associated with urological surgery
tract is opened and, in case of urinary
diversion, the intestinal tract, implying
an increased bacterial burden. In the case
of bacterial growth and surgery associated
with opening of the bowel with spillage –
contaminated operations – an individual
treatment strategy is prescribed [3].
Two types of infections dominate uro-
logic surgery: 1) urinary tract infection
(UTI), a space or organ infection, associ-
ated with both endoscopic, endoluminal
interventions and open or laparoscopic
surgery, mostly coinciding with catheter
and stent placement or undetected har-
boured bacterial load and 2) wound infec-
tion after open and laparoscopic surgery.
Furthermore, a third form of infection is
observed in terms of infection of the male
genital system (prostatitis, epididymitis
and orchitis). A fourth form of infection,
blood stream born sepsis, resulting from
urologic instrumentation, is feared by
patients and urologists, and is far from
negligible accounting for 12% of health-
care associated infections (HAI) in uro-
logic wards [4].
2. AIM
The present report focuses on the most
frequent diagnostic and therapeutic uro-
logic interventions (Table 1) and results
from a systematic review. It is out of
range to be comprehensive and cover all
specific or special procedures as several of
these have never been studied. Also pae-
diatric urologic surgery is not covered.
3. METHODS
A systematic search was performed in
Medline, Cochrane Library and EMBASE
and using the keywords antibiotic proph-
ylaxis, prophylaxis, antibiotics, urologi-
cal surgery, urogenital surgery and the
procedures one by one. Approximately
200 abstracts were identified of which
over 100 were not directly related to
688
the topic. Of the remaining 95 reports,
a majority was related to transurethral
resection of the prostate (TURP). As this
procedure has been reviewed by other
authors by means of systematic review
[5] and covered more recently by two
meta-analyses [6–7], the outcome was
built on these works. Also urodynamic
studies were critically reviewed [8] and
the conclusions reported. For all other
procedures, the articles were system-
atically reviewed and the conclusions
compared to those drawn by one other
recent systematic review by a group
from the Netherlands [9] and the conclu-
sions presented by a working group in
the USA [10].The quality of the studies
were found to vary largely, essentially in
terms of design, description of randomi-
sation, sample size, level of dropout,
power, and strength of the conclusion.
The procedures were divided between
diagnostic procedures (cystoscopy, uro-
dynamic studies and transrectal core
biopsy of the prostate) and therapeutic
endoscopic procedures (transurethral
resection of bladder tumours and of
the prostate, endourological interven-
tions including shock wave lithotripsy),
open and laparoscopic interventions
(nephrectomy, pelvic junction surgery,
total prostatectomy, cystectomy with uri-
nary diversion) and elective surgery for
benign scrotal surgery.
As far as possible, the expected natu-
ral history of infectious rates is presented
followed by the results of randomised
placebo/no antibiotic controlled studies
(RCT). Thereafter, RCTs of different anti-
biotic regimens are presented to detect
the most rational one (shortest, low cost
and effective course) when applicable.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[11–12]. The LoE and GoR are given at
the end of each surgical procedure and
the recommendation reported to the sum-
mary table.
 Antibiotic prophylaxis in urological surgery, a European viewpoint
4. RESULTS PER TYPE OF PROCEDURE
4.1 Cystoscopy
The natural history of the events fol-
lowing cystoscopy is important. In one
study from 1990, Clarks and Higgs [13]
showed the appearance of bacteriuria
three days after instrumentation in
12/161 (7.5%). In two recent studies, a
spontaneous acquired bacteriuria was
observed in 2.7% and 4.5% [14–15]. The
fate of this bacterial contamination is
not known and the spontaneous cure is
probably high. In a large British study
with flexible cystoscopy [16], a single
dose of trimethoprim or ciprofloxacin
reduced by more than half, 2% and
3.2% respectively, the post-cystoscopy
frequency of bacteriuria as compared
to placebo (6.8%). These results were in
accordance with an older study observ-
ing a significant reduction of post-cys-
toscopy bacteriuria and clinical UTI
[17]. Other studies were contradictory
in their results, some advocating antibi-
otic prophylaxis [18–19], others finding
it no use [20–23]. The overall conclu-
sions are that the frequency of bacteriu-
ria is low and that of clinical infections
even lower, and that the frequencies
of these events are, globally, margin-
ally reduced by antibiotic prophylaxis.
Thus, the recommendation of giving
systematically antibiotic prophylaxis to
all patients undergoing cystoscopy can-
not be advocated in view of the lack of
knowledge of the risk associated with
the bacterial contamination and its
fate, the low frequency of clinical infec-
tion, the recommendation and praxis
in most European countries, the enor-
mous amount of such instrumentation
and overtreatment, and the subsequent
amount of antibiotics that would be
used (LoE 1b-2b, GoR A).
4.2 Urodynamic studies
Most studies are carried out on women
investigated for incontinence. In a meta-
| 12.5 |
analysis of 995 patients including eight
RCT, bacteriuria (>105 cfu/ml) was
reduced by 40% by antibiotic prophylaxis
[8]. The authors concluded that it was
necessary to treat 13 individuals in order
to avoid one episode of bacteriuria. In one
other study combining cystoscopy and
urodynamic study in women, there was
found to be no difference between one day
of antibiotic prophylaxis and no antibiot-
ics [24]. In one Swedish study of 123 con-
secutive men undergoing a flow-pressure
investigation, 4.1% acquired bacteriuria
and 2.5% fever [25]. The overall inter-
pretation is, as for cystoscopy, that the
frequency of infectious events is low, that
the outcome and role of bacteriuria after
urodynamic investigation is unknown
and that there is a lack of support in the
literature for the systematic use of anti-
biotic prophylaxis in patients without
risk factors. For investigations of patients
with other underlying urological diseases
such as neurological bladder dysfunction,
refer to the chapter on “UTI in patients
with underlying urological diseases” (LoE
1a, GoR A).
4.3 Transrectal core prostate biopsy
There are only very few studies on the
natural history of infectious complica-
tions after transrectal prostate biopsy. In
a few cohort series, infectious complica-
tions such as febrile UTI, acute prostati-
tis and sepsis are reported in frequencies
between 2.9–10% [26–28]. In RCT, fre-
quencies of 5–26% bacteriuria and up to
10% febrile UTI are given in the control
groups [29–31]. In older studies, fre-
quencies up to 48% have been reported
[32–33]. There is a consistent significant
reduction of the frequencies of both bac-
teriuria and febrile urogenital infections
by antibiotic prophylaxis, below 5% in
low risk patients [29–34]. Recent stud-
ies have shown that one day [35–36]
and even one single dose [31, 37–38] is
appropriate to keep the infectious rate
at 1% or below, including less than 0.5%
689
Chapter | 12 | Prevention of infections associated with urological surgery
of sepsis. These low frequencies are con-
firmed by a few consecutive cohort series
with antibiotic prophylaxis [39–40]. The
antibiotic dose can be given in direct
conjunction with instrumentation and
there is now evidence for giving the
medication one to two hours before the
procedure [37]. Fluoroquinolones achieve
the highest concentrations in the pros-
tate [41] and are best documented for
prophylaxis. However, new studies have
to be done to avoid the overuse of fluo-
roquinolones wherever possible due to
the worldwide development of resistant
strains in both community and hospital
settings. It is unknown how long proph-
ylaxis should be given to risk patients
(risk factors are presented in the preced-
ing chapter). It is also unknown whether
spontaneous acquired bacteriuria after
core prostate biopsy can spontaneously
cure (LoE 1b; GoR A).
4.4 Transurethral resection of
bladder tumour (TURB)
Although TURB is one of the most fre-
quent urological procedures, there are
no base-line data. Only three older,
rather weak, small size studies cover-
ing antibiotic prophylaxis were dis-
closed [18, 42–43]. The data from the
studies do not give any evidence in
favour of antibiotic prophylaxis in
TURB. However, the studies focus only
on smaller tumours or fulguration, an
intervention very similar to standard
cystoscopy, and do not mirror the large
spectrum of resection of bladder cancer
from the single minor non-muscle inva-
sive bladder tumours (Ta, G1–2) to large
muscle-invasive ≥ T2, G3), sometimes
necrotic, tumours that are part of daily
practice. Future studies covering all
TURB procedures and breaking them
down according to the intervention’s
level of severity and difficulty, duration
and other risk factors has to be under-
taken (LoE 2b, GoR C).
690
4.5 Transurethral resection of the
prostate (TURP)
TURP is the most well studied of all uro-
logical studies. More than 50 studies have
been conducted, some of them of medium to
high quality. Postoperative bacteriuria has
been reported in up to 70% of the patients.
In a systematic review of subsequent stud-
ies from the 1980s, it was shown that anti-
biotic prophylaxis reduced the frequency
of bacteriuria in men with pre-operative
sterile urine from an average of 34% to
10% [5]. In recent years, two high quality
meta-analysis have been done including
32 and 28 participant controlled studies,
(respectively [6–7]). The conclusions are
similar: a short course of antimicrobial
agents reduces the risk of bacteriuria from
an average of 26% to 9%. Berry and Barrat
also analysed the impact on sepsis: the
impact was even more important, reduc-
ing the risk from 4.4% to less than 1%.
Both reviews show that a prolonged course
(< 72 hours) is more effective than a single
dose, but less effective than one week [6].
Any antibiotic except nitrofurantoin would
do. In a recent high quality multicentre
study conducted in Germany, Wagenlehner
[44] confirmed these results, although the
difference was less marked. Interestingly,
they also showed that the total amount of
antibiotics used in the study was lower in
the antibiotic prophylaxis group, confirm-
ing data from one older similar analysis
[45]. This observation is interesting in the
argument for antibiotic prophylaxis, as
nowadays there is a high level of concern
about the total amount of antibiotics used
in the community. Long operation time,
postoperative disconnection of drainage
system and longer catheterisation period
were associated with increased frequency
of bacteriuria despite antibiotic prophy-
laxis [46] (LoE 1a. GoR A).
Consequently, there is a scientifi-
cally high level of evidence for the use of
short regimens of antibiotic prophylaxis
in TURP to reduce the postoperative
 Antibiotic prophylaxis in urological surgery, a European viewpoint
frequencies of both bacteriuria and, espe-
cially, severe febrile infections and sep-
sis. The conclusions are not applicable to
other prostate interventions such as ade-
noma enucleation, micro-wave thermo-
therapy or laser ablation, as there are no
quality RCT studies on the matters.
4.6 Extracorporeal shock-wave
lithotripsy (ESWL)
A remarkably poor number of studies
have been conducted for such an enor-
mous worldwide procedure. In a few
follow-up studies, the frequency of post-
ESWL bacteriuria has been shown to be
≤ 5% in patients without known risk fac-
tors [47–49]. In only one [50] of five ran-
domised placebo/non antibiotic controlled
studies was a significant reduction dem-
onstrated [50–54]. In most studies, the
sample size or the frequencies of infec-
tions were low and no clear-cut conclu-
sions could be drawn. In a systematic
review and meta-analysis Pearle ana-
lysed eight prospective controlled studies
[55]. The frequencies of bacteriuria and/
or symptomatic UTI were reported to be
0–28 % in the non-antibiotic control group
and 0–7% in the intervention group. They
estimated the risk of acquiring a UTI to
be 5.7% and 2.1%, respectively.
The overall conclusion is that in
patients with sterile urine, uncompli-
cated kidney or ureteral stones and no
known risk factors, the risk of post-ESWL
bacteriuria/UTI is low, that the reduction
by antibiotic prophylaxis is marginal and
that, subsequently, there is no evidence
for antibiotic prophylaxis in this category
of low risk patients, which represents the
majority of patients undergoing ESWL
(LoE 1a-2b, GoR A).
4.7 Ureteroscopy (URS)
No studies on ureteroscopy as a diagnos-
tic tool were found. Two studies concerned
with stone management were identi-
fied [56–57]. Both show a reduction of
| 12.5 |
bacteriuria but not of symptomatic UTI.
One study comparing ESWL and URS
for mid and distal ureteral stones dem-
onstrated a higher frequency of complica-
tions including infectious complications
in the URS treated group as compared
to the ESWL group [58]. The studies do
not differentiate the degree of invasive-
ness in terms of stone burden and locali-
sation (impacted proximal stone versus
small mid and lower stones), surgical dif-
ficulty and complexity of the treatment,
duration of operation, experience of the
surgeon; a weakness, as it is known that
the risk of infectious complications varies
[59]. In conclusion, there is only a weak
level of evidence for antibiotic prophy-
laxis in URS, although it is probably of
value, especially in complex stone situa-
tions (Diagnostic: LoE 2b, GoR C. Stone
management: LoE 2b, GoR B).
4.8 Percutaneous stone extraction
(PCNL)
Bacteriuria is reported in up to 35% and
febrile UTI in around 10% of patients
receiving no antibiotics [60–61]. Only one
controlled study comparing antibiotic
prophylaxis with no antibiotics was identi-
fied [56] and one comparing two different
antibiotic regimens [62]. As for compli-
cated URS, the danger of PCNL in terms
of severe, febrile UTI and sepsis has been
underlined [59, 63]. Antibiotic prophy-
laxis appears to reduce the frequencies of
infectious complications and there seems
to be no difference between antibiotics.
As mid-stream urine culture is not a good
predictor for the endogenous presence
of pathogens [63], the urologist faces an
incertitude as to the real risk of infectious
complications. Moreover, following the
remarkable improvement of equipment,
older studies are not necessarily repre-
sentative of the present profile of renal
stone management. Consequently, as for
URS, there is a substantial lack of data on
the use of antibiotics in PCNL and only a
691
Chapter | 12 | Prevention of infections associated with urological surgery
very limited evidence for antibiotic proph-
ylaxis. Nonetheless, the infectious rates
being high and the potential complications
severe, there are reasons to believe that
antibiotic prophylaxis is of value. Large
multicentre controlled studies focusing on
antibiotic regimens and risk factor analy-
sis are required (LoE 2b; GoR B).
4.9 Open and laparoscopic
urologic surgery
An extensive search on open and laparo-
scopic surgery, nephrectomy, nephron
sparing surgery, pelvic junction recon-
struction bladder resection, cystectomy,
total/radical prostatectomy and scrotal
surgery has revealed the lack of RCT
and the weaknesses of available data
[9–10]. Expected data have to be extrap-
olated from bottom-line data on type
of surgery [3] and from colorectal and
abdominal gynaecologic surgery. There
are indications that infectious complica-
tions are fewer after laparoscopic and
robotic surgery in abdominal surgery
[64]. The issue has however not been
studied in RCT as far as urologic surgery
is concerned. A few examples of common
surgery by type of intervention follow.
4.9.1 Clean operations
Trans-abdominal open or laparoscopic
nephrectomy is classed as a clean opera-
tion. Only one RCT was identified [65].
Infectious complications in terms of
wound infection were 20.4% when no
antibiotics were given versus 0% for
patients receiving one single preopera-
tive dose. The results indicate a marked
impact of antibiotic prophylaxis but no
other study confirms the data. In one
report on SSI in which antibiotic prophy-
laxis was not in the protocol, Montgomery
reports wound infections in 6.8% (range
5.0–7.9%) in clean and clean contami-
nated hand assisted kidney surgery, with
no difference whether the urinary tract
was opened or not [66]. In one study of
clean surgery in patients with or without
692
a risk factor for SSI, antibiotic prophy-
laxis had no impact in low risk patients
whereas it reduced the frequency in
patients with at least one risk factor [67].
Scrotal surgery for elective benign con-
ditions, mainly hydrocele and sperma-
tocele, is a reasonably clean procedure. No
RCT was identified. In a few recent stud-
ies [68–69], including a Medline search
review, infectious complications were
reported in up to 9%. In most reports, no
antibiotic prophylaxis had been used. A
lower frequency of infections (3.6%) was
observed in patients receiving antibiotic
prophylaxis [70]. Multicentre RCT have
yet to be undertaken to confirm this find-
ing (LoE 3, GoR C).
4.9.2 Clean-contaminated operations
Nephroureterectomy, kidney resection
and pelvic junction surgery have, to the
best of our knowledge, never been studied
in RCT. The searches have revealed no
RCT on antibiotic prophylaxis versus pla-
cebo/no antibiotic in total prostatectomy.
Thus, there is a lack of baseline data on
the infectious profile of this nowadays so
frequent operation. There are a few ret-
rospective and prospective cohort studies
looking at SSI and catheter associated
bacteriuria following different antibiotic
regimens. The conclusion of this series
of publications is that the frequency of
wound infections is low and that a single
oral antibiotic dose is sufficient [70–73].
The importance of the post-operative
catheter associated bacteriuria, observed
in the majority of the patients at catheter
removal, is unknown as is whether it has
to be treated or not (LoE 3, GoR B).
There are no RCT on antibiotic proph-
ylaxis in urologic surgery including urine
deviation and the use of bowel. Post-
operative wound infection is reported in
up to one third of cases, usually 10–15%,
even when using antibiotic prophy-
laxis [74–76]. Also UTI, pyelonephritis
and sepsis are added to the burden of
infections.
 Antibiotic prophylaxis in urological surgery, a European viewpoint
4.9.3 Penile prosthesis
Implantation of penile prosthetic devices
is a special case. Infection of the pros-
thetic device remains the most trouble-
some complication. Infection may lead
to more surgery, loss of penile tissue and
even the inability to replace penile pros-
thesis. Antibiotic prophylaxis in addition
to standard sterility and good surgical
technique reduces the risk of infection
[77–78].
5. DISCUSSION
The present review requires a certain
number of remarks on the validity and
relevance of the references revealed by an
in-depth search of the literature. Firstly,
the remarkable technical development
and medical achievements in urology
during the past 25–30 years means that
older studies from the 1970s and 1980s
have partly lost their relevance. Secondly,
the quality of older studies in the present
view of good clinical practice is usually
poor in terms of sample size, consistency
in definitions, statistical estimates and
power. Thirdly, risk factors for infectious
complications are rarely debated and,
as shown in the preceding section about
preparation of the patient for surgery, our
knowledge of the relative importance of
individual risk factors and their cumula-
tive impact is limited. Fourthly, numerous
reports have given results on a mixture of
procedures and the breakdown has shown
so low a sample size per procedure that it
is difficult to draw a conclusion. Fifthly,
the lack of consistency in definitions of
infectious complications, especially UTI,
the level of bacterial growth and the rela-
tion between clinical symptoms and bac-
terial growth weakens the possibility of
comparison. Clear definitions are often
lacking. The results are therefore more
indicative, than proof. Against this back-
ground, large cohort studies and histori-
cal controls gain indicative importance by
giving a “natural history” of the events
| 12.5 |
after a defined intervention and therefore
have also been used to some extent.
It is remarkable that there are so few
studies on very frequent interventions
such as transurethral resection of blad-
der tumours and endoscopic stone man-
agement including ESWL. It is thus not
astonishing that Bootsma et al stated
that “except for TURP and prostate
biopsy, there is a lack of well performed
studies investigating the need for anti-
biotic prophylaxis in urologic interven-
tions” [9]. On the other hand, urologists
need a working hypothesis for antibiotic
prophylaxis.
One approach is to stick to the clas-
sification of surgical interventions in
clean, clean-contaminated and contami-
nated classes and follow the experience of
other surgical practices such as general,
orthopaedic and gynaecologic surgery.
Theoretically, there should be no need
for antibiotic prophylaxis in clean opera-
tions, while a single dose should be advo-
cated for clean-contaminated procedures.
In case of contaminated procedures (i.e.
urine deviation with bowel, presence of
asymptomatic bacteriuria in urine), the
antibiotic regiment’s start and length is
less obvious and documentation is insuffi-
cient. In standard colorectal surgery, usu-
ally a single dose or very short regiment
is advocated. Bacteriuria is a known risk
factor and, in conjunction with urological
procedures should therefore, reasonably,
be treated. Thus, individual adjustment
has to be suggested depending on patient
susceptibility, bacterial load and the
development of the procedure in terms
of spillage and duration. However this
approach is not totally satisfactory; it is
only indicative and usually no strong rec-
ommendations can be given in guidelines,
such as those of the European Association
of Urology, except in a few situations [79].
Therefore, there is an inevitable discre-
pancy between the level of evidence and
the grade of recommendation in Table 1.
The role of antibiotics is to reduce the
bacterial burden, not necessarily to cover
693
Chapter | 12 | Prevention of infections associated with urological surgery
all potential strains. Also, antibiotics for
prophylaxis should ideally be limited to a
few and usually different from those used
for therapeutics to avoid an overload of
drug doses and local environmental pres-
sure. Recommendations should be set in
cooperation with specialists in infectious
diseases and hospital environmental
hygiene.
6. FURTHER RESEARCH
This review underlines the absolute need
for serious, well-conducted studies and
large, multicentre quality registries per
type of procedure including breakdowns
in the level of severity of surgery and the
reporting of potential risk factors.
7. CONCLUSIONS
An extensive search of the literature and
systemic reviews has revealed a lack of
well-built data for antibiotic prophylaxis
in urological surgery. Strong recommen-
dations can only be given for transrectal
core biopsy of the prostate and transure-
thral resection of the prostate. As surgery
has markedly changed over the decades
and because older studies vary so much
in quality, it is mandatory to initiate new
large industry-independent, prospective,
randomized controlled studies and to set
up large prospective quality registries
and infectious control materials.
REFERENCES
1. Chodak GW and Plaut ME, Systemic anti-
biotics for prophylaxis in urologic surgery:
a critical review. J Urol, 1979. 121(6):
695–9.
2. Grabe M, Controversies in antibiotic
prophylaxis in urology. Int J Antimicrob
Agents, 2004. 23 Suppl 1: S17–23.
3. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline
for prevention of surgical site infection,
694
1999. Hospital Infection Control Practices
Advisory Committee. Infect Control Hosp
Epidemiol, 1999. 20(4): 250–78; quiz
279–80.
4. Bjerklund Johansen TE, Cek M, Naber K,
Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
5. Grabe M, Antimicrobial agents in
transurethral prostatic resection. J Urol,
1987. 138(2): 245–52.
6. Berry A and Barratt A, Prophylactic anti-
biotic use in transurethral prostatic resec-
tion: a meta-analysis. J Urol, 2002. 167
(2 Pt 1): 571–7.
7. Qiang W, Jianchen W, MacDonald R,
Monga M, and Wilt TJ, Antibiotic prophy-
laxis for transurethral prostatic resection
in men with preoperative urine contain-
ing less than 100,000 bacteria per ml: a
systematic review. J Urol, 2005. 173(4):
1175–81.
8. Latthe PM, Foon R, and Toozs-Hobson P,
Prophylactic antibiotics in urodynamics:
a systematic review of effectiveness and
safety. Neurourol Urodyn, 2008. 27(3):
167–73.
9. Bootsma AM, Laguna Pes MP, Geerlings
SE, and Goossens A, Antibiotic prophy-
laxis in urologic procedures: a systematic
review. Eur Urol, 2008. 54(6): 1270–86.
10. Wolf JS, Jr., Bennett CJ, Dmochowski
RR, Hollenbeck BK, Pearle MS, and
Schaeffer AJ, Best practice policy state-
ment on urologic surgery antimicro-
bial prophylaxis. J Urol, 2008. 179(4):
1379–90.
11. Department of Health and Human
Services, Public Health Service,. 1992,
Agency for Health Care Policy and
Research. p. 115–127.
12. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
13. Clark KR and Higgs MJ, Urinary infec-
tion following out-patient flexible cystos-
copy. Br J Urol, 1990. 66(5): 503–5.
14. Almallah YZ, Rennie CD, Stone J, and
Lancashire MJ, Urinary tract infection
 Antibiotic prophylaxis in urological surgery, a European viewpoint
and patient satisfaction after flexible
cystoscopy and urodynamic evaluation.
Urology, 2000. 56(1): 37–9.
15. Burke DM, Shackley DC, and O’Reilly PH,
The community-based morbidity of flexible
cystoscopy. BJU Int, 2002. 89(4): 347–9.
16. Johnson MI, Merrilees D, Robson WA,
Lennon T, Masters J, Orr KE, Matthews
JN, and Neal DE, Oral ciprofloxacin or
trimethoprim reduces bacteriuria after
flexible cystoscopy. BJU Int, 2007. 100(4):
826–9.
17. Jimenez Cruz JF, Sanz Chinesta S, Otero
G, Diaz Gonzalez R, Alvarez Ruiz F,
Flores N, Virseda J, Rioja LA, Zuluaga
A, Tallada M, and et al., [Antimicrobial
prophylaxis in urethrocystoscopy.
Comparative study]. Actas Urol Esp,
1993. 17(3): 172–5.
18. MacDermott JP, Ewing RE, Somerville JF,
and Gray BK, Cephradine prophylaxis in
transurethral procedures for carcinoma of
the bladder. Br J Urol, 1988. 62(2): 136–9.
19. Rane A, Cahill D, Saleemi A, Montgomery
B, and Palfrey E, The issue of prophylac-
tic antibiotics prior to flexible cystoscopy.
Eur Urol, 2001. 39(2): 212–4.
20. Manson AL, Is antibiotic administration
indicated after outpatient cystoscopy. J
Urol, 1988. 140(2): 316–7.
21. Karmouni T, Bensalah K, Alva A, Patard
JJ, Lobel B, and Guille F, [Role of anti-
biotic prophylaxis in ambulatory cystos-
copy]. Prog Urol, 2001. 11(6): 1239–41.
22. Tsugawa M, Monden K, Nasu Y, Kumon
H, and Ohmori H, Prospective rand-
omized comparative study of antibiotic
prophylaxis in urethrocystoscopy and
urethrocystography. Int J Urol, 1998. 5(5):
441–3.
23. Wilson L, Ryan J, Thelning C, Masters
J, and Tuckey J, Is antibiotic prophylaxis
required for flexible cystoscopy? A trun-
cated randomized double-blind controlled
trial. J Endourol, 2005. 19(8): 1006–8.
24. Cundiff GW, McLennan MT, and Bent AE,
Randomized trial of antibiotic prophy-
laxis for combined urodynamics and
cystourethroscopy. Obstet Gynecol, 1999.
93(5 Pt 1): 749–52.
25. Logadottir Y, Dahlstrand C, Fall M,
Knutson T, and Peeker R, Invasive uro-
dynamic studies are well tolerated by the
| 12.5 |
patients and associated with a low risk
of urinary tract infection. Scand J Urol
Nephrol, 2001. 35(6): 459–62.
26. Enlund AL and Varenhorst E, Morbidity
of ultrasound-guided transrectal core
biopsy of the prostate without prophylactic
antibiotic therapy. A prospective study in
415 cases. Br J Urol, 1997. 79(5): 777–80.
27. Larsson P, Norming U, Tornblom M, and
Gustafsson O, Antibiotic prophylaxis
for prostate biopsy: benefits and costs.
Prostate Cancer Prostatic Dis, 1999. 2(2):
88–90.
28. Puig J, Darnell A, Bermudez P, Malet
A, Serrate G, Bare M, and Prats J,
Transrectal ultrasound-guided prostate
biopsy: is antibiotic prophylaxis neces-
sary? Eur Radiol, 2006. 16(4): 939–43.
29. Kapoor DA, Klimberg IW, Malek GH,
Wegenke JD, Cox CE, Patterson AL,
Graham E, Echols RM, Whalen E, and
Kowalsky SF, Single-dose oral cipro-
floxacin versus placebo for prophylaxis
during transrectal prostate biopsy.
Urology, 1998. 52(4): 552–8.
30. Isen K, Kupeli B, Sinik Z, Sozen S, and
Bozkirli I, Antibiotic prophylaxis for tran-
srectal biopsy of the prostate: a prospective
randomized study of the prophylactic use
of single dose oral fluoroquinolone versus
trimethoprim-sulfamethoxazole. Int Urol
Nephrol, 1999. 31(4): 491–5.
31. Aron M, Rajeev TP, and Gupta NP,
Antibiotic prophylaxis for transrectal nee-
dle biopsy of the prostate: a randomized
controlled study. BJU Int, 2000. 85(6):
682–5.
32. Crawford ED, Haynes AL, Jr., Story MW,
and Borden TA, Prevention of urinary
tract infection and sepsis following tran-
srectal prostatic biopsy. J Urol, 1982.
127(3): 449–51.
33. Melekos MD, Efficacy of prophylactic
antimicrobial regimens in preventing
infectious complications after transrectal
biopsy of the prostate. Int Urol Nephrol,
1990. 22(3): 257–62.
34. Yamamoto S, Ishitoya S, Segawa T,
Kamoto T, Okumura K, and Ogawa O,
Antibiotic prophylaxis for transrectal
prostate biopsy: a prospective randomized
study of tosufloxacin versus levofloxacin.
Int J Urol, 2008. 15(7): 604–6.
695
Chapter | 12 | Prevention of infections associated with urological surgery
35. Sabbagh R, McCormack M, Peloquin
F, Faucher R, Perreault JP, Perrotte P,
Karakiewicz PI, and Saad F, A prospective
randomized trial of 1-day versus 3-day
antibiotic prophylaxis for transrectal
ultrasound guided prostate biopsy. Can J
Urol, 2004. 11(2): 2216–9.
36. Schaeffer AJ, Montorsi F, Scattoni V,
Perroncel R, Song J, Haverstock DC, and
Pertel PE, Comparison of a 3-day with a
1-day regimen of an extended-release for-
mulation of ciprofloxacin as antimicrobial
prophylaxis for patients undergoing tran-
srectal needle biopsy of the prostate. BJU
Int, 2007. 100(1): 51–7.
37. Lindstedt S, Lindstrom U, Ljunggren E,
Wullt B, and Grabe M, Single-dose anti-
biotic prophylaxis in core prostate biopsy:
Impact of timing and identification of risk
factors. Eur Urol, 2006. 50(4): 832–7.
38. Briffaux R, Merlet B, Normand G, Coloby
P, Leremboure H, Bruyere F, Pires C,
Ouaki F, Dore B, and Irani J, [Short or
long schemes of antibiotic prophylaxis for
prostate biopsy. A multicentre prospec-
tive randomised study]. Prog Urol, 2009.
19(1): 39–46.
39. Shandera KC, Thibault GP, and Deshon
GE, Jr., Efficacy of one dose fluoroqui-
nolone before prostate biopsy. Urology,
1998. 52(4): 641–3.
40. Griffith BC, Morey AF, Ali-Khan MM,
Canby-Hagino E, Foley JP, and Rozanski
TA, Single dose levofloxacin prophylaxis
for prostate biopsy in patients at low risk.
J Urol, 2002. 168(3): 1021–3.
41. Naber KG, Which fluoroquinolones are
suitable for the treatment of urinary tract
infections? Int J Antimicrob Agents, 2001.
17(4): 331–41.
42. Upton JD and Das S, Prophylactic antibi-
otics in transurethral resection of bladder
tumors: are they necessary? Urology, 1986.
27(5): 421–3.
43. Delavierre D, Huiban B, Fournier G,
Le Gall G, Tande D, and Mangin P,
[The value of antibiotic prophylaxis in
transurethral resection of bladder tumors.
Apropos of 61 cases]. Prog Urol, 1993.
3(4): 577–82.
44. Wagenlehner FM, Wagenlehner C,
Schinzel S, and Naber KG, Prospective,
randomized, multicentric, open,
696
comparative study on the efficacy of a
prophylactic single dose of 500 mg levo-
floxacin versus 1920 mg trimethoprim/
sulfamethoxazole versus a control group
in patients undergoing TUR of the pros-
tate. Eur Urol, 2005. 47(4): 549–56.
45. Grabe M, Risk Factors at TURP.
Discussion of RA Janknegt’s presentation.
Infection, 1992. 20(Suppl 3): S217–220.
46.Colau A, Lucet JC, Rufat P, Botto H,
Benoit G, and Jardin A, Incidence and
risk factors of bacteriuria after transure-
thral resection of the prostate. Eur Urol,
2001. 39(3): 272–6.
47. Charton M, Vallancien G, Veillon B,
Prapotnich D, Mombet A, and Brisset JM,
Use of antibiotics in the conjunction with
extracorporeal lithotripsy. Eur Urol, 1990.
17(2): 134–8.
48. Deliveliotis C, Giftopoulos A, Koutsokalis
G, Raptidis G, and Kostakopoulos A, The
necessity of prophylactic antibiotics dur-
ing extracorporeal shock wave lithotripsy.
Int Urol Nephrol, 1997. 29(5): 517–21.
49. Dincel C, Ozdiler E, Ozenci H, Tazici N,
and Kosar A, Incidence of urinary tract
infection in patients without bacteriuria
undergoing SWL: comparison of stone
types. J Endourol, 1998. 12(1): 1–3.
50. Claes H, Vandeursen R, and Baert
L, Amoxycillin/clavulanate prophy-
laxis for extracorporeal shock wave
lithotripsy--a comparative study. J
Antimicrob Chemother, 1989. 24
Suppl B: 217–20.
51. Gattegno B, Sicard F, Alcaidinho
D, Arnaud E, and Thibault P,
[Extracorporeal lithotripsy and prophylac-
tic antibiotic therapy]. Ann Urol (Paris),
1988. 22(2): 101–2.
52. Pettersson B and Tiselius HG, Are pro-
phylactic antibiotics necessary during
extracorporeal shockwave lithotripsy? Br
J Urol, 1989. 63(5): 449–52.
53. Knipper A, Bohle A, Pensel J, and
Hofstetter AG, [Antibiotic prophylaxis
with enoxacin in extracorporeal shock-
wave lithotripsy]. Infection, 1989. 17
Suppl 1: S37–8.
54. Bierkens AF, Hendrikx AJ, Ezz el Din KE,
de la Rosette JJ, Horrevorts A, Doesburg
W, and Debruyne FM, The value of anti-
biotic prophylaxis during extracorporeal
 Antibiotic prophylaxis in urological surgery, a European viewpoint
shock wave lithotripsy in the prevention
of urinary tract infections in patients with
urine proven sterile prior to treatment.
Eur Urol, 1997. 31(1): 30–5.
55. Pearle MS and Roehrborn CG,
Antimicrobial prophylaxis prior to shock
wave lithotripsy in patients with sterile
urine before treatment: a meta-analysis
and cost-effectiveness analysis. Urology,
1997. 49(5): 679–86.
56. Fourcade RO, Antibiotic prophylaxis with
cefotaxime in endoscopic extraction of
upper urinary tract stones: a randomized
study. The Cefotaxime Cooperative Group.
J Antimicrob Chemother, 1990. 26 Suppl
A: 77–83.
57. Knopf HJ, Graff HJ, and Schulze H,
Perioperative antibiotic prophylaxis in
ureteroscopic stone removal. Eur Urol,
2003. 44(1): 115–8.
58. Hendrikx AJ, Strijbos WE, de Knijff DW,
Kums JJ, Doesburg WH, and Lemmens
WA, Treatment for extended-mid and dis-
tal ureteral stones: SWL or ureteroscopy?
Results of a multicenter study.
J Endourol, 1999. 13(10): 727–33.
59. Rao PN, Dube DA, Weightman NC,
Oppenheim BA, and Morris J, Prediction
of septicemia following endourological
manipulation for stones in the upper uri-
nary tract. J Urol, 1991. 146(4): 955–60.
60. Charton M, Vallancien G, Veillon B, and
Brisset JM, Urinary tract infection in per-
cutaneous surgery for renal calculi.
J Urol, 1986. 135(1): 15–7.
61. Osman M, Wendt-Nordahl G, Heger
K, Michel MS, Alken P, and Knoll T,
Percutaneous nephrolithotomy with
ultrasonography-guided renal access:
experience from over 300 cases. BJU Int,
2005. 96(6): 875–8.
62. Dogan HS, Sahin A, Cetinkaya Y,
Akdogan B, Ozden E, and Kendi S,
Antibiotic prophylaxis in percutaneous
nephrolithotomy: prospective study in 81
patients. J Endourol, 2002. 16(9): 649–53.
63. Mariappan P, Smith G, Bariol SV, Moussa
SA, and Tolley DA, Stone and pelvic urine
culture and sensitivity are better than
bladder urine as predictors of urosepsis
following percutaneous nephrolithotomy:
a prospective clinical study. J Urol, 2005.
173(5): 1610–4.
| 12.5 |
64. Lunevicius R and Morkevicius M,
Systematic review comparing laparoscopic
and open repair for perforated peptic
ulcer. Br J Surg, 2005. 92(10): 1195–207.
65. Steiner T, Traue C, and Schubert J,
[Perioperative antibiotic prophylaxis in
transperitoneal tumor nephrectomy: does
it lower the rate of clinically significant
postoperative infections?]. Urologe A,
2003. 42(1): 34–7.
66. Montgomery JS, Johnston WK, 3rd, and
Wolf JS, Jr., Wound complications after
hand assisted laparoscopic surgery.
J Urol, 2005. 174(6): 2226–30.
67. Pessaux P, Atallah D, Lermite E, Msika
S, Hay JM, Flamant Y, and Arnaud JP,
Risk factors for prediction of surgical site
infections in “clean surgery”. Am J Infect
Control, 2005. 33(5): 292–8.
68. Kiddoo DA, Wollin TA, and Mador DR, A
population based assessment of complica-
tions following outpatient hydrocelectomy
and spermatocelectomy. J Urol, 2004.
171(2 Pt 1): 746–8.
69. Swartz MA, Morgan TM, and Krieger
JN, Complications of scrotal surgery for
benign conditions. Urology, 2007. 69(4):
616–9.
70. Stranne J, Aus G, Hansson C, Lodding
P, Pileblad E, and Hugosson J, Single-
dose orally administered quinolone
appears to be sufficient antibiotic proph-
ylaxis for radical retropubic prostatec-
tomy. Scand J Urol Nephrol, 2004. 38(2):
143–7.
71. Terai A, Ichioka K, Kohei N, Ueda N,
Utsunomiya N, and Inoue K, Antibiotic
prophylaxis in radical prostatectomy:
1-day versus 4-day treatments. Int J Urol,
2006. 13(12): 1488–93.
72. Takeyama K, Takahashi S, Maeda T,
Mutoh M, Kunishima Y, Matsukawa M,
and Takagi Y, Comparison of 1-day, 2-day,
and 3-day administration of antimicro-
bial prophylaxis in radical prostatectomy.
J Infect Chemother, 2007. 13(5): 320–3.
73. Sakura M, Kawakami S, Yoshida S,
Masuda H, Kobayashi T, and Kihara K,
Prospective comparative study of single
dose versus 3-day administration of anti-
microbial prophylaxis in minimum inci-
sion endoscopic radical prostatectomy. Int
J Urol, 2008. 15(4): 328–31.
697
Chapter | 12 | Prevention of infections associated with urological surgery
74. Takeyama K, Matsukawa M, Kunishima
Y, Takahashi S, Hotta H, Nishiyama
N, and Tsukamoto T, Incidence of and
risk factors for surgical site infection in
patients with radical cystectomy with uri-
nary diversion. J Infect Chemother, 2005.
11(4): 177–81.
75. Hara N, Kitamura Y, Saito T,
Komatsubara S, Nishiyama T, and
Takahashi K, Perioperative antibiotics
in radical cystectomy with ileal conduit
urinary diversion: efficacy and risk of
antimicrobial prophylaxis on the opera-
tion day alone. Int J Urol, 2008. 15(6):
511–5.
698
76. Studer UE, Danuser H, Merz VW,
Springer JP, and Zingg EJ, Experience in
100 patients with an ileal low pressure
bladder substitute combined with
an afferent tubular isoperistaltic segment.
J Urol, 1995. 154(1): 49–56.
77. Mould JW and Carson CC, Infectious
complications of penile prostheses.
Infections in Urology, 1989. 139: 50–52.
78. Carson CC, Diagnosis, treatment and pre-
vention of penile prosthesis infection. Int J
Impot Res, 2003. 15 Suppl 5: S139–46.
79. Grabe M, C BM, Bkerklund-Johansen, H B,
and et al, Guidelines on Urological Infections.
2009: European Association of Urology.
|12.6|

Antibiotic prophylaxis in
urological surgery: a USA
viewpoint of best practice
Anthony J. Schaeffer, J. Stuart Wolf Jr, Carol J. Bennett, Roger R. Dmochowski,
Brent K. Hollenbeck, Margaret S. Pearle
Corresponding author: Anthony J. Schaeffer, MD, Professor of Urology, Chairman, Department of Urology, Feinberg
School of Medicine, Northwestern University, 303 E. Chicago Ave., Tarry Bldg. 16-703, Chicago, Illinois 60611-3008
Tel 001 (312) 908-8145, Fax 001 (312) 908-7275, ajschaeffer@northwestern.edu

ABSTRACT SUMMARY OF RECOMMENDATIONS

Because SSIs and UTIs cause major post-
operative morbidity, antimicrobial proph-
ylaxis should be employed in conjunction
with other techniques to reduce postoper-
ative infections. The decision to use anti-
microbial prophylaxis in surgery and the
selection of the agent and dosing can be
based in part by the guidelines suggested
herein. However, it is up to the individ-
ual care giver to make decisions requir-
ing prophylaxis in individual patients
because of the wide variation in patients
and environmental circumstances in the
perioperative setting.
The recommendations given later in the
text are themselves a summary of the
recommendations reported in the origi-
nal article (1). Therefore, the reader is
directed to the main text “Best Practice
Policy Statement on Urologic Surgery
Antimicrobial Prophylaxis”.
1. INTRODUCTION
This chapter is abstracted from the “Best
Practice Policy Statement on Urologic
Surgery Antimicrobial Prophylaxis” which
Chapter | 12 | Prevention of infections associated with urological surgery
was chaired by J. Stuart Wolf, Jr. Other
members of the Best Practice Policy
panel included Carol J. Bennett, Roger R.
Dmochowski, Brent K. Hollenbeck,
Margaret S. Pearle and Anthony J.
Schaeffer [1]. This panel was convened
because surgical site infections and post-
operative urinary tract infections are
common problems affecting patients’
safety, cost of hospitalization, and
readmission rates [2–4]. In addition, the
panel was convened because of the wide
variation in periprocedural antimicro-
bial prophylaxis, procedure utilization,
timing of antimicrobials and duration of
prophylaxis [5]. Portions of this text were
taken directly from the “Best Practice
Policy Statement on Urologic Surgery
Antimicrobial Prophylaxis” by Wolf et al.,
originally appearing in The Journal of
Urology [1]. These sections, denoted with
a *, are referenced accordingly and repre-
sent best practice policy.
2. METHODS
Because initial assessment of the litera-
ture revealed there was insufficient infor-
mation available to draw up a guidelines
statement for antimicrobial prophylaxis
during urologic surgery based solely on
literature meta-analysis, the panel was
charged with developing a Best Practice
Policy Statement using published data
and expert opinions, but without employ-
ing formal meta-analysis of the literature.
The panel formulated recommendations
based on a review of all material revealed
in a Medline search and the panel mem-
bers’ expert opinions. The studies were
rated according to the level of evidence
(LoE) and the grade of recommenda-
tion (GoR) using ICUD standards (for
details see Preface) [6–7]. The document
was submitted for peer review and com-
ments from all 20 responding physicians
and researchers were considered in mak-
ing revisions. The final document was
submitted to the American Urological
700
Association (AUA) Practice Guidelines
Committee and Board of Directors for
approval. Funding of the panel was pro-
vided by the AUA. The members received
no compensation for their work and each
panel member provided a conflict of inter-
est disclosure to the AUA.
3. RESULTS OF REVIEW AND BEST
PRACTICE, THE U.S.A VIEWPOINT
3.1 Principles of surgical
antimicrobial prophylaxis
Five principles were delineated:
1. Antimicrobial prophylaxis is only
one of many factors associated with
the reduction in surgical site infec-
tions (SSI). Surgical antimicrobial
prophylaxis is defined as the peripro-
cedural systemic administration of
an antimicrobial agent in order to
reduce the risk of post-procedural
local and systemic infections. Other
commonly employed techniques
include bowel preparation, preopera-
tive hair removal, antiseptic bathing,
hand washing, double gloving, and
sterile preparation of the operative
field. These practices have varying
degrees of scientific support in the
surgical literature. For example, the
value of mechanical bowel prepara-
tion and removal of hair in prepara-
tion for surgery have recently been
called into question. Surgical hand
scrubbing or hand rubbing appeared
to have similar benefits in reducing
SSIs [8]. Many substances are effec-
tive for sterile preparation of the
operative site such as the formula-
tion of povidone-iodine and alcohol
which delivers effective antimicrobial
activity with only a 30-second appli-
cation [9].
2. The potential benefit of surgical anti-
microbial prophylaxis is determined
by three factors: A) patient-related
factors, i.e. the ability of the host to
 Antibiotic prophylaxis in urological surgery | 12.6 |

respond to bacterial invasion; B) pro- benefit of prophylaxis is directly

cedural factors, i.e. likelihood of bac- related to the severity of the patient’s
terial invasion at the operative site; underlying condition. For exam-
and C) the potential morbidity of the ple, a minor infection of the bladder
infection. Patient-related factors affect can cause severe complications in a
the host response and are listed in patient who is severely debilitated.
Table 1 [10]. (N.B. For more detailed 3. Surgical antimicrobial prophylaxis
discussion see also section 11.4. of this should be utilized only when the
chapter.) potential benefit exceeds the risks and
The likelihood of bacterial invasion anticipated costs. Though it is evident
is affected by the amount of bacteria that prevention of SSIs by appropriate
at the site of the surgical procedure antimicrobial prophylaxis will reduce
as classified in Table 2 [11]. (See also length of stay and hospital costs, inap-
section 11.4, Table 4 in this chapter.) propriate antimicrobial prophylaxis
Note that all procedures entering the will increase costs without benefit and
urinary tract are considered “clean- can lead to other complications such
contaminated”. Lastly, the potential as allergic reactions and development
of resistant bacteria. Hence, guide-
lines should stipulate the indication,
timing, duration and selection of anti-
Table 1 Patient-related factors affecting host response to
surgical infections.*† microbial therapies that are critical
for achieving optimal results.
Advanced age
4. The antimicrobial agent used for
Anatomic anomalies of the urinary tract prophylaxis should be effective against
Poor nutritional status the putative disease-relevant bacterial
Smoking flora at the operative site. Cost, ease
Chronic corticosteroid use
of administration and safety are also
important considerations. In order for
Immunodeficiency
effective antimicrobial prophylaxis,
Externalized catheters the appropriate agent must be present
Colonized endogenous/exogenous material in the serum and tissue levels at the
Distant coexistent infection surgical site in advance of the opera-
Prolonged hospitalization
tive procedure. Ideal agents will have
long enough half-lives to be present
*Modified from reference 8.
for the entire procedure. If necessary,
†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ,
Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best re-dosing for long procedures may
Practice Policy Statement on Urologic Surgery Antimicrobial be necessary. A variety of classes of
Prophylaxis, 1379–1390, ©2008, with permission from Elsevier.
agents including some beta lactams

Table 2 Surgical wound classification.*†

*modified from reference [11].

†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best Practice Policy
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier.

701
Chapter | 12 | Prevention of infections associated with urological surgery
and fluoroquinolones have been effec-
tive, but it is important to realize that
changing resistance patterns will have
dramatic impact on antimicrobial
prophylaxis efficacy.
5. The surgical antimicrobial prophylaxis
should precede the procedure and
extend throughout the period in which
bacterial invasion is facilitated and/
or is likely to establish an infection.
Infusion of the first dose should begin
within 60 minutes of the surgical pro-
cedure (with the exception of 120 min-
utes for intravenous fluoroquinolones
and vancomycin) [1]. The dose should
be adjusted to the patient’s body weight
or body mass index. Additional doses
are required intraoperatively if the pro-
cedure extends beyond two half-lives
of the initial dose [2]. In most cases,
antimicrobial prophylaxis should be
a single dose or at least discontinued
within 24 hours of the end of the proce-
dure. Exceptions to these guidelines in
which a longer duration of antimicrobi-
als are considered include placement of
a prosthetic material, the presence of
an existing infection, and the manipu-
lation of an indwelling tube.
There is little guidance in the duration
of antimicrobial prophylaxis after pros-
thesis, such as a penile implant, but data
from joint replacement literature indicate
that prophylaxis should be discontinued
within 24 hours of the procedure [2]. If
an existing infection is present, a thera-
peutic dose of antimicrobials should be
administered prior to the procedure. If
emergency procedures prevent steriliza-
tion of the surgical site prior to operation,
it would be reasonable to use therapeu-
tic rather than prophylactic dosing for
a period extending beyond the routine
24 hours after the procedure. The use of
antimicrobials in patients with indwell-
ing catheters does temporarily prevent
bacterial growth, but inevitably bac-
teriuria develops and the bacteria will
702
be resistant to the prophylactic agent.
Therefore, in most patients with indwell-
ing catheters, antimicrobial prophylaxis
should not extend beyond 24 hours.
3.2 Recommended antimicrobial
prophylaxis for urologic
procedures*
The Panels’ recommendations are pro-
vided in Tables 3 and 4 [12] of this
section, and levels of evidence with jus-
tifications are provided in the text below.
Recommended Antimicrobial Prophylaxis
for Urologic Procedures, Table 3a, lists
those procedures for which antimicrobial
prophylaxis is recommended, as well as
the agent(s) of choice, alternative agents,
and duration of therapy. Important con-
siderations are the limitation of prophy-
laxis to patients with risk factors in
some cases and the recommendation that
prophylaxis should not exceed 24 hours.
In cases where an external urinary cath-
eter is present prior to or is placed at the
time of the procedure, additional anti-
microbial treatment (≤24 hours) is rec-
ommended in patients with risk factors.
Alternatively, a full course of culture-
directed antimicrobial can be admin-
istered for documented bacteriuria, or
treatment can be omitted if the urine
culture shows no growth. Antimicrobials
and Dosages, Table 3b, lists the recom-
mended doses and dosing intervals for
the agents listed in Table 3a. For some
procedures, dosing may need to be more
frequent than the intervals listed in
Table 3b. Table 4 provides recommenda-
tions for Antimicrobial Prophylaxis for
Patients with Orthopedic Considerations
[12]. In all cases, the absence of an
agent in the Tables does not preclude its
appropriate use, depending on specific
situations – including medication intoler-
ance, agent compatibility, prior infection
history of the patient and community
resistance patterns. The Panel’s recom-
mendations are generally similar, but
 Antibiotic prophylaxis in urological surgery | 12.6 |

Table 3a Recommended antimicrobial prophylaxis for urologic procedures.†

†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best Practice Policy
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier [1].

differ in varying specific situations, to 4. BEST PRACTICE

guidelines from other groups and recog-
nized references [1, 13–18]. 4.1 Removal of external urinary
catheter (prophylaxis indicated
3.3 Prevention of infectious if risk factors)
endocarditis
The Panel concluded that the benefit of
It is important to note that the American antimicrobial prophylaxis at removal of an
Heart Association (AHA) no longer rec- external urinary catheter most likely is lim-
ommends antimicrobials in association ited to patients with risk factors (Table 1).
with genital urinary procedures solely to Alternatively, a full course of culture-
prevent infectious endocarditis [19]. directed antimicrobial therapy can be

703
Chapter | 12 | Prevention of infections associated with urological surgery

Table 3b Antimicrobial agents and doses for periprocedure use.†

†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best Practice Policy
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier [1].

Table 4 Antimicrobial prophylaxis for patients with orthopedic conditions.*†

*Modified from reference [12].

†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best Practice Policy
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier.

704
 Antibiotic prophylaxis in urological surgery
administered for documented bacteriuria,
or treatment can be omitted if the urine
culture shows no growth (LoE 1b, 3, 4).
4.2 Cystography, urodynamic study,
or simple cystourethroscopy
(prophylaxis indicated if risk
factors)
Antimicrobial prophylaxis is probably not
necessary if the urine culture shows no
growth. However, culture documentation
is often lacking and a negative urinalysis,
although reassuring, does not eliminate
the possibility of post-procedure urinary
tract infection (UTI). A decision-analysis
model based upon estimates from the
literature and consensus suggested that
prophylactic antimicrobials after urody-
namic studies are beneficial once the rate
of UTI without antimicrobials exceeds
10% [20]. In addition, a randomized con-
trolled trial (RCT) involving a single oral
dose of ciprofloxacin versus placebo in
patients who had negative urine cultures
before urodynamic studies found that
post-procedure UTIs decreased signifi-
cantly, from 14% to 1%, with prophylaxis
[21]. However, other RCTs demonstrated
no reduction by prophylaxis of infection
rates associated with urodynamic study
[22–23] as well as cystography [24] or
cystourethroscopy [25] (LoE 1b, 3, 4).
4.3 Cystourethroscopy with
manipulation (prophylaxis
indicated in all patients)
The most convincing evidence support-
ing the use of antimicrobial prophylaxis
for this category of procedures is in asso-
ciation with transurethral resection of the
prostate. Berry and Barratt [26] performed
a meta-analysis of 32 RCTs comprising
4,260 patients, and confirmed that anti-
microbial prophylaxis prior to transure-
thral resection of the prostate significantly
reduced the incidence of both bacteriuria
(26% to 9.1%) and clinical sepsis (4.4% to
| 12.6 |
0.7%). Clinical efficacy was proven for a
number of antimicrobial classes, includ-
ing fluoroquinolones, cephalosporins,
aminoglycosides, and trimethoprim-sul-
famethoxazole. A subsequent meta-analy-
sis using updated methodology came to the
same conclusion [27]. Similar results have
been shown with prophylaxis in patients
undergoing transurethral resection of
bladder tumor [28]. Although RCTs have
not been performed for other cystoscopic
procedures involving transurethral manip-
ulation, the Panel felt that data regarding
transurethral resection of the prostate and
bladder tumor can be reasonably extrapo-
lated to other cystoscopic procedures with
manipulation including bladder biopsy,
urethral catheterization, laser prostatec-
tomy, etc (LoE 1a, 1b, 4).
4.4 Prostate brachytherapy or
cryotherapy
There are no RCTs regarding the use of
antimicrobial prophylaxis for these proce-
dures. However, the destructive nature of
the treatments, coupled with entry near
a clean-contaminated space, makes the
use of antimicrobial prophylaxis by many
practitioners a reasonable consideration.
4.5 Transrectal prostate biopsy
A number of large RCTs have concluded
that a single dose of an antimicrobial,
such as a fluoroquinolone, is as effective
as 3-day therapy in reducing the incidence
of all types of complications, specifically
UTI. However, recent development of anti-
microbial resistance has led to significant
infectious sequelae in patients taking a
fluoroquinolone and antimicrobial prophy-
laxis; therefore, the urologic community
needs to be vigilant for post-infectious com-
plications after transrectal prostate biopsy.
4.6 Shock-wave lithotripsy*
A meta-analysis of eight RCTs assessing
the efficacy of antimicrobial prophylaxis
705
Chapter | 12 | Prevention of infections associated with urological surgery
for shock-wave lithotripsy demonstrated
a benefit of therapy in significantly
reducing the incidence of postopera-
tive bacteriuria from a median of 5.7%
to 2.1%, even with preoperative urine
showing no growth. Subgroup analysis
to assess the effectiveness of a particular
regimen could not be performed due to
the wide variability in practice patterns
[1, 29].
4.7 Percutaneous renal surgery
There are no RCTs that confirm the need
for antimicrobial prophylaxis for percu-
taneous renal surgery. However, non-
controlled studies suggest efficacy of
antimicrobial prophylaxis [30–31].
Single dose prophylaxis appears to be
as effective as multiple doses.
4.8 Ureteroscopy*
In a RCT involving 113 patients undergo-
ing ureteroscopy for stone removal rand-
omized to a single oral dose of levofloxacin
versus no antimicrobials, the treatment
arm had a significantly lower incidence
of postoperative bacteriuria (13% versus
2%) [32]. Another author suggests that
the expected rate of bacteriuria after ure-
teroscopy without prophylaxis might be
in excess of 30%, with an expected rate
of febrile urinary tract infection of 4% to
25% [1, 16].
4.9 Vaginal surgery
Randomized controlled trials involving
antimicrobial prophylaxis for vaginal
urologic surgery have not been reported,
but considerable evidence exists regard-
ing vaginal hysterectomy, which can be
considered similar to vaginal urologic
surgery in terms of infection risk† [1].
But considerable evidence exists regard-
ing vaginal hysterectomy wherein stud-
ies demonstrated dramatic decrease in
the incidence of pelvic infections when
antimicrobial prophylaxis was used [33].
A course of antimicrobials less than
706
24 hours was as effective as a long course
in preventing post-operative infections [34].
4.10 Open or laparoscopic surgery
without entering the urinary
tract
In a prospective but non-randomized com-
parison of hand-assisted laparoscopic
nephrectomies with and without antimi-
crobial prophylaxis (cephalosporin), wound
infections occurred significantly more
often in patients without prophylaxis (13%
versus 5.4%) [35]. However, meta-analysis
evaluating antimicrobial prophylaxis for
non-urologic “clean” abdominal surgery
provided mixed support for antimicrobial
prophylaxis in this setting [36–39].
4.11 Open or laparoscopic surgery
involving entry into urinary
tract
Limited data suggest that antimicrobial
prophylaxis would reduce significantly
the rate of febrile urinary tract infection.
Regarding duration of prophylaxis, one
RCT confirmed that one day of intrave-
nous cephalosporin was equivalent to
four days of the same agent after radical
prostatectomy [40].
4.12 Open or laparoscopic surgery
involving intestine†
Although RCTs involving urologic sur-
gery involving bowel (primarily urinary
diversion, with or without cystectomy)
have not been reported, meta-analyses
of percutaneous endoscopic gastrostomy
[41], appendectomy [42], and colorectal
surgery [43] confirm benefit to antimicro-
bial prophylaxis in the setting of surgery
involving intestinal components [1].
4.13 Open or laparoscopic
surgery involving implanted
prosthesis*
The implantation of foreign material
raises the specter of disastrous infectious
 Antibiotic prophylaxis in urological surgery
complications. Although there are no
RCTs regarding antimicrobial prophy-
laxis for insertion of penile prostheses,
meta-analyses of mesh hernia repair
[44] and orthopedic surgery [45] confirm
that antimicrobial prophylaxis is benefi-
cial when foreign material is implanted.
A prolonged course of antimicrobials has
been used by many practitioners fol-
lowing penile prosthesis insertion, but
evidence from the orthopedic literature
suggests that prophylaxis for 24 hours or
less is adequate [1–2].
REFERENCES
1. Wolf JS, Jr., Bennett CJ, Dmochowski RR,
Hollenbeck BK, Pearle MS, and Schaeffer
AJ, Best practice policy statement on uro-
logic surgery antimicrobial prophylaxis.
J Urol, 2008. 179(4): 1379–90.
2. Bratzler DW and Houck PM,
Antimicrobial prophylaxis for surgery:
an advisory statement from the National
Surgical Infection Prevention Project. Am
J Surg, 2005. 189(4): 395–404.
3. National Nosocomial Infections
Surveillance (NNIS) report, data
summary from October 1986-April
1996, issued May 1996. A report from
the National Nosocomial Infections
Surveillance (NNIS) System. Am J Infect
Control, 1996. 24(5): 380–8.
4. Kirkland KB, Briggs JP, Trivette SL,
Wilkinson WE, and Sexton DJ, The
impact of surgical-site infections in the
1990s: attributable mortality, excess
length of hospitalization, and extra costs.
Infect Control Hosp Epidemiol, 1999.
20(11): 725–30.
5. Bratzler DW, Houck PM, Richards C,
Steele L, Dellinger EP, Fry DE, Wright
C, Ma A, Carr K, and Red L, Use of
antimicrobial prophylaxis for major sur-
gery: baseline results from the National
Surgical Infection Prevention Project.
Arch Surg, 2005. 140(2): 174–82.
6. Department of Health and Human
Services, Public Health Service, 1992,
Agency for Health Care Policy and
Research. p. 115–127.
| 12.6 |
7. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. Parienti JJ, Thibon P, Heller R, Le Roux
Y, von Theobald P, Bensadoun H, Bouvet
A, Lemarchand F, and Le Coutour X,
Hand-rubbing with an aqueous alcoholic
solution vs traditional surgical hand-
scrubbing and 30-day surgical site infec-
tion rates: a randomized equivalence
study. JAMA, 2002. 288(6): 722–7.
9. Jeng DK and Severin JE, Povidone iodine
gel alcohol: a 30-second, onetime applica-
tion preoperative skin preparation. Am J
Infect Control, 1998. 26(5): 488–94.
10. Schaeffer A and Schaeffer E, Infections
of the urinary tract, in Campbell-Walsh
urology, Wein AJ, Kavoussi L, Novick
A, and Partin C, Editors. 2007, Elsevier
Saunders: Philadelphia, Pa. ; Edinburgh.
p. xxviii, 528 p.
11. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline
for prevention of surgical site infection,
1999. Hospital Infection Control Practices
Advisory Committee. Infect Control Hosp
Epidemiol, 1999. 20(4): 250–78; quiz
279–80.
12. Antibiotic prophylaxis for urological
patients with total joint replacements.
J Urol, 2003. 169(5): 1796–7.
13. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H, Lobel
B, Jinenez Cruz F, and Selvaggi FP,
EAU guidelines for the management of
urinary and male genital tract infec-
tions. Urinary Tract Infection (UTI)
Working Group of the Health Care Office
(HCO) of the European Association of
Urology (EAU). Eur Urol, 2001. 40(5):
576–88.
14. Botto H, Naber K, Bishop M, Jarlier V,
Lim V, and Norby R, Antimicrobial policy
in prophylaxis and treatment of nosocomial
urinary tract infections, in Nosocomial
and health care associated infections in
urology, Naber KG, Editor. 2001, Health
Publication Ltd: Plymouth. p. 207 p.
15. Grabe M, Perioperative antibiotic prophy-
laxis in urology. Curr Opin Urol, 2001.
11(1): 81–5.
707
Chapter | 12 | Prevention of infections associated with urological surgery
16. Grabe M, Controversies in antibiotic
prophylaxis in urology. Int J Antimicrob
Agents, 2004. 23 Suppl 1: S17–23.
17. Antimicrobial prophylaxis for surgery.
Treat Guidel Med Lett, 2006. 4(52): 83–8.
18. Gilbert DN, The Sanford guide to anti-
microbial therapy. 37th ed. ed. 2007,
Sperryville: Antimicrobial Therapy Inc.
19. Wilson W, Taubert K, Gewitz M, Lockhart
P, Baddour L, and Levison M, Prevention
of infective endocarditis. Guidelines from
the AHA. A Guideline From the AHA
Rheumatic Fever, Endocarditis, and
Kawasaki Disease Committee Council on
Cardiovascular Surgery and Anesthesia,
and the Quality of Care and Outcomes
Research Interdisciplinary Working
Group.
20. Lowder JL, Burrows LJ, Howden NL,
and Weber AM, Prophylactic antibiotics
after urodynamics in women: a decision
analysis. Int Urogynecol J Pelvic Floor
Dysfunct, 2007. 18(2): 159–64.
21. Kartal ED, Yenilmez A, Kiremitci A, Meric
H, Kale M, and Usluer G, Effectiveness
of ciprofloxacin prophylaxis in preventing
bacteriuria caused by urodynamic study:
a blind, randomized study of 192 patients.
Urology, 2006. 67(6): 1149–53.
22. Cundiff GW, McLennan MT, and Bent AE,
Randomized trial of antibiotic prophy-
laxis for combined urodynamics and
cystourethroscopy. Obstet Gynecol, 1999.
93(5 Pt 1): 749–52.
23. Peschers UM, Kempf V, Jundt K,
Autenrieth I, and Dimpfl T, Antibiotic
treatment to prevent urinary tract infec-
tions after urodynamic evaluation. Int
Urogynecol J Pelvic Floor Dysfunct, 2001.
12(4): 254–7.
24. Tsugawa M, Monden K, Nasu Y, Kumon
H, and Ohmori H, Prospective randomized
comparative study of antibiotic prophy-
laxis in urethrocystoscopy and urethro-
cystography. Int J Urol, 1998. 5(5): 441–3.
25. Wilson L, Ryan J, Thelning C, Masters
J, and Tuckey J, Is antibiotic prophylaxis
required for flexible cystoscopy? A trun-
cated randomized double-blind controlled
trial. J Endourol, 2005. 19(8): 1006–8.
26. Berry A and Barratt A, Prophylactic
antibiotic use in transurethral prostatic
708
resection: a meta-analysis. J Urol, 2002.
167(2 Pt 1): 571–7.
27. Qiang W, Jianchen W, MacDonald R,
Monga M, and Wilt TJ, Antibiotic prophy-
laxis for transurethral prostatic resection in
men with preoperative urine containing less
than 100,000 bacteria per ml: a systematic
review. J Urol, 2005. 173(4): 1175–81.
28. MacDermott JP, Ewing RE, Somerville JF,
and Gray BK, Cephradine prophylaxis in
transurethral procedures for carcinoma of
the bladder. Br J Urol, 1988. 62(2): 136–9.
29. Pearle MS and Roehrborn CG,
Antimicrobial prophylaxis prior to shock
wave lithotripsy in patients with sterile
urine before treatment: a meta-analysis
and cost-effectiveness analysis. Urology,
1997. 49(5): 679–86.
30. Charton M, Vallancien G, Veillon B, and
Brisset JM, Urinary tract infection in
percutaneous surgery for renal calculi. J
Urol, 1986. 135(1): 15–7.
31. Darenkov AF, Derevianko, II, Martov
AG, Kotliarova GA, Kondrat’eva EM, and
Siniukhin VN, [The prevention of infec-
tious-inflammatory complications in the
postoperative period in percutaneous surgi-
cal interventions in patients with urolithi-
asis]. Urol Nefrol (Mosk), 1994(2): 24–6.
32. Knopf HJ, Graff HJ, and Schulze H,
Perioperative antibiotic prophylaxis in
ureteroscopic stone removal. Eur Urol,
2003. 44(1): 115–8.
33. Duff P and Park RC, Antibiotic prophylaxis
in vaginal hysterectomy: a review. Obstet
Gynecol, 1980. 55(5 Suppl): 193S-202S.
34. Chang WC, Hung YC, Li TC, Yang TC,
Chen HY, and Lin CC, Short course of
prophylactic antibiotics in laparoscopi-
cally assisted vaginal hysterectomy. J
Reprod Med, 2005. 50(7): 524–8.
35. Montgomery JS, Johnston WK, 3rd, and
Wolf JS, Jr., Wound complications after
hand assisted laparoscopic surgery. J
Urol, 2005. 174(6): 2226–30.
36. Costa RJ and Krauss-Silva L, [Systematic
review and meta-analysis of antibiotic
prophylaxis in abdominal hysterectomy].
Cad Saude Publica, 2004. 20 Suppl 2:
S175–89.
37. Catarci M, Mancini S, Gentileschi P,
Camplone C, Sileri P, and Grassi GB,
 Antibiotic prophylaxis in urological surgery
Antibiotic prophylaxis in elective laparo-
scopic cholecystectomy. Lack of need or
lack of evidence? Surg Endosc, 2004.
18(4): 638–41.
38. Martins AC and Krauss-Silva L,
[Systematic reviews of antibiotic prophy-
laxis in cesareans]. Cad Saude Publica,
2006. 22(12): 2513–26.
39. Tejirian T, DiFronzo LA, and Haigh PI,
Antibiotic prophylaxis for preventing
wound infection after breast surgery: a
systematic review and metaanalysis. J Am
Coll Surg, 2006. 203(5): 729–34.
40. Terai A, Ichioka K, Kohei N, Ueda N,
Utsunomiya N, and Inoue K, Antibiotic
prophylaxis in radical prostatectomy:
1-day versus 4-day treatments. Int J Urol,
2006. 13(12): 1488–93.
41. Lipp A and Lusardi G, Systemic antimi-
crobial prophylaxis for percutaneous
| 12.6 |
endoscopic gastrostomy. Cochrane
Database Syst Rev, 2006(4): CD005571.
42. Andersen BR, Kallehave FL, and
Andersen HK, Antibiotics versus placebo
for prevention of postoperative infection
after appendicectomy. Cochrane Database
Syst Rev, 2005(3): CD001439.
43. Song F and Glenny AM, Antimicrobial
prophylaxis in colorectal surgery: a
systematic review of randomized control-
led trials. Br J Surg, 1998. 85(9): 1232–41.
44. Sanabria A, Dominguez LC, Valdivieso
E, and Gomez G, Prophylactic antibiotics
for mesh inguinal hernioplasty: a meta-
analysis. Ann Surg, 2007. 245(3): 392–6.
45. Southwell-Keely JP, Russo RR, March L,
Cumming R, Cameron I, and Brnabic AJ,
Antibiotic prophylaxis in hip fracture sur-
gery: a metaanalysis. Clin Orthop Relat
Res, 2004(419): 179–84.
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 Chapter |13|

Epididymitis, orchitis,
prostatitis (male adnexitis)
Chair: Wolfgang Weidner

CHAPTER OUTLINE
13.1 Introduction 712
13.2 Acute bacterial prostatitis 714
13.3 Treatment of chronic bacterial prostatitis 728
13.4 Epididymitis and orchitis 744
13.5 Chronic urogenital infections: alterations of
sperm quality and potential impact on male fertility 752
|13.1|
Introduction
Wolfgang Weidner
Corresponding Author: Wolfgang Weidner, MD, PhD, Professor of Urology and Head of Department of Urology, Pediatric
Urology and Andrology, Justus Liebig-University Giessen, Rudolf-Buchheim-Strasse 7, D-35392 Giessen, Germany
Tel. +49-641-99 44 501, Fax +49-641-99 44 509, Email: Wolfgang.Weidner@chiru.med.uni-giessen.de
Urogenital infections and inflammations
are common. Prevalence rates up to 15%
have been reported among men with andro-
logical problems [1]. In a urological setting,
UTIs and urogenital infections account for
8–10% of all inpatients. Unfortunately, the
majority of investigations focus on “male
accessory gland infection/inflammation”, a
suggestion by the WHO not differentiating
between prostatitis, epididymitis, orchitis,
and inflammatory alterations of the ure-
thral compartment [2]. This may be due
to the focus of many experts on the inter-
action with male infertility not related to
a specific location, but also due to rather
unspecific criteria to establish the diag-
nosis, the common inability to dissociate
affected compartments and last, but not
least, the occurrence of non-infectious, but
inflammatory alterations.
In 2010, clear definitions of the above
mentioned diseases were published [2–6].
Acute bacterial prostatitis, although rep-
resenting only a very small number of
patients in daily work, is well defined in
origin, diagnostic schedule and therapy.
Prostatic abscess always has to be ruled
out. The news for everybody is that ele-
vated serum PSA levels may be used as
simple tools for the diagnosis and therapy
control. Furthermore, it is very important
that long-term outcomes do not seem to be
clear, despite effective antibiotic therapy:
persistent bouts of symptoms and even
development of chronic bacterial prostati-
tis may result from the entity. Concerning
chronic bacterial prostatitis, we have to
accept that at least 8–10% of all men with
symptomatic “prostatitis/pelvic pain” have
a bacterial infection of the prostate. These
patients have to meet the criteria of the
two- or four-glass test. The regulations
for therapy are well defined. Nevertheless
for common E. coli infections the bacterial
cure rate is only up to 60–80% – meaning
no symptomatic relief or disappearance
of inflammatory signs in prostatic secre-
tions in a concordant way. This is an
aspect which needs to be addressed dur-
ing proper counselling of these men.
Finally, epididymitis, orchitis and the
interaction with male infertility have to

be addressed. Whereas the etiology and
therapy of acute epididymitis and orchi-
tis seem to be clear, the pathogenesis of
chronic epididymitis and orchitis remains
debatable until today. Recent experimental
data provide evidence that the hallmark
of chronic inflammatory reactions in the
human testis after ascending hematogenic
infection is a disturbance of the local
immunoregulation: infiltrating inflamma-
tory cells obviously overcome the immu-
nosuppressive influence in the testis [7].
These new aspects have to be proven in the
future in all our patients who become sub-
fertile in the follow-up of these diseases.
REFERENCES
1. Dohle GR, Colpi GM, Hargreave TB,
Papp GK, Jungwirth A, and Weidner W,
EAU guidelines on male infertility. Eur
Urol, 2005. 48(5): 703–11.
2. Weidner W, Wagenlehner FM, Marconi M,
Pilatz A, Pantke KH, and Diemer T, Acute
bacterial prostatitis and chronic prostati-
tis/chronic pelvic pain syndrome: andro-
logical implications. Andrologia, 2008.
40(2): 105–12.
Introduction | 13.1 |
3. Schaeffer AJ, Anderson RU, Krieger JN,
Lobel B, Naber K, Nakagawa M, Nickel
JC, Nyberg L, and Weidner W, The assess-
ment and management of male pelvic
pain syndrome including prostatitis, in
Male Lower Urinary Tract Dysfunction.
Evaluation and Management. 6th
International Consultation in Prostate
Cancer and Prostate Diseases, McConnel
J, Abrams P, Denis L, Khoury S, and
Roehrborn C, Editors. 2006, Health
Publications: Paris. p. 343–385.
4. Schneede P, Tenke P, and Hofstetter AG,
Sexually transmitted diseases (STDs) – a
synoptic overview for urologists. Eur Urol,
2003. 44(1): 1–7.
5. Horner PJ, European guideline for the
management of epididymo-orchitis and
syndromic management of acute scro-
tal swelling. Int J STD AIDS, 2001. 12
Suppl 3: 88–93.
6. Workowski KA and Berman SM, Sexually
transmitted diseases treatment guide-
lines, 2006. MMWR Recomm Rep, 2006.
55(RR-11): 1–94.
7. Bhushan S, Schuppe HC, Fijak M,
and Meinhardt A, Testicular infection:
microorganisms, clinical implications
and host-pathogen interaction. J Reprod
Immunol, 2009. 83(1–2): 164–7.
713
|13.2|
Acute bacterial prostatitis
U-Syn Ha, Yong-Hyun Cho
Department of Urology, Catholic University of Korea, Medical College, Seoul, South Korea
Corresponding author: Yong-Hyun Cho, Department of Urology, Catholic University of Korea, Medical College, Seoul,
South Korea
Tel: 82-2-3779-1024, FAX: 82-2-761-1626, cyh0831@catholic.ac.kr
ABSTRACT
Bacterial prostatitis represents a small
portion of the prostatitis spectrum,
and acute bacterial prostatitis (ABP) is
uncommon. But ABP is a urologic emer-
gency. Even if there is a wide consensus
for the diagnosis and treatment of ABP,
many physicians need detailed guide-
lines with clear evidence. We suggest the
diagnosis and treatment criteria of ABP
with extensive review of the current lit-
eratures. The initial diagnosis of ABP is
based on signs and symptoms like fever
or voiding problem. Patients with symp-
toms should undergo urine analysis and
culture of the urine. An imaging study of
the prostate including transrectal ultra-
sound (TRUS) is suggested to exclude
prostatic abscess (LoE 4). Elevated lev-
els of prostate-specific antigen (PSA) are
helpful to distinguish ABP from other
febrile UTI. The predominant causa-
tive organisms are Gram-negative bacte-
ria, mainly Escherichia coli. Appropriate
management of ABP includes rapid initi-
ation of broad-spectrum parenteral anti-
biotics and symptomatic support.
Key words: prostatitis; acute bacterial
prostatitis; infection; inflammation
SUMMARY OF RECOMMENDATIONS
For evaluation, the following should
be considered:
1. Patients with acute bacterial prosta-
titis present with typical signs and
symptoms of an acute urinary tract
infection including irritative and/or
obstructive voiding complaints, and
have additional symptoms of systemic
infections like malaise, nausea, vomit-
ing, chills and fever, and sometimes
present with signs of symptoms of uro-
sepsis. They also complain of perineal
and suprapubic pain due to a painful
swollen prostate and may have associ-
ated pain or discomfort of the external
genitalia (GoR B).

2. Digito-rectal examination reveals a
hot, boggy, and exquisitely tender
prostate gland (GoR B).
3. Prostatic massage for the expres-
sion of prostatic fluid is not indicated
and perhaps even harmful because
it could precipitate bacteremia or
sepsis (GoR B).
4. A midstream urine specimen is suffi-
cient and will show prominent leuko-
cyturia and bacteriuria with typical
uropathogens (GoR B).
Functional findings
5. The sonographic determination
of residual volume is an impor-
tant diagnostic procedure, because
infravesical obstruction may play an
important pathogenic role in acute
bacterial prostatitis (GoR B).
Imaging studies
6. Transrectal ultrasound (TRUS) does
not need to be performed on every
patient with suspected acute bacte-
rial prostatitis (GoR B), but can aid
in the diagnosis or exclusion of a pro-
static abscess (GoR B).
7. Computer tomography (CT) and mag-
netic resonance imaging (MRI) offer
no advantage over TRUS, unless the
abscess has penetrated the confines
of the prostate gland or there are fur-
ther abscess foci suspected (GoR B).
Serum prostate-specific antigen (PSA)
8. PSA is moderately to markedly
elevated in a patient with acute bac-
terial prostatitis, but is not a diag-
nostic requirement (GoR C).
9. In patients with elevated PSA serial
measurement is recommended as a
useful tool for follow-up (GoR B).
Microbiology
10. Escherichia coli is the most common
pathogen encountered in acute pros-
tatitis (GoR B).
Acute bacterial prostatitis | 13.2 |
11. There is a significantly higher rate
of mixed infection in prostatitis from
prior manipulation as compared with
spontaneous acute prostatitis (GoR B).
Treatment
12. Rapid initiation of broad-spectrum
parenteral antibiotics and sympto-
matic support are mandatory for the
patients with acute bacterial prosta-
titis (GoR B).
13. Supportive measures include i.v.
hydration and catheter drainage if
the patient cannot void (GoR B).
14. Insertion of a suprapubic cystotomy
tube is the optimal therapy for relief
from urinary obstruction (GoR B).
15. In-and-out catheterization to relieve
the initial obstruction or short-term
(<12 hours) indwelling catheteriza-
tion with a small-caliber Foley cath-
eter is appropriate (GoR B).
16. The selection and course of antibi-
otics should be adjusted according
to the pathogens isolated and the
results of bacterial susceptibility
testing (GoR B).
Prostatic abscess
17. Suspicion of a developing abscess
is raised if there is no response to
appropriate antibiotic therapy, and
can be confirmed by TRUS (GoR B).
18. If prostatic abscess is discovered,
initiation of broad-spectrum antibiot-
ics and prompt surgical drainage is
crucial (GoR B).
1. INTRODUCTION
Acute bacterial prostatitis constitutes
a urologic emergency. It is uncommon
and usually occurs in concert with a
UTI but can have a dramatic presenta-
tion. Usually, many clinicians diagnose
and treat the acute bacterial prostatitis
715
Chapter | 13 | Epididymitis, orchitis, prostatitis
empirically. A correct diagnosis has thera-
peutic implications since acute prostatitis
may require a longer course of treatment
than other forms of urinary tract infec-
tion and because the choice of antibiotic
to complete treatment after fever sub-
sides should be based on its ability to
penetrate into prostatic tissue. Thus, it is
of great necessity to define detailed and
consensual diagnosis and treatment cri-
teria for acute bacterial prostatitis.
2. METHODS
We surveyed the extensive literature
regarding acute bacterial prostatitis
available in Medline via Pubmed and also
considered other relevant publications
up to October 2008. We used terms pros-
tatitis, bacterial prostatitis, acute bacte-
rial prostatitis, combined with the terms:
diagnosis, evaluation, management or
treatment, for the search strategy. For the
purpose of this review a total of 74 pos-
sibly eligible publications were included
into the analysis, which were screened
by title and abstracts. The limitations for
this literature search were English lan-
guage (two eligible publications were not
fully reviewed because just only abstracts
were written in English). The studies
were rated according to the level of evi-
dence (LoE) and the grade of recommen-
dation (GoR) using ICUD standards (for
details see Preface) [1–2].
3. DISEASE OVERVIEW
Acute bacterial prostatitis represents an
acute infection of the prostate gland. It is
a male urinary tract infection (UTI) that
has some features in common with lower
UTI in females, including the etiologi-
cal organisms involved and some of their
urovirulence factors. The host response,
however, is very different from simple
cystitis and the treatment course is more
complicated [3].
716
The prostatitis syndrome is a common
healthcare issue affecting 10–14% of men
of all ages and ethnicities. Acute bacte-
rial prostatitis is associated with severe,
mainly Gram-negative infection [4]. In
the 1999, NIH consensus statement on
prostatitis, prostatitis and prostatitis-like
symptoms were classified into four broad
categories [5]. Type I prostatitis refers to
acute bacterial prostatitis.
Acute bacterial prostatitis is the rarest
category among the NIH classification.
It is diagnosed in less than 0.02% of all
patients seen for prostatitis [6]. However,
the potential morbidity and mortality of
acute prostatitis constitutes a true uro-
logic emergency [7]. It is characterized by
an acute onset of pain combined with irri-
tative and obstructive voiding symptoms
in a patient with manifestations of a sys-
temic febrile illness. The hospital admis-
sion rate for acute bacterial prostatitis in
the USA in 1994 was 12.7 in 100,000 as
the first, second or third principal diagno-
sis for hospital admission [8] (LoE 4).
4. EVALUATION OF ACUTE BACTERIAL
PROSTATITIS
The diagnosis of acute bacterial prostati-
tis does not generally present much dif-
ficulty for the urologist [9] (LoE 4) and
it is usually based on typical signs and
symptoms [10]. Patients with symptoms
of acute bacterial prostatitis have to
undergo urine analysis and culture of the
urine. An initial imaging of the prostate
is suggested to exclude prostatic abscess
[11] (LoE 4).
4.1 Symptoms and signs
There are no common key symptoms
of acute bacterial prostatitis. The NIH
revised classification of prostatitis deals
more with pathophysiology and labora-
tory diagnosis and describes the clinical
features of acute bacterial prostatitis only
briefly as “signs of acute UTI” [5] (LoE 4).

Irritative and/or obstructive voiding com-
plaints including dysuria, urinary fre-
quency and urgency are typical [5] (LoE
4). Obstructive voiding complaints includ-
ing hesitancy, poor interrupted stream,
and even acute urinary retention are com-
mon. The patients complain of perineal
and suprapubic pain and may have asso-
ciated pain or discomfort of the external
genitalia. The patients have a swollen
prostate which is extremely painful when
investigated. Patients with acute bacterial
prostatitis are often acutely ill and dis-
tressed. Symptoms of systemic infection
like malaise, nausea, vomiting, chills and
fever may vary. These patients may even
be systemically toxic, i.e. flushed, febrile,
tachycardic, tachypnoic, hypotensive, and
present even with all signs and symptoms
of an urosepsis [5–6, 12–14] (LoE 4).
Digito-rectal examination reveals a
hot, boggy, exquisitely tender and tense
prostate gland. Fluctuation during pal-
pation is suspicious for prostatic abscess.
Defecation may cause pain [10]. Perineal
pain and anal sphincter spasm may com-
plicate the digital rectal examination [14]
(LoE 4). Although a gentle rectal exami-
nation can be performed in patients who
have suspected acute bacterial prosta-
titis, prostatic massage for the expres-
sion of prostatic fluid is not indicated
and perhaps even harmful because it is
painful for the patient and it could pre-
cipitate bacteremia or sepsis [4, 13–14]
(LoE 4).
4.2 Urine analysis and culture
In patients presenting with acute bacte-
rial prostatitis, a midstream urine speci-
men will show prominent leukocyturia
and bacteriuria [10]. Midstream urine
culture is considered the only labora-
tory evaluation of the lower urinary tract
and usually shows typical uropathogens
[11, 15] (LoE 4).
The NIH revised classification of pros-
tatitis does not include the “four-glass-
test” for diagnosis [5], because prostatic
Acute bacterial prostatitis | 13.2 |
massage is not recommended during the
early phase of acute bacterial prostatitis
(see above) [16]. Moreover, expressed pro-
static secretion (EPS) or voided bladder
3 urine (VB3) are not necessary because
the diagnosis can be made from sympto-
matic presentation and midstream urine
culture [7] (LoE 4, GoR C).
4.3 Functional findings
The sonographic determination of resid-
ual volume is an essential diagnostic pro-
cedure, because infravesical obstruction
may play an important pathogenic role in
acute bacterial prostatitis [3, 17] (LoE 3).
And the difference in voiding problems
may reflect age differences and the pros-
tate volume. In addition, the frequency
of voiding problems, particularly urinary
retention, was remarkably higher in the
group that underwent prior manipulation
[18] (LoE 3).
Some investigators suggested that
bladder outlet obstruction may not be
the main cause of acute bacterial prosta-
titis [19] (LoE 3). For this reason, more
evidence is necessary to clarify the rela-
tionship between obstructive bladder dys-
function and acute bacterial prostatitis.
4.4 Imaging studies
No routine clinical, biological or imaging
test can currently provide evidence that
adequately rules out prostatic involve-
ment in male UTI [20]. The French
guideline and one American guideline
just consider that “any UTI in male has
the potential for a prostatic involvement”
[21–24] (LoE 4).
There are only a few studies which
describe ultrasonographic findings in
non-abscessed acute prostatitis [25–28].
Recently, in a prospective study of 45
patients with a clinical diagnosis of
acute bacterial prostatitis, transrec-
tal ultrasound (TRUS) was performed
upon admission as well as one month
after antibiotic therapy and the findings
717
Chapter | 13 | Epididymitis, orchitis, prostatitis
correlated with the clinical presenta-
tion of disease [24]. The authors con-
clude that TRUS does not need to be
performed on every patient with sus-
pected acute bacterial prostatitis (as only
47% had sonographically demonstrable
lesions on admission and 61% had lesions
improved or disappeared post treatment),
but TRUS would be indicated to exclude
the presence of prostatic abscess (LoE
2a, GoR B). In conclusion, carefully per-
formed TRUS can aid in the diagnosis
or exclusion of a prostatic abscess with-
out increasing the risk for urosepsis [24]
(LoE 2a, GoR B).
Current reports indicate that the more
cost-intensive computer tomography (CT)
and magnetic resonance imaging (MRI)
offer no advantage over TRUS, unless
the abscess has penetrated the confines
of the prostate gland or there are further
abscess foci suspected [3, 17] (LoE 3).
In some papers, the investigators
stated that intraprostatic color flow
in patients with acute prostatitis was
greater than in the normal prostate, or
those with chronic inflammation or carci-
noma [29] (LoE 3). According to the study,
in most of the patients, the vascularity of
the prostate was increased in the acute
phase of inflammation (15-spot scale).
With recovery from infection color flow
in the prostate decreased to ≤ 15 spots,
the pattern in healthy men [30] (LoE 3).
Hypoechoic areas in the peripheral zone
of the prostate can persist for a long time
in patients with acute prostatitis. Color
doppler ultrasonography of these areas
can helps to differentiate them from those
with carcinoma [31].
There are also two interesting imaging
studies – one performed with prostatic
Indium-labeled leukocyte scintigraphy
and one performed with a combination of
PSA levels and TRUS-provided evidence
supporting a frequent involvement of the
prostate in male UTI [32–33] (LoE 2a).
The former was carried out to deter-
mine whether indium-111 (111In)-labelled
leukocytes (ILLs) accumulated in the
718
infected tissue and whether uptake
responded to treatment [34]. Scintigraphs
prior to antibiotic treatment showed
uptake in prostates of all patients with
acute bacterial prostatitis; after treat-
ment no uptake was noted in nine out of
10 patients, and one out of 10 had mark-
edly decreased uptake. In the patients
with UTI, if there was no involvement in
the prostate, no uptake occurred in pros-
tates. ILLs could be useful for detecting
acute bacterial prostatitis in the future
[11].
The latter showed the prostate is con-
currently involved in men with febrile
UTI with a transient increase in prostate
volume and serum PSA during the acute
stage of disease [25, 33] (LoE 3). With
these two concepts, the presence of an
inflammatory reaction within the pros-
tate can inform us of acute prostatitis
when the diagnosis is not clear [20].
4.5 Serum prostate-specific
antigen (PSA)
Although prostate-specific antigen (PSA)
levels are not a mainstay of diagnosis,
they are generally moderately to mark-
edly elevated in the setting of acute bac-
terial prostatitis [35–37] (LoE 3). The
role of serum PSA in the differential
diagnosis and evaluation of acute bacte-
rial prostatitis is not clear. But elevated
levels of prostate-specific antigen (PSA)
have been described in 70% of men with
acute bacterial prostatitis [38] (LoE 3)
as a consequence of increased vascular
permeability and disrupted epithelium
of the gland. In a prospective study of 39
men with pyrexia (>38.3 °C), serum PSA
levels were used to categorise patients
according to an initial diagnosis of acute
bacterial prostatitis, pyelonephritis, uro-
genital infection or fever of unknown ori-
gin. All of the 20 cases with pyrexia and
elevated PSA were diagnosed and treated
as acute bacterial prostatitis [35]. Game´
et al. [39] demonstrated a decreased
free-to-total (f/t) PSA ratio up to 30 days

following adequate antimicrobial therapy,
indicating the significance of increased
bound PSA in acute prostatitis [39] (LoE
3). The decrease of f/t PSA ratio has been
correlated to systemic inflammation as
measured by serum C reactive protein
(CRP) levels. In a prospective study of
70 men with febrile UTI with prostatic
involvement as measured by tPSA, this
marker has been proven useful to assess
prostatic infection. Effective treatment
with antibiotics resulted in significantly
reduced serum PSA. A decline of tPSA
levels in patients after appropriate anti-
microbial treatment has been suggested
to indicate a healing process [25] (LoE
3). So the authors recommend PSA as a
concise, accurate, rapid and cost-effective
tool for identifying acute bacterial prosta-
titis and for follow-up [11] (GoR B).
5. AETIOLOGY
Acute bacterial prostatitis is the result of
severe infection of mainly Gram-negative
bacteria, which can be easily isolated
from the urine. Escherichia coli is the
most common pathogen encountered in
acute prostatitis, accounting for 87% of
cases [40–43]. However, other pathogens
include Pseudomonas, Proteus, Klebsiella,
Streptococcus, Enterobacter, and
Staphylococcus. Mixed flora infections
can occur in 2.5% of cases [40]. Some
investigators reported causative microor-
ganisms as below. Escherichia coli (64%),
Enterococcus (7%), Pseudomonas (6%)
and other Gram-negative rods (12%) [42]
(LoE 3). The spectrum of microbial etiolo-
gies reported is similar to those found in
complicated female UTI, both in the case
of community-acquired infections (two
third of Enterobacteriacae sp, 5–10% of
Enterococcus sp and P. aeruginosa) as well
as for nosocomial infections (large propor-
tion of resistant bacteria) [44–45] (LoE
3). The prevalence of venereal agents are
low, reported as 2%. These results do not
support the recommendations suggesting
Acute bacterial prostatitis | 13.2 |
to treat first for Neisseiria gonorrhea and
Chlamydiae trachomatis in young adults
[20, 46–47].
6. TREATMENT
Patients with acute bacterial prostati-
tis are easily diagnosed and successfully
treated with appropriate antibiotic ther-
apy and possible urinary drainage, as
long as the clinician keeps a high index of
suspicion for prostatic abscess in patients
who fail to respond quickly [14] (LoE 4).
6.1 Use of antibiotics
Appropriate management of acute bacte-
rial prostatitis includes rapid initiation
of broad-spectrum parenteral antibiotics
and symptomatic support [31]. Treatment
of acute bacterial prostatitis is well
standardised. Current guidelines for the
treatment of acute bacterial prostatitis
have only been worked out by the EAU
[21] (LoE 4).
Pharmacologic penetration of antibiot-
ics in the acutely inflamed prostatic tis-
sue is considered to be sufficient in the
case of susceptible bacteria. In severe
cases, parenteral administration of high
doses of bactericidal antibiotics, such as
a broad-spectrum penicillin derivative,
a third-generation cephalosporin with
or without aminoglycosides, or a fluo-
roquinolone, is required until fever and
other parameters of acute infection are
normalized. It can be performed alone
or in combination with supportive meas-
ures including i.v. hydration and cath-
eter drainage if the patient cannot void
[18, 48] (LoE 4).
In less severe cases, an oral fluoroqui-
nolone for 10 days may be sufficient [3]
(LoE 4). The selection and course of anti-
biotics can be adjusted according to the
pathogens isolated and the results of bac-
terial susceptibility testing [9].
In most cases the fever resolves in
36–48 h [31, 49] (LoE 2a-4). After successful
719
Chapter | 13 | Epididymitis, orchitis, prostatitis
initial therapy, switching to an oral regi-
men such as a fluoroquinolone is appro-
priate. The oral antibiotic therapy should
be continued at least for a total of two to
four weeks [21] (LoE 4) although currently
there is no consensus on the optimal treat-
ment duration.
The duration of therapy for acute pros-
tatitis has not been well studied. If the
patient is responding clinically and the
pathogen is sensitive to treatment, most
experts recommend that antibiotic therapy
be continued for three to four weeks to pre-
vent relapse, although a longer course is
sometimes necessary [49] (LoE 4, GoR C).
A patient with acute bacterial prostatitis
must be over-treated rather than under-
treated [50] (LoE 4, GoR C). Kravchick et
al. reported that three months after the
end of a six-week therapy, EPS cultures
were still positive in a third of the men.
Prolonged therapy (at least six weeks) and
subsequent follow-up with Stamey’s test
at the three-monthly visits are required to
prevent early recurrence [31] (GoR B).
6.2 Antibiotic resistance
In a recent guideline for antibiotic treat-
ment of acute bacterial prostatitis, the
administration of cephalosporins or a qui-
nolone alone or in combination with an
aminoglycoside has been recommended
[21] (LoE 4).
The susceptibility to ciprofloxacin of
E. coli was shown to be relatively low
(76.2%) in some local areas [18] (LoE 3).
A result as such probably reflects the
increase in resistant bacteria owing to
the recent excessive use of ciprofloxacin
at that local area. The guidelines for the
treatment of urinary tract infection of
the Infectious Disease Society of America
(IDSA) published in 1999 do not recom-
mend a specific antibiotic for empirical
treatment when the local level of resist-
ance among E. coli strains exceeds 20%.
The IDSA also emphasizes that physi-
cians should obtain information about
local resistance rates [18, 51] (GoR C).
720
As in the previous report, ciprofloxacin
alone may be an inadequate choice, espe-
cially in patients with prior manipula-
tion of the renal tract. Considering the
very low susceptibility to cephalosporins
(<60%) in pathogens other than E. coli,
and the relative high isolation rates
(>40%) of pathogens other than E. coli,
cephalosporins as single therapeu-
tic agents may have limited use in this
community. Most commonly, antibiotic
combination therapy for acute bacte-
rial prostatitis includes a cephalosporin
and an aminoglycoside. The second- and
third-generation cephalosporins have
been prescribed relatively frequently
for this purpose. Administration of an
aminoglycoside must be confined to the
group of patients without prior manipu-
lation owing to their susceptibility. In
the group of patients with prior manipu-
lation in which pathogens other than E.
coli constitute a substantial number of
isolates, a combination of a cephalosporin
and amikacin should be recommended for
empirical therapy [18] (GoR B).
6.3 Relief from obstruction
In acute bacterial prostatitis, urinary
obstruction is a very common symptom.
Because patients can have significant
obstruction from an acutely inflamed
prostate, bladder scanning for postvoid
residual urine is recommended. If the
residual urine is less than 100 mL, the
patient should be initiated on alpha
blocker therapy; if the residual is large,
consideration should be given to place-
ment of a small urethral catheter if short-
term drainage is required or a suprapubic
catheter if longer-term drainage is
required [6–7] (GoR B).
Traditionally, it has been suggested
that the insertion of a suprapubic cystot-
omy tube is the optimal therapy because
an indwelling Foley catheter may further
obstruct urethral ducts, resulting in the
potential to develop prostate abscesses
[52–54] (LoE 4). In most patients, however,

an in-and-out catheterization to relieve
the initial obstruction or short-term (<12
hours) indwelling catheterization with a
small-caliber Foley catheter is appropriate
[14] (GoR C).
6.4 Additional points to be
considered
Another supportive treatment options like
alpha blockers, antipyretics or anti-inflam-
matory agents may be beneficial, although
current data are lacking.3 Stool softeners
are also recommended [13] (GoR C).
Some investigators reported that
empirical antibiotic treatments lead to
inadequate antibiotic treatment in 42% of
the cases and a higher rate of bacteriolog-
ical failure. Moreover, the clinical failure
rate being much higher than the bacte-
riological failure rate suggests that anti-
biotic treatment frequently induces an
incomplete resolution of the symptoms,
even without any early infection relapse,
possibly because of a persistent underly-
ing urological disorder [20] (GoR B).
In the previous study of acute prosta-
titis, the abnormalities requiring surgi-
cal correction were detected in 24% of the
patients after a check-up including digital
rectal examination, prostatic ultrasound,
post-void residual urine measurement
and uroflow measurement [33] (GoR B).
7. PROGRESS AND FOLLOW-UP
Although the role of serum prostate-
specific antigen (PSA) in the differential
diagnostic evaluation of acute bacterial
prostatitis is not finally proven, elevated
PSA is common. Effective treatment with
antibiotics results in significantly reduced
serum PSA. Therefore some authors
recommend PSA as a concise, accurate,
rapid and cost-effective tool for identify-
ing acute bacterial prostatitis and for the
follow-up [11, 15] (LoE 4).
After antibiotic treatment, the long-
term response is unclear. A prospective
Acute bacterial prostatitis | 13.2 |
study found a bacterial persistence rate
at three months of 33% [31] (LoE 2a).
Therefore, prolonged therapy of fluoro-
quinolones for six weeks and reevaluation
after that has been recommended [31]
(GoR B). In this manner, patients with
acute prostatitis tend to have persistent
infection. Acute prostatitis tends to per-
sist and bacterial localization cultures
should be taken at subsequent follow-up
visits for at least three months [31]. Along
with this, PSA levels could be high even
up to three months after an acute episode
[31] (GoR B).
Morote et al. [55] showed that acute
inflammation contributed to PSA
increases but did not influence the per-
centage of free PSA in patients with can-
cer-free biopsies (LoE 3). Moreover, some
patients with carcinoma could be missed
during the acute phase of inflammation.
Therefore, PSA and TRUS monitoring are
strongly recommended (GoR B).
8. SPECIAL CONSIDERATIONS
8.1 Prostate abscess
Prostatic abscesses are uncommon but
potentially serious manifestations of acute
infection of the prostate and demand
prompt treatment. It represents a severe
complication of acute bacterial prostatits
with an estimated incidence of 2–18% [19]
(LoE 3) and a mortality rate of 3–30%.
Antibiotic treatment of acute bacterial
prostatitis is simple but abscess forma-
tion is well described and may have dev-
astating sequelae. Its clinical diagnosis
is somewhat difficult and suspicion of a
developing abscess is raised if there is no
response to appropriate antibiotic therapy,
and can be confirmed by TRUS [49] (LoE 4).
TRUS should not be postponed for > 48 h
in patients who do not respond to appro-
priate antibiotic therapy [31] (GoR B).
This is particularly important for the
patients with immunocompromised dis-
ease or diabetes [11, 24] (GoR C). Patients
721
Chapter | 13 | Epididymitis, orchitis, prostatitis
who are immunocompromised, especially
patients who have HIV/AIDS, seem to
be more susceptible to the development
of acute bacterial prostatitis and to the
occurrence of a potentially life-threatening
prostatic abscess. The incidence rate rises
to roughly 14% in those who have devel-
oped AIDS [56] (LoE 3). If a prostatic
abscess is discovered, initiation of broad-
spectrum antibiotics and prompt surgical
drainage is crucial [7, 57] (GoR C).
8.1.1 Diagnostics of prostatic abscess
As previously mentioned, the most impor-
tant urological investigation to exclude
the formation of prostatic abscesses
is transrectal ultrasound (TRUS) [15]
Although CT and MRI are effective
modalities for the diagnosis of prostatic
abscess, TRUS has been increasingly
recommended due to its high sensitivity,
greater cost-effectiveness, and ability to
provide diagnosis and directed treatment
in a single procedure, with CT being used
primarily in cases where the transrec-
tal ultrasound is non-diagnostic or sug-
gestive of more extensive involvement
[58–59] (LoE 3, GoR B).
8.1.2 Microbiology of prostatic abscess
Escherichia coli and Staphylococcus spe-
cies are the most commonly isolated
pathogens in prostatic abscess, although
other pathogens, such as Mycobacterium
tuberculosis, Actinomyces, Citrobacter,
Bacteroides fragilis, Aeromonas aerophyla,
and Klebsiella pneumonia have been
reported [17, 59–63] (LoE 3). Burkholderia
pseudomallei overwhelmingly predomi-
nates in the Thai population [62].
8.1.3 How to treat the prostatic
abscess
Recommended treatment of prostatic
abscess consists of broadspectrum anti-
biotic coverage and, in most cases, drain-
age of the abscess. Several surgical
procedures have been described to relieve
abscess formation. Transurethral incision
722
or resection, suprapubic adenectomy, peri-
neal incision and transrectal or transperi-
neal prostatic puncture and drainage
under sonographic guidance have been
applied according to location and exten-
sion of the abscess [3, 17] (GoR C & B).
Transperineal incision and drainage
[64] must be considered when the abscess
has penetrated beyond the prostatic cap-
sule or penetrated through the levator ani
muscle [14] (GoR C). Although transure-
thral unroofing and perineal drain-
age were once the mainstays of surgical
drainage, transrectal ultrasound-guided
aspiration of prostatic abscesses has been
increasingly used as an effective means
of drainage that may avoid the potential
morbidity associated with transurethral
drainage [58–59] (GoR B). Some authors
also support urinary diversion with a
suprapubic catheter [17, 60].
In small abscesses, patients may be
treated conservatively by the administra-
tion of antibiotic agents together with the
placement of a suprapubic catheter. The
follow-up requires regular TRUS controls
[3, 17] (GoR C & B).
8.2 Seminal vesiculitis
Seminal vesiculitis can occur as a conse-
quence of local bacterial infection in acute
and chronic bacterial prostatitis, and
patients can present with seminal vesicle
abscesses [65–66] (LoE 4 & 3). Seminal
vesicle abscesses, diagnosed clinically by
a positive ejaculate culture and imaged
traditionally by seminal vesiculography
[67–68] (LoE 3), but now with CT [69],
transrectal ultrasonography [70], or MRI
[71] can be managed with antibiotic ther-
apy, transrectal aspiration, and, if neces-
sary, an operation to remove the seminal
vesicles [14] (LoE 4).
8.3 Secondary to previous
manipulation
One of the most serious complications of
transrectal biopsy of the prostate is the
development of postbiopsy prostatitis

and septicemia. A recent report found
bacteremia in 44% patients undergoing
transrectal biopsy without preprocedural
antibiotics [72] (LoE 3). Besides, place-
ment of a urethral catheter can contrib-
ute to the acute prostatitis also [73].
Although these complications are rare,
the severity of symptoms often necessi-
tates an inpatient admission for admin-
istration of broad-spectrum intravenous
antibiotics [7] (GoR C).
In a retrospective study, Millán-
Rodríguez et al.[19] pointed out that two
different forms of acute prostatitis should
be differentiated according to their clini-
cal course. Patients with acute bacterial
prostatitis secondary to manipulation
have been found older and have larger
prostate volume [19] (LoE 3). In another
report, the difference in voiding problems
may reflect age differences and the pros-
tate volume. The frequency of voiding
problems, particularly urinary retention,
was significantly higher in the group
that underwent prior manipulation.
Consequently, the frequency of suprapu-
bic or urethral catheterization was rela-
tively high [18] (LoE 3).
Since infection from prior manipula-
tion is iatrogenic, there is a significantly
higher rate of mixed infection in pros-
tatitis from prior manipulation as com-
pared with spontaneous acute prostatitis,
and a higher rate of infections by patho-
gens other than Escherichia coli., like
Pseudomonas spp. Furthermore, there is
a higher percentage of patients with fever
or complications such as prostatic abscess
in case of secondary to manipulation com-
pared with spontaneous one [3, 19] (LoE
4 & 3).
Finally, acute bacterial prostatitis
with prior manipulation showed distinct
characteristics with regard to clinical
and microbiological features. As a con-
sequence, these patients may require
modified treatment options. Local micro-
biological sensitivity patterns and the
history of prior manipulation of the lower
urinary tract should be regarded [3,
Acute bacterial prostatitis | 13.2 |
18–19] (GoR B). In addition, some papers
suggested that patients older than 49
had both higher rates of clinical failure
and higher rates of underlying urological
disorders, and thus might be the target
population for prostate-centered investi-
gations [20] (LoE 3).
Proper antibiotic prophylaxis, generally
with a single dose of a fluoroquinolone,
prevents infectious complications effec-
tively (bacteremia develop in only 1% to
2%). But the timing of antibiotic prophy-
laxis may not be critical [72] (GoR B).
The role of prebiopsy enema is a matter
of debate. Some evidences suggest that a
prebiopsy enema is not beneficial when
patients are given preprocedural antibiot-
ics [73–74] (LoE 1b & 3).
9. FURTHER RESEARCH
The diagnosis of acute bacterial pros-
tatitis is usually based on signs and
symptoms and sometimes it is not dis-
tinguished from other febrile UTI ini-
tially. If there were some specialized
method to diagnose ABP, many physi-
cians would gain benefit from it. As
mentioned above, ILLs could be useful
for detecting acute bacterial prostatitis
in the future.
In the field of treatment, antibiotic
resistant microorganisms are increasing
in ratio with the lapse of time. The effort
to find a new range of antibiotics or the
best combination of antibiotics to sup-
press resistance should be continued. A
system to improve penetration of drugs to
prostatic tissue is as needed as ever.
Immunocompromised patients, espe-
cially those who have HIV/AIDS, are
considered to be more susceptible to
infectious disease including acute bac-
terial prostatitis or prostatic abscess.
However, the reports regarding the
incidence rate in immunocompromised
patients are quite old and not large
enough in number. More attentive
research is requested.
723
Chapter | 13 | Epididymitis, orchitis, prostatitis
10. CONCLUSIONS
Accurate diagnosis of acute bacterial pros-
tatitis is fundamental. With symptomatic
management, initial empiric broad-spec-
trum parenteral antibiotic therapy should
be considered carefully. In patients with
persistent infection, an evaluation for
prostate abscess including an antibiotics
sensitivity test is essential. Measurement
of serum PSA is useful for differential
diagnosis and follow-up. Throughout this
entire process, the evidence-based guide-
lines can help many physicians to make
a decision for patients. Further research
on prostatitis should be carried out and
the contents of this guideline need regular
update.
REFERENCES
1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
3. Ludwig M, Diagnosis and therapy of acute
prostatitis, epididymitis and orchitis.
Andrologia, 2008. 40(2): 76–80.
4. Naber KG, Management of bacterial
prostatitis: what’s new? BJU Int, 2008.
101 Suppl 3: 7–10.
5. Krieger JN, Nyberg L, Jr., and Nickel JC,
NIH consensus definition and classifica-
tion of prostatitis. JAMA, 1999. 282(3):
236–7.
6. Wagenlehner FM, Weidner W, Sorgel F,
and Naber KG, The role of antibiotics in
chronic bacterial prostatitis. Int
J Antimicrob Agents, 2005. 26(1): 1–7.
7. Benway BM and Moon TD, Bacterial
prostatitis. Urol Clin North Am, 2008.
35(1): 23–32; v.
8. US Department of Health and Human
Services Public Health Service, National
Center for Health Statistics. National
Hospital Discharge Survey Public Use
724
Data Tape Documentation 1994. 1996,
Hyattsville, MD: Centers for Disease
Control and Prevention.
9. Wagenlehner FM and Naber KG,
[Therapy of prostatitis syndrome].
Urologe A, 2001. 40(1): 24–8.
10. Neal DE, Acute bacterial prostatitis, in
Textbook of prostatitis, Nickel JC, Editor.
1999, Isis Medical Media: Oxford.
p. 115–122.
11. Weidner W and Anderson RU, Evaluation
of acute and chronic bacterial prostatitis
and diagnostic management of chronic
prostatitis/chronic pelvic pain syndrome
with special reference to infection/
inflammation. Int J Antimicrob Agents,
2008. 31 Suppl 1: S91–5.
12. Meares EM, Jr., Prostatitis. Med Clin
North Am, 1991. 75(2): 405–24.
13. Roberts RO, Lieber MM, Bostwick DG,
and Jacobsen SJ, A review of clinical
and pathological prostatitis syndromes.
Urology, 1997. 49(6): 809–21.
14. Nickel JC, Lower urinary tract evalua-
tion. Prostatitis and related conditions,
in Campbell’s urology, Walsh PC, Editor.
2002, Saunders: Philadelphia ; London.
p. 4 v. (xl, 3954 p.).
15. Weidner W, Wagenlehner FM, Marconi M,
Pilatz A, Pantke KH, and Diemer T, Acute
bacterial prostatitis and chronic prostatitis/
chronic pelvic pain syndrome: andrological
implications. Andrologia, 2008. 40(2):
105–12.
16. Lau CS and Sant GR, Urethritis,
Prostatitis, Epididymitis, and Orchitis,
in Infectious diseases, Gorbach SL,
Bartlett JG, and Blacklow NR, Editors.
2004, Lippincott Williams & Wilkins:
Philadelphia ; London. p. xxix, 2515 p.,
[2] p. of plates.
17. Ludwig M, Schroeder-Printzen I, Schiefer
HG, and Weidner W, Diagnosis and thera-
peutic management of 18 patients with
prostatic abscess. Urology, 1999. 53(2):
340–5.
18. Ha US, Kim ME, Kim CS, Shim BS, Han
CH, Lee SD, and Cho YH, Acute bacte-
rial prostatitis in Korea: clinical out-
come, including symptoms, management,
microbiology and course of disease. Int
J Antimicrob Agents, 2008. 31 Suppl 1:
S96–101.

19. Millan-Rodriguez F, Palou J, Bujons-Tur
A, Musquera-Felip M, Sevilla-Cecilia C,
Serrallach-Orejas M, Baez-Angles C, and
Villavicencio-Mavrich H, Acute bacterial
prostatitis: two different sub-categories
according to a previous manipulation of
the lower urinary tract. World J Urol,
2006. 24(1): 45–50.
20. Etienne M, Chavanet P, Sibert L, Michel
F, Levesque H, Lorcerie B, Doucet J,
Pfitzenmeyer P, and Caron F, Acute bacte-
rial prostatitis: heterogeneity in diagnostic
criteria and management. Retrospective
multicentric analysis of 371 patients diag-
nosed with acute prostatitis. BMC Infect
Dis, 2008. 8: 12.
21. Naber KG, Bishop MC, and Bjerklund-
Johansen TE, The management of uri-
nary and male genital tract infections,
in European Association of Urology
Guidelines, Office EG, Editor. 2006,
Drukkerij Gelderland: Arnhem, The
Netherlands. p. 1–126.
22. Société de Pathologie Infectieuse de
Langue Française (SPILF), Deuxième
conférence de consensus en thérapeu-
tique anti-infectieuses: antibiothérapie
des infections urinaires. Médecine et
Maladies infectieuses, 1991: 51–4.
23. Rubin RH, Shapiro ED, Andriole VT,
Davis RJ, and Stamm WE, Evaluation
of new anti-infective drugs for the treat-
ment of urinary tract infection. Infectious
Diseases Society of America and the Food
and Drug Administration. Clin Infect Dis,
1992. 15 Suppl 1: S216–27.
24. Horcajada JP, Vilana R, Moreno-Martinez
A, Alvarez-Vijande R, Bru C, Bargallo X,
Bunesch L, Martinez JA, and Mensa J,
Transrectal prostatic ultrasonography in
acute bacterial prostatitis: findings and
clinical implications. Scand J Infect Dis,
2003. 35(2): 114–20.
25. Ulleryd P, Zackrisson B, Aus G, Bergdahl
S, Hugosson J, and Sandberg T, Prostatic
involvement in men with febrile urinary
tract infection as measured by serum
prostate-specific antigen and transrectal
ultrasonography. BJU Int, 1999. 84(4):
470–4.
26. Resnick MI, Ultrasonic evaluation of the
prostate and bladder. Semin Ultrasound,
1980(1): 69.
Acute bacterial prostatitis | 13.2 |
27. Millan Rodriguez F, Orsola de los Santos
A, Vayreda Martija JM, and Chechile
Toniolo G, [Management of acute prostati-
tis: experience with 84 patients]. Arch Esp
Urol, 1995. 48(2): 129–36.
28. Rifkin MD and Resnick ML,
Ultrasonography of the prostate, in
Ultrasonography of the urinary tract,
Resnick MI and Rifkin MD, Editors.
1991, Williams & Wilkins: Baltimore, Md.
p. xviii, 502 p.
29. Veneziano S, Pavlica P, and Mannini D,
Color Doppler ultrasonographic scanning
in prostatitis: clinical correlation. Eur
Urol, 1995. 28(1): 6–9.
30. Cho IR, Keener TS, Nghiem HV, Winter T,
and Krieger JN, Prostate blood flow
characteristics in the chronic prostatitis/
pelvic pain syndrome. J Urol, 2000.
163(4): 1130–3.
31. Kravchick S, Cytron S, Agulansky L, and
Ben-Dor D, Acute prostatitis in middle-
aged men: a prospective study. BJU Int,
2004. 93(1): 93–6.
32. Velasco M, Mateos JJ, Martinez JA,
Moreno-Martinez A, Horcajada JP,
Barranco M, Lomena F, and Mensa J,
Accurate topographical diagnosis of uri-
nary tract infection in male patients with
(111)indium-labelled leukocyte scintig-
raphy. Eur J Intern Med, 2004. 15(3):
157–161.
33. Ulleryd P, Zackrisson B, Aus G, Bergdahl
S, Hugosson J, and Sandberg T, Selective
urological evaluation in men with febrile
urinary tract infection. BJU Int, 2001.
88(1): 15–20.
34. Mateos JJ, Velasco M, Lomena F,
Horcajada JP, Setoain FJ, Martin F,
Ortega M, Fuster D, Piera C, Pons F, and
Mensa J, 111Indium labelled leukocyte
scintigraphy in the detection of acute pros-
tatitis. Nucl Med Commun, 2002. 23(11):
1137–42.
35. Hara N, Koike H, Ogino S, Okuizumi M,
and Kawaguchi M, Application of serum
PSA to identify acute bacterial prostatitis
in patients with fever of unknown ori-
gin or symptoms of acute pyelonephritis.
Prostate, 2004. 60(4): 282–8.
36. Schaeffer AJ, Wu SC, Tennenberg AM,
and Kahn JB, Treatment of chronic
bacterial prostatitis with levofloxacin
725
Chapter | 13 | Epididymitis, orchitis, prostatitis
and ciprofloxacin lowers serum prostate
specific antigen. J Urol, 2005. 174(1):
161–4.
37. Neal DE, Jr., Clejan S, Sarma D, and
Moon TD, Prostate specific antigen and
prostatitis. I. Effect of prostatitis on serum
PSA in the human and nonhuman
primate. Prostate, 1992. 20(2): 105–11.
38. Pansadoro V, Emiliozzi P, Defidio L,
Scarpone P, Sabatini G, Brisciani A, and
Lauretti S, Prostate-specific antigen and
prostatitis in men under fifty. Eur Urol,
1996. 30(1): 24–7.
39. Game X, Vincendeau S, Palascak R,
Milcent S, Fournier R, and Houlgatte
A, Total and free serum prostate specific
antigen levels during the first month of
acute prostatitis. Eur Urol, 2003. 43(6):
702–5.
40. Collins MM, Stafford RS, O’Leary MP,
and Barry MJ, How common is prostati-
tis? A national survey of physician visits.
J Urol, 1998. 159(4): 1224–8.
41. Stamey TA, Pathogenesis and treatment of
urinary tract infections. 1980, Baltimore ;
London: Williams & Wilkins. ix,612p.
42. L’opez-Plaza L and Bostwick DG,
Prostatitis. Pathology of the prostate, ed.
Bostwick DG. 1990, New York: Churchill
Livingstone.
43. Dowling KJ, Roberts JA, and Kaack MB,
P-fimbriated Escherichia coli urinary
tract infection: a clinical correlation.
South Med J, 1987. 80(12): 1533–6.
44. Zhanel GG, Hisanaga TL, Laing NM,
DeCorby MR, Nichol KA, Palatnik LP,
Johnson J, Noreddin A, Harding GK,
Nicolle LE, and Hoban DJ, Antibiotic
resistance in outpatient urinary isolates:
final results from the North American
Urinary Tract Infection Collaborative
Alliance (NAUTICA). Int J Antimicrob
Agents, 2005. 26(5): 380–8.
45. Caron F, [Bacteriologic diagnosis and
antibiotic therapy of urinary tract infec-
tions]. Rev Prat, 2003. 53(16): 1760–9.
46. Krieger JN, Ross SO, and Simonsen JM,
Urinary tract infections in healthy univer-
sity men. J Urol, 1993. 149(5): 1046–8.
47. Domingue GJ, Sr. and Hellstrom WJ,
Prostatitis. Clin Microbiol Rev, 1998.
11(4): 604–13.
726
48. Schaeffer AJ, Diagnosis and treatment of
prostatic infections. Urology, 1990. 36(5
Suppl): 13–7.
49. Nickel JC, Prostatitis: evolving manage-
ment strategies. Urol Clin North Am,
1999. 26(4): 737–51.
50. Stevermer JJ and Easley SK, Treatment
of prostatitis. Am Fam Physician, 2000.
61(10): 3015–22, 3025–6.
51. Warren JW, Abrutyn E, Hebel JR,
Johnson JR, Schaeffer AJ, and Stamm
WE, Guidelines for antimicrobial treat-
ment of uncomplicated acute bacterial cys-
titis and acute pyelonephritis in women.
Infectious Diseases Society of America
(IDSA). Clin Infect Dis, 1999. 29(4):
745–58.
52. Dajani AM and O’Flynn JD, Prostatic
abscess. A report of 25 cases. Br J Urol,
1968. 40(6): 736–9.
53. Pai MG and Bhat HS, Prostatic abscess.
J Urol, 1972. 108(4): 599–600.
54. Weinberger M, Cytron S, Servadio C,
Block C, Rosenfeld JB, and Pitlik SD,
Prostatic abscess in the antibiotic era.
Rev Infect Dis, 1988. 10(2): 239–49.
55. Morote J, Lopez M, Encabo G, and
de Torres IM, Effect of inflammation
and benign prostatic enlargement on
total and percent free serum prostatic
specific antigen. Eur Urol, 2000. 37(5):
537–40.
56. Leport C, Rousseau F, Perronne C,
Salmon D, Joerg A, and Vilde JL,
Bacterial prostatitis in patients infected
with the human immunodeficiency virus.
J Urol, 1989. 141(2): 334–6.
57. Santillo VM and Lowe FC, The manage-
ment of chronic prostatitis in men with
HIV. Curr Urol Rep, 2006. 7(4): 313–9.
58. Gogus C, Ozden E, Karaboga R, and Yagci
C, The value of transrectal ultrasound
guided needle aspiration in treatment
of prostatic abscess. Eur J Radiol, 2004.
52(1): 94–8.
59. Chou YH, Tiu CM, Liu JY, Chen JD,
Chiou HJ, Chiou SY, Wang JH, and
Yu C, Prostatic abscess: transrectal
color Doppler ultrasonic diagnosis and
minimally invasive therapeutic manage-
ment. Ultrasound Med Biol, 2004. 30(6):
719–24.

60. Varkarakis J, Sebe P, Pinggera GM,
Bartsch G, and Strasser H, Three-
dimensional ultrasound guidance for per-
cutaneous drainage of prostatic abscesses.
Urology, 2004. 63(6): 1017–20; discussion
1020.
61. Oliveira P, Andrade JA, Porto HC, Filho
JE, and Vinhaes AF, Diagnosis and treat-
ment of prostatic abscess. Int Braz J Urol,
2003. 29(1): 30–4.
62. Aphinives C, Pacheerat K, Chaiyakum
J, Laopaiboon V, Aphinives P, and
Phuttharak W, Prostatic abscesses: radio-
graphic findings and treatment. J Med
Assoc Thai, 2004. 87(7): 810–5.
63. Tai HC, Emphysematous prostatic
abscess: a case report and review of litera-
ture. J Infect, 2007. 54(1): e51–4.
64. Granados EA, Riley G, Salvador J, and
Vincente J, Prostatic abscess: diagnosis
and treatment. J Urol, 1992. 148(1): 80–2.
65. Stearns DB, Seminal Vesiculitis: A
Diagnostic Problem. J Int Coll Surg,
1963. 40: 354–63.
66. Kennelly MJ and Oesterling JE,
Conservative management of a seminal
vesicle abscess. J Urol, 1989. 141(6):
1432–3.
67. Dunnick NR, Ford K, Osborne D, Carson
CC, 3rd, and Paulson DF, Seminal vesicu-
lography: limited value in vesiculitis.
Urology, 1982. 20(4): 454–7.
Acute bacterial prostatitis | 13.2 |
68. Baert L, Leonard A, D’Hoedt M, and
Vandeursen R, Seminal vesiculography in
chronic bacterial prostatitis. J Urol, 1986.
136(4): 844–5.
69. Patel PS and Wilbur AC, Cystic seminal
vesiculitis: CT demonstration. J Comput
Assist Tomogr, 1987. 11(6): 1103–4.
70. Littrup PJ, Lee F, McLeary RD, Wu D,
Lee A, and Kumasaka GH, Transrectal
US of the seminal vesicles and ejacula-
tory ducts: clinical correlation. Radiology,
1988. 168(3): 625–8.
71. Sue DE, Chicola C, Brant-Zawadzki
MN, Scidmore GF, Hart JB, and Hanna
JE, MR imaging in seminal vesiculitis.
J Comput Assist Tomogr, 1989. 13(4):
662–4.
72. Lindert KA, Kabalin JN, and Terris MK,
Bacteremia and bacteriuria after tran-
srectal ultrasound guided prostate biopsy.
J Urol, 2000. 164(1): 76–80.
73. Lindstedt S, Lindstrom U, Ljunggren
E, Wullt B, and Grabe M, Single-dose
antibiotic prophylaxis in core prostate
biopsy: Impact of timing and identifica-
tion of risk factors. Eur Urol, 2006. 50(4):
832–7.
74. Carey JM and Korman HJ, Transrectal
ultrasound guided biopsy of the prostate.
Do enemas decrease clinically significant
complications? J Urol, 2001. 166(1):
82–5.
727
|13.3|

Treatment of chronic bacterial

prostatitis
Florian M.E. Wagenlehner1, John N. Krieger2
1
Urologic Clinic, Justus-Liebig-University Gießen, Gießen, Germany
2
Department of Urology, University of Washington, Seattle, United States of America
Corresponding author: Florian M.E. Wagenlehner, MD, PhD, Department of Urology, Pediatric Urology and Andrology,
University of Giessen, Germany
Tel: +49-641/9944518, Fax: +49-641/9944509, Wagenlehner@aol.com

ABSTRACT of E. coli against fluoroquinolones in

Bacterial infection of the prostate can be
demonstrated by the Meares & Stamey
4-glass or the pre and post prostate
massage (PPM) 2-glass test in only about
10% of men with symptoms of chronic
prostatitis/chronic pelvic pain syndrome.
Chronic bacterial prostatitis is mainly
caused by Gram-negative uropathogens.
The role of Gram-positives, such as sta-
phylococci and enterococci, and atypicals,
such as chlamydia, ureaplasmas, myco-
plasmas, are still debateable. For treat-
ment, fluoroquinolones are considered the
drugs of choice because of their favoura-
ble pharmacokinetic properties and their
antimicrobial spectrum, with the best
evidence supporting ciprofloxacin and
levofloxacin. The optimal treatment dura-
tion is 28 days. Relapse and reinfection
due to antimicrobial resistant pathogens
are major problems in chronic bacterial
prostatitis. The increasing resistance
many countries is of great concern in
that respect. In patients with pathogens
resistant to fluoroquinolones, but suscep-
tible to trimethoprim-sulfamethoxazole,
a three month course of treatment with
trimethoprim-sulfamethoxazole can be
administered. In patients with patho-
gens resistant to fluoroquinolones and
trimethoprim-sulfamethoxazole, currently
no recommendation can be given. Clinical
trials with other antibiotics are urgently
needed in this patient population.
Key words: Chronic bacterial prostatitis;
refractory chronic bacterial prostatitis; anti-
biotic treatment; antimicrobial resistance.
SUMMARY OF RECOMMENDATIONS
1. The fluoroquinolone drug class is the
first choice systemic treatment for
chronic bacterial prostatitis, with the
 Treatment of chronic bacterial prostatitis
best evidence supporting use of cip-
rofloxacin and levofloxacin (GoR A).
2. Other drugs with evidence of efficacy
include: gatifloxacin (discontinued in
the US), lomefloxacin, moxifloxacin
(no clinical data), prulifloxacin (not
available in the US), and trimetho-
prim-sulfamethoxazole (GoR B).
3. The optimal duration of therapy is
at least 28 days, with some studies
supporting treatment for up to eight
weeks (GoR B).
4. The optimal length of clinical fol-
low-up is at least six months (GoR A).
5. The main unresolved issue is the
increasing rate of antimicrobial
resistance and lack of promising oral
alternatives to the fluoroquinolones.
In patients with pathogens resistant
to fluoroquinolones and trimetho-
prim-sulfamethoxazole, currently
no recommendation can be given.
Clinical trials with other antibiotics
are urgently needed in this patient
population (GoR A).
6. In refractory chronic bacterial pros-
tatitis repeated treatment or antimi-
crobial prophylaxis is recommended
using antimicrobials to which the
pathogen is susceptible. More studies
of this important issue are however
warranted (GoR C).
7. Interventions are only recommended
in patients with chronic bacterial
prostatitis who have proven bladder
outflow obstruction (GoR C).
8. There are insufficient data on alter-
native and complementary medicine
approaches for patients with chronic
bacterial prostatitis (GoR D).
1. INTRODUCTION
Approximately 10% of men with symp-
toms of chronic prostatitis/chronic pel-
vic pain syndrome have bacteriuria
with pathogens that can be proven to
| 13.3 |
originate from infection of the prostate
using the Meares and Stamey four-glass
or the pre- and post-prostate massage
two-glass test. These patients meet the
criteria for chronic bacterial prostati-
tis (NIH category II) and represent the
focus of this consultation. Most cases of
chronic bacterial prostatitis are caused
by Gram-negative uropathogens. The
role of Gram-positive and atypical bac-
teria is still debateable. The purpose of
this guideline is to evaluate the evidence
supporting current treatment options for
patients with chronic bacterial prostati-
tis, including treatment-refractory cases.
1.1 Prostatitis syndromes
Prostatitis syndrome is one of the most
common problems encountered in uro-
logic practice. Classification of the pros-
tatitis syndrome is based on the clinical
presentation of the patient, the presence
or absence of white blood cells in the
expressed prostatic secretions (EPS),
and the presence or absence of bacteria
in the EPS [1]. Prostatitis is described as
chronic when symptoms are present for
at least three months.
1.2 Classification
The internationally-accepted classifica-
tion of the prostatitis syndrome follows
the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK)/
National Institutes of Health (NIH) rec-
ommendations (Table 1) [2]. There are
four categories of prostatitis.
Acute bacterial prostatitis (NIH cat-
egory I) is defined as an acute bacterial
infection of the prostate, associated with
severe prostatitis symptoms, signs and
symptoms of systemic infection and acute
bacterial urinary tract infection [3].
Chronic bacterial prostatitis (NIH
category II) is defined as a chronic (≥ 3
months) bacterial infection of the pros-
tate, proven by adequate microbiologi-
cal tests, with documented bacteriuria
caused by the same bacterial strain. Only
729
Chapter | 13 | Epididymitis, orchitis, prostatitis
Table 1 National Institutes of Health Prostatitis Syndrome
Classification [2].
I Acute Bacterial Prostatitis
II Chronic Bacterial Prostatitis
III Chronic Prostatitis/Chronic Pelvic Pain Syndrome
a) Inflammatory
b) Non-inflammatory
IV Asymptomatic Inflammatory Prostatitis
about 10% of men with chronic prostatitis
symptoms have chronic bacterial infec-
tion of the prostate that can be demon-
strated by the four-glass test [4].
Other categories of prostatitis are not
associated with prostatic infection proven
by standard microbiological methods in
patients with chronic symptoms, termed
chronic prostatitis/chronic pelvic pain syn-
drome (NIH category III), or in patients
who have no symptoms but have proven
prostatic inflammation, termed asympto-
matic prostatitis (NIH category IV).
1.3 Epidemiology
The incidence of bacterial prostatitis may
be higher than previously reported [5].
A recent study evaluated new physician-
diagnosed prostatitis cases in a managed
care population over a two-year interval
[6]. The incidence of acute or chronic bac-
terial prostatitis was 1.26 cases per 1,000
men per year.
2. METHODS
We defined one major question, “What
is the optimal antimicrobial therapy for
patients with chronic bacterial prostati-
tis?” This question was then divided into
four issues:
1. What is the first choice antimicrobial
drug category and which drugs have
the best evidence for clinical efficacy?
2. What is the optimal duration of
therapy?
730
3. What is the desired length of
follow-up?
4. What is the major outstanding issue
for treatment?
2.1 Review of the literature
We searched the major databases covering
the last 10 years (e.g., Medline, Embase,
Cochrane Library, Biosis, Science Citation
Index) using the search term bacterial
prostatitis in binary combinations with
the terms: chronic, treatment, outcome,
complications, antibiotic and antimicro-
bial. Similar searches were also conducted
using the search term chronic bacte-
rial prostatitis in binary combinations
with the terms: trimethoprim, refrac-
tory, antibiotic resistance, surgery, TURP
and prostatectomy. To identify papers
not yet indexed in the major databases,
we reviewed the tables of contents of the
major journals of urology and other rel-
evant journals, for the last three months.
Papers published in non-reviewed sup-
plements were not included. There is
also a microbiological rationale support-
ing restriction of the literature search to
the last 10 years, because in most areas
a minimal inhibitory concentration (MIC)
shift has taken place in the pathogens
causing chronic bacterial prostatitis.
The studies were rated accord-
ing to the level of evidence (LoE) and
the grade of recommendation (GoR)
using ICUD standards (for details see
Preface) [7–8].
2.1.1 Results
These searches identified a total of 1,656
articles, including 1,014 articles pub-
lished from 1999–2008. Review of the
titles and abstracts of the 1,014 identi-
fied articles, identified a total of 72 arti-
cles that met the criteria for detailed
analysis and rating. These 72 articles
were reviewed in detail for how well each
study was designed and carried out using
a standard checklist adopted from the
 Treatment of chronic bacterial prostatitis
CONSORT statement (available at http:
//www.consort-statement.org).
2.2 Rating of the literature
Of the 72 articles reviewed in detail, in
total 57 papers met the criteria for rat-
ing (Table 2). According to the hierar-
chy of study types these papers included:
no systematic reviews or meta-analy-
ses, three randomized clinical trials,
three non-randomized cohort studies,
two case-control studies, six case series,
27 articles incorporating expert opin-
ion, two cost-effectiveness studies, and
14 in vitro, laboratory or animal model
studies (Table 2).
2.2.1 Results
Results are shown in table 2.
Three Level 1 studies (LoE 1b) were
identified: three randomized clinical tri-
als [9–11]. These studies included a total
of 655 participants (Table 2).
The committee identified four Level
2 studies (two studies with LoE 2a, two
studies with LoE 2b): two non-randomized
cohort studies [12–13] and two case series
[14–16]. These studies included a total o
359 participants (Table 2).
The committee identified 25 level
three studies including: one non-ran-
domized cohort study [17], two case-
control studies [18–19], four case series
[20–23], 16 expert opinion reviews
[24–39] and one cost-effectiveness study
[40]. These studies included a total of
652 participants with chronic prostatitis
(Table 2).
The committee identified 25 Level 4
studies including: 11 articles based on
expert opinion [41–51], one cost-effective-
ness study [52], and 14 in vitro, labora-
tory, or animal model studies [53–66].
These studies included no participants
with chronic bacterial prostatitis (Table
2). Although the Delphi process can be
used to give ‘expert opinion’ greater
authority, we identified no article that
used this approach.
| 13.3 |
3. CLINICAL PRESENTATION AND
RECOMMENDED EVALUATION OF
PATIENTS WITH CHRONIC
BACTERIAL PROSTATITIS
Chronic bacterial prostatitis is charac-
teristically associated with recurrent uri-
nary tract infections caused by the same
bacterial strain. Chronic bacterial prosta-
titis represents the most frequent cause
of recurrent urinary tract infections in
young and middle aged men. Chronic
bacterial prostatitis can be a devastating
disease, characterized by relapsing febrile
episodes, if not treated adequately from
the beginning. Potential complications
include: urosepsis, prostatic abscess and
acute urinary retention.
Accurate diagnosis of chronic bacterial
prostatitis (NIH category II) depends on
quantitative segmental bacteriological
localization cultures and EPS micros-
copy. The classical four-glass procedure,
first described by Meares and Stamey,
remains the gold standard [67]. Nickel
et al validated a simpler test to assess
inflammation/infection as a screening
test in primary care patient populations.
The two-glass test is a reasonable alter-
native when EPS cannot be obtained or
when microbiological assistance is not
available, because EPS should be exam-
ined expeditously. Interpretation of local-
ization test results can follow various
definitions that have been evaluated, but
the NIH definition is the most accepted.
3.1 Microbiology
A bacterial strain is considered a patho-
gen if the colony forming unit (CFU)
concentration in EPS or post-prostate
massage voided urine is at least 10 times
higher than in mid-stream or first-void
urine. The bacterial spectrum of chronic
bacterial prostatitis has been carefully
investigated in patients from tertiary care
institutions [4, 68]. Similar to the experi-
ence with acute prostatitis, these series
report that facultative Gram-negative
731
 Table 2 Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analysis, Expert Opinion, or Other Data (1999–2008).

732
Lead author, Rating of
Chapter

Study Type year, reference Subjects Design Aspects Critical Findings Evidence
Systematic
| 13 |

reviews and
Meta-analyses

None

Randomized
clinical trials

Naber, 2002[9] 182 Multicenter, lomefloxacin 400 mg At 5–9 days, 4–6 weeks, 3 and 6 months after therapy 1b, Positive
once daily vs. ciprofloxacin 500 mg eradication rates were 80, 72, 74, and 63% in the lom- (non-
twice daily for 4 weeks. efloxacin group and 84, 81, 82, and 72% in the cipro- inferiority)
floxacin group.

Bundrick, 2003[10] 377 Multi-center, levofloxacin 500 mg Microbiologic eradication rates 75% for levofloxacin and 1b, Positive
once daily or ciprofloxacin 500 mg 76.8% for ciprofloxacin; 6-month relapse rates were (non-
twice daily for 28 days similar. inferiority)

Giannarini, 2007[11] 96 randomized to receive a 4-week oral 6 months after therapy, microbiological cure rate was 1b, Positive
course of either prulifloxacin 600 mg 72.73% for prulifloxacin and 71.11% for levofloxacin (non-
Epididymitis, orchitis, prostatitis

or levofloxacin 500 mg once daily. (p=0.86) inferiority)

Non-randomized
cohort studies

Naber, 2000[12] 65 Multi-center study of ciprofloxacin Eradication rates were 32/39 (82.1%) after 3 months, 26/34 2a, Positive
500 mg bd for 28 days (76. 4%) after 6 months and 13/22 (59.1%) after 9 months.

Kunishima, 2008[17] 10 Multi-center, 200 mg gatifloxacin 58.1% symptomatic response rate 4 weeks after 3, Positive
twice daily for 4–8 weeks treatment

Naber, 2008[13] 117 Multi-center open-label study of Microbiological eradication rate was 82/98 (83.7%) at 2a, Positive
levofloxacin 500 mg once daily (p.o.) 1 month and the continued eradication rate was 52/57
for 28 days. Patients were followed (91.2%) at 6 months post treatment.
for 6 months.

Case-control
studies

Nickel, 2008[19] 146 (average symptom Multi-center study comparing levo- Bacteria eradication rate was 74.0% not different from 3, Positive
duration was 8.4 weeks, floxacin or ciprofloxacin for 4 weeks men with no localization of pathogenic bacteria.
median 3.5). with 6 months of follow-up
 Hu, 2002[18] 50 Amikacin 400 mg daily for 10 days “Cure rate” 33.3% for anal submucosal injection vs. 5% 3, Positive
via submucosal anal (30 cases) or for IM injection (P<0.05)
intramuscular injection (20 cases).

Case-series

Weidner, 1999[14] 40 E. coli chronic bacterial prostatitis Microbiological eradication was 92% at 3 months and 2b, Positive
treated with 4 weeks of ciprofloxacin 70–80% 12–24 months after treatment.
500 mg bid with 12–24 months
follow-up.

Nickel, 2001[23] 14 Various regimens 57% “moderate to marked improvement,” similar to 3, Positive
response in patients with category III.

Gutierrez, 2004[22] 105 Various regimens Symptoms either disappeared or diminished, irrespective 3, Positive
of whether positive cultures remained.

Guercini, 2005[21] 320 with symptoms of Antibiotic cocktails (based on cul- 68% of patients were “cured clinically.” 3, Positive
chronic prostatitis tures) with betamethasone by pros-
tate infiltration, weekly for 3 doses.

Chen, 2006[20] 7 Combination of ciprofloxacin, doxa- Bacterial eradication rate was 71% after ciprofloxacin 3, Positive
zosin, allopurinol and biofeedback treatment during a follow-up of 6 months.
perineal massage.

Magri, 2007[15–16] 137 Combination therapy with ciproflo-
xacin, azithromycin, alfuzosin and a
S. repens extract for 6 weeks.
64.2% microbiological response at the end of Rx. Of 49 2b, Positive
patients showing persistence or reinfection at the end of
treatment, 36 completed a second combination therapy
cycle: 27 patients (75%) showed eradication. The cumu-
lative eradication rate was 83.9%.

Expert opinion

Naber, 1999 Review of guidelines For chronic bacterial prostatitis, a category of its own is 4, Positive
proposed rather than using the general category of com-
plicated UTI.

Lipsky, 1999[45] Review Trimethoprim-sulfamethoxazole or, preferably, a 4, Positive

fluoroquinolone for 6 to 12 weeks.

Stevermer, 2000[50] Review Antibiotics are continued for at least 3 to 4 weeks, altho- 4, Positive
Treatment of chronic bacterial prostatitis

ugh some men require treatment for several months.

Shoskes, 2001[48] Review Ciprofloxacin has been shown to be effective. Newer 4, Positive
quinolones may be more effective against gram-

733
| 13.3 |

positive pathogens and anaerobes.

continued
 Table 2 Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analysis, Expert Opinion, or Other Data (1999–2008) – (Cont’d)

734
Lead author, Rating of
Chapter

Study Type year, reference Subjects Design Aspects Critical Findings Evidence
Naber, 2001[26] Review 3, Positive
| 13 |

Iakovlev, 2002[44] Review 4, Positive

Fowler, 2002[43] Review (minimal data) Fluoroquinolone antibiotics given for 2 to 4 weeks will 4, Positive
cure about 70%.

Wagenlehner, 2003, Reviews of pharmacokinetics and Fluoroquinolones are the first choice. 3, Positive
2004, 2005, 2006, pharmacodynamics
2007[32–38]

Croom, 2003[25] Review 28 days of oral levofloxacin 500mg daily achieved similar 3, Positive
clinical and bacteriological response rates to oral ciproflo-
xacin 500mg twice daily.

Fish, 2003[42] Review Important role of levofloxacin. 4, Positive

Naber, 2003[28] Review of antimicrobial penetration Fluoroquinolone concentrations at the site of infec- 3, Positive
into prostate tissue and seminal fluid tion should be sufficient for treatment of susceptible
Epididymitis, orchitis, prostatitis

pathogens.

Charalabopoulos, Review of antimicrobial penetration Of agents, beta-lactam drugs penetrate poorly. Good to 3, Positive
2003[24] into prostate tissue and secretions excellent penetration into prostatic fluid and tissue has
been demonstrated with many antimicrobial agents, in-
cluding tobramycin, netilmicin, tetracyclines, macrolides,
quinolones, sulfonamides and nitrofurantoin.
Pharmacokinetic studies of antimicrobials use heterogeno-
us methodology. Antibiotic concentrations in prostatic fluid
suitable for treatment of infections are only found with flu-
oroquinolones, macrolides, lincosamides and trimethoprim.

Skerk, 2004[49] Croatian guidelines Ciprofloxacin is the drug of choice. 4, Positive

Nickel, 2005[77] Review 3, Positive

Zvara,2002[51] Review Minimally invasive therapies (intraprostatic injections) in 4, negative

the treatment of chronic prostatitis are not a standard of
care.

Liu, 2005[46] Review Recommend fluoroquinolones, especially levofloxacin 4, Positive

and gatifloxacin.
 David, 2005 [41] Review Only trimethoprim and the fluoroquinolones possess 4, Positive
both the appropriate bactericidal activity and the ability
to diffuse into the prostate. Levofloxacin shows particu-
larly good penetration.

Wagenlehner, Review Follow up of at least 6 months is necessary. Most fluoro- 3, Positive

2008[29] quinolones with this indication should be sufficient for
susceptible pathogens.

Naber, 2008[27] Review The fluoroquinolones (2–4 weeks) are the first choice, in 3, Positive
particular levofloxacin is as effective as ciprofloxacin but
shows a better prostatic
penetration and is given once daily.

Cost-
effectiveness
Studies

Kurzer, 2002[40] hypothetical cohort of Model comparing 90 days of Ciprofloxacin 500 mg twice daily for 28 days appears to 3, Positive
100 men trimethoprim-sulfamethoxazole and be the most cost effective treatment.
14, 28 and 60 days of ciprofloxacin.

Sanchez-Navarro, 50 Analysis of pharmacy and chart 4, Positive

2002[52] records

In vitro, labora-
tory, or animal
model studies

Drusano, 2000[66] Population pharmacoki- Monte Carlo simulation of Mean prostate tissue/ plasma concentration ratio was 3, Positive
netic analysis of prostate Levofloxacin concentrations in 4.14. 70% of the population had a penetration ratio in
penetration by levofloxa- plasma and prostate tissue after excess of 1.0
cin 33 subjects repeated administration of 500 mg
levofloxacin orally

Wagenlehner, 2006, 12 healthy volunteers Concentrations of moxifloxacin in Moxifloxacin might be a good alternative for the prosta- 3, Positive
2008[30–31] and 39 TURP patients plasma, urine, prostatic fluid, prosta- titis treatment.
te tissue.

Rippere-Lampe, Rat model Cytotoxic necrotizing factor type 1-positive uropathoge- 4, Positive
2001[60] nic E. coli caused more inflammation-mediated and hi-
Treatment of chronic bacterial prostatitis

stological damage than isogenic CNF1-negative mutants

despite similar bacterial counts.

continued

735
| 13.3 |
 Table 2 Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analysis, Expert Opinion, or Other Data (1999–2008) – (Cont’d)

736
Chapter

Lead author, Rating of

Study Type year, reference Subjects Design Aspects Critical Findings Evidence

Velasco, 2001[63] 83 patients with FQ resi- Comparison of quinolone resistant Quinolone resistance of invasive cases was 8% versus 4, Positive
| 13 |

stant E. coli isolates E. coli isolates of invasive urinary 20% in cystitis cases. Quinolone resistant E. coli is less
tract infection and prostatitis cases likely to produce invasive disease than susceptible E. coli.
versus cystitis cases

Naber, 2001[59] 10 normal volunteers Gatifloxacin concentrations in plas- Good penetration into prostatic and seminal fluid sug- 4, Positive
ma, urine, ejaculate, prostatic and gest that gatifloxacin may be a good alternative.
seminal fluid, and sperm cells.

Giannopoulos, 50 Pefloxacin concentrations in serum
2001[54] and prostate tissue after 800 mg
intravenuous pefloxacin were deter-
mined in BPH tissue using a micro-
biological plate assay
Tissue levels of pefloxacin were well above MICs of 4, Positive
common bacteria causing bacterial prostatitis. Pefloxacin
could be a satisfactory alternative for surgical prophylaxis
and treatment of bacterial prostatitis

Scelzi, 2001[61] 12 TURP patients Lomefloxacin concentrations in Tissue/ serum ratio was > 2 in prostatic capsule and > 1.6 4, Positive
serum and prostate tissue after 400 in adenomatous tissue. Lomefloxacin could be an efficacio-
mg oral application us therapeutic option for treatment of chronic prostatitis
Epididymitis, orchitis, prostatitis

Horcajada, 2002[56] 23 E. coli isolates Emergence of quinolone-resistance in 11 of 23 patients, developed quinolone-resistant strains, 4, Positive
faeces of patients with prostatitis tre- during and just after therapy. 2 months after treatment, the-
ated with ciprofloxacin for 1 month. se were completely displaced by quinolone-susceptible E. coli.

Lee, 2005[58] Rat model Catechin, an extract of green tea. Combination treatment of catechin and ciprofloxacin had 4, Positive
synergistic effect.

Johnson, 2005[57] 17 E. coli prostatitis Molecular analysis Prostatitis isolates exhibited more virulence factors than 4, Positive
isolates cystitis isolates (n = 23).

Cattoir, 2006[53] 1 Quinolone resistance mechanisms in 4, Positive

an E. coli clinical isolate (Ar2).

Wang, 2006, 2008 Rat model Vancomycin and amikacin evaluated Higher antibiotic concentration in the prostate tissues 4, Positive
[64–65] than in sera.

Soto, 2007[62] 32 E. coli prostatitis Strains causing prostatitis produced biofilm in vitro more 4, Positive
isolates frequently than those causing other urinary tract infec-
tions and had a higher frequency of hemolysin
(p = 0.03 and 0.0002, respectively).

Han, 2008[55] Rat model Lycopene may have a synergistic effect with ciprofloxacin 4, Positive
in prostatitis treatment.
 Treatment of chronic bacterial prostatitis
bacilli (especially E. coli) were responsi-
ble for the great majority of cases. Recent
reports from clinical series of patients
have reported a preponderance of Gram-
positive cocci [10, 39]. In these latter
series, the median duration of patients’
symptoms was 3.5 weeks. One recent
report however describes that cultures
suggesting localization of Gram-positive
bacteria are not consistent in more than
90% of patients [69]. Nevertheless, most
reports suggest that the bacterial spec-
trum resembles that of complicated
urinary tract infections, with a prepon-
derance of enterobacteria. P. aeruginosa
and Enterococci are found less frequently,
but are more difficult to treat.
3.2 Other issues related to clinical
assessment
3.2.1 Semen culture
A comprehensive study of 40 men with
E. coli chronic bacterial prostatitis evalu-
ated the role of semen analysis and cul-
tures. Bacteriospermia (>103 CFU/ml)
was documented in 21 (53%) of the 40
men prior to treatment.[14]. Therefore,
semen culture is not sufficient to diagnose
chronic bacterial prostatitis [14].
3.2.2 Imaging studies and urodynamics
The role of transrectal prostate ultrasound
and urodynamic investigations was evalu-
ated in a prospective study of 164 men.
This study found that these investigations
had no role in discriminating chronic bac-
terial prostatitis from chronic prostatitis/
chronic pelvic pain syndrome [70].
In one study magnetic resonance
imaging of four acute bacterial prostati-
tis and five chronic bacterial prostatitis
cases were compared to prostate cancer,
benign prostatic hyperplasia and chronic
prostatitis/chronic pelvic pain cases [71].
Bacterial prostatitis showed some fea-
tures similar to carcinoma suggesting
that magnetic resonance imaging may
provide little diagnostic specificity.
| 13.3 |
In another study 19 patients with
chronic bacterial prostatitis were com-
pared to controls and patients with chronic
pelvic pain syndrome [72]. Hot uptake was
found in 68% of chronic bacterial pros-
tatitis patients and 70% of patients with
chronic pelvic pain syndrome. Therefore,
the data suggest that imaging procedures
are of limited or no benefit in diagnosing
chronic bacterial prostatitis or in predict-
ing response to treatment.
3.2.3 National Institutes of Health
Chronic Prostatitis Symptom Index
(NIH-CPSI)
The NIH-CPSI provides a standardized
assessment of prostatitis symptoms [73].
The NIH-CPSI was designed as a tool
for monitoring response in clinical trials
of chronic prostatitis/chronic pelvic pain
syndrome rather than as a diagnostic tool.
Only limited data are available to validate
use of this instrument in assessing the
clinical response to therapy in patients
with chronic bacterial prostatitis.
4. PRINCIPLES OF THERAPY
4.1 Antimicrobial treatment
Appropriate antimicrobial therapy rep-
resents the cornerstone of successful
treatment for patients with bacterial pros-
tatitis. For effective antimicrobial therapy
the pathogens at the site of infection must
be exposed to a drug concentration suf-
ficient to inhibit bacterial growth or even
eradicate the pathogens from that site.
Although it remains unproven in humans,
evidence suggests that bacteria in prostatic
tissue may survive in a milieu protected
by biofilms [62, 74]. Although the efficacy
of antimicrobial therapy is markedly less
against biofilm-associated bacteria, fluoro-
quinolones and macrolides are more active
in biofilm than other antimicrobials, e.g.
beta-lactams or aminoglycosides [75].
A rather extensive review on pharma-
cokinetic studies of antimicrobial agents
737
Chapter | 13 | Epididymitis, orchitis, prostatitis
and their penetration into the prostate has
been performed by Charalabopoulos et al.
[24]. If only studies with a suitable meth-
odology are used, e.g. assessment of antibi-
otic concentrations in prostatic fluid, than
antibiotic concentrations in prostatic fluid
sufficiently high to treat chronic infections
in the prostate are only found with fluoro-
quinolones, macrolides, lincosamides and
trimethoprim. Encompassing pharmacoki-
netic and pharmacodynamic aspects, the
fluoroquinolones are considered the drugs
of choice for antimicrobial treatment of
chronic bacterial prostatitis. All clinical
studies within the last 10 years have been
performed with fluoroquinolones.
Because clinical experience suggests
that relapse and reinfection are common
observed in patients with chronic bacte-
rial prostatitis, only the results of clini-
cal studies with a follow-up of at least
six months is recommended [76]. Overall,
it appears that 60–80% of patients with
E. coli and other Enterobacteriaceae can
be cured with a four-week course of fluoro-
quinolone therapy (Table 2). However, clin-
ical experience suggests that prostatitis
due to P. aeruginosa or enterococci seem
to cause more failures. Therefore fluo-
roquinolones with a broad anti-bacterial
spectrum, like levofloxacin, gatifloxacin,
or moxifloxacin with improved activity
against Gram-positive pathogens might
be a better option in case of enterococci,
although comparative RCT data suggest
that these agents are equivalent to results
of ciprofloxacin treatment. Levofloxacin
was investigated in two recent clini-
cal studies. The study by Bundrick et al.
[10] was a randomized double-blind mul-
ticenter study comparing levofloxacin
500mg once daily to ciprofloxacin 500mg
twice daily and found levofloxacin was
equivalent to ciprofloxacin. Microbiological
eradication was however only followed
up to four weeks and patients were not
required to have documented bacteriuria
with the localizing bacterial “pathogens.”
In this study, the microbiological eradiac-
tion rate by patient at four weeks was 75%
738
in the levofloxacin group and 77% in the
ciprofloxacin group.The specific eradica-
tion rate of E. faecalis was 72% with levo-
floxacin and 76% with ciprofloxacin. The
eradication rate of P. aeruginosa was not
indicated in this study. The other recent
study by Naber et al. [13] was a non-
randomized patient cohort study inves-
tigating levofloxacin 500mg once daily,
patients were not required to have docu-
mented bacteriuria with the localizing
bacterial “pathogens.” The study also used
different classification schemes for the
diagnosis of chronic bacterial prostatitis.
The corresponding [10] total eradica-
tion rate at four weeks was 79%, and at
six months 92%.
The specific eradication rate of E. faeca-
lis in the comparable classification scheme
to the Bundrick study [10] was 56%
(10/18) and of P. aeruginosa 100% (3/3).
4.2 Duration of antibiotic treatment
and clinical follow-up
We identified no clinical studies compar-
ing different durations of antibiotic treat-
ment. Almost all studies used a four week
treatment regimen [9–13, 19]. In one
study treatment with gatifloxacin was
four to eight weeks [17], but this was not
a comparative study. A cost effectiveness
study comparing different antibiotics and
duration concluded that ciprofloxacin 500
mg twice daily for 28 days was the most
cost-effective treatment [40]. Based upon
these results in chronic bacterial prosta-
titis, an oral fluoroquinolone should be
given for at least four weeks after the ini-
tial diagnosis (LoE 2, GoR B).
Follow up in most clinical studies was
at least 6 months [9–14, 19–20], which
therefore should also be performed in
clinical routine (LoE 2 GoR B).
4.3 Procedures
One study investigated amikacin 400 mg
daily administered for 10 days via submu-
cosal anal or intramuscular injection [18].
 Treatment of chronic bacterial prostatitis
This study reported inferior results. Non-
systemic application of antibiotics is there-
fore not recommended (LoE 3, GoR C).
No published study from the last 10
years evaluated interventions in chronic
bacterial prostatitis. Expert opinions only
recommend interventions in patients
with chronic bacterial prostatitis who
have proven bladder outflow obstruction
although this has not been validated in
studies (LoE 4, GoR C).
4.4 Alternative and complementary
medicine approaches
One animal study investigated cat-
echin, a green tea extract, in combina-
tion with ciprofloxacin in the treatment
of chronic bacterial prostatitis (58). The
authors reported a statistically signifi-
cant decrease in bacterial growth and
improvements in prostatic inflamma-
tion compared with the ciprofloxacin only
group [58]. Further studies are necessary
to validate these observations.
One retrospective clinical study evalu-
ated results of a 6-week course of com-
bination therapy with ciprofloxacin,
azithromycin, alfuzosin and a Serenoa
repens extract in patients with chronic
bacterial prostatitis [15]. Microbiological
eradication rates were between 75.5% and
82.3%, and clinical success rates between
78.8% and 85.7%, depending on the path-
ogens isolated and were thus not higher
than in those studies with antibiotics
alone [10, 13]. Thus, there are insufficient
data on alternative and complementary
medicine approaches for patients with
chronic bacterial prostatitis (LoE 4, GoR D,
no recommendation possible.)
4.5 Refractory patients
There are limited data available on
treatment outcomes for patients who
fail initial therapy for chronic bacterial
prostatitis. One study investigated 36
patients with relapsing chronic bacterial
| 13.3 |
prostatitis [16]. Of these 36 patients, 27
(75%) were cured by a second cycle of
combination pharmacological therapy
with antibacterial agents (ciprofloxacin/
azithromycin), alpha-blockers (alfu-
zosin) and the phytotherapeutic, Serenoa
repens. No other study evaluated patients
with recurrent disease. More studies of
this important issue are therefore war-
ranted, therefore currently no recom-
mendation can be given for refractory
patients.
5. DISCUSSION AND CONCLUSIONS
Antimicrobial resistance to fluoroquinolo-
nes is increasing world-wide. The impact
of fluoroquinolone resistance on the treat-
ment of chronic bacterial prostatitis
has not been evaluated systematically.
However, from a pharmacological view-
point, treatment failure with increasing
pathogen MICs has been observed anec-
dotally in our patients with chronic bac-
terial prostatitis, as we have seen with
urinary tract infections and other uro-
genital infections, such as gonorrhea (for
which fluoroquinolones are no longer
recommended in the USA). In patients
with pathogens susceptible to trimetho-
prim-sulfamethoxazole and resistant to
fluoroquinolones, expert opinion recom-
mends a three-month course of treatment
with trimethoprim-sulfamethoxazole LoE
4, GoR C). In patients with pathogens
resistant to fluoroquinolones and trimeth-
oprim-sulfamethoxazole, currently no rec-
ommendation can be given.
Clinical trials with other antibiotics are
therefore urgently needed in this patient
population (LoE 4, GoR A).
6. FUTURE RESEARCH
The microbiological success of treatment
of chronic bacterial prostatitis mainly
depends upon the antimicrobial´s phar-
macological properties in the prostate
739
Chapter | 13 | Epididymitis, orchitis, prostatitis
and the susceptibility of the pathogens.
Future research should therefore espe-
cially be directed to the activity of other
antibiotics, not tested up to now, and
substances active in biofilm, to evaluate
possible synergism, in the treatment of
chronic bacterial prostatitis.
REFERENCES
1. Schaeffer AJ, Prostatitis: US perspective.
Int J Antimicrob Agents, 1999. 11(3–4):
205–11; discussion 213–6.
2. Krieger JN, Nyberg L, Jr., and Nickel JC,
NIH consensus definition and classification
of prostatitis. Jama, 1999. 282(3): 236–7.
3. Nickel JC, Shoskes D, Wang Y, Alexander
RB, Fowler JE, Jr., Zeitlin S, O’Leary MP,
Pontari MA, Schaeffer AJ, Landis JR,
Nyberg L, Kusek JW, and Propert KJ,
How does the pre-massage and post-mas-
sage 2-glass test compare to the Meares-
Stamey 4-glass test in men with chronic
prostatitis/chronic pelvic pain syndrome?
J Urol, 2006. 176(1): 119–24.
4. Weidner W, Schiefer HG, Krauss
H, Jantos C, Friedrich HJ, and
Altmannsberger M, Chronic prostatitis: a
thorough search for etiologically involved
microorganisms in 1,461 patients.
Infection, 1991. 19 Suppl 3: S119–25.
5. Calhoun EA MR, O’Keeffe-Rosetti M, Gao
S, Brown S, Clemens JQ. Prevalence of
prostatitis-like symptoms in a managed
care population. in American Urological
Association Annual Meeting. 2005. San
Antonio: J Urol.
6. Clemens JQ MR, O’Keeffe-Rosetti M, Gao
SY, Calhoun EA. Incidence and clinical
characteristics of NIH type III prosta-
titis in a managed care population. in
American Urological Association Annual
Meeting. 2005. San Antonio: J Urol.
7. US Department of Health and Human
Services PHS, Agency for Health Care
Policy and Research. 1992. 115–127.
8. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
740
9. Naber KG, Lomefloxacin versus cipro-
floxacin in the treatment of chronic bacte-
rial prostatitis. Int J Antimicrob Agents,
2002. 20(1): 18–27.
10. Bundrick W, Heron SP, Ray P, Schiff WM,
Tennenberg AM, Wiesinger BA, Wright
PA, Wu SC, Zadeikis N, and Kahn JB,
Levofloxacin versus ciprofloxacin in the
treatment of chronic bacterial prostatitis:
a randomized double-blind multicenter
study. Urology, 2003. 62(3): 537–41.
11. Giannarini G, Mogorovich A, Valent F,
Morelli G, De Maria M, Manassero F,
Barbone F, and Selli C, Prulifloxacin
versus levofloxacin in the treatment of
chronic bacterial prostatitis: a prospective,
randomized, double-blind trial.
J Chemother, 2007. 19(3): 304–8.
12. Naber KG, Busch W, and Focht J,
Ciprofloxacin in the treatment of chronic
bacterial prostatitis: a prospective, non-
comparative multicentre clinical trial
with long-term follow-up. The German
Prostatitis Study Group. Int J Antimicrob
Agents, 2000. 14(2): 143–9.
13. Naber KG, Roscher K, Botto H, and
Schaefer V, Oral levofloxacin 500 mg once
daily in the treatment of chronic bacterial
prostatitis. Int J Antimicrob Agents, 2008.
32(2): 145–53.
14. Weidner W, Ludwig M, Brahler E, and
Schiefer HG, Outcome of antibiotic therapy
with ciprofloxacin in chronic bacterial pros-
tatitis. Drugs, 1999. 58 Suppl 2: 103–6.
15. Magri V, Trinchieri A, Ceriani I, Marras
E, and Perletti G, Eradication of unusual
pathogens by combination pharmacologi-
cal therapy is paralleled by improvement
of signs and symptoms of chronic prostati-
tis syndrome. Arch Ital Urol Androl, 2007.
79(2): 93–8.
16. Magri V, Trinchieri A, Pozzi G, Restelli
A, Garlaschi MC, Torresani E, Zirpoli
P, Marras E, and Perletti G, Efficacy of
repeated cycles of combination therapy for
the eradication of infecting organisms in
chronic bacterial prostatitis. Int
J Antimicrob Agents, 2007. 29(5): 549–56.
17. Kunishima Y, Takeyama K, Takahashi
S, Matsukawa M, Koroku M, Tanda
H, Tanaka T, Hirose T, Iwasawa A,
Nishimura M, Takeda K, Suzuki N, Horita
H, Yokoo A, and Tsukamoto T, Gatifloxacin
 Treatment of chronic bacterial prostatitis
treatment for chronic prostatitis: a pro-
spective multicenter clinical trial. J Infect
Chemother, 2008.14(2): 137–40.
18. Hu WL, Zhong SZ, and He HX, Treatment
of chronic bacterial prostatitis with ami-
kacin through anal submucosal injection.
Asian J Androl, 2002. 4(3): 163–7.
19. Nickel JC and Xiang J, Clinical signifi-
cance of nontraditional bacterial uropath-
ogens in the management of chronic
prostatitis. J Urol, 2008. 179(4): 1391–5.
20. Chen WM, Yang CR, Ou YC, Ho HC, Su
CK, Chiu KY, and Cheng CL, Combination
regimen in the treatment of chronic prosta-
titis. Arch Androl, 2006. 52(2): 117–21.
21. Guercini F, Pajoncini C, Bard R,
Fiorentino F, Bini V, Costantini E, and
Porena M, Echoguided drug infiltration
in chronic prostatitis: results of a multi-
centre study. Arch Ital Urol Androl, 2005.
77(2): 87–92.
22. Gutierrez J, Carlos S, Martinez JL,
Liebana JL, Soto MJ, Luna Jde D, and
Piedrola G, [A study of clinical response
to antibiotic treatment in subjects with
chronic bacterial prostatitis]. Rev Esp
Quimioter, 2004. 17(2): 189–92.
23. Nickel JC, Downey J, Johnston B, and
Clark J, Predictors of patient response to
antibiotic therapy for the chronic
prostatitis/chronic pelvic pain syndrome:
a prospective multicenter clinical trial.
J Urol, 2001. 165(5): 1539–44.
24. Charalabopoulos K, Karachalios G,
Baltogiannis D, Charalabopoulos A,
Giannakopoulos X, and Sofikitis N,
Penetration of antimicrobial agents into
the prostate. Chemotherapy, 2003. 49(6):
269–79.
25. Croom KF and Goa KL, Levofloxacin:
a review of its use in the treatment of
bacterial infections in the United States.
Drugs, 2003. 63(24): 2769–802.
26. Naber KG, Prostatitis. Nephrol Dial
Transplant, 2001. 16 Suppl 6: 132–4.
27. Naber KG, Management of bacterial
prostatitis: what’s new? BJU Int, 2008.
101 Suppl 3: 7–10.
28. Naber KG and Sorgel F, Antibiotic ther-
apy – rationale and evidence for optimal
drug concentrations in prostatic and
seminal fluid and in prostatic tissue.
Andrologia, 2003. 35(5): 331–5.
| 13.3 |
29. Wagenlehner FM, Diemer T, Naber KG,
and Weidner W, Chronic bacterial pros-
tatitis (NIH type II): diagnosis, therapy
and influence on the fertility status.
Andrologia, 2008. 40(2): 100–4.
30. Wagenlehner FM, Kees F, Weidner
W, Wagenlehner C, and Naber KG,
Concentrations of moxifloxacin in plasma
and urine, and penetration into prostatic
fluid and ejaculate, following single oral
administration of 400 mg to healthy vol-
unteers. Int J Antimicrob Agents, 2008.
31(1): 21–6.
31. Wagenlehner FM, Lunz JC, Kees F,
Wieland W, and Naber KG, Serum and
prostatic tissue concentrations of moxi-
floxacin in patients undergoing transure-
thral resection of the prostate.
J Chemother, 2006. 18(5): 485–9.
32. Wagenlehner FM and Naber KG,
Antimicrobial treatment of prostatitis.
Expert Rev Anti Infect Ther, 2003. 1(2):
275–82.
33. Wagenlehner FM and Naber KG,
Prostatitis: the role of antibiotic treat-
ment. World J Urol, 2003. 21(2): 105–8.
34. Wagenlehner FM and Naber KG,
Fluoroquinolone antimicrobial agents in
the treatment of prostatitis and recurrent
urinary tract infections in men. Curr Urol
Rep, 2004. 5(4): 309–16.
35. Wagenlehner FM and Naber KG,
Fluoroquinolone Antimicrobial Agents in
the Treatment of Prostatitis and Recurrent
Urinary Tract Infections in Men. Curr
Infect Dis Rep, 2005. 7(1): 9–16.
36. Wagenlehner FM and Naber KG, Current
challenges in the treatment of compli-
cated urinary tract infections and
prostatitis. Clin Microbiol Infect, 2006.
12 Suppl 3: 67–80.
37. Wagenlehner FM, Weidner W, and
Naber KG, Therapy for prostatitis, with
emphasis on bacterial prostatitis. Expert
Opin Pharmacother, 2007. 8(11):
1667–74.
38. Wagenlehner FM, Weidner W, Sorgel F,
and Naber KG, The role of antibiotics in
chronic bacterial prostatitis. Int
J Antimicrob Agents, 2005. 26(1): 1–7.
39. Nickel JC ZN, Spivey M, Wu SC. Clinical
significance of antimicrobial therapy in
chronic prostatitis associated with
741
Chapter | 13 | Epididymitis, orchitis, prostatitis
non-traditional uropathogens. in
American Urological Association Annual
Meeting. 2005. San Antonio: J Urol.
40. Kurzer E and Kaplan S, Cost effectiveness
model comparing trimethoprim sulfam-
ethoxazole and ciprofloxacin for the treat-
ment of chronic bacterial prostatitis. Eur
Urol, 2002. 42(2): 163–6.
41. David RD, DeBlieux PM, and Press R,
Rational antibiotic treatment of outpatient
genitourinary infections in a changing
environment. Am J Med, 2005. 118 Suppl
7A: 7S-13S.
42. Fish DN, Levofloxacin: update and per-
spectives on one of the original ‘respiratory
quinolones’. Expert Rev Anti Infect Ther,
2003. 1(3): 371–87.
43. Fowler JE, Jr., Antimicrobial therapy for
bacterial and nonbacterial prostatitis.
Urology, 2002. 60(6 Suppl): 24–6;
discussion 26.
44. Iakovlev SV, [Lemofloxacin: antimicrobial
ability and clinico-pharmacokinetic basis
for use in urogenital infections]. Urologiia,
2002(1): 11–4.
45. Lipsky BA, Prostatitis and urinary tract
infection in men: what’s new; what’s true?
Am J Med, 1999. 106(3): 327–34.
46. Liu H and Mulholland SG, Appropriate
antibiotic treatment of genitourinary infec-
tions in hospitalized patients. Am J Med,
2005. 118 Suppl 7A: 14S-20S.
47. Naber KG, Experience with the new guide-
lines on evaluation of new anti-infective
drugs for the treatment of urinary tract
infections. Int J Antimicrob Agents, 1999.
11(3–4): 189–96; discussion 213–6.
48. Shoskes DA, Use of antibiotics in chronic
prostatitis syndromes. Can J Urol, 2001. 8
Suppl 1: 24–8.
49. Skerk V, Krhen I, Kalenic S, Francetic I,
Barsic B, Kuzmic AC, Derezic D, Jeren
T, Kes P, Kraus O, Kuvacic I, Andrasevic
AT, Tesovic G, and Vrcic H, [Guidelines for
antimicrobial treatment and prophylaxis
of urinary tract infections]. Lijec Vjesn,
2004. 126(7–8): 169–81.
50. Stevermer JJ and Easley SK, Treatment
of prostatitis. Am Fam Physician, 2000.
61(10): 3015–22, 3025–6.
51. Zvara P, Folsom JB, and Plante MK,
Minimally invasive therapies for prostati-
tis. Curr Urol Rep, 2004. 5(4): 320–6.
742
52. Sanchez Navarro MD, Coloma Milano
C, Zarzuelo Castaneda A, Sayalero
Marinero ML, and Sanchez-Navarro A,
Pharmacokinetics of ciprofloxacin as a tool
to optimise dosage schedules in commu-
nity patients. Clin Pharmacokinet, 2002.
41(14): 1213–20.
53. Cattoir V, Lesprit P, Lascols C, Denamur
E, Legrand P, Soussy CJ, and Cambau E,
In vivo selection during ofloxacin therapy
of Escherichia coli with combined topoi-
somerase mutations that confer high
resistance to ofloxacin but susceptibility to
nalidixic acid. J Antimicrob Chemother,
2006. 58(5): 1054–7.
54. Giannopoulos A, Koratzanis G,
Giamarellos-Bourboulis EJ, Stinios
I, Chrisofos M, Giannopoulou M, and
Giamarellou H, Pharmacokinetics of
intravenously administered pefloxacin
in the prostate; perspectives for its appli-
cation in surgical prophylaxis. Int J
Antimicrob Agents, 2001. 17(3): 221–4.
55. Han CH, Yang CH, Sohn DW, Kim SW,
Kang SH, and Cho YH, Synergistic effect
between lycopene and ciprofloxacin on a
chronic bacterial prostatitis rat model. Int
J Antimicrob Agents, 2008. 31 Suppl 1:
S102–7.
56. Horcajada JP, Vila J, Moreno-Martinez A,
Ruiz J, Martinez JA, Sanchez M, Soriano
E, and Mensa J, Molecular epidemiology
and evolution of resistance to quinolo-
nes in Escherichia coli after prolonged
administration of ciprofloxacin in patients
with prostatitis. J Antimicrob Chemother,
2002. 49(1): 55–9.
57. Johnson JR, Kuskowski MA, Gajewski
A, Soto S, Horcajada JP, Jimenez de
Anta MT, and Vila J, Extended virulence
genotypes and phylogenetic background
of Escherichia coli isolates from patients
with cystitis, pyelonephritis, or prostatitis.
J Infect Dis, 2005. 191(1): 46–50.
58. Lee YS, Han CH, Kang SH, Lee SJ, Kim
SW, Shin OR, Sim YC, Lee SJ, and Cho
YH, Synergistic effect between catechin
and ciprofloxacin on chronic bacterial
prostatitis rat model. Int J Urol, 2005.
12(4): 383–9.
59. Naber CK, Steghafner M, Kinzig-
Schippers M, Sauber C, Sorgel
F, Stahlberg HJ, and Naber KG,
 Treatment of chronic bacterial prostatitis
Concentrations of gatifloxacin in plasma
and urine and penetration into prostatic
and seminal fluid, ejaculate, and sperm
cells after single oral administrations of
400 milligrams to volunteers. Antimicrob
Agents Chemother, 2001. 45(1): 293–7.
60. Rippere-Lampe KE, Lang M, Ceri H,
Olson M, Lockman HA, and O’Brien AD,
Cytotoxic necrotizing factor type 1-positive
Escherichia coli causes increased inflam-
mation and tissue damage to the prostate
in a rat prostatitis model. Infect Immun,
2001. 69(10): 6515–9.
61. Scelzi S, Travaglini F, Nerozzi S, Dominici
A, Ponchietti R, Novelli A, and Rizzo M,
The role of lomefloxacin in the treatment
of chronic prostatitis. J Chemother, 2001.
13(1): 82–7.
62. Soto SM, Smithson A, Martinez JA,
Horcajada JP, Mensa J, and Vila J, Biofilm
formation in uropathogenic Escherichia
coli strains: relationship with prostatitis,
urovirulence factors and antimicrobial
resistance. J Urol, 2007. 177(1): 365–8.
63. Velasco M, Horcajada JP, Mensa J,
Moreno-Martinez A, Vila J, Martinez JA,
Ruiz J, Barranco M, Roig G, and Soriano
E, Decreased invasive capacity of quinolo-
ne-resistant Escherichia coli in patients
with urinary tract infections. Clin Infect
Dis, 2001. 33(10): 1682–6.
64. Wang H, Chen ZH, Zhu YY, Wang T, and
Wu XJ, [Penetrability and therapeutic
effect of vancomycin to the prostates of
rats with bacterial prostatitis (BP) or
BPH-BP]. Zhonghua Nan Ke Xue, 2006.
12(6): 490–5.
65. Wang H, Li ZC, Luo ZH, and Chen ZH,
[Penetrability of amikacin into prostate
tissues in rat models of chronic bacterial
prostatitis]. Zhonghua Nan Ke Xue, 2008.
14(7): 583–9.
66. Drusano GL, Preston SL, Van Guilder
M, North D, Gombert M, Oefelein M,
Boccumini L, Weisinger B, Corrado M,
and Kahn J, A population pharmacoki-
netic analysis of the penetration of the
prostate by levofloxacin. Antimicrob
Agents Chemother, 2000. 44(8): 2046–51.
67. Meares EM and Stamey TA, Bacteriologic
localization patterns in bacterial prostati-
tis and urethritis. Invest Urol, 1968. 5(5):
492–518.
| 13.3 |
68. Krieger JN and McGonagle LA,
Diagnostic considerations and interpre-
tation of microbiological findings for
evaluation of chronic prostatitis. J Clin
Microbiol, 1989. 27(10): 2240–4.
69. Riley DE RS, Limaye AP, Krieger JN.
Inconsistent localization of Gram-positive
bacteria to prostate-specific specimens
from patients with chronic prostatitis. in
American Urological Association Annual
Meeting. 2005. San Antonio: J Urol.
70. Strohmaier WL and Bichler KH,
Comparison of symptoms, morphological,
microbiological and urodynamic findings
in patients with chronic prostatitis/pelvic
pain syndrome. Is it possible to differenti-
ate separate categories? Urol Int, 2000.
65(2): 112–6.
71. Ikonen S, Kivisaari L, Tervahartiala P,
Vehmas T, Taari K, and Rannikko S,
Prostatic MR imaging. Accuracy in
differentiating cancer from other pros-
tatic disorders. Acta Radiol, 2001. 42(4):
348–54.
72. Ryu JK, Lee SM, Seong DW, Suh JK, Kim
S, Choe W, Moon Y, and Pai SH, Tc-99m
ciprofloxacin imaging in diagnosis of
chronic bacterial prostatitis. Asian J
Androl, 2003. 5(3): 179–83.
73. Litwin MS, McNaughton-Collins M,
Fowler FJ, Jr., Nickel JC, Calhoun EA,
Pontari MA, Alexander RB, Farrar JT,
and O’Leary MP, The National Institutes
of Health chronic prostatitis symptom
index: development and validation of a
new outcome measure. Chronic Prostatitis
Collaborative Research Network. J Urol,
1999. 162(2): 369–75.
74. Nickel JC, Olson ME, and Costerton
JW, Rat model of experimental bacterial
prostatitis. Infection, 1991. 19 Suppl 3:
S126–30.
75. Goto T, Nakame Y, Nishida M, and Ohi
Y, Bacterial biofilms and catheters in
experimental urinary tract infection.
Int J Antimicrob Agents, 1999. 11(3–4):
227–31; discussion 237–9.
76. Naber KG and Giamarellou H, Proposed
study design in prostatitis. Infection,
1994. 22 Suppl 1: S59–60.
77. Nickel JC and Moon T, Chronic bacterial
prostatitis: an evolving clinical enigma.
Urology, 2005. 66(1): 2–8.
743
|13.4|

Epididymitis and orchitis

Thorsten Diemer, Florian M.E. Wagenlehner, Wolfgang Weidner
Department of Urology, Pediatric Urology and Andrology, University of Giessen, Giessen, Germany
Department for Urology, Pediatric Urology and Andrology, UKGM GmbH, Campus Giessen, Justus-Liebig-University
Giessen, Germany
Corresponding author: Thorsten Diemer, MD, PhD, Department of Urology, Pediatric Urology and Andrology, University
Hospital Giessen and Marburg GmbH – Campus Giessen, Justus Liebig-University Giessen, Rudolf-Buchheim-Str. 7,
D-35392 Giessen, Germany
Tel. +49 641 99 44 505, Fax +49 641 99 44 519, Email: Thorsten.Diemer@chiru.med.uni-giessen.de

ABSTRACT Bacterial persistence after acute

Acute epididymitis/epididymo-orchitis can
be considered a bacterial infection due to
sexually transmitted bacteria, namely
Neisseria gonorrhoeae and Chlamydia tra-
chomatis, or pathogens that cause urinary
tract infections (Enterobacteria). Acute
infections require urgent therapeutical
intervention based on anti-microbial ther-
apy. Oral fluoroquinolones represent the
medication of the first choice, severe infec-
tions require inpatient conditions and i.v.
application of fluoroquinolones or use of
third-generation cephalosporins, however,
the choice of anti-bacterial therapy should
be selected according to the underlying eti-
ology. Supportive physical means of ther-
apy such as ice packs are recommended.
Chronic epididymitis is typified by
induration, pain, and discomfort of the
epididymis, however, etiology and thera-
peutical strategies are not evidence-based.
epididymo-orchitis has been proposed as
pathophysiological mechanism suggest-
ing an infectious etiology.
Isolated orchitis that does not affcet
the epididymis is a rare condition usually
due to a viral infection (e.g. Mumps orchi-
tis). Severe forms that result in complete
distruction of the testicular tissue occur.
Post-infectious infertility due to azoosper-
mia respresents a classical cause of male
infertility. Therapy with interferon-alpha
2b is still discussed as protective mean
for testicular tissue and spermatogenesis.
Key words: orchitis, epididymitis,
epididymo-orchitis, testicular abszess,
acute scrotum, scrotal swelling, Mumps
SUMMARY OF RECOMMENDATIONS
1. In acute epididymitis/epididymo-
orchitis diagnostic work-up should

at least include general (testicular)
examination, scrotal ultrasound,
colour duplex ultrasound and urine
culture (LoE 2, GoR B).
2. Color-duplex ultrasound may be
helpful to distinguish epididymo-
orchitis from testicular torsion.
However, when in doubt, surgi-
cal scrotal exploration is strongly
recommended (LoE 1, GoR A).
3. Bacterial epididymitis/epididymo-
orchitis is caused by STD bacteria
or bacteria causing UTI. The choice
of medication should reflect the etio-
pathology in a respective patient.
Immediate treatment should there-
fore be commenced by use of fluoro-
quinolones (e.g. levofloxacine) if an
UTI etiology is suspected or third
generation cephalosporins (cefo-
taxime or ceftriaxone) plus doxy-
cycline, if the acute epididymitis is
most likely caused by gonococcal or
chlamydial infection (LoE 1, GoR A).
4. The sexual partner(s) should be
involved in the diagnostic protocol
and treatment respectively in case
of pathogenesis due to STD-bacteria.
This might also apply in cases
where pathogens cannot be
retrieved/identified in the diagnostic
work-up (LoE 2, GoR B).
5. Supportive therapy (anti-phlogistic
medication, cool packs) may be help-
ful to ease symptoms. There is no
evidence that these factors have an
impact on the duration and severity
of the disease (LoE 3, GoR C).
6. Isolated orchitis is always suspicious to
be of viral origin, e.g. Mumps orchitis.
Treatment is based on symptomatic
and anti-inflammatory treatment,
diagnosis is certified by serological
means. Treatment of Mumps orchitis
mit interferon-alpha 2b can exert an
protective effect on testicular tissue
and later testicular function (sperma-
togenesis) (LoE 2, GoR B).
Epididymitis and orchitis | 13.4 |
7. In epididymitis/epididymo-orchitis
resulting from subvesical obstruction
and urinary infection suprapubic
urinary diversion may be helpful in
cases of urinary retention. Urinary
diversion in general without residual
post-voiding urine is debatable
(LoE 2, GoR B).
8. Acute epididymitis/epididymo-
orchitis can result in epididymal
obstruction, however obstructive
azoospermia after epididymitis is
not frequent. Surgical exploration
followed by microsurgical reconstruc-
tion (e.g. tubulovasostomy) together
with sperm retrieval is recommended
in infertile patients (LoE 1, GoR A).
9. Rare forms of epididymitis due to
causes other than conventional bacte-
ria (STD, UTI) are difficult to diagnose.
Therapy is frequently based on reports
of case series and cannot be considered
standardized (LoE 4, GoR D).
10. Surgical intervention is recom-
mended in cases of large abscess for-
mation and testicular necrosis due to
perfusion damage of infectious origin
(LoE 3, GoR C).
1. INTRODUCTION
Acute epididymitis is an acute painful swell-
ing in the scrotum that usually occurs uni-
laterally [1–2]. The testes may be involved
in the inflammatory process in most cases
as ‘epididymo-orchitis’. Acute epididymitis/
epididymo-orchitis is considered a bacterial
infection that requires urgent therapeutical
intervention [2] (Table 1).
Chronic epididymitis appers to be a
narrowly defined clinical entity typified
by induration and/or swelling of the epidi-
dymis with localized pain and discomfort.
The etiology of the disease is uncertain,
however, bacterial persistence in the
epididymis following acute epididymitis
has been described and may occur in up
to 15% of all epididymitis patients [3].
745
Chapter | 13 | Epididymitis, orchitis, prostatitis
Table 1 Classification of epididymitis and orchitis.
Acute epididymitis or
epididymo-orchitis
Neisseria gonorrhoeae (STD)
Chlamydia trachomatis (STD)
Escherichia coli
Streptococcus pneumoniae, Enterococcus spp.
Klebsiella spp.
Salmonella spp.
Other urinary tract pathogens
Specific epididymitis/orchitis is defined
as a chronic form of epididymitis caused
by specific bacteria (e.g. M. tubercu-
losis, Treponema pallidum and Brucella
spp.) and is typified by chracteristic
histo-pathological features (Table 1)
[4–5]. Therapeutical approaches follow
the guidelines for treatment of the under-
lying disease. Epididymectomy under
anti-microbial therapy might be helpful
to particularly ease symptoms (such as in
tuberculosis) [6–7].
Inflammatory processes that primarily
involve the testicular tissue such as viral
orchitis usually do not involve the epidi-
dymes [8]. Viral orchitis can be isolated
meaning that viral infection specifically
locates to the testis or is observed for cer-
tain viruses that primarily cause a sys-
temic inflammatory reaction such as in
hemorrhagic fevers. For example, orchitis
has been described in systemic infections
with Lassa and Ebola virus in humans.
2. OBJECTIVES
The objective of this paper is to identify
accepted criteria for classification, diag-
nosis, and therapy of epididymitis, epidi-
dymo-orchitis and orchitis based on the
literature search. Special and rare forms
of the diseases are considered, recom-
mendations for diagnosis and therapy are
provided where available.
746
Granulomatous epididymitis or orchitis Viral
(specific orchitis) orchitis
Mycobacterium tuberculosis Mumps
Treponema pallidum Enteroviruses
Brucella spp. Lassa
Sarcoid Ebola
Fungal Other viruses
Parasitic
3. METHODS
We searched the Pubmed database for
original papers covering the last eight
years (English) using the search terms:
orchitis, epididymitis, epididymo-orchitis,
acute scrotum, scrotal pain, MAGI, ejac-
ulate infection, and MESH terms with
diagnosis and therapy. Furthermore,
all reviewed supplements (2000–2008),
covering the topic orchitis, epididymitis
and urogenital infections of Andrologia,
Human Reproduction, European Urology
and Fertility & Sterility have scanned for
issues addressing epididymitis, orchitis or
infectious impact on testicular function.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [9–10].
Published Meta-analyses have not
been available on the topic epididymitis/
orchitis. Review articles have been cited
in the text independently from the sys-
tematic search, reviews of older date of
publication than year 2000 have also
been considered, and so have “classical
papers”.
4. EPIDEMIOLOGY
Orchitis and epididymitis are classified
as acute or chronic processes according
to their cause and clinical features [2]

(Table 1). Chronic inflammation with
induration develops in about 15% of
patients following an episode of acute
epididymitis. Viral and bacterial
inflammation of the testes can lead to tes-
ticular atrophy and destruction of sper-
matogenesis, however, the natural course
of the disease cannot be predicted from
severity and clinical symptoms [11–12].
In general, acute epididymitis/epididymo-
orchitis is considered as a consequence
of STD-transmitted bacteria (namely
Neisseria gonorrhoeae and Chlamydia tra-
chomatis) in younger patients less than
35 years of age, and is considered a com-
plication of voiding disorders and UTI
in patients older than 35 years [13–15].
Epididymitis is particularly common
among individuals who have high-risk
sexual behavior (frequent change of sexual
partners) and is one of the leading causes
of acute admission to hospitals among
military personnel. It occurs in 1–2% of
patients who have gonococcal and chlamy-
dial urethritis, with an equal risk from each
pathogen. It is usually unilateral and is due
to an extension of the urethral infection via
the vas deferens to the epididymis (ascend-
ing) [2, 16].
In middle-aged and older men
(<35–40years), epididymitis is usu-
ally due to the same organisms as those
that cause UTI and is presumably a
direct extension from the urinary tract.
Epididymitis is more common in patients
with subvesical obstruction and particu-
larly in those who have indwelling cath-
eters. Bladder outlet obstruction and
LUTS of any origin and urogenital abnor-
malities are also risk factors for acute and
chronic epididymitis/epididymo-orchitis.
Prevalence studies of chronic epidi-
dymitis do not exist, and not much is
known about chronification of symptoms
after acute epididymitis. In a 14-day
representative prevalence study among
Canadian urologists about 1% of outpa-
tient visits accounted for office visits due
to epididymitis. Chronic epididymitis
defined as symptoms with a duration of
Epididymitis and orchitis | 13.4 |
more than two to three months has been
diagnosed in about 80% of these men [3].
Mumps orchitis has been common
before widespread vaccination in child-
hood. Mumps orchitis can be considered a
major complication of a general infection
with Mumps, a paramyxovirus. It has
become rare in the 1990s. Due to decreas-
ing vaccination coverage in western popu-
lations, mumps notifications and orchitis
cases have been rapidly increasing within
the last years. Mumps orchitis is said to
occur in 20–30% of postpubertal men who
have Mumps. Typically, Mumps orchitis
develops within athree to 10 day delay
to primary parotitis and occurs bilater-
ally in about 30% of all cases. However,
Mumps orchitis can also be found in
patients without recent parotitis [17].
Other viral infections can also cause
orchitis, particularly enteroviruses. The
testes can also be involved as a continu-
ation of epididymitis, particularly when
suppurative UTI pathogens are involved.
Granulomatous orchitis is a rare con-
dition of uncertain etiology [18]. With
regard to chronic inflammatory condi-
tions, a so-called ‘low-grade autoimmune
orchitis’ [19] has been described.
Epididymo-orchitis can lead to abscess
formation, testicular infarction, testicu-
lar atrophy, chronic epididymitis, infertil-
ity, and hypogonadism in some icidents
[4, 19]. In men who have azoospermia,
postinflammatory epididymal obstruction
can sometimes be cured by reconstructive
surgery [20]
5. CLINICAL FEATURES AND
DIAGNOSIS
Inflammation, pain, scrotal swelling and
tenderness of the epididymis character-
ize acute epididymitis [4]. Frequently
the tail of the epididymis is involved pre-
dominantly. In less than 10% of cases
both sides appear to be involved. The
spermatic cord is usually tender and
enlarged. The testes may be spared or
747
Chapter | 13 | Epididymitis, orchitis, prostatitis
may be involved to produce a contiguous
large painful mass. Studies indicate that
the testis is involved in up to 60% of cases
based on clinical evaluation [13]. Acute
epididymitis/epididymo-orchitis always
requires immediate evaluation by sonog-
raphy and Colour duplex scanning to dif-
ferentiate between acute epididymitis
and acute torsion of the spermatic cord
[21–23]. CRP determination in serum can
also be helpful to distinguish between
epididymitis and testicular torsion in
cases of acute scrotum [24–26].
Testicular torsion requires urgent sur-
gical intervention to prevent testicular
infarction and irreversible tissue necro-
sis [27–28]. An inflammatory hydrocele is
frequently seen in the acute event but it
does not distinguish between epididymi-
tis and testicular torsion.
The microbiologic diagnosis of acute
epididymitis must be made as specifically
as possible. A urethral Gram stain, urine
culture and other studies, such as ampli-
fication techniques, for identification of
Neisseria gonorrhoeae and Chlamydia
trachomatis should be obtained for all
patients when available [29]. Blood cul-
tures are valuable if the patient is febrile
or has systemic signs of toxicity. Ejaculate
analysis according to World Health
Organization (WHO) criteria, includ-
ing leukocyte analysis, may be of value,
however, this is usually not possible and
required in the acute and painful state
of the disease. A transiently decreased
sperm count or azoospermia is common.
Infertility due to obstructive azoosper-
mia is a rare complication unless there is
bilateral involvement [30–32].
Chronic epididymitis is character-
ized by thickening and induration of the
epididymis. Especially in patients who
are infertile, ejaculate analysis concern-
ing semen quality is a necessary inves-
tigation to exclude azoospermia [19] and
changes of sperm maturation [33].
Orchitis, an isolated inflammation
of the testis, is a rare event. Most fre-
quently it occurs in association with
748
epididymitis, as epididymo-orchitis (see
Table 1). Testicular swelling, frequently
accompanied by fever, is typical. Antibody
and other specific serum investigations
should be carried out to identify mumps,
enteroviruses and other potential viral
pathogens. In chronic infections, ejacu-
late analysis may demonstrate structural
sperm defects providing reduced sperm
motility and number [19]. Testicular
biopsy in these cases may demonstrate
focal inflammation, mixed atrophy and
complete Sertoli-cell-only syndrome in
the follow-up [17, 19].
The most frequent form of isolated orchi-
tis is Mumps orchitis. Mumps orchitis typ-
ically develops after Mumps parotitis with
a delay of three to 10 days in post-pubertal
men. In some incidences Mumps orchitis
may develop without preceeding paroti-
tis or with longer delay. The clinical hall-
marks are swelling of the testis (bilaterally
in about 30%), testicular pain, and fever
while the epididymis appears clinically
unaffected. The clinical picture together
with evidence of IgM antibodies in serum
provide the diagnosis in clinical suspicion
of Mumps orchitis. Testicular atrophy due
to Mumps orchitis is expected two to three
months after the acute event [17].
6. TREATMENT
In acute epididymitis (epididymo-orchitis),
antimicrobial agents should be chosen
for initial empiric treatment based on
the probability of the etiologic agent [24,
34–36]. In sexually active men who are
at risk of infection with C. trachomatis
or N. gonorrhoeae, a therapeutic regimen
that covers both these pathogens is man-
datory [37–38]. Antibiotic resistance in N.
gonorrhoeae increased dramatically over
the last years. The WHO surveillance of
antibiotic resistance in Neisseria gonor-
rhoeae in the Western Pacific Region,
carried out in 2005, revealed resistance
rates of penicillins and quinolones up to
100%, and of tetracyclines up to 80% in

some countries [39]. Penicillin and fluoro-
quinolone resistant strains have allready
reached the western countries. The CDC
therefore adapted to this resistance trend
and now recommend ceftriaxone as the
first line agent for the treatment of acute
epididymitis caused by N. gonorrhoeae in
a rather low single dose of 250 mg applied
intramuscularly [15]. Additional treatment
of non-gonococcal agents is also recom-
mended, which can be a tetracycline agent
(Doxycycline 100 mg /2x/day/10 days) [15].
Additional therapy includes physi-
cal means such as scrotal support, up-
positioning of the testes and bed rest.
Abscesses may require surgical drain-
age, however, microabszesses within the
epididymis can resolve spontaneously.
If urinary tract pathogens are consid-
ered to be the probable etiologic agent,
fluoroquinolones (ofloxacin 300 mg 2x/
day/10 days or levofloxacin 500 mg 1x/
day/10 days) are recommended as first
line agents [15]. The rational behind this
recommendation is represented by the
fact that ofloxacin/levofloxacin – imnstead
of ciprofloxacin – is considered to be effec-
tice versus urinary tract pathogens as
well as atypical bacteria and STD patho-
gens. Experimental [40] and clinical stud-
ies [36] suggest that the fluoro-quinolones
are very effective if the pathogens are
tested susceptible. However the dra-
matic increase of quinolone resistance
in uropathogens (particularly resistance
E. coli resistance versus fluorochinolones)
and will cause significant clinical prob-
lems in the empiric antibiotic treatment.
Antiphlogistic therapy with methyl-pred-
nisolone (40 mg a day) followed by dose
reduction over time may be considered,
although data from prospective ran-
domised studies are not available.
In acute mumps orchitis, interferon-
alpha 2b has been prescribed as sup-
portive therapy (3×106 IU daily/7 days)
intended to reduce the testicular dam-
age due to testicular inflammation and to
exert a protective effect on spermatogene-
sis [4, 19, 41]. However, clinical data after
Epididymitis and orchitis | 13.4 |
administration of interferon-alpha 2b in
Mumps orchitis have provided conflict-
ing results. Further studies performing
testicular biopsies after treatment have
shown, that systematic treatment with
interferon-alpha 2b is not completely
effective in preventing testicular atrophy
after mumps orchitis [42]. Therapy with
nonsteroidal anti-inflammatory agents
has also been recommended [43] as has
treatment with long-acting gonado-
trophin-releasing hormone agonists [43].
7. FURTHER RESEARCH
One of the future scientific goals will
be the development of rapid diagnostic
tools that can easily distinguish between
infections due to STD-bacteria and
enterobacteria. These tools will enable
physicians to specifically prescribe effec-
tive and targeted treatment with a low
rate of treatment failures. It is likely
that these tools will use molecular biol-
ogy techniques (available in more sophis-
ticated appications and protocols) in a
technical application that will allow rapid
diagnostic performance.
8. CONCLUSION
Correct diagnostic and therapeutic man-
agement of epididymo-orchitis is pri-
marily directed to deliver optimum
healthcare to the patients involved.
However, particularly in case of involve-
ment of bacteria responsible for STD,
this management has great implications
for actual and potential sexual partners
underlining the significance of these
problems for public healthcare in gen-
eral. From an economical point of view it
also appears important that therapeuti-
cal intervention due to current standards
might prevent cases of male and female
infertility as a consequence of epididymo-
orchitis and subsequently costs for infer-
tility treatment.
749
Chapter | 13 | Epididymitis, orchitis, prostatitis
REFERENCES
1. Weidner W, Schiefer HG, and Garbe
C, Acute nongonococcal epididymitis.
Aetiological and therapeutic aspects.
Drugs, 1987. 34 Suppl 1: 111–7.
2. Chan PT and Schlegel PN, Inflammatory
conditions of the male excurrent ductal sys-
tem. Part I. J Androl, 2002. 23(4): 453–60.
3. Nickel JC, Teichman JM, Gregoire M,
Clark J, and Downey J, Prevalence, diag-
nosis, characterization, and treatment of
prostatitis, interstitial cystitis, and epidi-
dymitis in outpatient urological practice:
the Canadian PIE Study. Urology, 2005.
66(5): 935–40.
4. Weidner W and Krause W, Orchitis,
in Encyclopedia of Reproduction 1999.
p. 524–527.
5. Akinci E, Bodur H, Cevik MA, Erbay A,
Eren SS, Ziraman I, Balaban N, Atan A,
and Ergul G, A complication of brucel-
losis: epididymoorchitis. Int J Infect Dis,
2006. 10(2): 171–7.
6. Padmore DE, Norman RW, and Millard
OH, Analyses of indications for and out-
comes of epididymectomy. J Urol, 1996.
156(1): 95–6.
7. Ludwig M, Velcovsky HG, and Weidner
W, Tuberculous epididymo-orchitis and
prostatitis: a case report. Andrologia,
2008. 40(2): 81–3.
8. Ludwig M, Diagnosis and therapy of acute
prostatitis, epididymitis and orchitis.
Andrologia, 2008. 40(2): 76–80.
9. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
11. Nistal M and Paniagua R, Testicular and
epididymal pathology. 1984, New York:
Thieme-Stratton. 358p.
12. Trei JS, Canas LC, and Gould PL,
Reproductive tract complications associated
with Chlamydia trachomatis infection in
US Air Force males within 4 years of test-
ing. Sex Transm Dis, 2008. 35(9): 827–33.
750
13. Luzzi GA and O’Brien TS, Acute epidi-
dymitis. BJU Int, 2001. 87(8): 747–55.
14. Wagenlehner FM, Weidner W, and Naber
KG, Chlamydial infections in urology.
World J Urol, 2006. 24(1): 4–12.
15. Prevention CfDCa. Sexually Transmitted
Diseases Treatment Guidelines 2006,
CDC, Editor. 2006, CDC.
16. Gift TL and Owens CJ, The direct medical
cost of epididymitis and orchitis: evidence
from a study of insurance claims. Sex
Transm Dis, 2006. 33(10 Suppl): S84–8.
17. Scholz M, Graf N, Steffens J, Schonkofer
H, Jeanelle JP, Schofer O, and Sitzmann
FC, Mumpsorchitis im Jugend und
Erwachsenenalter. Dt. Arztbl, 1996. 93:
2087–2090.
18. Aitchison M, Mufti GR, Farrell J,
Paterson PJ, and Scott R, Granulomatous
orchitis. Review of 15 cases. Br J Urol,
1990. 66(3): 312–4.
19. Weidner W, Krause W, and Ludwig M,
Relevance of male accessory gland infec-
tion for subsequent fertility with special
focus on prostatitis. Hum Reprod Update,
1999. 5(5): 421–32.
20. Schroeder-Printzen I, Zumbe J, Bispink
L, Palm S, Schneider U, Engelmann U,
and Weidner W, Microsurgical epididymal
sperm aspiration: aspirate analysis and
straws available after cryopreservation in
patients with non-reconstructable obstruc-
tive azoospermia. MESA/TESE Group
Giessen. Hum Reprod, 2000. 15(12):
2531–5.
21. Farriol VG, Comella XP, Agromayor
EG, Creixams XS, and Martinez De La
Torre IB, Gray-scale and power doppler
sonographic appearances of acute inflam-
matory diseases of the scrotum. J Clin
Ultrasound, 2000. 28(2): 67–72.
22. Drury NE, Dyer JP, Breitenfeldt
N, Adamson AS, and Harrison GS,
Management of acute epididymitis: are
European guidelines being followed? Eur
Urol, 2004. 46(4): 522–4; discussion 524–5.
23. Liu CC, Huang SP, Chou YH, Li CC, Wu
MT, Huang CH, and Wu WJ, Clinical pres-
entation of acute scrotum in young males.
Kaohsiung J Med Sci, 2007. 23(6): 281–6.
24. Horner PJ, European guideline for the
management of epididymo-orchitis and

syndromic management of acute scro-
tal swelling. Int J STD AIDS, 2001. 12
Suppl 3: 88–93.
25. Doehn C, Fornara P, Kausch I, Buttner
H, Friedrich HJ, and Jocham D, Value of
acute-phase proteins in the differential
diagnosis of acute scrotum. Eur Urol,
2001. 39(2): 215–21.
26. Schalamon J, Ainoedhofer H, Schleef J,
Singer G, Haxhija EQ, and Hollwarth ME,
Management of acute scrotum in children
– the impact of Doppler ultrasound. J
Pediatr Surg, 2006. 41(8): 1377–80.
27. Weidner W, Epididymitis, in Diagnostik
und Therapie sexuell übertragbarer
Erkrankungen. Leitlinien 2001 der
Deutschen STD Gesellschaft, Petzold D
and Gross G, Editors. 2001, Springer:
Berlin. p. 13–18.
28. Karmazyn B, Steinberg R, Kornreich L,
Freud E, Grozovski S, Schwarz M, Ziv N,
and Livne P, Clinical and sonographic cri-
teria of acute scrotum in children: a retro-
spective study of 172 boys. Pediatr Radiol,
2005. 35(3): 302–10.
29. Eley A, Oxley KM, Spencer RC, Kinghorn
GR, Ben-Ahmeida ET, and Potter CW,
Detection of Chlamydia trachomatis by
the polymerase chain reaction in young
patients with acute epididymitis. Eur J Clin
Microbiol Infect Dis, 1992. 11(7): 620–3.
30. Hendry WF, Levison DA, Parkinson MC,
Parslow JM, and Royle MG, Testicular
obstruction: clinicopathological studies. Ann
R Coll Surg Engl, 1990. 72(6): 396–407.
31. Osegbe DN, Testicular function after uni-
lateral bacterial epididymo-orchitis. Eur
Urol, 1991. 19(3): 204–8.
32. Huwe P, Menkveld R, Ludwig M, and
Weidner W, Effect of epididymitis on semen
biochemical and sperm morphology param-
eters. Urologe A, 2004. 43(Suppl 1): S81.
33. Haidl G and Opper C, Changes in lipids
and membrane anisotropy in human sper-
matozoa during epididymal maturation.
Hum Reprod, 1997. 12(12): 2720–3.
34. Weidner W, Garbe C, Weissbach L,
Harbrecht J, Kleinschmidt K, Schiefer
HG, and Friedrich HJ, [Initial therapy
of acute unilateral epididymitis using
ofloxacin. I. Clinical and microbiological
findings]. Urologe A, 1990. 29(5): 272–6.
Epididymitis and orchitis | 13.4 |
35. Weidner W, Garbe C, Weissbach L,
Harbrecht J, Kleinschmidt K, Schiefer
HG, and Friedrich HJ, [Initial therapy
of acute unilateral epididymitis using
ofloxacin. II. Andrological findings].
Urologe A, 1990. 29(5): 277–80.
36. Eickhoff JH, Frimodt-Moller N, Walter
S, and Frimodt-Moller C, A double-blind,
randomized, controlled multicentre study
to compare the efficacy of ciprofloxacin
with pivampicillin as oral therapy for
epididymitis in men over 40 years of age.
BJU Int, 1999. 84(7): 827–34.
37. Melekos MD and Asbach HW,
Epididymitis: aspects concerning etiology
and treatment. J Urol, 1987. 138(1): 83–6.
38. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H, Lobel
B, Jinenez Cruz F, and Selvaggi FP, EAU
guidelines for the management of urinary
and male genital tract infections. Urinary
Tract Infection (UTI) Working Group
of the Health Care Office (HCO) of the
European Association of Urology (EAU).
Eur Urol, 2001. 40(5): 576–88.
39. Surveillance of antibiotic resistance
in Neisseria gonorrhoeae in the WHO
Western Pacific Region, 2005. Commun
Dis Intell, 2006. 30(4): 430–3.
40. Vieler E, Jantos C, Schmidts HL, Weidner
W, and Schiefer HG, Comparative effi-
cacies of ofloxacin, cefotaxime, and
doxycycline for treatment of experimental
epididymitis due to Escherichia coli in
rats. Antimicrob Agents Chemother, 1993.
37(4): 846–50.
41. Ku JH, Kim YH, Jeon YS, and Lee NK,
The preventive effect of systemic treat-
ment with interferon-alpha2B for infertil-
ity from mumps orchitis. BJU Int, 1999.
84(7): 839–42.
42. Yeniyol CO, Sorguc S, Minareci S, and
Ayder AR, Role of interferon-alpha-2B
in prevention of testicular atrophy with
unilateral mumps orchitis. Urology, 2000.
55(6): 931–3.
43. Vicari E and Mongioi A, Effectiveness of
long-acting gonadotrophin-releasing hor-
mone agonist treatment in combination
with conventional therapy on testicular
outcome in human orchitis/epididymo-
orchitis. Hum Reprod, 1995. 10(8): 2072–8.
751
|13.5|

Chronic urogenital infections:

alterations of sperm quality and
potential impact on male fertility
Wolfgang Weidner, Thorsten Diemer
Department of Urology, Pediatric Urology and Andrology, University of Giessen, Giessen, Germany, Department of
Urology, Pediatric Urology and Andrology, Justus-Liebig-University of Giessen, Germany
Corresponding author: Wolfgang Weidner, MD, PhD, Professor of Urology and Head of Department of Urology, Pediatric
Urology and Andrology, Justus Liebig-University Giessen, Rudolf-Buchheim-Str. 7, D-35392 Giessen, Germany
Tel. +49 641 99 44 501, Fax +49 641 99 44 509, Email: Wolfgang.Weidner@chiru.med.uni-giessen.de

ABSTRACT Key words: urogenital infections, bacte-

Urogenital infections and inflamma-
tion are proven causes of male infertil-
ity. Underlying entities, e.g. the poorly
defined “Male Accessory Gland Infection”,
are often related to infections and inflam-
mation of the prostate gland, which con-
tributes about 70–90% to the ejaculate.
Bacteriospermia and leukocytospermia
are typical “markers” for chronic uro-
genital infections; the relevance for both
findings is debatable depending upon
cutpoints and status of infection and
inflammation. Alterations of sperm count,
motility and sperm morphology do occur
in this context, the biological significance
remains debatable. This is the same with
alterations of seminal plasma.
riospermia, leukozytospermia, male infer-
tility, chronic bacterial prostatitis, CP/
CPPS
SUMMARY OF RECOMMENDATIONS
1. OAT-syndrom appears not to be rel-
evant in CBP and CP/CPPS (LoE 2,
GoR B).
2. Increased morphological abnor-
malites of spermatozoa are detectable
in CP/CPPS (LoE 3, GoR C).
3. Bacteriospermia is common in CBP.
The definition of biological significance
is different for the pathogens (e.g.
E. coli, St. faecalis, U. urealyticum,

C. trachomatis) in urogenital infec-
tions (LoE 2, GoR B).
4. Leukozytospermia is debatable in cut-
points and relevance for bacteriosper-
mia. Addition of other inflammatory
parameters, e.g. elastase or IL-8, is
under debate for a better diagnosis of
inflammation in the seminal pathways
(LoE 4, GoR C).
5. Cytokine-evaluation may support
“inflammation” as diagnostic marker.
Negative effects on sperm motility are
debatable (LoE 3 GoR B). Oxidative
Stress (ROS↑) is correlated with rising
number of leukocytes and impaired
fertility (LoE 3, GoR C). ASA do not
demonstrate an association to urogeni-
tal infections (LoE 2, GoR A).
6. Seminal plasma alterations occur
in CP/CPPS. The significance remains
unclear.
1. INTRODUCTION
Urogenital infections and inflammation
are accepted causes of male infertility.
The percentage of men in andrological
populations with infectious and inflam-
matory entities is between 6.9% [1] and
8% [2]. Underlying diseases, diagnosed in
this context are chronic urethritis, chronic
bacterial prostatitis (CBP) and inflam-
matory chronic prostatitis/chronic pelvic
pain syndrome (CP/CPPS) [3]. Orchitits
and epididymitis, also significant for
male infertility [4], are covered in a sepa-
rate chapter of this book. Male accessory
gland infection (MAGI), as defined by the
WHO [5], is also addressed separately.
The purpose of this text is to define the
evidence of current data demonstrating
negative influence of the described enti-
ties on standard ejaculate parameters
including sperm count and morphology,
motility disorders due to bacteriospermia,
induction of sperm antibodies and inflam-
mation – related changes of the ejaculate
and seminal plasma alterations. Finally,
Chronic urogenital infections | 13.5 |
infection-associated therapeutic altera-
tions will be addressed.
2. OBJECTIVES
A short classification of chronic urethritis,
CBP, CP/CPPS and MAGI from an andro-
logical point of view will be provided.
Then we defined questions concerning
altered ejaculate parameters are defined
that influence male fertility in a nega-
tive way in men suffering from the above
mentioned entitities:
1. What is the relevance of OAT (oligo-
astheno-teratozoospermia) syndrome?
2. Are there infectious/inflammatory
related alterations of sperm
morphology?
3. Is there an accepted definition of bac-
teriospermia and a defined interaction
to spermatozoa?
4. What is the importance of leukocyt-
ospermia in this context?
5. What is the importance of cytokines,
ROS and sperm antibodies in the
inflammatory/infectious situation?
6. Do seminal plasma alterations play a
role in urogenital infections?
Finally, a short statement to infection-
related therapy is given.
3. METHODS
We searched the Pubmed database cover-
ing the last eight years (English-German)
using the search terms: male infertil-
ity, ejaculate parameters, chronic ure-
thritis, chronic bacterial prostatitis, CP/
CPPS, MAGI, ejaculate infection, ejacu-
late inflammation, sperm morphology,
sperm motility, seminal plasma altera-
tions, ROS, bacteriospermia, leukocyt-
ospermia, seminal plasma cytokines,
ASA. Furthermore, all reviewed sup-
plements (2000–2008), covering the
topic urogenital infections of Andrologia,
753
Chapter | 13 | Epididymitis, orchitis, prostatitis
Human Reproduction, European Urology
and Fertility & Sterility have been looked
through for issues addressing male
infertility in its relation to infections/
inflammations of the urogenital tract.
These searches identified a total of 127
articles, which were screened by title and
abstracts. 45 publications met the inclusion
criteria. Unfortunately there were not any
systematic reviews, metaanalyses, or ran-
domized clinical trial. They only included
non-randomized trials, case reports, case
report series and expert opinions.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [6–7].
4. CLASSIFICATION OF INFECTIOUS/
INFLAMMATORY DISEASES
4.1 Chronic urethritis
The definition of chronic urethritis is not
really clear. Patients, without urethral
discharge, suffer from burning and ure-
thral itching during voiding. Chlamydial
and gonococcal infections are typical etio-
logical causes [8]. Normally, the diagnosis
is based on the evidence of leukocytes in
the first voided urine and PCR findings of
the mentioned microorganisms. Taking
together, sexually transmitted infec-
tions represent the predominant causes
for chronic urethritis, but non-infectious
causes (physical, postendos-copy) also have
to be considered [9] (LoE 4, GoR C).
4.2 Chronic bacterial prostatitis
Chronic Bacterial Prostatitis (CBP) is
an accepted cause for bacteriospermia in
men [3, 10] 8). This entitity is covered in
a special chapter of this book by Krieger
& Wagenlehner.
4.3 CP/CPPS
The andrological relevance of the con-
sensus findings of the 6th International
754
Consultation on New Developments in
Prostate Cancer and Prostate Diseases
[10] has been discussed recently [3]. This
paper thoroughly evaluates the consensus
summary statement of the Paris expert
group with particular focus on the feasi-
bility of suggested diagnostic procedures
and therapeutic trials in the andrologi-
cal context [3]. Although not worldwide
accepted in Andrology, all statements
and suggestions [3, 10] are based on the
National Institutes of Health (NIH) classi-
fication of prostatitis syndromes (Table 1)
(LoE 4, GoR C).
4.4 MAGI
The WHO [5] suggests that two of the fol-
lowing criteria are required to diagnose
MAGI in men with oligo-, astheno- or
teratozoospermia: (i) history or physical
signs of UTI, epididymitis, or abnormal
rectal examination; (ii) abnormal urine
after prostatic massage (describing the
four-glass test); or (iii) elevated num-
bers of peroxidase positive white blood
cells (WBCs), high numbers of bacteria
in semen, C. trachomatis findings, and/
or abnormal biochemistry or elevated
inflammatory markers in the seminal
fluid. Analysis of prostatic fluid is not rec-
ommended. This suggested classification
does not clearly differentiate between
prostatitis, epididymitis, and inflamma-
tory alterations of the urethral compart-
ment [3] (LoE 4, GoR C).
Table 1 Prostatitis NIH Classification.
I Acute Bacterial (ABP)
II Chronic Bacterial (CBP)
III Chronic Prostatitis/Chronic Pelvic Pain Syndrome
(CP/CPPS)
a) inflammatory
b) non-inflammatory
IV Asymptomatic, Inflammatory
NIH (National Institutes of Health)

4.5 Evidence of OAT-syndrome
In men with evidence of DNA from sexu-
ally transmitted infectious pathogens
in semen a decrease of sperm concen-
tration and motility has been observed
[11]. Urethritis “per se” seems not to be
a major problem. After chronic urethri-
tis, the development of obstruction either
as normal stricture or at the level of the
veromontanum has been discussed as a
cause of decreased ejaculate volume [4].
HIV infections have a negative impact
on testicular function with progression
of immunodeficiency, but the percent-
age of OAT-syndrome is not described in
detail [12].
In this context, especially data for
CBP and CP/CPPS are of high impor-
tance. Available data on prostatitis do
not demonstrate reduced ejaculatory
volumina in men with non-inflamma-
tory CP/CPPS [13]; this is similar to
other data demonstrating no reduced
ejaculate volume in men with inflam-
matory signs in the ejaculate [14].
These examinations reconfirm earlier
findings that sperm count, motility and
morphology are unlikely to be affected
[14] (LoE 2, GoR B). Table 2 summa-
rizes abailable data demonstrating no
significant effect on sperm count, motil-
ity and morphology in infectious and
inflammatory prostatitis (NIH II and
NIH IIIa).
Table 2 OAT-syndrome in men with CBP (NIH II) and CP/CPPS (NIH III).
Cohort n Reference
276 [15]
44 [16]
112 [14]
30 [13]
*p.001 = s. better motility than controls; NS = not significant
Chronic urogenital infections | 13.5 |
5. MORPHOLOGY
5.1 Morphology according to “strict
criteria“
In cases with chronic epididymitis
increased numbers of macrophages and
disturbed epididymal maturation seem
to be predominant, as indicated by blue
immotilized flagella in SHORR stain
(overview in [17]). The clinical impact
of these findings remains in association
to DBP and CP/CPPS remains unclear.
Our data, using strict criteria, provide
evidence that a negative effect is evalu-
able in inflammatory chronic prostatitis/
chronic pelvic pain syndrome [18] (LoE 3,
GoR B).
5.2 Morphological findings affecting
the acrosome
It is evident that microorganisms adhere
to spermatozoal membranes resulting in
ultrastructural alterations and damage
of the plasma membrane also involving
the head of the spermatozoa including
the acrosome [19]. Leukozytospermia
has been discussed as cause for abnor-
mal morphology and midpiece abnormali-
ties not depending upon the underlying
entity [20]. Unfortunately clear study
results are not available, in inflammatory
CP/CPPS associated with leukocytosper-
mia significant morphological alterations
Significant changes to controls
NIH Groups Sperm count Motility Morphology
II, IIIa, IIIb NS NS NS
IIIa, IIIb NS NS NS
IIIa, IIIb NS NS NS
IIIb NS p.001* NS
755
Chapter | 13 | Epididymitis, orchitis, prostatitis
are not detectable [16], other data in
inflammatory and non inflammatory CP/
CPPS demonstrate poorer sperm mor-
phology compared to controls and a sig-
nificantly reduced acrosomal inducibility
[21] (LoE 3, GoR C).
6. BACTERIOSPERMIA
After exclusion of urethritis and blad-
der infection, the presence of ≥1,000,000
peroxidase-positive WBC/ml ejaculate
indicates an inflammatory process [3, 5].
In these cases a culture for common uri-
nary tract pathogens, especially gram-
negative bacteria, should be performed.
It must be kept in mind that ejaculate
analysis does not allow a definitive locali-
zation of the infectious process, because
ejaculate represents a mixture of dif-
ferent genital secretions and is usually
contaminated by flora of the anterior
urethra. The most common bacteria
are Escherichia coli, Enterococcus fae-
calis and Ureaplasma urealyticum [22].
Unfortunately, conventional counting of
WBCs has only a poor sensitivity/specifity
for the detection of bacteria due to
unclear cutpoints, different identification
techniques and spontaneous resolution
due to phagocytal activity and apoptosis
[23] (LoE 3, GoR B). Furthermore com-
parative data are available comparing
bacterial counts from first void urine,
midstream urine, semen, WBCs in semen
and pregnancy rates giving no correla-
tion [24]. A concentration ≥1000 cfu/ml of
urinary tract pathogens in the ejaculate
is regarded as significant bacteriosper-
mia [3–4] (LoE 4, GoR C). Cleaning of
the foreskin and the glans penis reduces
the bacterial content [25]. Nevertheless,
we know that about 70% of randomized
semen samples are contaminated with
non-pathogenic bacteria, so bacteriosper-
mia does not inevitably mean infection
[26]. On the other hand, bacteriospermia
is significantly represented (about 50%)
756
in patients with bacterial prostatitis
[3, 10] (LoE 2, GoR B).
6.1 Direct interactions between
spermatozoa and bacteria
Some pathogenic microorganisms have
the ability to directly interact with sper-
matozoa. Attachments between bacte-
ria and spermatozoa are followed by
agglutination phenomena and morpho-
logical alterations of spermatozoa [19].
The majority of observations of these
phenomena are derived from experi-
mental in vitro studies and their sig-
nificance for in vivo infections has been
questioned. Among bacterial species
that interact with spermatozoa are well-
established causative pathogens of geni-
tourinary infections such as Escherichia
(E.) coli, Ureaplasma (U.) urealyticum,
Mycoplasma (M.) hominis and Chlamydia
(C.) trachomatis [27]. E. coli likely rep-
resents the most frequently isolated
microorganism in cases of genitourinary
infections. E. coli rapidly adheres to
human spermatozoa in vitro, resulting
in agglutination of spermatozoa. A pro-
found decline in sperm motility is evident
over time caused by severe alterations in
sperm morphology [28]. Morphological
alterations involve both defects of the
plasma membrane and degeneration of
acrosomes. U. urealyticum also attaches
to plasma membranes of spermatozoa
and affects motility, but seems not to
have a clinical effect on sperm quality
[29]. Specific defects localized to heads
of spermatozoa including acrosomal
structures have been observed for C. tra-
chomatis [30]. Bacterial concentrations
utilized in vitro experiments undoubtedly
are much higher than ever recoverable
from ejaculate specimens. This condition
might contribute considerably to the out-
come of the studies. Similar discrepancies
have bee observed in tests for the induc-
ibility of the acrosome reaction in artifi-
cially infected semen samples. None of

these phenomena evident in vitro clearly
has been documented in semen speci-
mens of patients with MAGI. As bacte-
rial concentrations required for affecting
sperm motility, morphology, and function
are considerably high, the clinical impact
remains unclear also concerning interac-
tion to inflammation [27, 31].
6.2 C. trachomatis in semen
The diagnostic difficulty with C. trachom-
atis infections has provoked researchers to
develop new molecular methods to detect
this microorganism in semen. However,
until now an “ideal“ diagnostic test for
C. trachomatis in semen has not been
established [30]. In contrast to serological
findings in women, serological tests for
C. trachomatis in seminal plasma are not
indicative if no type-specific methods are
used. Unfortunately, the high frequency
of serum antibodies and seminal plasma
activity in both infertile and healthy men
hampers a clear differentiation [30]. This
problem is also the cause for the debate
on the association of chlamydial antibod-
ies with leukocytospermia. Questionable,
the interaction between IL-8 and anti-
chlamydial mucosal Ig-A in the ejaculate
provides a new chance for a better, clear
diagnosis [31]. Numerous publications
cover the problem of C. trachomatis infec-
tions and changes of semen quality, but
unfortunately the data are confusing and
provide no clear evidence for significant
alterations [32].
7. LEUKOCYTOSPERMIA
The clinical significance of an increased
concentration of WBCs in the ejaculate
is highly controversial [33]. It is gener-
ally accepted that only an increased
number of leukocytes (particularly poly-
morphonuclear granulocytes) and their
products secreted into the seminal fluid
(e.g. leukocyte elastase) are an indica-
tor of inflammation. According to WHO
Chronic urogenital infections | 13.5 |
Table 3 Cutpoints for expressed prostatic secretions
EPS, urine after P.M. (VB3) and ejaculate/seminal plasma
parameters indicative for inflammation (according to [36]).
Parameter Cutpoint
EPS Leukocytes ≥10–20/1000 x
VB3 Leukocytes ≥10/mm³
Semen PPL ≥0.113 x 106/ml
Seminal plasma Elastase ≥280 ng/ml
Seminal plasma IL-8 >10600 pg/ml
classification the presence of ≥1 × 1000
000 WBC/ml is defined as leukocytosper-
mia [3, 5, 10] (LoE 4, GoR C). The great
majority of leukocytes are polymorphnu-
clear granulocytes, (PMN) as suggested
by the specific staining of the peroxi-
dase reaction. Although most authors
consider leukocytospermia to be a sign
of bacterial induced inflammation, this
condition is not necessarily associated
with bacterial or viral infections. This
is in accordance with earlier findings
that elevated leukocyte numbers are not
a natural cause of male infertility [34].
Only a few studies have analyzed altera-
tions of WBC in the ejaculate of patients
with proven prostatitis (overview in
[27]) demonstrating a higher number of
leukocytes in men with proven bacterial
infections. There is also an obvious reso-
lution of leukocytospermia after antibi-
otic therapy [35]. Despite these data, the
influence of leukocytospermia on sperm
function is complex and not really clari-
fied in much detail. It is the suggestion
of the authors to re-establish the result
of inflammation in all men with leu-
kocytospermia using elastase and/or
IL-8 determination. In case of a proven
inflammatory situation, exclusion of a
bacterial infection including CBP and
Epididymitis appears seems to be man-
datory. Table 3 summarizes our current
inflammatory cut-points in prostatic
secretions (EPS) and ejaculate for the
routinely use [36] (LoE 4, GoR C).
757
Chapter | 13 | Epididymitis, orchitis, prostatitis
8. CYTOKINES, ROS AND SPERM
ANTIBODIES (ASA)
8.1 Cytokines
Cytokines are inflammatory mediators
secreted by activated leukocytes or other
immunocompetent cells in semen. The
role of these cytokines (IL-6, 8) is decisive
for the course of the inflammatory reac-
tion [37]. The deleterious effects of these
proinflammatory cytokines on the motil-
ity and the function of spermatozoa have
been observed in experimental and clini-
cal studies (overview in [38]) (LoE 3, GoR
B). The proinflammatory cytokines also
affect Leydig cells that, which produce
the gonadal steroids; this effect has been
verified after the induction of bacterial
Lipopolysaccharide (LPS) in mice, causing
immediate degradation of steroidogenesis
[39]. Since recent studies demonstrate
a high correlation between IL-8 levels
and elastase in seminal plasma [40], the
measurement of one of these both inflam-
matory parameters seems mandatory to
us mandatory in the suspected inflam-
matory situation of the urogenital tract
(LoE 3, GoR B).
8.2 Reactive oxygen species (ROS)
The ROS-source in semen are the poly-
morphonuclear granulocytes (PMN) and
the seminal macrophages in response to
cytokine-stimulating factors, enhanced in
the presence of cytokines and LPS. In a
normal situation, the antioxidant mech-
anisms of seminal plasma are likely to
quench these ROS and protect against
any spermatozoal damage. However, dur-
ing infection/inflammation these antioxi-
dant mechanisms may create a situation
called ‘oxidative stress’ due to the ele-
vated levels of ROS beyond the available
total antioxidant capacity in the semen
[41]. At present “oxidative stress” is cor-
related with rising WBCs and impaired
fertility [41] (LoE 3, GoR C).
758
8.3 Anti-sperm Antibodies (ASA)
The relevance of seminal plasma
antibodies in genitourinary infections
is still debatable. Some authors suggest
an association between increased levels
of sperm antibodies and prostatitis [42],
also associations between chlamydial
infections and sperm antibodies have
been described [43]. The prevalence of
MAGI in patients with a positive mixed
antiglobulin (MAR) test seems to be in
the range of 20%, whereby it is generally
accepted that only antibodies bound to
surface antigen of vital spermatozoa are
clinically significant [44]. Own data in
chronic urethritis, epididymitis and CP/
CPPS do not demonstrate an association
between proven inflammatory/infectious
diseases of the male reproductive tract
and the presence of ASA [45] (LoE 2,
GoR A).
9. SEMINAL PLASMA ALTERATIONS
The first demonstration that infection of
the sex glands could impair their excre-
tory function was made in the late 1960s.
Decreased quantities of citric acid, phos-
phatase, fructose concentration, zinc and
alpha-glutamyltransferase (α-γ-GT) activ-
ity have been evaluated as disturbed pro-
static secretory parameters and reduced
fructose concentration as indicator of
disturbed vesicular function (overview in
[4]) (LoE 4, GoR C). Epididymitis reduces
the quantity of the epididymal marker
alpha-glucosidase [46]. Fructose has been
found reduced in asymptomatic men with
leukocytospermia and in severe prostato-
vesiculitis (overview in [4]). Own data in
inflammatory CP/CPPS provide evidence
that in cases with elevated numbers of
granulocytes in EPS, secretory damage of
the prostate gland is detectable [14] (LoE
3, GoR B). Neverless, the biological role
remains unclear.

10. INFECTION-RELATED THERAPY
AND INTERACTIONS TO SPERM
QUALITY
Therapy in infectious diseases of the
urogenital tract is normally targeted to
relieve symptoms [3, 10]. Andrologically,
targets of therapy regarding altered semen
composition in male adnexitis include:
• Eradication or reduction of microor-
ganisms in prostatic secretions and in
semen.
• If possible, normalization of inflam-
matory parameters such as leuko-
cytes and inflammatory secretory
parameters.
• If possible, improvement of sperm
parameters to counteract impaired
fertility (3) (LoE 4, GoR C).
Modalities of therapy include surgi-
cal procedures, antibiotics, antiphlogistic
drugs, normalization of urine flow, physi-
cal therapy, and changes in general and
sexual behavior [10]. Transurethral sur-
gery in chronic bacterial prostatitis means
radical transurethral resection of the pros-
tate (TUR-P) [10]. It is generally accepted
that only patients with a stubborn resist-
ance to long-term medical treatment,
remaining symptomatic with a concomi-
tant obstruction can be considered for rad-
ical resection, e.g., including the removal
of prostatic calculi which act as perma-
nent foci of infection. This therapy results
in permanent retrograde ejaculation.
Unfortunately, until now only the
antibiotic therapy of CBP has proved to
be really efficacious in providing symp-
tomatic relief, eradication of microor-
ganisms and a decrease in cellular and
humoral inflammatory parameters in uro-
genital secretions [3, 10]. Although antibi-
otic therapy provides an improvement in
male sperm quality in some studies (over-
view in [3]), therapy does not enhance the
probability of conception. Why is it so dif-
ficult to demonstrate an antibiotic effect
Chronic urogenital infections | 13.5 |
on sperm quality in cases with prostati-
tis, if this infection is a major factor for
this disorder? It has been hypothesized
that only men with a chronic active infec-
tion, “where the pathological organism
is still present and where the degree of
damage is still limited”, may benefit from
a suitable therapy. However, when focus-
ing on prostatitis, only CBP is a type of
infection which may correctly fit into this
category. This is a type of infection, which
is evaluable in only 5–10% of Prostatitis/
chronic pelvic pain patients [10]. Modern
fluoroquinolones are ideal therapeutic
substances and show bacteriologic cure
rates between 60 to 86% (see the separate
chapter in this book). On the other hand,
we do not consider that common antibi-
otic substances in normal ‘in-vivo’ dosage
really affect spermatogenesis and sperm
function. Therefore, it seems to us abso-
lutely necessary to re-analyze the influ-
ence of antibacterial treatment on sperm
quality, sperm function and secretory
disorders following the new classification
proposal of prostatitis-syndrome [3]. If
this work is done, then new studies have
to be scheduled to analyse the outcome
for the infertile couple with pregnancy as
the goal of therapeutic effect.
11. FURTHER RESEARCH
Targets of research include the investi-
gation of molecular tools which interact
between microorganisms “triggering”
infection, development of inflammation
and disturbances of spermatogenesis.
Today, the testicular compartment seems
to be the “key” for understanding dis-
turbed semen quality and chronic inflam-
mation as sequaela of urogenital infection
in (sub-)fertile men with poor sperm qual-
ity. Clinically, infection-related therapy
has to be evaluated in prospective studies
for improvement of sperm quality and the
possible impact on male infertility.
759
Chapter | 13 | Epididymitis, orchitis, prostatitis

12. CONCLUSIONS 8. Schiefer HG, Microbiology of male ure-

throadnexitis: diagnostic procedures
The data provide evidence that in men and criteria for aetiologic classification.
with alterations of the ejaculate, chronic Andrologia, 1998. 30 Suppl 1: 7–13.
urogenital infections have to be con- 9. Schneede P, Tenke P, and Hofstetter AG,
Sexually transmitted diseases (STDs) – a
sidered. Clear diagnostic criteria are
synoptic overview for urologists. Eur Urol,
necessary to define underlying entities
2003. 44(1): 1–7.
especially chronic bacterial prostatitis
10. Schaeffer AJ, Anderson RU, Krieger JN,
and inflammatory CP/CPPS. Infection- Lobel B, Naber K, Nakagawa M, Nickel
related therapy does not improve the fer- JC, Nyberg L, and Weidner W, The assess-
tility status in most of these men with ment and management of male pelvic
chronic diseases. pain syndrome including prostatitis, in
Male Lower Urinary Tract Dysfunction.
REFERENCES Evaluation and Management. 6th
International Consultation in Prostate
Cancer and Prostate Diseases, McConnel
1. WHO Task Force on The Diagnosis and
J, Abrams P, Denis L, Khoury S, and
Treatment of Infertility, Towards more
Roehrborn C, Editors. 2006, Health
objectivity in diagnosis and manage-
Publications: Paris. p. 343–385.
ment of male infertility. Int J Androl
11. Bezold G, Politch JA, Kiviat NB,
1987(Suppl 7): 1–53.
Kuypers JM, Wolff H, and Anderson DJ,
2. Nieschlag E, Nosologie andrologischer
Prevalence of sexually transmissible path-
Krankheitsbilder, in Andrologie.
ogens in semen from asymptomatic male
Grundlagen und Klinik der reproduktiven
infertility patients with and without leu-
Gesundheit des Mannes., Nieschlag E and
kocytospermia. Fertil Steril, 2007. 87(5):
Behre H, Editors. 2002, Springer: Berlin.
1087–97.
p. 91–95.
12. Ochsendorf FR, Sexually transmit-
3. Weidner W, Wagenlehner FM, Marconi M,
ted infections: impact on male fertility.
Pilatz A, Pantke KH, and Diemer T, Acute
Andrologia, 2008. 40(2): 72–5.
bacterial prostatitis and chronic prostati-
13. Engeler DS, Hauri D, and John H, Impact
tis/chronic pelvic pain syndrome: andro-
of prostatitis NIH IIIB (prostatodynia)
logical implications. Andrologia, 2008.
on ejaculate parameters. Eur Urol, 2003.
40(2): 105–12.
44(5): 546–8.
4. Weidner W, Krause W, and Ludwig M,
14. Ludwig M, Vidal A, Diemer T, Pabst W,
Relevance of male accessory gland infec-
Failing K, and Weidner W, Seminal secre-
tion for subsequent fertility with special
tory capacity of the male accessory sex
focus on prostatitis. Hum Reprod Update,
glands in chronic pelvic pain syndrome
1999. 5(5): 421–32.
(CPPS)/chronic prostatitis with special
5. Rowe PJ, WHO manual for the stand-
focus on the new prostatitis classification.
ardized investigation and diagnosis of
Eur Urol, 2002. 42(1): 24–8.
the infertile couple. 1993: Cambridge
15. Weidner W, Jantos C, Schiefer HG, Haidl
University Press on behalf of the World
G, and Friedrich HJ, Semen parameters in
Health Organization.
men with and without proven chronic pros-
6. Abrams P, Khoury S, and Grant A,
tatitis. Arch Androl, 1991. 26(3): 173–83.
Evidence – based medicine overview of the
16. Pasqualotto FF, Sharma RK, Potts JM,
main steps for developing and grading
Nelson DR, Thomas AJ, and Agarwal A,
guideline recommendations. Prog Urol,
Seminal oxidative stress in patients with
2007. 17(3): 681–4.
chronic prostatitis. Urology, 2000. 55(6):
7. U.S. Department of Health and Human
881–5.
Services Public Health Service Agency for
17. Haidl G, Allam JP, and Schuppe HC,
Health Care Policy and Research, 1992:
Chronic epididymitis: impact on semen
115–127.

760

parameters and therapeutic options.
Andrologia, 2008. 40(2): 92–6.
18. Menkveld R, Huwe P, Ludwig M, and
Weidner W, Morphological sperm alter-
nations in different types of prostatitis.
Andrologia, 2003. 35(5): 288–93.
19. Diemer T, Huwe P, Michelmann HW,
Mayer F, Schiefer HG, and Weidner W,
Escherichia coli-induced alterations of
human spermatozoa. An electron micros-
copy analysis. Int J Androl, 2000. 23(3):
178–86.
20. Thomas J, Fishel SB, Hall JA, Green S,
Newton TA, and Thornton SJ, Increased
polymorphonuclear granulocytes in semi-
nal plasma in relation to sperm morphol-
ogy. Hum Reprod, 1997. 12(11): 2418–21.
21. Henkel R, Ludwig M, Schuppe HC,
Diemer T, Schill WB, and Weidner W,
Chronic pelvic pain syndrome/chronic
prostatitis affect the acrosome reaction in
human spermatozoa. World J Urol, 2006.
24(1): 39–44.
22. Lackner J, Schatzl G, Horvath S, Kratzik
C, and Marberger M, Value of counting
white blood cells (WBC) in semen samples
to predict the presence of bacteria. Eur Urol,
2006. 49(1): 148–52; discussion 152–3.
23. Weidner W, Editorial comment. Eur Urol,
2006. 49: 152–3.
24. Gdoura R, Kchaou W, Ammar-Keskes
L, Chakroun N, Sellemi A, Znazen A,
Rebai T, and Hammami A, Assessment
of Chlamydia trachomatis, Ureaplasma
urealyticum, Ureaplasma parvum,
Mycoplasma hominis, and Mycoplasma
genitalium in semen and first void urine
specimens of asymptomatic male partners
of infertile couples. J Androl, 2008. 29(2):
198–206.
25. Kim FY and Goldstein M, Antibacterial
skin preparation decreases the incidence
of false-positive semen culture results. J
Urol, 1999. 161(3): 819–21.
26. Cottell E, Harrison RF, McCaffrey M,
Walsh T, Mallon E, and Barry-Kinsella C,
Are seminal fluid microorganisms of sig-
nificance or merely contaminants? Fertil
Steril, 2000. 74(3): 465–70.
27. Diemer T, Ludwig M, Huwe P, Hales DB,
and Weidner W, Influence of urogenital
infection on sperm function. Curr Opin
Urol, 2000. 10(1): 39–44.
Chronic urogenital infections | 13.5 |
28. Diemer T, Huwe P, Ludwig M, Hauck EW,
and W W, Urogenital infections and sperm
motility. Andrologia, 2003. 35: 283–287.
29. Wang Y, Liang CL, Wu JQ, Xu C,
Qin SX, and Gao ES, Do Ureaplasma
urealyticum infections in the genital tract
affect semen quality? Asian J Androl,
2006. 8(5): 562–8.
30. Weidner W, Diemer T, Huwe P, Rainer
H, and Ludwig M, The role of Chlamydia
trachomatis in prostatitis. Int J
Antimicrob Agents, 2002. 19(6): 466–70.
31. Mazzoli S, Cai T, Rupealta V, Gavazzi
A, Castricchi Pagliai R, Mondaini N,
and Bartoletti R, Interleukin 8 and anti-
chlamydia trachomatis mucosal IgA
as urogenital immunologic markers in
patients with C. trachomatis prostatic
infection. Eur Urol, 2007. 51(5): 1385–93.
32. Gonzales GT, Munoz G, Sanchez R,
Henkel R, Gallegos-Avila G, Diaz-
Gutierrez O, Vigil P, Vasquez F, Kartebani
G, Mazzoli A, and Bustor-Obregon E,
Update on the impact of C. trachomatis
infection on male infertility. Andrologia,
2004. 36: 1–12.
33. Gdoura R, Kchaou W, Znazen A,
Chakroun N, Fourati M, Ammar-Keskes
L, and Hammami A, Screening for bacte-
rial pathogens in semen samples from
infertile men with and without leuko-
cytospermia. Andrologia, 2008. 40(4):
209–18.
34. Tomlinson MJ, Barratt CL, and Cooke ID,
Prospective study of leukocytes and leu-
kocyte subpopulations in semen suggests
they are not a cause of male infertility.
Fertil Steril, 1993. 60(6): 1069–75.
35. Branigan EF and Muller CH, Efficacy of
treatment and recurrence rate of leukocyt-
ospermia in infertile men with prostatitis.
Fertil Steril, 1994. 62(3): 580–4.
36. Wagenlehner FME, Naber KG,
Bschleipfer T, Brähler E, and Weidner
W, Diagnostik und Therapie der
Prostatitis und des männlichen
Beckenschmerzsyndroms. Dtsch
Ärzteblatt, in press.
37. Zalata A, Hafez T, Van Hoecke MJ, and
Comhaire F, Evaluation of beta-endorphin
and interleukin-6 in seminal plasma of
patients with certain andrological dis-
eases. Hum Reprod, 1995. 10(12): 3161–5.
761
Chapter | 13 | Epididymitis, orchitis, prostatitis
38. Diemer T, Hales DB, and Weidner W,
Immune-endocrine interactions and
Leydig cell function: the role of cytokines.
Andrologia, 2003. 35(1): 55–63.
39. Hales DB, Diemer T, and Hales KH,
Role of cytokines in testicular function.
Endocrine, 1999. 10(3): 201–17.
40. Penna G, Mondaini N, Amuchastegui S,
Degli Innocenti S, Carini M, Giubilei G,
Fibbi B, Colli E, Maggi M, and Adorini
L, Seminal plasma cytokines and
chemokines in prostate inflammation:
interleukin 8 as a predictive biomarker
in chronic prostatitis/chronic pelvic
pain syndrome and benign prostatic
hyperplasia. Eur Urol, 2007. 51(2):
524–33; discussion 533.
41. Agarwal A and Saleh RA, Role of oxidants
in male infertility: rationale, significance,
and treatment. Urol Clin North Am, 2002.
29(4): 817–27.
42. Hinting A, Soebadi DM, and Santoso RI,
Evaluation of the immunological cause of
762
male infertility. Andrologia, 1996. 28(2):
123–6.
43. Dimitrova D, Kalaydjiev S, Hristov L,
Nikolov K, Boyadjiev T, and Nakov L,
Antichlamydial and antisperm antibodies
in patients with chlamydial infections. Am
J Reprod Immunol, 2004. 52(5): 330–6.
44. Mazumdar S and Levine AS, Antisperm
antibodies: etiology, pathogenesis, diag-
nosis, and treatment. Fertil Steril, 1998.
70(5): 799–810.
45. Marconi M, Pilatz A, Wagenlehner F,
Diemer T, and Weidner W, Are antisperm
antibodies really associated with proven
inflammatory, infectious diseases of the
male reproductive tract. Eur Urol, in press.
46. Cooper TG, Weidner W, and Nieschlag
E, The influence of inflammation of the
human male genital tract on secretion of
the seminal markers alpha-glucosidase,
glycerophosphocholine, carnitine, fructose
and citric acid. Int J Androl, 1990. 13(5):
329–36.
 Chapter |14|

Sexually transmitted
infectious diseases
Chair: John N. Krieger

CHAPTER OUTLINE
14.1 Introduction 764
14.2 Sexually transmitted infectious diseases (STDs) – updated
synopsis for practicing urologists 765
14.3 Urethritis 777
14.4 Pelvic infections in women 804
14.5 HIV infection in urological practice 830
14.6 Male circumcision and HIV infection risk 847
|14.1|
Introduction
John N. Krieger
John N. Krieger, M.D., Department of Urology, University of Washington, School of Medicine, Seattle, WA USA 98195
Tel: 206-543-3640, Fax: 206-764-2239, Email: jkrieger@u.washington.edu
Since antiquity, urologists have had the
responsibility to diagnose and manage
sexually transmitted infections and their
sequelae. Much has changed since I was a
medical student. In those olden days, we
were taught that there were five venereal
diseases: syphilis, gonorrhoea, donovano-
sis, lymphogranuloma venereum and chan-
croid. In the US, gonorrhoea and syphilis
were far more important than the others.
Imagine my frustration when I arrived
in urology clinic to find that most patients
with urethral symptoms and inflamma-
tion did not respond to treatment for gon-
orrhoea! We saw patients with genital
ulcers, but very few had syphilis. Now, we
have much more sophisticated insights
into the range of clinical STI presenta-
tions and the etiological agents. We have
greatly improved tools for diagnosis,
treatment, and, often, prevention.
The chapters in this section present a
concise summary of critical clinical infor-
mation. Remarkably, this information is
presented from a practical clinical stand-
point by active consultants. These author-
ities present a world-wide consensus
of what the urologist needs to know.
Drs. Peter Schneede and Boris Schlenker
from Klinikum Memmingen (Germany)
summarize current recommendations for
diagnosis and management of the com-
mon STI syndromes based on extensive
review of available guidelines. Dr. Ryoichi
Hamasuna from the University of
Miyazaki (Japan) summarizes diagno-
sis and treatment of urethritis in males
emphasizing the role of Mycoplasma geni-
talium. Dr. Gilbert Donders from Leuven
University (Belgium) describes the man-
agement and consequences of ascending
STIs in women. The final chapters cover
what the urologist should know about
HIV infection. Dr. Seung-Ju Lee from
Catholic University College of Medicine
(Korea) provides a concise summary of
HIV infection in urological practice. The
section concludes with a review of the
evidence on male circumcision and HIV
infection risk (John N. Krieger, University
of Washington, USA). Together, this sum-
mary emphasizes what is new, differ-
ent and important for everyday clinical
practice.
|14.2|
Sexually transmitted infectious
diseases (STDs): updated synopsis
for practicing urologists
Peter Schneede1, Boris Schlenker2
1
Department of Urology, Klinikum Memmingen, Germany
2
Department of Urology, University of Munich-Großhadern, Germany
Corresponding author: Peter Schneede, MD, PhD, Head of Department of Urology, Klinikum Memmingen,
Bismarckstr. 23, 87700 Memmingen, Germany
Tel. 0049 8331 702373, Fax: 0049 8331 702374, E-mail: Schneede.peter@klinikum-memmingen.de
ABSTRACT
This chapter updates the practicing urol-
ogist on current recommendations for
sexually transmitted infectious disease
(STD) diagnosis and clinical management
based on updated recommendations from
the EAU Urinary Tract Infection (UTI)
Working Group STD review, 2003 [1]].
The EAU review incorporated many of
the recent US Centers for Disease Control
and Prevention (CDC) recommendations
[2]. Because this information is topical
and important for urological practice we
were charged with providing a clinically-
focused synopsis, rather than a lengthy
evidence-based review.We also incorpo-
rated new antimicrobial recommenda-
tions and the recently approved human
papilloma virus (HPV) vaccines.
1. INTRODUCTION
The classical bacteria that cause venereal
diseases, e.g. gonorrhoea, syphilis, chan-
croid and granuloma inguinale account
for a small proportion known STDs today.
Other bacteria and viruses, as well as
yeasts, protozoa and epizoa must also be
regarded as causative organisms of STD.
More than 30 relevant bacteria and viruses
are now recognized as causes of STDs.
However, not all pathogens that can be sex-
ually transmitted cause genital diseases.
Furthermore, not all infections of the geni-
tals are exclusively sexually transmitted.
Concise information and tables summa-
rising the diagnosis and management of
important urological STDs are presented
based on recent international guidelines
[2–5]. In addition, we provide a resource
Chapter | 14 | Sexually transmitted infectious diseases
for information on other clinical syndromes
and infections that may be encountered
by the urologist (e.g., HIV infection, preg-
nancy, infants, allergy). Consequently, this
overview does not offer a list of references,
levels of evidence or grades of recommen-
dation. These are included in the more
detailed chapters which follow or can be
found in the recent international guide-
lines this overview is based on [2–11].
2. DEFINITIONS AND CLASSIFICATION
STDs can be categorized as curable or
incurable by currently available thera-
pies. The common curable STDs are gon-
orrhoea, chlamydial, mycoplasmal and
ureaplasmal infections, syphilis, tricho-
moniasis, chancroid, lymphogranuloma
venereum and donovanosis. In addition,
STDs caused by yeasts, protozoa and
epizoa can be cured. The STDs that are
preventable but not curable are the viral
STDs, including: human immunodefi-
ciency viruses (HIV), human papillomavi-
ruses (HPV), hepatitis B/C viruses (HBV,
HCV), cytomegalovirus (CMV) and herpes
simplex viruses (HSV).
Only those genital infections that are
indeed transmitted exclusively sexually
will be dealt with below. Other pathogens
that lead to organ manifestations consid-
ered primarily by other specialities will be
mentioned briefly in terms of their sexual
transmissibility and co-morbidity. With
regard to further details on these patho-
gens, the reader should refer to guide-
lines from appropriate specialist societies
and internet links [2–4, 6–11]. Clinical
pictures such as urethritis, genital ulcers,
prostatitis, and epididymitis characteris-
tic of by various STD pathogens in men
are not included in this overview.
This synopsis considers the following
STDs that are important in urology:
Bacterial STDs
1. Syphilis
2. Gonorrhoea
766
3. Chancroid
4. Donovaniosis/granuloma inguinale
5. Lymphogranuloma venereum
6. Chlamydial, mycoplasmal and urea-
plasmal urethritis
Viral STDs
1. HPV lesions
2. Molluscum contagiosum
3. Genital herpes virus infections
STDs caused by protozoa and epizoa
1. Trichomoniasis
2. Phthirus pubis (“crab”) infestation
3. Sacroptes scabiei infestation
Images of the STDs:
Informations and images of the STDs are
provided by the Dermatology Online Atlas
(www.dermis.net/index_d.htm) or the CDC
(www.cdc.gov/std/training/clinicalslides)
websites.
3. BACTERIAL STDs (TABLE 1); [1-11]
3.1 Syphilis
Syphilis represents one of the first recog-
nized and most infectious systemic STDs,
particularly in its primary and second-
ary stages. Unless treated, the infection
will progress through a series of stages,
during which its symptoms often mimic
those of other diseases and make diagno-
sis difficult. There is a close bidirectional
epidemiological interrelationship between
syphilis and HIV infection, resulting
in high prevalence rates for both infec-
tions among commercial sex workers
and injecting drug users, particularly in
developing countries. Recommendations
should be made to test all patients who
have syphilis for HIV infection and
retesting should be recommended for HIV
infection after three months if the first
HIV test result was negative.
 Table 1 Bacterial STDs [1–11].
STDs Causes Symptoms
Syphilis Treponema pallidum Primary stage (lues I):
(spirochete bacterium), Chancre (not painful) at the
90% transmission location where the bacterium
by sexual contact, entered the body, usually with
transmission by non- regional lymphadenopathy.
sexual contact is rare.
Secondary stage (lues II):
Syphilis is classified as
2–12 weeks later the Treponemas spread
acquired or congenital.
throughout the body, causing a rash,
The incubation period
small open sores, flu-like fever, swelling of
ranges between 10 an
lymph nodes, condylomata lata
90 days.
Latent and tertiary stages (lues III):
Symptoms and infectiousness
disappear; one third of untreated
persons will progress to the tertiary stage
where the bacteria attacking the patients
heart, eyes, brain, nervous system, bones
and joints. Gummatous syphilis
Final Stage (lues IV):
Heart diseases, blindness, insanity, paralysis
and death
767
Diagnosis
Microscopic and direct fluorescent anti-
body (DFA) tests of the tissue taken from
a chancre or sore may identify the spiro-
chete for diagnosing early syphilis.
Serologic blood tests:
Screening by combination of the
Venereal Disease Research Laboratories
Test (VDRL) or Rapid Plasma Reagin
(RPR) and Treponema Pallidum
Hemagglutionation Test (TPHA);
Confirmation by IgG Fluorescence
Treponema Antibody Absorption Test
(IgG-FTA-Abs) or 19-S-IgM-FTA-Abs.
Follow-up testing by VDRL-test or
19-S-IgM-FTA-Abs-test 3, 6, 12 months
and annually for another 4 years after
treatment.
Some HIV infected patients can have
atypical serologic test results.
Treatment
The dosage and the length of treatment
depend on the stage and clinical
manifestations of the disease.
Primary/secondary stages:
Benzathine penicillin 1 × 2,4 Mio IU i.m.;
or Clemizolpenicillin G
1 Mio IU i.m. for 14 days
No comperative trials have been adequately
conducted to guide the selection of the
optimal penicillin regimen (i.e. the dose,
duration and preparation).
Persons allergic to penicillin:
Doxycycline 2 × 100 mg p.o. for 14 days
Erythromycin 4 × 500 mg for 14 days
Late or unknown stages:
Benzathine penicillin
2,4 Mio IU i.m. on day 1, 8, 15.
or Clemizolpenicillin G
1 Mio IU i.m. for 21 days
Persons allergic to penicillin:
Doxycycline 2 × 100 mg p.o. for 28 days
Erythromycin 4 × 500 mg p.o. for 28 days
Management of sex partners: Persons who
were exposed within the 90 day preceding
the diagnosis of primary, secondary, or early
Sexually transmitted infectious diseases (STDs)
latent syphilis in a sex partner should be
treated presumptively.
continued
| 14.2 |
 Table 1 Bacterial STDs [1–11] – (Cont’d)

768
Chapter

STDs Causes Symptoms Diagnosis Treatment

Gonorrhoea Caused by a Initial symptoms within two weeks: Fever, Microscopic examination of Gram-/ World-wide, different strains of gonorrhoea
bacterium (Neisseria chills, painful swelling of the genitals and methylene blue- stained and specially have become resistant to penicillin and
| 14 |

gonorrhoeae), which prostate in men. Men cultured pus samples will readily confirm quinolones. Due to the resistances found in
enters the body by report burning during urination, the clinical diagnosis by visualization different countries and co-infections with
mucous membranes urethral pus and painful bowel of diplococci in leucocytes. Amplified other STDs antibiotics such as Ceftriaxone
of the urethra, cervix, movements in rectal infections. In women, antigen detection tests or nucleic acid (1 × 125 mg i.m.), Spectinomycin (1 × 2 g
rectum, mouth, throat infections of the uterus and fallopian tubes amplification tests (NAAT) offer high i.m.) Cefixime (1 × 400 mg p.o.) should be
and eyes. are common, resulting in sterility, ectopic sensitivity and provide confirmation of preferred.
pregnancy, and pelvic inflammatoy disease the diagnosis in asymptomatic patients.
Gonorrhoea is nearly In general, if chlamydial infection is not
(PID). Newborns’ eyes might be affected. NAATs are FDA-cleared for use with
always transmitted by ruled out it is recommended that patients
After the bacteria enter the bloodstream, endocervical swabs, vaginal swabs, and
direct sexual contact. treated for gonococcal infection also
the disease can affect the joints, heart and female and male urine.
Transluminal spread of should be treated routinely with a regimen
brain. Asymptomatic infection of the ure-
infection may Follow-up: Patients who have that is effective against uncomplicated
thra is rare (<10%).
occur to involve the uncomplicated gonor-rhea and who are genital Chlamydia. trachomatis infection
epididymis and treated with any of the recommen-ded (Azithromycin 1 g p.o. single dose or
prostate. regimens do not need follow-up testing. Doxycyclin 2 × 100 mg for 7 days).
Patients who have symptoms that persist
Haematogenous Routine cotreatment might also hinder the
after treatment should be evaluated by
dissemination is development of antimicrobial-resistant N.
culture for antimicrobial susceptibility.
uncommon. gonorrhoeae. Azithromycin 1g p.o. might be
effective against uncomplicated gonococcal
All patients tested for
infection, but concerns over emerging
gonorrhoea should be
Sexually transmitted infectious diseases

antimicrobial resistance to macrolides

tested for other STDs,
should absolutely restrict its use to limited
including Chlamydia,
circumstances (e.g. allergy).
syphilis, and HIV.
Management of sex partners: All sex part-
ners of patients who have N. gonorrhoeae
infection should be evaluated and treated
for N. gonorrhoeae and C. trachomatis
infections if their last sexual contact was
within 60 days before symptoms or diagnosis
of infection in the patient. Patients should be
instructed to avoid sexual intercourse until
therapy completed.
 Chancroid Bacterial disease 3–14 days after contact, a tender bump Usually diagnosed by microscopic Chancroid has become resistant to penicillin,
caused by develops where the bacteria entered the examination ofa smear sample Tetracycline and Erythromycin in some
Haemophilus ducreyi, body. The bump transforms into one or (Gram-stained). This should be cases. Preferred treatments now involve
that is transmitted by more shallow sores, which will break confirmed by a culture. The presence Azithromycin (1 × 1 g p.o.), Ceftriaxone
direct sexual contact. open and become the typical painful soft of other STDs has to be ruled out. PCR (1 × 0.25 g i.m.) or Ciprofloxacin (2 × 500
Uncircumcised men chancre. The lymph nodes in the groin are testing is possible. mg p.o. for 3 days) or Erythromycin
are more likely to pus-filled (bubos), and often burst through 3 × 500 mg for 7 days. Bubos may need
Test for HSV performed on the ulcer
contract the disease the skin. to be drained.
exudates usually is negative.
than circumcised men.
Coinfections with T.
pallidum or HSV occur
in 10% of persons
who have chancroid.

Donovanosis/ A chronic, mildly con- Red, vulnerable, easily bleeding sores on Generally diagnosed by visual Azithromycin (1 × 1g per week, for 3 weeks)
Granuloma tagious STD caused and around the genitals and anus are typi- observation of the external symptoms. or
inguinale by an intracellular cally noticed one week to several months Gram-stained samples will show the
Erythromycin (4x 500 mg p.o. for 3 weeks)
gram-negative bac- after initial exposure to the bacteria. In bacteria, which can be cultured under
or
terium, Klebsiella men the lesions appear first on the head special conditions only. Donovan bodies
(Calymmatobacterium) or shaft of the penis. The sores are not are found in macrophages on tissue Doxycycline (2 × 100 mg for 3 weeks) or
granulomatis very painful, but can spread throughout crush preparation or biopsy. Coinfections Trimethoprim-Sulfamethoxazole
the groin and cause abscesses. In extreme with other STDs are known. (2 × 1 (800/160mg) die for 3 weeks) or
cases, their dissemi-nation can give rise to Ciprofloxacin 2 × 750 mg for 3 weeks or
cancer. until all lesions have completely healed.
Lymphadenopathy is unusual. Sometimes wound resection is necessary.
Scars left by the sores are regarded
as precancerous. Therefore, annual
examinations are recommended.

Lympho- Caused by Chlamydia First symptoms may be a sore resembling The chlamydia have to be cultu- Doxycycline (2 × 100 mg for 3 weeks) and
granuloma trachomatis (serotypes a pimple, blister or soft bump at the point red in special cell cultures (Mc Coy Erythromycin (4 × 500 mg for 3 weeks)
venereum L1-L3), that is spre- of infection 3–30 days after exposure. 1–2 cells) and can be diagnosed by direct
Azithromycin (1 × 1g p.o. per week for
ad by direct sexual weeks later, the lymph nodes swell mostly immunofluorescens or nucleic acid
3 weeks) is probably effective.
contact, particularly unilateral, creating a painful, pus-filled detection. Complement fixation titers ≥
in homosexuals who bulge. The disease progresses slowly 1:64 are consistent with the diagnosis of Buboes may require drainage.
engage in anal sex. causing fever, throbbing pain and breaking lymphogramuloma venereum.
Proctocolitis and of the skin, leaving masses of scartissue.
Sexually transmitted infectious diseases (STDs)

perianal or perirectal
fistulas and strictures
may result.

continued

769
| 14.2 |
 Table 1 Bacterial STDs [1–11] – (Cont’d)

770
Chapter

STDs Causes Symptoms Diagnosis Treatment

Chlamydial, Non-gonococcal 7–21 days after contact signs and The diagnosis of urethritis should Single dose Azithromycin (1 g) or Doxycycline
mycoplasmal uretritis (NGU) is symptoms are mainly due to urethritis and by confirmed by demonstrating (2 × 100 mg for 7 days);
| 14 |

and caused by Chlamydia complications like anorectal discomfort, polymor-phonuclear leucocytes in

Erythromycin (4 × 500 mg for 7 days);
ureaplasmal trachomatis (serotypes reactive arthritis and conjunctivitis Gram-stained urethral smears or first pass
D-K) in 30–50% (Reiter`s syndrome), prostatitis and urine specimens. Diagnostic tests include Ofloxacin (2 × 200 mg for 7 days);
urethritis
and Ureaplasma epididymo-orchitis. cell cultures (sensitivity range 40–85%),
urealyticum and direct antibody assays (sensitivity range Levofloxacin 1 × 500mg for 7 days
Important sequelae can result from C.
Mycoplasma hominis/ 50–90%), Enzyme- immunoassays Roxithromycin (2 × 150 mg for 7 days);
trachomatis infection in women (e.g. PID,
genitalium in 10–20%, (sensitivity range 20–85%) and PCR/ LCR
infertility, and ectopic pregnancy). Clarithromycin (2 × 250 mg for 7 days.
respectively. techniques (sensitivity range 70–95%).
First pass urine specimens can be used
All patients who Abstinence from sexual intercourse for 7 days
for PCR/LCR , and urethral swabs will be
have urethritis is recommended. Sex partners (within 60
needed for the othertests. Cooled (4–8°C)
should be evaluated days) should be evaluated, tested and treated.
special transport vehicles and cell cultures
for the presence
are mandatory.
of gonococcal and
non-gonococcal
infection. Some
cases of presistent or
recurrent urethritis are
due to Trichomonas
vaginalis, HSV, and
adenovirus. Enteric
Sexually transmitted infectious diseases

bacteria have been

identified as an
uncommon cause of
NGU and might be
associated with
insertive anal sex.
 Sexually transmitted infectious diseases (STDs)
3.2 Gonorrhoea
An annual incidence of approximately
62 million new cases of gonorrhoea is
estimated world-wide, with the greatest
number in South and South-East Asia,
followed by sub-Saharan Africa. A signifi-
cant proportion of infected people (up to
80% among women, 10% among men) are
asymptomatic. Co-infections with chlamy-
dia and other STDs are very common and
specific diagnostic testing and appropri-
ate treatment should be recommended.
The prevalence of gonococal infection
varies widely among communities and
patient populations.
3.3 Chancroid
Limited understanding of the epidemi-
ology and natural history of the disease
and the absence of routine clinical tests
make it difficult to reliably estimate
prevalence and duration of infection.
Definitive diagnosis of chancroid requires
isolation of the causative bacterial path-
ogen, Haemophilus ducreyi, on special
media that are not available commer-
cially. Probable diagnosis may be made
in a patient with the combination of geni-
tal ulcer(s) and inguinal adenapathy who
has a negative darkfield examination and
serology for syphilis plus negative test
results for HSV infection. It is estimated
that there are approximately 7 million
new cases of chancroid annually. The inci-
dence of chancroid varies greatly between
countries and regions. In the US, for
example, there are endemic areas and
also outbreaks of infection. In contrast, in
Africa and parts of Asia chancroid may be
a common cause of genital ulcers.
3.4 Donovanosis/Granuloma
inguinale
Donovanosis is a very rare genital
ulcerative STD in most areas. Infection
occurs primarily occurs in people who
engage in anal sex or oral-anal contact.
Donovanosis is endemic in certain tropical
| 14.2 |
and developing areas (India, Papua-New
Guinea, central Australia and Southern
Africa). Though only moderately conta-
gious it is transmitted most often when
the disease is in its early stages.
3.5 Lymphogranuloma venereum
(LGV)
This disease, also known as Durand-
Nicolas-Favre disease, is relatively rare
in developed countries. Most cases occur
in men having sex with men (MSM).
Lymphogranoloma venereum is most
prevalent in South East Asia, Africa,
Central and South America and the
Caribbean. Infection is characterized by
a painful swelling of the inguinal lymph
nodes and elephantiasis of the geni-
tals. The infection is invasive, systemic
and might lead to chronic fistulas and
strictures.
3.6 Nongonococcal urethritis
(chlamydial, mycoplasmal
and ureaplasmal urethritis)
The major pathogens causing nongono-
coccal urethritis are Chlamydia tracho-
matis, and Ureaplasma urealyticum.
Mycoplasma hominis and Mycoplasma
genitalium represent other probable
causes of non-gonococcal urethritis. These
organisms are estimated to account for
30–50% and 10–20% of cases, respec-
tively. 20–30% of men with non-gonococcal
urethritis have no organism detected.
Asymptomatic infection is common in
women, while approximately 70% of men
have symptoms like urethral discharge,
dysuria, penile irritation and signs of
epididymo-orchitis or prostatitis.Women
may suffer from C. trachomatis associ-
ated pelvic inflammatory disease, ectopic
pregnancy, or infertility.
3.7 Other bacterial and yeast STDs
Gardnerella vaginalis is characteristically
associated with a diffuse disturbance of
the normal vaginal flora associated with
771
Chapter | 14 | Sexually transmitted infectious diseases
bacterial vaginosis. Men may carry the
bacterium, but do not seem to be adversely
affected. Additionally, bacterial vaginosis
is not a STD per se, and the change in the
balance of bacterial organisms that exists
in the vagina is not clearly understood.
Other infections most frequently associ-
ated with vaginal discharge are tricho-
moniasis and candidiasis. Vulvovaginal
candidiasis is not usually acquired
through sexual intercourse. Treatment of
male sex partners is only recommended
in rare cases of balanitis or in women who
have recurrent infection. In contrast, tri-
chomoniasis is a common sexually trans-
mitted infection that merits diagnosis and
treatment (see below).
4. VIRAL STDs (TABLE 2); [1-11]
This section summarized viral STDs that
cause typical genital tract lesions includ-
ing: HPV, MCV and HSV infections.
Information on other viral STDs, i.e. HIV,
hepatitis, cytomegalic inclusion body dis-
ease and Epstein-Barr virus-associated
disease are considered in the guidelines
of other specialities.
4.1 HPV-associated lesions
(genital warts)
Condylomata acuminata caused by HPV
infection represent the most common
viral STD world-wide. More than 30 mil-
lion people develop genital warts every
year. HPV belongs to the same group of
viruses that produce common skin warts.
However, HPV can also be closely associ-
ated with intraepithelial neoplasia and
anogenital cancers in both genders. Most
HPV infections are subclinical or latent –
that means that they are not directly vis-
ible or that they can only be diagnosed
by laboratory testing. Visible signs of the
disease include condylomata, Bowen’s
disease, bowenoid papulosis, Buschke
Löwenstein tumors and anogenital can-
cers. Although men and women are
772
equally susceptible to infection, women
suffer a much higher risk of developing
the HPV-associated malignancies.
With the recently developed prophy-
lactic bivalent (HPV 16, 18) and quadri-
valent (HPV 6, 11, 16, 18) vaccines, it is
now possible to prevent (a) HPV infection
of the cervical epithelium and other squa-
mous epithelia, (b) the development of
premalignant lesions, and in the case of
the quadrivalent vaccine, (c) the develop-
ment of condylomata acuminata [4].
4.2 Molluscum contagiosum
Molluscum contagiosum is characterized
by self-limiting viral infection of the skin
which is spread by sexual contact as well
as manual and casual contact. Children
are often infected. High prevalence (13%)
of molluscum is noticed in HIV-positive
adults, justifying molluscum as an STD.
Individual blisters may disappear on
their own after several months or may
require local therapy.
4.3 Genital herpes
Genital herpes is a chronic, lifelong viral
infection that afflicts up to 80% of adults.
The human herpes viruses include: herpes
virus type 1 (HSV-1), herpes virus type 2
(HSV-2), cytomegalovirus, varicella-zoster
virus (VZV), Epstein-Barr virus (EBV),
human herpes virus type 6 (HHV-6),
human herpes virus type 7 (HHV-7), and
Kaposi’s sarcoma-associated herpes virus
(also knows as HHV-8). Of these, HSV,
CMV, EBV and HHV-8 can be transmitted
sexually. Although they are all spread by
direct skin-to-skin contact, urologists are
primarily concerned with management of
patients infected with HSV-1 and HSV-2.
HSV1 has been found historically on the
mouth, and can increasingly be isolated in
genital infections. This probably reflects
changes in sexual practices. Herpes is
incurable today. The associated symptoms
may never become manifest clinically or
symptoms may come and go periodically
 Table 2 Viral STDs [1–11].

STDs Causes Symptoms Diagnosis Treatment

Genital HPV low-risk Typically growing without symptoms External warts are usually diagnosed An update of the guidelines in
warts genotypes (i.e. untreated genital warts can spread and visually. Application of acetic acid dermatology, venereology, gynecologyand
90% HPV 6 or HPV multiply into large clusters. Giant warts solution (5%) causes the warts and subc- urology [3] unanimously recommends
11) transmitted (Buschke Löwenstein tumours) are rare. linical flat HPV lesions to whiten, making treatment options for medically prescri-
by intimate sexual Genital warts may cause a variety of health identification much easier. A magnifying bed self-treatment and for exclusively
contact. Warts develop complications depending on where they instrument should be used to diagnose physician-managed treatment. Topically
within 3 weeks to 8 are located. Symptoms may range from subclinical lesions. For demarcation of applied drugs such as Podophyllotoxin (0,5%
months. discomfort and pain, to bleeding and urethral HPV lesions, fluorescence ureth- solution or gel)or Imiquimod 5% cream
difficulty in urination. roscopyhad been used by analogy with are suitable for therapy at home. Medically
Immunodeficiency
the acetic acid test of the outer genitals applied treatment involves trichloracetic acid
leads to rapid and
[11]. Both the acetic acid test and flu- (TCA), cryotherapy, electro-surgery, laser
extensive growth of
orescence urethros copy are limited in treatment and surgical excisions of the HPV
HPV lesions, even
specificity. A tissue biopsy or Pap smear lesions. Irrespective of the therapy used,
affecting untypical
may be taken to determine whether the HPV may persist in the adjacent tissues,
epithelial tissue (e.g.
HPV lesions are cancerous. Generally, resulting in recurrences and the need for
urinary bladder), and is
both sexual partners should be tested for further courses of treatment. Substantial
associated with higher
warts. Routine HPV type analyses have breakthroughs in the prevention of HPV
rates of cancer.
not been recommended in genital warts. infection have been made in recent years.
Precancerous changes HPV nucleic acid testing may be useful in The FDA-approved quadrivalent HPV vaccine
in the cervix, vulva, Cervical Cancer Screening Programs. (HPV 6, 11, 16, 18) can effectively prevent
anus, or penis are due 90% of genital warts an 70% of cervical
to HPV high-risk-types cancers through preexposure vaccination.
(e.g. HPV 16, 18). Very
rarely, HPV infection
results in anal or
genital cancers.

Molluscum Caused by Molluscum Typical blisters can be flesh-colored, white, The blisters are distinctive, providing Blisters will regress spontaneously under
contagiosum contagiosum virus. 2–3 pink, yellow or clear. Itching is common, typical criteria for visual diagnosis. The the control of the immune system. If not,
months after infection, but pain is rare. Clusters of lesions may diagnosis can be confirmed by light surgical removal by laser, cryotherapy,
a waxy and rounded develop. In adults HIV coinfection has to be microscopy or electron microscopy of electro-surgery or chemical treatment is
blister with a dimple ruled out. biopsies taken from a blister. recommended.
on the top develops.
Scratching, picking or
Sexually transmitted infectious diseases (STDs)

breaking spreads the

virus.

continued

773
| 14.2 |
 Table 2 Viral STDs [1–11] – (Cont’d)

774
Chapter

STDs Causes Symptoms Diagnosis Treatment

Genital Herpes simplex viruses Symptoms can vary. Initially flu-like Sometimes the diagnosis can be Herpes is incurable. Systemic antiviral drugs
herpes (HSV 1(30%) and symptoms, swelling of lymph nodes, made by physical examination (Acyclovir 3 × 400mg or 5 × 200mg per os,
| 14 |

HSV 2 (70%)) can chills, fever may be noticed. Fluid-filled alone. Cell culturing (HSV is a labile Famciclovir 3 × 250mg per os, Valacyclovir
cause genital lesions blisters are then followed by eruption and virus and successful virus culture- 2 × 1g per os) may be used to reduce the
2–20 days after ulceration of the skin; both are painful. depends on main-taining the cool discomfort from the sores. Healing might be
infection. Most cases Clusters on the genitals, buttocks and (4C0), rapidly transporting speci- increased, and pain as well as viral shedding
of recurrent genital adjacent areas are typical.Other symptoms mens to the laboratory and avoiding can be reduced.
herpes are caused by may include tenderness, aching pain, freeze-thaw cycles) and type analysis by
Treatment of first clinical episode (for 7–10
HSV-2. Herpes virus itching, burning or tingling. Painful immunofluorescence tests are standard
days) or recurrent episodes of genital herpes
invades the body via urination and a sensation of abdominal options for diagnosis. Fluorescence tests
(for 3–5 days) requires initiation of therapy
breaks in the skin or pressure are known. can be done without viral amplification
within the first day of lesion onset. Patients
moist membranes in the cell culture, but sensitivity is only
Although HSV 1 and HSV 2 persist in who have frequent recurrences (i.e., ≥ 6
of the penis, vagina, fair. PCR and LCR amplification of HSV
the body of infected persons indefinitely, recurrences per year) may be treated by
urethra, anus, vulva show much better sensitivity, but the
symptoms tend to lessen with time. suppressive therapy ( i.e. Valacyclovir (1 × 1g
or cervix. All practices techniques are too expensive for
p.o./ die), Acyclovir (2x400mg) or Famciclovir
of intercourse may routine use.
(2 × 250mg), for 16 weeks up to years).
transmit HSV. HSV
may be passed on to Supressive therapy reduces the frequency of
the baby during birth genital herpes recurrences by 70–80%. Do
as well. not use topical creme.
The sex partners of patient who have genital
herpes likely benefit from evaluation and
Sexually transmitted infectious diseases

counselling.
 Sexually transmitted infectious diseases (STDs)
throughout a person’s lifetime. There are
even more people who have no symptoms
who can still transmit infection to their
sexual partners. A number of drugs have
proven effective for clinical management.
5. STDs CAUSED BY PROTOZOA
AND EPIZOA [2–3, 5]
5.1 Trichomoniasis
Trichomoniasis is caused by the parasitic
protozoon, Trichomonas vaginalis, and
is often diagnosed in patients that are
infected with other STDs. Trichomonas
can be transmitted by direct sexual con-
tact or by infected body fluids. Symptoms
in men are uncommon, and typically
include discharge from the urethra and
painful or difficult urination. The proto-
zoon can be found by dark-field micro-
scopy of specimens from the vagina,
urethral secretions or in the sediment of
urine. Culturing these samples before the
microscopic examination will improve sen-
sitivity substantially. Generally, treatment
should involve both sexual partners. A sin-
gle dose of Metronidazole (1 × 2 g p.o.) or
Tinidazole (1 × 2g p.o.) is usually effective.
An alternative regimen is Metronidazole
2 × 500 mg for 7 days.
5.2 Phthirus pubis (“crab”)
infestation
Phthirus pubis is a tiny insect that infects
the pubic hair and feeds on human blood.
They use crab-like claws to grasp the
host’s hair and can crawl several centime-
tres per day. Female lice lay two to three
eggs daily and affix them to the hairs
(nits). During direct sexual contact, the
insects can move from one partner to the
other. Itching in the pubic area is a telltale
sign. Microscopic examination of the lice or
the nits can confirm infection. Treatment
involves application of 1% gamma ben-
zene hexachloride ointment or lotion.
Permethrin 1% cream or Malathion 0,5%
lotion or Ivermecin 250ug/kg repeated in
| 14.2 |
two weeks are also recommended. The
scalp is treated with lindane shampoo.
Patients with pediculosis pubis should be
evaluated for other STDs.
5.3 Sacoptes scabiei infestation
Sarcoptes scabiei is a whitish-brown,
eight-legged mite that burrows into its
host to lay its eggs. This burrowing causes
a skin irritation or rash. The mites, their
feces and eggs cause a progressive sensi-
tivity in the host after about two weeks,
producing the characteristic itch. Finding
a mite or identifying its bumps and bur-
rows will corroborate the diagnosis. There
are a variety of topical medications that
will clear scabies infestations. Effective
treatments include: lindane, petroleum
jelly and 5% sulfar mixture. Permethrin
cream (5%) or Ivermecin 200 ug/kg p.o.
repeated in 2 weeks are also effective in
scabies treatment.
REFERENCES
1. Schneede P, Tenke P, and Hofstetter AG,
Sexually transmitted diseases (STDs)–a
synoptic overview for urologists. Eur Urol,
2003. 44(1): 1–7.
2. Smellie JM, Ransley PG, Normand IC,
Prescod N, and Edwards D, Development
of new renal scars: a collaborative study.
Br Med J (Clin Res Ed), 1985. 290(6486):
1957–60.
3. Kunin CM, Deutscher R, and Paquin
A, Jr., URINARY TRACT INFECTION
IN SCHOOL CHILDREN: AN
EPIDEMIOLOGIC, CLINICAL AND
LABORATORY STUDY. Medicine
(Baltimore), 1964. 43: 91–130.
4. Rushton HG and Majd M, Pyelonephritis
in male infants: how important is the
foreskin? J Urol, 1992. 148(2 Pt 2): 733–6;
discussion 737–8.
5. Shimada K, Matsui T, Ogino T, and
Ikoma F, New development and progres-
sion of renal scarring in children with
primary VUR. Int Urol Nephrol, 1989.
21(2): 153–8.
775
Chapter | 14 | Sexually transmitted infectious diseases
6. Wettergren B, Fasth A, and Jacobsson
B, UTI during the first year of life in a
Göteborg area 1977–79. Pediatr Res,
1980. 14: 981.
7. Wiswell TE and Hachey WE, Urinary
tract infections and the uncircumcised
state: an update. Clin Pediatr (Phila),
1993. 32(3): 130–4.
8. Winberg J, Andersen HJ, Bergstrom
T, Jacobsson B, Larson H, and Lincoln
K, Epidemiology of symptomatic urinary
tract infection in childhood. Acta Paediatr
Scand Suppl, 1974(252): 1–20.
9. Doganis D, Siafas K, Mavrikou M,
Issaris G, Martirosova A, Perperidis G,
Konstantopoulos A, and Sinaniotis K,
776
Does early treatment of urinary tract
infection prevent renal damage?
Pediatrics, 2007. 120(4): e922–8.
10. Hewitt IK, Zucchetta P, Rigon L, Maschio
F, Molinari PP, Tomasi L, Toffolo A,
Pavanello L, Crivellaro C, Bellato S,
and Montini G, Early treatment of acute
pyelonephritis in children fails to reduce
renal scarring: data from the Italian
Renal Infection Study Trials. Pediatrics,
2008. 122(3): 486–90.
11. Verber IG and Meller ST, Serial 99mTc
dimercaptosuccinic acid (DMSA) scans
after urinary infections presenting before
the age of 5 years. Arch Dis Child, 1989.
64(11): 1533–7.
|14.3|

Urethritis
Ryoichi Hamasuna1,2, Hiromasa Tsukino2
1
Department of Urology, University of Occupational and Environmental Health, Kitakyushu, Japan
2
Division of Urology, Department of Surgery, Faculty of Medicine, University of Miyazaki, Japan
Corresponding author: Ryoichi Hamasuna, Department of Urology,
University of Occupational and Environmental Health,1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu,
Fukuoka, 807-8555, Japan
Tel:+81 93 691 7446, fax:+81 93 603 8724, E-mail:hamaryo@med.uoeh-u.ac.jp

ABSTRACT SUMMARY OF RECOMMENDATIONS

Gonococcal urethritis (GU) remains a fre- 1. It should be considered that preva-

quent disease in the US, Eastern Europe,
Asian and African countries. Because
fluoroquinolon-resistant Neisseria gonor-
rhoeae strains have become widespread
worldwide, fluoroquinolone regimens
can no longer be recommended for GU.
Chlamydia trachomatis is the major caus-
ative bacteria for non-gonococcal urethri-
tis (NGU) and azithromycin (AZM)- or
doxycycline-regimens are recommended to
treat chlamydial urethritis. Mycoplasma
genitalium also appears to represent a fre-
quent cause of male urethritis, for which
AZM is the treatment of choice. Therefore
AZM should be considered the first line
treatment of NGU, but not tetracyclines.
Key words: Urethritis, STI, ICUD,
gonococcal urethritis, non-gonococcal ure-
thritis, N. gonorrhoeae, C. trachomatis,
M. genitalium
lence rates of gonococcal urethritis
remain high worldwide (GoR C).
2. Fluoroquinolone-regimens for gonococ-
cal urethritis cannot be recommended
(GoR B).
3. In some regions, cefixime-resistant
N. gonorrhoeae has increased sub-
stantially therefore cephalosporin
regimens should only be recommended
with caution (GoR C).
4. For the tratment of chlamydial ure-
thritis, azithromycin or doxycycline-
regimens are recommended (GoR A).
5. It is important to consider that M.
genitalium is an important causative
bacterium of male urethritis (GoR B).
6. For M. genitalium urethritis, azithro-
mycin is the the first line regimen
(GoR C).
Chapter | 14 | Sexually transmitted infectious diseases
1. INTRODUCTION
The most common sexually transmitted
infection (STI) that urologists see is male
urethritis. The management of urethritis
is proposed in the following guidelines:
i) CDC guidelines
• Sexually transmitted diseases treat-
ment guidelines, 2006 [1]
• Update to CDC’s sexually transmit-
ted diseases treatment guidelines,
2006: fluoroquinolones no longer
recommended for treatment of
gonococcal infections [2]
ii) Guidelines of the British Association
for Sexual Health and HIV
• National Guideline on the
Diagnosis and Treatment of
Gonorrhoea in Adults 2005 [3]
• 2006 UK National Guideline for
the Management of Genital Tract
Infection with Chlamydia tracho-
matis [4]
• 2008 National Guideline on the
Management of Nongonococcal
Urethritis [5]
iii) Guideline on the management of uri-
nary and genital tract infections by the
European Association of Urology [6]
Urologists should know and understand
the major evidence-based guidelines on
STI diagnosis and management. However,
these guidelines are not adapted to world-
wide medical practice because the avail-
ability of diagnostic tests, prevalence of
pathogens causing urethritis or the anti-
microbial susceptibilities of causative
pathogens differ subsantially. This review
evaluates the scientific evidence of the
prevalence for urethritis and of antimi-
crobial susceptibilities that determine the
appropriate treatment for male urethritis.
2. METHODS
We searched for peer-reviewed papers
in Medline. The search strategy used
778
the following key words: Neisseria gon-
orrhoeae, Chlamydia trachomatis or
Mycoplasma genitalium combined with
urethritis, prevalence, susceptibility, sus-
ceptibilities, treatment, clinical trials or
other related terms. Regarding the preva-
lence of pathogens for male urethritis, we
searched for peer-reviewed papers pub-
lished within the last five years, because
we were only interested in the most recent
data of prevalence. Papers not includ-
ing the numbers of patients or objective
population were excluded. Regarding the
pathogenicity of M. genitalium, papers
on non-gonococcal urethritis (NGU) were
included. We searched for peer-reviewed
papers published after the analysis by
Jensen’s review [7]. Regarding the sus-
ceptibilities of causative bacteria to anti-
biotics, only papers that contained the
numbers of strains and the year of test-
ing were accepted. The methodology for
antimicrobial susceptibility testing was
not evaluated because of a poor concord-
ance among laboratories on the definition
of resistant N. gonorrhoeae [8–9]. Papers
from developing countries were accepted
as much as possible, because antimicro-
bial susceptibility data in African, Asian
or South American countries are rare. We
searched for peer-reviewed papers pub-
lished in the last five years because only
recent susceptibilities data are important
for clinicians. Regarding clinical studies
of antimicrobial treatment for urethri-
tis, we searched for peer-reviewed papers
published within the last 10 years.
The papers about susceptibilities of
N. gonorrhoeae to antibiotics also inclu-
ded case series. The paper about suscepti-
bilities of M. genitalium to antibiotics also
included experimental results, because
laboratories which can measure the anti-
microbial susceptibility of M. genitalium
are limited in the world.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[10–11].

3. AETIOLOGY
Microorganisms usually considered as
causative pathogens of male urethritis
are listed in Table 1. N. gonorrhoeae and
C. trachomatis have been recognized as
the most important bacterial pathogens
causing urethritis. There is an assump-
tion that gonococcal urethritis (GU) has
decreased in the developed countries, but
the prevalence rates of GU remain high
in the developing countries. To confirm
this assumption, the prevalence data of
many countries were compared.
3.1 Prevalence
We searched for epidemiological data which
included the prevalence of both N. gonor-
rhoea and C. trachomatis. In addition, the
pathogenicity of M. genitalium in male
urethrits has been strongly supported by
a well-done recent meta-analysis. Jensen
performed a meta-analysis of epidemiologi-
cal studies of M. genitalium PCR positivity
and male urethritis from 1993–2003 [7].
We added new epidemiological data from
recently published articles to Jensen’s
analysis.
The prevalence of the major bacterial
pathogens in males with urethritis found
in 35 papers is summarized in Table 2.
Tabel 1 Microorganisms for considering the causative
pathogens for male urethritis.
• Gonococcal urethritis
Neisseria gonorrhoeae
• Non-gonococcal urethritis (NGU)
Chlamydia trachomatis
Mycoplasma genitalium
Ureaplasma urealyticum (biovar 2)
Neisseria meningitides
Haemophilus species
Gardnerella vaginalis
Candida species
Trichomonas vaginalis
Herpes simplex virus 1
Herpes simplex virus 2
adenovirus
Urethritis | 14.3 |
The parevalence of pathogens for male
urethritis were analysed by one meta-
analysis, three randomized cohorting
studies, 11 case-controlled studies, 12 case-
series and 12 non-randomized cohorting
studies. The rates of N. gonorrhoeae from
the males with urethritis in European
countries, Asian countries, USA, or South
Africa were 2–21%, 9–45%, 12–35% and
22–52%, respectively (Table 3). Prevalence
rates of gonococcal urethritis remain high
worldwide (GoR C). In these papers, seven
papers were written about the screenig
data of the pahogens for urethritis among
the sexually active general population
or men who have sex with men (MSM).
C. trachomatis or N. gonorrhoeae were
detected from 1–10% or 1–11%, respectively.
There were no differences in the prevalence
rates among the tested countries. In NGU,
the tested pathogens could not be compared
directly. The prevalence of C. trachomatis
was almost one to three times higher than
the prevalence of M. genitalium. Thus, urol-
ogists should consider both C. trachomatis
and M. genitalium as important pathogens
in NGU.
3.2 The pathogenicity of
M. genitalium in NGU
In the last five years, 13 papers were
identified including one meta-analysis
[7], seven case-controlled studies and five
case-series (Table 4). In patients with
NGU or non-chlamydial NGU, the prev-
alence of M. genitalium was 15.0% and
14.9%, respectively. The odds ratio in all
epidemiological studies of M. genitalium
PCR-positivity in patients with NGU was
3.61 (95%CI: 3.00–4.34). These findings
strongly suggest that that M. genitalium
is a causative agent for male urethritis
(GoR B).
4. ANTIMICROBIAL SUSCEPTIBILITY
To determine the appropriate treatment
for male urethritis, it was necessary to
779
Chapter | 14 | Sexually transmitted infectious diseases

Table 2 Evidence table for recent studies of the prevalence of pathogens for male urethritis that include original data,
systematic reviews or meta-analysis, expert opinion, or other data (2003–2008).

Lead author
Year Level of
Study type Reference Study area Design evidence

Systematic review,
Meta-analysis

(NGU) Jensen [7], 2006 Meta-analysis data, 2,261 men 1

with NGU and 2,107 men
without urethritis

Randomized
cohorting study

(urethritis) Geisler [55], 2005 North America, USA 2,266 men with urethritis 2

Newman [56], 2006 North America, USA 38,095 men attended to STD 2
clinic in USA

Massari [57], 2006 Western Europe, FRA 859 cases of urethritis 2

Case controlled
study

(urethritis) Dupin [53], 2003 Western Europe, FRA 83 men with urethritis, 3
60 men with urethral
symptoms but no urethritis,
and 50 asymptomatic men

Salari [58], 2003 Asia, IRI 125 men with NGU and 125 3
control

Schlicht [59], 2004 North America, USA 26 symptomatic men and 3

67 healthy men

Kohl [60], 2004 North America, USA 20,451 men with urethritis and 3
23,188 asymptomatic menf

Sturm [61], 2004 Africa, RSA 335 men with symptoms and 3
100 men without symptoms

Deguchi [62], 2004 Asia, JPN 572 men with urethritis and 3
141 men without urethritis

Iser [63], 2005 Oceania, AUS heterosexual men with 3

symptoms (80) and without
symptoms (79)

Gaydos [64], 2006 North America, USA 862 symptomatic men and 3
16,850 asymptomatic men

Bradshaw [65], 2006 Oceania, AUS 329 NGU and 307 control 3

Vesic [66], 2007 Eastern Europe, 630 men with urethral 3

Serbia symptoms

Lewis [67], 2008 Africa, RSA 27 symptomatic, 274 3

asymptomatic men

Yu [68], 2008 Asia, HKG 98 men with urethritis and 236 3

men without urethritis

780
 Urethritis | 14.3 |

Lead author
Year Level of
Study type Reference Study area Design evidence

Non-randomized
cohorting study

(urethritis) Varela [69], 2003 Western Europe, ESP 1116 men with urethritis 3

Jensen [70], 2004 Western Europe, DEN In 1,852 specimens, 6.8% was 3
positive for MG-PCR

Talor-Robinson [71], Western Europe, UK 52 men with recurrent or 3

2004 persistant NGU

Maeda [72], 2004 Asia, JPN 153 men with NGU 3

Anagrius [73], 2005 Western Europe, DEN Cross-section study. 501 male 3
STD clinic attendees

Dolapci [74], 2005 Asia, TUR 63 mne with urethral 3

symptoms

Leung [75], 2006 Western Europe, UK 680 men attending to 3

genitourinary medicine

Gubelin [76], 2006 South America, CHI 23 NGU and 14 NG 3

Stamm [38], 2007 North America, USA 170 men with urethritis 3

Lee [77], 2007 Asia, KOR 70 urine from men with 3

urethritis

Yokoi [78], 2007 Asia, JPN 309 men with NGU 3

Davies [79], 2007 Asia, INA 273 men with urethritis 3

(screening in the Kahn [80], 2005 North America, USA 98,296 males 3
general population)

Leutscher [81], 2005 Africa, MAD 240 men in MAD 3

Lee [82], 2005 Asia, KOR 202 male students 3

Amirkhanian [83], Eastern Europe, RUS 125 MSM 3

2006

Chen [84], 2006 Asia, CHN 530 track-drivers 3

Benn [85], 2007 Western Europe, UK 613 MSM 3

Gunn [86], 2008 North America, USA 7,333 MSM 3

Abbreviations:
CT: Chlamydia trachomatis, NG: Neisseria gonorrhoeae, MG: Mycoplasma genitalium, GU: gonococcal urethritis, NGU: non-gonococcal urethritis,
MSM: men who have sex with men.
Abbreviations of countries: CHI: Chile, CHN: China, DEN: Denmark, EST: Estonia, FRA: France, HKG: Hong Kong, INA: Indonesia, JPA: Japan, KOR:
Korea, MAD: Madagascar, NED: The Netherlands, TUR: Turkey, RSA: South Africa, RUS: Russia, UK: United Kingdom, USA: United State of America.

781
 Table 3 The detectionrates of causative pathogens fome urethritis in males with or without urethritis from recent published data.

782
Author Pub. year
Country Test year
n NG CT MG UU UP TV others n NG CT MG UU UP MH others

European countries

Dupin [53] FRA 2003 83 a 15.0 20.5 21.7 25.9 - 0 60 b 2.9 3.3 0 21.6 - -
2001

50c 4.0 1.0 0 - - 0

Varela [69] ESP 2003 1116d 2.4 3.9 - 33.5 - 0.9 HSV 0.2 - - - - - - - -
1995–2000 GV 0.4

Leung [75] UK 2006 302e 8.9 20.9 10.9 - - - - 378f 0.5 0.8 3.2 - - - -
unknown

Massari [57] FRA 2006 859g 21 25 8 5 - 3 - - - - - - - -

1997–2003

Vesic [66] Serbia 2007 320h 17.5 25.6 - 24.1 - 31.6 - - - - - - -

2004–2006

310i 0 14.5 - 18.7 - 26.5 - - - - - - - -

Asian countries

Deguchi [62] JPN 2004 572a 44.6 37.9 9.1 12.2 5.6 - - 141f 0 3.5 1.4 7.8 13.5 - -
1999–2002

Dolapci [74] TUK 2005 63a 9.5 6.3 6.3 4.8

2003–2004

Lee [77] KOR 2007 70d 32.9 22.9 27.1 7.1 - - - - - - - - - -

unknown

Yokio [78] JPN 2007 380j 10.0 21.8 4.2 8.5 2.1 - - - - - - - - -
1999–2005

Davies [79] INA 2007 273d 18.2 10.1 - - - - - - - - - - - -

1999
 Author Pub. year
Country Test year
n NG CT MG UU UP TV others n NG CT MG UU UP MH others

Schlicht [59] 2004 26g 11.5 15.4 11.5 Ureaplasma - 67k 0 0 2.2 - - -
USA 1999–2000 sp. 61.5

Geisler [55] USA 2005 2266g 28.1 23.3 - - - - -

1998–2002

Kohl [60] USA 2005 20451g 34.7 12.5 - - - - - 23188f 3.8 6.7
1995–1999

Gaydos [64] USA 2006 8629 20.4 22.6 - - - - 16850f 1.4 6.4 - - - - -
1999–2003

South American

Gubelin [76] CHI 2006 37g 37.8 21.6 8.1 Ureaplasma - - - - - - - -

unknown sp. 35.1
-

African countries

Sturm [61] RSA 2004 335a 51.9 16.4 5.1 36.1 - 5.7 HSV 5.7 100k 0 8.0 3.0 30.0 - - HSV
2000 31.0

Lewis [67] RSA 2008 27g 22.2 3.7 7.4 - - 22.2 - 274c 4.7 9.1 6.6 - - -
2006

screening for pathogens of urethritis among the general population of men

Lee [82] KOR 2005 - - - - - - - 202k 0.5 5.0 - - - - -

unknown

Kahn [80] USA 2005 - - - - - - - 31263k 1.8 6.2 -

2002

Leutscher [81] 2005 - - - - - - - - 240k 4.6 4.6 4.6 - - -

MAD unknown

Amirkhanian [83] 2006 - 125l 2.4 4.8 - - - -

RUS 2003

783
continued
 Table 3 The detectionrates of causative pathogens fome urethritis in males with or without urethritis from recent published data – cont'd

784
Chen [84] CHN 2006 - - - - - - - - 530m 10.6 8.1 - - - - -
2000

Benn [85] USA 2007 613i 7.2 4.3

1999–2001

Gunn [86] USA 2008 7333l 10.8

1997–2003

a
Patients with urethral symptoms and with microscopic signs of urethritis.
b
Patients with urethral symptoms and without microscopic signs of urethritis.
c
Asymptomatic men.
d
Patients who were screened for sexually transmitted infection.
e
Asymptomatic patients with microscopic signs of urethritis.
f
Patients without clinical signs of urethritis.
g
Patients who were diagnosed as urethritis by clinician.
h
Patients who were diagnosed as urethritis and with urethral discharge.
i
Patients who were diagnosed as urethritis and without urethral discharge.
j
Patients with gonococcal urethritis.
k
Men in general population.
l
Men who have sex with men (MSM).
m
Male military recrut.
Abbreviations: NG: Neisseria gonorrhoea, CT: Chlamydia trachomatis, MG: Mycoplasma genitalium, UU: Ureaplasma urealyticum, UP: Ureaplasma parvum, TV: Trichomonas vaginalis, HSV: Herpes simplex virus, GV: Gardnerella
vaginalis, AV: Adenovirus.
Abbreviations of countries: CHI: Chile, CHN: China, ESP: Spain, EST: Estonia, FRA: France, INA: Indonesia, JPN: Japan, KOR: Korea, MAD: Madagascar, RSA South Africa, RUS: Russia, TUR: Turkey, UK: United Kingdom, USA: United
State of America.
 Table 4 Clinical studies of the presence of M. genitalium by nucleic acid amplification tests.

Published Country No with No with No w/o Evidence

Author year for test NGU Mg(+) %MG NCNGU Mg(+) %MG NGU MG(+) %Mg Study type level

Jensen [7] 2005 2261 470 20.8 1336 290 21.7 2107 124 5.9 Meta-analysis 1

OR 4.20 (3.41–5.17)
P<0.001*

Salari [58] 2003 IRI 125 9 7.2 125 1 0.8 Case control 3

OR 9.62 (1.20–77.12)
P:0.024

Jensen [70] 2004 SWE 1852 126 6.8% 1610 116 7.2 Case series 3

Maeda [72] 2004 JPN 153 26 17.0 80 19 23.8 Case series 3

a
Taylor-Robinson [71] 2004 UK 52 11 21.2 Case series 3

Sturm [61] 2004 RSA 45 5 11.1 16 3 18.8 100 3 3.0 Case control 3

OR 4.04 (0.92–17.72) OR 7.46 (1.36–40.9)

P:0.11 P:0.043

Deguchi [62] 2004 JPN 317 40 12.6 161 28 17.4 141 2 1.4 Case control 3

OR 7.26 (1.71–30.85) OR 14.63 (3.42–62.63)

P:0.004 P<0.001

Anagurius [73] 2005 SWE 276b 26 9.4 252 26 10.3 222c 2 0.9 Case control 3

OR 11.44 (2.68–48.75) OR 12.65 (2.97–53.96)

P<0.001 P<0.001

Iser [63] 2005 AUS 80 5 6.0 79 1 1.3 Case control 3

OR 5.20 (0.59–45.56)
P:0.22

Bradshow [65] 2006 AUS 329 31 9.4 307 3 1 Case control 3

OR 10.54 (3.19–34.85)
P<0.001

Gubelin [76] 2006 CHI 23 3 13.0 Case series 3

785
continued
 Table 4 Clinical studies of the presence of M. genitalium by nucleic acid amplification tests. – cont'd

786
Published Country No with No with No w/o Evidence
Author year for test NGU Mg(+) %MG NCNGU Mg(+) %MG NGU MG(+) %Mg Study type level

Stamm [38] 2006 USA 111 28 25.2 Case series 3

Yu [68] 2008 HKG 98 10 10.2 236 5 2.1 Case control 3

OR 5.25 (1.75–15.79)
P:0.003

subtotal 3461 320 9.2 2119 192 9.1 1210 17 1.4

OR 7.15 (4.37–11.70) OR 6.99 (4.24–11.54)

P<0.001 P<0.001

Total 5722 790 13.8 3455 482 14.0 3317 141 4.3

OR 3.61 (3.00–4.34) OR 3.65 (3.01–4.43)

P<0.001 P<0.001

* Odds ratio (95% CI: conficence interval).

Abbreviations: MG: Mycoplasma genitalium, NGU: non-gonococcal urethritis, NCNGU: non-chlamydial non-gonococcal urethritis.
a
recurrent or persistent non-gnococcal urethritis.
b
Patients with more than 5 polymorphonuclear leukocytes in the urinary sediment of the first pass urine.
c
Patients with less than 4 polymorphonuclear leukocytes in the urinary sediment of the first pass urine.
Abbreviations of countries : AUS: Australia, CHI: Chile, DEN: Denmark, HKG: Hong Kong, IRI: Iran, JPN: Japan, SWE: Sweden, UK: United Kingdom, USA: United State of America.

analyse the data on the antimicrobial
susceptibilities of the causative bacteria,
e.g. N. gonorrhoeae, and M. genitalium.
In many countries, rates of fluoroqui-
nolones-resistant N. gonorrhoeae are
increasing. The CDC announced that
fluoroquinolones are no longer recom-
mended for gonococcal infections in 2007
[2]. Therefore, the susceptibility rates of
N. gonorrhoeae against fluoroquinolones
in particular were examined. In addition,
some reports about less susceptible strains
of N. gonorrhoeae against cefixime or
ceftriaxone are very important to detem-
ine the recommended regimens for GU.
Regarding the antimicrobial suscep-
tibilities of N. gonorrhoeae, we identi-
fied one systematic review [12] and 32
papers that met the inclusion criteria
including: five case reports of cefixime-
resistant strains and two experimental
papers (Table 5). The prevalence rates of
fluoroquinone-resistant N. gonorrhoeae
were shown in Newman’s review [12].
Geographic regions reporting the high-
est rates of ciprofloxacin (CIP)-resistance
were Asian countries where resistance
rates are up to 40–100% (Table 6). In
Europe, resistance rates varied from
10–50%. In the USA, a nationwide survey
found 13.8% resistance rates in 2006. In
New Caledonia, the CIP resistant strains
were not detected in 2006. These obser-
vations suggest that CIP-resistant N.
gonorrhoeae strains are spreading world-
wide. Resistance rates of N. gonorrhoeae
strains to penicillins or tetracyclines are
over 15% in many regions. In some coun-
tries such as Japan, Sweden or Australia,
cases of treatment failure after cefix-
ime therapy and detection of cefixime-
resistant strains were reported [13–17].
In addition, less susceptible strains to
ceftriaxone were reported from Italy [9],
Sweden [9, 18], Russia [19] Japan [16] and
South Africa [20]. Fortunately, N. gonor-
rhoeae resistance rates to ceftriaxone or
spectinomycin remain very low [21–25].
Recently, AZM-resisitant N. gonorrhoeae
Urethritis | 14.3 |
strains have been increasing [26–28].
We do not have sufficient information to
determine the grading of AZM-regimens
for GU [29–30] and this represents an
important concern.
We identified four papers that evalu-
ated antimicrobial susceptibilities of
M. genitalium including three experimen-
tal papers and one case report describing
an azithromycin (AZM)-resistant M. gen-
talium strain[31]. Papers of antimicrobial
susceptibility testing were very limited.
Antimicrobial susceptibility testing for
M. genitalium has been performed by
the broth-dilution method, but a newer
method by using real-time PCR is being
trialled [31–32] as the isolation of M.
genitalium strains which can grow in the
mycoplasma-broth has been difficcult and
time-consuming [32]. M. genitalium was
more susceptible to macrolides such as
AZM or clarithromycin (CLR) and newer
fluoroquinolones as moxifloxacin (MXF)
or sitafloxacin in vitro [32–34]. However,
azithromycin-resistant strains have been
reported [31, 35].
We identified only one paper describ-
ing the antimicrobial susceptibility of
C. Trachomatis. This paper was a case
report describing one AZM-resistant
strain [36]. We found another case report
describing multiple drug-resistant C. tra-
chomatis strains published in 2000 [37].
This study showed three clinical strans
resistant to DOX, AZM and ofloxacin.
5. TREATMENT
All clinical trials of antibiotics against male
urethritis were also listed. The clinical effi-
cacy of antimicrobials against each patho-
gen, e.g. N. gonorrhoeae, C. trachomatis
and M. genitalium was listed. Using these
data for antimicrobial susceptibilities and
clinical treatment trials, the recommended
regimens for male urethrits and their
grade of recommendation grade according
to ICUD standards [10–11] are shown.
787
Chapter | 14 | Sexually transmitted infectious diseases

Tabel 5 Evidence table for recent studies of antimicrobial susceptibilities of N. gonorrhoeae or M. genitalium that include
original data (susceptibility data), systematic reviews or meta-analysis, expert opinionand case reports of antimicrobial-resistant
strains of N. gonorrhoeae, M. genitalium or C. trachomatis, (2003–2008).

Lead author
Year Level of
Study type Reference Study area Design evidence

Systematic review

(N. gonorrhoeae) Newman [12], 2007 Systematic review of fluoroqu- 1

inolone-resistant NG

Non-randomized
cohorting study

(N. gonorrhoeae) Martin [9], 2006 Western Europe susceptibilities of NG in 2

coountries of Western Europe,
2004

GRASP [87], 2006 Western Europe, UK Susceptibilities of NG in UK, 2

2006

Tapsall [88], 2006 Western Pacific susceptibility of NG in 16 2

countries of the Western
Pacific Region, 2005

GISP-2005 [89], 2006 North America, USA Susceptibilities of NG in USA, 2

2005

Euro-GASP [90] 2007 Western Europe Suceptibilities of NG in 16 2

Western European counties,
2006–2007

AUS-GSP [91], 2007 Oceania, AUS Susceptibility of NG in AUS, 2

2006

CDC up-date [2], 2007 North America, USA CDC guideline up-date 2

GISP-2006 [92], 2007 North America, USA Susceptibilities of NG in USA, 2

2006

AUS-GSP [93], 2008 Oceania, AUS Susceptibility of NG in AUS, 2

2007

Case series (in vitro

susceptibility)

(N. gonorrhoeae) Arreaza [26], 2003 Western Europe, ESP MICs of NG against AZM, 3
1991–2001. AZM-resistant
strains were incresing.

Llanes [25], 2003 Central America, CUB MICs of NG in Cuba, 3

1995–1999

Su [22], 2004 Asia, CHN susceptibility of NG in China, 3

1999–2006

Yoo [94], 2004 Asia, KOR susceptibility of NG in KOR, 3

1999–200

Shigemura [95], 2004 Asia, JPN susceptibility of NG in Japan, 3

2002

Aydin [96], 2005 Asia, TUR MICs of NG in TUR 3

1998–2002

Enders [97], 2006 Western Europe, GER MICs of NG in GER 3

2004–2005

788
 Urethritis | 14.3 |

Lead author
Year Level of
Study type Reference Study area Design evidence

Stathi [98], 2006 Western Europe, GRE suceptibility and MICs of NG 3

in GRE, 1994–2004

Wang [23], 2006 Asia, CHN MICs of NG in CHN, 2003 3

Yang [99], 2006 Asia, CHN MICs of NG in CHN, 2004 3

Donegan [100], 2006 Asia, INA MICs of NG in INA 2004 3

Shigemura Shigemura

Moodley [20], 2006 Africa, RSA susceptibilities of NG in RSA, 3

2003

Vazquez [101], 2007 Western Europe, ESP susceptibility of NG in ESP, 2005 3

Vorobieva [19], 2007 Eastern Europe, RUS Susceptibility of NG in RUS, 3

2004

Hovhannisyan [102], Eastern Europe, ARM susceptibilities of NG in ARM, 3

2007 2003–2004

Belda Junior [24], 2007 South America, BRA MICs of NG in BRA 3

2004–2005

De Jongh [103], 2007 Africa, RSA susceptibility of NG in RSA, 3

2004–2005

Olsen [104], 2008 Western Europe, SWE susceptibility of NG in 3

Sweden, 2005

Palmer [27], 2008 Western Europe, UK AZM-resistant strains are 3

increasing in UK.

Kubanova [21], 2008 Eastern Europe, RUS susceptibilities of NG in RUS, 3

2005–2006

Ilina [105], 2008 Eastern Europe, RUS MICs of NG against in RUS, 3

2004

Khaki [30], 2008 Asia, IND susceptibility of NG in India, 3

2005–2006

Muratani [42], 2008 Asia, JPN Susceptibility of NG in JPN, 3

2004–2006

Case reports

(N. gonorrhoeae) Ito [13], 2006 Asia, JPN Cefixime-resistant NG in JPN 3

Lindberg [18], 2007 Western Europe, SWE reduce susceptible Ng strains 3

to Cefixime or ceftriaxone

Yokoi [14], 2007 Asia, JPN cefime-treatment failure in GU 3

Ochiai [15], 2008 Asia, JPN reduced susceptible NG to 3

cepharosporins in JPN

Osaka [16], 2008 Asia, JPN less susceptible strains to 3

cefixime or ceftriaxone

(C. trachomatis) Magbanua [36], 2007 Western Europe, UK A variant CT and AZM- 3
resistant in UK

(M. genitalium) Jensen [31], 2008 Western Europe, Analysis of AZM-resistant stra- 3
DEM ins, mutation in 23S rRNA

continued

789
Chapter | 14 | Sexually transmitted infectious diseases

Tabel 5 Evidence table for recent studies of antimicrobial susceptibilities of N. gonorrhoeae or M. genitalium that include
original data (susceptibility data), systematic reviews or meta-analysis, expert opinionand case reports of antimicrobial-resistant
strains of N. gonorrhoeae, M. genitalium or C. trachomatis, (2003–2008) – cont'd

Lead author Level of

Study type Year Study area Design evidence
Reference

Experimental study

(N. gonorrhoeae) Lundback [28], 2006 Western Europe, SWE 10 AZM-resistant NG strains 4

Whiley [17], 2007 Oceania, AUS penA mutation of NG 4

strains with less susceptible to
cefixime

(M. genitalium) Yasuda [34], 2005 Asia, JPN MICs of MG against 4

fluoroquionolones

Hamasuna [32], 2005 Asia, JPN MICs of MG 4

Bebear [33], 2008 Western Europe, FRA MICs of MG 4

Expert opinion

(N. gonorrhoeae) Geisler [55], 2005 North America, USA CDC guideline 4

Abbreviations:
CT: Chlamydia trachomatis, NG: Neisseria gonorrhoeae, MG: Mycoplasma genitalium, GU: gonococcal urethritis, AZM: azithromycin, MICs:
minimum inhibitory concentrations, GRASP The Gonococcal resistance to Antimicrobials Surveillance Programme, GISP: Gonococcal Isolate
Surveillance Project, Euro-GASP: European Gonococcal Antimicrobial Surveillance Program, AUS-GSP: Australian Gonococcal Surveillance Programme.
Abbreviations of countries:
ARM: Armenia, AUS: Australia, BRA: Brazil, CHN: China, CUB: Cuba, DEN: Denmark, ESP: Spain, FRA: France, GER: Germany, GRE: Greece, HKG:
Hong Kong, IND: India, INA: Indonesia, JPA: Japan, KOR: Korea, NOR: Norway, SWE: Sweden, TUR: Turkey, RSA: South Africa, RUS: Russia,
UK: United Kingdom, USA: United State of America.

5.1 Clinical studies [29–30], CIP [40], ceftibuten [41], ceftriax-

We identified 24 studies on antimicrobial
therapy of male urethritis that met our inclu-
sion criteria: 11 papers evaluating treatment
of GU, three papers for chlamydial urethri-
tis, 10 papers for M. genitalium urethritis
and one paper for the three causative bacte-
ria (Table 7). For gonococcal urethritis, one
sytematic review, one randomized controlled
study and eight case-series were included.
Newman performed a systematic review
of clinical studies of oral cephalosprins and
macrolides for gonorrhea, which were pub-
lished between 1988 and 2001. The RCT
compared Rafalazil to AZM [38]. Kojima et
al. conducted a case-series of 2 g spectino-
mycin for GU [39], providing an important
evaluation of the alternative regimen for
GU recommmended in most guidelines.
Other papers reported results of AZM
one [42] and cefodizime [43–44] for treat-
ment of GU.
For chlamydial urethrits, we identi-
fied one meta-analysis [45], two RCT [38,
46] and one case series [47]. Lau’s meta-
analysis [45] was important to determine
the recommendation for treatment with
AZM or doxycycline (DOX) for chlamydial
urethritis. The RCTs compared Rafalazil
to AZM [38] and travafloxacin to DOX
[46]. A case series was reported of travo-
floxacin for treatment of chlamydial ure-
thritis [47]. For M. genitalium urethritis,
we identified one review [7], two RCTs
[38, 48], three case-controlled studies
[35, 49–50] and four case series [51–54].
The most important RCT was written by
Jernberg et al., who evaluated the clinical
efficacy of AZM and MXF in Norway [48].

790
 Table 6 Antimicrobial susceptibilities of N.gonorhoeae isolated from any regions in recent published studies.

Penicillin (%) Tetracycline (%) Ciprofloxacin (%) Ceftriaxone (%) Spectinomycin (%) Azithromycin (%)

Less Less Less Less Less

Tested Tested Resistant susceptible Resistant susceptible Resistant susceptible susceptible Resistant susceptible Resistant
Country year strains ≥2 mg/l 0.12–1 mg/l ≥2 mg/l 0.5–1 mg/l ≥1 mg/l 0.12–0.5 mg/l >0.25 mg/l ≥125 mg/l 64 mg/l ≥1 mg/l Others Author

Western Europe

ESSTI 2006– PPNG:12.3,

2246 TRNG 16.5 52.0 0 0 NT NT 7.0 EGASP [90]
2007 CMRNG:31.1

AUT 2004 96 22.9a nd 55.2b nd 53.1 0 0 nd nd 31.2 Martin [9]

BEL 2004 64 26.5a nd 70.2b nd 46.9 0 0 nd nd 1.6 Martin [9]

a b
DEN 2004 98 28.3 nd 76.5 nd 46.0 5.1 0 nd nd 8.2 Martin [9]

ENG 2006 1313 9.5 nd 36.9 nd 26.5 1.7 0 0 0 2.0 GRASP [87]

ENG+WAL 2004 100 13.0a nd 72.0 b nd 12.0 0 0 nd nd 1.0 Martin [9]

FRA 2004 101 12.9a nd 75.2b nd 32.7 2.0 0 nd nd 0 Martin [9]

GER 2004–
65 21.5 70.5 29.2 63.1 47.7 0 0 0 0 7.7 Enders [97]
2005

GRE 2005 142 16.2 73.2 12.7 83.1 11.3 0 0 0 0 nd Stathi [98]

GRE 2004 79 14.0a nd 51.9 b* nd 7.6 1.3 0 nd nd 0 Martin [9]

a b
ITA 2004 42 19.0 nd 52.4 nd 33.3 4.8 4.8 nd nd 9.5 Martin [9]

NED 2004 81 25.9a nd 59.2b nd 16.0 0 0 nd nd 17.3 Martin [9]

POR 2004 17 11.8a nd 70.6b* nd 17.6 0 0 nd nd 0 Martin [9]

a b
SCO 2004 99 29.4 nd 48.6 nd 30.3 1.0 0 nd nd 5.1 Martin [9]

ESP 2005 204 31 59 36 49 43 7 0 nd nd nd Vazquez [101]

791
continued
 Table 6 Antimicrobial susceptibilities of N.gonorhoeae isolated from any regions in recent published studies – cont'd

792
Spectinomycin Azithro-
Penicillin (%) Tetracycline (%) Ciprofloxacin (%) Ceftriaxone (%)
(%) mycin (%)

Less Less Less Less Less

Tested Tested Resistant susceptible Resistant susceptible Resistant susceptible susceptible >0.25 Resistant susceptible Resistant
Country year strains ≥2 mg/l 0.12–1 mg/l ≥2 mg/l 0.5–1 mg/l ≥1 mg/l 0.12–0.5 mg/l mg/l ≥125 mg/l 64 mg/l ≥1 mg/l Others Author

ESP 2004 92 10.9a nd 54.4b nd 15.2 8.7 0 nd nd 2.2 Martin [9]

a b
SWE 2004 96 32.5 nd 71.8 nd 48.0 3.1 1.0 nd nd 13.5 Martin [9]

Eastern Europe

ARM 2003– Hovhannisyan

101 5.9 56.4 3.0 71.3 4.0 1.0 0 0 0 0
2004 [102]

RUS 2006 521 17.5 57.3 40.3 34.2 48.6 2.9 0 0.8 7.1 nd Kuvanova [21]

RUS 2004– Ilina [105]

464 11.9 62.2 38.1 26.0 45.5 0.4 nd nd nd nd
2005

RUS 2004 76 18.4 57.9 11.8 80.3 17.1 0 2.6 0 0 14.5d Vorobieva [19]

Asia

BRU 2006 PPNG:38.6,

208 nd nd 57.7 24.0 nd nd nd nd WP-GSP [88]
CMRNG:25.6

CHN 2006 TRNG:11.1

196 87.3 12.7 98.9 1.0 38.8e 2.0 0 nd Su [22]
PPNG/TRNG*21.7

CHN 2006 1134 PPNG:47.7 TRNG:35.2 94.2 5.4 nd nd nd nd WP-GSP [88]

CHN 2004– 159

81.2 6.9 56.6 26.4 98.7 0.6 0 0 1.9 nd Yang [99]
2005

CHN 2003 96 68.4 31.6 78.9 20.0 100 0 0 1.1 4.2 nd Wang [23]

HKG 2006 1622 PPNG:34.1,

TRNG:48.9 75.8 2.0 nd nd nd nd WP-GSP [88]
CMRNG:28.6

IND 2005– 75
32.0 66.7 30.1 22.7 98.7 1.3 0 0 0 0 Khaki [30]
2006

INA 2004 147 81.6 18.4 100 0 40.1 2.0 0 0 0 0 Donegan [100]
 JPN 2006 211 PPNG:0.9,CMRNG:21.8 TRNG:0.9 75.8 7.0 nd nd nd nd WP-GSP [88]
h
JPN 2002 87 CFX-LS
19.5 70.1 19.5 39.1 69.0 21.7 0 0 0 nd Shigemura [95]
:9.2%

KOR 2002 209 58.9 36.8 82.8 14.8 48.8 35.9 0 0 0 Nd Yoo [94]

MAS 2006 34.4 nd nd nd 44.8 17.2 nd nd nd nd WP-GSP [88]

PHI 2006 42 PPNG:50.0,

TRNG:31.0 69.0 0 nd nd nd nd WP-GSP [88]
CMRNG:28.5

SIN 2006 160 PPNG:49.4,

TRNG:76.8 61.8 8.2 nd nd nd nd WP-GSP [88]
CMRNG:10.0

TUR 1998– 78
25.6 38.5 18.0 57.7 1.3 1.3 0 nd nd nd Aydin [96]
2002

VIE 2006 212 PPNG:30.7,CMRNG:0.5 TRNG:16.5 56.6 25.5 nd nd nd nd WP-GSP [88]

North America

CFX-LS GISP-2006
USA 2006 6089 11.4f nd 20.1b nd 13.8 1.2 0 0 0 0.2g
1 strain [92]

USA 2005 6199 GISP-2005

13.0 f Nd 17.2 b Nd 9.4 1.1 0 0 0 2.9
[89]

South America or Caribbean countries

BRA 2004– 65
23.1 76.9 30.8 61.5 nd nd nd 0 9.2 nd Belda [24]
2005

CUB 1995– 120

60.2 5.0 54.2 10.0 0 0.9 0 0 1.7 0 Llanes [25]
1999

Africa

RSA 2003 139 35.4 60.6 79.0 15.0 22.0 0 2.0 0 0 nd Moodley [20]

RSA 2004– 141 De Jongh

29.1 53.9 nd 7.1 0 0 0 0 0 nd
2005 [103]

Oceania

AUS 2007 3042 PPNG:12.1,

TRNG:16.6 47.9 1.2 0 0 0 nd AUS-GSP [93]
CMRNG:26.2

NC 2006 93 PPNG:0,CMRNG:0 TRNG:2.1 0 0 nd nd nd nd WP-GSP [88]

793
continued
 Table 6 Antimicrobial susceptibilities of N.gonorhoeae isolated from any regions in recent published studies – cont'd

794
Spectinomycin Azithro-
Penicillin (%) Tetracycline (%) Ciprofloxacin (%) Ceftriaxone (%) (%) mycin (%)

Less Less Less Less Less

Tested Tested Resistant susceptible Resistant susceptible Resistant susceptible susceptible >0.25 Resistant susceptible Resistant
Country year strains ≥2 mg/l 0.12–1 mg/l ≥2 mg/l 0.5–1 mg/l ≥1 mg/l 0.12–0.5 mg/l mg/l ≥125 mg/l 64 mg/l ≥1 mg/l Others Author

NZL 2006 284 PPNG:1.0,CMRNG:20.4 TRNG:25.0 13.7 0 nd nd nd nd WP-GSP [88]

PNG 2006 53 PPNG:43.4 nd nd 1.8 0 nd nd nd nd WP-GSP [88]

nd: no description
a
Strains of PPNG, PP/TRNG or CMRNG.
b
Strains of TRNG, PP/TRNG, CMRNG or TetR.
c
Resistant rate to ampicillin.
d
Azithromycin less susceptible.
e
Strains with ≥0.06 of MIC were determined less susceptible.
f
Strains of PPNG, PPNG/TRNG, CMRNG or PenR.
g
Strains with ≥2 of MIC were determined resistant.
h
Cefixime-less susceptible strains.
PPNG: Penicillin:β-lactamase +ve and tetracycline:MIC< 16 mg/l.
TRNG: Tetracycline:MIC≥ 16 mg/l and paenicillin β-lactamase –ve.
PP/TRNG: Penicillin:β-lactamase +ve and tetracycline:MIC≥16 mg/l.
CMRNG: Penicillin:MIC≥1 mg/l but β-lactamese –ve and tetracycline:MIC between 2–8 mg/l.
PenR: Penicillin: ≥1 mg/l but β-lactamase –ve and tetracycline:MIC <2 mg/l.
TetR: Tetracycline:MIC between 2–8 mg/l and penicillin: <1 mg/l.
EGASP: Europe Gonococcal Antimicrobial Surveillance Programme. Euro-GASP Annual report No.2 2007[90].
GRASP: the Gonococcal Resintance to Antimicrobials Surveillance Programme, GRASP Annual report 2006[87].
GISP-2006: Gonococcal Isolate Surveillance Project (GISP), Annual Report 2006[92].
GISP-2005: Gonococcal Isolate Surveillance Project (GISP), Annual Report 2005[89].
WP-GSP: Surveillance of antibiotic reisistace in Neissseria gonorrhoeae in the WHO Western Pacific Region, 2006[88].
Aus-GSP: Annual report of the Australian Gonococcal Surveillance Program, 2007[93].
Aus-GSP: Annual report of the Australian Gonococcal Surveillance Program, 2006[91].
ARM: Armenia, AUS: Australia, AUT: Austria, BEL Belgium, BRA: Brazil, BRU: Brunei, CHN: China, CUB: Cuba, DEN: Denmark, ENG: England, ESP: Spain, FRA: France, GER: Germany, GRE: Greece, HKG: Hong Kong, IND: India, INA:
Indonesia, ITA: Italy, JPA: Japan, KOR: Korea, MAS: Malaysia, NC: New Caledonia, NED: The Netherlands, NZL: New Zealand, PHI: Philippines, PNG: Papua New Guinea , POR: Portugal, SCO: Scotland, SWE: Sweden, SIN:　Singapore,
TUR: Turkey, RSA: South Africa, RUS: Russia, USA: United State of America, VIE: Vietnam, WAL: Wales.
 Urethritis | 14.3 |

Tabel 7 Evidence table for recent studies of clinical trials of antibiotics to male urethritis that include systematic reviews or
meta-analysis, randomized controlled studies, case controlled studies, case series and expert opinion (1998–2008).

Study type Lead author Study area Design Level of

Year evidence
Reference
Systematic review,
meta-analysis

(N. gonorrhoea) Newman [12], 2007 Systematic review for treat- 1

ment of gonococcal infections

(C. trachomatis) Lau [45], 2002 Metaanalysis of treatment of 1

AZM and DOX for chlamydial
infection

(M. genitalium) Jensen [7], 2006 Review of MG studies 1

Randomized control-
led study

(N. gonorrhoea) Stamm [38], 2007 North America, USA Rafalazii, vs AZM, 111 men 1
with urethritis
(C. trachomatis)
(M. genitalium)

(C. trachomatis) MaComack [46], North America, USA Travafloxacin vs DOX, men 1
1999 202 with chlamydial urethritis

(M. genitalium) Jernberg [48], 2008 Western Europe, NOR Macrolides and moxyfloxacin, 1
234 MG-positive men

Case controlled study

(M. genitalium) Falk [49], 2003 Western Europe, SWE Clinical study of tetracyclines 2
(DOX or lymecycline) or AZM
1g, 16 men with NGU

Bradshaw [35], 2006 Oceania, AUS Clinical study of AZM 1g, 2

34 MG-positive men with or
without urethritis

Bjornelius [50], 2008 Western Europe, SWE Clinical study of AZM 1g and 2
DOX, 115 MG-positive men

Case series

(N. gonorrhoeae) Chong [41], 1998 Asia, HKG Clinical trial of ceftibuten, 112 3
men with G

Moodley [40], 2002 Africa, RSA Low dose of Ciprofloxacin, 3

442 men with GU

Matsumoto [43], Asia, JPN Clinical trial of cefodizime 1g, 3

2006 10 men with GU

Matsumoto [44], Asia, JPN Clinical trial of cefodizime 3

2006 1g for the NG-pharyngeal
infection

Habib [29], 2006 Asia, IND Clinical trial of AZM 1g, 135 3
men with GU

Kojima [39], 2008 Asia, JPN Clinical study of spectinomy- 3

cin 2g, 210 men with GU

Khaki [30], 2008 Asia, IND Clinical trial of AZM 2g, 52 3

men with GU

795
Chapter | 14 | Sexually transmitted infectious diseases

Tabel 7 Evidence table for recent studies of clinical trials of antibiotics to male urethritis that include systematic reviews or
meta-analysis, randomized controlled studies, case controlled studies, case series and expert opinion (1998–2008) – cont'd

Lead author
Year Level of
Study type Reference Study area Design evidence
Muratani [42], 2008 Asia, JPN Clinical trial of ceftroaxone 3
1g, 27 men and 40 women
with gonorrhoeae

(C. trachomatis) Martin [47], 1999 North America, USA Clinical trial of travafloxacin,
64 men with CU

(M. genitalium) Johannisson [51], Western Europe, SWE Clinical trial of tetracycline 22 3
2000 MG-positive men

Maeda [52], 2001 Asia, JPN Clinical trial of levofloxacin, 3

12 men with NGU

Dupin [53], 2003 Western Europe, FRA Clinical trial of minocycline or 3

DOX, 8 MG-positive men

Wikstrom [54], 2006 Western Europe, SWE Clinical trial of AZM, 22 men 3
with recurrent or persistent
urethritis

Expert opinion

(N. gonorrhoeae) CDC up-date [2], North America, USA CDC guideline up-date 4
2007

Geisler [55]　2005 North America, USA CDC guideline 4

Abbreviations:
MG: Mycoplasma genitalium, GU: gonococcal urethritis, CU: chlamydial urethritis, NGU: non-gonococcal urethritis, AZM: azithromycin,
DOX: doxycycline.
Abbreviations of countries:
AUS: Australia, DEN: Denmark, HKG: Hong Kong, IND: India, FRA: France, JPA: Japan, NOR: Norway, RSA: South Africa, SWE: Sweden.

5.2 Recommendations for the • Cefixime 400 mg orally in a single dose

treatment of male patients • (Quinolone regimens no longer recom-
with urethritis mended [2])
The recommended management of male Alternative regimens
patients with urethritis is based on the
• Spectinomycin 2 g intramuscurally in
CDC 2006 guidelines [1] and on our review
a single dose
of the literature described above.
• Single-dose cephalosporin regimens
5.2.1 Definition of GU and NGU
The presence of Gram-negative intracel-
5.2.3 Treatment of NGU
lular diplococci (GNID) on urethral smear
is indicative of GU. NGU is diagnosed Recommended regimens
when microscopy indicates inflammation
• AZM 1g orally in a single dose
without GNID.
• DOX 100 mg orally twice a day for
5.2.2 Treatment of GU 7 days
Recomended regimens Alternative regimens
• Ceftriaxone 125 mg intramuscurally • Erythromycin base 500 mg orally for
in a single dose times a day for 7 daya

796

• Erythromycin ethylsuccinate 800 mg
orally for times a day for 7 days
• Ofloxacin 300 mg orally twice a day
for 7 days
• Levofloxacin 500 mg orally once daily
for 7 days
6. FURTHER RESEARCH
N. gonorrhoeae can easily become resist-
ant to antimicrobials and resistant strains
can easily be spread worldwide. The sur-
veillance of antimicrobial susceptibilities
of N. gonorrhoeae is important for urolo-
gists in any region. Especially, the resist-
ance rate for cefixime should be paid
attention. The antimicrobial susceptibili-
ties of C. trachomatis or M. genitalium
are also necessary. For urethritis with
M. genitalium, further clinical studies are
necessary using CLR or newer fluoroqui-
nolones such as MXF or sitafloxacin.
7. CONCLUSIONS
In this review, we included papers evaluat-
ing the prevalence of the major bacterial
pathogens causing urethritis, antimicro-
bial susceptibility data and clinical treat-
ment trials. These data suggest that
GU remains a frequent disease in the
US, Eastern Europe, Asian and African
countries. Because luoroquinolon-resistant
N. gonorrhoeae strains have become wide-
spread worldwide, fluoroquinolone regi-
mens can no longer be recommended for
GU. C. trachomatis is the major causa-
tive bacteria for NGU and AZM- or DOX-
regimens are recommended to chlamydial
urethritis. M. genitalium also appears to
represent a frequent cause of male ure-
thritis that merits consideration when
selecting a treatment regimen for NGU,
for which AZM is the first line drug.
Therefore, AZM could be regarded as the
first line treatment of chlamydial urethri-
tis, but not tetracyclines.
Urethritis | 14.3 |
REFERENCES
1. Workowski KA and Berman SM, Sexually
transmitted diseases treatment guide-
lines, 2006. MMWR Recomm Rep, 2006.
55(RR-11): 1–94.
2. Update to CDC’s sexually transmitted
diseases treatment guidelines, 2006:
fluoroquinolones no longer recommended
for treatment of gonococcal infections.
MMWR Morb Mortal Wkly Rep, 2007.
56(14): 332–6.
3. British Association for Sexual health and
HIV B. National guideline on the diagno-
sis and treatment of gonorrhoea in adults
2005. 2005; Available from: http://www.
bashh.org/documents/116/116.pdf.
4. British Association for Sexual health and
HIV B. 2006 UK National guideline for
the management of genital tract infec-
tion with Chlamydia trachomatis. 2006;
Available from: http://www.bashh.org/
documents/61/61.pdf.
5. British Association for Sexual health and
HIV B. 2008 National guideline on the
management of non-gonococcal urethritis.
2008; Available from: http://www.bashh.
org/documents/89/89.pdf.
6. Grabe M, Bishop MC, T.E. Bjerklund-
Johansen, Botto H, Çek M, Lobel B, Naber
KG, Palou J, and Tenke P. Guideline on
the management of urinary and male geni-
tal tract infections. 2008; Available from:
http://www.uroweb.org/fileadmin/tx_eau-
guidelines/The%20Management%20of%20
Male%20Urinary%20and%20Genital%20
Tract%20Infections.pdf.
7. Jensen JS, Mycoplasma genitalium infec-
tions. Dan Med Bull, 2006. 53(1): 1–27.
8. Andrews JM, BSAC standardized disc
susceptibility testing method (version 7).
J Antimicrob Chemother, 2008. 62(2):
256–78.
9. Martin IM, Hoffmann S, and Ison CA,
European Surveillance of Sexually
Transmitted Infections (ESSTI): the first
combined antimicrobial susceptibility
data for Neisseria gonorrhoeae in Western
Europe. J Antimicrob Chemother, 2006.
58(3): 587–93.
10. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
797
Chapter | 14 | Sexually transmitted infectious diseases
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
11. US Department of Health and Human
Service, Public Health Service. Agency for
Healh Care Policy and Research. 1992.
115–127.
12. Newman LM, Moran JS, and Workowski
KA, Update on the management of
gonorrhea in adults in the United States.
Clin Infect Dis, 2007. 44 Suppl
3: S84–101.
13. Ito M, Deguchi T, Mizutani KS, Yasuda
M, Yokoi S, Ito S, Takahashi Y, Ishihara
S, Kawamura Y, and Ezaki T, Emergence
and spread of Neisseria gonorrhoeae
clinical isolates harboring mosaic-like
structure of penicillin-binding protein
2 in Central Japan. Antimicrob Agents
Chemother, 2005. 49(1): 137–43.
14. Yokoi S, Deguchi T, Ozawa T, Yasuda M,
Ito S, Kubota Y, Tamaki M, and Maeda
S, Threat to cefixime treatment for gon-
orrhea. Emerg Infect Dis, 2007. 13(8):
1275–7.
15. Ochiai S, Ishiko H, Yasuda M, and
Deguchi T, Rapid detection of the mosaic
structure of the Neisseria gonorrhoeae
penA Gene, which is associated with
decreased susceptibilities to oral cepha-
losporins. J Clin Microbiol, 2008. 46(5):
1804–10.
16. Osaka K, Takakura T, Narukawa K,
Takahata M, Endo K, Kiyota H, and
Onodera S, Analysis of amino acid
sequences of penicillin-binding protein
2 in clinical isolates of Neisseria gonor-
rhoeae with reduced susceptibility to cefix-
ime and ceftriaxone. J Infect Chemother,
2008. 14(3): 195–203.
17. Whiley DM, Limnios EA, Ray S, Sloots
TP, and Tapsall JW, Diversity of penA
alterations and subtypes in Neisseria gon-
orrhoeae strains from Sydney, Australia,
that are less susceptible to ceftriaxone.
Antimicrob Agents Chemother, 2007.
51(9): 3111–6.
18. Lindberg R, Fredlund H, Nicholas R, and
Unemo M, Neisseria gonorrhoeae isolates
with reduced susceptibility to cefixime
and ceftriaxone: association with genetic
polymorphisms in penA, mtrR, porB1b,
and ponA. Antimicrob Agents Chemother,
2007. 51(6): 2117–22.
798
19. Vorobieva V, Firsova N, Ababkova T,
Leniv I, Haldorsen BC, Unemo M, and
Skogen V, Antibiotic susceptibility of
Neisseria gonorrhoeae in Arkhangelsk,
Russia. Sex Transm Infect, 2007. 83(2):
133–5.
20. Moodley P, Martin IM, Pillay K, Ison CA,
and Sturm AW, Molecular epidemiology of
recently emergent ciprofloxacin-resistant
Neisseria gonorrhoeae in South Africa.
Sex Transm Dis, 2006. 33(6): 357–60.
21. Kubanova A, Frigo N, Kubanov A,
Sidorenko S, Priputnevich T, Vachnina T,
Al-Khafaji N, Polevshikova S, Solomka V,
Domeika M, and Unemo M, National sur-
veillance of antimicrobial susceptibility in
Neisseria gonorrhoeae in 2005–2006 and
recommendations of first-line antimicrobial
drugs for gonorrhoea treatment in Russia.
Sex Transm Infect, 2008. 84(4): 285–9.
22. Su X, Jiang F, Qimuge, Dai X, Sun H, and
Ye S, Surveillance of antimicrobial sus-
ceptibilities in Neisseria gonorrhoeae in
Nanjing, China, 1999–2006. Sex Transm
Dis, 2007. 34(12): 995–9.
23. Wang B, Xu JS, Wang CX, Mi ZH, Pu
YP, Hui M, Ling TK, and Chan CY,
Antimicrobial susceptibility of Neisseria
gonorrhoeae isolated in Jiangsu Province,
China, with a focus on fluoroquinolone
resistance. J Med Microbiol, 2006.
55(Pt 9): 1251–5.
24. Belda Junior W, Velho PE, Fagundes
LJ, and Arnone M, Evaluation of the in
vitro activity of six antimicrobial agents
against Neisseria gonorrhoeae. Rev Inst
Med Trop Sao Paulo, 2007. 49(1): 55–8.
25. Llanes R, Sosa J, Guzman D, Llop A,
Valdes EA, Martinez I, Palma S, and
Lantero MI, Antimicrobial susceptibility
of Neisseria gonorrhoeae in Cuba (1995–
1999): implications for treatment of gonor-
rhea. Sex Transm Dis, 2003. 30(1): 10–4.
26. Arreaza L, Vazquez F, Alcala B, Otero L,
Salcedo C, and Vazquez JA, Emergence
of gonococcal strains with resistance to
azithromycin in Spain. J Antimicrob
Chemother, 2003. 51(1): 190–1.
27. Palmer HM, Young H, Winter A, and
Dave J, Emergence and spread of azithro-
mycin-resistant Neisseria gonorrhoeae in
Scotland. J Antimicrob Chemother, 2008.
62(3): 490–4.

28. Lundback D, Fredlund H, Berglund T,
Wretlind B, and Unemo M, Molecular epi-
demiology of Neisseria gonorrhoeae- iden-
tification of the first presumed Swedish
transmission chain of an azithromycin-
resistant strain. Apmis, 2006. 114(1): 67–71.
29. Habib AR and Fernando R, Efficacy of azi-
thromycin 1g single dose in the manage-
ment of uncomplicated gonorrhoea. Int J
STD AIDS, 2004. 15(4): 240–2.
30. Khaki P, Bhalla P, Sharma A, and Kumar
V, Correlation between In vitro susceptibil-
ity and treatment outcome with azithro-
mycin in gonorrhoea: a prospective study.
Indian J Med Microbiol, 2007. 25(4): 354–7.
31. Jensen JS, Bradshaw CS, Tabrizi
SN, Fairley CK, and Hamasuna R,
Azithromycin Treatment Failure in
Mycoplasma genitalium-Positive
Patients with Nongonococcal Urethritis
Is Associated with Induced Macrolide
Resistance. Clin Infect Dis, 2008.
32. Hamasuna R, Osada Y, and Jensen
JS, Antibiotic susceptibility testing of
Mycoplasma genitalium by TaqMan
5’ nuclease real-time PCR. Antimicrob
Agents Chemother, 2005. 49(12): 4993–8.
33. Bebear CM, de Barbeyrac B, Pereyre
S, Renaudin H, Clerc M, and Bebear C,
Activity of moxifloxacin against the uro-
genital mycoplasmas Ureaplasma spp.,
Mycoplasma hominis and Mycoplasma
genitalium and Chlamydia trachomatis.
Clin Microbiol Infect, 2008. 14(8): 801–5.
34. Yasuda M, Maeda S, and Deguchi T, In
vitro activity of fluoroquinolones against
Mycoplasma genitalium and their bacte-
riological efficacy for treatment of M. geni-
talium-positive nongonococcal urethritis in
men. Clin Infect Dis, 2005. 41(9): 1357–9.
35. Bradshaw CS, Jensen JS, Tabrizi SN,
Read TR, Garland SM, Hopkins CA, Moss
LM, and Fairley CK, Azithromycin fail-
ure in Mycoplasma genitalium urethritis.
Emerg Infect Dis, 2006. 12(7): 1149–52.
36. Magbanua JP, Goh BT, Michel CE,
Aguirre-Andreasen A, Alexander S, Ushiro-
Lumb I, Ison C, and Lee H, Chlamydia
trachomatis variant not detected by plas-
mid based nucleic acid amplification tests:
molecular characterisation and failure
of single dose azithromycin. Sex Transm
Infect, 2007. 83(4): 339–43.
Urethritis | 14.3 |
37. Somani J, Bhullar VB, Workowski KA,
Farshy CE, and Black CM, Multiple drug-
resistant Chlamydia trachomatis associ-
ated with clinical treatment failure. J
Infect Dis, 2000. 181(4): 1421–7.
38. Stamm WE, Batteiger BE, McCormack
WM, Totten PA, Sternlicht A, and Kivel
NM, A Randomized, Double-Blind
Study Comparing Single-Dose Rifalazil
With Single-Dose Azithromycin for the
Empirical Treatment of Nongonococcal
Urethritis in Men. Sex Transm Dis, 2007.
39. Kojima M, Masuda K, Yada Y, Hayase Y,
Muratani T, and Matsumoto T, Single-dose
treatment of male patients with gonococcal
urethritis using 2g spectinomycin: micro-
biological and clinical evaluations. Int J
Antimicrob Agents, 2008. 32(1): 50–4.
40. Moodley P, Pillay C, Nzimande G,
Coovadia YM, and Sturm AW, Lower
dose of ciprofloxacin is adequate for the
treatment of Neisseria gonorrhoeae in
KwaZulu Natal, South Africa. Int J
Antimicrob Agents, 2002. 20(4): 248–52.
41. Chong LY, Cheung WM, Leung CS, Yu CW,
and Chan LY, Clinical evaluation of cefti-
buten in gonorrhea. A pilot study in Hong
Kong. Sex Transm Dis, 1998. 25(9): 464–7.
42. Muratani T, Inatomi H, Ando Y, Kawai S,
Akasaka S, and Matsumoto T, Single dose
1 g ceftriaxone for urogenital and pharyn-
geal infection caused by Neisseria gonor-
rhoeae. Int J Urol, 2008. 15(9): 837–42.
43. Matsumoto T, Muratani T, Takahashi
K, Ando Y, Sato Y, Kurashima M, Yokoo
D, Ikuyama T, Shimokawa H, and Yanai
S, Single dose of cefodizime completely
eradicated multidrug-resistant strain of
Neisseria gonorrhoeae in urethritis and
uterine cervicitis. J Infect Chemother,
2006. 12(2): 97–9.
44. Matsumoto T, Muratani T, Takahashi
K, Ikuyama T, Yokoo D, Ando Y, Sato Y,
Kurashima M, Shimokawa H, and Yanai
S, Multiple doses of cefodizime are neces-
sary for the treatment of Neisseria gon-
orrhoeae pharyngeal infection. J Infect
Chemother, 2006. 12(3): 145–7.
45. Lau CY and Qureshi AK, Azithromycin
versus doxycycline for genital chlamydial
infections: a meta-analysis of randomized
clinical trials. Sex Transm Dis, 2002.
29(9): 497–502.
799
Chapter | 14 | Sexually transmitted infectious diseases
46. McCormack WM, Dalu ZA, Martin DH,
Hook EW, 3rd, Laisi R, Kell P, Pluck ND,
and Johnson RB, Double-blind compari-
son of trovafloxacin and doxycycline in the
treatment of uncomplicated Chlamydial
urethritis and cervicitis. Trovafloxacin
Chlamydial Urethritis/Cervicitis
Study Group. Sex Transm Dis, 1999.
26(9): 531–6.
47. Martin DH, Jones RB, and Johnson RB, A
phase-II study of trovafloxacin for the treat-
ment of Chlamydia trachomatis infections.
Sex Transm Dis, 1999. 26(7): 369–73.
48. Jernberg E, Moghaddam A, and Moi H,
Azithromycin and moxifloxacin for micro-
biological cure of Mycoplasma genitalium
infection: an open study. Int J STD AIDS,
2008. 19(10): 676–9.
49. Falk L, Fredlund H, and Jensen JS,
Tetracycline treatment does not eradicate
Mycoplasma genitalium. Sex Transm
Infect, 2003. 79(4): 318–9.
50. Bjornelius E, Anagrius C, Bojs G,
Carlberg H, Johannisson G, Johansson
E, Moi H, Jensen JS, and Lidbrink P,
Antibiotic treatment of symptomatic
Mycoplasma genitalium infection in
Scandinavia: a controlled clinical trial.
Sex Transm Infect, 2008. 84(1): 72–6.
51. Johannisson G, Enstrom Y, Lowhagen
GB, Nagy V, Ryberg K, Seeberg S, and
Welinder-Olsson C, Occurrence and
treatment of Mycoplasma genitalium in
patients visiting STD clinics in Sweden.
Int J STD AIDS, 2000. 11(5): 324–6.
52. Maeda SI, Tamaki M, Kojima K, Yoshida
T, Ishiko H, Yasuda M, and Deguchi T,
Association of Mycoplasma genitalium
persistence in the urethra with recurrence
of nongonococcal urethritis. Sex Transm
Dis, 2001. 28(8): 472–6.
53. Dupin N, Bijaoui G, Schwarzinger M,
Ernault P, Gerhardt P, Jdid R, Hilab S,
Pantoja C, Buffet M, Escande JP, and
Costa JM, Detection and quantification of
Mycoplasma genitalium in male patients
with urethritis. Clin Infect Dis, 2003.
37(4): 602–5.
54. Wikstrom A and Jensen JS, Mycoplasma
genitalium: a common cause of persistent
urethritis among men treated with doxy-
cycline. Sex Transm Infect, 2006. 82(4):
276–9.
800
55. Geisler WM, Yu S, and Hook EW, 3rd,
Chlamydial and gonococcal infection in
men without polymorphonuclear leuko-
cytes on gram stain: implications for diag-
nostic approach and management. Sex
Transm Dis, 2005. 32(10): 630–4.
56. Newman LM, Warner L, and Weinstock
HS, Predicting subsequent infection in
patients attending sexually transmitted
disease clinics. Sex Transm Dis, 2006.
33(12): 737–42.
57. Massari V, Dorleans Y, and Flahault A,
Persistent increase in the incidence of
acute male urethritis diagnosed in general
practices in France. Br J Gen Pract, 2006.
56(523): 110–4.
58. Salari MH and Karimi A, Prevalence
of Ureaplasma urealyticum and
Mycoplasma genitalium in men with
non-gonococcal urethritis. East Mediterr
Health J, 2003. 9(3): 291–5.
59. Schlicht MJ, Lovrich SD, Sartin JS,
Karpinsky P, Callister SM, and Agger
WA, High prevalence of genital mycoplas-
mas among sexually active young adults
with urethritis or cervicitis symptoms in
La Crosse, Wisconsin. J Clin Microbiol,
2004. 42(10): 4636–40.
60. Kohl KS, Sternberg MR, Markowitz LE,
Blythe MJ, Kissinger P, Lafferty WE,
Groseclose SL, and Levine WC, Screening
of males for Chlamydia trachomatis and
Neisseria gonorrhoeae infections at STD
clinics in three US cities – Indianapolis,
New Orleans, Seattle. Int J STD AIDS,
2004. 15(12): 822–8.
61. Sturm PD, Moodley P, Khan N, Ebrahim
S, Govender K, Connolly C, and Sturm
AW, Aetiology of male urethritis in
patients recruited from a population with
a high HIV prevalence. Int J Antimicrob
Agents, 2004. 24 Suppl 1: S8–14.
62. Deguchi T, Yoshida T, Miyazawa T, Yasuda
M, Tamaki M, Ishiko H, and Maeda S,
Association of Ureaplasma urealyticum
(biovar 2) with nongonococcal urethritis.
Sex Transm Dis, 2004. 31(3): 192–5.
63. Iser P, Read TH, Tabrizi S, Bradshaw C,
Lee D, Horvarth L, Garland S, Denham
I, and Fairley CK, Symptoms of non-
gonococcal urethritis in heterosexual men:
a case control study. Sex Transm Infect,
2005. 81(2): 163–5.

64. Gaydos CA, Kent CK, Rietmeijer CA,
Willard NJ, Marrazzo JM, Chapin JB,
Dunne EF, Markowitz LE, Klausner JD,
Ellen JM, and Schillinger JA, Prevalence
of Neisseria Gonorrhoeae among men
screened for Chlamydia Trachomatis in
four United States cities, 1999–2003. Sex
Transm Dis, 2006. 33(5): 314–9.
65. Bradshaw CS, Tabrizi SN, Read TR,
Garland SM, Hopkins CA, Moss LM, and
Fairley CK, Etiologies of nongonococcal
urethritis: bacteria, viruses, and the asso-
ciation with orogenital exposure. J Infect
Dis, 2006. 193(3): 336–45.
66. Vesic S, Vukicevic J, Dakovic Z, Tomovic
M, Dobrosavljevic D, Medenica L, and
Pavlovic MD, Male urethritis with and
without discharge: relation to micro-
biological findings and polymorphonu-
clear counts. Acta Dermatovenerol Alp
Panonica Adriat, 2007. 16(2): 53–7.
67. Lewis DA, Pillay C, Mohlamonyane O,
Vezi A, Mbabela S, Mzaidume Y, and
Radebe F, The burden of asymptomatic
sexually transmitted infections among
men in Carletonville, South Africa: impli-
cations for syndromic management. Sex
Transm Infect, 2008. 84(5): 371–6.
68. Yu JT, Tang WY, Lau KH, Chong LY, and
Lo KK, Asymptomatic urethral infec-
tion in male sexually transmitted disease
clinic attendees. Int J STD AIDS, 2008.
19(3): 155–8.
69. Varela JA, Otero L, Garcia MJ, Palacio
V, Carreno F, Cuesta M, Sanchez C, and
Vazquez F, Trends in the prevalence of
pathogens causing urethritis in Asturias,
Spain, 1989–2000. Sex Transm Dis, 2003.
30(4): 280–3.
70. Jensen JS, Bjornelius E, Dohn B, and
Lidbrink P, Comparison of first void
urine and urogenital swab specimens for
detection of Mycoplasma genitalium and
Chlamydia trachomatis by polymerase
chain reaction in patients attending a
sexually transmitted disease clinic. Sex
Transm Dis, 2004. 31(8): 499–507.
71. Taylor-Robinson D, Gilroy CB, Thomas
BJ, and Hay PE, Mycoplasma genitalium
in chronic non-gonococcal urethritis. Int J
STD AIDS, 2004. 15(1): 21–5.
72. Maeda S, Deguchi T, Ishiko H, Matsumoto
T, Naito S, Kumon H, Tsukamoto T,
Urethritis | 14.3 |
Onodera S, and Kamidono S, Detection
of Mycoplasma genitalium, Mycoplasma
hominis, Ureaplasma parvum (biovar 1)
and Ureaplasma urealyticum (biovar 2)
in patients with non-gonococcal urethritis
using polymerase chain reaction-micro-
titer plate hybridization. Int J Urol, 2004.
11(9): 750–4.
73. Anagrius C, Lore B, and Jensen JS,
Mycoplasma genitalium: prevalence, clini-
cal significance, and transmission. Sex
Transm Infect, 2005. 81(6): 458–62.
74. Dolapci I, Tekeli A, Ozsan M, Yaman
O, Ergin S, and Elhan A, Detecting of
Mycoplasma genitalium in male patients
with urethritis symptoms in Turkey by
polymerase chain reaction. Saudi Med J,
2005. 26(1): 64–8.
75. Leung A, Eastick K, Haddon LE,
Horn CK, Ahuja D, and Horner PJ,
Mycoplasma genitalium is associated with
symptomatic urethritis. Int J STD AIDS,
2006. 17(5): 285–8.
76. Gubelin HW, Martinez TM, Cespedes
PP, Fich SF, Fuenzalida CH, Parra
CRL, Valderrama KL, and Zapata MS,
[Molecular detection of Mycoplasma geni-
talium in men and pregnant women.]. Rev
Chilena Infectol, 2006. 23(1): 15–9.
77. Lee SR, Chung JM, and Kim YG, Rapid
one step detection of pathogenic bacteria
in urine with sexually transmitted disease
(STD) and prostatitis patient by multiplex
PCR assay (mPCR). J Microbiol, 2007.
45(5): 453–9.
78. Yokoi S, Maeda S, Kubota Y, Tamaki M,
Mizutani K, Yasuda M, Ito S, Nakano
M, Ehara H, and Deguchi T, The role of
Mycoplasma genitalium and Ureaplasma
urealyticum biovar 2 in postgonococcal ure-
thritis. Clin Infect Dis, 2007. 45(7): 866–71.
79. Davies SC, Madjid B, Pardohudoyo S,
Wiraguna AA, Patten JH, and Upadisari
LP, Prevalence of sexually transmissible
infections (STI) among male patients
with STI in Denpasar and Makassar,
Indonesia: are symptoms of urethritis suf-
ficient to guide syndromic treatment? Sex
Health, 2007. 4(3): 213–5.
80. Kahn RH, Mosure DJ, Blank S, Kent
CK, Chow JM, Boudov MR, Brock J, and
Tulloch S, Chlamydia trachomatis and
Neisseria gonorrhoeae prevalence and
801
Chapter | 14 | Sexually transmitted infectious diseases
coinfection in adolescents entering selected
US juvenile detention centers, 1997–2002.
Sex Transm Dis, 2005. 32(4): 255–9.
81. Leutscher PD, Pedersen M, Raharisolo
C, Jensen JS, Hoffmann S, Lisse I,
Ostrowski SR, Reimert CM, Mauclere
P, and Ullum H, Increased prevalence of
leukocytes and elevated cytokine levels in
semen from Schistosoma haematobium-
infected individuals. J Infect Dis, 2005.
191(10): 1639–47.
82. Lee SJ, Cho YH, Ha US, Kim SW, Yoon
MS, and Bae K, Sexual behavior survey
and screening for chlamydia and gon-
orrhea in university students in South
Korea. Int J Urol, 2005. 12(2): 187–93.
83. Amirkhanian YA, Kelly JA, Kirsanova AV,
DiFranceisco W, Khoursine RA, Semenov
AV, and Rozmanova VN, HIV risk behav-
iour patterns, predictors, and sexually
transmitted disease prevalence in the
social networks of young men who have
sex with men in St Petersburg, Russia. Int
J STD AIDS, 2006. 17(1): 50–6.
84. Chen XS, Yin YP, Gong XD, Liang GJ,
Zhang WY, Poumerol G, Shi MQ, Wu
SQ, and Zhang GC, Prevalence of sexu-
ally transmitted infections among long-
distance truck drivers in Tongling, China.
Int J STD AIDS, 2006. 17(5): 304–8.
85. Benn PD, Rooney G, Carder C, Brown
M, Stevenson SR, Copas A, Robinson AJ,
and Ridgway GL, Chlamydia trachomatis
and Neisseria gonorrhoeae infection and
the sexual behaviour of men who have sex
with men. Sex Transm Infect, 2007. 83(2):
106–12.
86. Gunn RA, O’Brien CJ, Lee MA, and
Gilchick RA, Gonorrhea screening among
men who have sex with men: value of
multiple anatomic site testing, San Diego,
California, 1997–2003. Sex Transm Dis,
2008. 35(10): 845–8.
87. The Gonococcal Resistance to
Antimicrobials Surveillance
Programmem G. GRASP annual report
2006. 2007; Available from: http://
www.hpa.org.uk/web/HPAwebFile/
HPAweb_C/1194947393147.
88. Tapsall J, Surveillance of antibiotic resist-
ance in Neisseria gonorrhoeae in the WHO
Western Pacific region 2006. Commun Dis
Intell, 2008. 32(1): 48–51.
802
89. Gonococcal Isolate Surveillance Project
G. Sexually Transmitted Diseases
Surveillance 2005 Supplement, GISP
Annual report 2005. 2006; Available from:
http://www.cdc.gov/std/gisp/.
90. Europe Gonococcal Antimicrobial
Surveillance Programme E-G. Euro-
GASP Anual report No.2, 2007. 2008;
Available from: http://www.essti.org/
microbiology.php#micro_gasp.
91. Australian Gonococcal Surveillance
Programme A-G. Annual report of the
Australian Gonococcal Surveillance
Program, 2006. 2007; Available from:
http://www.aodgp.gov.au/internet/main/
publishing.nsf/Content/cda-pubs-annlrpt-
gonoanrep.htm.
92. Gonococcal Isolate Surveillance Project
G. Sexually Transmitted Diseases
Surveillance 2005 Supplement, GISP
Annual report 2006. 2007; Available from:
http://www.cdc.gov/std/gisp/.
93. Australian Gonococcal Surveillance
Programme A-G. Annual report of the
Australian Gonococcal Surveillance
Program, 2007. 2008; Available from:
http://www.aodgp.gov.au/internet/main/
publishing.nsf/Content/cda-pubs-annlrpt-
gonoanrep.htm.
94. Yoo J, Yoo C, Cho Y, Park H, Oh HB, and
Seong WK, Antimicrobial resistance pat-
terns (1999–2002) and characterization
of ciprofloxacin-resistant Neisseria gonor-
rhoeae in Korea. Sex Transm Dis, 2004.
31(5): 305–10.
95. Shigemura K, Okada H, Shirakawa T,
Tanaka K, Arakawa S, Kinoshita S, Gotoh
A, and Kamidono S, Susceptibilities of
Neisseria gonorrhoeae to fluoroquinolones
and other antimicrobial agents in Hyogo
and Osaka, Japan. Sex Transm Infect,
2004. 80(2): 105–7.
96. Aydin D, Kucukbasmaci O, Gonullu N,
and Aktas Z, Susceptibilities of Neisseria
gonorrhoeae and Ureaplasma urealyticum
isolates from male patients with urethritis
to several antibiotics including telithromy-
cin. Chemotherapy, 2005. 51(2–3): 89–92.
97. Enders M, Turnwald-Maschler A, and
Regnath T, Antimicrobial resistance of
Neisseria gonorrhoeae isolates from the
Stuttgart and Heidelberg areas of south-

ern Germany. Eur J Clin Microbiol Infect
Dis, 2006.
98. Stathi M, Flemetakis A, Miriagou V,
Avgerinou H, Kyriakis KP, Maniatis
AN, and Tzelepi E, Antimicrobial sus-
ceptibility of Neisseria gonorrhoeae in
Greece: data for the years 1994–2004.
J Antimicrob Chemother, 2006. 57(4):
775–9.
99. Yang Y, Liao M, Gu WM, Bell K, Wu L,
Eng NF, Zhang CG, Chen Y, Jolly AM,
and Dillon JA, Antimicrobial
susceptibility and molecular deter-
minants of quinolone resistance in
Neisseria gonorrhoeae isolates from
Shanghai. J Antimicrob Chemother,
2006. 58(4): 868–72.
100. Donegan EA, Wirawan DN, Muliawan
P, Schachter J, Moncada J, Parekh
M, and Knapp JS, Fluoroquinolone-
resistant Neisseria gonorrhoeae in Bali,
Indonesia: 2004. Sex Transm Dis, 2006.
33(10): 625–9.
101. Vazquez JA, Martin E, Galarza P,
Gimenez MJ, Aguilar L, and Coronel P,
In vitro susceptibility of Spanish isolates
of Neisseria gonorrhoeae to cefditoren
Urethritis | 14.3 |
and five other antimicrobial agents. Int J
Antimicrob Agents, 2007. 29(4): 473–4.
102. Hovhannisyan G, von Schoen-Angerer T,
Babayan K, Fenichiu O, and Gaboulaud
V, Antimicrobial susceptibility of
Neisseria gonorrheae strains in three
regions of Armenia. Sex Transm Dis,
2007. 34(9): 686–8.
103. De Jongh M, Dangor Y, Adam A, and
Hoosen AA, Gonococcal resistance: evolv-
ing from penicillin, tetracycline to the
quinolones in South Africa – implica-
tions for treatment guidelines. Int J STD
AIDS, 2007. 18(10): 697–9.
104. Olsen B, Hadad R, Fredlund H, and
Unemo M, The Neisseria gonorrhoeae
population in Sweden during 2005-
phenotypes, genotypes and antibiotic
resistance. Apmis, 2008. 116(3): 181–9.
105. Ilina EN, Vereshchagin VA, Borovskaya
AD, Malakhova MV, Sidorenko SV,
Al-Khafaji NC, Kubanova AA, and
Govorun VM, Relation between genetic
markers of drug resistance and sus-
ceptibility profile of clinical Neisseria
gonorrhoeae strains. Antimicrob Agents
Chemother, 2008. 52(6): 2175–82.
803
|14.4|

Pelvic infections in women

Gilbert G.G. Donders1,2,3, Jasper Verguts1
1
Department of Obstetrics and Gynaecology, University Hospitals Gasthuisberg, Leuven University, Belgium
2
Regional Hospital Heilig Hart, Tienen, Belgium
3
Citadelle Hospital, Liège University, Belgium
Corresponding author: Gilbert GG Donders MD PhD, Department of Obstetrics and Gynecology, University Hospital
Gasthuisberg, Herestraat 45, 3000 Leuven, Belgium
Tel +32344204, Fax +32813440, E mail: gilbert.donders@femicare.net

ABSTRACT these areas and often accounts for a major

Pelvic Inflammatory Disease (PID) is diffi-
cult to define, and therefore difficult to diag-
nose and to treat. In order to be complete,
we include the diagnosis and treatment
of cervicitis, endometritis, salpingitis and
pelvic/ovarian abscesses in the discussion.
PID is caused by the ascension of bacte-
ria present or deposited in the vagina, and
the most important risk factors for severe
disease are related to sexual behaviour. As
long term sequalae such as infertility, extra-
uterine pregnancy and chronic pelvic pain
can be a consequence, increased considera-
tion of upper genital tract infection and low
threshold treatment are recommended,
however, not without extensive prior efforts
to have a proper well documented and
refined diagnosis, as this greatly helps in
adjusting treatment if the response to syn-
dromic management is not optimal. Care
was taken to leave open adequate diagno-
sis and treatment in low resource settings,
as PID is more frequently encountered in
part of healthcare expenses. Therefore,
ambulatory treatment with oral antibiot-
ics is preferred in most cases, to be followed
by hospitalisation and laparoscopy only in
those cases where the response to therapy
is inadequate or the likelihood of compli-
cations is high. Finally, screening, preven-
tion and treatment of etiologic factors of
PID are most cost effective and should be
encouraged wherever possible.
Key words: pelvic infection, ascending
infection, vaginitits, complications, infer-
tility, syndromic management
SUMMARY OF RECOMMENDATIONS
1. Former definitions of PID suggest
sexual activity is the obligate cause
of the disease, but in a vast number
of women with PID, no STI can be
discovered; often Gram-positive
cocci, Gram-negative bacilli and

mycoplasmata such as the newly
discovered M. genitalis, are associated
with PID and also have to be
considered (GoR A).
2. Clinical diagnosis is not always
straightforward. However, it is crucial
to invest in a proper diagnosis of PID:
laparoscopy should be performed in
case of doubt (GoR A).
3. Antibiotic treatment should be started
as soon as PID is suspected, however,
if an insufficient clinical response is
obtained after 48 hours, the diagnosis
should be reconsidered and therapy
adjusted (GoR A).
4. Perioperative antisepsis and antibiotics,
sexual education, and systematic
screening in adolescent women are the
mainstays of prevention (GoR B)
1. INTRODUCTION
Pelvic Inflammatory disease (PID) is one
of the first and most prominent infec-
tious syndromes ever described in the
discipline of obstetrics and gynecology.
Before the discovery of the transmission
mode of bacterial infection, PID was a
frequent condition and a major killer,
especially amongst postpartum women,
caused by medical staff examining con-
secutive women without what is now con-
sidered proper antiseptic hand care. Soon
after this the ascending nature of these
bacterial infections, mainly by sexually
transmitted microorganisms, led to effi-
cient antibiotic treatment. However, even
now, the diagnosis of PID may be diffi-
cult and the clinical presentation vari-
able, often causing delay in recognition
and the timely commencement of proper
antibiotherapy, leading to major seque-
lae like pelvic pain, tubal infertility and
extrauterine pregnancies. Hence a sys-
tematic overview of the known and less
well known pitfalls and diagnostic tips
may be useful, and an update of a practi-
cal therapeutic algorithm is given.
Pelvic infections in women | 14.4 |
2. METHODS
This review aims to summarize in a
structured way an enormous body of lit-
erature on pelvic inflammatory disease
in women. We focused on recent dis-
coveries and insights in an effort to fill
some of the huge number of gaps and
missing links of a syndrome that used to
be ill-defined and lacked coherent treat-
ment guidelines. Using the terms: pelvic
infection, supracervical infection, genital
infection and pelvic inflammatory disease
as basic keywords, differential lists of
searches about pathogenesis, risk factors,
diagnosis and management were saved
and scanned for proper manuscripts. If
decent papers containing evidence based
data (LoE 1, 2) were found during the
last 10 years, no further reading of older
papers was encouraged. Only if those
were not available, were older litera-
ture data from publications or textbooks
used. The recommendations given were
therefore based on recent Level 1 or 2
evidence.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[1–2].
3. DEFINITION AND CLASSIFICATION
3.1 Definition
Pelvic inflammatory disease (PID) is
defined as an infection of the uterus, fal-
lopian tubes or ovaries related to sexual
contact. Therefore, other pelvic infections
caused by surgery, during pregnancy or
due to other abdominal processes are not,
strictly considered, ‘PID’. This stringent
diagnosis implying the need for sexual
contact is controversial because very often
only endogenous intestinal microorganisms
can be recovered from the genital tracts
of women with pelvic infections, espe-
cially in IUCD users and post-pregnancy
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Chapter | 14 | Sexually transmitted infectious diseases
complications, and their sexual partners
do not seem to be infected [3–8].
3.2 Classification
PID has characteristically been consid-
ered to have three grades of severity
based on laparoscopic findings. PID grade
1 means there is either endometritis or
erythema of the salpinx, or a combina-
tion of both. In a grade 2 PID, the salp-
inges are dark red and swollen (edema).
In a grade 3 PID the salpinx is filled with
pus (pyosalpinx) and exudation is found
in the pelvis. Tubo-ovarian abcedation
(TOA) is also PID grade 3 according to
the definition. A tubo-ovarian complex is
a name used for oedema of the salpinx
which is adherent to the ovaria, uterus,
pelvic wall, and/or bowel, but without
abscedation. In clinical practice the grad-
ing is not always clear.
4. ETIOLOGY, PATHOGENESIS AND
RISK FACTORS
In the US about one million women suf-
fer from a symptomatic PID each year. Of
women with symptomatic PID, 15–20%
suffer complications requiring surgical
intervention. The prevalence of asympto-
matic PID is unknown.
The normal vaginal micro-flora con-
sists of a large spectrum of commensal
and/or potentially pathogenic bacteria
and fungi. These flora include different
types of lactobacilli that contribute to a
healthy environment of the vagina not
allowing pathogenic bacteria to overgrow
and transcend through the cervical canal.
These normal vaginal lactobacilli have
varied properties that serve to maintain
the normal vaginal microenvironment,
including: adhesive capacity, produc-
tion of H2O2, bacteriocins and lactic acid.
Disturbance of the normal flora can
cause anaerobic bacterial vaginosis (BV),
with typical absence of the inflammatory
immune response [9]. In patients with
806
aerobic vaginitis (AV) intestinal faculta-
tive aerobic bacteria are mostly present,
usually accompanied by a more or less
severe inflammatory response [9–10]. In
both conditions lactobacilli are depressed
and the vagina has an increased pH. In
one out of seven women with BV, a sub-
clinical PID can be diagnosed, charac-
terized by endometritis on subsequent
biopsy [11]. However, the precise role of
BV in the pathogenesis of PID remains
controversial.
Whenever the cervical barrier becomes
damaged, bacteria can ascend from the
vagina to infect the upper genital tract
[12]. The importance of this ascending
route is emphasized by the finding that
75% PID of cases begin during the first
seven days after menstruation [13–14].
4.1 Etiology
A number of urogenital pathogens have
established roles in PID.
4.1.1 Chlamydia trachomatis
C. trachomatis is a non motile, obliga-
tory intracellular bacterium. In the mid
1970s it became clear that this micro-
organism was a frequent cause of PID.
After a dramatic decline in prevalence of
both incidence and complications (neona-
tal conjunctivitis, tubal factor infertility,
ectopic pregnancy) as was noted in Europe
[15–21], and in many developing coun-
tries [22–23] a resurge of C. trachomatis
infected women appeared first in Sweden,
and subsequently in other European coun-
tries [24–26]. This apparent increase may
reflect better detection methods, higher
sampling frequencies, or an increase in
unsafe sexual practices in at risk popula-
tions [27]. Also, some formerly unknown
strains were detected in Scandinavia
that were not detected using routine PCR
techniques, including PCR [24]. Recently
some fluoroquinolone-resistant strains
have been discovered [28].
The incubation period for C. tracho-
matis infection is 2 to 3 weeks. Once

infected, C. trachomatis can remain silent
for months if left untreated. The PID
rate after an untreated infection is esti-
mated to be 8-to-40% [14]. It is estimated
that approximately 70% of C. tracho-
matis infections remain asymptomatic.
Asymptomatic salpingitis can cause tubal
damage and subfertility without any
clinical signs.
After initial infection with C. tracho-
matis the risk of silent progression with
intra-tubal scarring is high, in part due
to upregulation of heat shock proteins
[29–30]. Chlamydial antigens can mimic
the autologous human antigens triggering
reflex production of heat shock proteins
that normally provide a useful defense
against nonspecific challenges such as
extreme temperatures or environmental
toxins. With recurrent infections and pro-
duction of heat shock proteins nonspecific
inflammation may be triggered by various
causes, resulting in extensive scarring,
even if no active Chlamydial organisms
are present. The result is an increased
risk of ectopic pregnancies and infertility
[31–32]. Besides salpingitis, Chlamydia
may also cause mucopurulent cervicitis,
urethritis and endometritis.
The diagnostic method of choice for
detection of C. trachomatis is polymer-
ase chain reaction’ (PCR)-based testing.
These tests have an estimated sensitivity
of 86%, a specificity of 99.5%, and provide
the opportunity for simultaneous testing
for N gonorrhoea [33–35]. Testing can be
performed on urethral or cervical swabs,
or on urine, produced without washing
or disinfecting the urethra, preferably
from the first void in the morning, or at
least four hours after micturition. Care
has to be taken that the first part of the
sample is included. Alternative, but less
accurate testing is antigen detection by
ELISA. Culture methods have a specifi-
city of 100%, but their sensitivity is only
50 to 80%.
Chlamydial cervicitis or urethritis
can be treated by single oral dose of 1 g
azithromycin or seven days of oral
Pelvic infections in women | 14.4 |
doxycycline (100 mg by mouth twice
daily). During pregnancy, C. trachomatis
can cause amnionitis and post-partum
endometritis (see below). Although off-
label, azithromycin can be used safely
during pregnancy, and represents the
treatment of choice [36–37].
4.1.2 Neisseria gonorrhoeae
N. gonorrhoeae is a Gram-negative aero-
bic diplococus that was the first identi-
fied cause of PID. Following availability
of penicillin, gonorrhoea became less fre-
quent. However, worldwide 1/3 of all PID
cases are caused by N gonorrhoeae.
Although 30–60% of women harbour-
ing N. gonorrhoeae have no symptoms,
such asymptomatic carriers can transmit
the infection to others. If not detected and
treated, N. gonorrhoeae will cause PID in
10–30% of infected women [14]. 20–30%
of the women harbouring N. gonorrhoeae
are also infected with C. trachomatis [38].
The most frequent symptoms include a
yellow-green leucorrhoea and pelvic pain;
on inspection a mucopurulent cervicitis is
often visualized.
Although PCR is very reliable and
much faster, culture remains the best
test for N. gonorrhoeae as it also allows
sensitivity testing for antibiotics [34–35].
Ideally, Thayer-Martin medium (choco-
late agar with antibiotics inhibiting other
bacteria) is used, providing 65–85% sen-
sitivity for asymptomatic infections and
100%, specificity of but a regular choco-
late agar can also be used. Fast transport
is crucial, due to the short ex vivo sur-
vival time of N. gonorrhoeae. To increase
sensitivity, the endocervical and/or (ure-
thral swab should be inoculated into a
specific transport medium.
In some areas, treatment options
include: 500 mg ciprofloxacin, 1g azy-
thromicin, or ceftriaxone 125 mg IM of
IV. However, also increasing fluoroqui-
nolone resistance (up to 30%) has limited
oral options in many areas [39–43]. For
example, in the US the CDC recommends
807
Chapter | 14 | Sexually transmitted infectious diseases
ceftriaxone 125 mg IM or IV as the treat-
ment of choice. In Belgium ceftriaxone is
only available in a 1g formulation.
4.1.3 Facultative aerobic Gram-negative
bacteria
Gram-negative rods, such as Escherichia
coli, Enterobacter spp., Klebsiella spp.,
Proteus spp., Gardnerella vaginalis are
often recovered in PID cases [38] and
Pseudomonas spp. rather seldom and only
after surgery. The etiology is unclear, as
these organisms can also be seen as fac-
ultative pathogens and in cluster analy-
sis their presence in the vagina was not a
primary risk factor for PID [44]. Recently
Salmonella spp. were also found to be
associated with PID [45–49].
4.1.4 Aerobic Gram-positive cocci
Staphylococcus spp, Streptococcus spp
(especially Streptococci Lancefield groups
A and B) and Enterococcus sp. (Streptococci
groups D and F) are often found as sole
pathogens [50], but as with Gram-negative
rods, their exact role in the etiology is
unclear. The importance Gram-positive
cocci clinical management, however, is
emphasized by the fact that presence of
beta-lactamase producing enterococci may
require adjust of treatment by addition of
clavulanate to tricarcillin regimens to pre-
vent clinical failures [51].
4.1.5 Anaerobes
Anaerobic bacteria, such as Bacteroides
fragilis, Clostridium spp, and Peptostre-
ptococcus, are present in many PID
patients and are always treated [44,
52–54]. Most, if not all, of these anaerobic
bacteria are highly sensitive to nitroimi-
dazol derivates (i.e., metronidazole,
ornidazole, and tinidazole) and to amoxi-
cillin/clavulanic acid. In the US, several
life-threatening cases with ascending
Clostridium spp. were observed after
the use of vaginal misoprostol to induce
an abortion [55–58]. Because vaginally
applied misoprostol may cause this lethal
808
infection [59], misoprosotol should only
be used orally, as is common in Europe.
4.1.6 Tuberculosis
Genital tuberculosis characteristically
presents as a chronic, latent infection
diagnosed an an infertility evaluation. The
infection is often secondary to hematog-
enous spread from a non-genital source.
The fallopian tubes and endometrium are
most often infected. When associated with
ascites and peritonitis, genital tubercu-
losis can present a diagnostic dilemma
often confused with carcinomatosis peri-
tonitis or ovarian malignancies [60–65].
Confirmation requires biopsy with spe-
cific endometrial cultures, preferably
during menstruation. Specific cultures
of intra-abdominal abscesses may also
lead diagnosis. If suspected, detection of
tuberculosis in other organs such as the
lungs can be helpful. Patients at high risk
are immigrants, HIV-infected patients,
imprisoned women, or patients with a his-
tory of alcohol or injection drug use.
4.1.7 Actinomyces
Actinomyces israelii is a Gram-positive
anaerobic bacterium usually recovered
from the upper respiratory or gastrointes-
tinal tracts. PID is rarely caused by this
organism due to hematogeneous spread
from another location, or ascending infec-
tion from the vagina in women with cop-
per-containing intrauterine contraceptive
devices (IUCDs) [66]. Colonization of
the lower genital tract is frequent in the
presence IUCDs and increases with dura-
tion of use [66–68]. In rare cases severe
pelvic infections may occur, mimick-
ing pelvic malignancies [69]. Incidental
detection of Actinomyces spp. on Pap
smears does not need to be treated if
asymptomatic. In contrast, if the IUCD is
in place for longer than four years, or if
the infection is found on more than one
occasion during 12 months, then IUCD
removal should be considered. After
removal of the IUCD, infection usually

disappears spontaneously without com-
plications. A new IUCD can be inserted
one or two months later. A. israelii is sen-
sitive to penicillin, but once endometri-
tis is present, treatment with low dose
penicillin should be continued for weeks
to months. Care has to be taken not to
misdiagnose pelvic actinomycosis as
a pelvic cancer, because infection can
mimic locally extensive ovarian cancer,
both on diagnostic imaging, or during
surgical procedures like laparoscopy and
laparotomy [69–73]. Attempts to remove
the ovaries and uterus in patients with
actinomyces have led to lethal complica-
tions [74–75].
4.1.8 Mycoplasmata
Mycoplasma hominis (Mh) is one of the
smallest known bacteria. Because these
bacteria do not have a cell wall, diagno-
sis cannot be made by microscopic exam-
ination of fresh vaginal fluid or Gram
stains. Also, antibiotics inhibiting cell
wall synthesis have no effect, and antibi-
otics targeting protein synthesis are rec-
ommended. The treatment of choice is 1g
azithromycin once or doxycycline 100mg
twice daily for seven days [76]. Studies
from the 1970s found Mh more often in
fallopian tubes of women with clinical PID
(4/50), but not in asymptomatic women
(0/50) [77] and serologic evidence linked
Mycoplasma with PID [78–79]. Also, Mh
in relation to BV posed an increased risk
of PID [44]. Still, the exact role of Mh in
PID remains controversial [44].
Ureaplasma urealyticum (Uu) is also a
intracellular bacterium of the Mycoplasma
group that is frequently encountered in
the cervix and endometrium of patients
with pelvic infection and/or bacteriemic
sepsis [80]. However, Uu is found so uni-
versally in both men and women, in the
urethra, vagina, cervix, endometrial
cavity and pouch of Douglas, and with-
out a clear link to pathogenesis, that it
is doubtful whether Uu has any causa-
tive link with PID [81–84]. Still, if it is
Pelvic infections in women | 14.4 |
present, antibiotics should be adjusted to
cover the organism [85–86].
4.1.8.1 Mycoplasma genitalium
Taylor-Robinson and co-workers showed
that M. genitalium (Mg), a former
Mycoplasma, was ubiquitous worldwide
and was associated with pelvic infections
[87–88]. Later studies clearly confirmed
the link between Mg and clinical PID in
the absence of concomitant STIs, such as
Ct and gonorrhea [89–92]. In a study of
722 women with suspicion of PID, women
with M. genitalium infection were less
likely to have elevated systemic inflam-
matory markers (erythrocyte sedimen-
tation rate >15 mm/hr, (p = .002), white
blood cell count >10,000 cells/mL (p = .018),
oral temperature ≥ 38.3 °C (p = .001)) than
women with gonococcal PID. In addi-
tion, they were less likely to present with
mucopurulent cervicitis (p = .001), elevated
vaginal pH (p = .018), and high pelvic pain
score (p = .014). In contrast, women with
chlamydial PID had signs and symptoms
that were similar to those in women with
M. genitalium infection [93]. These find-
ings supported different PID treatment
regimens for women harbouring M. geni-
talium, because metronidazole – doxycy-
cline regimens had success rates of only
35-to-55% [94]. Furthermore, treatment
with cefoxitin and Doxycycline plus azy-
thromycin do not provide reliable eradica-
tion of M. genitalium [95–96]. Hence more
studies about the pathogenesis and treat-
ment of this novel microorganism seem
warranted [89].
4.2 Risk factors
The risk of PID is related to the number
of lifetime sexual partners of both the
woman and her sexual partners [97].
Apart from this, the frequency of sexual
contact increases the risk of bacterial
vaginosis, a condition linked to STIs, such
as C trachomatis, trichomoniasis and gon-
orrhea [98] and with PID [44]. PID due to
Chlamydia is primarily found in young
809
Chapter | 14 | Sexually transmitted infectious diseases
women (15–25 years of age). In general
PID is seldom encountered in women
older than 35 years of age [99–100].
Possible explanations include an
increased immunity, differences in sexual
behaviors, or other factors.
Use of barrier methods (e.g., condom,
pessary, etc) is largely protective against
PID. However, in some studies barrier
contraception reduces transmission of C.
trachomatis and N. gonorrhoeae only by
50% [101–102]. This can be explained by
the fact that protection against transmis-
sion is only significant in perfect users, an
aim that is seldom achieved even in well
controlled studies incorporating extensive
counseling [101–102]. Oral contraceptives
and intramuscular depot medroxyproges-
terone also seem to protect against ascend-
ing infection and PID, but not against
Chlamydial cervicitis [103–104]. Copper-
containing IUCDs do not increase PID risk,
unless the device is inserted in a women
with an STI [105–106] or when an older
type of IUCD was used [107]. Randomized
studies found a lower PID risk with
levonorgestrel-containing IUCDs than with
copper-containing IUCDs [108–110].
5. CLINICAL PRESENTATION
5.1 Medical history
Specific information should be elicited
about presence of fever during the last
two weeks, general malaise, bilateral
lower abdominal pain, or pain when mov-
ing or being transported. Genital symp-
toms should be evaluated including the
amount and characteristics of vaginal dis-
charge, post-coital bleeding, dyspareunia
and abdominal pain with radiation to the
interior thighs. Typically, the symptoms
appear during the first seven days after
menses [14]. Presence of predisposing and
risk factors (described above) increase the
likelihood of PID. At least one third of the
patients with PID have irregular vagi-
nal bleeding. If a patient presents with
810
metrorrhagia, postcoital or intermen-
strual bleeding and/or menorrhagia, PID
should always be considered [111–112].
5.2 Clinical findings
There is no clear consensus on the con-
firmatory clinical criteria supporting PID
diagnosis. Minimal diagnostic criteria
should include: 1) lower abdominal sensi-
tivity and 2) painful adnexae or cervix on
palpation. Urinary infection, lumbar disk
disease and torsion of an ovary have to be
excluded. Additional criteria supporting
PID diagnosis are: T >38.5°C, purulent
cervical discharge (microscopy), pelvic
imaging (sonar, CRT scan) suggesting
tubo-ovarian abscess, increased inflamma-
tory parameters (e.g., elevated C-reactive
protein, leucocytosis >10.000 /ml, elevated
erythrocyte sedimentation rate, etc.),
presence of C. trachomatis or N. gonor-
rhoeae, (Mycoplasma genitalium) or his-
topathologic evidence of endometritis.
In older studies, an elevated erythrocyte
sedimentation rate, temperature above
38°C and adnexal tenderness were pre-
dictive for 65% of laparoscopy-confirmed
PID. C-reactive protein represents a more
accurate marker than the erythrocyte
sedimentation rate for assessing inflam-
matory activity and is typically used for
monitoring patients [113–115].
5.2.1 Abdominal examination
During abdominal palpation, attention
must be given to muscular resistance,
rebound tenderness and pain on percus-
sion. Pain localized in the right upper
abdomen suggests possible perihepatitis
with formation of local adhesions, also
known as Fitz-Hugh Curtis syndrome of.
In a first episode of PID, the pain never
lasts longer than two weeks [116].
5.2.2 Genital examination
Redness and edema of the vulva, vagina
and, most importantly, the cervix sug-
gest an infectious process. The vaginal
discharge can vary from grayish watery

and foamy, to yellow green and muco-
purulent. An inflamed cervix has deep
red to blue color, appears edematous and
bleeds easily when touched. Typically,
thick green-yellow mucus may be vis-
ible, but mucopurulent cervicitis can be
diagnosed microscopically even when the
mucus appears clinically normal.
Bimanual vagino-abdominal palpation
may show motion tenderness of the uterus
and pain upon pushing the uterus towards
the abdomen. Tenderness and pain in the
adnexal region is suspicious for PID grade
2 or 3; bilateral pain is more suggestive
for this than unilateral tenderness or
pain. Sensitivity of this criterion of uter-
ine and/or adnexal tenderness is 96%, but
specificity of this finding is extremely low
(4%) [117]. Therefore, starting antibiotics
based on this symptom alone would lead
to a tremendous risk of over treatment
and should be discouraged.
Clinical diagnosis of PID is imprecise
and misses one third of cases proven by
laparoscopy. Therefore, laparoscopic diag-
nosis remains the ‘gold standard’, and
in doubtful cases laparoscopy is advised
before starting therapy. Cultures from
the vagina, cervix and urethra taken at
the initial visit before starting therapy
are sometimes crucial for adjusting the
antibiotic choice if to the patients does
not respond to treatment.
5.2.3 Fever
Fever only occurs in 50% of women with
PID. Therefore, fever not a reliable sign.
Temperature above 38.5°C is always
alarming and requires intensive diagnos-
tic work-up.
6. DIAGNOSTIC TESTING
6.1 Laboratory tests
6.1.1 Serum
Signs of acute infection are accompa-
nied by leucocytosis above 10.000/ml and
C-reactive protein (CRP) is invariably
Pelvic infections in women | 14.4 |
increased. CRP represents an excellent
marker to follow the course of the disease
and the effect of treatment [113–115].
Even when clinical signs and leukocyto-
sis resolve, persistence of elevated CRP
suggests the beginning of abscess forma-
tion [118]. Human chorionic gonadotropin
(b HCG) should be evaluated to exclude
ectopic pregnancy, imminent abortion or
septic abortion, as these conditions may
mimic PID.
Serum CA-125 is in general a fol-
low up marker to monitor the treatment
effect, but in menopause it can be used to
exclude malignant intra-abdominal proc-
esses of ovaries, uterus, stomach, liver or
pancreas. However, CA-125 can be also be
elevated in patients with endometriosis,
PID and hepatitis, although the former
two are only sporadically encountered
after menopause. This test is only recom-
mended in case of doubt about the dif-
ferential diagnosis, in which case further
diagnostic workout is needed.
6.1.2 Microbiology
Cervical cultures for gonococci, aerobic
bacteria, and PCR for Chlamydia (cervix,
urethra and/or urine) should be performed,
as well as urinary cultures. In patients
with PID, microscopic examination of a
fresh endocervical smear reveals more
than 30 leukocytes per high power field,
or more than 10 per epithelium cell [9, 99].
Increased leukocytosis is very sensitive
(91%) and has a high negative predictive
value (90%) for diagnosis of cervicitis [119].
However, this examination lacks specifi-
city (19%) thereby erroneously diagnosing
PID in four out of five women [119–120].
Two additional microscopic criteria can
provide additional help; the concomitant
finding of abnormal vaginal flora whereby
the lactobacilli are replaced by cocci or
anaerobic morphotypes (AVF, Lactobacilli
grade 3 [121], and the finding of palisades
of leucocytes lining up in the cervical
mucus (Figure 1). Although the latter sign
is considered typical, it has not yet been
811
Chapter | 14 | Sexually transmitted infectious diseases
Figure 1 Cogwheel sign.
adequately validated in large clinical stud-
ies. Absence of leukocytosis, certainly if in
the presence of Lactobacilli grade 1 (nor-
mal), however, almost certainly excludes
cervicitis and PID [10, 122].
During laparoscopy samples from
the retro-uterine pouch of Douglas and
endotubal swabs are recommended for
aerobic, anaerobic and Chlamydial cul-
tures or PCR. If there is a suspicion of
tuberculosis, a biopsy, with a specific
request for the pathologist, is necessary.
Initially, PID should be considered a
potential STI. Therefore screening for
possible concomitant STI’s is recom-
mended. This includes blood tests for
HIV, hepatitis B and C, syphilis are
required as well as cervical testing for
HPV infection. As PID can originate from
causes other than sexual contact (see
above), this is not obligatory for pelvic
infections secondary to a surgical inter-
vention, delivery or a known gastrointes-
tinal infectious process.
Clinical diagnosis of PID is difficult due
to the lack of accurate (in terms of sensi-
tivity and specificity) at present. However,
the potential for severe sequelae means
812
that clinical diagnosis should have a low
threshold. A number of tests may provide
further support for PID diagnosis.
6.2 Imaging techniques
6.2.1 Ultrasonographic examination
After clinical examination, pelvic ultra-
sound is the next step in the PID diagno-
sis. The level of severity of the infection
is the basis of the sonographic grading of
PID, but in studies neither sensitivity nor
specificity are well defined. In resource
limited settings, sonographic examination
should therefore be limited to a subset of
patients, e.g. the women not responding
to therapy.
In mild disease the uterus may be
painful on palpation with the abdomi-
nal or endovaginal probe, but adnexal
regions are normal and the pouch of
Douglas (retrouterine area) may show
some fluid at the most. If the fallopian
tubes can be visualized by a thicker
tubal wall and increased vascularity
on Doppler flow examination, then the
disease is usually more severe. In typi-
cal cases the “cog wheel sign,” can be

Figure 2 Beads-on-a-string sign.
visualized (Figure 1). In severe PID the
fallopian tubes are extended with inho-
mogeneous purulent fluid, sometimes
with fluid-air levels (pyosalpinx) and
pseudo-septation. In cases of chronic
salpingitis, the pyosalpinx will gradu-
ally be replaced by anechogenic fluid and
a “beads-on-a-string” image typical for a
hydrosalpinx: the remnants of the endos-
alpingeal plicae are seen as small excres-
cences against the tubal wall (Figure 2).
With extension, the tubal wall becomes
thinner (<3mm), Later in the process,
peritoneal pseudo cysts form due to
inclusion of peritoneal fluid in pockets of
adhesions of the bowel, internal genitals
and pelvic wall.
Patients with tubo-ovarian abscess
exhibit collections of pus with a thick,
hypervascularised wall surrounding an
inhomogenous echogenic fluid, sometimes
with air /fluid levels. When a tubo-ovarian
complex has formed, the tubes, uterus
and ovaries are all stuck together and
cannot be moved or palpated separately:
Pelvic infections in women | 14.4 |
they move ‘en bloc’ on pressure from the
vaginal probe. Pelvic adhesions can be
responsible for the “flapping sail” sign,
usually reflecting large amounts of pel-
vic fluid confined by the loose adhesions.
A painful, retroverted and fixated uterus
often result from reduced mobility of the
uterus caused by such adhesions. The
typical ultrasonographic appearance of
such a fixated retroplicated uterus is
sometimes called the “ear-sign”, due to
the appearance of the uterus resembling
an auricle.
6.2.3 Computerized tomography
(CT)-scan
By scanning a larger area CT can pro-
vide additional information in selected
cases. Indications for a CT scan in
the diagnosis of pelvic inflamma-
tory processes are outlined in Table 1.
Thrombosis of the ovarian vein is most
often seen in the postpartum period,
(frequency 1/3000), but is also a known
complication of pelvic surgery and PID.
813
Chapter | 14 | Sexually transmitted infectious diseases

Table 1 Indications for CT-scan in patient suspected of a pelvic infection.

Adequate sonography not possible (stenotic vagina)

Uncertain diagnosis on clinical and sonographical grounds

Failing antibiotic therapy

To complete full staging of inflammatory process like perihepatitis (Fitz-Hugh-Curtis)

Detection of possible complications, e.g. septic trombo-phlebitis

Differential diagnosis with other intra-abdominal conditions (e.g. appendicular plastron, dermoid cyst, avarian endometriosis. . .)

Figure 3 Microscopic sign of infected endocervcical mucus: palisades of polymorphonuclear leucocytes

lined up in mucus (Bioletz Leitz, Warfurt Germany, 400 times magnification, phase contrast). ©GGG
Donders, Femicare.

80 to 90% of thrombosis is encountered fuzzy hyper-intense zone (so called “halo”)

at the right side. To detect this compli-
cation CT-scan is a superior technique to
echo-Doppler [123].
6.2.4 Nuclear magnetic resonance (NMR)
NMR images showing parametrial inflam-
mation are very specific: T2 weighted
images suppressing fat densities show a
with intensification on T1 weighted
images. The formation of an abscess is
seen as a thick-walled mass filed with
fluid in the adnexal area. The pyosalpinx
also presents a very clear appearance of a
twisted and dilated fluid-filled structure.
The content of such abscesses are lightly
hyper-intense on T1 weighted images
and hypo-intense on T2 weighted images,

814

indicative of blood or inflammatory debris
[124–125].
7. LONG-TERM SEQUELAE
Tubal infertility represents a major
worldwide outcome after PID [126]. The
pathogenesis is best studied in women
with recurrent Chlamydial infections
causing immune modulation (i.e., the
immune system does not ‘see’ the latent
intracellular infection) and subsequent
intratubal scarring. Because such recur-
rent infections often remain asympto-
matic these infections typically often
cause substantially more damage than
those that are clinically suspected (see
above) [127]. A particular set of signs
and symptoms due to intra-abdominal
adhesion formation is the so-called Fitz-
Hugh-Curtis syndrome [128]. This syn-
drome reflects a peri-hepatitis with upper
abdominal pain, and typical adhesions
found on laparoscopy. Other STIs, like
gonorrhea and perhaps M. genitalium
(see above), may cause tubal infertility
after a single PID episode.
Ectopic pregnancy represents a second
important consequence of mucosal dam-
age to the fallopian tubes. Ectopic preg-
nancies are linked to a history of PID,
presence of Chlamydia antibodies [129]
and Chlamydia induced heat shock pro-
tein 60 and 70 reactivity [130–131]. The
tubal damage or ectopic pregnancy risk
after infection with M genitalium is not
yet fully elucidated [132], but identifica-
tion of Mycoplasma at laparoscopy for
PID, either in the lower genital tract or
the upper genital tract, is a risk factor for
later ectopic pregnancy [133].
Chronic pelvic pain is the third major
long-term complication of PID. Many
women suffer from chronic pelvic pain
after a symptomatic or asymptomatic PID
episode of PID [134]. Differential diagno-
sis includes: interstitial cystitis, pelvic
congestion syndrome and endometriosis.
[135–136].
Pelvic infections in women | 14.4 |
8. MANAGEMENT
Treatment goals are to treat the most
important causative microorganisms and
minimize sequelae of PID. Because most
women with early PID do not have major
complaints, diagnosis and effective ther-
apy often increase the likelihood of adhe-
sions and late sequelae. It is important to
examine and treat partners even if they
have no symptoms.
8.1 Antibiotics
Empirical, antibiotic therapy based on
the expected microorganisms should
start before the culture results are avail-
able. Local resistance patterns vary in
different areas. Most empiric treatment
regimens combine agents to treat aero-
bic and anaerobic bacteria as well as
C. trachomatis.
In Europe, the indications for intrave-
nous therapy coincide with those for hos-
pital admission (see below), but in the US
patients do not need to be hopsitalised
to get IV treatment. When the patient is
afebrile and C-reactive protein is decreas-
ing, the patient can be discharged and
oral therapy started for 14 days. Although
other regimens may be effective, most
guidelines are consistent with the recom-
mendations in Table 2 [137]. Some recom-
mended antibiotics may not be available
in all countries, necessitating other alter-
native regimens. In general, therapy
should be prolonged to limit the chance
of relapse. Reassessment is recommended
after 48 to 72 hours. If the patient is
not responding as expected, the patient
should be reassessed by additional diag-
nostic workout, after which alternative
therapy and/or hospital admission are
considered. For mild to moderate PID,
antibiotics are given for 14 days, while
for grade 3 PID several weeks of therapy
may be necessary.
As noted above, increasing antibicrobial
resistance, especially to fluoroquinolones,
has been documented in N. gonorrhoeae
815
Chapter | 14 | Sexually transmitted infectious diseases

Table 2 Antibiotics of choice in women with pelvic infections.

Cervicitis

Daycare

Option 1 Azithromycin 1 g PO Single dose

5-nitro-imidazole* 500 mg PO 7 days

Option 2 Ceftriaxon 1 g IM or IV Single dose

Azithromycine* 1 g PO Single dose

* Association of metronidazole with azythromycin is a perfect alternative option on condition of low prevalence and/or exclusion of
N gonorrhoea. In other cases ceftriaxon is necessary.

Salpingitis / PID

Ambulatory

Option 1 Ceftriaxon 1 g IM or IV Single dose

Moxifloxacine 400 mg PO 10–14 days

5-nitro-imidazole (metronidazole, 2 × 500 mg PO 10–14 days

ornidazole, tinidazole)

duration of therapy may differ according to clinical / hematological evolution (i.e. abscess: therapy up to 6 weeks
recommended)

Option 2 Ceftriaxon 1g IM or IV Single dose

Levofloxacine 500 mg PO 10–14 days

5-nitro-imidazole 2 × 500 mg PO 10–14 days

(metronidazole, ornidazole,
tinidazole)

Hospitalisation

Option 1 Ceftriaxon 1 g IM of IV Single dose

Levofloxacine 500 mg IV 10–14 days

5-nitro-imidazole (metronidazole, 1 g IV 10–14 days

ornidazole, tinidazole)

Option 2 Ceftriaxon 1 g IM of IV Single dose

Amoxi-Clav 4 x 1 g IV 10–14 days

Levofloxacine 500 mg IV 10–14 days

Option 3 Ceftriaxon 1g IM of IV Single dose

Amoxi-Clav 4 x 1g IV 10–14 days

doxycycline 2 x 100 mg PO 10–14 days

Switch to ambulatory setting possible after 48 hours IV therapy in case of clinical / hematological improvement.

in many areas. Thus, the treatments of Recent reports suggest that moxi-
choice are 125 mg IM or IV or cefixime floxacin 400mg once daily is effective for
400mg orally (not available in the US). PID grade 1. this regimen has shown
This therapy should be included in all similar cure rates to ofloxacin plus met-
grades of PID. ronidazole and to ciprofloxacin plus

816

doxycycline and metronidazole for uncom-
plicated PID [138]. Future guidelines will
perhaps incorporate moxifloxacine, but
these need to be validated first.
Specific therapy determined by anti-
microbial sensitivity testing is indicated
when the microorganisms and their anti-
biotic sensitivity are known. However,
care has to be taken to assure anaerobic
coverage. Also, it is important to consider
the possibility that non-cultivated germs
(i.e., those not detected by standard cul-
ture techniques) may also be present,
necessitating alternative therapy if the
patient does not improve as expected.
8.2 Hospitalization
Indications for hospitalization are sum-
marized in Table 3. For PID grade 1
and 2, cure rates were similar for ambu-
latory treatment and hospitalization
[139]. Intravenous fluids are indicated
for patients with vomiting or ileus.
Thrombosis prophylaxis is also indicated
with low molecular heparin for hospital-
ized patients.
8.3 Indications for laparoscopy
Laparoscopy is not very accurate in PID
grades 1 and 2, and is not able to diagnose
the presence of endometritis unless it is
Table 3 Indications for hospitalization and intravenous
therapy.
Surgical intervention not excluded
Severe clinical picture
PID grade3 (including tubo-ovarian abces)
Pregnancy
Failure to respond on oral antibiotics within 48 hours
Immune compromised patients (HIV, transplantation,. . .)
Intolerant for peroral antibiotics
Inconsequent patient not taking medication properly
Pelvic infections in women | 14.4 |
combined with hysteroscopy and endome-
trial sampling for histologic examination.
However, in doubtful cases or when the
patient does not improve or deteriorates
(clinically or by increase of the infectious
parameters after 72 hours of antibiotic
therapy), laparoscopy is indicated. Intra-
abdominal cultures can be taken, and
other possible pathology, such as endome-
triosis, can be assessed. Excessive rins-
ing with saline is advised and if abscesses
are encountered they should be opened,
rinsed and drained [140–142].
9. SPECIAL TYPES OF PID
9.1 Tubo-ovarian abscess
A tubo-ovarian abscess (TOA) is the ulti-
mate attempt of the body to conceal a life
threatening infection.
9.1.1 Pathogenesis
TOA can originate from either ascending
PID (primary TOA) or as a consequence
of surgery or intestinal infectious proc-
esses. One has to be aware that a TOA
can always mimic or complicate a malig-
nant process, especially in postmenopau-
sal women (secondary TOA) [143]. There
are no known risk factors that promote
TOA development after PID.
The inflammatory reaction caused
by ascending aerobic bacteria causes
endothelial damage and intra-tubal adhe-
sions in which bacteria, debris and leu-
kocytes accumulate. Once large enough,
this accumulation will not allow sufficient
oxygen to diffuse into the center of the
abscess. Within 24 to 48 hours anaerobes
and facultative anaerobic microorganisms
can thrive in this anaerobic environment
(the so-called ‘anaerobic shift’).
9.1.2 Diagnosis
The most prominent clinical findings
include abdominal and pelvic pain,
present in over 90% of affected women,
817
Chapter | 14 | Sexually transmitted infectious diseases
followed by fever and leukocytosis in
60–80% [144]. The “gold standard” for
diagnosis is ultrasonography (see above).
TOA, with cystic structures and often air/
fluid levels should be clearly distinguished
from a ‘tubo-ovarian complex’, where
edema, adhesions and inflammation are
present, leading to more heterogeneuous
and hypervascularized sonographic find-
ings. Patients with tubo-ovarian complex
often respond well to sensitive to anti-
microbial therapy (>95%), in contrast to
patients with TOA (see below). Differential
diagnosis including a dermoïd or endome-
triosis cyst can be particularly difficult,
especially if secondary infection is present,
as often in the case of endometriosis.
9.1.3 Management: ubi pus, ibi
evacua (where there is pus,
you have to drain?)
More than 80% of the women who do
not respond to appropriate PID therapy
have TOAs. Still, some authors report
cure rates as high as 75% with antibiot-
ics alone [145]. Therefore, the need for
laparoscopic intervention and timing of
this intervention remain controversial.
Surgical drainage is required if the
TOA does not respond to medical ther-
apy. This can be done laparoscopically
[142], by CT- or ultrasound-guided per-
cutaneous aspiration [146–148], or more
recently also by transvaginal puncture
[149]. These procedures should only be
done with broad antibiotic coverage, as
the drainage procedure may dissemi-
nate infection [149]. As diagnostic work-
up to exclude malignancy is crucial in
post-menopausal women, laparoscopy is
always mandatory in this group.
Conservative treatment is only possible
if the patient is well informed that close
follow up is needed and surgical interven-
tion may still prove necessary. Resolution
of a TOA can take weeks to months.
Weekly follow up with bimanual exami-
nation and ultrasonography are neces-
sary, especially during the first weeks.
818
Patients should be instructed about
possible relapse of the TOA.
9.2 Acute, subacute and chronic
endometritis
Endometrial inflammation is a histo-
logic diagnosis and can be subdivided
in acute, subcute, chronic and fibrotic.
Fibrosis can occur with intracavitary
adhesions between anterior and posterior
walls of the uterine cavity (Asherman
syndrome).
9.2.1 Acute endometritis
True acute endometritis is rare and is
characterized by finding polymorpho-
nuclear neutrophils in the endometrial
glands. It may occur subsequent to intra-
uterine surgery, during the postpartum
period when infected placental tissue rem-
nants are still in place, and can also be the
transient first phase of an ascending infec-
tion leading to PID. In particular M. geni-
talium and group A streptococci have been
found in association with acute endometri-
tis [92, 150]. Diagnosis requires endome-
trial biopsy and cultures. Treatment is
outlined above. If placental remnants are
suspected they have to be removed.
9.2.2 Subacute endometritis
This is less known among pathologists but
is more common clinically. This condition
is characterized by presence of lympocytes
around the endometrial glands that infil-
trate both the surrounding stroma and
the glandular lumen, together with cellu-
lar debris. Typically, plasma cells are lack-
ing. Subacute endometritis is often been
associated with C. trachomatis infection
and should be treated accordingly [151].
9.2.3 Chronic endometritis
Chronic endometritis is characterized by
typical plasma cells in the endometrial
stroma [152–153]. Chronic endometritis
can also be a consequence of placental rem-
nants [154], after insertion of a intrauterine

contraceptive device [155–157], pelvic radi-
otherapy, ascending infection by Chlamydia
[153–154, 157] or tuberculosis (granuloma-
tous endometritis). In one third of women
no cause can be found.
Treatment is directed at known or sus-
pected pathogens. In other cases, empiric
use of doxycycline 100mg twice per day is
advised for 10 to 14 days or azythromycin
1 g per week for two weeks, with a cure rate
of 86 to 98% [158], although other stud-
ies found lower cure rates for doxycyclin
and favour eiter azythromycin or quinolo-
nes [94]. Biphasic estro-progestogens are
sometimes used for three months to induce
shedding of the endometrium (‘hormonal
curettage’). This type of therapy is most
often used after postpartum endometritis.
9.3 Post-abortion
After instrumentation, especially in prim-
igravidas, cervical stenosis can occur,
leading to retention, hematometra and
pyometra. Diagnosis is made by combin-
ing clinical findings of a painful enlarged
uterus and fever with a fluid filled uter-
ine cavity. Dilatation and drainage are
combined with amoxicillin with clavu-
lanic acid and doxycycline.
9.4 Post-partum
Endometritis during the post-partum
period is associated with prolonged labor,
preterm rupture of the membranes, or
remnants of blood clots and/or placental
tissue after delivery [154, 159]. Presence
of air in the uterine cavity is a normal
finding on ultrasound or CT scan for up
to six weeks post-partum and should not
be mistaken for abscess or pyometra.
Treatment is similar to that described
above for post-abortion entometritis.
10. PREVENTION
10.1 Perioperative antibiotics
Before or during certain surgical interven-
tions, routine administration of antibiotics
Pelvic infections in women | 14.4 |
has proven effective for preventing
endometritis and secondary post-surgery
PID. The best studied intervention cae-
sarian section (C-section). However, rou-
tine peri-operative antibiotics are still
under discussion due to the possible dis-
advantages like allergic reactions, and
resistance with the emergence of diffi-
cult to treat Staphylococcus aureus and
Clostridium difficile infections [160]. For
both elective and non-elective C-sections,
a Cochrane review concluded that pro-
phylactic antibiotics are recommended
because treatment results in a 30 to 80%
decrease in maternal infectious morbid-
ity [63, 161]. In elective C-sections, some
authors concluded in a meta-analysis
that early administration at the time of
incision instead of after cord-clamping
results in a reduced rate of postpartum
endometritis, (RR 0.47) and wound infec-
tion (RR 0.60) [162]. They also found a
difference in these complication rates
when the policy in their hospital was
changed with respect to timing of the
antibiotic delivery [163]. In contrast,
other authors did not find a difference
in infectious morbidity between early or
late (after cord clamping) administra-
tion of antibiotics [164]. Metronidazole
should be added to cefazolin because
combination therapy proved superior
for preventing complications [160, 165].
Remarkably, none of the antibiotic regi-
mens evaluated have been shown to
benefit the neonate. Updated guidelines
for other gynecological procedures are
summarized in the Practice Bulletins of
the American College of Obstetrics and
Gynecology [166].
10.2 Screening
Standard STI screening and treat-
ment policies offer the potential for sub-
stantially reducing a PID rates [167].
In high risk groups of women (e.g., sex
workers, abused women, women with
a history of PID, women undergoing
counseling for abortion, etc.) routine
819
Chapter | 14 | Sexually transmitted infectious diseases
screening for Chlamydia and other STIs
is recommended [168–170]. Another high
risk group that is likely to benefit from
screening is teenagers at schools, during
visits in family planning clinics or where
contraception is discussed [171–172].
10.3 Sexual education
Abstinence is the most secure guarantee
of avoiding PID, at least according to the
strict definition wherein PID is consid-
ered to be an STD [173]. The abstention,
beware and condom use methods (ABC
policy) have been successful in some set-
tings such Uganda [174] and in US mili-
tary clinics [175]. However, many barriers
must be addressed to make safe sex prac-
tices an accepted and commonly adopted
approach [176].
11. FOLLOW UP
After the initial PID episode, it is impor-
tant to monitor infectious parameters and
any abscess or mass seen on ultrasound.
Officially, there is no need to retest for
Chlamydia after recommended treatment.
However, some guidelines (i.e., Belgian
Societies of Gynecology and Obstetrics)
test of cure testing is strongly advised
because persistence of a Chlamydia infec-
tion is seen in 10–15% of cases. Patients
with persistent symptoms or doubtful
compliance to therapy should also be
tested again three weeks post treatment.
False negative (still viable Chlamydia in
low numbers) or false positive (shedding
of non viable Chlamydia) testing may
occur the first weeks after treatment.
Frequent complications of PID are
chronic pelvic pain, dyspareunia, infertil-
ity (RR × 6 after 1 episode, × 17 after 2
episodes), and ectopic pregnancy. Every
woman experiencing a PID episode should
be aware of these risks. Unfortunately, no
study has compared rates of such long-
term sequelae after different treatment
regimens.
820
12. FURTHER RESEARCH
There is a great need of more research,
as new microbiological techniques have
become available. Polymerase chain
reaction allows detection of new and
formerly undetectable microorganisms,
opening an interesting field to close the
gap of the ‘unexplained PID like syn-
dromes’ in which no causative organ-
ism could be detected with conventional
techniques. The epidemiology, which is
now increasingly mapping a growing
number of women in which non-sexually
transmitted organisms are responsible
for ascending pelvic infection as well as
the specific genetic susceptibility of cer-
tain women to certain complications like
tubal infertility, needs more attention in
future studies. Finally, accessible and
more focused screening programs have
to be developed and exercised, espe-
cially in low resource countries, where
the sequelae of PID create a tremendous
burden for young women in their repro-
ductive years. Although it is the only
system manageable at hoc, the adapta-
tion of ‘syndromic management’ does not
seem to be sufficient to stem the spread
of the disease.
13. CONCLUSIONS
1. PID still remains a silent cause of
major genital pathology worldwide
2. Diagnosis of PID may be difficult
due to a blurry, composite definition
of the condition, and the lack of a
single cause. Instead a flexible and
attentive mind is needed to consider
the diagnosis with a low treshold for
therapy.
3. Laparoscopy is still the ‘gold standard’
of diagnosis, but the increasing
technical resolution of imaging
techniques like sonography, CT scan
and MRI and the increasing
sensitivity of blood analysis allow

better non-invasive diagnostic
approaches than ever before.
4. However, the clinical syndrome
remains the cornerstone of the
presumed diagnosis of PID, and needs
treatment as soon as the diagnosis is
suspected.
5. Within 48 hours, the treatment
needs to be adjusted as soon as the
diagnosis is refined, or if the response
to therapy is inadequate.
REFERENCES
1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of
the main steps for developing and grad-
ing guideline recommendations. Prog
Urol, 2007. 17(3): 681–4.
2. U.S. Department of Health and Human
Services Public Health Service Agency
for Health Care Policy and Research,
1992: 115–127.
3. Gibbs RS, O’Dell TN, MacGregor RR,
Schwarz RH, and Morton H, Puerperal
endometritis: a prospective microbio-
logic study. Am J Obstet Gynecol, 1975.
121(7): 919–25.
4. Lewis CM and Zervos MJ, Clinical mani-
festations of enterococcal infection. Eur J
Clin Microbiol Infect Dis, 1990. 9(2): 111–7.
5. Martens MG, Faro S, Hammill H,
Phillips LE, and Riddle GD, Comparison
of two endometrial sampling devices.
Cotton-tipped swab and double-lumen
catheter with a brush. J Reprod Med,
1989. 34(11): 875–9.
6. Martens MG, Faro S, Maccato M,
Hammill HA, and Riddle G, Prevalence
of beta-lactamase enzyme production
in bacteria isolated from women with
postpartum endometritis. J Reprod Med,
1993. 38(10): 795–8.
7. Sokolova IE, [Antibiotic sensitivity of
the microflora isolated from the uter-
ine cavity of patients with postabortion
endometritis]. Antibiot Med Biotekhnol,
1986. 31(9): 687–90.
8. Tsanadis G, Kalantaridou SN, Kaponis
A, Paraskevaidis E, Zikopoulos K,
Pelvic infections in women | 14.4 |
Gesouli E, Dalkalitsis N, Korkontzelos
I, Mouzakioti E, and Lolis DE,
Bacteriological cultures of removed
intrauterine devices and pelvic inflam-
matory disease. Contraception, 2002.
65(5): 339–42.
9. Donders GG, Definition and classifica-
tion of abnormal vaginal flora. Best
Pract Res Clin Obstet Gynaecol, 2007.
21(3): 355–73.
10. Donders GG, Vereecken A, Bosmans E,
Dekeersmaecker A, Salembier G, and
Spitz B, Definition of a type of abnormal
vaginal flora that is distinct from bacte-
rial vaginosis: aerobic vaginitis. BJOG,
2002. 109(1): 34–43.
11. Wiesenfeld HC, Hillier SL, Krohn MA,
Amortegui AJ, Heine RP, Landers DV,
and Sweet RL, Lower genital tract
infection and endometritis: insight into
subclinical pelvic inflammatory disease.
Obstet Gynecol, 2002. 100(3): 456–63.
12. Eschenbach DA, Hillier S, Critchlow
C, Stevens C, DeRouen T, and Holmes
KK, Diagnosis and clinical manifesta-
tions of bacterial vaginosis. Am J Obstet
Gynecol, 1988. 158(4): 819–28.
13. Korn AP, Hessol NA, Padian NS, Bolan
GA, Donegan E, Landers DV, and
Schachter J, Risk factors for plasma
cell endometritis among women with
cervical Neisseria gonorrhoeae, cervi-
cal Chlamydia trachomatis, or bacterial
vaginosis. Am J Obstet Gynecol, 1998.
178(5): 987–90.
14. Holmes KK, Eschenbach DA, and Knapp
JS, Salpingitis: overview of etiology and
epidemiology. Am J Obstet Gynecol,
1980. 138(7 Pt 2): 893–900.
15. Di Bartolomeo S, Mirta DH, Janer
M, Rodriguez Fermepin MR, Sauka
D, Magarinos F, and de Torres RA,
Incidence of Chlamydia trachomatis and
other potential pathogens in neonatal
conjunctivitis. Int J Infect Dis, 2001.
5(3): 139–43.
16. van der Snoek EM, Chin ALRA, de
Ridder MA, Willems PW, Verkooyen RP,
and van der Meijden WI, [Prevalence of
sexually transmitted diseases (STD) and
HIV-infection among attendees of STD
Outpatient Clinic, Dijkzigt University
Hospital in Rotterdam; comparative
821
Chapter | 14 | Sexually transmitted infectious diseases
analysis of years 1993 and 1998]. Ned
Tijdschr Geneeskd, 2000. 144(28):
1351–5.
17. Bjartling C, Osser S, and Persson K,
The frequency of salpingitis and ectopic
pregnancy as epidemiologic markers of
Chlamydia trachomatis. Acta Obstet
Gynecol Scand, 2000. 79(2): 123–8.
18. Skjeldestad FE, Nordbo SA, and Hadgu
A, Sentinel surveillance of Chlamydia
trachomatis infection in women termi-
nating pregnancy. Genitourin Med, 1997.
73(1): 29–32.
19. Cleavenger RL, Juckett RG, and Hobbs
GR, Trends in chlamydia and other sexu-
ally transmitted diseases in a university
health service. J Am Coll Health, 1996.
44(6): 263–5.
20. Katz BP, Blythe MJ, Van der Pol B,
and Jones RB, Declining prevalence of
chlamydial infection among adolescent
girls. Sex Transm Dis, 1996. 23(3):
226–9.
21. Persson K, Mansson A, Jonsson E, and
Nordenfelt E, Decline of herpes simplex
virus type 2 and Chlamydia trachomatis
infections from 1970 to 1993 indicated
by a similar change in antibody pattern.
Scand J Infect Dis, 1995. 27(3): 195–9.
22. Lujan J, de Onate WA, Delva W, Claeys
P, Sambola F, Temmerman M, Fernando
J, and Folgosa E, Prevalence of sexu-
ally transmitted infections in women
attending antenatal care in Tete province,
Mozambique. S Afr Med J, 2008. 98(1):
49–51.
23. Riedner G, Hoffmann O, Rusizoka M,
Mmbando D, Maboko L, Grosskurth
H, Todd J, Hayes R, and Hoelscher M,
Decline in sexually transmitted infection
prevalence and HIV incidence in female
barworkers attending prevention and
care services in Mbeya Region, Tanzania.
AIDS, 2006. 20(4): 609–15.
24. Edgardh K, [Strong increase of
Chlamydia trachomatis. A new mutant
and current sexual habits have had
“favourable” effects for the transmission].
Lakartidningen, 2007. 104(47): 3539–42.
25. Sylvan S and Christenson B, Increase
in Chlamydia trachomatis infection in
Sweden: time for new strategies. Arch
Sex Behav, 2008. 37(3): 362–4.
822
26. Velicko I, Kuhlmann-Berenzon S, and
Blaxhult A, Reasons for the sharp increase
of genital chlamydia infections reported in
the first months of 2007 in Sweden. Euro
Surveill, 2007. 12(10): E5–6.
27. Gotz H, Lindback J, Ripa T, Arneborn
M, Ramsted K, and Ekdahl K, Is the
increase in notifications of Chlamydia
trachomatis infections in Sweden the
result of changes in prevalence, sampling
frequency or diagnostic methods? Scand
J Infect Dis, 2002. 34(1): 28–34.
28. Dessus-Babus S, Bebear CM, Charron
A, Bebear C, and de Barbeyrac B,
Sequencing of gyrase and topoisomerase
IV quinolone-resistance-determining
regions of Chlamydia trachomatis and
characterization of quinolone-resistant
mutants obtained In vitro. Antimicrob
Agents Chemother, 1998. 42(10):
2474–81.
29. Witkin SS, Immunological aspects of
genital chlamydia infections. Best Pract
Res Clin Obstet Gynaecol, 2002. 16(6):
865–74.
30. Witkin SS, Neuer A, Giraldo P, Jeremias
J, Tolbert V, Korneeva IL, Kneissl D, and
Bongiovanni AM, Chlamydia trachoma-
tis Infection, Immunity, and Pregnancy
Outcome. Infect Dis Obstet Gynecol,
1997. 5(2): 128–32.
31. Sziller I, Fedorcsak P, Csapo Z, Szirmai
K, Linhares IM, Papp Z, and Witkin SS,
Circulating antibodies to a conserved
epitope of the Chlamydia trachomatis
60-kDa heat shock protein is associated
with decreased spontaneous fertility rate
in ectopic pregnant women treated by
salpingectomy. Am J Reprod Immunol,
2008. 59(2): 99–104.
32. Witkin SS and Linhares IM, Chlamydia
trachomatis in subfertile women under-
going uterine instrumentation: an
alternative to direct microbial testing or
prophylactic antibiotic treatment. Hum
Reprod, 2002. 17(8): 1938–41.
33. Yip PP, Chan WH, Yip KT, Que TL,
Kwong NS, and Ho CK, The use of
polymerase chain reaction assay versus
conventional methods in detecting neona-
tal chlamydial conjunctivitis. J Pediatr
Ophthalmol Strabismus, 2008. 45(4):
234–9.

34. Lee SH, Vigliotti VS, and Pappu S, DNA
sequencing validation of Chlamydia
trachomatis and Neisseria gonorrhoeae
nucleic acid tests. Am J Clin Pathol,
2008. 129(6): 852–9.
35. Bhalla P, Baveja UK, Chawla R, Saini
S, Khaki P, Bhalla K, Mahajan S, and
Reddy BS, Simultaneous detection of
Neisseria gonorrhoeae and Chlamydia
trachomatis by PCR in genitourinary
specimens from men and women attend-
ing an STD clinic. J Commun Dis, 2007.
39(1): 1–6.
36. Donders GG, Management of genital
infections in pregnant women. Curr Opin
Infect Dis, 2006. 19(1): 55–61.
37. Donders GG, Treatment of sexu-
ally transmitted bacterial diseases in
pregnant women. Drugs, 2000. 59(3):
477–85.
38. Lyss SB, Kamb ML, Peterman TA,
Moran JS, Newman DR, Bolan G,
Douglas JM, Jr., Iatesta M, Malotte CK,
Zenilman JM, Ehret J, Gaydos C, and
Newhall WJ, Chlamydia trachomatis
among patients infected with and treated
for Neisseria gonorrhoeae in sexually
transmitted disease clinics in the United
States. Ann Intern Med, 2003. 139(3):
178–85.
39. Garcia S, Casco R, Perazzi B, De Mier C,
Vay C, and Famiglietti A, [Ciprofloxacin
resistance of Neisseria gonorrhoeae
according to sexual habits]. Medicina
(B Aires), 2008. 68(5): 358–62.
40. Cao V, Ratsima E, Van Tri D, Bercion
R, Fonkoua MC, Richard V, and
Talarmin A, Antimicrobial susceptibil-
ity of Neisseria gonorrhoeae strains iso-
lated in 2004–2006 in Bangui, Central
African Republic; Yaounde, Cameroon;
Antananarivo, Madagascar; and Ho Chi
Minh Ville and Nha Trang, Vietnam. Sex
Transm Dis, 2008. 35(11): 941–5.
41. Lewis DA, Scott L, Slabbert M, Mhlongo
S, van Zijl A, Sello M, du Plessis N,
Radebe F, and Wasserman E, Escalation
in the relative prevalence of cipro-
floxacin-resistant gonorrhoea among men
with urethral discharge in two South
African cities: association with HIV
seropositivity. Sex Transm Infect, 2008.
84(5): 352–5.
Pelvic infections in women | 14.4 |
42. Le Lin B, Pastore R, Liassine N,
Aramburu C, and Sudre P, A new
sexually transmitted infection (STI)
in Geneva? Ciprofloxacin-resistant
Neisseria gonorrhoeae, 2002–2005. Swiss
Med Wkly, 2008. 138(15–16): 243–6.
43. Morris SR, Knapp JS, Moore DF, Trees
DL, Wang SA, Bolan G, and Bauer HM,
Using strain typing to characterise a
fluoroquinolone-resistant Neisseria gon-
orrhoeae transmission network in south-
ern California. Sex Transm Infect, 2008.
84(4): 290–1.
44. Ness RB, Kip KE, Hillier SL, Soper
DE, Stamm CA, Sweet RL, Rice P, and
Richter HE, A cluster analysis of bac-
terial vaginosis-associated microflora
and pelvic inflammatory disease. Am J
Epidemiol, 2005. 162(6): 585–90.
45. Valayatham V, Salmonella: the pelvic
masquerader. Int J Infect Dis, 2009.
13(2): e53–5.
46. Hung TH, Jeng CJ, Su SC, and
Wang KG, Pelvic abscess caused by
Salmonella: a case report. Zhonghua Yi
Xue Za Zhi (Taipei), 1996. 57(6): 457–9.
47. Kostiala AA and Ranta T, Pelvic inflam-
matory disease caused by Salmonella
panama and its treatment with cip-
rofloxacin. Case report. Br J Obstet
Gynaecol, 1989. 96(1): 120–2.
48. Saltzman DH, Evans MI, Robichaux AG,
3rd, Grossman JH, 3rd, and Friedman
AJ, Nongonococcal pelvic abscess caused
by Salmonella enteritidis. Obstet
Gynecol, 1984. 64(4): 585–6.
49. Duncan ME, Perine PL, and Krause DW,
Pelvic infection caused by Salmonella
typhi. Two unusual cases. East Afr Med
J, 1981. 58(9): 703–7.
50. Hillier S, Watts DH, Lee MF, and
Eschenbach DA, Etiology and treatment
of post-cesarean-section endometri-
tis after cephalosporin prophylaxis. J
Reprod Med, 1990. 35(3 Suppl): 322–8.
51. Lucas MJ, Cox SM, Roark ML, and
Cunningham FG, Ticarcillin/clavu-
lanate in the treatment of pelvic infec-
tions. J Reprod Med, 1990. 35(3 Suppl):
343–7.
52. Chaudhry R, Thakur R, Talwar V, and
Aggarwal N, Anaerobic and aerobic
microflora of pouch of Douglas aspirate
823
Chapter | 14 | Sexually transmitted infectious diseases
v/s high vaginal swab in cases of pelvic
inflammatory disease. Indian J Pathol
Microbiol, 1996. 39(2): 115–20.
53. Rees E, The treatment of pelvic inflam-
matory disease. Am J Obstet Gynecol,
1980. 138(7 Pt 2): 1042–7.
54. Sweet RL, Bartlett JG, Hemsell DL,
Solomkin JS, and Tally F, Evaluation
of new anti-infective drugs for the
treatment of acute pelvic inflamma-
tory disease. Infectious Diseases Society
of America and the Food and Drug
Administration. Clin Infect Dis, 1992.
15 Suppl 1: S53–61.
55. Sicard D, Deaths from Clostridium sor-
dellii after medical abortion. N Engl
J Med, 2006. 354(15): 1645–7; author
reply 1645–7.
56. Fischer M, Bhatnagar J, Guarner J,
Reagan S, Hacker JK, Van Meter SH,
Poukens V, Whiteman DB, Iton A,
Cheung M, Dassey DE, Shieh WJ, and
Zaki SR, Fatal toxic shock syndrome
associated with Clostridium sordellii
after medical abortion. N Engl J Med,
2005. 353(22): 2352–60.
57. Murray S and Wooltorton E, Septic
shock after medical abortions with mife-
pristone (Mifeprex, RU 486) and misopr-
ostol. CMAJ, 2005. 173(5): 485.
58. Wiebe E, Guilbert E, Jacot F, Shannon
C, and Winikoff B, A fatal case of
Clostridium sordellii septic shock syn-
drome associated with medical abor-
tion. Obstet Gynecol, 2004. 104(5 Pt 2):
1142–4.
59. Aronoff DM, Hao Y, Chung J, Coleman
N, Lewis C, Peres CM, Serezani CH,
Chen GH, Flamand N, Brock TG, and
Peters-Golden M, Misoprostol impairs
female reproductive tract innate immu-
nity against Clostridium sordellii. J
Immunol, 2008. 180(12): 8222–30.
60. Afshan A, Pelvic tuberculosis mimick-
ing malignant ovarian tumour. J Coll
Physicians Surg Pak, 2006. 16(1): 64–6.
61. Tapisiz OL, Reyhan H, Cavkaytar S, and
Aydogdu T, Pelvic tuberculosis mimick-
ing ovarian carcinoma. Int J Gynaecol
Obstet, 2005. 90(1): 76–7.
62. Odejinmi F, Annan HG, and Hussein SY,
Tuberculosis, the great mimic again? A
report of two cases of pelvic tuberculosis
824
initially suspected to be advanced ovar-
ian carcinoma. J Obstet Gynaecol, 2000.
20(5): 544–5.
63. Chow TW, Lim BK, and Vallipuram
S, The masquerades of female pelvic
tuberculosis: case reports and review of
literature on clinical presentations and
diagnosis. J Obstet Gynaecol Res, 2002.
28(4): 203–10.
64. Barutcu O, Erel HE, Saygili E, Yildirim
T, and Torun D, Abdominopelvic tuber-
culosis simulating disseminated ovarian
carcinoma with elevated CA-125 level:
report of two cases. Abdom Imaging,
2002. 27(4): 465–70.
65. Ozalp S, Yalcin OT, Tanir HM,
Kabukcuoglu S, and Akcay A, Pelvic
tuberculosis mimicking signs of abdomi-
nopelvic malignancy. Gynecol Obstet
Invest, 2001. 52(1): 71–2.
66. Westhoff C, IUDs and coloniza-
tion or infection with Actinomyces.
Contraception, 2007. 75(6 Suppl):
S48–50.
67. Cleghorn AG and Wilkinson RG,
The IUCD-associated incidence of
Actinomyces israelii in the female genital
tract. Aust N Z J Obstet Gynaecol, 1989.
29(4): 445–9.
68. Maenpaa J, Taina E, Gronroos M,
Soderstrom KO, Ristimaki T, and
Narhinen L, Abdominopelvic actino-
mycosis associated with intrauterine
devices. Two case reports. Arch Gynecol
Obstet, 1988. 243(4): 237–41.
69. Akhan SE, Dogan Y, Akhan S, Iyibozkurt
AC, Topuz S, and Yalcin O, Pelvic actino-
mycosis mimicking ovarian malignancy:
three cases. Eur J Gynaecol Oncol, 2008.
29(3): 294–7.
70. Ko TL, Li YT, Chu YC, Chen TH, Chen
CS, Chen FM, and Kuo TC, An uncom-
mon case of pelvic and abdominal wall
mass: presumed pelvic actinomycosis.
Taiwan J Obstet Gynecol, 2007. 46(3):
299–303.
71. Sehouli J, Stupin JH, Schlieper U,
Kuemmel S, Henrich W, Denkert
C, Dietel M, and Lichtenegger W,
Actinomycotic inflammatory disease and
misdiagnosis of ovarian cancer. A case
report. Anticancer Res, 2006. 26(2C):
1727–31.

72. Atay Y, Altintas A, Tuncer I, and Cennet
A, Ovarian actinomycosis mimicking
malignancy. Eur J Gynaecol Oncol,
2005. 26(6): 663–4.
73. Malik AI, Papagrigoriadis S, Leather
AJ, Rennie JA, Salisbury JR, and Beese
RC, Abdominopelvic mass secondary to
Actinomyces israelii mimicking cancer:
report of two cases. Tech Coloproctol,
2005. 9(2): 170–1.
74. Wang YH, Tsai HC, Lee SS, Mai MH,
Wann SR, Chen YS, and Liu YC, Clinical
manifestations of actinomycosis in
Southern Taiwan. J Microbiol Immunol
Infect, 2007. 40(6): 487–92.
75. Doberneck RC, Pelvic actinomycosis
associated with use of intrauterine
device: a new challenge for the surgeon.
Am Surg, 1982. 48(1): 25–7.
76. Burstein GR and Workowski KA,
Sexually transmitted diseases treatment
guidelines. Curr Opin Pediatr, 2003.
15(4): 391–7.
77. Mardh PA, Lind I, Svensson L,
Westrom L, and Moller BR, Antibodies
to Chlamydia trachomatis, Mycoplasma
hominis, and Neisseria gonorrhoeae in
sera from patients with acute
salpingitis. Br J Vener Dis, 1981.
57(2): 125–9.
78. Mardh PA, Increased serum levels of
IgM in acute salpingitis related to the
occurrence of Mycoplasma hominis. Acta
Pathol Microbiol Scand B Microbiol
Immunol, 1970. 78(6): 726–32.
79. Mardh PA and Westrom L, Antibodies
to Mycoplasma hominis in patients with
genital infections and in healthy con-
trols. Br J Vener Dis, 1970. 46(5): 390–7.
80. Plummer DC, Garland SM, and Gilbert
GL, Bacteraemia and pelvic infection in
women due to Ureaplasma urealyticum
and Mycoplasma hominis. Med J Aust,
1987. 146(3): 135–7.
81. Wong ES and Stamm WE, Urethral
infections in men and women. Annu Rev
Med, 1983. 34: 337–58.
82. Fahmy NW, Honore LH, and Cumming
DC, Subacute focal endometritis.
Association with cervical colonization
with ureaplasma urealyticum, pelvic
pathology and endometrial maturation.
J Reprod Med, 1987. 32(9): 685–7.
Pelvic infections in women | 14.4 |
83. Hackel H, Hartmann AA, Elsner P, and
Burg G, Prevalence of Ureaplasma urea-
lyticum in the urethra of men without
urethritis in relation to clinical diagno-
sis. Dermatologica, 1990. 180(2): 76–8.
84. Chatwani A, Nyirjesy P, and Amin-
Hanjani S, Chronic endometritis and
positive Mycoplasma cultures: is there a
correlation? Infect Dis Obstet Gynecol,
1995. 3(1): 3–6.
85. Miettinen A, Laine S, Teisala K, and
Heinonen PK, The effect of ciprofloxacin
and doxycycline plus metronidazole on
lower genital tract flora in patients with
proven pelvic inflammatory disease.
Arch Gynecol Obstet, 1991. 249(2):
95–101.
86. Onrust SV, Lamb HM, and Balfour JA,
Ofloxacin. A reappraisal of its use in the
management of genitourinary tract infec-
tions. Drugs, 1998. 56(5): 895–928.
87. Taylor-Robinson D, Gilroy CB, and Hay
PE, Occurrence of Mycoplasma genital-
ium in different populations and its clini-
cal significance. Clin Infect Dis, 1993. 17
Suppl 1: S66–8.
88. Moller BR, Taylor-Robinson D, Furr PM,
and Freundt EA, Acute upper genital-
tract disease in female monkeys provoked
experimentally by Mycoplasma geni-
talium. Br J Exp Pathol, 1985. 66(4):
417–26.
89. Haggerty CL, Evidence for a role of
Mycoplasma genitalium in pelvic inflam-
matory disease. Curr Opin Infect Dis,
2008. 21(1): 65–9.
90. Cohen CR, Mugo NR, Astete SG, Odondo
R, Manhart LE, Kiehlbauch JA, Stamm
WE, Waiyaki PG, and Totten PA,
Detection of Mycoplasma genitalium in
women with laparoscopically diagnosed
acute salpingitis. Sex Transm Infect,
2005. 81(6): 463–6.
91. Simms I, Eastick K, Mallinson H,
Thomas K, Gokhale R, Hay P, Herring
A, and Rogers PA, Associations between
Mycoplasma genitalium, Chlamydia tra-
chomatis and pelvic inflammatory dis-
ease. J Clin Pathol, 2003. 56(8): 616–8.
92. Cohen CR, Manhart LE, Bukusi EA,
Astete S, Brunham RC, Holmes KK,
Sinei SK, Bwayo JJ, and Totten PA,
Association between Mycoplasma
825
Chapter | 14 | Sexually transmitted infectious diseases
genitalium and acute endometritis.
Lancet, 2002. 359(9308): 765–6.
93. Short VL, Totten PA, Ness RB, Astete
SG, Kelsey SF, and Haggerty CL,
Clinical presentation of Mycoplasma
genitalium Infection versus Neisseria
gonorrhoeae infection among women
with pelvic inflammatory disease. Clin
Infect Dis, 2009. 48(1): 41–7.
94. Haggerty CL and Ness RB, Newest
approaches to treatment of pelvic inflam-
matory disease: a review of recent ran-
domized clinical trials. Clin Infect Dis,
2007. 44(7): 953–60.
95. Bradshaw CS, Chen MY, and Fairley
CK, Persistence of Mycoplasma geni-
talium following azithromycin therapy.
PLoS One, 2008. 3(11): e3618.
96. Haggerty CL, Totten PA, Astete SG, Lee
S, Hoferka SL, Kelsey SF, and Ness RB,
Failure of cefoxitin and doxycycline to
eradicate endometrial Mycoplasma geni-
talium and the consequence for clinical
cure of pelvic inflammatory disease. Sex
Transm Infect, 2008. 84(5): 338–42.
97. Lee NC, Rubin GL, and Grimes DA,
Measures of sexual behavior and the risk
of pelvic inflammatory disease. Obstet
Gynecol, 1991. 77(3): 425–30.
98. Donders G, De Wet HG, Hooft P,
and Desmyter J, Lactobacilli in
Papanicolaou smears, genital infections,
and pregnancy. Am J Perinatol, 1993.
10(5): 358–61.
99. Westrom L and Wolner-Hanssen P,
Pathogenesis of pelvic inflammatory dis-
ease. Genitourin Med, 1993. 69(1): 9–17.
100. Westrom L, Incidence, prevalence, and
trends of acute pelvic inflammatory dis-
ease and its consequences in industrial-
ized countries. Am J Obstet Gynecol,
1980. 138(7 Pt 2): 880–92.
101. Artz L, Macaluso M, Meinzen-Derr J,
Kelaghan J, Austin H, Fleenor M, Hook
EW, 3rd, and Brill I, A randomized trial
of clinician-delivered interventions pro-
moting barrier contraception for sexu-
ally transmitted disease prevention. Sex
Transm Dis, 2005. 32(11): 672–9.
102. Finer LB, Darroch JE, and Singh S,
Sexual partnership patterns as a behav-
ioral risk factor for sexually transmitted
826
diseases. Fam Plann Perspect, 1999.
31(5): 228–36.
103. Mohllajee AP, Curtis KM, Martins SL,
and Peterson HB, Hormonal contra-
ceptive use and risk of sexually trans-
mitted infections: a systematic review.
Contraception, 2006. 73(2): 154–65.
104. Rubin GL, Ory HW, and Layde PM, Oral
contraceptives and pelvic inflammatory
disease. Am J Obstet Gynecol, 1982.
144(6): 630–5.
105. Campbell SJ, Cropsey KL, and
Matthews CA, Intrauterine device use in
a high-risk population: experience from
an urban university clinic. Am J Obstet
Gynecol, 2007. 197(2): 193 e1–6; discus-
sion 193 e6–7.
106. Mohllajee AP, Curtis KM, and Peterson
HB, Does insertion and use of an intrau-
terine device increase the risk of pelvic
inflammatory disease among women
with sexually transmitted infection? A
systematic review. Contraception, 2006.
73(2): 145–53.
107. Copper IUDs, infection and infertility.
Drug Ther Bull, 2002. 40(9): 67–9.
108. Pakarinen P, Toivonen J, and
Luukkainen T, Randomized comparison
of levonorgestrel- and copper-releasing
intrauterine systems immediately
after abortion, with 5 years’ follow-up.
Contraception, 2003. 68(1): 31–4.
109. Andersson K, Odlind V, and Rybo G,
Levonorgestrel-releasing and copper-
releasing (Nova T) IUDs during five
years of use: a randomized comparative
trial. Contraception, 1994. 49(1): 56–72.
110. Grimes DA, Intrauterine device and
upper-genital-tract infection. Lancet,
2000. 356(9234): 1013–9.
111. Jacobson L and Westrom L, Objectivized
diagnosis of acute pelvic inflammatory
disease. Diagnostic and prognostic value
of routine laparoscopy. Am J Obstet
Gynecol, 1969. 105(7): 1088–98.
112. Simms I, Warburton F, and Westrom L,
Diagnosis of pelvic inflammatory dis-
ease: time for a rethink. Sex Transm
Infect, 2003. 79(6): 491–4.
113. Hemila M, Henriksson L, and Ylikorkala
O, Serum CRP in the diagnosis and
treatment of pelvic inflammatory

disease. Arch Gynecol Obstet, 1987.
241(3): 177–82.
114. Reljic M and Gorisek B, C-reactive pro-
tein and the treatment of pelvic inflam-
matory disease. Int J Gynaecol Obstet,
1998. 60(2): 143–50.
115. Teisala K and Heinonen PK, C-reactive
protein in assessing antimicrobial treat-
ment of acute pelvic inflammatory dis-
ease. J Reprod Med, 1990. 35(10): 955–8.
116. Haggerty CL and Ness RB, Epidemiology,
pathogenesis and treatment of pelvic
inflammatory disease. Expert Rev Anti
Infect Ther, 2006. 4(2): 235–47.
117. Peipert JF, Ness RB, Blume J, Soper
DE, Holley R, Randall H, Sweet
RL, Sondheimer SJ, Hendrix SL,
Amortegui A, Trucco G, and Bass DC,
Clinical predictors of endometritis in
women with symptoms and signs of pel-
vic inflammatory disease. Am J Obstet
Gynecol, 2001. 184(5): 856–63; discus-
sion 863–4.
118. Reljic M and But I, Monitoring param-
eters in the management of patients with
tubo-ovarian complexes. Int J Gynaecol
Obstet, 1999. 64(3): 273–9.
119. Peipert JF, Ness RB, Soper DE, and
Bass D, Association of lower genital tract
inflammation with objective evidence of
endometritis. Infect Dis Obstet Gynecol,
2000. 8(2): 83–7.
120. Peipert JF, Boardman L, Hogan JW,
Sung J, and Mayer KH, Laboratory
evaluation of acute upper genital tract
infection. Obstet Gynecol, 1996. 87
(5 Pt 1): 730–6.
121. Donders GG, Microscopy of the bacterial
flora on fresh vaginal smears. Infect Dis
Obstet Gynecol, 1999. 7(4): 177–9.
122. Yudin MH, Hillier SL, Wiesenfeld HC,
Krohn MA, Amortegui AA, and Sweet
RL, Vaginal polymorphonuclear leuko-
cytes and bacterial vaginosis as markers
for histologic endometritis among women
without symptoms of pelvic inflamma-
tory disease. Am J Obstet Gynecol, 2003.
188(2): 318–23.
123. Twickler DM, Setiawan AT, Evans RS,
Erdman WA, Stettler RW, Brown CE,
and Cunningham FG, Imaging of puer-
peral septic thrombophlebitis: prospective
Pelvic infections in women | 14.4 |
comparison of MR imaging, CT, and
sonography. AJR Am J Roentgenol, 1997.
169(4): 1039–43.
124. Nishino M, Hayakawa K, Iwasaku K,
and Takasu K, Magnetic resonance
imaging findings in gynecologic emer-
gencies. J Comput Assist Tomogr, 2003.
27(4): 564–70.
125. Ueda H, Togashi K, Kataoka ML, Koyama
T, Fujiwara T, Fujii S, and Konishi J,
Adnexal masses caused by pelvic inflam-
matory disease: MR appearance. Magn
Reson Med Sci, 2002. 1(4): 207–15.
126. Infertility and sexually transmitted dis-
ease: a public health challenge. Popul
Rep L, 1983(4): L114–51.
127. Leblanc MM, When to refer an infer-
tile mare to a theriogenologist.
Theriogenology, 2008. 70(3): 421–9.
128. Mesurolle B, Mignon F, and Gagnon
JH, Fitz-Hugh-Curtis syndrome caused
by Chlamydia trachomatis: atypical CT
findings. AJR Am J Roentgenol, 2004.
182(3): 822–4; author reply 824.
129. Svensson L, Mardh PA, Ahlgren M, and
Nordenskjold F, Ectopic pregnancy and
antibodies to Chlamydia trachomatis.
Fertil Steril, 1985. 44(3): 313–7.
130. Ault KA, Statland BD, King MM,
Dozier DI, Joachims ML, and Gunter J,
Antibodies to the chlamydial 60 kilodal-
ton heat shock protein in women with
tubal factor infertility. Infect Dis Obstet
Gynecol, 1998. 6(4): 163–7.
131. Sziller I, Witkin SS, Ziegert M, Csapo
Z, Ujhazy A, and Papp Z, Serological
responses of patients with ectopic preg-
nancy to epitopes of the Chlamydia
trachomatis 60 kDa heat shock protein.
Hum Reprod, 1998. 13(4): 1088–93.
132. Jurstrand M, Jensen JS, Magnuson A,
Kamwendo F, and Fredlund H, A sero-
logical study of the role of Mycoplasma
genitalium in pelvic inflammatory dis-
ease and ectopic pregnancy. Sex Transm
Infect, 2007. 83(4): 319–23.
133. Hadgu A, Koch G, and Westrom L,
Analysis of ectopic pregnancy data using
marginal and conditional models. Stat
Med, 1997. 16(21): 2403–17.
134. Goldstein DP, deCholnoky C, Leventhal
JM, and Emans SJ, New insights into
827
Chapter | 14 | Sexually transmitted infectious diseases
the old problem of chronic pelvic pain. J
Pediatr Surg, 1979. 14(6): 675–80.
135. Theoharides TC, Whitmore K, Stanford
E, Moldwin R, and O’Leary MP,
Interstitial cystitis: bladder pain and
beyond. Expert Opin Pharmacother,
2008. 9(17): 2979–94.
136. Liddle AD and Davies AH, Pelvic con-
gestion syndrome: chronic pelvic pain
caused by ovarian and internal iliac
varices. Phlebology, 2007. 22(3): 100–4.
137. Walker CK and Wiesenfeld HC,
Antibiotic therapy for acute pelvic
inflammatory disease: the 2006 Centers
for Disease Control and Prevention
sexually transmitted diseases treatment
guidelines. Clin Infect Dis, 2007. 44
Suppl 3: S111–22.
138. Heystek MJ, Tellarini M, Schmitz H,
and Krasemann C, Efficacy and safety
of moxifloxacine vs ciprofloxacine plus
doxycycline plus metronidazole for
the treatment of uncomplicated pelvic
inflammatory disease. abstract.
139. Hillis SD, Joesoef R, Marchbanks
PA, Wasserheit JN, Cates W, Jr., and
Westrom L, Delayed care of pelvic
inflammatory disease as a risk factor for
impaired fertility. Am J Obstet Gynecol,
1993. 168(5): 1503–9.
140. Henry-Suchet J, PID: clinical and lapar-
oscopic aspects. Ann N Y Acad Sci, 2000.
900: 301–8.
141. Henry-Suchet J and Tesquier L, Role of
laparoscopy in the management of pelvic
adhesions and pelvic sepsis. Baillieres
Clin Obstet Gynaecol, 1994. 8(4):
759–72.
142. Molander P, Cacciatore B, Sjoberg J, and
Paavonen J, Laparoscopic management
of suspected acute pelvic inflammatory
disease. J Am Assoc Gynecol Laparosc,
2000. 7(1): 107–10.
143. Hoffman M, Molpus K, Roberts
WS, Lyman GH, and Cavanagh D,
Tuboovarian abscess in postmenopausal
women. J Reprod Med, 1990. 35(5): 525–8.
144. Dulin JD and Akers MC, Pelvic inflam-
matory disease and sepsis. Crit Care
Nurs Clin North Am, 2003. 15(1): 63–70.
145. Reed SD, Landers DV, and Sweet RL,
Antibiotic treatment of tuboovarian
828
abscess: comparison of broad-spectrum
beta-lactam agents versus clindamycin-
containing regimens. Am J Obstet
Gynecol, 1991. 164(6 Pt 1): 1556–61; dis-
cussion 1561–2.
146. Shulman A, Maymon R, Shapiro A, and
Bahary C, Percutaneous catheter drain-
age of tubo-ovarian abscesses. Obstet
Gynecol, 1992. 80(3 Pt 2): 555–7.
147. Casola G, vanSonnenberg E, D’Agostino
HB, Harker CP, Varney RR, and Smith
D, Percutaneous drainage of tubo-ovar-
ian abscesses. Radiology, 1992. 182(2):
399–402.
148. Worthen NJ and Gunning JE,
Percutaneous drainage of pelvic
abscesses: management of the tubo-ovar-
ian abscess. J Ultrasound Med, 1986.
5(10): 551–6.
149. Goharkhay N, Verma U, and Maggiorotto
F, Comparison of CT- or ultrasound-
guided drainage with concomitant
intravenous antibiotics vs. intravenous
antibiotics alone in the management
of tubo-ovarian abscesses. Ultrasound
Obstet Gynecol, 2007. 29(1): 65–9.
150. Ooe K and Udagawa H, A new type of
fulminant group A streptococcal infection
in obstetric patients: report of two cases.
Hum Pathol, 1997. 28(4): 509–12.
151. Eckert LO, Thwin SS, Hillier SL, Kiviat
NB, and Eschenbach DA, The antimicro-
bial treatment of subacute endometritis:
a proof of concept study. Am J Obstet
Gynecol, 2004. 190(2): 305–13.
152. Rotterdam H, Chronic endometritis. A
clinicopathologic study. Pathol Annu,
1978. 13 Pt 2: 209–31.
153. Thurman AR, Livengood CH, and Soper
DE, Chronic endometritis in DMPA users
and Chlamydia trachomatis endometri-
tis. Contraception, 2007. 76(1): 49–52.
154. Rufener SL, Adusumilli S, Weadock
WJ, and Caoili E, Sonography of uter-
ine abnormalities in postpartum and
postabortion patients: a potential pitfall
of interpretation. J Ultrasound Med,
2008. 27(3): 343–8.
155. Pujari SB, Joshi SK, Bhatt RV, and
Patel BC, Complications following use of
Lippes’ Loop. J Obstet Gynaecol India,
1968. 18(2): 257–61.

156. Marty R, Hysteroscopy necessary before
IUD? Acta Eur Fertil, 1986. 17(6):
449–50.
157. Ingerslev HJ, Moller BR, and Mardh
PA, Chlamydia trachomatis in acute and
chronic endometritis. Scand J Infect Dis
Suppl, 1982. 32: 59–63.
158. Savaris RF, Teixeira LM, Torres
TG, Edelweiss MI, Moncada J, and
Schachter J, Comparing ceftriaxone plus
azithromycin or doxycycline for pelvic
inflammatory disease: a randomized
controlled trial. Obstet Gynecol, 2007.
110(1): 53–60.
159. Michels TC, Chronic endometritis. Am
Fam Physician, 1995. 52(1): 217–22.
160. Ledger WJ, Prophylactic antibiotics in
obstetrics-gynecology: a current asset, a
future liability? Expert Rev Anti Infect
Ther, 2006. 4(6): 957–64.
161. Smaill F and Hofmeyr GJ, Antibiotic
prophylaxis for cesarean section.
Cochrane Database Syst Rev, 2002(3):
CD000933.
162. Costantine MM, Rahman M, Ghulmiyah
L, Byers BD, Longo M, Wen T, Hankins
GD, and Saade GR, Timing of periopera-
tive antibiotics for cesarean delivery:
a metaanalysis. Am J Obstet Gynecol,
2008. 199(3): 301 e1–6.
163. Kaimal AJ, Zlatnik MG, Cheng YW,
Thiet MP, Connatty E, Creedy P, and
Caughey AB, Effect of a change in policy
regarding the timing of prophylactic
antibiotics on the rate of postcesarean
delivery surgical-site infections. Am J
Obstet Gynecol, 2008. 199(3): 310 e1–5.
164. Yildirim G, Gungorduk K, Guven HZ,
Aslan H, Celikkol O, Sudolmus S, and
Ceylan Y, When should we perform pro-
phylactic antibiotics in elective cesar-
ean cases? Arch Gynecol Obstet, 2009.
280(1): 13–8.
165. Meyer NL, Hosier KV, Scott K, and
Lipscomb GH, Cefazolin versus cefazolin
plus metronidazole for antibiotic prophy-
laxis at cesarean section. South Med J,
2003. 96(10): 992–5.
166. ACOG Practice Bulletin No. 74.
Antibiotic prophylaxis for gynecologic
Pelvic infections in women | 14.4 |
procedures. Obstet Gynecol, 2006.
108(1): 225–34.
167. Stokes T, Screening for Chlamydia in
general practice: a literature review
and summary of the evidence. J Public
Health Med, 1997. 19(2): 222–32.
168. Champion JD, Piper J, Holden A, Korte
J, and Shain RN, Abused women and
risk for pelvic inflammatory disease.
West J Nurs Res, 2004. 26(2): 176–91;
discussion 192–5.
169. Stevenson MM and Radcliffe KW,
Preventing pelvic infection after abortion.
Int J STD AIDS, 1995. 6(5): 305–12.
170. Lande RE, Health care providers can
prevent and treat PID. Indian Med Trib,
1994: 11.
171. Huppert JS and Adams Hillard PJ,
Sexually transmitted disease screen-
ing in teens. Curr Womens Health Rep,
2003. 3(6): 451–8.
172. Bishop-Townsend V, STDs: Screening,
therapy, and long-term implications for
the adolescent patient. Int J
Fertil Menopausal Stud, 1996. 41(2):
109–14.
173. Stone KM, Avoiding sexually transmit-
ted diseases. Obstet Gynecol Clin North
Am, 1990. 17(4): 789–99.
174. Jacobs B, Whitworth J, Kambugu F, and
Pool R, Sexually transmitted disease
management in Uganda’s private-for-
profit formal and informal sector and
compliance with treatment. Sex Transm
Dis, 2004. 31(11): 650–4.
175. Jenkins PR, Jenkins RA,
Nannis ED, McKee KT, Jr.,
and Temoshok LR, Reducing risk of
sexually transmitted disease (STD)
and human immunodeficiency virus
infection in a military STD clinic:
evaluation of a randomized preventive
intervention trial. Clin Infect Dis, 2000.
30(4): 730–5.
176. Rassjo EB and Darj E, “Safe sex advice
is good - but so difficult to follow”. Views
and experiences of the youth in a health
centre in Kampala. From Kiswa Youth
Clinic, Kampala, Uganda. Afr Health
Sci, 2002. 2(3): 107–13.
829
|14.5|
HIV Infection in urological practice
Seung-Ju Lee
Department of Urology, The Catholic University, College of Medicine, Seoul, Korea
Corresponding author: Seung-Ju Lee, MD, PhD Urology, St. Vincent’s Hospital, The Catholic University,
93-6 Ji-dong, Paldal-gu, Suwon 442-723, Korea
Tel: +82-31-249-8305, Fax: +82-31-253-0949, E mail: lee.seungju@gmail.com
ABSTRACT
This review evaluates the scientific evi-
dence suggesting that urological factors
increase the efficiency of human immu-
nodeficiency virus (HIV) transmission
and discusses the important urological
manifestations of HIV infection. Level 1
evidence suggests that sexually trans-
mitted infections (STIs) are substantially
associated with an increased risk of HIV
infection. Several randomized control-
led trials show that improved STI control
can play a vital role in comprehensive
programs to prevent sexual transmis-
sion of HIV. However, there is limited
evidence that control of STIs reduces HIV
incidence at a population level. HIV has
become a chronic manageable condition
thanks to highly active antiretroviral
therapy. Urologists face a challenge in
trying to manage the genitourinary mani-
festations of HIV infection.
Key words: HIV infection, sexually trans-
mitted infection, transmission, urology.
SUMMARY OF RECOMMENDATIONS
1. Control of sexually transmitted infec-
tions (STI) can reduce HIV incidence
(GoR B).
2. Immediate diagnostic evaluation and
appropriate treatment of an indi-
vidual with any symptomatic STIs can
reduce HIV acquisition (GoR B).
3. Prompt and effective treatment of
HIV-infected individuals experiencing
genital symptoms can limit the trans-
mission of HIV (GoR B).
4. Behavioral interventions can reduce
HIV-related sexual risk behavior
(GoR B).
5. Interventions targeting people living
with HIV are efficacious in reducing
unprotected sex and acquisition of
STIs (GoR B).
1. INTRODUCTION
Acquired immunodeficiency syndrome
(AIDS) is defined by the development of

serious opportunistic infections, neoplasms,
or other life-threatening conditions result-
ing from progressive immunosuppression
caused by human immunodeficiency virus
(HIV) infection.
Although deaths attributed to AIDS
have declined in the Western world with
the introduction of effective antiretroviral
therapy, AIDS remains the leading cause
of death in many African cities [1]. The
three main modes of HIV transmission
have changed little: unprotected inter-
course, contact with blood, and trans-
mission from mother to child [2]. Among
them, HIV acquired through unprotected
heterosexual intercourse is on the rise
and considered to be a urological factor
for HIV transmission [1]. This review
evaluates the scientific evidence suggest-
ing that urological factors increase the
efficiency of HIV transmission and dis-
cusses the important urological manifes-
tations of HIV infection.
2. METHODS
A systematic literature search and
review of existing scientific evidence
published in peer reviewed journals
was performed in MEDLINE/PubMed
for the last 20 years with the following
key words: HIV transmission, sexually
transmitted infection; and the follow-
ing limitations: human, clinical studies,
randomized controlled trials (RCTs) or
studies, meta-analysis, English. 173 arti-
cles were found and screened by the title
and abstract of each electronic citation.
Full-text copies of potentially relevant
studies were obtained and 20 articles
were finally included in this review.
References from retrieved study reports
and reviews were also screened for addi-
tional studies.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [3–4].
HIV infection in urological practice | 14.5 |
3. EPIDEMIOLOGY OF HIV/AIDS1
The global percentage of people liv-
ing with HIV has stabilized since 2000.
However, the overall number of people
living with HIV has increased as a result
of the ongoing number of new infec-
tions each year and the beneficial effects
of more widely available antiretroviral
therapy. Sub-Saharan Africa remains
most heavily affected by HIV, account-
ing for 67% of all people living with HIV
and for 72% of AIDS deaths in 2007. The
global epidemic is stabilizing but at an
unacceptably high level. Globally, there
were an estimated 33 million (30.3 mil-
lion–36.1 million) people living with HIV
in 2007. The annual number of new HIV
infections declined from 3.0 million (2.6
million–3.5 million) in 2001 to 2.7 mil-
lion (2.2 million–3.2 million) in 2007. The
rate of new HIV infections has fallen in
several countries, although globally these
favorable trends are at least partially off-
set by increases in new infections in other
countries [1].
4. DYNAMICS OF HIV TRANSMISSION
HIV is transmitted from person to per-
son via bodily fluids because the virus is
present in varying concentrations in the
blood, sexual fluids such as semen and
vaginal fluid, and breast milk. Risk and
exposure varies dramatically depending
on many systemic factors as well as local
urogenital factors. Potential explanations
for this variability include biological dif-
ferences in infectiousness, susceptibility
or both, or differences in sexual behav-
iors [2, 5–6]. The concentration of HIV
in genital tract secretions from males
and females is increased at times when
enhanced transmission is suspected, such
as in primary infection or in later stages
of HIV disease and in patients with sexu-
ally transmitted infections (STIs) [7–11].
Chakaraborty et al. estimated the effects
of semen viral burden on heterosexual
831
Chapter | 14 | Sexually transmitted infectious diseases
transmission [12]. They concluded that
when HIV RNA in semen was low (<5000
copies/mL) transmission was unlikely
to occur, at one per 10,000 episodes of
intercourse. Conversely, when the con-
centration of HIV in semen was high
(eg, 1 million copies/mL) the probabil-
ity of transmission rose to three per 100
episodes of intercourse. In general, viral
levels in the female genital tract [13] and
in semen [14–15] correlate with systemic
viral loads. The probability of HIV trans-
mission per episode of vaginal intercourse
has been estimated from studies of HIV-
discordant couples: such estimates vary
from one per 7,000 to one per 700 in the
USA, Europe and Africa [5, 16–19] and to
one per 500 in Thailand [20]. As will be
discussed further below, one of the most
important determinants of genital viral
load is the presence of STIs [21–23]. In
women, bacterial vaginosis (BV), herpes
simplex virus (HSV), human papilloma-
virus, Chlamydia trachomatis, Neisseria
gonorrhoeae, Candida, genital ulceration
and vaginal discharge have been associ-
ated with increased HIV shedding. In
men, N. gonorrhoeae, Trichomonas vagi-
nalis, cytomegalovirus (CMV), urethri-
tis and genital ulcer disease have been
linked to HIV shedding in semen [23].
The risk and exposure may also depend
on the particular viral clade and circu-
lating recombinant form (CRF) [24]. The
cocirculation of subtype B among intrave-
nous drug users (IDUs) and CRF01_AE
(originally defined as subtype E) among
heterosexuals was originally described
in Thailand [25]; the segregation of sub-
type B to homosexuals and subtype C to
heterosexuals was described in South
Africa [26]; more recently, two concur-
rent epidemics in Argentina have been
reported, one among men who have sex
with men, sustained by subtype B, and
the other among heterosexuals and IDUs,
sustained by BF recombinants [27]. In
Europe, where subtype B has sustained
the HIV-1 epidemic among the “historical”
IDU and homosexual risk groups, non-B
832
subtypes and CRFs are progressively being
introduced in association with increased
heterosexual transmission of HIV-1
between migrants and/or immigrants
from regions where HIV-1 is endemic and
their European partners [28–30].
5. RELATIVE RISK FOR SPECIFIC
EXPOSURE
Evidence studies for STIs as a risk fac-
tor of HIV transmission are summarized
in Table 1. Classic sexually transmit-
ted diseases (STDs) (genital ulcers and
mucosal inflammatory diseases) occur
in the same geographic areas as HIV,
and compelling epidemiological evidence
supports the view that such diseases
increase HIV transmission; indeed, the
interaction between classic STDs and
HIV is referred to as “epidemiologi-
cal synergy” [21]. Several large RCTs
were undertaken to investigate whether
controlling STIs can reduce the inci-
dence of HIV in a community. The first
RCT enrolled 12,537 adults aged 15–54
years from six intervention communi-
ties and six pair-matched comparisons
[31]. Baseline HIV prevalence was 3.8%
and 4.4% in the intervention and con-
trol communities, respectively. There
was a reduction in syphilis and symp-
tomatic urethritis in the intervention
group. The incidence of HIV infection
was 1.2% and 1.9% in the intervention
and control groups, respectively (odds
ratio (OR) 0.58, 95% confidence inter-
val (CI) 0.42–0.70), corresponding to a
38% reduction (95% CI 15–55%) in the
intervention group. The intervention
reduced both the incidence/prevalence of
STIs and the incidence of HIV infection.
Since then, other trials in Rakai [32–33]
and Masaka [34] showed that there was
no significant effect on HIV prevention.
Possible hypotheses have been suggested
to explain these contrasting results. The
relative contribution of individual STIs
to an epidemic varies at different times
 HIV infection in urological practice | 14.5 |

Table 1 Evidence Table for Studies of Sexually Transmitted Infections (STIs) as Risk Factor of both HIV Transmission and
Acquisition that Include Original Data, Systematic Reviews, Meta-analyses, or Other Human Data (1988–2008).

Level of Evidence
Positive (role of
Lead author, a risk factor) or
Study Type STI type year, reference Design Negative

Systematic reviews, Meta-analyses and Modeling

STIs Sangani, 2004 [101] Systematic review and 1, Positive

meta-analysis of the five
RCTs

STIs Hay, 2008 [35] Systematic reviews 1, Positive

Bacterial vaginosis Atashili, 2008 [102] Systematic review and 2, Positive

meta-analysis of the 23
eligible publications

Randomized-controlled trials

STIs Grosskurth, 1995 12,537 adults aged 1, Positive

[31] 15–54 in six intervention
communities and six pair-
matched comparisons
communities in Mwanza,
Tanzania

STIs Wawer, 1999 [32] 12,726 adults aged 15–59 1, Negative

in Rakai, rural Uganda

STIs Gray, 2001 [33] 2,070 pregnant women in 1, Positive

Rakai, Uganda

STIs Kamali, 2003 [34] 12,819 individuals aged 1, Negative

13 and older in Masaka,
rural Uganda

HSV-2 Nagot, 2007 [36] 140 seropositive women 1, Positive

for HIV-1 and HSV-2 in
Burkina Faso

CMV Casper, 2008 [40] 16 HIV-positive men and 1, Positive

10 HIV-negative men in
Seattle, USA

Non-randomized cohort studies

Genital ulcers Cameron, 1989 [103] Prospective study of 422 2, Positive

men who had acquired
STD from female CSWs in
Nairobi

Genital ulcers, Plummer, 1991 [104] 124 seronegative female 2, Positive

Chlamydia CSWs in Nairobi
trachomatis

Neisseria gonor- Laga, 1995 [105] Cohort study of 431 HIV- 2, Positive
rhoeae, Chlamydia negative female CSWs in
trachomatis, Kinshasa, Zaire followed
Trichomonas for 2 years
vaginalis

continued

833
Chapter | 14 | Sexually transmitted infectious diseases

Table 1 Evidence Table for Studies of Sexually Transmitted Infections (STIs) as Risk Factor of both HIV Transmission and
Acquisition that Include Original Data, Systematic Reviews, Meta-analyses, or Other Human Data (1988–2008). – (Cont’d)

Level of Evidence
Positive (role of
Lead author, a risk factor) or
Study Type STI type year, reference Design Negative

Bacterial vaginosis Taha, 1998 [106] 1,196 antenatal pregnant 2, Positive

and 1169 postnatal
seronegative women in
Malawi

Bacterial vaginosis Martin, 1999 [107] 657 seronegative female 2, Positive

CSWs in Kenya

Bacterial vaginosis Myer, 2005 [108] 410 women screened 2, Positive

for cervical cancer in
South Africa

CMV Sheth, 2006 [39] 26 HIV-infected MSMs 2, Positive

and 15 uninfected con-
trols (6 MSMs; 9 heterose-
xuals) in Toronto, Canada

HSV-2 Rebbapragada, 2007 55 HIV-infected and 36 2, Positive

[37] uninfected female CSWs
in Nairobi, Kenya

Case-control studies

Urethritis Cohen, 1997 [109] 135 HIV-1-seropositive 3, Positive

men in Malawi

Neisseria gonor- Ghys, 1997 [110] 609 HIV-1-seropositive 3, Positive

rhoeae, Chlamydia women in Abidjan, Côte
trachomatis, geni- d’Ivoire
tal ulcers

Case-series

HSV, syphilis Stamm, 1988 [111] 200 homosexual men 3, Positive

with acute proctitis
and 111 asymptomatic
homosexuals

The hierarchy of study types was: systematic reviews and meta-analysis of randomized controlled trials, non-randomized cohort studies,
case-control studies, case series, and expert opinion (as the lowest level).

and places depending on the maturity of
the epidemic and the relative prevalence
of HIV and STI infection in the commu-
nity [35]. Although they did not show a
reduction in HIV acquisition, there were
reductions in adverse other outcomes
such as neonatal mortality.
Recently, a randomized, double-blind,
placebo-controlled trial of herpes simplex
virus (HSV) suppressive therapy with val-
acyclovir was undertaken in Burkina Faso
among women who were seropositive for
HIV-1 and HSV-2 [36]. All were ineligible
for highly active antiretroviral therapy
and followed for 24 weeks with 12 weeks
before and 12 weeks after randomization.
Valacyclovir therapy was found to be asso-
ciated with a significant decrease in the
frequency of genital HIV-1 RNA (OR 0.41,
95% CI 0.21–0.80) and in the mean quan-
tity of the virus (log(10) copies per millili-
ter -0.29, 95% CI -0.44 – -0.15). Genital

834

herpes infection is now thought to be the
most important cofactor in mature epi-
demics of HIV [35]. Interestingly, HSV-2
also drives secondary transmission of
HIV from HSV2-HIV co-infected individu-
als. Rebbapragada et al. [37] conducted a
well-defined cohort study among 55 HIV-
infected and 36 uninfected Kenyan female
commercial sex workers (CSWs). HSV-2
shedding is much more common in HIV-
infected than HIV-uninfected women,
perhaps due to HIV-induced depletion of
mucosal immature dendritic cells exerting
local HSV-2 immune control.
CMV may act as an important factor in
HIV secondary transmission [38]. Sheth
et al. [39] enrolled 26 HIV infected men who
have sex with men (MSMs) and 15 unin-
fected controls (six MSMs; nine heterosexu-
als). CMV shedding was associated with
a 10-fold increase in HIV levels in semen,
independent of HIV blood viral load and
CD4+ T cell count, and there was a strong
linear correlation between the semen lev-
els of HIV RNA and CMV DNA. In the US
RCT trial, anti-CMV treatment reduced
shedding of human herpesvirus-8 (HHV-8)
and CMV [40]. A total of 16 HIV–positive
men and 10 HIV-negative men were ran-
domized to receive valganciclovir or pla-
cebo administered orally. Valganciclovir
reduced oropharyngeal shedding of HHV-8
by 46% (OR 0.54, 95% CI 0.33–0.90) and
cytomegalovirus by 80% (OR 0.20, 95%
CI 0.08–0.48). Lack of male circumcision
[41–43] can be considered as a facilitating
factor or high levels of male circumcision
and condom use can be considered as pro-
tective factors (please refer to the chapter
on male circumcision). Facilitating factors
are virtually all positively correlated with
high-risk sex behaviors and are essential
for epidemic HIV transmission, but they
are difficult to quantify. Anal intercourse
poses a higher risk of HIV transmission
compared with vaginal intercourse because
of the greater amount of tissue trauma
that may occur [44–45] (please refer to the
recent NEJM review on this and male cir-
cumcision in homosexual men).
HIV infection in urological practice | 14.5 |
6. SCREENING FOR STIs
STIs facilitate both transmission and
acquisition of HIV with relative risks of
2 to 5 [21]. Presence of any symptoms or
signs suggestive of STIs should prompt
immediate diagnostic evaluation and
appropriate treatment [46]. Because
STIs are frequently asymptomatic, rou-
tine laboratory screening for STIs should
be undertaken in high-risk populations
where resources are available [47].
7. HIV COUNSELING AND TESTING
Since the first diagnostic HIV test in 1985,
HIV testing has become easier, more sen-
sitive, more accessible and less invasive.
Unfortunately, national data indicate that
a large percentage of new human immuno-
deficiency virus (HIV) diagnoses are made
in the late stages of disease. In the United
States, 40% of patients with newly diag-
nosed HIV infection develop AIDS within
one year of testing [25]. Furthermore,
it has been estimated that one-fourth
of the people living with HIV infection
in the United States do not know they
are infected and, thus, miss the opportu-
nity to receive life-saving antiretroviral
therapy [48]. That lack of awareness of
infection is critical from the public-health
perspective as it is estimated that over
50% of new sexually transmitted HIV
infections are due to people unaware of
their HIV infection; and evidence strongly
suggests that once individuals are made
aware of their infection, they reduce their
risk behavior and decrease the prob-
ability of transmitting infection [49]. In
addition, people with acute HIV infection
(which is defined as the first three weeks
of infection) or early infection (the first six
months) represent the greatest risk for
transmission [2]. Therefore, HIV testing
provides an opportunity for decreasing
the continued incidence of HIV infection
and for providing life-saving therapy to
newly diagnosed patients. To decrease the
835
Chapter | 14 | Sexually transmitted infectious diseases
number of people unaware of their HIV
infection, in 2006, the Center for Disease
Control and Prevention (CDC) expanded
its HIV-testing recommendations [50].
The new CDC recommendations advo-
cate voluntary “opt-out” HIV screening in
healthcare settings for all adults instead
of just screening traditionally “high-risk”
patients. The recommendations also sug-
gest eliminating requirements for written
consent for HIV testing, annual re-testing
for persons with known risk factors, and
third-trimester screening for women who
test negative for HIV early in pregnancy.
To date, the enzyme immunoassay
(EIA) format is still the primary HIV
antibody screening test in most settings.
Assays are available to assess HIV-1 and
HIV-2 separately or in combination [51].
The recent introduction of alternative
fluids as suitable samples has allowed
testing to go beyond the clinic setting.
Oral fluid (mucosal transudate) testing
is a valuable tool for outreach projects
[52]. These noninvasive sample collec-
tions such as oral fluid and urine tend to
decrease the chance of occupational expo-
sure among health care workers.
8. HIGHLY ACTIVE ANTI-RETROVIRAL
THERAPY (HAART)
Taking a combination of three or more
anti-HIV drugs is sometimes referred to
as highly active anti-retroviral therapy
(HAART). If only one drug was taken,
HIV could quickly become resistant to it
and the drug would stop working. Taking
two or more anti-retrovirals at the same
time vastly reduces the rate at which
resistance might develop, making treat-
ment more effective in the long-term
[53]. There are five groups and more
than 20 approved anti-retroviral drugs
(Table 2). Each of these groups attacks
HIV in a different way. Thus, combin-
ing different treatment approaches can
provide synergy [54–56] (please refer to
the numerous studies that demonstrate
836
the superiority of HAART to single
agents). These continued improvements
have prompted a change in HIV from an
almost uniformly fatal disease to one that
is a manageable chronic illness requiring
continued evaluation and therapy.
9. UROLOGICAL MANIFESTATIONS
OF HIV INFECTION
HIV infection in either early or late
stages affects each of the major organs in
the genitourinary system.
9.1 Urinary tract infections
The risk of bacterial and opportun-
istic infection, including UTIs, rises
dramatically when the CD4 counts
fall below 500/mm3 [57–58]. The most
common bacterial pathogens in HIV-
infected patients are Escherichia coli,
Enterobacter (Enterococci), Pseudomonas
aeruginosa, Proteus spp, Klebsiella,
Acinetobacter, Staphylococcus aureus,
group D Streptococcus, Serratia, and
Salmonella spp [58–62]. Atypical patho-
gens including fungi (Candida albicans,
Aspergillus, Blastomyces, Cryptococcus
neoformans, Cryptosporidia, Histoplasma
capsulatum), parasites (Toxoplasma
gondii, Pneumocystis carinii), myco-
bacteria (Mycobacterium tuberculosis,
Mycobacterium avium complex), and
viruses (cytomegalovirus and adenovirus)
are often widely disseminated in patients
with very low CD4 counts (usually <100/
mm3) [61–65]. They may potentially affect
any portion of the genitourinary tract,
including the adrenals kidneys, bladder,
prostate, testes and epididymedes. When
urinary cultures from 98 HIV-infected
men were collected prospectively at six-
monthly intervals over two years, and
when they had signs and symptoms of
UTI, one or more positive urinary cultures
were found in 30% whose CD4 count was
<200/mm3 and in 11% with a CD4 count
of 200–500/mm3. No bacteriuria or symp-
tomatic infective episodes were found
 HIV infection in urological practice | 14.5 |

Table 2 FDA-Approved Antiretroviral Drugs for Treating HIV/AIDS.

Anti-retroviral drug class Abbreviation Generic name Mechanism of Action

Nucleoside/Nucleotide Reverse 3TC lamivudine NRTIs interfere with the action of an HIV pro-
Transcriptase Inhibitors (NRTIs, tein called reverse transcriptase, which the
ABC abacavir
nucleoside analogues) virus needs to make new copies of itself.
AZT or ZDV zidovudine
d4T stavudine
ddC zalcitabine
ddI didanosine
FTC emtricitabine
TDF tenofovir

Non-Nucleoside Reverse DLV delavirdine NNRTIs also stop HIV from replicating within
Transcriptase Inhibitors cells by inhibiting the reverse transcriptase
EFV efavirenz
(NNRTIs, non-nucleosides) protein.
ETR etravirine
NVP nevirapine

Protease Inhibitors (PIs) APV amprenavir PIs inhibit protease, which is another protein
involved in the HIV replication process.
FOS-APV fosamprenavir
ATV atazanavir
DRV darunavir
IDV indinavir
LPV/RTV lopinavir +
ritonavir
NFV
nelfinavir
RTV
ritonavir
SQV
saquinavir
TPV
tipranavir

Fusion or Entry Inhibitors T-20 enfuvirtide Fusion or entry inhibitors prevent HIV from
binding to or entering human immune cells.
MVC maraviroc

Integrase Inhibitors RAL raltegravir Integrase inhibitors interfere with the integrase
enzyme, which HIV needs to insert its genetic
material into human cells.

Data from U.S. Food and Drug Administration. Drugs used in the treatment of HIV infection. http://www.fda.gov/oashi/aids/
virals.html. Accessed 31 December 2008.

in those with CD4 counts of >500/mm3
[57]. In autopsy studies of patients with
AIDS, renal tuberculosis was identified in
6–23%. Although most of these patients
had symptoms and signs of pulmonary
tuberculosis, 20% had subclinical disease.
The clinical diagnosis is made with urine
tuberculosis culture, excretory urogra-
phy, cystoscopy and biopsy with staining
for acid-fast bacilli. Treatment requires
at least three and sometimes four agents,
including rifampicin, isoniazid, pyrazi-
namide and ethambutol for six to nine
months, depending on sensitivity results
[58, 61]. The incidence of acute bacte-
rial prostatitis is 1% to 2% in the general
population, whereas it is 3% in asympto-
matic, HIV-infected patients and 14% in
patients who have AIDS [66]. The inci-
dence of prostatic abscesses in AIDS has

837
Chapter | 14 | Sexually transmitted infectious diseases
decreased significantly with the advent
of HAART, because they occur only in
patients with very low CD4 counts [59].
In autopsy studies of patients with AIDS
and systemic opportunistic infections, the
prevalence of concomitant testicular infec-
tion is 25–39%. The causative organisms
include Salmonella, Cytomegalovirus
(CMV), Mycobacterium avium intracellu-
lar (MAI), Toxoplasma, Histoplasma and
Candida albicans [62, 67].
9.2 Malignancies
Many malignancies occur in HIV-infected
patients. Possible mechanisms proposed
that support malignancy formation
include decreased immune surveillance,
a direct effect of viral proteins, cytokine
dysregulation, or other immunologic or
viral cofactors [68–69]. Vascular and
lymphoreticular malignancies have been
associated most strongly with HIV infec-
tion, particularly Kaposi’s sarcoma (KS)
and non-Hodgkin’s lymphoma (NHL).
The risk of KS and NHL are increased
1000- and 100-fold, respectively, among
HIV-infected patients compared with the
general population [70]. KS, systemic
intermediate/high-grade B-cell NHL, and
invasive cervical cancer are considered
to be AIDS-defining malignancies. Many
non-AIDS-defining malignancies have,
however, also been found in greater fre-
quency among those with HIV, includ-
ing germ cell testicular tumors, renal
cell carcinoma, and prostate cancer [71].
HAART radically changed the clinical
spectrum of HIV infection in industrial-
ized countries. The incidence of AIDS-
associated malignancies decreased
significantly after the introduction
of HAART [72]. Systemic NHL inci-
dence decreased less than KS and later
than the other AIDS-defining illnesses.
Consequently, lymphoma has become the
most common AIDS-associated malig-
nancy among patients receiving HAART
[73]. KS can present as a systemic
disease that affects internal organs,
838
including the kidneys and testes [74–75].
A new herpes virus, called KS herpes
virus or human herpes virus type 8,
transmitted by sexual contact or through
blood may be related to the develop-
ment of KS in the HIV-positive popu-
lation [59, 63]. Genital lesions appear
in approximately 20% of patients who
have KS, with <3% having the initial
lesion on the penis [76]. Renal involve-
ment of NHL in patients who have AIDS
is 6% to 12%, and presentation may be
bilateral [59, 61]. Renal cell carcinoma
carries an 8.5-fold greater risk for HIV-
infected patients compared with non-
infected patients [77]. Retrospective
review of 3,000 patients enrolled in an
HIV clinic found a 50 times greater rate
of testicular malignancy in the general
population [78]. Compared with HIV
noninfected patients, there is a greater
risk of tumor bilaterality and a greater
risk of high-grade testicular lymphoma
[79]. Recently, Vianna and colleagues
[80] examined a cohort of 534 men aged
49 years and older who had risk fac-
tors for HIV. Among older men, PSA
levels increased with age but did not
differ by HIV status. The study recom-
mended that standard prostate-specific
antigen evaluations can be made with
HIV-positive patients without the need
for adjustments. HIV infection is associ-
ated with human papillomavirus (HPV)-
related anogenital malignancies. HPV
types 16 and 18 are considered high risk
in anogenital malignancy formation of
carcinoma in situ and squamous cell car-
cinoma [81]. Bowen’s disease (Carcinoma
in situ) of the penis, considered a prema-
lignant lesion, appears more common in
the HIV-infected population [82].
9.3 HIV-associated nephropathy
(HIVAN)
HIV-associated nephropathy (HIVAN)
is the most well-known and aggressive
kidney disease in HIV-infected patients.
With the widespread use of HAART, its

prevalence is declining in industrialized
countries [83]. The prevalence of HIVAN
is reported to be 3.5% in HIV-infected
clinic patients and 6.9% in autopsy series
of HIV-infected patients [84]. Scientific
evidence suggests that HAART can pre-
vent the development of HIVAN [85–87].
Furthermore, HAART, corticosteroids and
inhibition of the renin-angiotensin axis
are potentially helpful in delaying disease
progression, as well as the need for renal
replacement therapy [88].
9.4 Voiding dysfunction
Of patients with AIDS, 30–40% have neu-
rological involvement, and in 20% this is
the initial manifestation. In HIV-infected
patients who present with voiding dis-
turbances, an underlying neurological
cause is present in 60%, and 90% of those
already have AIDS-associated infections or
tumors [61]. Urinary retention is the most
common voiding dysfunction (54%) seen
by urologists, although detrusor hyper-
reflexia (27%) and outflow obstruction
(18%) have been documented during uro-
dynamic study of AIDS patients with void-
ing symptoms [89–90]. Voiding complaints
often reflect the degree of systemic impair-
ment and poor prognosis, although such
symptoms often improve substantially
after effective antiretroviral therapy [61].
9.5 Other urological manifestations
Several complications related to HAART
such as urolithiasis and sexual dysfunc-
tion have been reported. The strongest
association is with protease inhibitors,
especially indinavir [91]. Current lit-
erature have reported that 10–28% of
patients receiving indinavir may develop
a new form of urinary stones, known as
‘‘indinavir urolithiasis’’ [91–93]. Pure
indinavir stones are radiolucent and can-
not be detected with either conventional
radiography or CT. However, mixed
stones consisting of indinavir and calcium
oxalate or phosphate salts have occa-
sionally been reported in HIV-positive
HIV infection in urological practice | 14.5 |
patients [94]. This adverse effect may be
managed by the discontinuation of indi-
navir administration, urine acidification,
hydration, alpha-blockers to facilitate
stone passage, as well as the possible
early insertion of bilateral double-J ure-
teral stents [95]. HAART, especially pro-
tease inhibitor-based therapy, also plays
a role in sexual dysfunction [96–97].
In a cohort study [98], the incidence of
erectile dysfunction (ED) and decreased
libido in HIV-positive homosexual men is
26%. In that study, in patients who were
taking HAART, the incidence of reduced
libido was 48% and the rate of ED was
25%. Decreased libido may be a result of
raised estradiol level, low testosterone
level, fatigue, depression and hypogo-
nadism. However, Lallemand et al. [99]
oppose the occurrence of sexual dysfunc-
tion in HIV-positive men taking protease
inhibitors in their cross-sectional study.
Phosphodiesterase type-5 (PDE-5) inhibitors
also may interact with protease inhibitors,
which increase the blood concentrations of
PDE-5 inhibitors. Starting PDE-5 inhibitors
at a lower dose with a caution for side-effect
may be more appropriate in patients taking
protease inhibitors [100].
10. FURTHER RESEARCH
Further community-based RCTs should
carefully test a range of alternative STI
control strategies in a variety of differ-
ent settings. Improved trials - especially
more detailed estimates that measure a
range of factors that include health seek-
ing behavior and quality of treatment, as
well as HIV, STI and other biological end-
points - will help us to identify the best
possible intervention strategies for slow-
ing the epidemic’s spread.
11. CONCLUSIONS
The current world-wide expansion of the
AIDS epidemic is primarily driven by
839
Chapter | 14 | Sexually transmitted infectious diseases
the sexual transmission of HIV. Evidence
from intervention studies indicates that
in the presence of other STIs, individuals
are more likely to acquire HIV if exposed
to the virus through sexual contact.
Therefore, early detection and treatment
of curable STIs can play a vital role in
comprehensive programs to prevent sex-
ual transmission of HIV. However, there is
limited evidence from randomized control-
led trials that control of STIs reduce HIV
incidence at a population level. HIV both
primarily and secondarily affects virtually
every part of the genitourinary system.
The availability of HAART has resulted
in prolonging time to development of
AIDS and improving AIDS survival rates.
Urologists who treat genitourinary mani-
festations of HIV infection face a signifi-
cant challenge in trying to restore and
maintain normal genitourinary function.
REFERENCES
1. Joint United Nations Programme on
HIV/AIDS (UNAIDS) and World Health
Organization (WHO). 2008 Report on
the global AIDS epidemic. [10 January
2009]; Available from: http://www.unaids.
org/en/KnowledgeCentre/HIVData/
GlobalReport/2008/2008_Global_report.
asp.
2. Galvin SR and Cohen MS, The role of
sexually transmitted diseases in HIV
transmission. Nat Rev Microbiol, 2004.
2(1): 33–42.
3. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
4. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
5. Royce RA, Sena A, Cates W, Jr., and
Cohen MS, Sexual transmission of HIV.
N Engl J Med, 1997. 336(15): 1072–8.
6. Chin J and Bennett A, Heterosexual HIV
transmission dynamics: implications for
840
prevention and control. Int J STD AIDS,
2007. 18(8): 509–13.
7. Dyer JR, Gilliam BL, Eron JJ, Jr., Grosso L,
Cohen MS, and Fiscus SA, Quantitation
of human immunodeficiency virus type
1 RNA in cell free seminal plasma: com-
parison of NASBA with Amplicor reverse
transcription-PCR amplification and cor-
relation with quantitative culture. J Virol
Methods, 1996. 60(2): 161–70.
8. Vernazza PL, Gilliam BL, Dyer J, Fiscus
SA, Eron JJ, Frank AC, and Cohen MS,
Quantification of HIV in semen: correla-
tion with antiviral treatment and immune
status. AIDS, 1997. 11(8): 987–93.
9. Uvin SC and Caliendo AM, Cervicovaginal
human immunodeficiency virus secretion
and plasma viral load in human immu-
nodeficiency virus-seropositive women.
Obstet Gynecol, 1997. 90(5): 739–43.
10. Coombs RW, Speck CE, Hughes JP, Lee
W, Sampoleo R, Ross SO, Dragavon J,
Peterson G, Hooton TM, Collier AC,
Corey L, Koutsky L, and Krieger JN,
Association between culturable human
immunodeficiency virus type 1 (HIV-1) in
semen and HIV-1 RNA levels in semen
and blood: evidence for compartmentali-
zation of HIV-1 between semen and blood.
J Infect Dis, 1998. 177(2): 320–30.
11. Dyer JR, Gilliam BL, Eron JJ, Jr.,
Cohen MS, Fiscus SA, and Vernazza PL,
Shedding of HIV-1 in semen during pri-
mary infection. AIDS, 1997. 11(4): 543–5.
12. Chakraborty H, Sen PK, Helms RW,
Vernazza PL, Fiscus SA, Eron JJ,
Patterson BK, Coombs RW, Krieger JN,
and Cohen MS, Viral burden in genital
secretions determines male-to-female sex-
ual transmission of HIV-1: a probabilistic
empiric model. AIDS, 2001. 15(5): 621–7.
13. Hart CE, Lennox JL, Pratt-Palmore
M, Wright TC, Schinazi RF, Evans-
Strickfaden T, Bush TJ, Schnell C, Conley
LJ, Clancy KA, and Ellerbrock TV,
Correlation of human immunodeficiency
virus type 1 RNA levels in blood and the
female genital tract. J Infect Dis, 1999.
179(4): 871–82.
14. Chakraborty H, Helms RW, Sen PK,
and Cohen MS, Estimating correlation
by using a general linear mixed model:
evaluation of the relationship between the

concentration of HIV-1 RNA in blood and
semen. Stat Med, 2003. 22(9): 1457–64.
15. Gupta P, Mellors J, Kingsley L, Riddler
S, Singh MK, Schreiber S, Cronin M, and
Rinaldo CR, High viral load in semen
of human immunodeficiency virus type
1-infected men at all stages of disease and
its reduction by therapy with protease
and nonnucleoside reverse transcriptase
inhibitors. J Virol, 1997. 71(8): 6271–5.
16. Padian NS, Shiboski SC, Glass SO, and
Vittinghoff E, Heterosexual transmission
of human immunodeficiency virus (HIV) in
northern California: results from a ten-year
study. Am J Epidemiol, 1997. 146(4): 350–7.
17. Nicolosi A, Correa Leite ML, Musicco M,
Arici C, Gavazzeni G, and Lazzarin A,
The efficiency of male-to-female and
female-to-male sexual transmission of the
human immunodeficiency virus: a study
of 730 stable couples. Italian Study Group
on HIV Heterosexual Transmission.
Epidemiology, 1994. 5(6): 570–5.
18. de Vincenzi I, A longitudinal study of
human immunodeficiency virus trans-
mission by heterosexual partners.
European Study Group on Heterosexual
Transmission of HIV. N Engl J Med, 1994.
331(6): 341–6.
19. Gray RH, Wawer MJ, Brookmeyer R,
Sewankambo NK, Serwadda D, Wabwire-
Mangen F, Lutalo T, Li X, vanCott T, and
Quinn TC, Probability of HIV-1 trans-
mission per coital act in monogamous,
heterosexual, HIV-1-discordant couples in
Rakai, Uganda. Lancet, 2001. 357(9263):
1149–53.
20. Mastro TD and Kitayaporn D, HIV type 1
transmission probabilities: estimates from
epidemiological studies. AIDS Res Hum
Retroviruses, 1998. 14 Suppl 3: S223–7.
21. Fleming DT and Wasserheit JN, From
epidemiological synergy to public health
policy and practice: the contribution of
other sexually transmitted diseases to
sexual transmission of HIV infection. Sex
Transm Infect, 1999. 75(1): 3–17.
22. Rottingen JA, Cameron DW, and Garnett
GP, A systematic review of the epidemio-
logic interactions between classic sexually
transmitted diseases and HIV: how much
really is known? Sex Transm Dis, 2001.
28(10): 579–97.
HIV infection in urological practice | 14.5 |
23. Coombs RW, Reichelderfer PS, and
Landay AL, Recent observations on HIV
type-1 infection in the genital tract of men
and women. AIDS, 2003. 17(4): 455–80.
24. Buonaguro L, Tornesello ML, and
Buonaguro FM, Human immunodefi-
ciency virus type 1 subtype distribution in
the worldwide epidemic: pathogenetic and
therapeutic implications. J Virol, 2007.
81(19): 10209–19.
25. Gao F, Robertson DL, Morrison SG, Hui
H, Craig S, Decker J, Fultz PN, Girard M,
Shaw GM, Hahn BH, and Sharp PM, The
heterosexual human immunodeficiency
virus type 1 epidemic in Thailand is
caused by an intersubtype (A/E) recom-
binant of African origin. J Virol, 1996.
70(10): 7013–29.
26. van Harmelen J, Wood R, Lambrick
M, Rybicki EP, Williamson AL, and
Williamson C, An association between
HIV-1 subtypes and mode of transmission
in Cape Town, South Africa. AIDS, 1997.
11(1): 81–7.
27. Avila MM, Pando MA, Carrion G, Peralta
LM, Salomon H, Carrillo MG, Sanchez
J, Maulen S, Hierholzer J, Marinello M,
Negrete M, Russell KL, and Carr JK, Two
HIV-1 epidemics in Argentina: different
genetic subtypes associated with differ-
ent risk groups. J Acquir Immune Defic
Syndr, 2002. 29(4): 422–6.
28. Buonaguro L, Tagliamonte M, Tornesello
M, and Buonaguro FM, Evolution of the
HIV-1 V3 region in the Italian epidemic.
New Microbiol, 2007. 30(1): 1–11.
29. Buonaguro L, Tagliamonte M, Tornesello
ML, and Buonaguro FM, Genetic and
phylogenetic evolution of HIV-1 in a low
subtype heterogeneity epidemic: the Italian
example. Retrovirology, 2007. 4: 34.
30. Tagliamonte M, Vidal N, Tornesello
ML, Peeters M, Buonaguro FM, and
Buonaguro L, Genetic and phylogenetic
characterization of structural genes from
non-B HIV-1 subtypes in Italy. AIDS Res
Hum Retroviruses, 2006. 22(10): 1045–51.
31. Grosskurth H, Mosha F, Todd J,
Mwijarubi E, Klokke A, Senkoro K,
Mayaud P, Changalucha J, Nicoll A,
ka-Gina G, and et al., Impact of improved
treatment of sexually transmitted dis-
eases on HIV infection in rural Tanzania:
841
Chapter | 14 | Sexually transmitted infectious diseases
randomised controlled trial. Lancet, 1995.
346(8974): 530–6.
32. Wawer MJ, Sewankambo NK, Serwadda
D, Quinn TC, Paxton LA, Kiwanuka
N, Wabwire-Mangen F, Li C, Lutalo T,
Nalugoda F, Gaydos CA, Moulton LH,
Meehan MO, Ahmed S, and Gray RH,
Control of sexually transmitted diseases
for AIDS prevention in Uganda: a ran-
domised community trial. Rakai Project
Study Group. Lancet, 1999. 353(9152):
525–35.
33. Gray RH, Wabwire-Mangen F, Kigozi G,
Sewankambo NK, Serwadda D, Moulton
LH, Quinn TC, O’Brien KL, Meehan M,
Abramowsky C, Robb M, and Wawer MJ,
Randomized trial of presumptive sexually
transmitted disease therapy during preg-
nancy in Rakai, Uganda. Am J Obstet
Gynecol, 2001. 185(5): 1209–17.
34. Kamali A, Quigley M, Nakiyingi J,
Kinsman J, Kengeya-Kayondo J, Gopal R,
Ojwiya A, Hughes P, Carpenter LM, and
Whitworth J, Syndromic management
of sexually-transmitted infections and
behaviour change interventions on trans-
mission of HIV-1 in rural Uganda: a com-
munity randomised trial. Lancet, 2003.
361(9358): 645–52.
35. Hay P, HIV transmission and sexually
transmitted infections. Clin Med, 2008.
8(3): 323–6.
36. Nagot N, Ouedraogo A, Foulongne V,
Konate I, Weiss HA, Vergne L, Defer
MC, Djagbare D, Sanon A, Andonaba
JB, Becquart P, Segondy M, Vallo R,
Sawadogo A, Van de Perre P, and Mayaud
P, Reduction of HIV-1 RNA levels with
therapy to suppress herpes simplex virus.
N Engl J Med, 2007. 356(8): 790–9.
37. Rebbapragada A, Wachihi C, Pettengell C,
Sunderji S, Huibner S, Jaoko W, Ball B,
Fowke K, Mazzulli T, Plummer FA, and
Kaul R, Negative mucosal synergy between
Herpes simplex type 2 and HIV in the female
genital tract. AIDS, 2007. 21(5): 589–98.
38. Kaul R, Pettengell C, Sheth PM, Sunderji
S, Biringer A, MacDonald K, Walmsley
S, and Rebbapragada A, The genital tract
immune milieu: an important determi-
nant of HIV susceptibility and secondary
transmission. J Reprod Immunol, 2008.
77(1): 32–40.
842
39. Sheth PM, Danesh A, Sheung A,
Rebbapragada A, Shahabi K, Kovacs
C, Halpenny R, Tilley D, Mazzulli T,
MacDonald K, Kelvin D, and Kaul R,
Disproportionately high semen shedding
of HIV is associated with compartmental-
ized cytomegalovirus reactivation. J Infect
Dis, 2006. 193(1): 45–8.
40. Casper C, Krantz EM, Corey L, Kuntz
SR, Wang J, Selke S, Hamilton S, Huang
ML, and Wald A, Valganciclovir for sup-
pression of human herpesvirus-8 rep-
lication: a randomized, double-blind,
placebo-controlled, crossover trial. J Infect
Dis, 2008. 198(1): 23–30.
41. Auvert B, Taljaard D, Lagarde E,
Sobngwi-Tambekou J, Sitta R, and Puren
A, Randomized, controlled intervention
trial of male circumcision for reduction of
HIV infection risk: the ANRS 1265 Trial.
PLoS Med, 2005. 2(11): e298.
42. Bailey RC, Moses S, Parker CB, Agot
K, Maclean I, Krieger JN, Williams CF,
Campbell RT, and Ndinya-Achola JO,
Male circumcision for HIV prevention
in young men in Kisumu, Kenya: a ran-
domised controlled trial. Lancet, 2007.
369(9562): 643–56.
43. Gray RH, Kigozi G, Serwadda D,
Makumbi F, Watya S, Nalugoda F,
Kiwanuka N, Moulton LH, Chaudhary
MA, Chen MZ, Sewankambo NK,
Wabwire-Mangen F, Bacon MC, Williams
CF, Opendi P, Reynolds SJ, Laeyendecker
O, Quinn TC, and Wawer MJ, Male cir-
cumcision for HIV prevention in men
in Rakai, Uganda: a randomised trial.
Lancet, 2007. 369(9562): 657–66.
44. Powers KA, Poole C, Pettifor AE, and
Cohen MS, Rethinking the heterosexual
infectivity of HIV-1: a systematic review
and meta-analysis. Lancet Infect Dis,
2008. 8(9): 553–63.
45. Katz IT and Wright AA, Circumcision –
a surgical strategy for HIV prevention
in Africa. N Engl J Med, 2008. 359(23):
2412–5.
46. Centers for Disease Control and
Prevention (CDC). Incorporating HIV
Prevention into the Medical Care of
Persons Living with HIV. CDC Morbidity
& Mortality Weekly Report (MMWR) July
18, 2003/ 52, RR 12; 1–24. Available

from: http://www.cdc.gov/mmwr/preview/
mmwrhtml/rr5212a1.htm.
47. Marrazzo J, Syphilis and other sexually
transmitted diseases in HIV infection. Top
HIV Med, 2007. 15(1): 11–6.
48. Centers for Disease Control and
Prevention (CDC), Twenty five years of
HIV/AIDS-United States 1981–2006.
MMWR Morb Mortal Wkly Rep 2006. 55:
585–589.
49. Marks G, Crepaz N, Senterfitt JW, and
Janssen RS, Meta-analysis of high-risk
sexual behavior in persons aware and
unaware they are infected with HIV in the
United States: implications for HIV pre-
vention programs. J Acquir Immune Defic
Syndr, 2005. 39(4): 446–53.
50. Centers for Disease Control and
Prevention (CDC), Revised recommenda-
tions for HIV testing of adults, adoles-
cents, and pregnant women in the health
care setting. MMWR Recom R, 2006.
51. Branson BM, State of the art for diagnosis
of HIV infection. Clin Infect Dis, 2007. 45
Suppl 4: S221–5.
52. Wesolowski LG, MacKellar DA, Facente
SN, Dowling T, Ethridge SF, Zhu JH, and
Sullivan PS, Post-marketing surveillance
of OraQuick whole blood and oral fluid
rapid HIV testing. AIDS, 2006. 20(12):
1661–6.
53. Yeni P, Update on HAART in HIV. J
Hepatol, 2006. 44(1 Suppl): S100–3.
54. Hammer SM, Katzenstein DA, Hughes
MD, Gundacker H, Schooley RT,
Haubrich RH, Henry WK, Lederman
MM, Phair JP, Niu M, Hirsch MS, and
Merigan TC, A trial comparing nucle-
oside monotherapy with combination
therapy in HIV-infected adults with CD4
cell counts from 200 to 500 per cubic mil-
limeter. AIDS Clinical Trials Group Study
175 Study Team. N Engl J Med, 1996.
335(15): 1081–90.
55. Deeks SG, Smith M, Holodniy M, and
Kahn JO, HIV-1 protease inhibitors.
A review for clinicians. JAMA, 1997.
277(2): 145–53.
56. Hammer SM, Eron JJ, Jr., Reiss P,
Schooley RT, Thompson MA, Walmsley
S, Cahn P, Fischl MA, Gatell JM,
Hirsch MS, Jacobsen DM, Montaner JS,
HIV infection in urological practice | 14.5 |
Richman DD, Yeni PG, and Volberding
PA, Antiretroviral treatment of adult HIV
infection: 2008 recommendations of the
International AIDS Society-USA panel.
JAMA, 2008. 300(5): 555–70.
57. Hoepelman AI, van Buren M, van den
Broek J, and Borleffs JC, Bacteriuria in
men infected with HIV-1 is related to their
immune status (CD4+ cell count). AIDS,
1992. 6(2): 179–84.
58. Lee LK, Dinneen MD, and Ahmad S, The
urologist and the patient infected with
human immunodeficiency virus or with
acquired immunodeficiency syndrome.
BJU Int, 2001. 88(6): 500–10.
59. Hyun G and Lowe FC, AIDS and the urol-
ogist. Urol Clin North Am, 2003. 30(1):
101–9.
60. Miles BJ, Melser M, Farah R, Markowitz
N, and Fisher E, The urological manifes-
tations of the acquired immunodeficiency
syndrome. J Urol, 1989. 142(3): 771–3.
61. Heyns CF and Fisher M, The urological
management of the patient with acquired
immunodeficiency syndrome. BJU Int,
2005. 95(5): 709–16.
62. Kwan DJ and Lowe FC, Acquired immu-
nodeficiency syndrome. A venereal disease.
Urol Clin North Am, 1992. 19(1): 13–24.
63. Steele BW and Carson CC, Recognizing
the urologic manifestations of HIV and
AIDS. Contemp Urol 1997. 9: 39–53.
64. Kaplan MS, Wechsler M, and Benson MC,
Urologic manifestations of AIDS. Urology,
1987. 30(5): 441–3.
65. O’Regan S, Russo P, Lapointe N, and
Rousseau E, AIDS and the urinary tract.
J Acquir Immune Defic Syndr, 1990. 3(3):
244–51.
66. Leport C, Rousseau F, Perronne C,
Salmon D, Joerg A, and Vilde JL,
Bacterial prostatitis in patients infected
with the human immunodeficiency virus.
J Urol, 1989. 141(2): 334–6.
67. De Paepe ME and Waxman M, Testicular
atrophy in AIDS: a study of 57 autopsy
cases. Hum Pathol, 1989. 20(3): 210–4.
68. Blattner WA, Human retroviruses: their
role in cancer. Proc Assoc Am Physicians,
1999. 111(6): 563–72.
69. Bellan C, De Falco G, Lazzi S, and
Leoncini L, Pathologic aspects of AIDS
843
Chapter | 14 | Sexually transmitted infectious diseases
malignancies. Oncogene, 2003. 22(42):
6639–45.
70. Dal Maso L, Serraino D, and Franceschi
S, Epidemiology of AIDS-related tumours
in developed and developing countries.
Eur J Cancer, 2001. 37(10): 1188–201.
71. Silverberg MJ and Abrams DI, AIDS-
defining and non-AIDS-defining
malignancies: cancer occurrence in the
antiretroviral therapy era. Curr Opin
Oncol, 2007. 19(5): 446–51.
72. Bower M, Palmieri C, and Dhillon T,
AIDS-related malignancies: changing epi-
demiology and the impact of highly active
antiretroviral therapy. Curr Opin Infect
Dis, 2006. 19(1): 14–9.
73. Grulich AE, Li Y, McDonald AM, Correll
PK, Law MG, and Kaldor JM, Decreasing
rates of Kaposi’s sarcoma and non-Hodg-
kin’s lymphoma in the era of potent com-
bination anti-retroviral therapy. AIDS,
2001. 15(5): 629–33.
74. Pollok RC, Francis N, Cliff S, Nelson N,
and Gazzard B, Kaposi’s sarcoma in the
kidney. Int J STD AIDS, 1995. 6(4): 289–90.
75. Weil DA, Ruckle HC, Lui PD, and Saukel
W, Kaposi’s sarcoma of the testicle. AIDS
Read, 1999. 9(7): 455–6, 461.
76. Lowe FC, Lattimer DG, and Metroka CE,
Kaposi’s sarcoma of the penis in patients
with acquired immunodeficiency syn-
drome. J Urol, 1989. 142(6): 1475–7.
77. Baynham SA, Katner HP, and Cleveland
KB, Increased prevalence of renal cell
carcinoma in patients with HIV infection.
AIDS Patient Care STDS, 1997. 11(3):
161–5.
78. Wilson WT, Frenkel E, Vuitch F, and
Sagalowsky AI, Testicular tumors in men
with human immunodeficiency virus. J
Urol, 1992. 147(4): 1038–40.
79. Armenakas NA, Schevchuk MM,
Brodherson M, and Fracchia JA, AIDS
presenting as primary testicular lym-
phoma. Urology, 1992. 40(2): 162–4.
80. Vianna LE, Lo Y, and Klein RS, Serum
prostate-specific antigen levels in older
men with or at risk of HIV infection. HIV
Med, 2006. 7(7): 471–6.
81. zur Hausen H and de Villiers EM,
Human papillomaviruses. Annu Rev
Microbiol, 1994. 48: 427–47.
844
82. Wang CY, Brodland DG, and Su WP, Skin
cancers associated with acquired immu-
nodeficiency syndrome. Mayo Clin Proc,
1995. 70(8): 766–72.
83. Schwartz EJ, Szczech LA, Ross MJ,
Klotman ME, Winston JA, and Klotman
PE, Highly active antiretroviral therapy
and the epidemic of HIV+ end-stage renal
disease. J Am Soc Nephrol, 2005. 16(8):
2412–20.
84. Shahinian V, Rajaraman S, Borucki
M, Grady J, Hollander WM, and Ahuja
TS, Prevalence of HIV-associated neph-
ropathy in autopsies of HIV-infected
patients. Am J Kidney Dis, 2000.
35(5): 884–8.
85. Winston JA, Bruggeman LA, Ross MD,
Jacobson J, Ross L, D’Agati VD, Klotman
PE, and Klotman ME, Nephropathy and
establishment of a renal reservoir of HIV
type 1 during primary infection. N Engl
J Med, 2001. 344(26): 1979–84.
86. Szczech LA, Edwards LJ, Sanders LL,
van der Horst C, Bartlett JA, Heald AE,
and Svetkey LP, Protease inhibitors are
associated with a slowed progression of
HIV-related renal diseases. Clin Nephrol,
2002. 57(5): 336–41.
87. Atta MG, Gallant JE, Rahman MH,
Nagajothi N, Racusen LC, Scheel PJ, and
Fine DM, Antiretroviral therapy in the
treatment of HIV-associated nephropathy.
Nephrol Dial Transplant, 2006. 21(10):
2809–13.
88. Atta MG, Lucas GM, and Fine DM, HIV-
associated nephropathy: epidemiology,
pathogenesis, diagnosis and management.
Expert Rev Anti Infect Ther, 2008. 6(3):
365–71.
89. Kane CJ, Bolton DM, Connolly JA, and
Tanagho EA, Voiding dysfunction in
human immunodeficiency virus infections.
J Urol, 1996. 155(2): 523–6.
90. Hermieu JF, Delmas V, and Boccon-Gibod
L, Micturition disturbances and human
immunodeficiency virus infection. J Urol,
1996. 156(1): 157–9.
91. Bruce RG, Munch LC, Hoven AD, Jerauld
RS, Greenburg R, Porter WH, and Rutter
PW, Urolithiasis associated with the pro-
tease inhibitor indinavir. Urology, 1997.
50(4): 513–8.

92. Gentle DL, Stoller ML, Jarrett TW,
Ward JF, Geib KS, and Wood AF,
Protease inhibitor-induced urolithiasis.
Urology, 1997. 50(4): 508–11.
93. Salahuddin S, Hsu YS, Buchholz NP,
Dieleman JP, Gyssens IC, and Kok DJ,
Is indinavir crystalluria an indicator for
indinavir stone formation? AIDS, 2001.
15(8): 1079–80.
94. Daudon M, Estepa L, Viard JP, Joly D,
and Jungers P, Urinary stones in HIV-1-
positive patients treated with indinavir.
Lancet, 1997. 349(9061): 1294–5.
95. Kalaitzis C, Passadakis P,
Giannakopoulos S, Panagoutsos S,
Mpantis E, Triantafyllidis A, Touloupidis
S, and Vargemezis V, Urological man-
agement of indinavir-associated acute
renal failure in HIV-positive patients. Int
Urol Nephrol, 2007. 39(3): 743–6.
96. Schrooten W, Colebunders R, Youle
M, Molenberghs G, Dedes N, Koitz G,
Finazzi R, de Mey I, Florence E, and
Dreezen C, Sexual dysfunction associ-
ated with protease inhibitor containing
highly active antiretroviral treatment.
AIDS, 2001. 15(8): 1019–23.
97. Sollima S, Osio M, Muscia F, Gambaro
P, Alciati A, Zucconi M, Maga T, Adorni
F, Bini T, and d’Arminio Monforte A,
Protease inhibitors and erectile dysfunc-
tion. AIDS, 2001. 15(17): 2331–3.
98. Lamba H, Goldmeier D, Mackie NE,
and Scullard G, Antiretroviral therapy is
associated with sexual dysfunction and
with increased serum oestradiol levels
in men. Int J STD AIDS, 2004. 15(4):
234–7.
99. Lallemand F, Salhi Y, Linard F, Giami
A, and Rozenbaum W, Sexual dysfunc-
tion in 156 ambulatory HIV-infected men
receiving highly active antiretroviral
therapy combinations with and without
protease inhibitors. J Acquir Immune
Defic Syndr, 2002. 30(2): 187–90.
100. Merry C, Barry MG, Ryan M, Tjia JF,
Hennessy M, Eagling VA, Mulcahy F,
and Back DJ, Interaction of sildenafil
and indinavir when co-administered
to HIV-positive patients. AIDS, 1999.
13(15): F101–7.
101. Sangani P, Rutherford G, and Wilkinson
D, Population-based interventions
HIV infection in urological practice | 14.5 |
for reducing sexually transmitted
infections, including HIV infection.
Cochrane Database Syst Rev, 2004(2):
CD001220.
102. Atashili J, Poole C, Ndumbe PM,
Adimora AA, and Smith JS, Bacterial
vaginosis and HIV acquisition: a meta-
analysis of published studies. AIDS,
2008. 22(12): 1493–501.
103. Cameron DW, Simonsen JN, D’Costa
LJ, Ronald AR, Maitha GM, Gakinya
MN, Cheang M, Ndinya-Achola JO, Piot
P, Brunham RC, and et al., Female to
male transmission of human immuno-
deficiency virus type 1: risk factors for
seroconversion in men. Lancet, 1989.
2(8660): 403–7.
104. Plummer FA, Simonsen JN, Cameron
DW, Ndinya-Achola JO, Kreiss JK,
Gakinya MN, Waiyaki P, Cheang
M, Piot P, Ronald AR, and et al.,
Cofactors in male-female sexual
transmission of human immunodefi-
ciency virus type 1. J Infect Dis, 1991.
163(2): 233–9.
105. Laga M, Manoka A, Kivuvu M, Malele
B, Tuliza M, Nzila N, Goeman J, Behets
F, Batter V, Alary M, and et al., Non-
ulcerative sexually transmitted diseases
as risk factors for HIV-1 transmission
in women: results from a cohort study.
AIDS, 1993. 7(1): 95–102.
106. Taha TE, Hoover DR, Dallabetta
GA, Kumwenda NI, Mtimavalye LA,
Yang LP, Liomba GN, Broadhead
RL, Chiphangwi JD, and Miotti PG,
Bacterial vaginosis and disturbances of
vaginal flora: association with increased
acquisition of HIV. AIDS, 1998. 12(13):
1699–706.
107. Martin HL, Richardson BA,
Nyange PM, Lavreys L, Hillier SL,
Chohan B, Mandaliya K, Ndinya-Achola
JO, Bwayo J, and Kreiss J, Vaginal
lactobacilli, microbial flora, and risk
of human immunodeficiency virus type
1 and sexually transmitted disease
acquisition. J Infect Dis, 1999.
180(6): 1863–8.
108. Myer L, Denny L, Telerant R, Souza M,
Wright TC, Jr., and Kuhn L, Bacterial
vaginosis and susceptibility to HIV infec-
tion in South African women: a nested
845
Chapter | 14 | Sexually transmitted infectious diseases
case-control study. J Infect Dis, 2005.
192(8): 1372–80.
109. Cohen MS, Hoffman IF, Royce RA,
Kazembe P, Dyer JR, Daly CC, Zimba
D, Vernazza PL, Maida M, Fiscus SA,
and Eron JJ, Jr., Reduction of concentra-
tion of HIV-1 in semen after treatment of
urethritis: implications for prevention of
sexual transmission of HIV-1. AIDSCAP
Malawi Research Group. Lancet, 1997.
349(9069): 1868–73.
110. Ghys PD, Fransen K, Diallo MO,
Ettiegne-Traore V, Coulibaly IM, Yeboue
846
KM, Kalish ML, Maurice C, Whitaker
JP, Greenberg AE, and Laga M, The
associations between cervicovaginal HIV
shedding, sexually transmitted diseases
and immunosuppression in female sex
workers in Abidjan, Cote d’Ivoire. AIDS,
1997. 11(12): F85–93.
111. Stamm WE, Handsfield HH, Rompalo
AM, Ashley RL, Roberts PL, and Corey
L, The association between genital ulcer
disease and acquisition of HIV infec-
tion in homosexual men. JAMA, 1988.
260(10): 1429–33.
|14.6|
Male circumcision and HIV
infection risk
John N. Krieger
John N. Krieger, M.D., Department of Urology, University of Washington, School of Medicine,
Seattle, WA USA 98195
Tel: 206-543-3640, FAX: 206-764-2239, E mail: jkrieger@u.washington.edu
ABSTRACT
This review evaluates the scientific evi-
dence suggesting that male circumcision
reduces the risk of human immunodefi-
ciency virus type 1 (HIV) infection risk.
Level 1 evidence that male circumcision
substantially reduces the risk of HIV
infection is summarized below. Three
lines of evidence support this conclusion:
biological evidence, data from observa-
tional studies supported by high-quality
meta-analysis, and the results of three
randomized clinical trials supported
by high quality meta-analysis. The evi-
dence from biological studies, observa-
tional studies, randomized controlled
clinical trials, meta-analyses, and cost-
effectiveness studies is conclusive. The
challenges to implementation must now
be faced.
Key words: Male circumcision, HIV
infection, risk, complications.
SUMMARY OF RECOMMENDATIONS
There is a need to provide safe male cir-
cumcision services for high-risk popu-
lations because this is one of very few
proven HIV prevention strategies (GoR A).
1. INTRODUCTION
This review evaluates the scientific evi-
dence suggesting that male circumcision
reduces the risk of human immunodefi-
ciency virus type 1 (HIV) infection risk.
First, we present an executive summary
of the best available scientific data sup-
porting our findings, then we discuss
the methods and detail the supporting
evidence.
One major question was defined, “How
strong is the scientific evidence that male
circumcision reduces the risk of HIV
infection?” If the evidence supporting
Chapter | 14 | Sexually transmitted infectious diseases

male circumcision as an HIV preven- systematic reviews and meta-analysis

tion strategy is robust, then a number
of secondary issues merit consideration,
such as, cost-effectiveness, potential for
adverse events or behavioral changes and
other important issues.
2. METHODS
We searched for papers published, or
accepted for publication in the peer
reviewed issues of journals, papers
accepted for publication by the peer
reviewed journals but not yet published,
but excluded papers published in non
peer reviewed supplements. The search
included the last 10 years of data in the
major databases (e.g., Medline, Embase,
Cochrane Library, Biosis, and Science
Citation Index). We reviewed the table of
contents of the major urology journals and
other relevant journals, for the last three
months, to take into account the possible
delay in the indexation of the published
papers in the databases. In addition, we
reviewed critical articles that were more
than 10 years old to provide relevant
background and context for this analysis.
For inclusion in the final analysis, we
required papers published within the last
10 years that either contained original
data or original data analyses, such as
systematic reviews or meta-analyses. We
also included relevant articles on possi-
ble biological mechanisms and published
articles that reviewed selected data and
opinion to represent the full range of
expert opinion. The search strategy used
the term male circumcision combined
with the terms: HIV infection, complica-
tions, acceptability and sexually transmit-
ted infection, plus the combination of the
search terms foreskin and HIV receptor to
identify 1,048 unique articles.
Because papers in peer-reviewed
journals differ in quality and level of
evidence, included papers were rated
according to levels of evidence (see
below). The hierarchy of study types was:
or modeling, randomized controlled tri-
als, non-randomized cohort studies, case-
control studies, case series, and expert
opinion (as the lowest level). In addition,
we included other relevant biological
studies that and cost-effectiveness stud-
ies. We reviewed the titles and abstracts
of the articles identified in the initial
search to identify 278 articles meriting
detailed review.
This detailed review considered how
well individual studies were designed
and carried out using a standard check
list to assure that a consistent approach
was used in the methodological assess-
ment of the evidence. The objective of
the checklist was to provide a system-
atic quality rating for individual stud-
ies. The checklist included items rating
how well the study was conducted and
reported using the CONSORT state-
ment and its widely accepted checklist
(http://www.consort-statement.org). This
process identified a total of 80 papers,
representing every study type category
(Table 1).
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [1–2].
After selecting the 79 papers and rat-
ing of the level of evidence of each study,
a table was constructed to summarize the
evidence of the individual studies and the
overall direction of evidence in an evi-
dence table (Table 1).
3. BEST EVIDENCE THAT MALE
CIRCUMCISION REDUCES THE
RISK OF HIV INFECTION
The highest quality evidence that male
circumcision substantially reduces the
risk of HIV infection is summarized
below. Three lines of evidence support
this conclusion: biological evidence, data
from observational studies supported
by high-quality meta-analysis, and the

848
 Male circumcision and HIV infection risk
results of three randomized clinical trials
supported by high quality meta-analysis.
3.1 Biological evidence
Plausible biological mechanisms could
explain the increased risk of HIV and
other sexually transmitted infections (STI)
among uncircumcised men. These mecha-
nisms include: an increased rate of inflam-
matory conditions, susceptibility of the
mucosal surface of the prepuce to trauma,
and the longer survival of pathogens in
the warm, moist subpreputial space. The
inner foreskin is especially susceptible to
HIV infection due to lack of keratinization
and the high density of HIV target cells
that are relatively accessible to infection
compared with their deeper location [3]
under the keratinized surface of the outer
foreskin and the glans [4–6].
3.2 Observational study evidence
The hypothesis that male circumcision
might protect against HIV infection was
first suggested in 1986 [7]. Subsequent
support was provided by ecological stud-
ies in areas with low prevalence of male
circumcision and high HIV prevalence
in sub-Saharan Africa in the late 1980s
[8], and later across 118 developing coun-
tries.[9] Further evidence comes from
two well-done systematic reviews of the
observational study data comparing HIV
infection rates in circumcised and uncir-
cumcised men from the same populations
[3, 10]. One review was restricted to 27
studies from sub-Saharan Africa, [3] and
the other was a global review including
37 studies [10]. Circumcised men had
substantially lower risk of HIV infection.
A well-done meta-analysis of the 15 stud-
ies that adjusted for potential confound-
ers showed this reduction to be large and
highly significant (adjusted risk ratio
(RR) 0.42, 95% confidence interval (CI)
0.34–0.54) [3]. Subsequent studies have
found similar large risk reductions among
circumcised men [11].
| 14.6 |
3.3 Randomized controlled clinical
trial evidence
While statistically significant and pro-
vocative, observational studies can-
not prove causality. Three randomized
clinical trials of adult male circumci-
sion among consenting, healthy men
in South Africa [12], Kenya [13], and
Uganda [14], were started in 2002–2003.
All three trials were stopped early fol-
lowing recommendations by independ-
ent Data and Safety Monitoring Boards
after interim analyses found highly sig-
nificant decreases in HIV infection risk
among participants randomly assigned
to circumcision.
The three trials enrolled a total of
10,908 uncircumcised, HIV-negative adult
men. Participants were randomly assigned
to circumcision or control arms and
then followed for up to 2 years (Table 2).
Retention rates were high (86–92%).
Table 2 shows the cumulative HIV infec-
tion risk among men estimated using
intention-to-treat Kaplan-Meier analy-
sis. Subsequent meta-analysis using a
random-effects model of the trial results,
following the QUORUM statement rec-
ommendations found no evidence of het-
erogeneity among the trials.[11] The
overall rate ratio (RR) was 0.42 (95%
confidence interval (CI) 0.31–0.57), cor-
responding to a protective effect of 58%
(95% CI 43–69%), identical to that found
in the observational studies (58%, 95% CI
46–66%).
The true protection provided by male
circumcision may be better estimated
by an “as-treated” analysis, assigning
outcomes according to the actual cir-
cumcision status of participants. All
participants did not adhere to the arm
they were randomly assigned to. Meta-
analysis of the “as-treated” results of the
three trials shows even stronger protec-
tion against HIV infection in the circum-
cision group (summary RR 0.35, 95% CI
0.24–0.54) [11].
849
Chapter | 14 | Sexually transmitted infectious diseases

Table 1 Evidence Table for Studies of Male Circumcision and HIV Infection Risk that Include Original Data, Systematic Reviews
or Meta-analysis, Expert Opinion, or Other Human Data (1999–2008).

Level of Evidence
Positive (favoring
Lead author, year, circumcision) or
Study Type reference Design Negative

Systematic reviews, Meta-analyses and Modeling

Van Howe, 1999 [19] Meta-analysis of 29 published articles 4, Negative

with serious technical flaws.

O’Farrell, 2000 [20] Meta-analysis of 33 diverse obser- 2, Positive

vational studies, stratifying by study
type.

Weiss, 2000 [3] Systemic review and meta-analysis of 2, Positive

27 studies

Siegfried, 2003, 2005 Systematic reviews [10] 3, Positive

[10, 21]

Desai, 2006 [22] Stochastic prevention trial simulator 2, Positive

and RCT* data.

Williams, 2006 [23] Dynamical simulation models using 2, Positive

country level data.

Drain, 2006 [9] Country-specific data from 118 2, Positive

developing countries evaluated with
multivariate linear regression.

Orroth, 2007 [24] Individual-based stochastic model 3, Positive

fitted to characteristics four urban
African populations.

Hallet, 2008 [25] Mathematical model parameterised 3, Positive

RCT findings.

Londish, 2008 [26] Mathematical model simulated obser- 3, Positive

ved levels of HIV prevalence in sub-
Saharan Africa

Weiss, 2008 [11] Systematic review and meta-analysis 1, Positive

of the three RCTs.

Randomized-controlled trials

Auvert, 2005 [12] 3,274 uncircumcised men randomi- 1, Positive

zed 1:1

Bailey, 2007 [13] 2,784 uncircumcised HIV-negative 1, Positive

men randomized 1:1

Gray, 2007 [14] 4,996 uncircumcised, HIV-negative 1, Positive

men randomized 1:1

Non-randomized cohort studies

Kelly, 1999 [27] Survey of 6,821 men aged 15–59 3, Positive

years in rural Uganda

Quinn, 2000 [28] 415 Ugandan couples in which one 2, Positive

partner was HIV-positive and one was
initially HIV-negative followed pro-
spectively for up to 30 months

850
 Male circumcision and HIV infection risk | 14.6 |

Level of Evidence
Positive (favoring
Lead author, year, circumcision) or
Study Type reference Design Negative

Reynolds, 2004 [29] Prospective study of 2,298 HIV- 2, Positive

negative men attending sexually
transmitted infection clinics in India.

Meier, 2006 [30] 150 Kenyan sex partners of women 3, Positive

with genital symptoms,

Shaffer, 2007 [31] Prospective cohort of 1,378 men in 2, Positive

rural Kenya followed for 2 years.

Millet, 2007 [32] Respondent-driven sampling of 1154 3, Negative

black and 1091 Latino men who have
sex with men in the US.

Case-control studies

Auvert, 2001 [33–34] Random population samples from 3, Positive

2 circumcising African populations
compared to 2 non-circumcising pop-
ulations (approximately 4,000 men)

MacDonald, 2001 [35] 38 HIV-positive and 94 HIV-negative 3, Positive

Kenyan men with genital ulcers.

Gray, 2004 [36] Rural Uganda 3, Positive

Agot, 2004 [37] 398 circumcised and 447 uncircum- 3, Positive

cised Kenyan men

Jewkes, 2006 [38] 1277 sexually experienced men from 3, Positive

70 villages in South Africa

Kapiga, 2006 [39] Community-based study of 1,418 3, Positive

women and 566 of their regular male
partners in Tanzania

Johnson, 2006 [40] Cross-sectional, population-based 3, Positive

survey including 2,941 Kenyan men.

Talukdar, 2007 [41] Probability sample of homeless men 3, Positive

aged in Kolkata, India

Mishra, 2007 [42] Data are from eight national surveys 3, Positive
in sub-Saharan Africa.

Klavs, 2008 [43] National probability sample of the 3, Negative

general population in Slovenia.

Foglia, 2008 [44] Population-based study of Kenyan 3, Positive

men

Mermin, 2008 [45] Cross-sectional nationally representa- 3, Positive

tive survey 10,227 women and 8,298
men in Uganda.

Case-series

Halpern, 2005 [46] Zimbabwe 3, Positive

Buchbinder, 2005 [47] 3257 men who have sex with men in 3, Positive
6 US cities

continued

851
Chapter | 14 | Sexually transmitted infectious diseases

Table 1 Evidence Table for Studies of Male Circumcision and HIV Infection Risk that Include Original Data, Systematic Reviews
or Meta-analysis, Expert Opinion, or Other Human Data (1999–2008) – (Cont’d)

Level of Evidence
Positive (favoring
Lead author, year, circumcision) or
Study Type reference Design Negative

Expert opinion

Moses, 1999 [8] Review 3, Positive

Halpern, 1999 [48] 4, Positive

Green, 2000 [49] 4, Positive

Szabo, 2000 [50] 4, Positive

Quigley, 2001 [51] Review 4, Positive

Lerman, 2001 [52] Review 4, Positive

Shapiro, 2002 [53] Social perspective 4, Positive

Gisselquist, 2004 [54] 4, Negative

Sahasrabuddhe, 2004 [55] Review 3, Positive

Short, 2004, 4, Positive

2006 [56–57]

Nyindo, 2005 [58] Review 3, Positive

Inungu, 2005 [59] 4, Neutral

Jones, 2005 [60] 4, Positive

Flynn, 2005 [61] Review 3, Positive

Van Howe, 2005 [62] 4, Negative

Auerbach, 2006 [63] Review 3, Positive

Chan, 2006 [64] 4, Positive

Mboto, 2006 [65] 4, Positive

Islugo-Abanlhe, 2006 4, Positive

[66]

Weiss, 2007 [67] Review 3, Positive

Sawires, 2007 [68] Review 3, Positive

Schenker, 2007 [69] Data on complications of infant 3, Positive

and adult complications in Israel

Sharp, 2007 [70] Conference review 4, Positive

Quinn, 2007 [71] Review 3, Positive

Schoen, 2007 [72] 4, Positive

Clark, 2000, 2007 4, Positive

[73–74]

Morris, 2007 [75] Review 4, Positive

Mor, 2007 [76] 3, Positive

852
 Male circumcision and HIV infection risk | 14.6 |

Level of Evidence
Positive (favoring
Lead author, year, circumcision) or
Study Type reference Design Negative

Jayasuriya, 2007 [77] Review 3, Positive

Landovitz, 2007 [78] Review 3, Positive

Vardi, 2007, 2008 [79] 4, Neutral

Cohen, 2008 [80] Review 3, Positive

Gray, 2008 [81] Review of RCT data 3, Positive

Potts, 2008 [82] 3, Positive

Cost-Effectiveness Studies

Kahn, 2006 [17] Cost-effectiveness models for a gen- 2, Positive

eral adult male population in South
Africa.

Gray, 2007 [18] Stochastic simulation model with 2, Positive

empirically derived parameters.

Fieno, 2008 [83] Cost-effectiveness models for 2, Positive

Mozambique.

Pertinent Biological Studies

Patterson, 2002 [4] Immunological and in vivo infection 4, Positive

of human foreskins.

Soilleux, 2004 [5] HIV-receptor studies of human 4, Positive

foreskins.

McCombe, 2006 [6] HIV-receptor studies of human 4, Positive

foreskins.

The hierarchy of study types was: systematic reviews and meta-analysis of randomized controlled trials, randomized controlled trials,
non-randomized cohort studies, case-control studies, case series, and expert opinion (as the lowest level).

3.4 Complications of male negative men [12]. In the Ugandan trial,

circumcision
Complications of adolescent or adult cir-
cumcision include bleeding, wound infec-
tions, delayed wound healing and other
less common events. Comparing the
adverse event rates in the three trials
is complicated. The studies had differ-
ent visit schedules, adverse event defini-
tions and criteria. In the Kenyan trial,
adverse events possibly, probably or defi-
nitely related to circumcision occurred
in 23 of 1,334 circumcised participants
(1.7%) [15–16]. All adverse events were
mild or moderate and resolved quickly. In
the South African trial, the adverse event
rate was 54 per 1,495 (3.6%) in HIV-
the surgery-related adverse event was
7.6% (178/2328) [14]. This may reflect dif-
ferences in management. The risk of mod-
erate adverse events related to surgery
was 3% in the Uganda trial, including
five severe adverse events (0.2%). All of
these events were managed successfully.
3.5 Cost-effectiveness
Detailed analyses of the African trials
indicate that male circumcision is likely
to be very cost-effective, likely even cost-
saving [17]. The South African estimate
modeled using data from their trial found
the cost per HIV infection averted was
US$181 (80% CI US$117–306), with net

853
Chapter | 14 | Sexually transmitted infectious diseases

Table 2 Summary of the Three Randomized Controlled Trials of Male Circumcision on HIV Infection in sub-Saharan Africa.

South Africa [12] Kenya [13] Uganda [14]

Participants 1,582 1,393 2,522

Control 1,546 1.391 2,474
Circumcision

Age range (years) 18–24 18–24 15–49

Setting Peri-urban Urban Rural

Circumcision method Forceps-guided by local Forceps-guided by study Sleeve method by study

general practitioners, clinicians, clinicians
Monopolar cautery
No cautery Bipolar cautery

Visit schedule (months) 3, 12 and 21 1, 3, 6, 12. 18 and 24 6, 12 and 24

Retention rate 92% at 21 months 86% at 24 months 90% at 24 months

Person-years of follow-up 4,693 4,428 6,744

HIV infections 20:49 19:46 22:45

(circumcision:control)

Risk ratio (95% CI) 0.41 (0.24–0.69) 0.41 (0.24–0.70) 0.43 (0.24–0.75)

Summary risk ratio for all three 0.42 (0.31–0.57)

trials (95% CI)

CI = confidence interval.
Modified from Weiss, et al.[11]

savings of US$2.4 million over 20 years expanding male circumcision services,

(cost savings of US$2,631 per circumci-
sion). Using data from the Kenyan trial,
the estimated cost was $200 per HIV
infection averted [11]. Costs were higher
in Uganda, where 39 circumcisions would
be needed to prevent one HIV infec-
tion over 10 years at a cost of US$2,631
per HIV infection averted over 10 years
[18]. Because benefits of circumcision are
life-long, and economies of scale should
decrease costs, male circumcision is very
likely to prove extremely cost-effective in
high-risk African settings.
4. OUTSTANDING ISSUES
Many issues remain, including the cul-
tural acceptability of male circumcision
in non-circumcising African communi-
ties, socio-cultural and economic issues of
and the relevance of the findings for other
populations. Below we will briefly con-
sider two important issues that require
resolution, the potential differences
between clinical trial and field condi-
tions, and the potential for ‘behavioral
disinhibition.’
5. DIFFERENCES BETWEEN CLINICAL
TRIAL AND FIELD CONDITIONS
These trial data indicate that adult
male circumcision can be safe in limited-
resource settings when performed by
experienced, well-trained providers.
However, when male circumcision is
undertaken in septic conditions by inex-
perienced providers or with poor after-
care, serious complications or even death
can result. Thus, implementation safe

854
 Male circumcision and HIV infection risk
adult male circumcision in many African
settings will require considerable effort
and national policies.
6. POTENTIAL FOR ‘BEHAVIORAL
DISINHIBITION’
The potential for an increase in unsafe sex
practices (known as, ‘risk compensation’ or
‘behavioral disinhibition’) after circumci-
sion could potentially offset the protective
effect of male circumcision. The Ugandan
trial found no difference in sexual behavior
during the trial by circumcision status [14].
The South African trial showed a signifi-
cantly increased mean number of sex acts
between four and 21 months among men
in the circumcision arm, but no increase in
the number of sexual partners or a change
in condom use [12]. The Kenyan trial
reported a decrease in reported risk-taking
behaviors during the 24 months of follow-up
in both study arms [13].
The trial findings are reassuring but
these data may not be generalizable. The
trials provided the highest standards of
preventative care, with intensive individ-
ual counseling. Further, participants did
not know that circumcision reduced their
risk of HIV infection. The challenges of
expanding services within already over-
stretched health systems include the need
to provide adequate counseling to convey
the message that male circumcision is a
risk-reduction strategy that provides par-
tial protection only.
7. FURTHER RESEARCH
The major issues at present involve imple-
mentation of safe male circumcision as
a public health intervention in high-risk
settings. Considerable efforts are actively
underway to assure access to this proven
intervention to reduce HIV infection risk
and for other proven health benefits.
Other issues concern the need to improve
our understanding of the potential risks
| 14.6 |
and benefits of male circumcision in
settings in addition to the high-risk het-
erosexual populations that have been
extensively investigated to date.
8. CONCLUSIONS
The positive findings in the male cir-
cumcision trials are in stark contrast to
recent negative of other HIV prevention
interventions, including: microbicides, the
female diaphragm and gel, treatment to
suppress genital herpes infections, and,
most recently, an andenovirus-based HIV
vaccine. There is a need to provide safe
male circumcision services for high-risk
populations because this is one of very
few proven HIV prevention strategies.
In addition to other health benefits, male
circumcision provides a much-needed
addition to the limited HIV prevention
armamentarium. Male circumcision is
possibly the oldest, and certainly the
most common surgical procedure. The
evidence from, biological studies, obser-
vational studies, randomized controlled
clinical trials, meta-analyses, and cost-
effectiveness studies is conclusive. The
challenges to implementation must now
be faced.
REFERENCES
1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17: 681–4.
2. US Department of Health and Human
Services, Public Health Service, Agency
for Health Care Policy and Research,
1992: 115–27.
3. Weiss HA, Quigley MA, and Hayes RJ,
Male circumcision and risk of HIV infec-
tion in sub-Saharan Africa: a systematic
review and meta-analysis. Aids, 2000.
14(15): 2361–70.
4. Patterson BK, Landay A, Siegel JN,
Flener Z, Pessis D, Chaviano A, and
855
Chapter | 14 | Sexually transmitted infectious diseases
Bailey RC, Susceptibility to human
immunodeficiency virus-1 infection of
human foreskin and cervical tissue grown
in explant culture. Am J Pathol, 2002.
161(3): 867–73.
5. Soilleux EJ and Coleman N, Expression of
DC-SIGN in human foreskin may facili-
tate sexual transmission of HIV. J Clin
Pathol, 2004. 57(1): 77–8.
6. McCoombe SG and Short RV, Potential
HIV-1 target cells in the human penis.
Aids, 2006. 20(11): 1491–5.
7. Fink AJ, A possible explanation for hetero-
sexual male infection with AIDS. N Engl J
Med, 1986. 315: 1167.
8. Moses S, Nagelkerke NJ, and Blanchard
J, Analysis of the scientific literature on
male circumcision and risk for HIV infec-
tion. Int J STD AIDS, 1999. 10(9): 626–8.
9. Drain PK, Halperin DT, Hughes JP,
Klausner JD, and Bailey RC, Male
circumcision, religion, and infectious
diseases: an ecologic analysis of 118
developing countries. BMC Infect Dis,
2006. 6: 172.
10. Siegfried N, Does male circumcision
prevent HIV infection? PLoS Med, 2005.
2(11): e393.
11. Weiss HA, Halpernr D, Bailey RC, Hayes
RJ, Schmid G, and Hankins C, Male
circumcision for HIV prevention: from
evidence to action? AIDS, 2008. 22(5):
567–574.
12. Auvert B, Taljaard D, Lagarde E,
Sobngwi-Tambekou J, Sitta R, and Puren
A, Randomized, controlled intervention
trial of male circumcision for reduction of
HIV infection risk: the ANRS 1265 Trial.
PLoS Med, 2005. 2(11): e298.
13. Bailey RC, Moses S, Parker CB, Agot
K, Maclean I, Krieger JN, Williams CF,
Campbell RT, and Ndinya-Achola JO,
Male circumcision for HIV prevention
in young men in Kisumu, Kenya: a ran-
domised controlled trial. Lancet, 2007.
369(9562): 643–56.
14. Gray RH, Kigozi G, Serwadda D,
Makumbi F, Watya S, Nalugoda F,
Kiwanuka N, Moulton LH, Chaudhary
MA, Chen MZ, Sewankambo NK,
Wabwire-Mangen F, Bacon MC,
Williams CF, Opendi P, Reynolds SJ,
856
Laeyendecker O, Quinn TC, and Wawer
MJ, Male circumcision for HIV preven-
tion in men in Rakai, Uganda: a ran-
domised trial. Lancet, 2007.
369(9562): 657–66.
15. Krieger JN, Bailey RC, Opeya J, Ayieko
B, Opiyo F, Agot K, Parker C, Ndinya-
Achola JO, Magoha GA, and Moses
S, Adult male circumcision: results of
a standardized procedure in Kisumu
District, Kenya. BJU Int, 2005. 96(7):
1109–13.
16. Krieger JN, Bailey RC, Opeya JC, Ayieko
BO, Opiyo FA, Omondi D, Agot K, Parker
C, Ndinya-Achola JO, and Moses S, Adult
male circumcision outcomes: experience
in a developing country setting. Urol Int,
2007. 78(3): 235–40.
17. Kahn JG, Marseille E, and Auvert B,
Cost-effectiveness of male circumcision for
HIV prevention in a South African set-
ting. PLoS Med, 2006. 3(12): e517.
18. Gray RH, Li X, Kigozi G, Serwadda D,
Nalugoda F, Watya S, Reynolds SJ, and
Wawer M, The impact of male circumci-
sion on HIV incidence and cost per infec-
tion prevented: a stochastic simulation
model from Rakai, Uganda. Aids, 2007.
21(7): 845–50.
19. Van Howe RS, Circumcision and HIV
infection: review of the literature and
meta-analysis. Int J STD AIDS, 1999.
10(1): 8–16.
20. O’Farrell N and Egger M, Circumcision
in men and the prevention of HIV infec-
tion: a ‘meta-analysis’ revisited. Int J STD
AIDS, 2000. 11(3): 137–42.
21. Siegfried N, Muller M, Volmink J, Deeks
J, Egger M, Low N, Weiss H, Walker S,
and Williamson P, Male circumcision for
prevention of heterosexual acquisition of
HIV in men. Cochrane Database Syst Rev,
2003(3): CD003362.
22. Desai K, Boily MC, Garnett GP, Masse
BR, Moses S, and Bailey RC, The role
of sexually transmitted infections in
male circumcision effectiveness against
HIV – insights from clinical trial simu-
lation. Emerg Themes Epidemiol,
2006. 3: 19.
23. Williams BG, Lloyd-Smith JO, Gouws
E, Hankins C, Getz WM, Hargrove J, de
 Male circumcision and HIV infection risk
Zoysa I, Dye C, and Auvert B, The poten-
tial impact of male circumcision on HIV
in Sub-Saharan Africa. PLoS Med, 2006.
3(7): e262.
24. Orroth KK, Freeman EE, Bakker R,
Buve A, Glynn JR, Boily MC, White
RG, Habbema JD, and Hayes RJ,
Understanding the differences between
contrasting HIV epidemics in east and
west Africa: results from a simulation
model of the Four Cities Study. Sex
Transm Infect, 2007. 83 Suppl 1: i5–16.
25. Hallett TB, Singh K, Smith JA, White
RG, Abu-Raddad LJ, and Garnett GP,
Understanding the impact of male circum-
cision interventions on the spread of HIV
in southern Africa. PLoS ONE, 2008. 3(5):
e2212.
26. Londish GJ and Murray JM, Significant
reduction in HIV prevalence according
to male circumcision intervention in sub-
Saharan Africa. Int J Epidemiol, 2008.
27. Kelly R, Kiwanuka N, Wawer MJ,
Serwadda D, Sewankambo NK, Wabwire-
Mangen F, Li C, Konde-Lule JK, Lutalo
T, Makumbi F, and Gray RH, Age of male
circumcision and risk of prevalent HIV
infection in rural Uganda. Aids, 1999.
13(3): 399–405.
28. Quinn TC, Wawer MJ, Sewankambo N,
Serwadda D, Li C, Wabwire-Mangen F,
Meehan MO, Lutalo T, and Gray RH,
Viral load and heterosexual transmission
of human immunodeficiency virus type 1.
Rakai Project Study Group. N Engl J Med,
2000. 342(13): 921–9.
29. Reynolds SJ, Shepherd ME, Risbud
AR, Gangakhedkar RR, Brookmeyer
RS, Divekar AD, Mehendale SM, and
Bollinger RC, Male circumcision and
risk of HIV-1 and other sexually trans-
mitted infections in India. Lancet, 2004.
363(9414): 1039–40.
30. Meier AS, Bukusi EA, Cohen CR, and
Holmes KK, Independent association
of hygiene, socioeconomic status, and
circumcision with reduced risk of HIV
infection among Kenyan men. J Acquir
Immune Defic Syndr, 2006. 43(1): 117–8.
31. Shaffer DN, Bautista CT, Sateren WB,
Sawe FK, Kiplangat SC, Miruka AO,
Renzullo PO, Scott PT, Robb ML, Michael
| 14.6 |
NL, and Birx DL, The protective effect of
circumcision on HIV incidence in rural
low-risk men circumcised predominantly
by traditional circumcisers in Kenya: two-
year follow-up of the Kericho HIV Cohort
Study. J Acquir Immune Defic Syndr,
2007. 45(4): 371–9.
32. Millett GA, Ding H, Lauby J, Flores S,
Stueve A, Bingham T, Carballo-Dieguez A,
Murrill C, Liu KL, Wheeler D, Liau A,
and Marks G, Circumcision status and
HIV infection among Black and Latino
men who have sex with men in 3 US cities.
J Acquir Immune Defic Syndr, 2007.
46(5): 643–50.
33. Auvert B, Buve A, Ferry B, Carael M,
Morison L, Lagarde E, Robinson NJ,
Kahindo M, Chege J, Rutenberg N,
Musonda R, Laourou M, and Akam E,
Ecological and individual level analysis
of risk factors for HIV infection in four
urban populations in sub-Saharan Africa
with different levels of HIV infection. Aids,
2001. 15 Suppl 4: S15–30.
34. Auvert B, Buve A, Lagarde E, Kahindo
M, Chege J, Rutenberg N, Musonda R,
Laourou M, Akam E, and Weiss HA, Male
circumcision and HIV infection in four cit-
ies in sub-Saharan Africa. Aids, 2001.
15 Suppl 4: S31–40.
35. MacDonald KS, Malonza I, Chen DK,
Nagelkerke NJ, Nasio JM, Ndinya-Achola
J, Bwayo JJ, Sitar DS, Aoki FY, and
Plummer FA, Vitamin A and risk of HIV-1
seroconversion among Kenyan men with
genital ulcers. Aids, 2001. 15(5): 635–9.
36. Gray R, Azire J, Serwadda D, Kiwanuka
N, Kigozi G, Kiddugavu M, Nalugoda F,
Li X, and Wawer M, Male circumcision
and the risk of sexually transmitted infec-
tions and HIV in Rakai, Uganda. Aids,
2004. 18(18): 2428–30.
37. Agot KE, Ndinya-Achola JO, Kreiss JK,
and Weiss NS, Risk of HIV-1 in rural
Kenya: a comparison of circumcised and
uncircumcised men. Epidemiology, 2004.
15(2): 157–63.
38. Jewkes R, Dunkle K, Nduna M, Levin J,
Jama N, Khuzwayo N, Koss M, Puren A,
and Duvvury N, Factors associated with
HIV sero-positivity in young, rural South
African men. Int J Epidemiol, 2006.
35(6): 1455–60.
857
Chapter | 14 | Sexually transmitted infectious diseases
39. Kapiga SH, Sam NE, Mlay J, Aboud S,
Ballard RC, Shao JF, and Larsen U, The
epidemiology of HIV-1 infection in north-
ern Tanzania: results from a community-
based study. AIDS Care, 2006. 18(4):
379–87.
40. Johnson K and Way A, Risk factors for
HIV infection in a national adult popu-
lation: evidence from the 2003 Kenya
Demographic and Health Survey. J Acquir
Immune Defic Syndr, 2006. 42(5): 627–36.
41. Talukdar A, Khandokar MR,
Bandopadhyay SK, and Detels R, Risk of
HIV infection but not other sexually trans-
mitted diseases is lower among home-
less Muslim men in Kolkata. Aids, 2007.
21(16): 2231–5.
42. Mishra V, Assche SB, Greener R, Vaessen
M, Hong R, Ghys PD, Boerma JT, Van
Assche A, Khan S, and Rutstein S, HIV
infection does not disproportionately affect
the poorer in sub-Saharan Africa. Aids,
2007. 21 Suppl 7: S17–28.
43. Klavs I and Hamers FF, Male circumci-
sion in Slovenia: results from a national
probability sample survey. Sex Transm
Infect, 2008. 84(1): 49–50.
44. Foglia G, Sateren WB, Renzullo PO,
Bautista CT, Langat L, Wasunna MK,
Singer DE, Scott PT, Robb ML, and Birx
DL, High prevalence of HIV infection
among rural tea plantation residents in
Kericho, Kenya. Epidemiol Infect, 2008.
136(5): 694–702.
45. Mermin J, Musinguzi J, Opio A, Kirungi
W, Ekwaru J, Hladik W, Kaharuza F,
Downing R, and Bunnell R, Risk Factors
for Recent HIV Infection in Uganda.
JAMA, 2008. 300(5): 540–49.
46. Halperin DT, Fritz K, McFarland W, and
Woelk G, Acceptability of adult male cir-
cumcision for sexually transmitted disease
and HIV prevention in Zimbabwe. Sex
Transm Dis, 2005. 32(4): 238–9.
47. Buchbinder SP, Vittinghoff E, Heagerty
PJ, Celum CL, Seage GR, 3rd, Judson
FN, McKirnan D, Mayer KH, and Koblin
BA, Sexual risk, nitrite inhalant use,
and lack of circumcision associated with
HIV seroconversion in men who have sex
with men in the United States. J Acquir
Immune Defic Syndr, 2005. 39(1): 82–9.
858
48. Halperin DT and Bailey RC, Male circum-
cision and HIV infection: 10 years and
counting. Lancet, 1999. 354(9192): 1813–5.
49. Green EC, Male circumcision and HIV
infection. Lancet, 2000. 355(9207): 927.
50. Szabo R and Short RV, How does male cir-
cumcision protect against HIV infection?
Bmj, 2000. 320(7249): 1592–4.
51. Quigley MA, Weiss HA, and Hayes RJ,
Male circumcision as a measure to control
HIV infection and other sexually trans-
mitted diseases. Curr Opin Infect Dis,
2001. 14(1): 71–5.
52. Lerman SE and Liao JC, Neonatal cir-
cumcision. Pediatr Clin North Am, 2001.
48(6): 1539–57.
53. Shapiro RL, Drawing lines in the sand:
the boundaries of the HIV pandemic in
perspective. Soc Sci Med, 2002. 55(12):
2189–91.
54. Gisselquist D, Potterat JJ, and Brody S,
Running on empty: sexual co-factors are
insufficient to fuel Africa’s turbocharged
HIV epidemic. Int J STD AIDS, 2004.
15(7): 442–52.
55. Sahasrabuddhe VV and Vermund SH,
The future of HIV prevention: control of
sexually transmitted infections and cir-
cumcision interventions. Infect Dis Clin
North Am, 2007. 21(1): 241–57, xi.
56. Short RV, The HIV/AIDS pandemic:
new ways of preventing infection in men.
Reprod Fertil Dev, 2004. 16(5): 555–9.
57. Short RV, New ways of preventing HIV
infection: thinking simply, simply think-
ing. Philos Trans R Soc Lond B Biol Sci,
2006. 361(1469): 811–20.
58. Nyindo M, Complementary factors con-
tributing to the rapid spread of HIV-I in
sub-Saharan Africa: a review. East Afr
Med J, 2005. 82(1): 40–6.
59. Inungu J, MaloneBeach E, and Betts J,
Male circumcision and the risk of HIV
infection. AIDS Read, 2005. 15(3):
130–1, 135, 138.
60. Jones R, Gazzard B, and Halima Y,
Preventing HIV infection. Bmj, 2005.
331(7528): 1285–6.
61. Flynn P, Havens P, Brady M, Emmanuel
P, Read J, Hoyt L, Henry-Reid L,
Van Dyke R, and Mofenson L, Male
 Male circumcision and HIV infection risk
circumcision for prevention of HIV and
other sexually transmitted diseases.
Pediatrics, 2007. 119(4): 821–2.
62. Van Howe RS, Svoboda JS, and Hodges
FM, HIV infection and circumcision:
cutting through the hyperbole. J R Soc
Health, 2005. 125(6): 259–65.
63. Auerbach JD, Hayes RJ, and Kandathil
SM, Overview of effective and promising
interventions to prevent HIV infection.
World Health Organ Tech Rep Ser, 2006.
938: 43–78; discussion 317–41.
64. Chan DJ, Fatal attraction: sex, sexually
transmitted infections and HIV-1. Int J
STD AIDS, 2006. 17(10): 643–51.
65. Mboto CI, Davies A, Fielder M, and Jewell
AP, Human immunodeficiency virus and
hepatitis C co-infection in sub-Saharan West
Africa. Br J Biomed Sci, 2006. 63(1): 29–37.
66. Isiugo-Abanihe UC, Sociocultural aspects
of HIV/AIDS infection in Nigeria. Afr J
Med Med Sci, 2006. 35 Suppl: 45–55.
67. Weiss HA, Male circumcision as a pre-
ventive measure against HIV and other
sexually transmitted diseases. Curr Opin
Infect Dis, 2007. 20(1): 66–72.
68. Sawires SR, Dworkin SL, Fiamma A,
Peacock D, Szekeres G, and Coates TJ,
Male circumcision and HIV/AIDS:
challenges and opportunities. Lancet,
2007. 369(9562): 708–13.
69. Schenker I and Gross E, [Male circumci-
sion and HIV/AIDS: convincing evidence
and their implication for the state of
Israel]. Harefuah, 2007. 146(12):
957–63, 997.
70. Sharp M, 14th annual retrovirus confer-
ence (CROI). HIV prevention update.
Some bad news, some good news. Posit
Aware, 2007. 18(3): 26–7.
71. Quinn TC, Circumcision and HIV trans-
mission. Curr Opin Infect Dis, 2007.
20(1): 33–8.
72. Schoen EJ, Should newborns be
circumcised? Yes. Can Fam
| 14.6 |
Physician, 2007. 53(12): 2096–8,
2100–2.
73. Clark PA, Eisenman J, and Szapor S,
Mandatory neonatal male circumcision in
Sub-Saharan Africa: medical and ethical
analysis. Med Sci Monit, 2007.
13(12): RA205–13.
74. Clark S, Male circumcision could help
protect against HIV infection. Lancet,
2000. 356(9225): 225.
75. Morris BJ, Why circumcision is a bio-
medical imperative for the 21(st) century.
Bioessays, 2007. 29(11): 1147–58.
76. Mor Z, Kent CK, Kohn RP, and Klausner
JD, Declining rates in male circumcision
amidst increasing evidence of its public
health benefit. PLoS ONE, 2007. 2(9): e861.
77. Jayasuriya A, Robertson C, and Allan PS,
Twenty-five years of HIV management. J R
Soc Med, 2007. 100(8): 363–6.
78. Landovitz RJ, Recent efforts in biomedi-
cal prevention of HIV. Top HIV Med, 2007.
15(3): 99–103.
79. Vardi A, Guy L, and Boiteux JP,
[Circumcision and HIV.]. Prog Urol, 2008.
18(6): 331–336.
80. Cohen MS, Hellmann N, Levy JA, DeCock
K, and Lange J, The spread, treatment,
and prevention of HIV-1: evolution of a
global pandemic. J Clin Invest, 2008.
118(4): 1244–54.
81. Gray RH, Wawer MJ, Polis CB, Kigozi
G, and Serwadda D, Male Circumcision
and Prevention of HIV and Sexually
Transmitted Infections. Curr Infect Dis
Rep, 2008. 10(2): 121–7.
82. Potts M, Halperin DT, Kirby D, Swidler
A, Marseille E, Klausner JD, Hearst N,
Wamai RG, Kahn JG, and Walsh J, Public
health. Reassessing HIV prevention.
Science, 2008. 320(5877): 749–50.
83. Fieno JV, Costing adult male circumcision
in high HIV prevalence, low circumcision
rate countries. AIDS Care, 2008.
20(5): 515–20.
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 Chapter |15|

Special urogenital
infections
Chair: Tetsuro Matsumoto

CHAPTER OUTLINE
15.1 Introduction 862
15.2 Urinary tuberculosis 864
15.3 Male genital tuberculosis 877
15.4 Genitourinary tuberculosis in a developing country
(Vietnam): diagnosis and treatment 892
15.5 Guidelines for the treatment of fungal urinary
tract infections 903
15.6 Vulvovaginal candidosis 912
15.7 Viral genitourinary infections 928
15.8 Genitourinary schistosomiasis 943
15.9 Brucellosis: genitourinary involvement 959
15.10 Echinococcus/hydatid disease: genitourinary involvement 968
|15.1|
Introduction
Tetsuro Matsumoto
Professor of Urology, Chairman of the Department of Urology, School of Medicine,
University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807–8555 Japan
Fax +81-93-6038724, Tel +81-93-6031611/7446, t-matsu@med.uoeh-u.ac.jp
This section includes various infectious
diseases of the urinary tract, such as
tuberculosis, fungal infections, para-
site infections, viral infections and bru-
cellosis. While some of these infections
are not so common, some infections are
very bothersome in specialist areas or
in patients with special conditions, e.g.
immunodeficiency. The authors of this
section developed general guidelines for
diagnosis, treatment and follow-up of
infectious diseases based on the evidence
available. However, most of the guide-
lines are expert opinions, because studies
with higher evidence are quite limited.
Tuberculosis (TB) is not so rare. The
World Health Organization (WHO) esti-
mated that one third of the world’s pop-
ulation is infected with Mycobacterium
tuberculosis and there are 8 to 10 million
new active cases of TB each year. The
most important problems in TB are its
increase in patients with human immu-
nodeficiency virus (HIV) infection and
the emergence and increase of multid-
rug resistant strains. Urogenital TB is a
rare type of TB and its diagnosis is based
on aseptic pyuria, culture method and/
or PCR. The treatment for urogenital TB
consists of a combination therapy with 3
or 4 antituberculous antibiotics.
Candida infection of the urinary tract
is common and is diagnosed by the pres-
ence of fungi in urine and a positive urine
culture of candida species. Candida albi-
cans is the most common pathogen of
funguria followed by C. tropicalis, C. kru-
sei and C. parapsilosis. In general, treat-
ment of asymptomatic candiduria is not
recommended, but high risk patients may
be treated to prevent dissemination and
symptomatic patients can be treated with
antifungal agents or surgical intervention
to remove a fungal ball.
Parasitic diseases including urogeni-
tal schistosomiasis and echinococcocis
are a major health problem, especially in
developing countries. Schistosomiasis is
diagnosed by the presence of eggs in uri-
nary sediment. The adequate treatment
is praziquantel. Hydatid cysts caused by
Echinococcus granulosus, E. multilocularis

or E. vogeli are seldom seen in the kidney
and the urogenital area.
Several kinds of viral infections involve
the urinary tract. Hemorrhagic cystitis
is sometimes caused by viruses includ-
ing BK virus, adenovirus and cytomega-
lovirus. HIV, Herpes simplex virus and
human papilloma virus cause sexually
transmitted infections of the urogenital
area.
Brucellosis is a zoonotic infection of the
urinary tract caused by Brucella melitensis,
B. abortus, B. suis, B. canis etc. Urogenital
Introduction | 15.1 |
involvement is seen in the male genital
organ, female pelvic inflammatory dis-
eases and/or pyelonephritis. Brucellosis is
usually treated by a combination of doxy-
cycline plus streptomycin, rifampcin or
gentamycin.
We thank all authors of this section for
their hard work on developing general
guidelines for relatively rare and special
infections of the urogenital tract and we
hope that these recommendations are
useful for all urologists taking care of
such patients.
863
|15.2|

Urinary tuberculosis
Severin Lenk1*, Mitsuru Yasuda2
*Corresponding author:
1
Prof. Dr. med. Severin Lenk, MD, PhD, Professor, Private practice for Urology/Andrology, Reinhardtstraße 3, D-10117 Berlin
Telephone: 0049/30/4251229, Fax: 0049/30/64169096, e-mail: privatpraxis_prof.lenk@yahoo.de
2
Dr. Mitsuru Yasuda, Department of Urology, Division of Disease Control, Research Field of Medical Sciences,
Graduete School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501194, Japan
Tel.: +81-58-230-6338, Fax: +81-58-230-6339, super7@gifu-u.ac.jp

ABSTRACT The diagnosis of tuberculosis of the

More than 100 years after Robert Koch
discovered the acid-fast bacillus, tuber-
culosis is still counted amongst the most
important infectious diseases in the world,
especially in the context of HIV infection.
In 2006 there were 9.6 millon new
cases of tuberculosis and 1.7 million fatal-
ities from disease worldwide.
In contrast to this, as the result of
intensive tuberculosis control measures,
the incidence of tuberculosis in Germany
has constantly decreased.
However, the rate of new cases of
extrapulmonary manifestations includ-
ing genitourinary tuberculosis (GUTB)
decreases rather slowly.
GUTB usually results from the reac-
tivation of old, dormant tuberculous dis-
ease by members of the Mycobacterium
(M.) tuberculosis complex.
Renal tuberculosis mostly presents uni-
laterally, but post mortem studies show
the disease is bilateral.
urinary tract is based on the finding of
pyuria in the absence of infection as judged
by culture on routine media.
Radiological imaging can be helpful to
detect urinary tuberculosis by intravenous
pyelogram and/or computertomography.
A positive yellow egg culture and/or histo-
logical analysis of biopsy specimens possibly
combined with polymerase chain reaction
(PCR) is still required in most patients to
establish a definitive diagnosis of GUTB.
In GUTB drug treatment is the first
line therapy.
According to the World Health
Organisation (WHO), antituberculous
drug treatment is based on an initial
2-month intensive phase with three or
four drugs daily (rifampicin, isoniazid,
pyrazinamide, and ethambutol or strepto-
mycin) followed by a four-month continu-
ation phase with only two drugs, mostly
rifampicin and isoniazid.
These two drugs may be given twice or
thrice weekly.

Surgery as a treatment option in
GUTB has clearly lost its importance. It
might be indicated in complicated uri-
nary tuberculosis (obstruction, abscess)
or secondary urinary tract infection such
as pyelonephritis or urinary stones.
After antituberculous treatment of uri-
nary tuberculosis, follow-up surveillance
over five years is recommended.
Although the incidence of GUTB in
Germany is relatively low, it is still nec-
essary to impart and deepen scientific
knowledge of the diagnosis and therapy
of GUTB.
Special problems present themselves
with patients with immunosuppres-
sion (AIDS or after transplantation) and
migrants with tuberculosis from the so-
called Third World.
Key words: tuberculosis epidemiology,
urinary tuberculosis: pathogenesis, diag-
nosis, medical treatment, surgical treat-
ment, follow-up
SUMMARY OF RECOMMENDATIONS
Epidemiology and pathogenesis
1. In 2006 there were 9.6 million new
cases of tuberculosis and 1.7 million
fatalities from the disease (LoE 2).
2. Of the 1.7 million people who died
from tuberculosis, 229,000 were
co-infected with HIV (LoE 2).
3. As a result of intensive control meas-
ures, the incidence of tuberculosis in
Germany has constantly decreased,
whereas the incidence of GUTB shows
only a slow downward trend (LoE 1).
4. The kidney usually is infected by a
hematogenous spread of bacilli of the
Mycobacterium tuberculosis complex
from a focus of infection in the lungs
and/or bowel (LoE 1).
5. Usually, GUTB is a reactivation
of the tuberculosis from a period of
dormancy (LoE 1).
Urinary tuberculosis | 15.2 |
Diagnosis
6. Around 40% of patients with GUTB
in the developed countries and 50%
in the developing countries have a
history of tuberculosis. The case
history must be an important step
in the diagnostic procedure of GUTB
(GoR A).
7. The main symptoms in urinary
tuberculosis are voiding problems
and chronic urgency non-responding
to antibacterial drug treatment regi-
mens. In such cases a screening for
GUTB is recommended (GoR A).
8. The diagnosis of tuberculosis of the
urinary tract is based on the findings
of pyuria in the absence of infec-
tion as judged by culture on routine
media (GoR A).
9. Characteristic signs on intravenous
pyelogram and computer tomography
are useful in depicting GUTB (GoR B).
10. Relatively few studies have spe-
cifically evaluated polymerase chain
reaction (PCR) for detection of GUTB,
but these show the technique to be
sensitive and specific. Especially, PCR
should be used to detect mycobacte-
rial DNA in urine in HIV related
disseminated tuberculosis (GoR B).
11. A positive yellow egg culture or
histological analysis of biopsy speci-
mens possibly combined with PCR
is still required in the majority for a
definite diagnosis (GoR A).
12. The biological activity of tuberculo-
sis should be assessed by cultivating
mycobacteria (urine, smear, secretion,
ejaculate, tissue samples) (GoR A).
Treatment
13. According to the World Health
Organization (WHO), antitubercu-
lous drug treatment is based on an
initial two-month intensive phase of
treatment with three or four drugs
865
Chapter | 15 | Special urogenital infections
daily (rifampicin, isoniazid, pyrazina-
mide and ethambutol), followed by a
four-month continuation phase with
only two drugs, mostly rifampicin
and isoniazid (GoR A).
14. Drug treatment is recommended
as the first line therapy in GUTB
(GoR A).
15. Only in complicated cases (recur-
rences of tuberculosis, immunosup-
pression and HIV/AIDS) is nine- to
12-month therapy recommended
(GoR B).
16. Surgery has clearly lost its importance
as a treatment option. It must be done
in complicated GUTB (obstruction,
abscess) or secondary urinary tract
infections such as pyelonephritis or
nephrolithiasis (GoR B).
1. INTRODUCTION
Since Robert Koch’s discovery of the acid-
fast bacillus in 1882, intensive research
of the diagnosis and treatment modalities
of tuberculosis has taken place [1–3].
Currently, in most industrial countries,
the incidence of newly diagnosed cases of
tuberculosis is decreasing each year, but
the worldwide prevalence of tuberculo-
sis has remained almost as it was at the
beginning of the 20th century.
More than 95% of patients diagnosed
with tuberculosis live in the so-called Third
World countries. In these countries, a dra-
matic increase in the incidence of tuber-
culosis has been observed, which appears
to be closely linked to infection with HIV.
Patients with AIDS are at a high risk of
developing secondary infections such as
tuberculosis. Prospective real-time sur-
veillance of tuberculosis in HIV patients is
needed in order to detect case-clustering
and to improve control of tuberculosis [4–5].
Nearly 20% of patients with tubercu-
losis develop extrapulmonary manifesta-
tions. Involvement of the genitourinary
system is seen in 4–8% of all patients
866
with tuberculosis. Tuberculosis is the
most common extrapulmonary manifes-
tation after tuberculosis of the peripheral
lymph nodes [2, 6].
2. METHODS
Up to 1997 meta-analysis of genitouri-
nary tuberculosis publications was done
of the basis of journals. A systematic lit-
erature search up to 2008 was performed
in MEDLINE and PubMed with the key
words: tuberculosis, genitourinary tuber-
culosis, extrapulmonary tuberculosis,
non-pulmonary tuberculosis, tuberculosis
and HIV-infection with the following limi-
tations: English abstract available.
A total of 225 publications were iden-
tified, which were screened by title and
abstract. After exclusion of duplicates, a
total of 25 publications were included in
the review.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [7–8].
3. EPIDEMIOLOGY
In 2006 there were 9.6 million new cases
of tuberculosis and 1.7 million fatalities
due to the disease worldwide. Besides
social poverty and insufficient medi-
cal care, tuberculosis mainly still counts
among the most important infectious dis-
eases of the world because of HIV infec-
tions. Of the 1.7 million people who died
of tuberculosis, 229,000 were co-infected
with HIV [9].
There were 445.000 new TB cases in
Europe in 2005, representing 6% of the
global TB burden [10].
The Russian Federation had the
ninth highest burden of TB in the world.
Within Europe, TB incidence varies enor-
mously, from 2.9 per 100.000 population
in Monaco to 208.4 per 100.000 popula-
tion in Kazakhstan in 2003 [9–10].

The female/male ratio was 0.4 among
new pulmonary TB cases with a positive
sputum smear. This may require research
on gender inequality in accessing TB
services in some settings.
High rates of TB are associated with
socioeconomic crisis, weaknesses in health
systems, epidemics of HIV and multidrug-
resistant TB, and poor interventions to
control TB among vulnerable populations.
Recent analysis shows that 2.6% of all
new TB cases in Europe in 2000 were
attributable to HIV co-infection. In the
Russian Federation, 1% of all new cases
of TB were estimated to be HIV-positive
and 35% of adults with AIDS died from
TB [9–10].
In Europe and in the United States
after lymphadenopathy, the most com-
mon form of non-pulmonary tuberculosis
is GUTB, accounting for 27% (range from
14 to 41%) of non-pulmonary cases.
As a result of intensive control meas-
ures, the incidence of tuberculosis in
Non-pulmonary
(extrapulmonary)
tuberculosis
1091
(20.7%)
Figure 1 Tuberculosis in Germany 2006.
Urinary tuberculosis | 15.2 |
Germany has been constantly decreasing.
The incidence of pulmonary tuberculosis
especially was reduced, whereas the rate
of new cases of extrapulmonary tuber-
culosis failed to decrease. The same ten-
dency can be observed with GUTB, the
incidence of which shows an only a slow
downward trend [6, 11].
Over the last 40 years, the incidence of
tuberculosis in Germany decreased more
rapidly. In 1999, for the first time, less
than 10,000 new cases were registered
and up to 2006 (5280 new cases, inci-
dence 6.6/100.000 inhabitants) the posi-
tive trend was continuing [9, 12].
In contrast to this, the proportion of
tuberculosis in the foreign population
did not decrease (incidence 45.2/100.000
foreigners).
The rate of new cases of extrapul-
monary tuberculosis barely dropped at
all over the last 20 years (figure 1). In
Germany, GUTB ranks second amongst
extrapulmonary forms of tuberculosis,
Pulmonary
tuberculosis
4189
(79.3%)
867
Chapter | 15 | Special urogenital infections

180 46
(3.4%) (0.9%)

411
(7.8%)

46
(0.9%) Peripheral lymphnodes
Bones and spinal
medullary
Urogenital system

Gastrointestinal tract

21 Meningitis and central

(0.4%) nervous system
Others (pleura,
114 mediastinum)
(2.2%) Dissiminated

132
(2.5%)

Figure 2 Non-pulmonary (extrapulmonary) tuberculosis in Germany 2006.

after tuberculosis of the peripheral lymph bacillus. Tuberculosis caused by the

nodes (figure 2).
However, the proportion of foreigners
with GUTB (16.5%) as opposed to tuber-
culosis of the peripheral lymph nodes
(62.5%) is comparatively low [12].
In our own case material the aver-
age age of patients (52 years) clearly
increased over the course of 40 years, as
did the latency period (30 years), whilst
the yearly number of cases and the time
of treatment decreased.
4. ETIOLOGY AND PATHOGENESIS
Tuberculosis of the kidney, the urinary
tract, and the male genital tract, like
other forms of tuberculosis (pulmonary
and non-pulmonary), is caused by mem-
bers of the Mycobacterium (M.) tubercu-
losis complex. By far the most common
causative organism is the human tubercle
bovine tubercle bacillus M. bovis is now
uncommon in industrially developed
nations. It is usually due to reactiva-
tion of old, dormant disease, although
cases have occurred in younger, HIV-
positive patients. In approximately 25%
of cases caused by reactivation of M.
bovis infection, the genitourinary system
is involved.
Other species of mycobacterium, the
so-called environmental mycobacteria,
occasionally cause human disease similar
to the tuberculosis disease, particularly
in immunosuppressed individuals includ-
ing transplant patients. Tuberculosis
may involve the kidney as part of gener-
alized disseminated infection or as local-
ized genitourinary disease. The kidney is
usually infected by hematogenous spread
of bacilli from a focus of infection in the
lungs and/or bowel. Mostly, GUTB is a
reactivation of dormant tuberculosis.

868

Clinically, renal tuberculosis usually
presents unilaterally, but post mortem
studies show that the disease is fre-
quently bilateral [2].
Genital tuberculosis in males most
commonly involves the epididymis fol-
lowed by the prostate. Testicular involve-
ment is less common and usually a result
of direct invasive epididymitis.
Tuberculous prostatitis results from
antegrade infection within the urinary
tract; tuberculous epididymitis is prob-
ably a result of blood-borne infection
because it is often an isolated finding
without urinary tract involvement. It is
important to be aware that a high propor-
tion (50–75%) of men with genital tuber-
culosis have radiologic abnormalities in
the urinary tract. The urinary tract of
all patients with primary tuberculous
infection of the epididymis should be
investigated [13].
5. DIAGNOSTIC PROCEDURES
The diagnosis of GUTB is difficult
because its symptoms are non-specific.
The most important step in diagnosis
is the patient history. Knowledge of an
earlier tuberculosis infection either asp-
rimary pulmonarymanifestation or as
an extrapulmonary manifestation is an
important clue in a large number of cases.
Around 40% of patients with GUTB in
developed countries and 50% in develop-
ing counties have a past history of tuber-
culosis [14].
One has to be aware that the latency
between pulmonary manifestation and
GUTB is enormous. In some cases it could
take more than 30 years before GUTB
becomes evident [2, 15].
Symptoms suggestive of GUTB,
especially in urinary tuberculosis, are
voiding problems and chronic urgency non-
responding to antibacterial drug regi-
mens. In men, chronic epididymitis is the
typical manifestation of tuberculosis of
Urinary tuberculosis | 15.2 |
the male genital tract, mostly combined
with scrotal fistulas.
Other symptoms that sometimes occur
include back, flank, and suprapubic
pain, hematuria, frequency, and noctu-
ria. Renal colic is uncommon, occurring
in fewer than 10% of patients, and con-
stitutional symptoms such as fever,
weight loss, and night sweats also are
unusual.
Only one third of patients have an
abnormal chest X-ray.
Physical examination should include
the male genital tract (testes, epidi-
dymides) and digital-rectal examination
(prostate gland) to differentiate between
unspecific inflammatory diseases, tuber-
culosis and tumours, respectively.
The diagnosis of tuberculosis of the uri-
nary tract is based on the finding of pyu-
ria in the absence of infection as judged
by culture on routine media.
Radiological imaging can be helpful
to detect GUTB. Characteristic signs on
intravenous pyelogram and computed
tomography are useful in depicting
GUTB. Radiologically detectable mani-
festations of tuberculosis allow for ear-
lier diagnosis and the timely initiation
of appropriate therapy, thus reducing
patient morbidity [16–17].
In the early course of disease it is
often possible to detect changes in a sin-
gle calyx with evidence of parenchymal
necrosis on intravenous urography, and
typically there is calcification on the
plain film. In more advanced disease
urography will show calyceal distortion,
ureteric strictures, and bladder fibrosis
(figures 3–5).
Ultrasound examination of the uri-
nary tract may reveal renal calyceal
dilation and more overt evidence of
obstruction.
Computed tomography (CT) and
nuclear magnetic imaging are impor-
tant for differential diagnosis (renal
parenchymal masses, scarring, auton-
ephrectomy).
869
Chapter | 15 | Special urogenital infections
Figure 3 Intravenous pyelogram: plain film showing
abnormal upper calyx with intrarenal stricture, dilatation of the
right renal pelvis and a dilated right ureter (M. tuberculosis was
isolated from the urine).
Figure 4 Intravenous pyelogramm: progressive renal
tuberculosis on both sides, strictures and dilatations on the
right side, intrarenal strictures of the calices on the left side.
870
Figure 5 Progressive bladder tuberculosis with scarring
and vesicoureteral reflux on both sides.
A positive skin test supports the diag-
nosis of tuberculosis, but a negative
skin test does not necessarily exclude an
extrapulmonary manifestation. This is
especially true in cases of GUTB.
A microbiologic diagnosis of tubercu-
losis is usually made by isolation of the
causative organism from urine or biopsy
material on conventional solid media or
by an automated system such as radiom-
etry [18].
In recent years, nucleic-acid ampli-
fication techniques, such as polymer-
ase chain reaction (PCR), have been
investigated extensively for the detec-
tion of M. tuberculosis complex (M.
tuberculosis, M. bovis, M. microti, M.
africanum) and other mycobacteria in
clinical specimens, notably sputum.
Relatively few studies have specifi-
cally evaluated PCR for detection of
GUTB, but these show the technique
to be sensitive and specific, although

some urine specimens contain inhibi-
tory substances [13, 19–20].
In addition, PCR has been used to
detect mycobacterial DNA in urine in
cases of HIV-related disseminated tuber-
culosis [19, 21].
A positive culture or histological
analysis of biopsy specimens possibly
combined with PCR is still required in
most patients for a definite diagnosis.
In 25–30% the diagnosis of GUTB is
established on the basis of the histologi-
cal pattern and/or by detection of the
Mycobacterium tuberculosis complex by
PCR [19].
Detection of acid-fast bacilli from urine
samples by microscopy (Ziehl-Neelson
acid-fast stain) is not reliable because of
the possible presence of M. smegmatis,
which are acid-fast bacilli too.
However, the biological activity of
tuberculosis can only be assessed by cul-
tivating mycobacteria [22].
Table 1 Detection of mycobacteria from renal tissue specimens before and
after a 3-month course of anti-tuberculosis treatment.
Anti-tuberculosis
treatment
No (n = 26)
Yes (n = 40)
Summary (n = 66)
Table 2 Diagnostic procedures of GUTB.
Suspected diagnosis
• Case history (earlier pulmonary or extrapulmonary
tuberculosis)
• Symptoms
• Physical examination
• Skin test
• Urine analysis (leucocytes, erythrocytes, bacteria)
• Radiological imaging
• intravenous pyelogram
• CT
• Cystoscopy (only for differential diagnosis, figure 6)
Urinary tuberculosis | 15.2 |
In a study of 118 patients mostly suf-
fering from renal tuberculosis, tissue
specimens were minced and dispersed
in 0.9% sterile saline and examined by
microscopy, culture and animal experi-
ment. Mycobacteria were detected in
34 of 118 tissue samples (29%). The
renal tissue samples were divided into
two groups, one before and one after a
three-month course of antituberculo-
sis treatment. Interestingly, the latter
group demonstrated a higher amount
of detected mycobacteria (table 1).
This finding clearly questions the use
of short-term treatment modalities in
UGT. The results also show that direct
proof of the presence of mycobacteria
enables a reliable assessment of the bio-
logical activity of GUTB, which is desir-
able for treatment planning and therapy
control. In all cases suspected for GUTB
a diagnostic algorithm is recommended
(table 2).
Mycobacteria No mycobacteria
present present
7 (27%) 19 (73%)
14 (35%) 26 (65%)
21 (32%) 45 (68%)
Definite diagnosis
• Microscopic examination (Ziehl-Neelson
acid-fast stain)
• Yellow egg culture media (urine, smear,
secretion, ejaculate, tissue samples)
• PCR
• Histological examination (tissue samples)
• Combined with Ziehl-Neelson acid- fast stain
and/or PCR
871
Chapter | 15 | Special urogenital infections
Figure 6 Endophotography of the urinary bladder shows
typical tubercle near the orifice of the ureter.
6. MEDICAL TREATMENT
Modern short-course antitubercuIous
drug regimens are effective in all forms
of tuberculosis. According to the World
Health Organization (WHO), anti-tuber-
culous drug treatment is based on an
initial two-month intensive phase of
treatment with three or four drugs daily,
including rifampicin, isoniazid, pyrazina-
mide, and ethambutol (or streptomycin),
to destroy almost all tubercle bacilli. This
is followed by a four-month continua-
tion phase with only two drugs, usually
rifampicin and isoniazid. In the continua-
tion phase the drug may be given twice or
thrice weekly.
In GUTB, drug treatment is the first
line therapy. Over the course of a fol-
low-up of more than 40 years the treat-
ment time was reduced from 24 months
to six months [9, 12].
Only in complicated cases (recurrences
of tuberculosis, immunosuppression and
HIV/AIDS) is a nine- to 12-month ther-
apy necessary [2].
A serious problem at present is the
high percentage of primary drug resist-
ance in patients with tuberculosis. In
a study from the Russian Research
Institute of Phthisiopulmology, 50 iso-
lates of M. tuberculosis obtained from
patients referred from various parts
of Russia were analysed by PCR and
872
sequenced to study the mechanism of
rifampicin resistance [23].
Drug resistance was detected in 33
patients out of the 50 from whom cul-
tures were isolated. Most of the isolates
were resistant to rifampicin (n=25), iso-
niazid (n=14), and streptomycin (n=7).
Multi-drug resistance was common. Only
6% of the isolates were resistant to one
drug, whereas resistance to two, three,
four, and five drugs was seen in 14, 32,
40, and 8%, respectively. Fully suscep-
tible isolates were derived from only 17
patients. ln rifampicin-resistant strains,
a number of previously unrecognized
genetic alterations (point mutations and
deletions) were found in the rpoB locus.
The rpoB locus is responsible for a high
level of rifampicin resistance (>500 ug/ml
in egg-based medium).
ln cases with multi-drug-resistant tuber-
culosis by definition (WHO), caused by bacilli
resistant to rifampicin and isoniazid, with or
without resistance to other drugs, therapy
requires the use of at least four drugs that
are selected on the basis of a drug suscep-
tibility test (ethionamide, prothionamide,
quinolones, clarithromycin, cycloserin, kan-
amycin, viomycin, capreomycin, thiaaceta-
zone, and para-amino-salicide acid). These
drugs are less effective and often more toxic
than the first line drugs [24].
The duration of therapy is based on
the bacteriologic response but may be 18
months and longer.
Mycobacterium bovis harbours a pri-
mary resistance to pyrazinamide and
is found in a high percentage of elderly
patients with GUTB.
In clinical practice, pyrazinamide should
be avoided in those cases not only because
of the likelihood of primary resistance but
also because of the induction of hyperuri-
caemia and hyperuricuria which might be
detrimental in patients with GUTB.
Patients with GUTB caused by M.
tuberculosis who are treated with pyrazi-
namide in the intensive treatment phase
should be given a xanthinoxydase-inhibi-
tor in addition.
 Urinary tuberculosis | 15.2 |

Table 3 First line antituberculous drug therapy.

Antituberculous Dose Body Daily

drug mg/kg BW weight (BW) dose

Isoniazid (INH) 5 <50 kg 300 mg

Rifampicin (RMP) 10 >50 kg 450 mg

600 mg

Pyrazinamide (PZA) 25–35 <50 kg 1,5 g

<50 kg 2,0 g
>75 kg 2,5 g

Streptomycin (SM) 15–20 >50 kg 0,75 g

>50 kg 1,0 g

Ethambutol (EMB)¹ 25² 0,8–2,0 g

Prothionamide (PTA) 5–15 0,5–1,0 g

¹not for children younger than 10 years.

²after two months 20 mg.

A six-month short course of antituber-

Table 4 six-month regimes for the treatment of
culous drug regimen is also effective in
uncomplicated GUTB.
uncomplicated GUTB [2, 12, 25–26].
Special considerations apply to the Intensive phase Continuation phase
treatment of tuberculosis in patients with
impaired renal function. Rifampicin, iso- 3 months 3 months

niazid, pyrazinamide, prothionamide, INH, RMP, EMB (or SM) INH, RMP
and ethionamide may be given in nor- daily twice or thrice per week
mal dosage. They are eliminated in the
bile or broken down to metabolites that 2 months 4 months

are not excreted by the kidney. Care is
required in the use of streptomycin, other
aminoglycosides, and ethambutol. These
are wholly excreted via kidney.
Ethambutol causes optic neuritis, which
may be irreversible, and reduced dose
should be given according to the glomeru-
lum fitration rate (GFR). Streptomycin
and other aminoglycosides are ototoxic and
nephrotoxic, and should not be given to
patients with renal failure, especially after
renal transplantation, because cyclosporine
involves also a high risk of nephrotoxity.
Encephalopathy is an uncommon compli-
cation of isoniazide and can be prevented
by pyroxidine (25 to 50 mg per day).
Rifampicin increases the rate of metab-
olism, of corticosteroids, cyclosporine, and
lacrolimus.
INH, RMP, PZA, EMB INH, RMP
daily twice or thrice per week
Regular measurements of the concen-
tration of cyclosporine and Iacrolimus
in the blood of such patients (mostly
patients after transplantation) are
recommended.
In HIV-patients, antiretroviral therapy
interacts adversely with rifampicin. When
rifabutin is given instead of rifampicin
the therapy must be extendend to nine to
12 months.
The drug treatment recommendations
for GUTB are summarized (according to
pulmonary tuberculosis) in tables 3 and
table 4.

873
Chapter | 15 | Special urogenital infections
7. SURGERY
Surgery as a treatment option has clearly
lost its importance, but it might be indi-
cated in complicated GUTB (obstruc-
tion, abscess, etc.) or secondary urinary
tract infections such as pyelonephritis or
nephrolithiasis.
Surgical excision of non-functioning
kidneys (figure 7) or because of extensive
lesion in partiallly functioning kidneys is
controversial. Nephrectomy is indicated
by complications such as upper urinary
tract infection (UTI) with Gram-negative
or Gram-positive bacteria and/or urinary
stones, and hypertension.
Early stenting or percutaneous neph-
rostomy may aid functional recovery of
disturbed renal function in patients with
tuberculous ureteric obstruction [2].
Overall, open surgical management
and minimally invasive procedures [27]
in UGT can be categorized into seven
groups [15]:
• drainage for hydronephrosis (ureter
stenting, percutaneous nephrostomy)
• drainage for abscesses/caverns (only in
septic cases)
• definitive local treatment of kid-
ney tuberculosis (partial or total
nephrectomy)
Figure 7 Tuberculous “pyonephrosis“ with extensive caseous
necrosis and renal parenchymal destruction.
874
• reconstruction of the upper urinary
tract (pyeloureterostomy, ureterocysto-
neostomy, ureter replacement)
• bladder augmentation
• reconstruction of the urethra (seldom)
• management of genital tuber-
culosis (orchiepididymectomy /
epididymectomy)
Over the course of more than 40 years
of investigation of our case material
with GUTB (n=764) the operation rate
decreased from 80.4% (1961) to 24.5%
(2007), whereas the nephrectomy rate
was unchanged (approximately 20 to 25%
of all patients with GUTB).
8. FOLLOW-UP
Normally no tuberculous infection is
found in uncomplicated cases of GUTB
after a treatment period of six months
with antituberculous drugs.
Only in high risk patients with GUTB
(HIV/AIDS, immunosuppressed patients,
drug resistance) is a longer treatment
period (nine to 12 months or more)
necessary.
In the follow-up of patients with GUTB
after antituberculous drug treatment,
five-year surveillance is recommended.
Urine examination and urine cultures
should be done twice a year for the first
two years, afterwards once a year.
Blood examinations (creatinine, uric
acid), urosonography, and if necessary,
x-ray controls (intravenous pyelogram,
chest) are important to detect complica-
tions as early as possible (renal insuffi-
ciency, obstruction, renal damage).
9. FURTHER RESEARCH
The main problems of tuberculosis are the
high prevalence of mycobacterial infec-
tions and multi-drug resistance (MDR).
A better tuberculosis control (in
developing countries) and an effective

treatment of patients with HIV and
tuberculosis is a first step to reduce the
incidence of tuberculosis worldwide.
The development of new antitubercu-
lous drugs for patients with multi-drug
resistance (MDR) is very important.
Case control studies are necessary to
detect patients with GUTB earlier, before
their renal function is destroyed.
10. CONCLUSIONS
More than 125 years after Robert Koch`s
discovery of tubercle bacilli worldwide,
tuberculosis is still not eradicated.
The main problems are insufficient
tuberculosis control and the high preva-
lence of HIV infections in developing
countries. Another important problem is
MDR in patients with tuberculosis.
More than 4% of all new cases with
tuberculosis are suffering from GUTB.
Although the incidence of GUTB in
Germany is relatively low, it is still nec-
essary to impart and deepen scientific
knowledge of the diagnosis and therapy
of GUTB.
Special problems present themselves
with patients with immunosuppres-
sion (AIDS or after transplantation) and
migrants with tuberculosis from countries
with a high prevalence of tuberculosis.
REFERENCES
1. Harries AD, Robert Koch and the dis-
covery of the tubercle bacillus: the chal-
lenge of HIV and tuberculosis 125 years
later. Int J Tuberc Lung Dis, 2008. 12(3):
241–9.
2. Lenk S and Schroeder J, Genitourinary
tuberculosis. Curr Opin Urol, 2001. 11:
93–96.
3. Migliori GB, Loddenkemper R, Blasi
F, and Raviglione MC, 125 years after
Robert Koch’s discovery of the tubercle
bacillus: the new XDR-TB threat. Is “sci-
ence” enough to tackle the epidemic? Eur
Respir J, 2007. 29(3): 423–7.
Urinary tuberculosis | 15.2 |
4. World Health Organization, Treatment
of Tuberculosis: Guidelines for National
Programs. Third Edition ed. 2003,
Geneva: WHO.
5. World Health Organization, Global
Tuberculosis Control 2008: Surveillance,
Planning, Financing. 2008, Geneva:
WHO. WHO/HTM/TB 2008.39.
6. Lenk S, Epidemiology of genitourinary
tuberculosis in Germany. Eur Urol, 2004.
Suppl 3(2): 206.
7. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
8. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
9. German “Zentralkommitee zur
Bekämpfung der Tuberkulose”: 31st
Information Report 2008, Berlin.
10. German “Zentralkommitee zur
Bekämpfung der Tuberkulose”: 30th
Information Report 2007, Berlin.
11. Forssbohm M, Zwahlen M,
Loddenkemper R, and Rieder HL,
Demographic characteristics of patients
with extrapulmonary tuberculosis in
Germany. Eur Respir J, 2008. 31(1):
99–105.
12. Robert-Koch-Institute, Report of
Epidemiology of Tuberculosis in Germany
2006 2006, Berlin: Robert-Koch-Institute
13. Barisic Z, Vrsalovic-Carevic N, Milostic
K, Alfirevic D, Babic-Erceg A, Borzic E,
Zoranic V, Kaliterna V, and Carev M,
Tuberculous orchiepididymitis diagnosed by
nucleic acid amplification test: a case report.
Int Urol Nephrol, 2003. 35(2): 203–5.
14. Figueiredo AA, Lucon AM, Junior RF,
and Srougi M, Epidemiology of urogenital
tuberculosis worldwide. Int J Urol, 2008.
15(9): 827–32.
15. Carl P and Stark L, Indications for surgi-
cal management of genitourinary tubercu-
losis. World J Surg, 1997. 21(5): 505–10.
16. Engin G, Acunas B, Acunas G, and Tunaci
M, Imaging of extrapulmonary tuberculo-
sis. Radiographics, 2000. 20(2): 471–88;
quiz 529–30, 532.
875
Chapter | 15 | Special urogenital infections
17. Harisinghani MG, McLoud TC, Shepard
JA, Ko JP, Shroff MM, and Mueller
PR, Tuberculosis from head to toe.
Radiographics, 2000. 20(2): 449–70; quiz
528–9, 532.
18. Watterson SA and Drobniewski FA,
Modern laboratory diagnosis of myco-
bacterial infections. J Clin Pathol, 2000.
53(10): 727–32.
19. Hemal AK, Gupta NP, Rajeev TP, Kumar
R, Dar L, and Seth P, Polymerase chain
reaction in clinically suspected genitouri-
nary tuberculosis: comparison with intra-
venous urography, bladder biopsy, and
urine acid fast bacilli culture. Urology,
2000. 56(4): 570–4.
20. Takahashi S, Hashimoto K, Miyamoto S,
Takeyama K, Takagi Y, and Tsukamoto T,
Clinical relevance of nucleic acid amplifi-
cation test for patients with urinary tuber-
culosis during antituberculosis treatment.
J Infect Chemother, 2005. 11(6): 300–2.
21. Moussa OM, Eraky I, El-Far MA, Osman
HG, and Ghoneim MA, Rapid diagnosis of
genitourinary tuberculosis by polymerase
876
chain reaction and non-radioactive DNA
hybridization. J Urol, 2000. 164(2): 584–8.
22. Lenk S, Detection of mycobacterica in
specimens of genitourinary tract. J Urol
Urogynäkologie, 2000. 7: 7–13.
23. Stepanshina VN, Panfertsev EA,
Korobova OV, Shemyakin IG, Stepanshin
YG, Medvedeva IM, and Dorozhkova IR,
Drug-resistant strains of Mycobacterium
tuberculosis isolated in Russia. Int J
Tuberc Lung Dis, 1999. 3(2): 149–52.
24. World Health Organization,
Antituberculosis drug resistance in the
world. Report No.4 (2008). 2008, Geneva:
WHO. WHO/HTM/TB/2008.394.
25. Gow JG, Genitourinary tuberculosis: a
study of short course regimes. J Urol,
1997. 115: 707–711.
26. Skutil V, Varsa J, and Obsitnik M, Six-
month chemotherapy for urogenital tuber-
culosis. Eur Urol, 1985. 11(3): 170–6.
27. Kim HH, Lee KS, Park K, and Ahn H,
Laparoscopic nephrectomy for nonfunc-
tioning tuberculous kidney. J Endourol,
2000. 14(5): 433–7.
|15.3|
Male genital tuberculosis
1
Ekaterina Kulchavenya, 2Chul-Sung Kim
1
Novosibirsk Research TB Institute, Novosibirsk, Russia
2
Department of Urology, Chosun University Hospital, Gwangju, Korea
Address of Corresponding Author: Ekaterina Kulchavenya, MD, Professor and Head of Urogenital Department of Research TB
Institute, Okhotskaya 81-a, Novosibirsk 630040, Russian Federation
Tel +7-383-203-79-89, Fax +7-383-203-68-75, ku_ekaterina@mail.ru
The diagnosis Male Genital Tuberculosis
is rare, but the disease is not

ABSTRACT MGTB presents non-specific symptoms

Tuberculosis (TB) and HIV/AIDS have
reached such proportions worldwide that
the development of civil societies is seri-
ously endangered. TB caused by immuno-
deficiency due to HIV or malnutrition is
enhanced by more aggressive tuberculous
Mycobacteria (MBT). 425,000 multi-drug
resistant (MDR) TB cases emerge every
year throughout the world. 67% of the
estimated MDR-TB cases exist in China,
India and the Russian Federation. The
highest MDR-TB prevalences are found
in the former USSR and China.
Urogenital TB is the second most com-
mon form of TB in countries with severe
epidemic situation and the third most
common form in regions with low inci-
dence of TB. Male genital TB (MGTB)
seems to be a rare disease. Nevertheless,
77% of men who died from TB of all locali-
zations had prostate TB, which had mostly
been overlooked during their life time.
and laboratory findings, except for a posi-
tive MBT culture, but only about 36% of
cases are culture-positive. Co-morbidity
with other forms of TB is common for
MGTB (45–79%), but isolated tubercu-
lous epididymitis was diagnosed in 21.5%
of cases in one study.
In countries with low incidence of TB,
three antituberculous drugs may be suf-
ficient for treatment. In epidemic regions
MGTB should be treated with four to five
antituberculous drugs such as isoniazid
10 mg/kg, rifampicin 10 mg/kg, pyrazi-
namid 20 mg/kg, streptomycin 15 mg/kg
and PAS 150 mg/kg (or ofloxacin 800 mg
or levofloxacin 500 mg), simultaneously
over two to four months, followed by six
to eight months of chemotherapy with
isoniazid and rifampicin only.
A caseating abscess with firm swell-
ing not responding to chemotherapy and
remaining unchanged or slowly increas-
ing in size despite the administration of
Chapter | 15 | Special urogenital infections
antibiotics and antituberculous chemo-
therapy is an indication for surgery.
Key words: male genital tuberculo-
sis, Mycobacterium tuberculosis, diag-
nosis, antituberculous chemotherapy,
urogenital.
SUMMARY OF RECOMMENDATIONS
Epidemiology and Pathogenesis
1. Male genital tuberculosis (MGTB)
is a rare form of tuberculosis (TB),
but in countries with epidemic TB
a large proportion of patients are
underdiagnosed (LoE 2).
2. MGTB is usually (over 50%) associ-
ated with lung and/or renal TB (actual
or cured), but isolated forms are also
possible. Usually the epididymis and
prostate are involved (LoE 1).
3. The main route of infection is via
hematogenous spread, but direct
extension from infected urine and lym-
phatic spread is also possible (LoE 1).
Diagnosis
4. All patients with genital TB should
be screened for chest and upper
urinary tract involvement and HIV
infection (GoR A).
5. The urine should be examined for
red blood cell and leucocytes in three
consequent portions (three-glass-test)
during urine voiding without inter-
ruption (GoR A). Leucocyturia in the
first portion means an inflammation
in the urethra, in the second portion
an inflammation in the urinary blad-
der or upper urinary tract, and in the
third portion an inflammation in the
prostate. Leucocyturia in all three
portions mirrors a severe inflamma-
tion of the total urinary system.
6. The three-glass-test should be
performed before digital rectal
878
examination to avoid contamination
of urine with prostatic fluid (GoR B).
7. At least three, but preferably five
serial microbiologic studies with
urine, ejaculate and prostate secretion
including smears, cultures (GoR A)
and PCR (GoR B) should be performed
to make the diagnosis of MGTB.
8. In isolated external genital TB with-
out renal and prostate involvement,
diagnosis of MBT is often only possi-
ble by pathomorphology (GoR B).
9. In difficult cases a provocative sub-
cutaneous tuberculin test is recom-
mended (GoR B).
10. Radiologic studies including renal
ultrasonography, TRUS, CT, and
MRI may be helpful to visualize a
prostate cavern (GoR C).
11. For cavernous prostate tuberculosis
retrograde urethrography is crucial
(GoR A)
12. Fine needle aspiration cytology
(FNAC) is an accurate and rapid
diagnostic tool for scrotal TB (GoR C).
Treatment
Comment: The principles of antitubercu-
lous chemotherapy in MGTB are different
between various forms and between coun-
tries with different epidemic situations.
13. Short term treatment for six to nine
months is suitable in uncomplicated
cases in regions with low incidence of
TB (GoR B).
14. In complicated cases (retreatment,
immunosuppression, drug-resistance
and HIV/AIDS) and in epidemic
regions it should be longer, up to
12–14 months with four to five drugs
(GoR B).
1. INTRODUCTION
Urogenital tuberculosis (UGTB) is the sec-
ond most common form of TB in countries

with a severe epidemic situation and the
third most common form in regions with
low incidence of TB. MGTB seems to be
a rare disease. Nevertheless, 77% of men
who died from tuberculosis of all locali-
zations had prostate tuberculosis which
had mostly been overlooked during their
life time [1]. In actual figures, this means
about 19,000 men yearly in Russia.
MGTB presents non-specific symptoms
and laboratory findings, except for posi-
tive Mycobacteria tuberculosis (MBT)
culture, but only about 36% cases are
culture-positive. This is one of the main
reasons for late and poor diagnosis of
MGTB. The significance of genital TB may
be considerable when the high prevalence
of overall TB and the asymptomatic nature
of genital TB are taken into account.
2. METHODS
A Medline/PubMed research with key
words “male genital tuberculosis” resulted
in a total of 825 titles, 159 within the last
10 years (since 1999). Among the articles
of the last 10 years, 63 (39.6%) were case
reports, including cases of tuberculous
epididymorchitis and prostatitis follow-
ing intravesical BCG for superficial blad-
der cancer, 16 (10.1%) were associated
with AIDS, 32 (20.1%) mentioned MGTB
in the context of other diseases, and only
48 were specifically dedicated to MGTB,
describing the experience of single cent-
ers. To estimate the real prevalence of
MGTB worldwide is almost impossible,
since genital tuberculosis accounts for
relatively small fractions of tuberculosis.
Most studies have been published under
the topic of ‘genitourinary tuberculosis’,
but focus mainly on urinary tract tuber-
culosis and the proportion of genital
involvement varying by region. Only one
meta-analysis was found and two guide-
lines (one in Russian), also seven mono-
graphs in Russian, but all of them were
dedicated to urogenital TB or extrapul-
monary TB, but none to MGTB exactly.
Male genital tuberculosis | 15.3 |
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [2–3].
3. TERMS AND CLASSIFICATIONS
The first note of urogenital TB was
made by Porter in 1894 [4]; later in 1937
Wildbolz [5] suggested the term genitouri-
nary TB. We prefer the term urogenital
TB (UGTB), because kidney TB, which is
usually primary, is diagnosed more often
than genital TB. Only 53% of patients
with kidney TB have genital lesions, but
in 61.9% patients with epididymorchitis
and in 79.3% patients with TB of the pros-
tate a renal lesion can be diagnosed [6].
MGTB includes tuberculous epididy-
morchitis (uni- and bilateral), TB of the
prostate, TB of a seminal vesicle (only in
combination with other forms of UGTB),
unilaterally or bilaterally, and TB of the
penis (very rarely).
4. EPIDEMIOLOGY
TB and HIV/AIDS have reached such
proportions worldwide that the develop-
ment of civil societies is seriously endan-
gered. It is therefore mandatory that the
fight against infections should be a mat-
ter of concern to all, including “big poli-
ticians”. Consequently, these infections
have been on the agenda of both the G-8
summit in 2006 and 2007. At both meet-
ings, the G-8 nations committed them-
selves to act now [7].
According to the World Health
Organization (WHO) 425,000 multi-drug
resistant (MDR) TB cases emerge every
year throughout the world [8]. With inad-
equate and poor quality treatment or with-
out treatment at all, MDR-TB can develop
and spread throughout communities. 67%
of the estimated MDR-TB cases are found
in China, India and the Russian Federation
[8], with the highest MDR-TB prevalences
879
Chapter | 15 | Special urogenital infections
in the former USSR and China. The most
severe drug resistance patterns are found
in the former USSR. Now a new threat to
TB control has appeared – the extensively
drug resistant TB (XDR-TB), which is
completely resistant to all antituberculous
chemotherapeutics [8].
Based on surveys and death registra-
tions, 8.9 million new cases of TB were esti-
mated in 2004, less than half of which were
reported to public health authorities and to
WHO [7]. Approximately 3.9 million cases
were sputum-smear positive, the most
infectious form of the disease. The WHO
African region has the highest estimated
incidence rate (356 per 100,000 habitants
per year) but the highest number of TB
patients live in the most densely populated
countries of Asia. Bangladesh, China, India,
Indonesia and Pakistan together account
for half of the new cases arising each year
[7]. According to the WHO report 2008, the
worldwide estimated incidence of new cases
of TB increased in 2006 to 9.2 million (139
per 100 000 on average). Large proportions
of cases occur in Asia (South-East Asia and
Western Pacific region) and Africa; 55% and
31%, respectively [9].
One-third of the world’s population is
currently infected with MBT.
TB kills more youths and adults than
any other infectious disease.
Every four seconds someone falls ill
with TB and every 10 seconds someone
dies from TB.
Left untreated, a person with active
TB can infect between 10 and 15 people
every year.
TB accounts for 9% of deaths among
women between 15 and 44 years of ages
compared with war, which accounts for
4%, HIV for 3% and heart diseases for 3%
of deaths. Of all causes of death TB holds
the eighth place, of all infectious diseases
the fourth place and of infectious diseases
in adults the first place [10].
Besides social property and insufficient
medical care, the HIV/AIDS epidemic is
the main cause of TB, which is still one
of the most important infectious diseases
880
of the world more than 100 years after
Robert Koch discovered its pathogen in
1882. In Africa and Eastern Europe, the
incidence of TB is increasing as a result
of AIDS spreading widely, emergence of
resistant organisms, low socioeconomic
status, and of human migration [11–13].
25–50% of HIV patients worldwide have
active TB. Pulmonary TB is more danger-
ous and obvious, but extrapulmonary TB
is also contagious and potentially lethal,
and it affects the quality of life much
more than pulmonary TB [14].
BCG-therapy of bladder cancer and
kidney transplantation may also play a
role in the incidence of urogenital tuber-
culosis [15].
In countries with severe epidemic
TB, UGTB is the most common form of
extrapulmonary TB. In countries with low
incidence lymphonodal TB predominates.
5. PATHOPHYSIOLOGY
The lungs are the most common primary
entry site for Mycobacterium tuberculosis.
The renal seeding of mycobacteria occurs
via haematogenous route. However, ini-
tiation of genital organ involvement by
mycobacteria has several routes, the
main one is also haematogenous. The fact
that over 50% of patients with MGT have
renal lesions suggests that MGTB origi-
nates from direct extension of infected
urine by reflux into the prostate. But hae-
matogenous spread may also be signifi-
cant in isolated genital TB [16].
TB when induced by immunodefi-
ciency due to HIV infection or malnutri-
tion shows enhanced aggression of MBT.
A weakened human organism with lack
of antibodies and not enough sensitized
immunocompetent cells is not able to
resist a causative agent with extreme
reproduction. Generalized and polycav-
ernous processes increase the mycobacte-
rial population rapidly and consequently
also mutants accumulate which may be
resistant to antibiotics or chemodrugs [7].

In MGTB the epididymis and the pros-
tate are the most common sites, followed
by the seminal vesicles, and the testicles
[17–18]. Tuberculous foci in the epidi-
dymis are caused by metastatic spread of
MBT via the blood stream. The disease
usually starts in the lobus minor, because
it has a greater blood supply than other
parts of the epididymis. During mycobac-
teriaemia there is an inoculation of myco-
bacteria both in the epididymis and in
the testicle. But the pathological process
originally develops in the epididymis and
then passes on to the testicle. The absence
of visual signs of an orchitis in a patient
with tuberculous epididymitis however
does not mean that he has healthy tes-
ticles. Therefore we continue to use the
term “epididymorchitis”, even if only the
epididymis appears indurated.
TB of the testis is almost always second-
ary to infection of the epididymis, which
in most cases is blood-borne because of
the extensive blood supply of the epidi-
dymis, particularly the lobus minor.
Isolated tuberculous orchitis is extremally
rare [11]; we have found two cases in the
literature, and actually both had epidi-
dymal lesion, too. The route of infection
is through the hematogenous spread of
organisms, as in infection of the kidney.
Prostate TB seems to be rare, it is usu-
ally asymptomatic and found after a
transurethral resection. Nevertheless, 77%
men died from tuberculosis of all localiza-
tions, had prostate tuberculosis, mostly
overlooked during life time [6]. In patients
with AIDS, large tuberculous abscesses of
the prostate have been reported [19–20].
There are also unusual pathways of pri-
mary infection. Recent data showed that
TB is also a sexually transmitted disease.
Patients with pulmonary TB presented
MBT in ejaculate in 0.08%, in case of
co-morbidity of TB and hepatitis in 18.8%.
Patients suffering from TB, hepatitis
and syphilis simultaneously have shown
growth of MBT in ejaculate in 48.5% [21].
Penile TB is very rare but can occur
after sexual coitus with infected females
Male genital tuberculosis | 15.3 |
[22] or via a direct infection through a
penile wound during ritual circumcision.
Penile lesions present as ulcers on the
glans or penile skin [23].
6. CLINICAL FEATURES
TB of the epididymis may involve the tes-
tis, in which case the lesion mimics acute
non-specific epididymorchitis. Tuberculous
epididymorchitis has local rather than
systemic symptoms, which may be mild,
intermittent and often asymptomatic.
TB of the scrotal organs may be the first
and only symptom of UGTB. In 66.7%
the onset of the disease was acute, with
fever, pain, edema, and hyperaemia.
Tuberculous epididymorchitis without
any other focuses of TB was diagnosed in
21.5%. All those patients had acute onset
mimicking acute non-specific epididymor-
chitis. All patients were operated on and
diagnosis was established by pathomor-
phological investigation [24].
The usual presentation of tuberculous
epididymorchitis is a painful, inflamed
scrotal swelling. Occasionally, a discharg-
ing sinus may be found posteriorly, fistu-
lous forms were seen in 11.9% (Figure 1).
In these patients only the diagnosis may
be made by culture of MTB from a dis-
charging sinus, in other cases by patho-
morphology after epididymectomy. In case
of a testicular mass, genital TB is difficult
to differentiate from malignancy [25].
Frequency and nocturia are the most
common symptoms of prostate TB. Other
urinary tract symptoms such as dysuria,
haematuria, and haematospermia are also
present in prostate TB. Urgency is usually
present if the bladder is involved [24–25].
The physical findings suggesting genital
TB are the following: an enlarged, hard,
and non-tender epididymis; thickened or
beaded vas deferens; prostatic indura-
tions or nodules on rectal examination; or
a non-tender testicular mass. As inflam-
mation progresses, fistula formation on
the scrotum or perineum may also be seen
881
Chapter | 15 | Special urogenital infections
Figure 1 Tuberculous orchiepididymitis with fistula,
metatuberculous dermatitis.
Figure 2 TB epididymitis. In the tissue of the epididymis –
focuses of caseous necrosis, surrounded by epithelioid cells
and fibrosis with different maturity. X100. van Gieson.
in 11–50% of patients [1, 26] (Figure 2).
Hydrocele and inguinal lymphadenopathy
may be present infrequently [17, 27].
7. MALE GENITAL TUBERCULOSIS
IN WEST SIBIRIA
Over the last five years the inci-
dence of TB stayed constant in Siberia
882
(126.1/100000 in 2003 and 128.8 in 2007).
However, during the same period the inci-
dence of extrapulmonary forms decreased
from 4.3 to 3.2 in 100000 habitants. In
2003, 1078 new patients with extrapul-
monary TB were diagnosed in Siberia;
in 2007 only 854. The proportion of clini-
cal forms was identical throughout these
years: urogenital TB was the prevalent
form (46.0–33.5%); TB of bone and joints
was in the second place (20.1–32.7%),
followed by lymphonodal TB (14.7–
14.9%) [16, 28]. The clinical findings of
newly revealed extrapulmonary TB in
Russian Federation is demonstrated in
Diagram 1. There is, however, a big dif-
ference between the clinical appearance
of extrapulmonary TB in Germany and in
Russian (Diagram 2) [11].
From 514 patients with UGTB in West
Siberia, 58 (11.3%) had prostate TB and
42 (8.2%) – scrotal TB. The mean age of
the patients was about 40 years. 11.9% of
the patients were 20–30 years old; there
were no patients under 20 years. Most
patients were between 30 to 50 years old
(61.9%). 33.6% of patients had a previous
history of TB; the present disease was a
relapse of TB [24].
Tuberculous epididymorchitis may be
associated with renal disease, but not
always. Nevertheless in 61.9% of cases
besides epididymorchitis, nephrotuber-
culosis was diagnosed. In 30.9% bilat-
eral lesion of the epididymis was marked.
Co-morbidity of scrotal organs and pros-
tate was diagnosed in 35.7% [24]. A case
of generalized UGTB with TB of kidney,
ureter, bladder, prostate, seminal vesicles
is demonstrated on Figure 3.
The culture of MTB in urine was posi-
tive in 38.1% of patients with tuberculous
epididymorchitis. All of them had also
kidney TB, none had a growth of MBT in
ejaculate or prostate secretion [24].
Every fifth patient (21.4%) was diag-
nosed after orchidectomy, performed
while misdiagnosed as non-specific acute
epididymorchitis in general urological
clinics (Figure 4) [21].
 Male genital tuberculosis | 15.3 |

The mean age of patients with pros-
tate TB was 49 years. Half of the
patients complained of dysuria, 39.6%
had perineal pain, 58.6% had flank pain.
Laboratory findings showed leucocyturia
in 84.5%, and leucocytes in prostate secre-
tions or ejaculate in 77.6%. Erythrocytes
in urine were presented in 53.4%, and in
prostatic secretions in 29.3%. MBT was
found only in 36.2%, but in 9.5% with
drug resistance to ethambutol and strep-
tomycin (Diagram 3) [24].
In 79.3% tuberculous prostatitis was
combined with nephrotuberculosis, in
31.0% with TB of a testicle and epidi-
dymis; in 17.2% with bladder TB [24].

As whole

Male Bone and joints

Urogenital
Female Lymphonadal
Eyes
Children under 17 Others

Adult

0% 20% 40% 60% 80% 100%

Diagram 1 Clinical appearance of newly diagnosed Extrapulmonary Tuberculosis in Russia in 2005 [12].

Extrapulmonary TB in Russian Extrapulmonary TB in Germany

11% 6% 6%
26%
8% 17%
Bone and joints
UGT
Lymph. nodes
17%
Eyes
Others 50%
21%

38%
Diagram 2 Clinical appearance of extrapulmonary TB in Germany and in Russian.

Figure 3 TB epididymitis. Forming cavity within epididymis, Figure 4 Generalized Urogenital Tuberculosis: Tuberculosis
different maturity fibrosis is around. X100. van Gieson. of kidney, ureter, bladder, prostate, seminal vesicles.

883
Chapter | 15 | Special urogenital infections
84,5
90
80
70
53,4
60
50
40
30
20
10
0
Diagram 3 Laboratory findings of prostate tuberculosis [19].
8. DIAGNOSIS
The main reason for late diagnosis of
UGTB is probably poor knowledge of
the doctors and the population of this
disease. Also the clinical picture has
changed over the last years, which makes
an on-time diagnosis difficult. For a cor-
rect diagnosis a careful investigation of
the epidemiological history (contact with
tuberculous infection, TB in history, espe-
cially in childhood) and special diagnostic
algorithms, including provocative tests, is
necessary.
In patients with suspected genital TB
the clinical investigation should aim to
detect concomitant urinary and pulmo-
nary TB, since most genital TB cases are
combined with renal or pulmonary TB.
The Mantoux test is positive in more than
90% of patients, but it has no value in
regions with a severe epidemic situation
(China, Russia, India, Africa), where all
adults are infected with MBT and thus all
have positive skin tuberculin test [29–31].
Chest films reveal lung lesions in about
50% of patients [29–31]. All patients with
suspected or confirmed genital TB should
be screened for HIV.
Abnormal urinalysis can be seen in
up to 90% of UGTB [26]. Sterile pyu-
ria was the classic finding in kidney TB,
but now up to 75% patients with UGTB
have associated non-specific pyelonephri-
tis. Thus, the growth of uropathogens in
urine is not uncommon in TB patients
[6]. Haematuria is presented in about
884
77,6
Leucocyturia
Erythrocyturia
Leucocytes in
36,2 secretion
29,8 Erythrocytes in
secretion
MBT
50% of patients. MTB can be identified in
urine in 64% of UGTB patients by urine
acid-fest bacteria (AFB) cultures, AFB
smears, or nucleic acid amplification tests
(NAATs) [32], but actually bacteriologi-
cal verification is significantly lower due
to the widespread use of fluorquinolons.
Because TB is epidemic in Russia the
National Russian Urological Congress
approved a resolution in 2007, that all
cases of infections of the urogenital
tract should be suspicious for TB, and
first line therapy should exclude anti-
bacterials affecting MBT (fluorquinolons,
rifampicin, streptomycin or amycacin).
All patients with an infection of the uro-
genital tract should be investigated for
TB by culture and/or microscopy. Only
after TB is excluded, they may be treated
with fluorquinolons.
The detection rates of MGTB may be
lower than that of renal TB, because the
quantity of mycobacteria in urine can be
lower, the affected sites may not be in
direct contact with urine, and the urine
itself may not be infected [33]. Therefore
bacteriological investigations of prostate
secretion and ejaculate are obligatory for
patients with suspected MGTB.
Since tuberculous prostatitis is mostly
associated with renal and bladder TB,
urinalysis should be performed prima-
rily, before digital rectal examination or
prostatic massage, to exclude renal and
bladder lesions. If urinalysis shows any
pathology, complete investigation of the
urinary tract is indicated.

The urine should be examined for red
blood cell and leucocytes in three con-
sequent portions (three-glass-test) dur-
ing urine voiding without interruption.
As the prostate is part of the external
sphincter of the bladder, it contracts
at the end of a micturition. Therefore
it is necessary, that urination into the
three glasses should be performed with-
out interruption of the urine stream to
avoid earlier contraction of the external
sphincter including the prostate gland.
Leucocyturia in the first portion means
an inflammation in the urethra, in the
second portion an inflammation in the
urinary bladder or upper urinary tract,
and in the third portion an inflammation
in the prostate. Leucocyturia in all three
portions mirrors a severe inflammation
of the total urinary system. In our opin-
ion the classical four-glass test (initial
urine, midstream urine, prostatic secre-
tion obtained by prostatic massage, and
urine after prostatic massage) is more
difficult for the physician and more both-
ersome for the patient and also is of less
informative value. Therefore, we consider
it unsuitable. Moreover, in the case of
prostate TB the four-glass test may show
false-positive results of midstream urine
if micturition was interrupted after the
first voided portion due to contamination
of the urine with prostatic secretion.
Digital rectal examination (DRE) with
soft massage of the prostate should be
performed only after urinalysis, because
DRE before urinalysis may lead to false
positive leucocyturia. The prostatic secre-
tion and/or ejaculate have to be investi-
gated microscopically and by culture for
both, uropathogens and MBT, as soon as
possible after DRE or ejaculation, opti-
mally not later than 40 min after. At least
three to five consecutive early morning
specimens of urine and prostatic secre-
tion or ejaculate should be cultured by
two slants [34]. The antimicrobial suscep-
tibility of the strain should be estimated.
Prostatic secretion and ejaculate should
also be investigated with PCR.
Male genital tuberculosis | 15.3 |
Ultrasound investigation of the uri-
nary system should be performed in all
patients with inflammation of the geni-
tals. Epididymal or testicular TB has
nonspecific findings. The presence of
various pathologic components, includ-
ing caseous necrosis, granulation tissues
and fibrosis, are responsible for the diver-
sity of findings. Tuberculous epididymitis
and orchitis present as diffusely enlarged
lesions, which may be homogeneous or
heterogeneous and can also present as
nodular enlarged heterogeneously hypoe-
choic lesions [35–36].
Transrectal ultrasonogram findings
of prostatic disease are irregular hypoe-
choic lesions in the peripheral zone [37].
On contrast-enhanced CT scan, TB of the
prostate or seminal vesicles can be seen
as low density or cavitation lesions due
to necrosis and caseation with or without
calcification. Without calcification, the
findings may be similar to pyogenic pros-
tatic abscess [38–39]. Reports about MRI
findings of prostatic TB are relatively
rare. Diffuse radiating streaky low signal
intensity lesion in the prostate (water-
melon skin sign) on T2-weighted images
may be specific for tuberculosis of the
prostate [40].
Complex radiography is indicated for
patients suspected on UGT: plain X-ray
films of the urinary tract detect calcifica-
tion in the renal areas and in the lower
urogenital tract; intravenous urography
is indicated for patients with leucocy-
turia and/or abnormality on ultrasound
investigations. Retrograde urethrography
should be performed in all patients with
genital tuberculosis to exclude caverns
of the prostate. Some cases of cavernous
tuberculosis of the prostate are demon-
strated on Figures 5–8.
The FNAC may be useful in the diag-
nosis of TB of external male genitals
[41–44]. FNAC has been helpful in pre-
venting aggressive and inappropriate sur-
gical procedures by providing an accurate
and rapid diagnosis. Even though FNAC
of epididymal nodules is not easy to
885
Chapter | 15 | Special urogenital infections
Figure 5 Tuberculosis of a prostate gland with fistula.
Duration of disease is 17 years.
Figure 6 Tuberculosis of a prostate. Giant multinucleated
cell (left) is surrounded by lymphocytic infiltration. X100.
Hematoxylin and eosin.
perform since the nodules are small and
slippery, it has a reported successful rate
of 90.3% for diagnosis of epididymal nod-
ules [41] and a reported sensitivity and
specificity of 87% and 93%, respectively,
for tuberculous epididymitis [44]. A few
studies have reported successful diag-
nosis of tuberculous orchitis by FNAC
[42–43]. However, scrotal violation should
be considered if the mass is malignant.
The correct diagnosis of the urogenital
tuberculosis is difficult in general uro-
logical clinics; it is a prerogative of the
urologist with a special skill in phthisiol-
ogy. The diagnostic algorithm includes a
886
Figure 7 Retrograde urethrogram: tuberculous caverns of a
prostate.
Figure 8 Retrograde urethrogram: tuberculous caverns of a
prostate.
subcutaneous tuberculin provocative test
in modification Kulchavenya [45].
The indications for the provocative test
are the following:
• Epidemiological anamnesis (contact
with people or animal, suffering from
tuberculosis);
• Recurrent pyelonephritis with simul-
taneous cystitis, chronic prostatitis,
chronic epididymorchitis when stand-
ard medical treatment did not solve
the symptoms
• Suspicion of a destruction of calyxes
seen by intravenous urography;

Figure 9 TB of right seminal vesicle in stage of calcification.
Contraindications are: fever, gross
haematuria.
Technique of the provocative test is
as follows:
1. 48 hours before the test, survey of
body temperature
2. Initial laboratory investigation
includes analyses of urine and blood,
microscopy of the prostatic secretion
and ejaculate, culture of urine, pros-
tate secretion and ejaculate, including
PCR investigation.
3. Injection of 50 unit tuberculin
subcutaneously
4. All laboratory investigations including
body temperature are repeated 24 and
48 hours after tuberculin injection.
The test is positive if leucocytosis, lym-
phocytopenia, leucocyturia, leucocytosper-
mia and body temperature have increased
by more than one degree. Also local
Male genital tuberculosis | 15.3 |
Figure 10 Small cavern of a prostate.
reaction (hyperemia, induration in place
of injection tuberculin) is to be taken into
account. After provocative subcutaneous
tuberculin test identification of MBT by
culture or PCR increased by 16% [45]. On
the whole, this test improved the diag-
nostics of UGTB, especially the hidden,
latent forms, to 63.4% [45].
9. TREATMENT
Drugs that can cure most TB patients
have been available since the 1950s,
yet TB remains the world’s second most
important cause of death by infectious
diseases [46]. Unfortunately, after half a
century of phthisiology there is no new
drug. In the same time resistance of
mycobacteria has increased enormously.
Mono-, poly, and multi-drug resistant
MBT to the basic antituberculous drugs
was found in up to 52.2% of extrapulmo-
nary TB patients and up to 78.7% in pul-
monary TB patients [47].
Medical treatment of genital TB is
somewhat different from that of other TB,
because prostatotropic drugs have to be
preferred. In countries with low incidence
of TB three antituberculous drugs with
bactericidal activity may be sufficient for
bacterial eradication and prevention of
resistance. In epidemic regions patients
with MGTB should be treated with four
or five antituberculous drugs: isoniazid
887
Chapter | 15 | Special urogenital infections
10 mg/kg + rifampicin 10 mg/kg + pyrazin-
amid 20 mg/kg + streptomycin 15 mg/kg +
PAS 150 mg/kg (or ofloxacin 800 mg or
levofloxacin 500 mg daily) simultaneously
for two to four months, followed by six to
eight months of chemotherapy with isoni-
azid and rifampicin only [48].
Table 1 shows WHO recommended
essential antituberculous drugs [49]. The
treatment time has been reduced from
two years to nine or six months with
these combination therapies, in compli-
cated or combined cases the length of
the therapy may be 12–14 months. Table
2 summarizes a six month therapy of
uncomplicated extrapulmonary TB rec-
ommended from WHO [49]. In cases of
re-treatment, immunosuppression and
HIV/AIDS the treatment time increases
to nine or 12 months. In epidemic regions
a scheme of chemotherapy, approved by
the Russian Ministry of Public Health
should be used (Table 3) [1].
Surgical managements of genital
tuberculosis are abscess drainage and
epididymectomy. At least four weeks of
antituberculous chemotherapy should
be performed before surgery. There are
two indications for epididymectomy:
a caseous abscess that is not respond-
ing to chemotherapy, and a firm swell-
ing that has remained unchanged or has
slowly increased in size despite the use
Table 1 Essential antituberculosis drugs.
Recommended dosage (dosage range) in mg.kg
Essential drug (abbreviation)
Daily
Isoniazide (H) 5 (4–6)
Rifampicin (R) 10 (8–12)
Pyrazinamide (Z) 25 (25–30)
Streptomycin (S) 15 (12–18)
Ethambutol (E) 15 (15–20)
Thioacetazone (T) 2.5
888
of antibiotics and antituberculous chemo-
therapy [50].
10. FOLLOW-UP
After antituberculous therapy patients
should be observed for at least three
years, because the cavities of the prostate
do not close earlier. Therefore the risk of
relapse is high.
11. FURTHER RESEARCH
Up to now late diagnosis of MGTB domi-
nates. It is necessary to develop a screen-
ing system for early detection of MGTB
patient. Also the improvement of pharma-
cotherapy of MGTB should be improved
in order to avoid unnecessary surgical
interventions, as MGTB like other infec-
tions should be cured without surgery.
12. CONCLUSIONS
The incidence of MGTB is not high, but
diagnosis is difficult because genital TB
has no pathognomonic signs. We recom-
mend following an algorithm to improve
the management of patients with prosta-
titis or epididymitis:
3 times weekly
10 (8–12)
10 (8–12)
35 (30–40)
15 (12–18)
30 (25–35)
Not applicable
 Male genital tuberculosis | 15.3 |

Table 2 Male genital TB treatment regimens.

Initial phase Continuation phase

Preferred Preferred

2 HRZE 4 HR
4 (HR)

Optional Optional
2 (HRZE) 4 (HR)
or or
2 HRZE 6 HE

Table 3 Standard schemes of a chemotherapy.

Phase
Regime
Intensive Continuation phase

I 2 H R Z E/S 6 H R / 6 H 3 R3

II-a 2HRZES+1HRZE 5 H R E / 5 H3 R3 E3

II-b 3 H R Z E [Pt] [Cap] / [K] [Fq] According to sensitivity of MBT

III 2HRZE 4 H R / 4 H 3 R3
6HE

IV Not less then 5 drugs Not less then 3 drugs

[Z E Pt Cap/K Fq] [E Pt Fq]
[Rb] [Cs] [PAS] [Rb] [Cs] [PAS]
Length not less then 6 mo. Length not less then 12 mo.

i. Careful study of the history: if the antituberculous effects (fluorquino-

patient had TB or contact with tuber-
culous infection earlier, he has a high
risk of relapsing UGTB.
ii. Complex examination is necessary:
a three-glass test before digital rec-
tal examination, full investigation of
the prostatic secretion, provocative
subcutaneous tuberculin test. In the
case of relapse retrograde urethrog-
raphy is indicated. Co-morbidity
with pyelonephritis, prostatitis and
epididymitis, especially bilateral
epididymitis or fistula are strongly
suspicious for TB.
iii. In regions with epidemic TB the pre-
scription of antibiotics with possible
lons, streptomycin, and rifampicin)
should be restricted unless TB can be
excluded after full examination of the
patient.
REFERENCES
1. Kulchavenya E, Filimonov P, and
Shvetsova O, An Atlas of a Urogenital
tuberculosis and other extrapulmo-
nary localizations (monograph). 2007:
Novosibirsk: «Tirazh-Sibir».
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.

889
Chapter | 15 | Special urogenital infections
3. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
4. Porter MF, III. Uro-Genital Tuberculosis in
the Male. Ann Surg, 1894. 20(4): 396–405.
5. Wildbolz H, Ueber urogenical tuberkulose.
Schweiz Med Wochenschr 1937. 67: 1125.
6. Kulchavenya E, Tuberculosis of urogeni-
tal system in Urology: National Manual
Lopatkin N, Editor. 2009, Geotar-Media:
Moscow. p.584–601.
7. World Health Organization, Global
Tuberculosis Control: Surveillance,
Planning, Financing. 2006, Geneva:
World Health Organization. 362.
8. Zaleskis R, Global epidemiology of
MDR-TB and the role of WHO in
fighting MDR-TB //Pres. on Interagency
Coordinating Committee – 4th meet-
ing focusing on TB. Prioritized Areas
of TB Control in Modern Social and
Epidemiological Enironment. 28 Nov – 1
Dec 2006, Yekaterinburg, Russia 2006.
9. World Health Organization. Global
Tuberculosis Control, Surveillance,
Planning, Financing. 2008; Available
from: http://www.who.int/tb/publications/
global_report/2008/pdf/report_without_
annexes.pdf.
10. World Health Organization, WHO Stop
TB Programme. Global Tuberculosis
Control, WHO Report 2005. 2005, Geneva:
World Health Organization.
11. Schubert GE, Haltaufderheide T,
and Golz R, Frequency of urogenital
tuberculosis in an unselected autopsy
series from 1928 to 1949 and 1976 to
1989. Eur Urol, 1992. 21(3): 216–23.
12. Flechner SM and Gow JG, Role of nephrec-
tomy in the treatment of non-functioning or
very poorly functioning unilateral tubercu-
lous kidney. J Urol, 1980. 123(6): 822–5.
13. Ferrie BG and Rundle JS, Genito-urinary
tuberculosis in Glasgow 1970 to 1979: a
review of 230 patients. Scott Med J, 1985.
30(1): 30–4.
14. World Health Organization, WHO Fact
Sheet N 104, August, 2002. 2002.
15. Kul’chavenia EV and Muzyko LV, [Two
cases of tuberculosis after transplantation
of the kidney]. Urologiia, 2007(6): 80–2.
890
16. Shcherban MN, Kul’chavenia EV,
Brizhatiuk EV, Kaveshnikova E, and
Sveshnikova NN, [Male and female geni-
tal tuberculosis. Reproductive function in
a patient with tuberculosis]. Probl Tuberk
Bolezn Legk, 2008(9): 3–6.
17. Medlar EM, Spain DM, and Holliday
RW, Post-mortem compared with clinical
diagnosis of genito-urinary tuberculosis in
adult males. J Urol, 1949. 61(6): 1078–88.
18. Madeb R, Marshall J, Nativ O, and
Erturk E, Epididymal tuberculosis:
case report and review of the literature.
Urology, 2005. 65(4): 798.
19. Wolf LE, Tuberculous abscess of the
prostate in AIDS. Ann Intern Med, 1996.
125(2): 156.
20. Trauzzi SJ, Kay CJ, Kaufman DG, and
Lowe FC, Management of prostatic abscess
in patients with human immunodeficiency
syndrome. Urology, 1994. 43(5): 629–33.
21. Aphonin AB, Perezmanas EO, Toporkova
EE, and Khodakovsky EP Tuberculous
infection as sexually transmitted infection.
Vestnik poslediplomnogo obrazovaniya
2006. 3–4: 69–71.
22. Narayana AS, Kelly DG, and Duff FA,
Tuberculosis of the penis. Br J Urol, 1976.
48(4): 274.
23. Lewis E, Tuberculosis of the penis: a
report of 5 new cases and a complete
review of the literature. J Urol, 1946.
56: 737–45.
24. Kul’chavenia EV, Khomiakov VT, and
Zhukova, II, [Male genital tuberculosis in
West Siberia]. Urologiia, 2004(4): 34–7.
25. Sporer A and Oppenheimer G,
Tuberculosis of prostate and seminal
vesicles. J Urol, 1957. 78(3): 278–86.
26. Gokce G, Kilicarslan H, Ayan S, Tas
F, Akar R, Kaya K, and Gultekin EY,
Genitourinary tuberculosis: a review of
174 cases. Scand J Infect Dis, 2002. 34(5):
338–40.
27. Oben FT, Wright RD, and Ahaghotu CA,
Tuberculous epididymitis with extensive
retroperitoneal and mediastinal involve-
ment. Urology, 2004. 64(1): 156–8.
28. Kul’chavenia EV, [Extrapulmonary tuber-
culosis control in Siberia and the Far East].
Probl Tuberk Bolezn Legk, 2008(9): 16–9.
29. Gorse GJ and Belshe RB, Male genital
tuberculosis: a review of the literature

with instructive case reports. Rev Infect
Dis, 1985. 7(4): 511–24.
30. Marszalek WW and Dhai A, Genito-
urinary tuberculosis. A 4-year review.
S Afr Med J, 1982. 62(6): 158–9.
31. Heaton ND, Hogan B, Michell M,
Thompson P, and Yates-Bell AJ,
Tuberculous epididymo-orchitis: clinical
and ultrasound observations. Br J Urol,
1989. 64(3): 305–9.
32. Figueiredo AA, Lucon AM, Junior RF,
and Srougi M, Epidemiology of urogenital
tuberculosis worldwide. Int J Urol, 2008.
15(9): 827–32.
33. Jacob JT, Nguyen TM, and Ray SM, Male
genital tuberculosis. Lancet Infect Dis,
2008. 8(5): 335–42.
34. Laboratory Service in Programmes
on Fight with Tuberculosis. Culture
Investigation: World Health
Organization/TB, 2008. 258: 48.
35. Turkvatan A, Kelahmet E, Yazgan C,
and Olcer T, Sonographic findings in
tuberculous epididymo-orchitis. J Clin
Ultrasound, 2004. 32(6): 302–5.
36. Muttarak M, Peh WC, Lojanapiwat B,
and Chaiwun B, Tuberculous epididymi-
tis and epididymo-orchitis: sonographic
appearances. AJR Am J Roentgenol, 2001.
176(6): 1459–66.
37. Engin G, Acunas B, Acunas G, and Tunaci
M, Imaging of extrapulmonary tuberculo-
sis. Radiographics, 2000. 20(2): 471–88;
quiz 529–30, 532.
38. Wang LJ, Wong YC, Chen CJ, and Lim
KE, CT features of genitourinary tuber-
culosis. J Comput Assist Tomogr, 1997.
21(2): 254–8.
39. Premkumar A and Newhouse JH,
Seminal vesicle tuberculosis: CT appear-
ance. J Comput Assist Tomogr, 1988.
12(4): 676–7.
40. Wang JH, Sheu MH, and Lee RC,
Tuberculosis of the prostate: MR appear-
ance. J Comput Assist Tomogr, 1997.
21(4): 639–40.
Male genital tuberculosis | 15.3 |
41. Gupta N, Rajwanshi A, Srinivasan R,
and Nijhawan R, Fine needle aspiration
of epididymal nodules in Chandigarh,
north India: an audit of 228 cases.
Cytopathology, 2006. 17(4): 195–8.
42. Sah SP, Bhadani PP, Regmi R, Tewari
A, and Raj GA, Fine needle aspiration
cytology of tubercular epididymitis and
epididymo-orchitis. Acta Cytol, 2006.
50(3): 243–9.
43. Kumar PV, Owji SM, and Khezri AA,
Tuberculous orchitis diagnosed by fine
needle aspiration cytology. Acta Cytol,
1996. 40(6): 1253–6.
44. Viswaroop B, Johnson P, Kurian S, Chacko
N, Kekre N, and Gopalakrishnan G, Fine-
needle aspiration cytology versus open
biopsy for evaluation of chronic epididy-
mal lesions: a prospective study. Scand
J Urol Nephrol, 2005. 39(3): 219–21.
45. Kul’chavenia EV, [Ex juvantibus therapy
in the differential diagnosis of urogeni-
tal tuberculosis]. Probl Tuberk, 2001(2):
29–31.
46. Kul’chavenia EV, [Low-intensity laser
irradiation in the treatment of patients
with tuberculosis of the urinary system].
Probl Tuberk, 2002(6): 39–41.
47. Vishnevskiy BI and Steklova LN,
Frequency and structure of drug resist-
ance Mycobacteria tuberculosis in different
localizations. Probl Tuberk, 2008. 12: 5–8.
48. Kul’chavenia EV, [Polychemotherapy com-
bined with low-intensity laser therapy in
treating patients with renal tuberculosis].
Urologiia, 2002(2): 34–7.
49. World Health Organization, Treatment
of tuberculosis : guidelines for national
programmes. Revision approved by STAG,
June 2004. 3rd ed. 2004, Geneva: World
Health Organization. vii, 43 p.
50. Cek M, Lenk S, Naber KG, Bishop MC,
Johansen TE, Botto H, Grabe M, Lobel B,
Redorta JP, and Tenke P, EAU guidelines
for the management of genitourinary tuber-
culosis. Eur Urol, 2005. 48(3): 353–62.
891
|15.4|

Genitourinary tuberculosis in a
developing country (Vietnam):
diagnosis and treatment
Chuyen Vu Le, Nguyen Phuc Cam Hoang
Corresponding Author: Chuyen Vu Le, MD, Professor of Urology, Chief of Department of Urology,
Binh Dan Hospital, 371 Dien Bien Phu Q.3, Hochi Minh City, Vietnam
Tel +84 903 840514, Fax +84 8 8391315, vulechuyen@hotmail.com

ABSTRACT 1. INTRODUCTION

In this chapter, genitourinary tuberculo- Vietnam is one among 22 countries in

sis is reviewed in its entirety. Seen in a
single institution in a developing country
where the incidence remains important,
the disease is presented in terms of epi-
demiology, clinical manifestations, inves-
tigation, treatment and follow-up with
an emphasis on diagnosis and treatment
attitudes. Some outcomes of local studies
are also presented in terms of diagnos-
tic tools, treatment modalities, and min-
imally-invasive surgical interventions.
The diagnostic strategy and treatment
attitudes are presented according to local
clinical aspects and health-care facilities.
Key words: Genitourinary tuberculosis
(GUTB); directly observed treatment, short-
course (DOTS); Tuberculosis ureteric stric-
ture, Tuberculosis nonfunctioning kidney.
the world who faces the most serious
tuberculosis endemic with infectious risk
around 2% per year and incidence of 100
per 100,000 population [1]. Genitourinary
tuberculosis (GUTB) in South Vietnam
remains relatively common with many
retardative complications such as urinary
tract deformation, nonfunctioning kidney
and renal insufficiency [2–3].
These days, physicians are provided with
many modern therapeutic means includ-
ing many novel antituberculous drugs,
minimally invasive endourological inter-
ventions and various constructive surgical
techniques, but the therapeutic point-of-
view and management strategy vary from
one physician or one centre to another. The
diagnosis of GUTB remains a difficult one,
the concept of medico surgical therapy and
 Genitourinary tuberculosis in a developing country (Vietnam) | 15.4 |

surveillance is a complicated issue and ureteric strictures: 12.6%, contracted urinary

there is no universal consensus. The clinical
diagnosis, the duration of antituberculous
therapy and the timing of surgical interven-
tions remain questions to be clarified.
bladder: 7.2%, scrotal abscess: 16.2%, mixed
complications: 5.4%. (Figure 4)
3. CLINICAL MANIFESTATIONS

2. EPIDEMIOLOGY Clinical symptoms: in a more recent

In our institution, on average, 35 new
cases of genitourinary tuberculosis are
seen per year [4]. In our former series of
five years (1989–1994) with 167 new cases
of GUTB [21], young age (31–50 years old)
predominates: 73 / 167 cases (43.7%), with
the male: female ratio = 1.8 (Figure 1.).
In this series, isolated GUTB accounted
for 77.2% (129/167 cases), GUTB con-
comitant with pulmonary tuberculosis
accounted for 19.2% (32/167 cases), GUTB
concomitant with other extra-pulmonary
tuberculosis accounted for 3.54% (6/167
cases) (Figure 2.).
In terms of organ involvement, in this
series of 50 GUTB patients complicated
with ureteric strictures over seven years
(1998–2005), flank pain and dysuria pre-
dominated [4].
In this series, the mean duration of
onset of symptoms is 6.3 months (1–36).
Five patients had history of pulmonary TB
(10%), one had lymph node TB (2%) and
one had reactivated GUTB. Forty-seven
patients had positive urine, two had nega-
tive urine in which one had been previously
77.2
80
70

series of 167 new cases of GUTB, iso- 60

lated kidney disease accounted for 13.2% 50
(22/167 cases); kidney and ureter disease 40
accounted for 25.7% (43/167 cases); kid- 30
19.2
ney, ureter, bladder disease accounted 20
for 26.3% (44/167 cases); kidney and 3.54
10
epididymis: 6% (10/167 cases); epidi-
0
dymis: 27.5% (46/167 cases); complex GUTB+PTB GUTB+EPTB GUTB
involvements: 1.2% (2/167) (Figure 3).
The complications of GUTB in this Figure 2 Genitourinary tuberculosis (GUTB) in 167 new
cases (1989–1994)(PTB: Pulmonary tuberculosis, EPTB: other
series: renal insufficiency: 9.6%, pyonephro- extrapulmonary tuberculosis).
sis: 8.9%, TB nonfunctioning kidneys: 3%,
30 27.5
43.7 25.7 26.3
45 25
40
32.9 20
35
30 15 13.2

25 19.8 10
20 6
15 5
1.2
10 0
3.6 Kidney, Kidney, Kidney,
5 Kidney
Ureter Ureter, BL Epidydy-
Epidydy- Complex
mis mis
0
0-15 16-30 31-50 > 50 13.2 25.7 26.3 6 27.5 1.2

Figure 1 Age distribution of 167 new cases of GUTB Figure 3 Organs involment in 167 new cases of GUTB
(1989–1994). (1989–1994).

893
Chapter | 15 | Special urogenital infections

18
16.2
• Urine culture for non-specific
16
organisms.
14 12.6
12 • Ziehl-Neelsen stain for AFB (three
10 9.6
8.9 to six consecutive urine samples)
8 7.2
6 5.4 • Polymerase Chain Reaction (PCR):
4 2.99 for detection of M. tuberculosis
2
(reaction IS6110-PCR).
0
Renal Pyone- Atrop- Ureteric Contra- Scrotal
insuffi- phrosis hied strictu- cted abscess
Combi-
nation • Culture on Löwenstein-Jensen
ciency kidney res bladder
9.6 8.9 2.99 12.6 7.2 16.2 5.4 medium to isolate M. tuberculosis
and nontuberculous mycobacteria
Figure 4 Complications in 167 new cases of GUTB (three consecutive urine samples).
(1989–1994).
In our recent series of 50 GUTB
patients complicated with uret-
Table 1 Clinical manifestation in a series of 50 GUTB eric strictures over seven years
patients complicated with ureteric strictures. (1998–2005) [4], we had the following
results: Ziehl-Neelsen stain for AFB
Clinical symptoms Cases %
in urine: positive: 39 / 50 (78%); nega-
Flank pain 37 74 tive: 11 / 50 (22%). Urine culture on
Löwenstein-Jensen: positive with
Haematuria 10 20
M. tuberculosis: 20 / 47 (42.6%);
Frequency 22 44
positive with M. nontuberculosis:
4 / 47 (8.5%); spoiled urine sample:
Clouded urine 8 16 1 / 47 (2.1%). PCR for M. tuberculosis
Dysuria 25 50
(IS6110-PCR) in 33 patients: posi-
tive: 14 / 33 (42.4%); negative: 19 / 33
Recurrent UTIs 7 14 (57.6%) with PCR sensitivity about
45.2–73.7%. This sensitivity is consid-
Hemospermia 1/12* 8,3
ered inferior to those of the authors.
*In 12 male patients
Moussa, 2000 [5], by using two
reactions: IS6110-PCR and 16S
treated with antituberculous drugs in rRNA gene-PCR had the sensitivity
another centre (decapitated-pretreated TB). of reaction IS6110-PCR and reaction
rRNAgene-PCR being 95.59% and
87.05%, respectively.
4. INVESTIGATION Nevertheless, in this series, with
the combination of AFB, urine
Over the last 10 years, for the diagnosis culture, and PCR, 47 / 50 patients
of GUTB in our institution, these are per- (94%) had mycobacterium positive
formed routinely: urine. This makes the diagnosis of
1. Erythrocyte sedimentation rate, GUTB easier in comparison with
tuberculin test only 38% patients with AFB (+) in
our former series of 167 patients
2. Chest X-ray and acid-fast bacilli
(1989–1994) [6].
(AFB) in sputum in case of suspicious
pulmonary images. 4. Radiography: Intravenous urography
3. Urine examination, including: (IVU) remains the key investigation.
• Urinalysis, for red blood cells and • Ultrasonography and IVU are
leukocytes; urine pH and concentra- performed in all cases with suspi-
tion documented. cion of GUTB. Standard IVU was

894
 Genitourinary tuberculosis in a developing country (Vietnam) | 15.4 |

performed to detect hydronephro- indicated in 9/50 patients, revealing

sis, ureteric strictures and dila-
tion, split renal function (Figure
5). However, in case of poor quality
IVU or poor functioning kidney,
retrograde pyelography is indicated.
In the series of 50 GUTB patients
complicated with ureteric strictures
over seven years (1998–2005) [4],
retrograde pyelography was done in
5. Cystoscopy and/or bladder biopsy
26/50 patients (52%) (Figure 6).
• Voiding cystourethrography (VCUG)
was indicated for detecting deformities
of the urinary bladder and/or vesi-
coureteral reflux (VUR) (Figure 7).
In this series, cystography was
contracted bladder in 1 / 50 cases, and
VUR in 9 / 50 cases
• Computed tomography (CT) or multi
sliced CT is indicated for visual-
izing difficult intrarenal lesions
(Figure 8). It was indicated in 4 / 50
patients: one had renal abscess and
fistula, two had hydronephrosis.
is of limited diagnostic value (Figure
9). Cystoscopy was indicated in 34/50
cases in which bladder biopsy were
performed in two cases. In these two
cases, the results were nonspecific
chronic inflammation.

Figure 5 IVU in GUTB patients.A. Left juxtavesical ureteric stricture. B. Bilateral hydronephrosis with deformity of
urinary bladder. C. Right nonfunctioning kidney, left hydronephrosis and contracted urinary bladder.

Figure 6 Retrograde pyelography. A. Left upper and mid-ureter strictures. B. Left distal ureteric stricture.

895
Chapter | 15 | Special urogenital infections

Figure 7 Voiding cystourethrography in GUTB. A. Contracted urinary bladder with bilateral

VUR in a 59-years-old woman. B. Same condition in another woman patient.

Figure 8 CT, MSCT. A. Right perinephric abscess. B. Pseudotumoral image of a TB nonfunctioning kidney on the right side.
C. MSCT with image reconstruction which reveals contracted urinary bladder, calcifications on left nonfunctioning kidney.

5. TREATMENT urinary bladder, for patients with

All GUTB patients received directly
observed treatment, short course (DOTS).
The patients are referred to local antitu-
berculous establishments for antituber-
culous drugs but they are monitored by
the urologists during the whole treat-
ment course. Patients with complications
of ureteric strictures are recommended
not to take Streptomycin for prevention
of accelerated healing fibrosis leading to
acute upper tract obstruction.
The national antituberculous program
comprises two regimens [1]. Regimen 1: 2
SHRZ / 6 HE for new GUTB patients;
regimen 2: 2 SHRZE / 1 HRZE / 5 H3 R3
E3 for recurrent GUTB patients.
Surgery is indicated for patients with
complications of urinary tract deformi-
ties, e.g. Ureteric strictures, contracted
destroyed organs such as nonfunctioning
kidneys, epididymal abscess. Extirpation
surgery is indicated after 2 months of
attacking chemotherapy [3, 7–9].
In our former series of 167 new patients
(1989–1994) [6], chemotherapy alone
accounted for 70%, chemotherapy in combi-
nation with surgery accounted for 30% with
over-all satisfactory outcome being 85.1%.
Upper tract obstructions (ureteric stric-
tures) are managed by staged treatment
[4, 10]: antituberculous drugs are admin-
istered first, if there is deterioration or no
improvement after three weeks, corticos-
teroids (prednisolone 20 mg tid) are added
for four to six weeks. If there is deteriora-
tion or no improvement after a six-week
period, ureteral dilation is attempted,
from one to three sessions. If there is
no improvement after three sessions of

896
 Genitourinary tuberculosis in a developing country (Vietnam) | 15.4 |

Figure 9 A.B. Velvet bladder mucosa in TB cystitis. C. Tuberculosis golf-hole ureter.

Figure 10 A. Balloon catheter dilation. B. Catheter dilation. C. Endoincision of ureter [4].

Table 2 Treatment modalities in a series of 50 GUTB patients complicated with

ureteric strictures (59 ureters) (1998–2005) [4].

Treatment Ureters %

Chemotherapy 11 18,6

Chemotherapy + Corticoids 6 10,2

Chemotherapy + Corticoids + Ureteral dilation 10 16,9

Chemotherapy + Ureteral dilation 11 18,6

Chemotherapy, corticoids, ureteral dilation, surgery 14 23,7

Chemotherapy + Corticoids + surgery 3 5,1

Chemotherapy + ureteral dilation + surgery 1 1,7

Chemotherapy + surgery 3 5,1

Total 59 100

ureteral dilation, reconstructive surgery (1998–2005) [4], medical treatment

is indicated. brought in satisfactory outcomes only in
In a series of 50 GUTB patients compli- case of mild hydronephrosis (11/12 ure-
cated with ureteric strictures (59 ureters) ters, 91.7%) with overall satisfactory

897
Chapter | 15 | Special urogenital infections

Figure 11 Ureteral reimplantation [22]. A. Lich-Grégoir. B. Boari. C. Specimen of TB strictured ureter.

outcome of 26.8% (11/41 ureters). The role Table 3 Ureteric strictures: endoscopic dilation in 33
of corticosteroids was not statistically sig- patients with 36 strictured ureters.
nificant with rate of satisfactory outcomes
only 41.5% (17/41 ureters) (p=0.162). Endourological technique Ureters %
Bennani et al. [11] had a good outcome Placement of a Double-J 6 16,7
with corticosteroids in 8/16 strictured ure-
ters (50%), in 5/8 contracted urinary blad- Ureteral dilation using ureteroscope 6 16,7

der, and 2/3 contracted renal pelvis. He Balloon catheter dilation 1 2,8
advocates corticosteroids and endoscopic
Catheter dilation 7 19,4
dilation. Hamburger [12] recommends
prednisone 30–40 mg per day in no more Endoincision 6 16,7
than 2 months for fear of disseminated TB. Endoincision + balloon catheter
1 2,8
On the contrary, Le Guillou et al. [13] dilation
argued against the role of corticosteroids Endoincision + catheter dilation 3 8,3
in prevention or treatment of tuberculosis
Failure of endoscopic dilation 6 16,7
fibrosis in GUTB. He used it only in case
of acute TB cystitis. Total 36 100
In this series [4], 33 patients (66%) with
36 ureters (61%) were managed endo-
scopically (one to four sessions per ure- had good outcome in 55–79% cases. He
ter, mean of 1.47). Endoscopic procedures recommends ureteral dilations before
ranged from placement of a DJ stent (six surgical reconstruction in all patients.
ureters) to balloon or catheter dilations Similarly, Wemeau et al. [15], using the
(14 ureters) and to endo-incision of ure- molding ureteral catheter, had the suc-
ter (10 ureters) (Table 3). Failure rate cess rate of 73%.
of endoscopic dilations were 16.7% (six In this series [4], 18 patients (36%)
ureters). The role of endoscopy was sta- with 21 ureters underwent surgical
tistically significant with satisfactory out- reconstruction: one UPJ reconstruction
comes of 65.9% (27/41 ureters) (p=0.0267). (Hynes-Anderson), 17 ureteral reim-
Of the 36 ureters managed by endoscopic platations (Lich-Grégoir: 12, LeDuc:1,
dilation, 13 ureters had encouraging out- Politano:1, Boari: 3), two placements of
comes (36.1%). Six out of 10 ureters (60%) DJ stent, one augmentation ileocysto-
with the length of the stricture ≤ 1cm had plasty for contracted urinary bladder
encouraging outcomes. associated with ureteral reimplantation
Murphy et al. [14], in 25 years and in (Table 4). Surgical reconstruction had
92 patients, reported good outcomes with the rate of encouraging outcomes of 85%
endoscopic dilation of 64% (on average (17/20 ureters, one patient-ureter was lost
four sessions per patient). Other authors of follow-up).

898
 Genitourinary tuberculosis in a developing country (Vietnam) | 15.4 |

Globally, with the staged regimen of or 2) the bladder is severely distorted.

management for these 50 patients with
complication of ureteric strictures, the
rate of encouraging outcomes was 79.3%
(46/58 ureters, one patient was lost of
final follow-up IVU), failure rate was
10.2% (5/49 patients), the theoretical
nephrectomy rate was 10% (5/50 patients)
For TB contracted urinary bladder, aug-
mentation ileocystoplasty is indicated in
cases where 1) bladder capacity < 100 mL
The technique is Goodwin “cup-patch”
ileocystoplasty. In recent cases, laparo-
scopic ileocystoplasty was performed with
encouraging outcomes [16].
For TB nonfunctioning kidneys,
nephrectomy is indicated because: 1) short-
course chemotherapy is administered
in all cases [17], 2) the rate of pyoneph-
rosis is quite high [3] (Figure 13), 3) the
necessity of removal of a potential source

Figure 12 Augmentation ileocystoplasty. A,B. Open surgery [22]. C.D.. Laparoscopy [16].

Figure 13. Specimen of TB nonfunctioning kidneys. A. Caseous necrosis and cavities. B. C. Tuberculosis
pyonephrosis [4]

Figure 14 Epididymal abscess and epididymectomy [21].

899
Chapter | 15 | Special urogenital infections
Table 4 Ureteric strictures: reconstructive surgery in 18
patients with 21 strictured ureters.
Technique Ureters
Placement of a ureteral catheter
Hynes-Anderson
Lich-Gregoir
LeDuc
Politano
Boari
LeDuc + Aug. Cystoplasty
Total
of bacterial persistence [18], 4) the fear
that renal carcinoma can develop [19]. In
recent years, in our institution, laparo-
scopic nephrectomy is indicated if preop-
erative CT reveals little or no perinephric
inflammation and adhesions.
In a review of our 14 initial cases of
laparoscopic nephrectomy for TB non-
functioning kidneys from May 2003 to
November 2006 [20], six patients under-
went left nephrectomy, eight underwent
right nephrectomy. There were four intra-
peritoneal laparoscopic nephrectomies
and 10 retroperitoneoscopic nephrecto-
mies. Operative technique: extracapsular
perirenal dissection: 13 cases, extracapsu-
lar and subcapsular perirenal dissection:
one case. Mean operating time: 163.3 min-
utes (140–180), estimated blood loss: 60
ml (30–150), intraoperative incident: one
small-hole peritoneal penetration (retro-
peritoneoscopic nephrectomy). There were
five conversions (35.7%): four cases with
dense perinephric adhesions, in which one
pseudotumoral TB; one case with active
hemorrhage due to perinephric inflam-
matory oozing. There was no preoperative
blood transfusion. Postoperative hospital
stay was 4.3 days (1–7).
Despite high conversion rate, our expe-
rience suggests that TB nonfunctioning
kidneys should not be considered as a
900
contraindication to laparoscopic nephrec-
tomy anymore.
%
2 9,5
6. FOLLOW-UP
1 4,8
All patients are followed-up by urologist
12 57,1 during the whole treatment course. After
1 4,8
the initiation of antituberculous chemo-
therapy, if the patient has signs of upper
1 4,8 tract obstruction, he is seen every three
3 14,3 weeks according to the staged treatment
regimen furnished with a IVU for early
1 4,8
detection of acute upper tract obstruction
21 100 (healing fibrosis precipitated by antitu-
berculous drugs [22]) or for early relief
of urinary tract obstruction to improve
renal function [23–24]; if he has no sign
of upper tract obstruction, he will be
seen every four weeks for the first three
months, then every three months in the
first year, then every six months in the
second year. Urine negatization of AFB on
Ziehl stain and/or M. tuberculosis on cul-
ture are monitored during the first three
months of treatment course to detect
multidrug resistance or bacterial per-
sistence due to excluded foci somewhere
in upper tract that may require surgical
removal. IVU of control is required every
three months in the first year to detect
the eventual healing fibrosis and urinary
tract deformities. After the second year,
the patient is seen every year for urine
examinations of control.
7. CONCLUSIONS
GUTB in (South) Vietnam remains a top-
ical issue in terms of prevalence as well
as severity. The diagnosis of GUTB is
currently not a too difficult one because
the combination of AFB, PCR, urine cul-
ture can make the diagnosis up to 94% of
cases.
Short-course chemotherapy is cost-
effective. GUTB is a medico-surgical
disease, a timely intervention and an
 Genitourinary tuberculosis in a developing country (Vietnam)
effective management could prevent seri-
ous complications. Minimally invasive
procedures might be helpful in patients
who require surgical treatment.
REFERENCES
1. Do Chau Giang, The current situation of
Tuberculosis in the World and in Vietnam.
Seminar on the National Antituberculous
Program 2004: 1–11.
2. Ngo Gia Hy, Pham Van Bui, Vo Thi
Hong Lien, and Nguyen Phuc Cam
Hoang, Some particular clinical aspects
of Genitourinary Tuberculosis and
Reconstructive Surgeries. Ho Chi Minh
city’s Medico-pharmacology Actualities
1995. 5: 33–35.
3. Ngo Gia Hy, Overview on Genitourinary
tuberculosis. Ho Chi Minh city’s Medico-
pharmacology Actualities, 2000: 68–72.
4. Nguyen Phuc Cam Hoang, Tuberculosis
ureteric strictures: diagnosis and outcome
of treatment. Vietnamese National Thesis
for PhD Degree 2008. (Abstract), Urology
74 (Supplement 4A), 30th Congress of the
Société Internationale d’Urologie, 2009: S90.
5. Moussa OM, Eraky I, El-Far MA, Osman
HG, and Ghoneim MA, Rapid diagnosis
of genitourinary tuberculosis by polymer-
ase chain reaction and non-radioactive
DNA hybridization. J Urol, 2000. 164(2):
584–8.
6. Nguyen Phuc Cam Hoang, Ngo Gia Hy,
Pham Van Bui, and Vo Thi Hong Lien,
A propos of 167 cases of Genitourinary
Tuberculosis treated at Binh Dan hospital
in 5 years (1990–1994). Binh Dan hospi-
tal’s Science and Technology actualities
1994. 7: 293–305.
7. Cibert J, La tuberculose rénale sous
l’angle de la thérapeutique. 1946, Paris,:
Masson. 533 p.
8. el Khader K, Lrhorfi MH, el Fassi J,
Tazi K, Hachimi M, and Lakrissa A,
[Urogenital tuberculosis. Experience in 10
years]. Prog Urol, 2001. 11(1): 62–7.
9. Wong SH, Lau WY, Poon GP, Fan ST, Ho
KK, Yiu TF, and Chan SL, The treatment
of urinary tuberculosis. J Urol, 1984.
131(2): 297–301.
| 15.4 |
10. McAleer SJ, Johnson CW, and Johnson
Jr. WD, Genitourinary Tuberculosis, in
Campbell-Walsh urology : ninth edition,
Wein AJ, Editor. 2007, Elsevier
Saunders: Philadelphia, Pa. ; Edinburgh.
p. xxviii, 528 p.
11. Bennani S, Aboutaieb R, el Mrini M, and
Benjelloun S, [The role of corticotherapy
and endoscopy in the treatment of uro-
genital tuberculosis]. Ann Urol
(Paris), 1994. 28(5): 243–9.
12. Hamburger J, Renal tuberculosis, in
Nephrology, Saunders C, Editor. 1969:
Philadelphia. p. 1157–78.
13. Guillou ML, Pariente J-L, and et Guege
S-M, Tuberculose urogénitale, in Encycl.
Med.Chir. 1993, Néphrologie-Urologie,
18–078-A-10. p. 11p.
14. Murphy DM, Fallon B, Lane V, and
O’Flynn JD, Tuberculous stricture of
ureter. Urology, 1982. 20(4): 382–4.
15. Wemeau L, Mazeman E, Biserte J,
Schauvliège T, and Bailleul JP, Aspects
actuels de la tuberculose urinaire. Ann
Urol, 1982. 16(4): 235–38.
16. Nguyen Phuc Cam Hoang, Le Van Hieu
Nhan, Tran Ngoc Khac Linh, Nguyen Viet
Cuong, and Vu Le Chuyen, Laparoscopic
augmentation ileocystoplasty for TB
contracted bladder: Our initial case report.
(Abstract). 20th World Congress Video
Urology, Jul.2009. Program Book, 2009: 83.
17. Abbou CC, Chopin D, Kouri G, Daloubeix
H, Estève C, Lavarenne V, Bottine H,
and Auvert J, Faut-il opérer les reins
muets tuberculeux? Ann.Urol 1982. 16(4):
254–56.
18. Wong SH and Lau WY, The surgical man-
agement of non-functioning tuberculous
kidneys. J Urol, 1980. 124(2): 187–91.
19. Tostain J and Gilloz A, Cancer développé
sur rein mastic tuberculeux. Une nouv-
elle observation. Ann Urol, 1982. 16(4):
245–46.
20. Nguyen Phuc Cam Hoang, Le Van Hieu
Nhan, Phan Van Hoang, Tran Ngoc Khac
Linh, and Vu Le Chuyen, Are tubercu-
losis nonfunctioning kidneys amenable
to laparoscopic nephrectomy? Abstract),
Urology 74 (Supplement 4A), 30th
Congress of the Société Internationale
d’Urologie, Nov. 2009, 2009: S189.
901
Chapter | 15 | Special urogenital infections
21. Nguyen Phuc Cam Hoang, Le Van Hieu
Nhan, and Vu Le Chuyen, Genitourinary
tuberculosis: diagnosis and treatment.
(Abstract), Urology 74 (Supplement
4A), 30th Congress of the Société
Internationale d’Urologie, Nov. 2009,
2009: S241.
22. Psihramis KE and Donahoe PK, Primary
genitourinary tuberculosis: rapid progres-
sion and tissue destruction during treat-
ment. J Urol, 1986. 135(5): 1033–6.
902
23. Ramanathan R, Kumar A, Kapoor R,
and Bhandari M, Relief of urinary
tract obstruction in tuberculosis to
improve renal function. Analysis of
predictive factors. Br J Urol, 1998.
81(2): 199–205.
24. Shin KY, Park HJ, Lee JJ, Park HY, Woo
YN, and Lee TY, Role of early endouro-
logic management of tuberculous ureteral
strictures. J Endourol, 2002. 16(10):
755–8.
|15.5|

Guidelines for the treatment of

fungal urinary tract infections
Jack D. Sobel1, John Fisher2, Carol A. Kauffman3
1
Division of Infectious Diseases, Department of Medicine, Wayne State University School of Medicine, Detroit, MI
2
Division of Infectious Diseases, Medical College of Georgia, Augusta, GA
3
Division of Infectious Diseases, University of Michigan Medical School and Veterans Affairs Ann Arbor Healthcare
System, Ann Arbor, MI
Correspondence: Jack D. Sobel, M.D., Chief, Division of Infectious Diseases, Professor of Medicine,
Harper University Hospital, 3990 John R – 5 Hudson, Detroit, MI 48201
Tel: (313) 745-7105, Fax: (313) 993-0302, E-mail: jsobel@med.wayne.edu

ABSTRACT Key words: candiduria, Candida spp.,

Fungal infections of the urinary
tract are extremely common espe-
cially those caused by Candida spe-
cies. Epidemiological studies reveal a
significant increase in Candida spp.
UTI’s (candiduria) predominantly the
result of health care (nosocomial) asso-
ciated infection. Progress has followed
identifying risk factors for candiduria,
however diagnostic criteria including
microbiologic remain elusive. While
numerous effective antifungal agents
are now available, widespread imple-
mentation of approved indications for
therapy has been slow in forthcoming.
This review summaries new treatment
guidelines for treating funguria and
provides a rational basis for use of anti-
fungal agents.
antifungal drugs, fluconazole, amphoteri-
cin B, flucytosine
SUMMARY OF RECOMMENDATIONS
Asymptomatic candiduria
1. Treatment is not recommended unless
the patient falls into a high-risk group
for dissemination (GoR A).
2. Elimination of predisposing fac-
tors often results in resolution of
candiduria (GoR A).
3. High-risk patients include neutropenic
patients, low birth weight infants,
and patients who will undergo uro-
logic manipulations. Neutropenic
patients and neonates should be man-
aged as for invasive candidiasis. For
Chapter | 15 | Special urogenital infections
those undergoing urologic procedures,
fluconazole 400 mg daily or AmB-d
(0.3–0.6 mg/kg daily) for several days,
before and after the procedure is
recommended (GoR B).
4. Imaging of the kidneys and collecting
system to exclude abscess, fungus ball,
or urologic abnormality is prudent for
persistent candiduria among asympto-
matic patients with predisposing fac-
tors (GoR B).
Symptomatic candiduria
5. For candiduria with suspected dis-
seminated candidiasis, treatment with
systemic antifungals for candidemia is
recommended (GoR A).
5.1. For cystitis due to fluconazole-
susceptible Candida species, oral
fluconazole, 200 mg daily for 2
weeks, is recommended (GoR B).
For fluconazole-resistant organ-
isms, AmB-d 0.3–0.6 mg/kg daily
for 1–7 days or oral flucytosine 25
mg/kg qid for 7–10 days are alter-
natives (GoR B).
5.2. AmB bladder irrigation is gener-
ally not recommended, but may
be useful for fluconazole-resistant
Candida species, especially C. gla-
brata (GoR B).
5.3. For pyelonephritis due to
fluconazole-susceptible organisms,
oral fluconazole 200–400 mg daily for
2 weeks is recommended (GoR B).
Table 1 Urinary Tract Involvement by Invasive Mycoses.
Infection Prostate
Blastomycosis +++
Histoplasmosis ++
Coccidioidiomycosis + +
Aspergillosis + +
Cryptococcosis +++
Candidiasis +++
904
5.4. For fluconazole-resistant Candida
isolates, especially C. glabrata,
alternatives include AmB-d (0.8–
0.7 mg/kd daily) +/- flucytosine 25
mg/kg qid (GoR A), or flucytosine
alone 25 mg/kg qid (GoR B).
5.5. For fungus balls, surgical inter-
vention is strongly recommended
(GoR A). Fluconazole 200–400
mg daily is recommended (GoR
B). AmB-d 0.5–0.7 mg/kg daily
with or without flucytosine, 25
mg/kg qid is an alternative (GoR
B). If access to the renal collect-
ing system is available, irriga-
tion with AmB-d 50 mg/L sterile
water is recommended as an
adjunct to systemic therapy (GoR
B). Treatment duration should
be until symptoms have resolved
and urine cultures no longer yield
Candida (GoR B).
1. INTRODUCTION
Although many fungal genera and species
can involve the urinary tract, more than
95% of UTI’s due to fungi are caused by
Candida species (see Table 1). Accordingly
these guidelines will focus on the treat-
ment of Candida urinary tract infections
recognizing that treatment principles,
pharmacokinetic and pharmacodynamic
issues of antifungal agents used to treat
Candida species apply equally to all gen-
era of fungi.
Bladder Kidney Penis/Cutaneous
± + +
+ ++ ++
++ +
+++ +
+ +++ +
++++ ++++ ++
 Guidelines for the treatment of fungal urinary tract infections
2. METHODS
In 2008, the Infectious Diseases Society of
America commissioned a select committee
of Infectious Diseases experts to update
previous guidelines for the treatment
of Candida infections including those
involving the urinary tract [1]. These
peer reviewed guidelines form the foun-
dation of this document and no inconsist-
encies are expressed. Levels of evidence
and grading of guideline recommendation
were modified by the authors of this docu-
ments to be consistent with ICUD stand-
ards [2–3]. A Medline search identified 70
articles dealing with fungal urinary tract
infections during 1979 until 2009. The
studies were rated according to the level
of evidence (LoE) and the grade of recom-
mendation (GoR) using ICUD standards
(for details see Preface) [2–3].
3. EPIDEMIOLOGY OF CANDIDA
URINARY TRACT INFECTIONS
Candida microorganisms exist as sapro-
phytes on the external genitalia or ure-
thra; however, yeast in measurable
quantities are found in <1% of clean
voided urine specimens. Candida infec-
tions currently account for 5% of urine
isolates in the general hospital and 10%
of positive urinary cultures in tertiary-
care centers [4–5]. Candiduria occurs in
patients throughout medical centers but
is especially common in surgical ICU’s
and Candida urinary isolates are sec-
ond only to E. coli in combined medical-
surgical ICU’s [6]. Twenty-two percent
of critically ill patients admitted for
more than seven days in the ICU devel-
oped candiduria in a large multicenter
study in Spain [7]. Moreover ICU studies
have consistently reported a relationship
between candidiasis and heavy coloniza-
tion, suggesting that candiduria could be
considered as a marker for heavy colo-
nization [8]. Presently 10–15% of noso-
comial UTI’s are caused by Candida
| 15.5 |
species [9–14]. Nosocomial candidiasis
is also common in the neonatal and pedi-
atric ICU’s [11]. It has been estimated
that the incidence of candiduria in the
ICU setting to be approximately 25,000
cases per year in the United States [14].
Nosocomial candiduria is by no means
confined to ICU’s. Candiduria is often
transient and most positive cultures
represent colonization rather than true
infection. On occasion candiduria may
be associated with symptomatic UTI and
fungemia [15].
4. MICROBIOLOGY
C. albicans is the most common fungal
species isolated from the urine and in one
large study was found in 446 (52%) of 861
patients with funguria [16]. C. glabrata
accounts for 25–35% of infections whereas
8–28% of infections are due to C. tropi-
calis, C. krusei, and C. parapsilosis [12,
16]. Nevertheless, many recent epidemio-
logic microbiologic studies have reported
a marked increase in infections caused
by non-albicans Candida species espe-
cially C. glabrata and C. tropicalis [15,
17–18]. Unusual species are common in
hospitalized patients, especially diabetics
and those with chronic indwelling blad-
der catheters. Mixed infections caused by
more than one Candida species are not
infrequent, as is concomitant bacteriuria.
5. PATHOGENESIS AND
PREDISPOSING FACTORS
Candiduria is rare in the absence of pre-
disposing factors. Most infections are
associated with use of Foley catheters
(50–70%), internal stents, percutane-
ous nephrostomy tubes and recent sur-
gery. Diabetic patients, especially when
their diabetes is poorly controlled, are
particularly at risk primarily because of
increased instrumentation, urinary stasis,
and obstruction secondary to autonomic
905
Chapter | 15 | Special urogenital infections
neuropathy. Concomitant bacteriuria
is common and bacterial adherence to
bladder epithelium may play a key role
in pathogenesis of Candida infection.
Antimicrobials (50–100%) similarly play
a critical role, in that candiduria almost
always emerges during or immediately
after antibiotic therapy. Antibiotics, espe-
cially broad-spectrum agents, act by sup-
pressing protective indigenous bacterial
flora in the gastrointestinal (GI) tract and
lower genital tract, facilitating Candida
colonization of these sites and subsequent
access to the urinary tract. Nosocomial
candiduria is more common among
women than men in an ICU setting, per-
haps related to the contribution of vagi-
nal Candida colonization to urinary tract
colonization [19]. The pool of critically ill,
immunosuppressed medical and surgical
patients has increased, and this increase,
together with improved technology, pro-
vides an expanded population at risk of
developing Candida infection.
Most lower UTIs are caused by retro-
grade infection associated with an ind-
welling catheter or genital and perineal
colonization [20]. The upper urinary tract
is uncommonly involved during ascending
retrograde infection and then only in the
presence of urinary obstruction, reflux, or
diabetes. Renal candidiasis is usually the
consequence of secondary hematogenous
seeding of the renal parenchyma; Candida
species have a unique tropism for the kid-
ney and hematogenous renal infection
results in anterograde candiduria.
6. CLINICAL ASPECTS
Most patients with candiduria are asymp-
tomatic, especially those with indwelling
bladder catheters. Even if asymptomatic,
several studies indicate that ICU patients
with candiduria have a higher in ICU
and hospital mortality [15]. Candiduria
in this context reflects Candida coloniza-
tion but also is a major marker of overall
sickness of the individual patient. Clinical
906
manifestations depend on the site of infec-
tion. Candida cystitis may present with
frequency, dysuria, urgency, hematuria,
and pyuria. Ascending infection resulting
in Candida pyelonephritis is characterized
by fever, leukocytosis, and rigors and is
indistinguishable from bacterial pyelone-
phritis. Excretory urography and CT
scanning may reveal ureteropelvic fungus
balls or papillary necrosis. Renal candi-
diasis is difficult to diagnose when second-
ary to hematogenous spread and presents
with fever and other signs of sepsis. By
the time renal candidiasis is considered,
blood cultures are usually no longer posi-
tive; however, unexplained deteriorating
renal function is often evident.
7. DIAGNOSIS
Because isolation of Candida from a urine
specimen may represent contamination,
colonization, or superficial or deep infec-
tion of the lower or upper urinary tract,
determining the significance of candiduria
is difficult. Management also depends on
the determination of the most likely site
of infection. Contamination of the urine
sample is particularly common in women
with vulvovaginal colonization and may
be excluded by repeating urine culture
with special attention to proper collec-
tion techniques. Differentiating infection
from colonization may be extremely dif-
ficult if not impossible in some patients,
especially if they are catheterized.
Accompanying clinical features may facil-
itate identifying the source of candiduria,
but unfortunately these are often nonspe-
cific in critically ill patients, and accom-
panying fever and leukocytosis may be
related to several different sources.
Quantitative urine colony counts have
little value in separating infection from
colonization and then only in the absence
of a Foley catheter. The latter negates
any diagnostic value even of quantita-
tive cultures in distinguishing coloniza-
tion from infection. In noncatheterized
 Guidelines for the treatment of fungal urinary tract infections
patients, counts greater than 104 CFU/ml
are usually associated with infection. It is
rare for patients with invasive disease of
the kidney, pelvis, or bladder to have 103
CFU/ml or less. Most patients with uri-
nary tract Candida infection have pyuria,
but the value of this finding is similarly
diminished in the presence of a catheter
or concomitant bacteriuria and in neutro-
penic subjects. Serologic tests of Candida
tissue invasion are not available however
tests such as beta-glucan titer may be use-
ful. Treatment is preceded by attempts
to localize the source or anatomic level of
infection. Unfortunately, no reliable tests
to differentiate renal candidiasis from the
more frequent lower tract infections exist.
The extremely rare finding of Candida
microorganisms and pseudohyphae
enmeshed in renal tubular casts is useful
when present. Ultrasonography and com-
puted tomography (CT) scans have a useful
but limited role in localization. A five-day
bladder irrigation with amphotericin B
Table 2
Class
Polyene
Amphotericin B desoxycholate
Liposomal A (Ambisome®)
(Abelcet®)
Nystatin
Flucytosine
Azoles
Ketoconazole
Itraconazole
Fluconazole
Voriconazole
Posaconazole
Echinocandin
Caspofungin
Micafungin
Anidulafungin
| 15.5 |
may be of value in localizing the source
of candiduria in catheterized subjects in
that post-irrigation persistent candiduria
originates from above the bladder, thus
identifying patients with need for further
studies. Unfortunately, the lengthy nature
of this diagnostic test excludes its utility
in most febrile, critically ill subjects.
8. PRINCIPLES OF MANAGEMENT
8.1 Drug therapy
Since the original availability of ampho-
tericin B desoxycholate (AmB-d) used
parenterally or for bladder catheter irri-
gation, washout or retention, a vari-
ety of new antifungals including azoles
and echinocandins are now available
[21]. New antifungal agents are listed
in Table 2. None of the new agents have
proved more useful than fluconazole for
the treatment of Candida urinary tract
infection. Critical factors by which these
Achieves therapeutic urine
concentration
Yes (√)
No
No
No
Yes (√) [Not in renal failure]
No
No
Yes (√)
No
No
No
No
No
907
Chapter | 15 | Special urogenital infections
numerous agents are judged include: i)
toxicity especially nephrotoxicity, ii) spec-
trum of activity, iii) excretion into urine
to achieve concentrations capable of
inhibiting fungal pathogens even in the
presence of renal failure.
8.2 Clinical evidence supporting
treatment principles
The presence of yeast in the urine,
whether microscopically visualized or
grown in culture, must be evaluated in
the context of the particular clinical set-
ting to determine its relevance and the
need for antifungal therapy. If no pre-
disposing condition is uncovered as is
the case in the majority of asymptomatic
patients only observation is warranted
[1]. Unfortunately unnecessary treat-
ment of asymptomatic candiduria is wide-
spread [22]. In a multicenter U.S. study,
43% of patients, most of whom were
asymptomatic with Candida isolates in
urine were treated [16]. Among patients
with predisposing conditions, manage-
ment of that condition alone may be suf-
ficient to eliminate candiduria without
specific antifungal therapy. Several pre-
disposing conditions require an aggres-
sive approach to persistent candiduria,
even among asymptomatic patients.
Disseminated candidiasis should be con-
sidered in low birth weight neonates and
severely immunocompromised patient
with fever and candiduria, independent
of urinary symptoms or anatomic geni-
tourinary abnormality.
The major principle underlying the
concept of not treating asymptomatic
nosocomial candiduria in patients with
indwelling bladder drainage devices is
based upon the frequently documented
observation that lower urinary tract can-
didiasis rarely results in ascending infec-
tion (retrograde) and candidemia [15,
23–24]. Exceptions to this observation
include following instrumentation of uri-
nary tract and when urinary obstruction
is present.
908
For symptomatic Candida cystitis, flu-
conazole is the drug of first choice. It is
highly water-soluble, primarily excreted
in urine in its active form, and eas-
ily achieves urine levels exceeding the
MIC for most Candida isolates [25]. No
other currently available azole is use-
ful because of minimal excretion of the
active compound into urine. For patients
who have cystitis and who are allergic
to fluconazole or who clearly fail therapy
despite maximum doses and optimal
management of urologic abnormalities,
oral flucytosine, systemic AmB-d, or blad-
der irrigation with AmB-d can be tried.
Flucytosine demonstrates good activ-
ity against most Candida isolates and
is concentrated in urine [26]. It is par-
ticularly useful for C. glabrata infection.
Treatment with flucytosine is limited by
toxicity and the development of resist-
ance when used alone; it is not recom-
mended as primary therapy for patients
with uncomplicated Candida cystitis [1]
and should not be used in the presence of
renal failure.
Irrigation of the bladder with a sus-
pension of amphotericin B, 50 mg/L ster-
ile water for five to seven days resolves
candiduria in more than 90% of patients
[27] but there is a high relapse rate. This
approach is generally discouraged except
as a measure to treat refractory cystitis
due to azole resistant organisms, such as
C. glabrata and C. krusei.
Fluconazole is the drug of choice for
most patients with Candida pyelone-
phritis. C. glabrata accounts for approxi-
mately 20% of urine isolates [15, 17] and
is frequently resistant to fluconazole.
Amb-d has demonstrated efficacy for
pyelonephritis, and remains the choice of
many clinicians for upper urinary tract
candidiasis in critically ill patients [28].
The reduced nephrotoxicity of lipid for-
mulations of AmB suggests that tissue
penetration in the renal parenchyma is
reduced. There are both experimental
animal data and clinical case report that
demonstrate failure of lipid formulation
 Guidelines for the treatment of fungal urinary tract infections
AmB to clear Candida from the kidneys
and lower urinary tract [29–30].
There are very limited data, includ-
ing several animal studies and a few
reports of a small number of patients, in
which echinocandins were used success-
fully for treatment of renal parenchymal
infections [31–33]. There are no data
regarding the use of voriconazole or posa-
conazole for renal candidiasis.
Candida prostatitis and epidymo-orchitis
are rare and can present as either acute or
chronic infection [34–36]. Most patients
require surgical drainage of abscesses or
other surgical debridement as well as fun-
gal therapy. Fluconazole is the agent of
choice, but treatment recommendations
are based on anecdotal data.
Fungus balls can occur anywhere in the
urinary collecting system. Aggressive sur-
gical debridement is central to successful
treatment in most cases. Systemic treat-
ment with AmB-d with or without flucy-
tosine, or fluconazole has been used most
often [15, 21, 37–38]. If a percutaneous
device provides direct access to the renal
pelvis, ureters, or bladder, local irrigation
with AmB-d should be considered, but the
optimal dose and duration of therapy have
not been defined [39–42]. Other methods
to facilitate the breakdown and passage
of fungus balls include intermittent saline
irrigation, debulking of the fungal mass
by the insertion of thrombectomy devices
through a percutaneous nephrostomy
[43], percutaneous endoscopic disruption
and drainage, and percutaneous irriga-
tion with streptokinase [44].
9. FURTHER RESEARCH
Future research should be directed at
elucidation of the pathogenesis of can-
diduria. Only when causation is under-
stood can effective preventative steps be
undertaken. Additional antifungal drugs
are needed that achieve therapeutic con-
centrations in urine. Finally validated
diagnostic criteria need to be determined
| 15.5 |
that differentiate tissue invasion and
true infection from lower urinary tract
colonization.
10. CONCLUSIONS
Considerable progress has been made in
determining the epidemiology and risk
factors for fungal UTI`s. Although many
fungal genera may invade the urinary
tract, Candida species continue to be
responsible for the overwhelming major-
ity. Based upon in vitro susceptibility and
pharmacokinetics of antifungal drugs
together with an increased number of
randomised controlled studies, rational
guidelines for antifungal use have been
developed.
REFERENCES
1. Pappas PG, Kauffman CA, Andes D,
Benjamin DK, Jr., Calandra TF, Edwards
JE, Jr., Filler SG, Fisher JF, Kullberg
BJ, Ostrosky-Zeichner L, Reboli AC, Rex
JH, Walsh TJ, and Sobel JD, Clinical
practice guidelines for the management of
candidiasis: 2009 update by the Infectious
Diseases Society of America. Clin Infect
Dis, 2009. 48(5): 503–35.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
3. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
4. Rivett AG, Perry JA, and Cohen J, Urinary
candidiasis: a prospective study in hospital
patients. Urol Res, 1986. 14(4): 183–6.
5. Colodner R, Nuri Y, Chazan B, and Raz R,
Community-acquired and hospital-acquired
candiduria: comparison of prevalence
and clinical characteristics. Eur J Clin
Microbiol Infect Dis, 2008. 27(4): 301–5.
6. Richards MJ, Edwards JR, Culver DH,
and Gaynes RP, Nosocomial infections in
combined medical-surgical intensive care
909
Chapter | 15 | Special urogenital infections
units in the United States. Infect Control
Hosp Epidemiol, 2000. 21(8): 510–5.
7. Alvarez-Lerma F, Nolla-Salas J, Leon C,
Palomar M, Jorda R, Carrasco N, and
Bobillo F, Candiduria in critically ill
patients admitted to intensive care
medical units. Intensive Care Med, 2003.
29(7): 1069–76.
8. Toya SP, Schraufnagel DE, and Tzelepis
GE, Candiduria in intensive care units:
association with heavy colonization and
candidaemia. J Hosp Infect, 2007. 66(3):
201–6.
9. Bougnoux ME, Kac G, Aegerter P,
d’Enfert C, and Fagon JY, Candidemia
and candiduria in critically ill patients
admitted to intensive care units in France:
incidence, molecular diversity, manage-
ment and outcome. Intensive Care Med,
2008. 34(2): 292–9.
10. Jacobs LG, Skidmore EA, Cardoso LA,
and Ziv F, Bladder irrigation with ampho-
tericin B for treatment of fungal urinary
tract infections. Clin Infect Dis, 1994.
18(3): 313–8.
11. Phillips JR and Karlowicz MG,
Prevalence of Candida species in hospital-
acquired urinary tract infections in a neo-
natal intensive care unit. Pediatr Infect
Dis J, 1997. 16(2): 190–4.
12. Febre N, Silva V, Medeiros EA, Wey
SB, Colombo AL, and Fischman O,
Microbiological characteristics of yeasts
isolated from urinary tracts of intensive
care unit patients undergoing urinary
catheterization. J Clin Microbiol, 1999.
37(5): 1584–6.
13. Kobayashi CC, de Fernandes OF,
Miranda KC, de Sousa ED, and Silva
Mdo R, Candiduria in hospital patients: a
study prospective. Mycopathologia, 2004.
158(1): 49–52.
14. Shay AC and Miller LG, An estimate of
the incidence of Candiduria among hos-
pitalized patients in the United States.
Infect Control Hosp Epidemiol, 2004.
25(11): 894–5.
15. Kauffman CA, Candiduria. Clin Infect
Dis, 2005. 41 Suppl 6: S371–6.
16. Kauffman CA, Vazquez JA, Sobel JD,
Gallis HA, McKinsey DS, Karchmer AW,
Sugar AM, Sharkey PK, Wise GJ, Mangi
910
R, Mosher A, Lee JY, and Dismukes
WE, Prospective multicenter surveillance
study of funguria in hospitalized patients.
The National Institute for Allergy and
Infectious Diseases (NIAID) Mycoses
Study Group. Clin Infect Dis, 2000. 30(1):
14–8.
17. Sobel JD, Kauffman CA, McKinsey D,
Zervos M, Vazquez JA, Karchmer AW, Lee
J, Thomas C, Panzer H, and Dismukes
WE, Candiduria: a randomized, double-
blind study of treatment with fluconazole
and placebo. The National Institute of
Allergy and Infectious Diseases (NIAID)
Mycoses Study Group. Clin Infect Dis,
2000. 30(1): 19–24.
18. Berrouane YF, Herwaldt LA, and Pfaller
MA, Trends in antifungal use and epide-
miology of nosocomial yeast infections in
a university hospital. J Clin Microbiol,
1999. 37(3): 531–7.
19. Silva V, Hermosilla G, and Abarca C,
Nosocomial candiduria in women under-
going urinary catheterization. Clonal
relationship between strains isolated from
vaginal tract and urine. Med Mycol, 2007.
45(7): 645–51.
20. Tambyah PA and Maki DG, Catheter-
associated urinary tract infection is rarely
symptomatic: a prospective study of 1,497
catheterized patients. Arch Intern Med,
2000. 160(5): 678–82.
21. Gubbins PO, McConnell SA, and Penzak
SR, Current management of funguria.
Am J Health Syst Pharm, 1999. 56(19):
1929–35; quiz 1936.
22. Chen SC, Tong ZS, Lee OC, Halliday C,
Playford EG, Widmer F, Kong FR, Wu
C, and Sorrell TC, Clinician response
to Candida organisms in the urine of
patients attending hospital. Eur J Clin
Microbiol Infect Dis, 2008. 27(3): 201–8.
23. Simpson C, Blitz S, and Shafran SD,
The effect of current management on
morbidity and mortality in hospitalised
adults with funguria. J Infect, 2004.
49(3): 248–52.
24. Ang BS, Telenti A, King B, Steckelberg
JM, and Wilson WR, Candidemia from
a urinary tract source: microbiological
aspects and clinical significance. Clin
Infect Dis, 1993. 17(4): 662–6.
 Guidelines for the treatment of fungal urinary tract infections
25. Lazar JD and Hilligoss DM, The clini-
cal pharmacology of fluconazole. Semin
Oncol, 1990. 17(3 Suppl 6): 14–8.
26. Auger P, Dumas C, and Joly J, A study of
666 strains of Candida albicans: correla-
tion between serotype and susceptibility
to 5-fluorocytosine. J Infect Dis, 1979.
139(5): 590–4.
27. Wise GJ, Kozinn PJ, and Goldberg P,
Amphotericin B as a urologic irrigant in
the management of noninvasive candi-
duria. J Urol, 1982. 128(1): 82–4.
28. Fisher JF, Woeltje K, Espinel-Ingroff A,
Stanfield J, and DiPiro JT, Efficacy of a
single intravenous dose of amphotericin B
for Candida urinary tract infections: fur-
ther favorable experience. Clin Microbiol
Infect, 2003. 9(10): 1024–7.
29. van Etten EW, van den Heuvel-de Groot C,
and Bakker-Woudenberg IA, Efficacies of
amphotericin B-desoxycholate (Fungizone),
liposomal amphotericin B (AmBisome)
and fluconazole in the treatment of sys-
temic candidosis in immunocompetent and
leucopenic mice. J Antimicrob Chemother,
1993. 32(5): 723–39.
30. Agustin J, Lacson S, Raffalli J, Aguero-
Rosenfeld ME, and Wormser GP, Failure
of a lipid amphotericin B preparation to
eradicate candiduria: preliminary find-
ings based on three cases. Clin Infect Dis,
1999. 29(3): 686–7.
31. Petraitis V, Petraitiene R, Groll AH,
Roussillon K, Hemmings M, Lyman CA,
Sein T, Bacher J, Bekersky I, and Walsh
TJ, Comparative antifungal activities and
plasma pharmacokinetics of micafungin
(FK463) against disseminated candi-
diasis and invasive pulmonary aspergil-
losis in persistently neutropenic rabbits.
Antimicrob Agents Chemother, 2002.
46(6): 1857–69.
32. Sobel JD, Bradshaw SK, Lipka CJ, and
Kartsonis NA, Caspofungin in the treat-
ment of symptomatic candiduria. Clin
Infect Dis, 2007. 44(5): e46–9.
33. Lagrotteria D, Rotstein C, and Lee CH,
Treatment of candiduria with micafun-
gin: A case series. Can J Infect Dis Med
Microbiol, 2007. 18(2): 149–50.
| 15.5 |
34. Wise GJ and Shteynshlyuger A, How to
diagnose and treat fungal infections in
chronic prostatitis. Curr Urol Rep, 2006.
7(4): 320–8.
35. Jenkin GA, Choo M, Hosking P, and
Johnson PD, Candidal epididymo-orchitis:
case report and review. Clin Infect Dis,
1998. 26(4): 942–5.
36. Jenks P, Brown J, Warnock D, and
Barnes N, Candida glabrata epididymo-
orchitis: an unusual infection rapidly
cured with surgical and antifungal treat-
ment. J Infect, 1995. 31(1): 71–2.
37. Chung BH, Chang SY, Kim SI, and Choi
HS, Successfully treated renal fungal ball
with continuous irrigation of fluconazole.
J Urol, 2001. 166(5): 1835–6.
38. Fisher J, Mayhall G, Duma R, Shadomy
S, Shadomy J, and Watlington C, Fungus
balls of the urinary tract. South Med J,
1979. 72(10): 1281–4, 1287.
39. Baetz-Greenwalt B, Debaz B, and Kumar
ML, Bladder fungus ball: a reversible
cause of neonatal obstructive uropathy.
Pediatrics, 1988. 81(6): 826–9.
40. Bartone FF, Hurwitz RS, Rojas EL,
Steinberg E, and Franceschini R, The
role of percutaneous nephrostomy in the
management of obstructing candidiasis of
the urinary tract in infants. J Urol, 1988.
140(2): 338–41.
41. Chitale SV, Shaida N, Burtt G, and
Burgess N, Endoscopic management
of renal candidiasis. J Endourol, 2004.
18(9): 865–6.
42. Morello FA, Jr., Mansilla AV, and
Wallace MJ, Removal of renal fungus
balls using a mechanical thrombectomy
device. AJR Am J Roentgenol, 2002.
178(5): 1191–3.
43. Shih MC, Leung DA, Roth JA, and
Hagspiel KD, Percutaneous extraction of
bilateral renal mycetomas in premature
infant using mechanical thrombectomy
device. Urology, 2005. 65(6): 1226.
44. Kabaalioglu A, Bahat E, and Boneval C,
Renal candidiasis in a 2-month-old
infant: treatment of fungus balls with
streptokinase. AJR Am J Roentgenol,
2001. 176(2): 511–2.
911
|15.6|

Vulvovaginal candidosis
Werner Mendling
Corresponding author: Werner Mendling, MD, PhD, Professor and Head of Department of Gynecology and Obstetrics,
Hospital Vivantes Am Urban, Dieffenbachstr. 1, 10967 Berlin, Germany, and
Hospital Vivantes im Friedrichshain, Landsberger Allee 49, 10249 Berlin, Germany
Tel +49-30-130-23 1442, Fax +49-30-130-23 2043, werner.mendling@vivantes.de

ABSTRACT Diagnostic tools are anamnesis, clinical

The estrogenized vagina is colonized
by Candida (C.) species, mostly by
C. albicans, in at least 20% of women
in late pregnancy and at least 30% of
immunosuppressed patients. The risk
of Candida vulvovaginitis is influ-
enced by host factors, especially local
defence deficiencies, gene polymor-
phisms, allergic factors, serum glu-
cose levels, antibiotics, psychosocial
stress and estrogen induced vaginal
factors. In less than 10% of cases, with
regional differences, non-albicans spe-
cies (especially C. glabrata, but in rare
cases also Saccharomyces cerevisiae,)
cause vulvovaginitis, often with fewer
clinical signs and symptoms. Typical
symptoms are premenstrual itching,
burning, redness and non-odorous dis-
charge. Although pruritus and inflam-
mation of the vaginal introitus are
typical symptoms, fewer than 50% of
women with genital pruritus are suf-
fering from Candida vulvovaginitis.
signs, microscopic investigation of the
vaginal fluid by phase contrast (400 ´),
vaginal ph-value, and in clinically and
microscopically uncertain or in recur-
rent cases, a yeast culture with species
determination. In sporadic acute cases,
therapy is easy and successful in about
80% of patients. Vaginal preparations of
polyenes, imidazoles, ciclopyroxolamine
or oral triazoles (which are not allowed
during pregnancy) are equally success-
ful. C. glabrata is resistant to the usual
dosages of all local antimycotics and
so vaginal boric acid suppositories or
vaginal flucytosine are recommended.
As these are not allowed or not avail-
able in some countries, a high dose of
800 mg fluconazole per day for two to
three weeks is also recommended, and
nowadays also oral posaconazole 800
mg for 15 days is discussed. C. kru-
sei is resistant against triazoles. Side
effects, toxicity, embryotoxicity and
allergy are of no clinical importance.
In two studies, vaginal clotrimazole

treatment during the first trimester
of pregnancy was shown to reduce the
rate of preterm births. The resistance
of C. albicans does not play a clinically
important role in vulvovaginal candi-
dosis. Although it is not necessary to
treat vaginal Candida colonization in
healthy women, in Germany it is rec-
ommended during the third trimester of
pregnancy, because it reduces the rate
of oral thrush and napkin dermatitis
induced by colonization during vaginal
delivery in mature healthy newborns.
Until immunological therapies become
available, chronic recurrent vulvovagi-
nal candidosis requires “chronic recur-
rent” suppression therapy. Weekly to
monthly oral fluconazole regimes sup-
press relapses well, but cessation of
therapy after 6 or 12 months leads to
relapse in 50% of patients. The decreas-
ing-dose maintenance regime of 200 mg
fluconazole three times a week initially,
decreasing to once monthly [1] leads to
more acceptable results. Future studies
should include candida autovaccination,
antibodies against candida virulence
factors and other immunological trials.
Probiotics should also be considered in
further studies. Over-the-counter ther-
apy needs to be reduced.
Key words: guideline, vulvovaginal
candidosis, candida, pregnancy, diagno-
sis, therapy, immunology.
SUMMARY OF RECOMMENDATIONS
1. A diagnosis of vulvovaginal candidosis
is made from a combination of clinical
signs and symptoms and the presence
of yeasts, usually proven by microscopic
investigation (400 fold phase contrast)
of the vaginal fluid. A yeast culture
with species determination is necessary
in doubtful, recurrent or complicated
cases. Serological blood tests are not
recommended (LoE 1b, GoR B).
Vulvovaginal candidosis | 15.6 |
2. Therapy for acute vulvovaginal can-
didosis is possible with: polyenes,
imidazoles or ciclopyroxolamine in
the form of vaginal tablets; ovules
or creams for a one day to one week
treatment duration; skin cream for
the vulva; or with one day oral tria-
zole treatment. The results of all
clinical and mycological therapies
are similar. Asymptomatic coloni-
zation must not be treated unless
there is immunosuppression, it is a
complicated case or there is chronic
recurrent vulvovaginal candidosis
(LoE 1a, GoR A). For treatment of
vaginal colonization duringpregnancy
see 3.5.
3. Treatment for chronic recurrent C.
albicans vulvovaginitis is (due to the
lack of immunological therapy) sup-
pressive intermittent antimycotic
therapy over a period of months with
an oral triazole. The best results are
obtained with the fluconazole regime
described by Donders et al. (table 4)
(LoE 2a, GoR B).
4. C. glabrata vaginitis is resistant to
the common vaginal or oral treat-
ments. Therefore the recommenda-
tions are: vaginal boric acid 600 mg
capsules for 14 days; amphotericin
B ovules; vaginal 17% flucytosine; or
800 mg oral fluconazole per day for
2–3 weeks (LoE 2a, GoR B) or posa-
conazole 800 mg orally for 15 days
(LoE 4, GoR C). C. krusei vaginitis is
resistant to oral triazoles and should
therefore be treated with local clot-
rimazole, imidazoles or boric acid
(LoE 2b, GoR B).
5. In Germany, antimycotic local treat-
ment for vaginal C. colonization
is recommended during the last 6
weeks of pregnancy to inhibit ver-
tical transmission during vaginal
delivery. Thus, neonatal C. infection
rates are significantly reduced (LoE
2a, GoR B).
913
Chapter | 15 | Special urogenital infections

1. INTRODUCTION recommendation (GoR) using ICUD stand-

Vulvovaginal candidosis is an infection
of the estrogenized vagina and the vesti-
bulum, which can extend to the outside
of the labia minora, the labia majora and
the intercrural region. Candidosis of the
cervix or the endometrium is unknown.
Connatal foetal candidosis and Candida
amnionitis are rare events. The terms
“vulvovaginal candidosis” or “Candida albi-
cans vulvovaginitis” are recommended [2].
The ending “-iasis” should be used for par-
asitic infections (e.g. trichomoniasis) [3–4].
2. METHODS
A MedLine/PubMed search with the
keywords “vulvovaginal candidosis”
resulted in 2812 titles and a search
with the keywords “vulvovaginal can-
didosis therapy studies” resulted in 286
titles. All were screened for title and
abstract, but only very few recent stud-
ies were randomized and/or prospective
controlled trials [1, 5–10]. Only three
metanalyses or Cochrane analyses were
found [11–13] and only two guidelines
[4, 14].
The studies were rated according to the
level of evidence (LoE) and the grade of
ards (for details see Preface) [15–16].
3. MICROBIOLOGY
Candida albicans is able to form blast-
ospores, pseudomycelia, true mycelia and
chlamydospores. Candia glabrata forms
only blastospores. Blastospores are usu-
ally formed in colonized women together
with (pseudo)mycelia in vaginitis patients
[17–18]. In premenopausal, pregnant,
asymptomatic and healthy women, and
women with acute Candida vaginitis,
Candida albicans constitutes 85–95% of
the colonizing vaginal candida species,
whereas non-albicans species (especially
Candida glabrata) are more frequent in
postmenopausal, diabetic and immuno-
suppressed women [19–25]. There are
regional differences in the distribution of
candida species (Tables 1 and 2 contain
examples for Berlin, Germany). Candida
krusei, Candida guilliermondii, Candida
tropicalis, Candida parapsilosis and oth-
ers can cause vulvovaginitis with typical
symptoms [17, 25–28]. Saccharomyces
cerevisiae rarely causes vaginal symp-
toms [18, 29], but is identified in about
1–2% of cultures.[23, 25] (Table 3).
Candida albicans is found in 80–95% of

Table 1 Candida colonization of the vagina in healthy HIV-positive and HIV-negative women [25].

Species HIV-neg. HIV-pos.

n = 383 100% n = 66 100%

Candida positive 88 22.9 p = 0.02 24 36.4

all 88 100 24 100

C. albicans 77 87.5 14 58.3

C. glabrata 6 6.8 8 33.3

¯˘˙

C. krusei 2 2.3 0 0

C. dubliniensis 1 1.1 p = 0.001 0 0

C parapsilosis 1 1.1 1 4.2

C. famata 1 1.1 0 0

C. magnoliae 1 4.2

914
 Vulvovaginal candidosis | 15.6 |

Table 2 Distribution of vaginal Candida species in HIV-negative colonized women [25].

Patients premenopausal postmenopausal pregnant not pregnant

all patients n = 338 n = 45 n = 192 n = 146

with positive culture n = 92 (23.3%) n = 6 (13.3%) n = 52 (27.1%) n = 30 (20.5%)

p = 0.003 p = 0.02

n % n % n % n %

C. albicans 75 91.5 2 33.3 48 92.3 27 90.0

C. glabrata 4 4.9 2 33.3 2 3.8 2 6.7

C. krusei 1 1.2 1 16.7 1 1.9 0 –

C. dubliniensis 1 1.2 0 – 1 1.9 0 –

C. famata 0 – 1 16.7 0 – 0 –

C. parapsilosis 1 1.2 0 – 0 – 1 3.3

vagina[32] and the estrogen receptors of

Table 3 Distribution of Candida species in 472 cases of
acute vaginal candidosis in Poland and Germany [101].
acute Candida vulvovaginitis
C. albicans
C. glabrata
C. krusei
Others (C. tropicalis, C. kefyr,
C. africana, S. cereviciae)
chronically recurrent vulvovaginal candi-
dosis cases (with small differences region-
ally), making it the most frequent yeast
in these cases [1, 17–18]. There is no evi-
dence (although proven in intensive care
and hematooncology and thus often men-
tioned in gynaecology) for an increase of
non-albicans species either in acute or
recurrent vaginal candidosis [1, 5, 30].
There is evidence for different genotypes
of Candida albicans strains in asymp-
tomatic women and in those with acute
Candida vaginitis [31].
4. GENITAL COLONISATION
Premenstrual girls and postmenopausal
women are less frequently vaginally col-
onized due to the estrogenization of the
C. albicans [33–34], and therefore do not
usually not suffer from candida vaginitis.
n % 20–30% of healthy, non pregnant and
472 100 premenopausal women are vaginally col-
450 95.3 onized, compared to at least 30% of preg-
10 2.1 nant women in the third trimester and
4 0.9 30% of women with immunodeficiences
2.3
[19, 25] (Tables 1–2). However, vaginal
11
colonization can alter in individuals from
time to time: in a longitudinal cohort
study with 1248 asymptomatic healthy
young women over one year, 70% were
colonized once, but only 4% at all three-
monthly visits. Recent sexual intercourse,
injection of medroxyprogesteronacetate
and concurrent colonization with lacto-
bacilli and B-streptococci were identified
as risk factors [35]. The sexual partner’s
sperm can also be colonized by the identi-
cal Candida strain as in the vagina [36],
despite the partner being free of symp-
toms. However, Candida prostatits is a
very rare event found only in immuno-
suppressed men [37]. However, the role
of the partner’s genital colonization, or
the orointestinal colonization of both
partners, as the source of recurrence of
Candida vaginitis is unclear [17]. The
progression from colonization to vagin-
itis is not well understood and seems
to underline host factors [38]. Because

915
Chapter | 15 | Special urogenital infections
infection is colonization plus disposition
(“candidosis is illness of the ill”), immu-
nosuppressed people are especially prone
to developing candidosis. However, 75%
of healthy women develop vaginal candi-
dosis at least once during their lives, and
up to 10% suffer more than 4 episodes
per year (chronic recurrent vulvovaginal
candidosis/CRVVD) [17, 22].
5. CANDIDA VIRULENCE FACTORS
The first step from colonization to infec-
tion is the adherence of a Candida cell to
the vaginal wall using mannoproteins
[39–41]. Aspartate proteinases (SAP 1–10)
and proteases mainly secreted from the top
of germinating pseudomycelia [42–44] are
probably the most important virulence fac-
tors and these correlate with pathogenic-
ity [45–46]. Other important virulence
factors are: iron binding from host cells
by siderophores [47–48]; the immunosup-
pressive mykotoxin gliotoxin of C. albicans
[49]; a strong pH-tolerance from 2–11 [50];
and enzymes which enable C. albicans to
survive in macrophages [51].
6. PREDISPOSING HOST FACTORS
Candida strains and species differ in
pathogenicity and thus candidosis devel-
ops due to a combination of Candida
strain and weak local defence mecha-
nisms [52]. Impaired glucose tolerance
was found in approximately 25% or more
of women with CRVVC than in controls
[53]. Although C. glabrata is less “viru-
lent”, more women with type 2 diabetes
are colonized than healthy women [21,
54], which underlines the importance
of host factors. Diabetic patients suffer
from both vaginal candidosis and therapy
failure more frequently, if serum glucose
levels are not normalized [55]. Modern
oral contraceptives with low estrogen
levels, which do not significantly influ-
ence carbohydrate metabolism [56], do
916
not increase vaginal Candida coloniza-
tion [57] or infection rates [58], but some
results are contradictory [59]. Vaginal
colonization rates are higher in women
with a well estrogenized vagina, espe-
cially in pregnancy. There is up to a 33%
risk of women who already have vaginal
Candida colonization developing Candida
vaginitis after antibiotic treatment
[60–63]. Although vaginal candidosis
often occurs in women with normal lacto-
bacillus flora, lower numbers of lacto-
bacilli have been found in women with
vaginal candidosis [64]. The possibly
protective role of lactobacilli (or special
strains of them) against yeasts is not yet
understood. Sobel stresses the potentially
underestimated role of sexual behaviour
in the recurrence of vaginal candidosis
[17], based on repeated infections follow-
ing sexual intercourse [60, 65]. Last but
not least, genetic factors are responsible
for recurrences, as both mannose-binding
lectin gene polymorphisms [66–67] and
the blood group ABO-Lewis non-secre-
tor phenotype [68] have been identified
as risk factors. Women with atopy and
allergies develop vaginal candidosis more
frequently than others [69] and allergic
phenomena are found to be important in
development of clinical signs, especially
redness and itching [17, 70]. Women with
a history of recurrent Candida vagin-
itis express immunologically important
vaginal heat shock proteins during the
symptom-free interval [71]. Psychosocial
stress is also an important risk factor for
Candida vulvovaginitis [6, 72], as this
may potentially cause immunosuppres-
sion. Conversely, recurrent vaginal can-
didosis may cause psychosocial stress
and have a negative impact on both work
and social life [28, 73].
7. CLINICAL SIGNS
Due to the estrogen-induced conditions,
premenopausal women usually suffer pri-
marily from vaginal candidosis (which can

extend to the vulva) and postmenopausal
women only from vulval and/or intercru-
ral candidosis. Clinical symptoms typi-
cally occur premenstrually due to higher
sugar levels in the vagina after ovulation
[18, 60]. In about 90% of patients, pruri-
tus is the most typical symptom, but not
reliable as only 35–40% of women with
itching have Candida vaginitis [25, 74].
Discharge can vary from thinly-fluent
(often at the beginning of acute vaginal
candidosis), to cottage-cheese-like, to no
discharge at all [75]. From the clinical
and therapeutical perspective, classifi-
cation of vulvovaginal candidosis [17] is
useful, although in uncomplicated can-
didosis (pseudo)hyphae are not found
microscopically in all cases. Symptoms
include vaginal redness, soreness, burn-
ing, dyspareunia and dysuria. Symptoms
alone do not allow patients or clinicians
to confidently distinguish the cause
of vaginitis, but a lack of itching and
inflammation makes vaginal candido-
sis less likely [74]. In contrast to bacte-
rial vaginosis there is no unusual odour.
The labia minora can be swollen, and
in recurrent cases burning fissures can
occur. Dermatologically, vulval candido-
sis is divided into three forms: vesiculo-
pustulous, eczematoid and follicular [4].
In heavy cases an adherent white layer
of discharge can be seen on the vagi-
nal wall, which can cause bleeding if
removed. C. glabrata vaginitis (usu-
ally occuring during the late pre- and
perimenopausal decades) [26, 76–78],
C. parapsilosis vaginitis [28], and (rare)
Saccharomyces cerevisiae vaginitis
[18, 29] are associated with mild clinical
symptoms and complaints. The cervix is
not infected. (LoE 1b)
8. DIAGNOSIS
A diagnosis of vaginal candidosis is
made from a combination of clinical
signs and symptoms and the presence of
yeasts.
Vulvovaginal candidosis | 15.6 |
8.1 Necessary/obligate
Anamnestic questions, a gynaecologi-
cal inspection, pH measurement and
either 10% potassium hydroxid investi-
gation or saline solution of the vaginal
fluid (400fold phase contrast) are essen-
tial. Budding cells or (pseudo)hyphae
can only be detected in approximately
50–80% of patients with vaginal can-
didosis [17, 79]. Unfortunately there is
a lack of practice and teaching in many
hospitals and practices around the world
[18, 80–81]. However, if no blastospores or
(pseudo)hyphae are seen microscopically
or in chronic recurrent or complicated
cases, then cultural species determination
is necessary [18, 60, 82–83]. Routine cul-
tures are usually not necessary, if yeasts
are found microscopically. The typical
culture medium is Sabouraud agar, but
there are equally sensitive media com-
mercially available, e.g. CHROMagar®,
Microstix®-Candida and others. It is pos-
sible for two different Candida species
to be cultured in one Candida vagin-
itis, for example C. albicans and C.
glabrata. In such as case, the patient
is suffering from C. albicans vaginitis.
After treatment, resistant C. glabrata
remains in situ, mostly only colonizing
the vagina.
8.2 Not effective
Serological tests are not useful for the
diagnosis of vulvovaginal candidosis
because low antibody levels are found in
most people with or without vaginal can-
didosis due to intestinal colonization, and
because this superficial vaginal disease
does not affect antibody levels.
9. THERAPY
There are many conventional and alter-
native therapies [84]. Polyenes form com-
plexes with the ergosterole of the yeast
cell wall and thus alter permeability
[85]. Azoles inhibit the transformation of
917
Chapter | 15 | Special urogenital infections
lanosterole to the ergosterole of the yeast
cell wall [86]. Ciclopyroxolamine inhibits
potentially important iron-needing
enzymes via chelate formation [87].
Patients prefer oral treatment if they are
asked to choose [88].
9.1 Colonisation
Asymptomatic, vaginally colonized
women do not require treatment if they
are immunocompetent and if there is no
chronically recurrent candidosis.
9.2 Colonisation during pregnancy
Nearly all healthy, mature neonates who
have been colonized by Candida during
vaginal delivery develop oral thrush and
napkin dermatitis within their first year,
with a peak of 10–13% during 2–4 weeks
of life [89–90]. In Germany, prophylac-
tic treatment of asymptomatic vaginal
Candida colonization is recommended
during the last weeks of pregnancy in
order to protect the baby during vaginal
delivery. This significantly reduces the
risk of neonatal candidosis to approxi-
mately 2% during the 4th week of life [89,
91–92].
A retrospective randomized [93–95] and
a prospective randomized [96] study sur-
prisingly showed a decrease of preterm
deliveries after vaginal treatment with
clotrimazole in the first trimester; this
needs further investigation. There are no
teratogenic effects after vaginal clotrima-
zole therapy during pregnancy [93].
9.3 Acute Candida vulvovaginitis
Acute vulvovaginal candidosis can be
treated locally with polyenes (Nystatin,
Amphotericin B or Pimaricin), imida-
zoles (clotrimazole, miconazol-nitrate,
econazole-nitrate, fenticonazole-nitrate,
sertaconazole-nitrate, tioconazole-nitrate,
terconazole-nitrate and others,) [17, 97]
or with ciclopyroxolamine [98]. Oral
treatment with the imidazole ketocona-
zole, or better the triazole fluconazole or
918
itraconazole, or others, is also possible.
Vaginal suppositories or vaginal creams
are also available with varying dosages,
formulations and treatment durations
varying from 1, 3, 6 or 7 days without
toxicity [99]. All mycological and clinical
cure results are equal and range between
approximately 85% after 1–2 weeks and
75% after 4–6 weeks [11, 17, 100–102].
Cure rates during pregnancy are signifi-
cantly better with imidazoles than with
polyenes [12]. If the candidosis involves
the region of the vulva outside the introi-
tus or inguinal region, a twice daily
antimycotic skin cream for up to 6 days is
recommended. Treatment of the asympto-
matic sexual partner is of no benefit for
the patient [103–104].
9.4 Side effects
All local antimycotics are well tolerated,
but topical azoles and ciclopyroxolamine
can cause local burning in 1–10% [97,
101]. Allergic reactions are rare, but
possible. The oral imidazole ketocona-
zole can cause side effects in about 5%
of patients, e.g. headache and non-viral
hepatitis in 1:500000–1000000 gynae-
cological patients [105]. The hydrophile
fluconazole and the lipophile itraconazole
cause far fewer side effects due to yeast-
selective cytochrome P450-depending
ergosterole-inhibition, but like ketocon-
zole they are not recommended during
pregnancy. However, as yet, no neonatal
teratogenecity after therapy during the
first trimester of pregnancy has been
detected [106].
9.5 Resistance of Candida albicans?
Although vaginal C. albicans strains
with higher minimum inhibitory con-
centrations (MIC) to fluconazole can be
found[107], cases of azole resistance are
rare in gynecology [107–108]. Clinical
resistance does not correlate to labora-
tory MIC tests and vice versa, a well
 Vulvovaginal candidosis | 15.6 |

known problem in medical mycology. dose of 3 ´ 200 mg fluconazole in the first

Therefore, MIC tests are usually not
recommended [109].
9.6 Non-albicans vaginitis
week followed by a decreasing dose main-
tenance regime (Table 4). They found that
90% of patients were disease-free after 6
months and 77 % disease-free after one
year.

The common vaginal or oral treatments

usually fail in C. glabrata vaginitis. Sobel Table 4 Individualized decreasing – dose maintenance
et al. [109] therefore recommend vaginal fluconazole regime for recurrent vulvovaginal
candidosis [1].
boric acid 600 mg capsules for 14 days,
and Philips [110] recommends ampho-
tericin B ovules. In refractory cases a 2
week course of topical 17% flucytosine is Fluconazole
3 × 200 mg
90% successful [109]. In some countries
boric acid is not allowed and vaginal flu- during
one week
cytosine is not available. In this case, a
daily high dose of 800 mg fluconazole for
2–3 weeks is recommended depending Microscopy
on resistance tests [4, 111]. Recently oral
Culture if not okay
posaconazole 2 ´ 400 mg for 15 days was
recommended due to resistance against Symptoms
fluconazole [112]. C. krusei vaginitis is
resistant to fluconazole and flucytosine,
200 mg once/week
but local clotrimazole, other imidazoles × 8 weeks
or boric acid are mostly successful [27].
As cases are rare, systematic studies are
missing.
Microscopy
Culture if not okay
9.7 Chronically recurrent Candida Symptoms
albicans vulvovaginitis
Since infection is colonization plus dis- 200 mg once/2 weeks
position and no therapy against disposi- × 4 months
tion (immunological local incompetence)
exists, local or oral maintenance thera-
pies to prevent relapse are recommended Microscopy
[5, 113–115]. The results for local clot-
Culture if not okay
rimazole 500 mg, oral ketozonazole 100
mg or fluconazole 150 mg are comparably Symptoms
effective, but recurrence occurs in 50%
of patients shortly after therapy cessa-
200 mg once/month
tion [5, 114]. In a placebo-controlled trial × 6 months
with 387 women randomly assigned 150
mg fluconazole weekly for 6 months, the
proportions of disease-free women after
Microscopy
12 months were 42.9% in the fluconazole
group and 21.9% in the placebo group [5]. Culture if not okay
Donders et al. [1] gave 117 women (with- Symptoms
out a placebo control group) an initial

919
Chapter | 15 | Special urogenital infections
10. DISCUSSION
There are many questions. Many healthy
women are colonized without complaint:
why is the immunological system of the
vagina in some women with Candida
prone to recurrent infection or inflamma-
tion? Antimycotics are not the solution
and provide only acute relief.
10.1 Immunological therapies?
There is currently no satisfactory
proven immunotherapy for (chronic
recurrent) vaginal candidosis, although
30 years ago Rosedale and Brown [116]
reported encouraging first results
with hypersensitation. In vitro stud-
ies using both the autologous mem-
brane bound C. albicans antigen and
T-Lymphozytes of a chronic recurrent C.
albicans vaginitis patient, showed bet-
ter immunological reactions than with
commercially available Candida anti-
gens [117]. Meanwhile, Rigg et al. [118]
has reported on Candida allergen ther-
apy and Moraes et al. [119] and Rusch
and Schwiertz [120] have reported first
clinical results with Candida autovac-
cination. Antibodies against aspartyl-
proteases, adhesins or allergen therapy
could potentially play a role in future
[121]. However, a therapeutical break-
through does not currently exist despite
multiple efforts to understand the
immunopathogenesis of Candida vagin-
itis [38, 43, 67, 69, 73, 121–125].
10.2 Lactobacilli? Alternatives?
Intramuscular injections of non-H2O2-
producing lactobacilli to induce antibodies
[73] and probiotics [126–129] have shown
encouraging but controversial results,
which need further investigation.
Watson and Calabretto [130] have com-
plained about the lack of randomized con-
trolled trials for both conventional and
920
non-conventional management of recur-
rent vulvovaginal candidosis.
10.3 Over-the-counter (OTC)
therapy?
Over 80% of treatment for vulvovaginal
candidosis with clotrimazole or (in some
countries) fluconazole is in the form of
OTC therapy. However, the hopeful expec-
tation in the early 1990s that patients
would be able to correctly diagnose cand-
ida vaginitis, is obviously not correct [30,
35, 83], as only about 33% of 95 women
who buy vaginal antimycotics are indeed
suffering from Candida vaginitis [131].
It is therefore only appropriate to treat
after a correct diagnosis.
11. FURTHER RESEARCH
There are a lot of holes in our knowledge
of Candida host interactions which need
further research. How can Candida viru-
lence factors (aspartate proteases and oth-
ers) be weakened? How can adhesion to
vaginal epithelial cells be inhibited? How
can host resistance be improved? (T-cell-
stimulation? Humoral factors? Allergy?) Is
a vaccination against Candida possible?
Which new antimycotics are able to
treat C. glabrata or C. krusei vaginitis?
12. CONCLUSIONS
Vulvovaginal candidosis is, in the major-
ity of cases, an acute and uncomplicated
local infection of the estrogenized vagina,
and in over 80% of cases is caused by cC.
albicans. Non albicans species arise in
higher frequency (especially C. glabrata)
in postmenopausal women and in women
with immunosuppression or diabetes
mellitus. Whilst yeast-host interactions
remain unclear, the cure for chronically

recurrent vaginal candidosis will con-
tinue to be a challenge.
REFERENCES
1. Donders G, Bellen G, Byttebier G,
Verguts L, Hinoul P, Walckiers R,
Stalpaert M, Vereecken A, and Van
Eldere J, Individualized decreasing-
dose maintenance fluconazole regimen
for recurrent vulvovaginal candidiasis
(ReCiDiF trial). Am J Obstet Gynecol,
2008. 199(6): 613 e1–9.
2. Odds FC, Arai T, Disalvo AF, Evans
EG, Hay RJ, Randhawa HS, Rinaldi
MG, and Walsh TJ, Nomenclature of
fungal diseases: a report and recom-
mendations from a Sub-Committee of
the International Society for Human and
Animal Mycology (ISHAM). J Med Vet
Mycol, 1992. 30(1): 1–10.
3. Loeffler W, Terminology of human
mycoses. Nomenclature of mycotic dis-
eases of man. List of accepted German
terms translated, arranged and pub-
lished, together with comments, for the
International Society for Human and
Animal Mycology (ISHAM). Mykosen,
1983. 26(7): 346–84.
4. Mendling W and Seebacher C,
Vulvovaginalkandidose. AWMF-
Guideline 013/004 (S1) 2008.
5. Sobel JD, Wiesenfeld HC, Martens
M, Danna P, Hooton TM, Rompalo A,
Sperling M, Livengood C, 3rd, Horowitz B,
Von Thron J, Edwards L, Panzer H, and
Chu TC, Maintenance fluconazole therapy
for recurrent vulvovaginal candidiasis. N
Engl J Med, 2004. 351(9): 876–83.
6. Meyer H, Goettlicher S, and Mendling
W, Stress as a cause of chronic recurrent
vulvovaginal candidosis and the effec-
tiveness of the conventional antimycotic
therapy. Mycoses, 2006. 49(3): 202–9.
7. Fong IW, The value of chronic suppres-
sive therapy with itraconazole versus
clotrimazole in women with recurrent
Vulvovaginal candidosis | 15.6 |
vaginal candidiasis. Genitourin Med,
1992. 68(6): 374–7.
8. Quereux C, Gelas B, Chevallier T, Petit F,
and Micheletti MC, [Evaluation of the effi-
cacity and speed of action of sertaconazole
nitrate suppository and cream combined
treatment for vulvovaginal candidiasis].
Gynecol Obstet Fertil, 2000. 28(3): 238–44.
9. Upmalis DH, Cone FL, Lamia CA,
Reisman H, Rodriguez-Gomez G,
Gilderman L, and Bradley L, Single-
dose miconazole nitrate vaginal ovule in
the treatment of vulvovaginal candidia-
sis: two single-blind, controlled studies
versus miconazole nitrate 100 mg cream
for 7 days. J Womens Health Gend
Based Med, 2000. 9(4): 421–9.
10. Lowe NK, Neal JL, and Ryan-Wenger
NA, Accuracy of the clinical diagnosis
of vaginitis compared with a DNA probe
laboratory standard. Obstet Gynecol,
2009. 113(1): 89–95.
11. Pitsouni E, Iavazzo C, and Falagas ME,
Itraconazole vs fluconazole for the treat-
ment of uncomplicated acute vaginal and
vulvovaginal candidiasis in nonpregnant
women: a metaanalysis of randomized
controlled trials. Am J Obstet Gynecol,
2008. 198(2): 153–60.
12. Young GL and Jewell D, Topical treat-
ment for vaginal candidiasis (thrush) in
pregnancy. Cochrane Database Syst Rev,
2001(4): CD000225.
13. Watson MC, Grimshaw JM, Bond CM,
Mollison J, and Ludbrook A, Oral versus
intra-vaginal imidazole and triazole
anti-fungal agents for the treatment of
uncomplicated vulvovaginal candidiasis
(thrush): a systematic review. BJOG,
2002. 109(1): 85–95.
14. Bond CM and Watson MC, The develop-
ment of evidence-based guidelines for
over-the-counter treatment of vulvovagi-
nal candidiasis. Pharm World Sci, 2003.
25(4): 177–81.
15. Abrams P, Khoury S, and Grant A,
Evidence--based medicine overview of the
921
Chapter | 15 | Special urogenital infections
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
16. U.S. Department of Health and Human
Services Public Health Service Agency
for Health Care Policy and Research,
1992: 115–127.
17. Sobel JD, Vulvovaginal candidosis.
Lancet, 2007. 369(9577): 1961–71.
18. Mendling W and Seebacher C,
Vulvovaginalkandidose. AWMF-
Guideline 013/004 (S1), 2008.
19. Odds FC, Candida and Candidosis. 2nd
Edition ed. 1988, England:
W B Saunders.
20. Goswami R, Dadhwal V, Tejaswi S,
Datta K, Paul A, Haricharan RN,
Banerjee U, and Kochupillai NP, Species-
specific prevalence of vaginal candidiasis
among patients with diabetes mellitus
and its relation to their glycaemic status.
J Infect, 2000. 41(2): 162–6.
21. de Leon EM, Jacober SJ, Sobel JD, and
Foxman B, Prevalence and risk factors
for vaginal Candida colonization in
women with type 1 and type 2 diabetes.
BMC Infect Dis, 2002. 2: 1.
22. Corsello S, Spinillo A, Osnengo G, Penna
C, Guaschino S, Beltrame A, Blasi N,
and Festa A, An epidemiological survey
of vulvovaginal candidiasis in Italy. Eur
J Obstet Gynecol Reprod Biol, 2003.
110(1): 66–72.
23. Paulitsch A, Weger W, Ginter-
Hanselmayer G, Marth E, and Buzina
W, A 5-year (2000–2004) epidemiologi-
cal survey of Candida and non-Candida
yeast species causing vulvovaginal
candidiasis in Graz, Austria. Mycoses,
2006. 49(6): 471–5.
24. Goswami D, Goswami R, Banerjee U,
Dadhwal V, Miglani S, Lattif AA, and
Kochupillai N, Pattern of Candida species
isolated from patients with diabetes mel-
litus and vulvovaginal candidiasis and
their response to single dose oral flucona-
zole therapy. J Infect, 2006. 52(2): 111–7.
25. Mendling W, Niemann D, and Tintelnot
K, Vaginal Colonisation with Candida
Species with Special Focus on Candida
dubliniensis. A Prospective Study.
922
Geburtshilfe Frauenheilkd, 2007. 67:
1132–7.
26. Spinillo A, Capuzzo E, Egbe TO, Baltaro
F, Nicola S, and Piazzi G, Torulopsis
glabrata vaginitis. Obstet Gynecol, 1995.
85(6): 993–8.
27. Singh S, Sobel JD, Bhargava P, Boikov
D, and Vazquez JA, Vaginitis due to
Candida krusei: epidemiology, clinical
aspects, and therapy. Clin Infect Dis,
2002. 35(9): 1066–70.
28. Nyirjesy P, Alexander AB, and Weitz MV,
Vaginal Candida parapsilosis: pathogen
or bystander? Infect Dis Obstet Gynecol,
2005. 13(1): 37–41.
29. Sobel JD, Vazquez J, Lynch M,
Meriwether C, and Zervos MJ, Vaginitis
due to Saccharomyces cerevisiae: epide-
miology, clinical aspects, and therapy.
Clin Infect Dis, 1993. 16(1): 93–9.
30. Walker PP, Reynolds MT, Ashbee HR,
Brown C, and Evans EG, Vaginal yeasts
in the era of “over the counter” antifun-
gals. Sex Transm Infect, 2000. 76(6):
437–8.
31. Li J, Fan SR, Liu XP, Li DM, Nie ZH,
Li F, Lin H, Huang WM, Zong LL, Jin
JG, Lei H, and Bai FY, Biased geno-
type distributions of Candida albicans
strains associated with vulvovaginal
candidosis and candidal balanoposthitis
in China. Clin Infect Dis, 2008. 47(9):
1119–25.
32. Dennerstein GJ and Ellis DH,
Oestrogen, glycogen and vaginal can-
didiasis. Aust N Z J Obstet Gynaecol,
2001. 41(3): 326–8.
33. Tarry W, Fisher M, Shen S, and
Mawhinney M, Candida albicans: the
estrogen target for vaginal colonization.
J Surg Res, 2005. 129(2): 278–82.
34. Powell BL and Drutz DJ, Identification
of a high-affinity binder for estradiol
and a low-affinity binder for testosterone
in Coccidioides immitis. Infect Immun,
1984. 45(3): 784–6.
35. Beigi RH, Meyn LA, Moore DM, Krohn
MA, and Hillier SL, Vaginal yeast
colonization in nonpregnant women:

a longitudinal study. Obstet Gynecol,
2004.
104(5 Pt 1): 926–30.
36. Mendling W, Gutschmidt J, Gantenberg
R, Andrade P, and Schönian G, Vergleich
der Stammspezifität von Hefepilzen ver-
schiedener Lokalisationen bei Frauen
mit Vaginalcandidosen. Mykosen, 1998.
41(Suppl 2): 22–5.
37. Golz R and Mendling W, Candidosis of
the prostate: a rare form of endomycosis.
Mycoses, 1991. 34(9–10): 381–4.
38. Fidel PL, Jr., Immunity in vaginal can-
didiasis. Curr Opin Infect Dis, 2005.
18(2): 107–11.
39. Trumbore DJ and Sobel JD, Recurrent
vulvovaginal candidiasis: vaginal epithe-
lial cell susceptibility to Candida albi-
cans adherence. Obstet Gynecol, 1986.
67(6): 810–2.
40. Farrell SM, Hawkins DF, and Ryder
TA, Scanning electron microscope study
of Candida albicans invasion of cul-
tured human cervical epithelial cells.
Sabouraudia, 1983. 21(3): 251–4.
41. Sobel JD, Myers PG, Kaye D, and
Levison ME, Adherence of Candida albi-
cans to human vaginal and buccal epi-
thelial cells. J Infect Dis, 1981. 143(1):
76–82.
42. Ruchel R, Tegeler R, and Trost M, A
comparison of secretory proteinases from
different strains of Candida albicans.
Sabouraudia, 1982. 20(3): 233–44.
43. De Bernardis F, Agatensi L, Ross IK,
Emerson GW, Lorenzini R, Sullivan
PA, and Cassone A, Evidence for a
role for secreted aspartate proteinase
of Candida albicans in vulvovaginal
candidiasis. J Infect Dis, 1990. 161(6):
1276–83.
44. Naglik J, Albrecht A, Bader O, and
Hube B, Candida albicans proteinases
and host/pathogen interactions. Cell
Microbiol, 2004. 6(10): 915–26.
45. Cassone A, De Bernardis F, Mondello F,
Ceddia T, and Agatensi L, Evidence for a
correlation between proteinase secretion
and vulvovaginal candidosis. J Infect
Dis, 1987. 156(5): 777–83.
46. Ghannoum MA, Potential role of phos-
pholipases in virulence and fungal
Vulvovaginal candidosis | 15.6 |
pathogenesis. Clin Microbiol Rev, 2000.
13(1): 122–43, table of contents.
47. Ismail A and Lupan DM, Utilization
of siderophores by Candida albicans.
Mycopathologia, 1986. 96(2): 109–13.
48. Ghannoum MA and Abu-Elteen KH,
Pathogenicity determinants of Candida.
Mycoses, 1990. 33(6): 265–82.
49. Shah DT, Glover DD, and Larsen B, In
situ mycotoxin production by Candida
albicans in women with vaginitis.
Gynecol Obstet Invest, 1995. 39(1): 67–9.
50. Meinhof W, [Hydrochloric acid tolerance
of Candida albicans]. Mykosen, 1974.
17(12): 339–47.
51. Lattif AA, Prasad R, Banerjee U, Gupta
N, Mohammad S, and Baquer NZ, The
glyoxylate cycle enzyme activities in the
pathogenic isolates of Candida albicans
obtained from HIV/AIDS, diabetic and
burn patients. Mycoses, 2006. 49(2): 85–90.
52. Bernardis Fd, Boccabera M, and Casone
A, The role of immunity against vaginal
candida infection, in Fungal immunol-
ogy: from an organ perspective, Fidel
PL and Huffnagle GB, Editors. 2005,
Springer: New York. p. xv, 492 p.
53. Donders GG, Prenen H, Verbeke G, and
Reybrouck R, Impaired tolerance for
glucose in women with recurrent vaginal
candidiasis. Am J Obstet Gynecol, 2002.
187(4): 989–93.
54. Ray D, Goswami R, Banerjee U,
Dadhwal V, Goswami D, Mandal
P, Sreenivas V, and Kochupillai N,
Prevalence of Candida glabrata and its
response to boric acid vaginal supposito-
ries in comparison with oral fluconazole
in patients with diabetes and vulvovagi-
nal candidiasis. Diabetes Care, 2007.
30(2): 312–7.
55. Bohannon NJ, Treatment of vulvovagi-
nal candidiasis in patients with diabetes.
Diabetes Care, 1998. 21(3): 451–6.
56. Gaspard U, Scheen A, Endrikat J,
Buicu C, Lefebvre P, Gerlinger C, and
Heithecker R, A randomized study over
13 cycles to assess the influence of oral
contraceptives containing ethinylestra-
diol combined with drospirenone or
desogestrel on carbohydrate metabolism.
Contraception, 2003. 67(6): 423–9.
923
Chapter | 15 | Special urogenital infections
57. Davidson F and Oates JK, The pill does
not cause ‘thrush’. Br J Obstet Gynaecol,
1985. 92(12): 1265–6.
58. Foxman B, The epidemiology of vul-
vovaginal candidiasis: risk factors. Am J
Public Health, 1990. 80(3): 329–31.
59. Cetin M, Ocak S, Gungoren A, and
Hakverdi AU, Distribution of Candida
species in women with vulvovaginal
symptoms and their association with
different ages and contraceptive meth-
ods. Scand J Infect Dis, 2007. 39(6–7):
584–8.
60. Eckert LO, Hawes SE, Stevens CE,
Koutsky LA, Eschenbach DA, and
Holmes KK, Vulvovaginal candidiasis:
clinical manifestations, risk factors,
management algorithm. Obstet Gynecol,
1998. 92(5): 757–65.
61. Pirotta MV, Gunn JM, and Chondros P,
“Not thrush again!” Women’s experience
of post-antibiotic vulvovaginitis. Med J
Aust, 2003. 179(1): 43–6.
62. Pirotta MV and Garland SM, Genital
Candida species detected in samples
from women in Melbourne, Australia,
before and after treatment with anti-
biotics. J Clin Microbiol, 2006. 44(9):
3213–7.
63. Xu J, Schwartz K, Bartoces M, Monsur
J, Severson RK, and Sobel JD, Effect of
antibiotics on vulvovaginal candidiasis:
a MetroNet study. J Am Board Fam Med,
2008. 21(4): 261–8.
64. Auger P and Joly J, Microbial flora
associated with Candida albicans vul-
vovaginitis. Obstet Gynecol, 1980. 55(3):
397–401.
65. Reed BD, Zazove P, Pierson CL, Gorenflo
DW, and Horrocks J, Candida transmis-
sion and sexual behaviors as risks for a
repeat episode of Candida vulvovagin-
itis. J Womens Health (Larchmt), 2003.
12(10): 979–89.
66. Donders GG, Babula O, Bellen G,
Linhares IM, and Witkin SS, Mannose-
binding lectin gene polymorphism and
resistance to therapy in women with
recurrent vulvovaginal candidiasis.
BJOG, 2008. 115(10): 1225–31.
67. Babula O, Lazdane G, Kroica J,
Linhares IM, Ledger WJ, and Witkin SS,
Frequency of interleukin-4 (IL-4)-589
924
gene polymorphism and vaginal con-
centrations of IL-4, nitric oxide, and
mannose-binding lectin in women with
recurrent vulvovaginal candidiasis. Clin
Infect Dis, 2005. 40(9): 1258–62.
68. Chaim W, Foxman B, and Sobel JD,
Association of recurrent vaginal can-
didiasis and secretory ABO and Lewis
phenotype. J Infect Dis, 1997. 176(3):
828–30.
69. Neves NA, Carvalho LP, De Oliveira
MA, Giraldo PC, Bacellar O, Cruz AA,
and Carvalho EM, Association between
atopy and recurrent vaginal candidia-
sis. Clin Exp Immunol, 2005. 142(1):
167–71.
70. Witkin SS, Jeremias J, and Ledger WJ,
A localized vaginal allergic response in
women with recurrent vaginitis.
J Allergy Clin Immunol, 1988. 81(2):
412–6.
71. Giraldo P, Neuer A, Korneeva IL,
Ribeiro-Filho A, Simoes JA, and Witkin
SS, Vaginal heat shock protein expression
in symptom-free women with a history
of recurrent vulvovaginitis. Am J Obstet
Gynecol, 1999. 180(3 Pt 1): 524–9.
72. Ehrstrom SM, Kornfeld D, Thuresson J,
and Rylander E, Signs of chronic stress
in women with recurrent candida vul-
vovaginitis. Am J Obstet Gynecol, 2005.
193(4): 1376–81.
73. Birkner V, Essers M, Bühring M,
Koldovsky U, and Mendling W,
Randomisierte 3-armige, offene, kon-
trollierte, klinische Therapiestudie
zur Behandlung der chronisch-rez-
idivierenden vaginalen Kandidose
mit einer systematischen apparativen
Heliotherapie im Vergleich zu einer
antimykotischen Standardtherapie
und einer Vakzinationsbehandlung mit
Gynatren. Mycoses, 2005. 48(5): 310.
74. Anderson MR, Klink K, and Cohrssen
A, Evaluation of vaginal complaints.
JAMA, 2004. 291(11): 1368–79.
75. Spacek J, Jilek P, Buchta V, Forstl M,
Hronek M, and Holeckova M, The serum
levels of calcium, magnesium, iron and
zinc in patients with recurrent vulvovagi-
nal candidosis during attack, remission
and in healthy controls. Mycoses, 2005.
48(6): 391–5.

76. Sobel JD, Vulvovaginitis due to Candida
glabrata. An emerging problem.
Mycoses, 1998. 41 Suppl 2: 18–22.
77. Fidel PL, Jr., Vazquez JA, and Sobel JD,
Candida glabrata: review of epidemiol-
ogy, pathogenesis, and clinical disease
with comparison to C. albicans. Clin
Microbiol Rev, 1999. 12(1): 80–96.
78. Mendling W, [Torulopsis in gynecology].
Geburtshilfe Frauenheilkd, 1984. 44(9):
583–6.
79. Muller J, Wold B, Kubitta D, and
Baument J, Quantitative intersuchangen
uber die doderlein-flora gesunder sowie
mykosekranker probandinnen unter
lokaler isconatol-nitrat therapie, in
Mongraphic excerpta medica, Seelinger
HPR, Editor. 1981: Amsterdam, Oxford,
Princeton. p. 81–93.
80. Donders G, We, specialists in vulvovagin-
itis. Am J Obstet Gynecol, 2001. 184(2):
248–9.
81. Ledger WJ, Polaseczky MM, Yih MC,
Jeremias J, Tolbert V, and Witkin SS,
Difficulties in the diagnosis of candida
vaginitis. Inf Dis Clin Bact 2000.
9: 66–69.
82. Nyirjesy P, Seeney SM, Grody MH,
Jordan CA, and Buckley HR, Chronic fun-
gal vaginitis: the value of cultures. Am J
Obstet Gynecol, 1995. 173(3 Pt 1): 820–3.
83. Hoffstetter SE, Barr S, LeFevre C,
Leong FC, and Leet T, Self-reported
yeast symptoms compared with clinical
wet mount analysis and vaginal yeast
culture in a specialty clinic setting. J
Reprod Med, 2008. 53(6): 402–6.
84. Wilson C, Recurrent vulvovaginitis can-
didiasis; an overview of traditional and
alternative therapies. Adv Nurse Pract,
2005. 13(5): 24–9; quiz 30.
85. Scheklakow ND, Deletorski WW,
and Goldoa OA, Veränderungen der
Ultrastruktur von Candida albi-
cans unter Einwirkung von Polyen-
Antibiotika. Mykosen, 1980. 24:
140–52.
86. Plempel M, [Pharmacokinetics of imi-
dazole-antimycotics (author’s transl)].
Mykosen, 1980. 23(1): 16–27.
87. Niewerth M, Kunze D, Seibold M,
Schaller M, Korting HC, and Hube B,
Vulvovaginal candidosis | 15.6 |
Ciclopirox olamine treatment affects the
expression pattern of Candida albicans
genes encoding virulence factors, iron
metabolism proteins, and drug resistance
factors. Antimicrob Agents Chemother,
2003. 47(6): 1805–17.
88. Tooley PJ, Patient and doctor preferences
in the treatment of vaginal candidosis.
Practitioner, 1985. 229(1405): 655–60.
89. Blaschke-Hellmessen R, [Vertical trans-
mission of Candida and its consequences].
Mycoses, 1998. 41 Suppl 2: 31–6.
90. Blaschke-Hellmessen R,
[Epidemiological studies of the occur-
rence of yeasts in children and their
mothers]. Mykosen, 1968. 11(9): 611–6.
91. Schnell JD, Epidemiology and the
prevention of peripartal mycoses.
Chemotherapy, 1982. 28 Suppl 1:
66–72.
92. Mendling W and Spitzbart H,
Antimykotische Therapie der vaginalen
Hefepilz-Kolonisation von Schwangeren
zur Verhütung von Kandidamykosen
beim Neugeborenen. AMWF, Guideline
015/042 (S1) 2008.
93. Czeizel AE, Toth M, and Rockenbauer M,
No teratogenic effect after clotrimazole
therapy during pregnancy. Epidemiology,
1999. 10(4): 437–40.
94. Czeizel AE, Fladung B, and Vargha P,
Preterm birth reduction after clotrima-
zole treatment during pregnancy. Eur
J Obstet Gynecol Reprod Biol, 2004.
116(2): 157–63.
95. Hay P and Czeizel AE, Asymptomatic tri-
chomonas and candida colonization and
pregnancy outcome. Best Pract Res Clin
Obstet Gynaecol, 2007. 21(3): 403–9.
96. Kiss H, Petricevic L, and Husslein P,
Prospective randomised controlled trial
of an infection screening programme to
reduce the rate of preterm delivery. BMJ,
2004. 329(7462): 371.
97. Mendling W, Azoles in the therapy of
vaginal candidosis, in Sterol biosyn-
thesis inhibitors, Berg D and Plempel
M, Editors. 1988, Ellis Horwood:
Chichester. p. 480–506.
98. Wajnberg M and Wajnberg A, [A com-
parative double blind trial with vagi-
nal creams of cyclopyroxolamine and
925
Chapter | 15 | Special urogenital infections
miconazole in vulvovaginal candido-
sis (author’s transl)]. Mykosen, 1981.
24(12): 721–30.
99. Ritter W, Pharmacokinetics of azole com-
pounds, in Sterol biosynthesis inhibitors,
Berg D and Plempel M Editors. 1988,
Ellis Horwood: Chichester. p. 397–429.
100. Cohen L, Is more than one application
of an antifungal necessary in the treat-
ment of acute vaginal candidiasis? Am J
Obstet Gynecol, 1985. 152(7 Pt 2): 961–4.
101. Mendling W, Krauss C, and Fladung
B, A clinical multicenter study compar-
ing efficacy and tolerability of topical
combination therapy with clotrimazole
(Canesten, two formats) with oral single
dose fluconazole (Diflucan) in vulvovagi-
nal mycoses. Mycoses, 2004. 47(3–4):
136–42.
102. Nurbhai M, Grimshaw J, Watson M,
Bond C, Mollison J, and Ludbrook A,
Oral versus intra-vaginal imidazole
and triazole anti-fungal treatment of
uncomplicated vulvovaginal candidiasis
(thrush). Cochrane Database Syst Rev,
2007(4): CD002845.
103. Buch A and Skytte Christensen E,
Treatment of vaginal candidosis with
natamycin and effect of treating the
partner at the same time. Acta Obstet
Gynecol Scand, 1982. 61(5): 393–6.
104. Bisschop MP, Merkus JM, Scheygrond
H, and van Cutsem J, Co-treatment of
the male partner in vaginal candidosis:
a double-blind randomized control study.
Br J Obstet Gynaecol, 1986. 93(1): 79–81.
105. Cauwenberg G, International experience
with Ketoconazole in vaginal candido-
sis, in Oral therapy in vaginal candi-
dosis, Eliot BW, Editor. 1984, Medicine
Publishing Foundation: Oxford.
106. Mastroiacovo P, Mazzone T, Botto LD,
Serafini MA, Finardi A, Caramelli L,
and Fusco D, Prospective assessment of
pregnancy outcomes after first-trimester
exposure to fluconazole. Am J Obstet
Gynecol, 1996. 175(6): 1645–50.
107. Richter SS, Galask RP, Messer SA,
Hollis RJ, Diekema DJ, and Pfaller MA,
Antifungal susceptibilities of Candida
species causing vulvovaginitis and epi-
demiology of recurrent cases. J Clin
Microbiol, 2005. 43(5): 2155–62.
926
108. Mathema B, Cross E, Dun E, Park S,
Bedell J, Slade B, Williams M, Riley L,
Chaturvedi V, and Perlin DS, Prevalence
of vaginal colonization by drug-resistant
Candida species in college-age women
with previous exposure to over-the-coun-
ter azole antifungals. Clin Infect Dis,
2001. 33(5): E23–7.
109. Sobel JD, Zervos M, Reed BD, Hooton
T, Soper D, Nyirjesy P, Heine MW,
Willems J, and Panzer H, Fluconazole
susceptibility of vaginal isolates
obtained from women with complicated
Candida vaginitis: clinical implications.
Antimicrob Agents Chemother, 2003.
47(1): 34–8.
110. Phillips AJ, Treatment of non-albicans
Candida vaginitis with amphotericin
B vaginal suppositories. Am J Obstet
Gynecol, 2005. 192(6): 2009–12; discus-
sion 2012–3.
111. Kunzelmann V, Tietz HJ, Roßner D,
Czaika V, Hopp M, Schmalreck A, and
Sterry W, Voraussetzungen für eine effek-
tive Therapie chronisch rezidivierender
Vaginalkandidosen. Mycoses, 1996.
39(Suppl 1): 65–72.
112. Tietz HJ, Gezieltes vorgehen gegen prob-
lemkeine. Gyn Geburtsh, 2009. 7–8:
41–44.
113. Davidson F and Mould RF, Recurrent
genital candidosis in women and the
effect of intermittent prophylactic treat-
ment. Br J Vener Dis, 1978. 54(3):
176–83.
114. Sobel JD, Management of recurrent
vulvovaginal candidiasis with intermit-
tent ketoconazole prophylaxis. Obstet
Gynecol, 1985. 65(3): 435–40.
115. Roth AC, Milsom I, Forssman L, and
Wahlen P, Intermittent prophylac-
tic treatment of recurrent vaginal
candidiasis by postmenstrual applica-
tion of a 500 mg clotrimazole vaginal
tablet. Genitourin Med, 1990. 66(5):
357–60.
116. Rosedale N and Browne K,
Hyposensitisation in the management
of recurring vaginal candidiasis. Ann
Allergy, 1979. 43(4): 250–3.
117. Koldowsky H, Kariger U, and Mendling
W, Herstellung eines autologen mem-
brangebundenen Candida-Antigens

und in-vitro-Untersuchungen zu
seinen immunologischen Reaktionen,
in Candida-Infektionen des weibli-
chen Genitaltraktes, Metzner G and
Weissenbacher ER, Editors. 1999,
Medifact: München. p. 25–32.
118. Rigg D, Miller MM, and Metzger WJ,
Recurrent allergic vulvovaginitis: treat-
ment with Candida albicans allergen
immunotherapy. Am J Obstet Gynecol,
1990. 162(2): 332–6.
119. Moraes PS, de Lima Goiaba S, and
Taketomi EA, Candida albicans allergen
immunotherapy in recurrent vaginal
candidiasis. J Investig Allergol Clin
Immunol, 2000. 10(5): 305–9.
120. Rusch K and Schwiertz A, Candida auto-
vaccination in the treatment of vulvovag-
inal Candida infections. Int J Gynaecol
Obstet, 2007. 96(2): 130.
121. Cassone A, De Bernardis F, and
Torososantucci A, An outline of the role
of anti-Candida antibodies within the
context of passive immunization and pro-
tection from candidiasis. Curr Mol Med,
2005. 5(4): 377–82.
122. Witkin SS, Giraldo P, and Linhares D,
New insights into the immune pathogene-
sis of recurrent vulvovaginal candidiasis.
Int J Gynaecol Obstet, 2000. 3: 114–8.
123. Ip WK and Lau YL, Role of mannose-
binding lectin in the innate defense
against Candida albicans: enhance-
ment of complement activation, but lack
of opsonic function, in phagocytosis by
human dendritic cells. J Infect Dis,
2004. 190(3): 632–40.
124. Wozniak KL, Palmer G, Kutner R,
and Fidel PL, Jr., Immunotherapeutic
approaches to enhance protective
Vulvovaginal candidosis | 15.6 |
immunity against Candida vaginitis.
Med Mycol, 2005. 43(7): 589–601.
125. Mendling W and Koldovsky U,
Investigations by cell-mediated immu-
nologic tests and therapeutic trials with
thymopentin in vaginal mycoses. Infect
Dis Obstet Gynecol, 1996. 4(4): 225–31.
126. Hilton E, Isenberg HD, Alperstein P,
France K, and Borenstein MT, Ingestion
of yogurt containing Lactobacillus aci-
dophilus as prophylaxis for candidal
vaginitis. Ann Intern Med, 1992. 116(5):
353–7.
127. Jeavons HS, Prevention and treatment
of vulvovaginal candidiasis using exog-
enous Lactobacillus. J Obstet Gynecol
Neonatal Nurs, 2003. 32(3): 287–96.
128. Pirotta M, Gunn J, Chondros P, Grover
S, O’Malley P, Hurley S, and Garland S,
Effect of lactobacillus in preventing post-
antibiotic vulvovaginal candidiasis: a
randomised controlled trial. BMJ, 2004.
329(7465): 548.
129. Falagas ME, Betsi GI, and Athanasiou
S, Probiotics for prevention of recurrent
vulvovaginal candidiasis: a review.
J Antimicrob Chemother, 2006. 58(2):
266–72.
130. Watson C and Calabretto H,
Comprehensive review of conventional
and non-conventional methods of man-
agement of recurrent vulvovaginal can-
didiasis. Aust N Z J Obstet Gynaecol,
2007. 47(4): 262–72.
131. Ferris DG, Nyirjesy P, Sobel JD, Soper
D, Pavletic A, and Litaker MS, Over-
the-counter antifungal drug misuse
associated with patient-diagnosed vul-
vovaginal candidiasis. Obstet Gynecol,
2002. 99(3): 419–25.
927
|15.7|

Viral genitourinary infections

Laurent Vaucher1,2,3, Darius A. Paduch1,2
1
Department of Urology, Weill Cornell Medical College, New York, NY 10021, USA
2
The Population Council, Center for Biomedical Research, New York, NY 10021, USA
3
Department of Urology, CHUV, Lausanne CH-1011, Switzerland
Corresponding author’s address: Darius A. Paduch, MD, PhD, Assistant Professor of Urology, Assistant Professor of
Reproductive Medicine, Staff Scientist, CBR, Department of Urology, Weill Cornell Medical College,
525 East 68th St.ST-924A, New York, NY 10021
Tel: 212-746-5309, Fax: 212-746-7287, E-mail: darius.paduch@mac.com

ABSTRACT 18 is modifying the prevention and the

In immunocompetent hosts, viruses are
an uncommon cause of urinary tract
infections (UTI’s). However, in immuno-
compromised patients, they are increas-
ingly recognized as the cause of UTI’s,
especially hemorrhagic cystitis (HC).
The diagnosis of viral lower UTI, based
on molecular techniques and real time
PCR, is often the method of choice since it
allows for quantification of viral load. BK
virus, adenovirus, and CMV are the pre-
dominant pathogens involved in HC after
stem cell and solid organ transplantation,
and their early diagnosis and treatment
may prevent significant morbidity of HC.
Viruses are also responsible for geni-
tal cutaneous or mucosal lesions and
ulcerations. HPV is the most commonly
diagnosed sexually transmitted infec-
tion. The recent availability of vaccine
preparations against HPV 6, 11, 16, and
approach of this viral infection. Herpes
simplex is also a common cause for geni-
tal ulcers; treatment depends on host age,
as well as immune and serological status.
Key words: urinary tract infection, gen-
ital infection, virus, human polyomavi-
rus, adenovirus, CMV, hantavirus, herpes
virus, HPV.
SUMMARY OF RECOMMENDATIONS
Urinary tract infections
1. Human polyomavirus (BKV) and
Adenoviruses: Treatment of BKV
infection and its urological complica-
tions focus on supportive measures
and reduction in immunosuppression
(GoR A). Presently, no controlled tri-
als have demonstrated any benefits of
antiviral agents in these infections.

2. Cytomegalovirus (CMV): Universal
prophylaxis and preemptive strategies
are beneficial in preventing CMV infec-
tions and related complications in solid
organ transplant recipients (GoR A).
3. Hantaviruses: There are no accepted
antiviral therapies for Hantavirus
infections. Because of high mortal-
ity, prevention of transmission from
rodents to humans, and increased
awarness will be critical in controling
this emerging viral infection.
Dermatological lesions
4. Herpes simplex viruses (HSV): Among
patients with a primary episode of
genital HSV, antiviral therapy is rec-
ommended (GoR A). Suppressive treat-
ment with oral Famciclovir extends
the time between symptomatic out-
breaks in patients with frequent
recurrences of genital herpes (GoR A).
5. Human papiloma virus (HPV):
Quadrivalent and bivalent HPV vac-
cines demonstrate efficacy in pre-
venting incident and persistent HPV
infection (GoR A). Indications, and
risk to benefits ratio of systematic
immunization with HPV vaccine
for women and men is still under
investigation.
1. INTRODUCTION
Viral infections of the genito-urinary (GU)
system can manifest as a GU tract infec-
tion (fever, dysuria, pain, hematuria),
and/or genital cutaneous/mucosal lesions
and ulcerations. Depending on most
likely infectious organism, predominant
presentation (localized v. generalized
infection), age of patient, involvment of
other than GU systemts (like pulmonary
system in hemorrhagic fever), and hosts
immune defense status, initial diagnos-
tic and therapeutic approaches may be
quite different and have to be individu-
alized based on clinical picture and as in
Viral genitourinary infections | 15.7 |
case of HPV or HSV presence of infection
in sexual partner. For didactic purposes,
we will divide all GU-related viral infec-
tions into two major categories based on
predominant presentation: urinary tract
infections and dermatological lesions.
2. METHODS
As viral infections in the genitourinary
tract also include HIV and immunosup-
pression related infections, which are
treated in a different section of this book,
the authors selected the six major viral
pathogens (Human polyoma virus [BKV],
Adenovirus, CMV, Hantaviruses, Herpes
simplex virus and Human Papilloma
virus) responsible for urogenital infec-
tions, based on a PubMed search using
the terms: virus, viral and urinary infec-
tion. A systematic review of published
literature, beginning in 1980, using
PubMed and Scopus was performed,
using as key words urinary tract infection
and genital infection associated with each
of the pathogens. Limitations used were
English language, human and abstract
available. 211 Publications were found.
The publications were screened by title
and abstract and 48 were included into
this review.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [1–2].
3. URINARY TRACT INFECTIONS
3.1 Introduction
Urinary tract infections (UTI) due to bac-
teria are commonly seen in urological
practices, but viral pathogens, which can
also cause UTI, are less often encountered.
One of the main differences between bac-
terial and viral pathogens affecting the
urinary tract is that no bacteria should
be found in the urine of healthy persons,
especially in men; the same cannot be
929
Chapter | 15 | Special urogenital infections
assumed with viruses. Some of them, like
the BK virus, can be found in healthy indi-
viduals. The other difference is the ability
of some viruses to integrate into the host
genome, often indefinitely, leading to reac-
tivation and delayed symptomatology;
although some bacteria, like tuberculosis,
can persist in the host in dormant state
for a long time; this is rather an excep-
tion. Hence viral infection is defined as
the presence of an identifiable viral organ-
ism and of symptoms due to an inflamma-
tory response. The presentation, as well as
the natural history of viral UTI, depends
on existing anatomical abnormalities, and
most importantly on the immune status of
the host.
With the emergence of new chemothera-
peutic agents, immune modulators, and
immunosuppressants to treat systemic
diseases or prevent graft rejection, the
number of immunocompromised patients is
increasing accordingly, and may be respon-
sible for the increased prevalence of viral-
related disorders of the GU tract (Table 1).
Dissemeninated viral UTI in immunocom-
promised patients, often associated with
viremia, can quickly lead to multiorgan
viral infections, multiorgan failure, and the
Table 1 Syndromes and conditions associated with increased risk of viral urinary tract infection.
Condition
Bone marrow transplantation
Solid organ transplantation
Hematopoietic malignancies
Chemotherapy for malignancies
HIV infection; immunosuppression
Congenital immunodeficiency
Wiskott-Aldrich syndrome
Wegener’s granulomatosis
Rheumatologic diseases and their treatment
Pregnancy
Diabetes, alcoholism, malnutrition, liver cirrhosis
930
quick demise of the patient. This scenario
is almost never seen in healthy patients
with a normal immune system.
3.2 Symptoms and signs
The typical symptomatology of lower UTI
(dysuria, frequency, urgency, and lack of
high-grade fever) may be altered by the
immune status of the host. Gross hematu-
ria, fever and malaise are seen more com-
monly in immunocompromised patients.
The symptom most commonly presented
with viral UTI is hemorrhagic cystitis
(HC). Less commonly seen are irritative
bladder symptoms such as frequency of
urination and pelvic pain. In the recent
past, HC was considered a direct result of
chemotherapy. However, with improved
methods of viral detection, it became
clear that viruses are commonly identi-
fied in urine and most likely are respon-
sible for HC. In a prospective study of
over 100 children who underwent bone
marrow transplant, hemorrhagic cystitis
occurred in 25.5% of patients, and a viral
cause was identified in over 95% of them
[3]. As bacteria still causes the majority
of UTI’s, bacteriological cultures have to
Mechanism of increased risk to viral infections
immunosuppression and chemical bladder irritation
immunosuppression
abnormal function of immune system, immunosuppression
myelosuppression, chemical bladder damage
abnormal function of immune system
abnormal function of immune system
abnormal function of immune system
abnormal function of immune system
immunosuppression
abnormal function of immune system, changed hormonal status
abnormal function of immune system

be obtained in every patient. However, in
patients not improving clinically despite
antibiotic treatment, or in patients with a
compromised immunity, viral UTI has to
be strongly considered.
3.3 Diagnosis of Viral UTI
Diagnosis of viral UTI is challenging since
viruses cannot be visualized with even
the best optical microscope, and viral cul-
tures may take up to 14 to 28 days, delay-
ing the treatment accordingly. Molecular
and immunofluorescence techniques are
therefore frequently used nowadays. The
reliability of diagnosis depends on an ade-
quate technique obtaining and transport-
ing the specimen, as well as on method of
detection. These methods include:
Culture
Viruses live in the host cells, and the pres-
ence of some viruses (CMV, BKV) may be
suspected by characteristic changes on
urine cytology [4]. Otherwise, the virus
has to be grown in a culture, determining
the type of virus based on characteristic
cytopathological changes of the cell culture
inoculated with the specimen. This diag-
nostic method is cumbersome and prone to
false negative results, and not all viruses
can be cultured (hepatitis viruses, parvo-
virus, human papillomavirus, etc.). Since
each of these viruses require a specific
cell line, media and method of detection,
it is important to provide adequate clini-
cal information and to be specific about
the type of virus to be detected. However,
due to the cost and time required for diag-
nosis using cultures, most laboratories
have shifted to other techniques, which
can be divided into methods which detect
the presence of a pathogen (antigen), and
methods which detect the genetic material
(DNA or RNA) of the virus.
3.3.1 Direct immunofluorescence
of organism
In bodily fluid or cells, antibodies against a
specific antigen is used, and then detected
Viral genitourinary infections | 15.7 |
under a fluorescent microscope by second-
ary antibodies coupled with fluorochrome
[5]. This method is relatively simple and
fast, but is not quantitative and cannot be
used for viruses with genomic instability
and rapidly changing antigens.
3.3.2 ELISA – enzyme linked
immunosorbent assay – and
competitive ELISA
The enzyme-linked immunosorbent assay
(ELISA) and competitive ELISA are used
to detect viral antigens and antibodies
against the viruses in a specimen. The
sample is set on a styrene plate with an
antibody against a specific antigen, and
a fluorochrome-coupled secondary anti-
body is applied with chemiluminescence
or colorimetric detection reagents. In
competitive ELISA, a “tracer” antigen of
known concentration competes with the
specimen antigen for a set number of
binding sites, which allows quantitative
detection. ELISA is a relatively simple
and fast technique, and is often used in
automatic assays; however, small changes
in the volumes of reagents affecting the
results (pipetting error) and contamina-
tion between different runs of the assay
are known problems. The ELISA method
can also detect changes in titers of anti-
bodies against a known pathogen. Since
the development of antibodies against a
virus takes time, and the use of an immu-
nosuppressant may modulate immune
response, the lack or presence of anti-
bodies may not exclude or confirm cur-
rent infection. This is especially true in
viruses with a high prevalence among
the immunocompetent population such
as HSV (17% in USA), CMV (>60%), and
BKV (>90%) [6].
3.3.3 Genomic amplification;
quantitative or qualitative
Due to problems with the detection of anti-
bodies, and the fact that many viruses are
present in immunocompetent hosts, the
current state-of-the-art detection methods
931
Chapter | 15 | Special urogenital infections
are based on molecular techniques [7].
Those techniques use PCR, which allows
specific and fast amplification of small
regions of the viral genome. Since the
genome of most clinically important
viruses are known, it is relatively easy to
amplify viral DNA or RNA, and to detect
amplicon by gel electrophoresis, chroma-
tography or real time PCR. Although PCR
is a very sensitive diagnostic method, its
sensitivity is also one of its drawbacks.
First of all, the genomes of viruses are not
stable, and even a single change in the
nucleotide sequence can affect the bind-
ing of primers, resulting in a false nega-
tive result. Furthermore, viruses occur in
multiple genotypes (i.e. HPV or adenovi-
rus) and a single assay is often not able
to detect them all. Since the PCR reaction
produces millions of copies of viral DNA
“amplicon”, it is very easy to obtain false
positive results from airborne amplicon
contamination. The real time PCR, which
eliminates the transfer of amplified prod-
uct to the gel, avoids many of the contam-
ination problems, and therefore became a
method of choice for molecular detection
of clinically important viruses. Real time
PCR also allows relative or absolute quan-
tification of viral load, which is especially
usefull in monitoring response to therapy.
3.4 Most common viral pathogens
causing UTI
Since viruses with extremely different
genomes and biology may cause simi-
lar diseases, the classification of clini-
cally important viruses becomes difficult.
The most commonly used classification
is called Baltimore classification, and
divides viruses into seven groups based
on the nucleic acid of their genome (DNA
or RNA) and subsequently based on bio-
chemical properties (single or double
strand, etc.) (Table 2). Basic knowledge
of viral classification is useful since the
majority of antiviral drugs are active
against viruses with similar biochemical
and molecular properties [8].
932
3.4.1 Human polyoma virus (BKV)
BKV, a double strand DNA virus, is ubiqui-
tous in the human population, and approx-
imately 97% of adults have antibodies
against BKV [6]. Infection with BKV prob-
ably occurs early in life, and is asympto-
matic or is associated with fever and mild
upper respiratory symptoms. It is hypoth-
esized that primary infection viremia
results in seeding in uroepithelial cells [9].
Viral infection is reactivated during peri-
ods of immunosuppression, causing hem-
orrhagic cystitis, interstitial nephritis or
urethral stenosis. Polyomavirus-associated
nephropathy (PVAN) is an emerging cause
of kidney transplant failure, effecting
1–10% of patients [10]. Late-onset hemor-
rhagic cystitis of long duration (> 7 days)
after hematopoietic stem-cell transplanta-
tion (HSCT) is associated with BKV infec-
tion in 55% cases [11].
3.4.1.1 Diagnosis
BKV infection should be suspected in
immunodeficient patients who present
with haematuria (micro- to gross hae-
maturia), hydronephrosis and increased
creatinemia. Urine cytology can be indic-
ative of BKV infection by identifying so
called “decoy” cells; however, the sensi-
tivity of this method is low. High grade
TCC can be difficult to distinguish from
BKV on cytology, and cytology follow-up
may be considered in patients with risk
factors for TCC [12]. Because of the high
prevalence of positive antibodies in the
serum, and a lack of reliable viral cell
cultures, the diagnosis of BKV infection
requires molecular techniques. Real time
PCR quantification of viral loads has a
significant prognostic value in predicting
clinical outcomes [13], and can be used to
monitor response to therapy. Recipients
of a renal transplant may also have BKV-
associated graft dysfunction, however
because of high prevalence of BKV sero-
conversion in general population, 2005
Consensus conference stated that allo-
graft biopsy is mandatory to confirm BKV
nephropathy [10].
 Viral genitourinary infections | 15.7 |

Table 2 Baltimore classification of viruses.

Group I: double-stranded DNA: Adenoviruses, Herpesviruses, Human Papilloma Virus, Polyoma viruses
(BKV), smallpox, molluscum contagiosum virus

Group II: single-stranded DNA: Parvoviruses (parvovirus B19)

Group III: double-stranded RNA: Reoviruses, Birnaviruses (rotaviruses)

Group IV: positive-sense single-stranded RNA: Picornaviruses; Togaviruses (coronavirus, SARS, West Nile virus, hepatitis
A, E, and C, rubella virus, polio virus)

Group V: negative-sense single-stranded RNA: Orthomyxoviruses, Rhabdoviruses (influenza, mumps, measles viruses,
rabies virus)

Group VI: reverse-transcribing RNA: Retroviruses (HIV-1, AMV, M-MLV)

Group VII: reverse-transcribing DNA: Hepadnaviruses (hepatitis B virus)

AMV – avian myeloblastosis virus; BKV – BK virus; HIV-1 – human immunodeficiency virus type 1; JCV – JC virus; M-MLV – Moloney murine leukemia
virus; SARS – Severe Acute Respirtory Syndrome.
Baltimore classification is based on genomic methods of replication and has been created by Dr. David Baltimore.

3.4.1.2 Treatment there are no reports on treatment of

Until recently, the treatment of BKV BKV-associated HC in HSCT.
infection, and its urological complications, The standard use of these treatments
focused primarily on supportive meas- needs, however, to be further addressed
ures (i.e. hydration, analgesia, correction in randomized, multicentre trials. One
of coagulopathy, bladder irrigation) and non-randomized clinical trial showed that
reduction in immunosuppression [14] ciprofloxacin prophylaxis decreased the
(LoE 1b). More recently, antiviral therapy viral load of BKV viruria in adult patients
has been considered, especially in those with HSCT, as compared to cephalosporin
with renal allograft dysfunction, despite (LoE 2b). The mechanism of this finding
immunosuppressive therapy decrease. is unclear [19]. It is important to remem-
Antiviral agents include: ber that BKV may be associated with
• Intravenous Immune Globulin (IVIG), increased risk of bladder cancer, and follow
which has immunomodulatory proper- up with cytological studies once hematuria
ties and contains polyomavirus-reactive resolves may be indicated [20] (LoE 3).
antibodies. Favorable treatment out-
come was reported in 88% of patients 3.4.2 Adenoviruses
with BKV nephropathy [15].
Adenoviruses (AdV) are double strand
• Cidofovir, despite moderate in-vitro DNA viruses with at least 51 serological
activity against polyomaviruses, has subtypes, and are known to cause upper
shown efficiency in treating hemat- respiratory, GI and conjunctival infections
opoietic stem-cell transplantation- in healthy people and children. However,
related HC [16]. Due to nephrotoxicity, a variety of clinical symptoms, including
intravesical instillation represents genito-urinary tract infection, can occur in
an acceptable alternative [17]. Use of immunocompromised patients with AdV
Cidofovir in BKV-related nephropa- infection; among these, hemorrhagic cys-
thy is not FDA approved and consid- titis is the most common clinical presen-
ered an off label use and still under tation. The adenoviral infections are more
investigation. common in stem-cell transplantation and
• Leflunomide has shown efficacy in solid organ transplants [21]. Children,
treating BKV nephropathy [18], but recipients of allogeneic versus autogeneic

933
Chapter | 15 | Special urogenital infections
stem-cell graft, and patients with graft ver-
sus host disease (GVHD) are much more
prone to adenoviral diseases, which is a
reflection of the more pronounced immuno-
suppression used in the above conditions.
3.4.2.1 Diagnosis
Infection with adenovirus is defined as
the presence of the virus in culture, the
presence of viral antigens by immunoflu-
orescence, or the presence of AdV DNA
by PCR, irrespective of symptoms. The
diagnosis using molecular techniques is
faster since the culture can take up to 21
days. AdV is never present in the urine of
healthy individuals, and the detection of
AdV in the urine of patients with HC is
pathognomic of adenoviral cystitis [22].
Since adenoviral infection can coexist
with Aspergillosis and CMV in immuno-
compromised patients, multiviral cultures
should be obtained.
3.4.2.2 Treatment
Adenoviral infections are associated with
significant mortality and morbidity, and
some have advocated preemptive treat-
ment in immunocompromised patients if
AdV can be detected in the blood by PCR
[23] (LoE 3). However, at this time, no
consensus exists regarding the treatment
of asymptomatic patients with detectable
adenoviremia. Adenoviral HC is usually
self-limiting. As for other serious infec-
tions in immunocompromised patients,
supportive measures and reduced immu-
notherapy are the cornerstone of treat-
ment. Presently, no controlled trials have
demonstrated any benefits of antiviral
agents in human adenoviral disease.
• Cidofovir is the most commonly used
treatment of adenoviral infections. A
lower dose (1 mg/kg three times a week
for three weeks) is used in renal trans-
plant patients because of concerns of
nephrotoxicity, but this regiment fails
to prevent HSV or CMV infections and
a higher dose (iv or intravesical) may
be a better choice [24].
934
• Ribavirin and Vidarabine have rela-
tively poor activity against AdV in-
vitro [25], but have been successfully
used in the treatment of hemorrhagic
cystitis and may be a viable alterna-
tive to Cidofovir (LoE 3).
• Ganciclovir is mostly used for the pre-
vention of CMV infection, however, it
has also been used in the treatment
of hemorrhagic cystitis in transplant
patients [26].
3.4.3 CMV
Cytomagalovirus (CMV) infection is com-
mon (>60 % adults are seropositive) and
like other members of the Herpes virus
family, CMV establishes latent infection
after the resolution of acute infection.
CMV reactivation, or new infection, is one
of the most important infections in renal
transplant [27] patients; it is a rare cause
of lower UTI’s, however, evidence sup-
ports association between CMV and HC
[28]. Although very rare, CMV cystitis
can occur in immunocompetent patients
[29]. CMV is also believed to cause uret-
eritis and ureteral stenosis [30].
3.4.3.1 Diagnosis
CMV can be detected by seroconversion
in negative hosts, and by an increase in
IgM and IgG antibody titers in previ-
ously seropositive patients [31], however,
molecular amplification of CM antigen
(pp65), RNA or DNA is now more com-
monly used [32]. As the comparison of
quantitative results obtained using dif-
ferent techniques is not possible, it is
important to use the same test method
when monitoring changes of viral load in
patients over time.
3.4.3.2 Treatment
Prophylaxis and preemptive strategies
are beneficial in preventing CMV organ
disease in solid organ transplant recipi-
ents (LoE 1a). Most patients receive
prophylaxis with gancyclovir, however, in

active disease, other agents like Foscarnet
can be used [33]. Cidofovir is active
against both BKV and CMV and may
become the drug of choice in patients who
present with hemorrhagic cystitis after
solid organ or bone marrow transplant.
3.4.4 Hantavirus
Hantavirus causes two major forms of
disease, depending on virus subtype:
hemorrhagic fever with renal syndrome
(HFRS) and hantavirus cardiopulmonary
syndrome [34]. Infections occur in sea-
sonal outbreaks; Hantavirus is carried by
rodents and transmitted to humans via
inhalation of aerosolized excreta. Renal
manifestations vary depending on the
type of hantavirus; the European form
causes fever and mild renal failure [35],
whereas manifestations due to the Asian
strain are more severe, potentially lead-
ing to renal failure and requiring dialysis.
Diagnosis is made with a serologic test.
There are no accepted antiviral thera-
pies, and therapy is therefore restricted
to supportive care.
4. DERMATOLOGICAL LESIONS
4.1 Herpes simplex
Herpes simplex virus (HSV) infection is
a common cause of genital ulcers world-
wide. Although HSV-2 remains the main
causative agent, HSV-1 is associated with
an increasing proportion of cases of geni-
tal herpes [36]. Infection, resulting in
varying clinical manifestations, can be of
primary, non-primary (infection with HSV
in a patient seropositive for the alternate
type) or of recurrent type. Primary infec-
tions are usually the most severe, with
multiple painful ulcerating vesicular
lesions, inguinal adenopathia and consti-
tutional symptoms, resolving in a mean of
19 days [37]; urinary retention and HSV
cystitis can occur in immunocompetent
patients who have some other predispos-
ing factors such as diabetes mellitus or
Viral genitourinary infections | 15.7 |
rheumatologic disorders [38]. Recurrent
episodes are usually shorter and less
severe.
4.1.1 Diagnosis
Diagnosis is relatively easy since HSV
can be detected by cell culture (active
lesion) or by serology (non-active lesion).
Direct immunofluorescence and PCR are
alternative methods [39].
4.1.2 Treatment
HSV infection treatment depends on
host age, immune and serological status.
Among patients with a primary episode
of general HSV, antiviral therapy is rec-
ommended (LoE 1a). Acyclovir or valacy-
clovir are commonly used in symptomatic
subjects with primary infection (Table 3).
Suppressive treatment with oral famciclo-
vir extends the time between symptomatic
outbreaks in patients with frequent recur-
rences of genital herpes [40] (LoE 1b).
Routine screening for HSV-1 or HSV-2
infection by serologic testing is not recom-
mended [41].
4.2 HPV
HPV has a worldwide prevalence of
approximately 10% [42] and it is the most
commonly diagnosed sexually transmitted
infection (STI). It is associated with con-
dyloma acuminatum, squamous intraepi-
thelial lesions and anogenital malignancy,
including cervical, vaginal, vulvar, penile,
and anal carcinoma, as well as some
oropharyngeal squamous cell cancers.
Risk factors for acquiring HPV include
multiple sexual partners, early age of
onset of sexual intercourse, and having a
sexual partner with HPV.
Human papillomaviruses are small,
non-enveloped DNA viruses infecting
basal epithelial cells by entering the
nucleus. Their life cycle is integrally
linked to keratinocyte maturation. Most
people who are infected with HPV have
no signs or symptoms and approximately
935
936
Table 3 Common antivirals in urologic practice: spectrum, use, and therapeutic implications.
Name, function Viral activity
Acyclovir, inhibits viral DNA HSV-1, HSV-2 herpes simiae,
polymerase and incorporates VZV; acyclovir is more
into viral DNA active against HSV-1 than HSV-2
than VZV, respectively; potential
activity against EBV
Famcilovir, inhibits DNA HSV-1 and HSV-2, VZV; limited
polymerase activity against EBV and HBV
Valacyclovir, inhibits DNA HSV-1 and HSV-2, VZV
polymerase
Ganciclovir, inhibits DNA CMV, HSV-1, HSV-2, EBV, VZV;
polymerase very active against CMV and HSV;
requires intracellular conversion to
triphosphate
FDA-approved use
Genital HSV: primary, acute
Genital HSV, recurrent
Genital HSV, suppression
Herpes zoster
HSV encephalitis
Varicella, primary
Herpes zoster
Genital HSV primary
Genital HSV recurrent
Genital HSV suppression
Genital herpes, primary
Genital herpes, recurrent
Genital herpes, suppression
Reducing transmission in
discordant couples
Herpes zoster
CMV: prophylaxis, transplantation
CMV prophylaxis, HIV-related
CMV retinitis
Typical dose
200 mg PO 5x/d 10 d
400 mg PO 3x/d 5 d
400 mg PO 2x/d 12 mo*
800 mg PO 5x/d 10 d
10 mg/kg IV 3x/d 10 d
800 mg PO 4x/d 5 d
500 mg PO 3x/d 7 d
250 mg PO 3x/d 10 d
125 mg PO 2x/d 5 d
125 mg PO 2x/d 12 mo*
1000 mg PO 2x/dx10 d
500 mg PO 2x/d 3 d
500-1000 mg 1x/d 12 mo*
500 mg PO QD together with safe
sex practices
1000 mg PO 3x/d 7 d
5 mg/kg IV Q12 h x7–14 d then
5 mg/kg IV Q24 h
1000 mg PO 3x/d
1000 mg PO 3x/d”
5 mg/kg IV Q12h 14–21 d
Chapter
| 15 |
Comments
Adjust for renal and liver function;
contraindicated with cidofovir
(increased risk of nephrotoxicity);
avoid aminoglycosides,
clofarabine, and gallium nitrate
Adjust for renal function; monitor
digoxin levels if used together;
may increase digoxin level
Special urogenital infections
Adjust for renal function;
adequate hydration; avoid
carboplatin, cimetidine, entecavir,
and phenytoins
Granulocytopenia; anemia;
thrombocytopenia; carcinogenic
and teratogenic in animal studies;
causes azoospermia; adjust
for renal function; do not
use with cidofovir; multiple drug
interactions and adverse effects
 Foscarnet, selectively inhibits viral
DNA polymerase, reverse tran-
scriptase inhibitor
CMV, HSV-1, HSV-2, EBV, VZV, CMV retinitis in AIDS 90 mg/kg IV Q12h 3 wk then Renal toxicity: severe seizures (cip-
herpes virus-6; limited data on Q24h rofloxacin [contraindicated]); exac-
activity for hepatitis B and HIV erbates electrolyte abnormalities;
HSV and VZV infections mucocu- 40 mg/kg IV Q12h 3 wk multiple drug interactions; adjust
taneous, resistant to other agents for renal function

Cidofovir, active intracellular
metabolite – cidofovir diphos-
phate – inhibits viral polymerase
CMV, adenovirus, HSV-1 and
HSV-2, VZV, EBV, BKV
CMV 5 mg/kg IV Q7d for 14 d then Acute renal failure; death; highly
5 mg/kg IV Q14 d, nephrotoxic and concomitant
use probenecid before injection use of nephrotoxic drugs to be
1–2 gm avoided; hydrate well; probenecid
prevents nephrotoxicity

Imiquimod (Aldara®)Immune HPV, pox virus HPV 1x/d bedtime 3d/we intil lesion is non specific inflammation,
modulator, Enhance T-cell activity gone, max 16 we dermatitis

Podophyllotoxin antimitotic action HPV (anogenital wart) HPV (anogenital wart) 10–25% solution during 1–4 transient burning, erythema,
hours/d 3x/we tenderness, abdominal pain and
cerebral toxicity reported

Gardasil® vaccine HPV 16, 18, 6, 11 Female 9–26 years to prevent HPV 3 IM injections (month 0, 1, 6) local reaction at injection site
16, 18, 6, 11

Cervarix® vaccine HPV 16, 18 (31, 45) not approved yet (approved in 3 IM injections (month 0, 1, 6) local reaction at injection site
Europe Union)

CMV – cytomegalovirus; HSV-1 – herpes simplex virus type-1; HSV-2 – herpes simplex virus type-2; IM – intramuscular; IV – intravenous; PO – by mouth; Q – every; VZV – herpes varicella-zoster virus; we – week.
*suppressive treatment should be discontineud for one or two month after one year, to reassess the frequency of recurrence.
The treating physician should be familiar with multiple drug interactions and labeling for each drug because many of the antiviral drugs have well-proven teratogenic and reproductive side effects in animals.
Viral genitourinary infections

937
| 15.7 |
Chapter | 15 | Special urogenital infections
75% to 90% of HPV infections will clear
up within two years of the initial infec-
tion [43–44]. In 10% to 20% of patients,
however, the infection persists.
There are more than 100 types of HPV;
over 30 types can infect the genital area.
Genital or anal warts (condyloma acu-
minata) are the most recognized sign of
genital HPV infection, mostly caused by
types 6 and 11. Infection with high-risk
types, including HPV 16 and 18, may
lead to high-grade lesions and eventually
anogenital malignancies.
4.2.1 Diagnosis
Diagnosis of HPV infection is made by
clinical examination. After application
of acetic acid 3%-5%, lesions develop a
characteristic acetowhite appearance,
resulting from cytokeratins coagulation.
Biopsy is recommended in atypical cases,
or when the benign nature of the lesion
is unclear. Molecular detection meth-
ods (PCR, Hybrid capture assay) allows
HPV detection; it has been suggested in
optimal follow-up of women with atypical
squamous cells of undetermined signifi-
cance (ASCUS) [45]. No indications have
been yet described for men.
4.2.2 Treatment
Podophyllotoxin is a mitotic poison
applied on an every-other-day basis for
three weeks. Imiquimod (Aldara®) is an
immune modulator, applied three times
a week; treatment is continued until the
lesions clear, or for a maximum of 16
weeks. A number of surgical options exist
for the treatment of anogenital warts
including cryotherapy, laser therapy, elec-
trosurgery, and surgical excision
4.2.3 Prevention
While the efficacy of condoms in prevent-
ing HPV infection is unknown, condom
use has been associated with a lower
rate of HPV infection [46]. The recent
availability of a vaccine preparation has
dramatically altered the approach to
938
prevention of HPV infection. Two vac-
cines are now available: the bivalent HPV
16/18 VLP vaccine (Cervarix®), and the
quadrivalent HPV 6/11/16/18 VLP vac-
cine (Gardasil®). Both demonstrate effi-
cacy against incident and persistent HPV
infection and abnormal histology (LoE
1a). It is estimated that HPV protection
with the bivalent or quadrivalent vaccine
would prevent as much as 70% of all cer-
vical cancers. The quadrivalent vaccine
would also prevent most genital warts
[43]. With both vaccines, it is important
to be vaccinated before becoming sexu-
ally active, since the vaccine most likely
does not eliminate HPV infection after
it has occurred. Immunization for men
is still under investigation. Female vac-
cination has proven to be cost effective
as compared to Pap smear screening, at
least in the 46 richest countries [47]. It
will, however, not replace the need for
preventive strategies, such as cervical
screening. Since HPV infection in men
contributes to cervical disease in women,
vaccinating both men and women is pre-
dicted to be more beneficial than vacci-
nating women only [48]. Whether boys
and men routinely receive the HPV vac-
cine will depend primarily on efficacy and
cost effectiveness [49]. Because a quanti-
fiable clinical endpoint is more difficult to
define in males than in females (i.e. geni-
tal HPV infection), it will be difficult in
the near future to define efficacy of vac-
cination in males.
5. FURTHER RESEARCH
As described previously, Polyomavirus
BK-associated nephropathy (PVAN) is an
emerging cause of early renal transplant
failure. To date, no antiviral agent has
demonstrated any proven benefits. Further
research is needed to learn more about
the cellular response to BK virus in graft
recipients. This will help to develop new
strategies for the treatment of graft rejec-
tion due to viral infections. New antiviral

therapies with proven efficacy and safety
are also under investigation for patients
with progressive allograft dysfunction,
despite decreased immunosuppressive 3.
therapy. Research in HPV will focus on a
better understanding of disease transmis-
sion, and on the efficacy and cost-effective-
ness of male and female immunization.
The effect of circumcision in disease trans-
mission is currently under investigation.
One can’t forget that viruses are able to 4.
adapt and change not only their nucleic
sequence making detetion more compli-
cated, but they can overcome differences
in host biology much better than any
other microorganism. As most of us stud-
ing virology two decades ago would teach
that that certain viral disorders never 5.
occur in humans, same can’t be assumed
today, as each year a new virus believed
to infect only rodents, is discovered to
cause clinically signicant and very often
letal infection in humans (for example
6.
Lujo virus was identified in 2009). Thus
only through increase in research and
awarness of microbiology and pathology
of GU important viruses, will be be able
to serve our patients the best.
6. CONCLUSIONS 7.
As urologists, we need to include the
most recent developments in GU virology
in our practices, since knowledge of viral
biology and clinical pathology may pre-
vent viral transmission (HSV and HPV),
8.
and early management of viral infections
may decrease mortality in immunocom-
promised patients. 9.
REFERENCES
10.
1. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
2. Abrams P, Khoury S, and Grant A,
Evidence-based medicine overview of the
Viral genitourinary infections | 15.7 |
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
Gorczynska E, Turkiewicz D, Rybka K,
Toporski J, Kalwak K, Dyla A, Szczyra Z,
and Chybicka A, Incidence, clinical out-
come, and management of virus-induced
hemorrhagic cystitis in children and
adolescents after allogeneic hematopoietic
cell transplantation. Biol Blood Marrow
Transplant, 2005. 11(10): 797–804.
Boldorini R, Brustia M, Veggiani C, Barco
D, Andorno S, and Monga G, Periodic
assessment of urine and serum by cytology
and molecular biology as a diagnostic tool
for BK virus nephropathy in renal trans-
plant patients. Acta Cytol, 2005. 49(3):
235–43.
Hogan TF, Padgett BL, Walker DL,
Borden EC, and McBain JA, Rapid detec-
tion and identification of JC virus and BK
virus in human urine by using immun-
ofluorescence microscopy. J Clin Microbiol,
1980. 11(2): 178–83.
Zhong S, Randhawa PS, Ikegaya H,
Chen Q, Zheng HY, Suzuki M, Takeuchi
T, Shibuya A, Kitamura T, and Yogo Y,
Distribution patterns of BK polyomavirus
(BKV) subtypes and subgroups in American,
European and Asian populations suggest
co-migration of BKV and the human race.
J Gen Virol, 2009. 90(Pt 1): 144–52.
Schmutzhard J, Merete Riedel H,
Zweygberg Wirgart B, and Grillner L,
Detection of herpes simplex virus type 1,
herpes simplex virus type 2 and varicella-
zoster virus in skin lesions. Comparison
of real-time PCR, nested PCR and virus
isolation. J Clin Virol, 2004. 29(2): 120–6.
Paduch DA, Viral lower urinary tract
infections. Curr Urol Rep, 2007. 8(4):
324–35.
Arthur RR and Shah KV, Occurrence and
significance of papovaviruses BK and JC
in the urine. Prog Med Virol, 1989. 36:
42–61.
Hirsch HH, Brennan DC, Drachenberg
CB, Ginevri F, Gordon J, Limaye AP,
Mihatsch MJ, Nickeleit V, Ramos
E, Randhawa P, Shapiro R, Steiger
J, Suthanthiran M, and Trofe J,
Polyomavirus-associated nephropathy in
renal transplantation: interdisciplinary
939
Chapter | 15 | Special urogenital infections
analyses and recommendations.
Transplantation, 2005. 79(10): 1277–86.
11. Arthur RR, Shah KV, Baust SJ, Santos
GW, and Saral R, Association of BK viru-
ria with hemorrhagic cystitis in recipients
of bone marrow transplants. N Engl J
Med, 1986. 315(4): 230–4.
12. Boon ME, van Keep JP, and Kok LP,
Polyomavirus infection versus high-grade
bladder carcinoma. The importance of
cytologic and comparative morphometric
studies of plastic-embedded voided urine
sediments. Acta Cytol, 1989. 33(6): 887–93.
13. Vera-Sempere FJ, Rubio L, Moreno-
Baylach MJ, Garcia A, Prieto M, Camanas
A, Mayordomo F, Sanchez-Plumed J,
Beneyto I, Ramos D, Zamora I, and Simon
J, Polymerase chain reaction detection
of BK virus and monitoring of BK neph-
ropathy in renal transplant recipients at
the University Hospital La Fe. Transplant
Proc, 2005. 37(9): 3770–3.
14. Dropulic LK and Jones RJ, Polyomavirus
BK infection in blood and marrow
transplant recipients. Bone Marrow
Transplant, 2008. 41(1): 11–8.
15. Sener A, House AA, Jevnikar AM,
Boudville N, McAlister VC, Muirhead
N, Rehman F, and Luke PP, Intravenous
immunoglobulin as a treatment for BK
virus associated nephropathy: one-year
follow-up of renal allograft recipients.
Transplantation, 2006. 81(1): 117–20.
16. Ison MG, Adenovirus infections in trans-
plant recipients. Clin Infect Dis, 2006.
43(3): 331–9.
17. Bridges B, Donegan S, and Badros A,
Cidofovir bladder instillation for the
treatment of BK hemorrhagic cystitis after
allogeneic stem cell transplantation. Am J
Hematol, 2006. 81(7): 535–7.
18. Josephson MA, Gillen D, Javaid B,
Kadambi P, Meehan S, Foster P, Harland
R, Thistlethwaite RJ, Garfinkel M,
Atwood W, Jordan J, Sadhu M, Millis
MJ, and Williams J, Treatment of renal
allograft polyoma BK virus infection with
leflunomide. Transplantation, 2006. 81(5):
704–10.
19. Leung AY, Chan MT, Yuen KY, Cheng VC,
Chan KH, Wong CL, Liang R, Lie AK,
and Kwong YL, Ciprofloxacin decreased
polyoma BK virus load in patients who
940
underwent allogeneic hematopoietic stem
cell transplantation. Clin Infect Dis, 2005.
40(4): 528–37.
20. Geetha D, Tong BC, Racusen L,
Markowitz JS, and Westra WH, Bladder
carcinoma in a transplant recipient: evi-
dence to implicate the BK human polyo-
mavirus as a causal transforming agent.
Transplantation, 2002. 73(12): 1933–6.
21. Legrand F, Berrebi D, Houhou N,
Freymuth F, Faye A, Duval M, Mougenot
JF, Peuchmaur M, and Vilmer E, Early
diagnosis of adenovirus infection and
treatment with cidofovir after bone mar-
row transplantation in children. Bone
Marrow Transplant, 2001. 27(6): 621–6.
22. Hofland CA, Eron LJ, and Washecka RM,
Hemorrhagic adenovirus cystitis after
renal transplantation. Transplant Proc,
2004. 36(10): 3025–7.
23. Chakrabarti S, Mautner V, Osman H,
Collingham KE, Fegan CD, Klapper PE,
Moss PA, and Milligan DW, Adenovirus
infections following allogeneic stem cell
transplantation: incidence and outcome in
relation to graft manipulation, immuno-
suppression, and immune recovery. Blood,
2002. 100(5): 1619–27.
24. Runde V, Ross S, Trenschel R, Lagemann E,
Basu O, Renzing-Kohler K, Schaefer UW,
Roggendorf M, and Holler E, Adenoviral
infection after allogeneic stem cell transplan-
tation (SCT): report on 130 patients from
a single SCT unit involved in a prospec-
tive multi center surveillance study. Bone
Marrow Transplant, 2001. 28(1): 51–7.
25. Baba M, Mori S, Shigeta S, and
De Clercq E, Selective inhibi-
tory effect of (S)-9-(3-hydroxy-2-
phosphonylmethoxypropyl)adenine
and 2’-nor-cyclic GMP on adenovirus
replication in vitro. Antimicrob Agents
Chemother, 1987. 31(2): 337–9.
26. Chen FE, Liang RH, Lo JY, Yuen KY,
Chan TK, and Peiris M, Treatment of
adenovirus-associated haemorrhagic
cystitis with ganciclovir. Bone Marrow
Transplant, 1997. 20(11): 997–9.
27. Kotton CN and Fishman JA, Viral infec-
tion in the renal transplant recipient.
J Am Soc Nephrol, 2005. 16(6): 1758–74.
28. Spach DH, Bauwens JE, Myerson
D, Mustafa MM, and Bowden RA,

Cytomegalovirus-induced hemorrhagic
cystitis following bone marrow transplan-
tation. Clin Infect Dis, 1993. 16(1): 142–4.
29. Basquiera AL, Calafat P, Parodi JM, De
Diller AB, Zlocowski JC, and Caeiro JP,
Cytomegalovirus-induced haemorrhagic
cystitis in a patient with neurogenic blad-
der. Scand J Infect Dis, 2003. 35(11–12):
902–4.
30. Mueller BU, MacKay K, Cheshire LB,
Choyke PL, Kitchen B, Widemann B, and
Pizzo PA, Cytomegalovirus ureteritis as a
cause of renal failure in a child infected
with the human immunodeficiency virus.
Clin Infect Dis, 1995. 20(4): 1040–3.
31. Kalil AC, Levitsky J, Lyden E, Stoner J,
and Freifeld AG, Meta-analysis: the effi-
cacy of strategies to prevent organ disease
by cytomegalovirus in solid organ trans-
plant recipients. Ann Intern Med, 2005.
143(12): 870–80.
32. Mengoli C, Cusinato R, Biasolo MA,
Cesaro S, Parolin C, and Palu G,
Assessment of CMV load in solid organ
transplant recipients by pp65 antigenemia
and real-time quantitative DNA PCR
assay: correlation with pp67 RNA detec-
tion. J Med Virol, 2004. 74(1): 78–84.
33. Bielorai B, Shulman LM, Rechavi G,
and Toren A, CMV reactivation induced
BK virus-associated late onset hemor-
rhagic cystitis after peripheral blood
stem cell transplantation. Bone Marrow
Transplant, 2001. 28(6): 613–4.
34. Pettersson L, Klingstrom J, Hardestam
J, Lundkvist A, Ahlm C, and Evander M,
Hantavirus RNA in saliva from patients
with hemorrhagic fever with renal syn-
drome. Emerg Infect Dis, 2008. 14(3):
406–11.
35. Vapalahti O, Mustonen J, Lundkvist A,
Henttonen H, Plyusnin A, and Vaheri A,
Hantavirus infections in Europe. Lancet
Infect Dis, 2003. 3(10): 653–61.
36. Xu F, Sternberg MR, Kottiri BJ,
McQuillan GM, Lee FK, Nahmias AJ,
Berman SM, and Markowitz LE, Trends
in herpes simplex virus type 1 and type
2 seroprevalence in the United States.
JAMA, 2006. 296(8): 964–73.
37. Corey L, Adams HG, Brown ZA, and
Holmes KK, Genital herpes simplex virus
infections: clinical manifestations, course,
Viral genitourinary infections | 15.7 |
and complications. Ann Intern Med, 1983.
98(6): 958–72.
38. McClanahan C, Grimes MM, Callaghan
E, and Stewart J, Hemorrhagic cystitis
associated with herpes simplex virus.
J Urol, 1994. 151(1): 152–3.
39. Cone RW, Hobson AC, Palmer J,
Remington M, and Corey L, Extended
duration of herpes simplex virus DNA in
genital lesions detected by the polymerase
chain reaction. J Infect Dis, 1991. 164(4):
757–60.
40. Bartlett BL, Tyring SK, Fife K, Gnann
JW, Jr., Hadala JT, Kianifard F, and
Berber E, Famciclovir treatment options
for patients with frequent outbreaks of
recurrent genital herpes: the RELIEF
trial. J Clin Virol, 2008. 43(2): 190–5.
41. Krantz I, Lowhagen GB, Ahlberg BM, and
Nilstun T, Ethics of screening for asymp-
tomatic herpes virus type 2 infection.
BMJ, 2004. 329(7466): 618–21.
42. de Sanjose S, Diaz M, Castellsague X,
Clifford G, Bruni L, Munoz N, and Bosch
FX, Worldwide prevalence and genotype
distribution of cervical human papilloma-
virus DNA in women with normal cytol-
ogy: a meta-analysis. Lancet Infect Dis,
2007. 7(7): 453–9.
43. Frazer IH, Cox JT, Mayeaux EJ, Jr.,
Franco EL, Moscicki AB, Palefsky JM,
Ferris DG, Ferenczy AS, and Villa LL,
Advances in prevention of cervical cancer
and other human papillomavirus-related
diseases. Pediatr Infect Dis J, 2006. 25(2
Suppl): S65–81, quiz S82.
44. Franco EL, Villa LL, Sobrinho JP, Prado
JM, Rousseau MC, Desy M, and Rohan
TE, Epidemiology of acquisition and
clearance of cervical human papillomavi-
rus infection in women from a high-risk
area for cervical cancer. J Infect Dis, 1999.
180(5): 1415–23.
45. Workowski KA and Berman SM, Sexually
transmitted diseases treatment guide-
lines, 2006. MMWR Recomm Rep, 2006.
55(RR-11): 1–94.
46. Winer RL, Hughes JP, Feng Q, O’Reilly
S, Kiviat NB, Holmes KK, and Koutsky
LA, Condom use and the risk of genital
human papillomavirus infection in young
women. N Engl J Med, 2006. 354(25):
2645–54.
941
Chapter | 15 | Special urogenital infections
47. Techakehakij W and Feldman RD,
Cost-effectiveness of HPV vaccination
compared with Pap smear screening
on a national scale: a literature review.
Vaccine, 2008. 26(49): 6258–65.
48. Taira AV, Neukermans CP, and Sanders
GD, Evaluating human papillomavirus
942
vaccination programs. Emerg Infect Dis,
2004. 10(11): 1915–23.
49. Elbasha EH, Dasbach EJ, and Insinga
RP, A multi-type HPV transmission
model. Bull Math Biol, 2008. 70(8):
2126–76.
|15.8|
Genitourinary schistosomiasis
Ismail M. Khalaf1, Ahmed A. Shokeir2
1
Professor of Urology, Al-Azhar Faculty of Medicine, Cairo Egypt
2
Professor of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
Correspondence: Ismail Khalaf, MD, PhD, Professor of Urology, Al Azhar Faculty of Medicine, Cairo
Mailing address: P O Box 2477, Elhorria, Heliopolis, Cairo 11361, Egypt
Tel: +20 12 2137100, Fax: +20 2 26709709, E-mail: ismkhalaf@yahoo.com

ABSTRACT neck obstruction, contracted bladder and

Schistosomiasis is a parasitic infesta-
tion; ≈200 million people are infested and
1,000 million are at risk of the disease
worldwide. Humans infected through
skin contact with cercariae and any per-
son complaining of skin itching after con-
tact with contaminated water must be
considered infected. Bilharzial lesions
in the urinary tract result from variable
tissue reactions to bilharzial eggs with
subsequent healing or progression and
complications. Subsequent changes may
assume an atrophic, proliferative, meta-
plastic or neoplastic pattern. Although
the pathology is usually extensive in the
submucosa, all layers from the mucous
membrane through the musculosa and
up to the perivesical or periureteral tis-
sue may be implicated. Bladder lesions
are the most common and vary between
active bilharzial cystitis, chronic bilharzial
cystitis, bilharzial bladder ulcer, bladder
bladder carcinoma. The lower ureters are
the second most favorable site for the bil-
harzial worms after the urinary bladder.
Ureteric lesions include simple epithelial
hyperplasia, sandy patches, ureteritis
cystica, calcinosa and glandularis, ureteral
polyps, muscular atrophy, obliterated ure-
teritis, ureteral strictures and carcinoma.
The prostate, seminal vesicles, spermatic
cord and epididymis are affected in cases
with severe bilharzial infestation while the
testis has a remarkable immunity against
bilharzial invasion. Immunoblast assay
has the highest sensitivity and specificity
of detection of adult worm antigens in the
urine or serum and tissue diagnosis is the
most precise method for diagnosis of uri-
nary tract schistosomiasis. Praziquantil is
the drug of choice and metrifonate can be
used after failure of praziquantil. Proper
sanitation and avoidance of contaminated
water would minimize the prevalence of
human infestation with schistosomiasis.
Chapter | 15 | Special urogenital infections
Key words: epidemiology of schistoso-
miasis, pathology and pathogenesis of
schistosomiasis, genitourinary bilhar-
ziasis, genitourinary schistosomiasis,
ureteric bilharzial strictures, bladder car-
cinoma, squamous cell carcinoma
SUMMARY OF RECOMMENDATIONS
1. Use of sanitation and avoidance
of contaminated water would
minimize the prevalence of human
infestation with schistosomia-
sis (GoR A), because humans are
infected through skin contact with
cercariae.
2. Any person complaining of skin itch-
ing after contact with contaminated
water must be considered infected
(GoR B).
3. Immunoblast assay has the highest
sensitivity and specificity of detec-
tion of adult worm antigens in the
urine or serum (GoR B).
4. Tissue diagnosis is the most precise
method for diagnosis of urinary tract
schistosomiasis (GoR A).
5. Praziquantel is the drug of choice of
all forms of schistosomiasis with a
65–90% cure rate after a single oral
dose (GoR A).
6. Metrifonate can be used after failure
of praziquantel (GoR B).
7. Bilharzial bladder carcinoma is
mostly locally advanced and radio-
resistant. Radical cystectomy with
some form of urinary diversion is the
optimum treatment option (GoR A).
8. Bilharzial contracted bladder (store
<100 cc urine) might need augmenta-
tion cystoplasty (GoR B).
9. Chronic superficial Bilharzial blad-
der ulcer is mostly treated endo-
scopically by transurethral resection
944
while chronic deep type needs open
surgery (GoR B).
10. Chronic bilharzial ureteric stric-
ture mostly affects its lower third.
Endourological treatment can give
success in < 50% of cases while open
surgery gives better satisfactory
results (GoR C).
1. INTRODUCTION
Genitourinary schistosomiasis (bilharzia-
sis) is a communicable parasitic disease
caused by Schistosoma haematobium
(S.haematobium). It affects a high propor-
tion of the population in developing coun-
tries especially children under 14 years,
causing major socioeconomic and pub-
lic health consequences. An estimated
100 million people in developing countries
are currently infected; more than 80% of
them live in Africa [1] (LoE 1b). Being a
worldwide communicable disease, the
purpose of this guideline is to update the
disease risks, transmission, epidemiology,
pathologic lesions, and prophylaxis.
2. METHODS
For the period 1998–2009 a system-
atic literature search was performed in
Medline, Cochrane, PubMed, etc with
the following key words: epidemiology of
schistosomiasis, pathology and pathogen-
esis of schistosomiasis, genitourinary bil-
harziasis, genitourinary schistosomiasis,
and the following limitations; English
language abstracts available, double
blind studies, large clinical studies and
multi-institutions collective data.
A total of 90 publications were identi-
fied, which were screened by title and
abstract. After exclusion of duplicates, a
total of 61 were included into the review
analysis, supplemented by citations
known to the authors.

The studies were rated according to
the level of evidence and the strength of
recommendations as given by the Oxford
Centre for Evidence Based Medicine [2].
The ICUD consultations use a modified
version of the Oxford system [3].
3. EPIDEMIOLOGY
S. haematobium is found in 53 countries
in the Middle East and Africa. Human
infection is caused by skin contact, dur-
ing swimming or bathing, with fresh
water that harbors infected snails. In
Europe and United states, schistosomia-
sis is always an imported disease mainly
present in travelers or immigrants from
endemic areas [4] (LoE 3). The preva-
lence of infection is linked to the economic
level, adequacy of sanitation and contact
to contaminated water. Survey in 2000 of
disease specific mortality reported 70 mil-
lion of 682 millions in Africa had experi-
enced haematuria and 32 million suffered
dysuria with S. haematobium infection.
Moreover, 18 million suffered bladder wall
pathology, and 10 million suffered hydrone-
phrosis [1] (LoE 1b). Schistosomiasis is
directly responsible for an annual death of
20,000 patients [5] (LoE 1b).
4. LIFE CYCLE OF SCHISTOSOMA
HAEMATOBIUM AND MODE OF
TRANSMISSION
Schistosomes are digenetic, which means
that their life cycle involves a definitive
human host, in which sexual maturity of
the worms occur, and an intermediate snail
host in which processes of asexual multi-
plication of larval forms occur. Humans
are infected by skin contact with cer-
cariae which can reach the subepider-
mis and start the sexual part of the life
cycle passing through peripheral venules
or lymphatic vessels to reach the sys-
temic circulation. Only cercariae that gain
Genitourinary schistosomiasis | 15.8 |
access to the mesenteric arteries survive
[6] (LoE 3).These migrate into the infe-
rior mesenteric veins, proceeding further
to reside in the pelvic plexus of veins.
There, the worms become sexually mature
and the fertilized females lay eggs. From
this venous plexus the worms proceed to
different urinary and genital organs [7]
(LoE 3). The worms can remain active and
discharge ova for five to 18 years, but peri-
ods of 27 to 40 years have been reported [8]
(LoE 3). Each female worm produces and
deposits approximately 200 to 500 eggs per
day. Thus, during its estimated mean life
span of three to six years, a single worm
pair spawns 250,000 to 600,000 eggs; in
nature, the ova hatch if they fall into fresh
water where the ciliated larva or miracid-
ium emerges. The miracidium can remain
alive in water for 16–32 hours looking for
the snail of the genus Bulinus. Within the
snail the miracidium develops into cer-
cariae. From a single miracidium 100–250
thousand cercariae are produced by a proc-
ess of asexual multiplication and are subse-
quently discharged from the snail into fresh
water to infect human host [9] (LoE 3).
5. PATHOGENESIS AND PATHOLOGY
5.1 Initial tissue reaction and repair
Bilharzial lesions in the urinary tract
result from variable tissue reactions to
bilharzial eggs with subsequent heal-
ing or progression and complications.
Ova entrapped in the tissues of the
genitourinary tract will induce delayed
hypersensitivity cell-mediated TH1 and
TH2 responses with local cytokine pro-
duction. Granulomata form in the lam-
ina propria by accumulation of plasma
cells, lymphocytes, and eosinophils [6]
(LoE 3) (Figure 1). Subsequently, wide-
spread collagen deposition occurs and the
whole cellular reaction is replaced by a
laminated fibrotic nodule. Blood vessels
undergo thromboangitis and endarteritis
945
Chapter | 15 | Special urogenital infections
Figure 1 Histopathological picture of active bilharzial cystitis
showing multiple active schistosomal ova containing mera-
cidia inside with moderate to dense inflammatory infiltrate
composed of lymphocytes, plasma cells and eosinophils.
obliterans [7] (LoE 3). Degeneration of
muscle fibers and dense interstitial fibro-
sis often occur. Following the granuloma-
tous bilharzial reaction in the submucosa,
subsequent epithelial changes ensue.
5.2 Subsequent pathology
Subsequent changes may assume an
atrophic, proliferative or metaplastic
pattern. Although the pathology is usu-
ally extensive in the submucosa, all lay-
ers from the mucous membrane through
the musculosa and up to the perivesical
or periureteral tissues may be implicated
[10] (LoE 2b). As ovideposition ceases,
entrapped eggs are destroyed or calcified
and inflammation wanes, being replaced
by fibrous tissue. In sites of recent
ovideposition, perioval granulomatous
inflammation results in large, bulky and
Figure 2 Cystoscopic view showing polypoid lesion
covered by intact mucosa (bilharzial granuloma).
946
hyperemic polypoid masses projecting
into the lumen (bilharzial granuloma)
(Figure 2).
Specific bilharzial pathologic lesions
in the genitourinary tract can occur with
variable degrees of severity according to
the organ affected, severity and frequency
of egg deposition, reinfection, and second-
ary microbial infection [8, 11] (LoE 3).
5.3 Bilharziasis of the bladder
5.3.1 Active bilharzial cystitis
Active bilharzial cystitis commonly occurs
at school age of five to 15 years represent-
ing the period of ovideposition in the blad-
der wall, the immediate tissue reaction to
deposited ova, and the release of ova in
the urine. Presenting symptoms include
painful micturition, frequency and ter-
minal haematuria. On cystoscopy, the
mucous membrane shows multiple hyper-
emic patches, with pinpoint yellowish bil-
harzial tubercles [7] (LoE 3) (Figure 3).
5.3.2 Chronic bilharzial cystitis
Chronic bilharzial cystitis may assume an
atrophic or hyperplastic pattern. All blad-
der layers from the mucous membrane
through the musculosa and up to the
perivesical tissue may be implicated [10]
(LoE 2b): Mucosal lesions include simple
atrophy, sandy patches, cystitis cystica,
bladder ulcers and mucosal transforma-
tions. Bilharzial infiltrations in the sub-
mucosa diminish the vascularity of the
Figure 3 Cystoscopic view of active bilharzial cystitis showing
yellowish tubercles and confluent mucosal hyperaemia.

Figure 4 Cystoscopic view of chronic bilharzial cystitis
showing diminished vascularity and pale mucosa.
overlying mucous membrane leading to
its atrophy (Figure 4). Submucosal lesions
include bilharzial fibrosis, nodules, pol-
yps, and calcification. Muscular lesions
include muscular degeneration and fibro-
sis, bladder-neck fibrosis and contracted
bladder. Perivesical lesions appear as bil-
harzial pericystitis.
5.3.2.1 Bilharzial nodules
Heavy egg deposits excite massive reac-
tion around aggregations of bilharzial
tubercles and develop spheroid grayish
nodules, covered by pale anemic intact
mucosa. These occur mainly in children
through their early teens. Polyps may
obstruct ureters or, rarely, the bladder
outlet. Nodules can reach large dimen-
sions mimicking bladder carcinoma on
cystoscopy and urography.
5.3.2.2 Bilharzial fibrosis and calcification
This results from healing of mild bilhar-
zial infiltrations of the submucosa reduc-
ing the pliability of the overlying mucosa.
When calcification of dead ova in the sub-
mucosa occurs, the bladder wall becomes
dull pale yellow in color. Calcification will
cast a linear or circumferential shadow on
a plain radiogram [7] (LoE 3) (Figure 5).
5.3.2.3 Cystitis cystica and glandularis
Cystitis cystica appears as tiny rounded
translucent yellowish cysts of uniform
Genitourinary schistosomiasis | 15.8 |
Figure 5 Plain radiograph of the pelvis showing dense
bladder calcification pathognomic of bilharzial infestation.
appearance lined by one layer of cuboi-
dal epithelial cells. Cystitis glandularis
appears as rounded or oval gland-like
structures filled with mucoid secretion
and lined with a single layer of cuboidal
cells with strictly basal nuclei. It is fre-
quently met with in chronic bilharzial
bladders and is regarded by some as pre-
cancerous as it is found in 32–50% of bil-
harzial bladder carcinoma [12] (LoE 2a).
On cystoscopy, they appear as velvety red
elevations of the mucosa.
5.3.2.4 Squamous metaplasia and
leukoplakia
Squamous metaplasia and leukopla-
kia may be encountered in long stand-
ing chronic bilharzial cystitis but mostly
in association with squamous cell blad-
der carcinoma [12] (LoE 2a) (Figure 6).
They result from chronic irritation of the
mucous membrane by the bilharzial ova.
On cystoscopy, they appear as well-defined,
white, slightly raised patches surrounded
by inflamed mucosa. Follow up is man-
datory as it is considered a precancerous
lesion [13] (LoE 2b).
5.3.3 Bladder ulcer
Bilharzial bladder ulcer is most com-
monly met with in patients between 20
and 40 years of age. Microscopically, there
947
Chapter | 15 | Special urogenital infections
Figure 6 Keratinizing squamous metaplasia of bladder
mucosa with bilharzial ova laid in the submucosa.
is complete loss of the surface epithelium.
In active ulcers, the surface layer is com-
posed of necrotic tissue with foci of meta-
plasia at the margins of the ulcer. The
underlying layers show bilharzial cellular
reaction, with little ova, oedema, hemor-
rhages and degeneration of muscle fib-
ers. In other cicatricial types of ulcers,
the predominant feature is the presence
of dense fibrous tissue and endarteritis
obliterans causing relative avascularity
[13] (LoE 2b). A bilharzial bladder ulcer
rarely heal spontaneously due to the
presence of calcific or fibrotic plaque in its
floor and associated secondary infection.
Diagnosis is settled by cystoscopy,
where ulcers appear as; 1) Active ulcers
with a bleeding surface from the base
of active bilharzial granuloma, and 2)
Cicatricial ulcers characterized by dense
fibrosis and appear as stellate or linear
ulcers [14] (LoE 2a) (Figure 7). The ulcers
are usually single, situated in the poste-
rior wall or the dome of the bladder. The
trigone and anterior walls are almost
exempt from ulceration [13] (LoE 2b).
5.4 Bilharzial bladder neck
obstruction (BNO)
This could be encountered as a signifi-
cant entity in 7.5% of patients with com-
plicated cystitis [14] (LoE 2a). Bilharzial
infiltration of the bladder neck results
in fibrous scarring of the submucosa and
destruction of the muscle bundles. The
948
Figure 7 Cystoscopic view showing chronic deep bilharzial
bladder ulcer.
suggestive history is difficulty in initiat-
ing voiding, straining and weak inter-
rupted stream in a young-aged male [15]
(LoE 2b). The diagnosis can only be set-
tled by urodynamic pressure flow study
with simultaneous imaging.
5.5 Contracted bladder
This results from heavy infestation with
severe body reaction affecting submucosa,
musulosa and perivesical tissues, sparing
the trigone resulting in marked decrease
in the size and capacity of the bladder. In
severe forms the reduced bladder capac-
ity will lead to ureteric reflux and renal
impairment [16] (LoE 3) (Figure 8).
5.6 Carcinoma of the bladder
associated with bilharziasis
Bladder carcinoma is common in countries
where schistosomiasis is endemic such as
Egypt, Sudan, Iraq, Mozambique, Gold
Coast and Nigeria. No such increased
incidence is found in South Africa or in
West Africa for unknown cause.
The association between urinary schis-
tosomiasis and vesical carcinoma can be
explained by many etiologic factors that
work together including chronic mucosal
irritation by bilharzial ova, recurrent bac-
terial infection, carcinogenic toxins pro-
duced by the miracidium or worms and

Figure 8 Ascending cystography showing contracted bladder
with dilated refluxing ureters with marked hydronephrosis.
a raised level of carcinogenic tryptophan
metabolites, nitrates, serotonin and uri-
nary beta-glucuronidase enzyme in bil-
harzial patients [7, 12, 17–18] (LoE 2b,
GoR B). Immunohistochemical studies
showed P53 protein over-accumulation in
71% of cases of squamous cell carcinoma
of bilharzial bladder. Moreover, molecular
genetic studies showed P53 mutations in
33% of tumors [19–20] (LoE 2b).
Bilharzial bladder carcinoma arises
from any wall of the bladder except the
trigone (only in 2% of cases) [17] (LoE
2b). The tumor is usually single and
bulky one. Its gross appearance is most
commonly the nodular fungating type
(85%); less common types are the ulcera-
tive (8%), the diffuse infiltrative (4%)
papillary (1.5–3%) and Verrucus carci-
noma (3.6%). The latter is a rare pecu-
liar type to bilharzial squamous cell
carcinoma (SCC). It presents as a hyper-
keratotic exophytic growth with filamen-
tous white projections locally malignant
without any tendency to spread to
regional lymph nodes or distant organs
[21] (LoE 2a, GoR B).
Genitourinary schistosomiasis | 15.8 |
Figure 9 Dilated ureter at operation showing group of large
ureteritis cystica in its opened lumen.
The tumor histology in bilharzial cases
is squamous cell type in 54% to 77%.
80% of these are low-grade tumor [21]
(LoE 2a). Transitional cell tumors consti-
tute 21% to 39% in bilharzial bladders,
and the majority are grade II or III [17]
(LoE 2b). Adenocarcinoma constitutes 4%
to 9.6% of bilharzial bladder cases [21]
(LoE 2b). The pathologic stage is mostly
advanced; P3 (64%) and P4 (23%). Lymph
node spread is encountered in 18–24% of
cases [22–24] (LoE 2a, GoR B).
5.7 Bilharziasis of the ureter
The lower ureters are the second most
favorable site for the bilharzial worms
after the urinary bladder. The intramu-
ral part is affected almost as frequently
as the bladder. Other common sites are
the juxtavesical part, pelvic segment and
lumbar spindle opposite the third lumbar
vertebra [7, 25] (LoE 3). In the chronic
stage, ureteric lesions include simple
epithelial hyperplasia, sandy patches,
ureteritis cystica, calcinosa and glandu-
laris, ureteral polyps, muscular atrophy,
949
Chapter | 15 | Special urogenital infections
obliterated ureteritis, ureteral strictures
and carcinoma [25] (LoE 2b, GoR B).
Calcification of the ureter may appear as
pseudocalculus on plain UT [26] (LoE 2a).
Ureteritis cystica may reach large size
mimicking stones (Figure 9).
The bilharzial ureter takes one of
three forms: thick ureter, stricture ure-
ter, dilated ureter or any combination of
them. The thick ureter is rigid like a pipe-
stem. The lumen is slightly narrowed
and the mucosa is degenerated. The wall
cuts with a gritty sensation and minimal
bleeding. The peri-ureteric fascia forms
a thick scaffold adherent to the ureter.
Sometimes a fibrolipomatous mass is
formed around the ureter, especially its
pelvic segment. The ureter can prima-
rily form or traps migrating stones from
the kidney allowing these to enlarge and
reach giant dimensions [25] (LoE 2a).
In the stricture ureter, stenosis or
almost complete obliteration of the lumen
is the end result of contraction of the
dense fibrosis involving all the layers of
the ureteral wall. In a study on 804 bil-
harzial strictures of the ureter, involve-
ment of the lower third was found in
91.7% [25] (LoE 2a). In the lower ureter,
45% of the strictures were juxtavesical,
37.5% intramural, 8.9% combined jux-
tavesical and intramural 7.7% pelvic,
and 0.9% meatal strictures. Bilateral
involvement was noted in 63.7% of cases
[27–28] (LoE 2b). Gradual lengthening
and widening of the ureter result in tor-
tuosity and kinking. Dilatation of the
renal pelvis and calyces will necessarily
follow, and migratory stones proximal to
the stricture are a common complication
[28] (LoE 3).
Dilatation without a distal stricture
(dilated ureter) may result from bilhar-
zial degeneration of the muscles and neu-
ral elements in the wall of the ureter or
due to vesico-ureteral reflux. It is usually
restricted to the pelvic segment, but may
involve the whole ureter. Only one-quar-
ter of dilated bilharzial ureters are truly
obstructive [28] (LoE 3).
950
5.8 Bilharziasis of the prostate,
seminal vesicles, spermatic cord
and epididymis
In severe and repeated bilharzial infesta-
tion the worms navigate to other organs
such as the prostate, seminal vesicles,
and the intrascrotal structures. Notably,
the testis has a remarkable immunity
against bilharzial invasion [29] (LoE 3).
Subsequent bilharzial infiltrations in
these structures will progress to severe
fibrosis. In the seminal vesicles, fibro-
sis invited marked calcification and the
organs become firm, nodular and smaller
in size [29]
(LoE 3, GoR C). Prostatic and semi-
nal calcifications should alert physicians
to the possibility of schistosoma infection
when they are found in young patients
who have been in endemic areas [30–31]
(LoE 2b).
The concomitant presence of adeno-
carcinoma of the prostate and schisto-
somiasis is very rare. Up to the present
time, only eight cases of prostatic schis-
tosomiasis associated with adenocarci-
noma of the prostate have been reported,
three of which were associated with
S.heamatobium, three with S. mansoni
and in two cases the species of parasite
was not specified [32–33] (LoE 3).
In epididymal affection a solitary mass
is commonly found in the globus major.
Bilharziasis of the spermatic cord may be
manifested as firm mass in its lower part
or as one big irregular mass along the
intrascrotal cord. Ironically, the lumen
of the tubules of the epididymis and the
lumen of the vas remain patent and
unobstructed.
5.9 Urinary stones in relation to
bilharziasis
Comparison of the incidence rate of uri-
nary stones in bilharzial and non-bilhar-
zial patients suggests that bilharziasis
does not contribute to the high incidence
of urinary stones in Egypt [34] (LoE 3),
nor in Sudan [35] (LoE 3, GoR C). Other

Figure 10 Plain urinary tract showing giant stones in the bladder (left figure), lower part of the right ureter with calcified left
ureter (middle figure) and left renoureteral stone (right figure).
predisposing factors of stone formation
may be considered. However, Bilharziasis
may re-distribute the stone location along
the urinary tract with a relative increase
in the number of ureteral calculi in bil-
harzial ureters. Giant forms of stones
may form at the bladder and ureteric lev-
els [34] (LoE 3, GoR C) (Figure 10).
5.10 Nephropathy and renal failure
Nephrotic syndrome occasionally develops
in patients with S. haematobium. Severe
renal changes are seen in up to 25% of
patients with bilharzial infections [36]
(LoE 2b). Clinical features include pro-
tienuria and oedema. Immune complexes
formed in response to Schistosoma infec-
tion may be deposited on glomerular cap-
illaries and renal basement membrane,
leading to 5 classes of glomerulonephritis:
mesangioproliferative, exudative, mesan-
giocapillary, focal segmental sclerosis and
amyloidosis [5, 37] (LoE 1b). Although the
acute and early chronic lesions regress
under antiparasitic treatment, chronic
sequelae are irreversible and may cause
Genitourinary schistosomiasis | 15.8 |
end-stage renal failure [5] (LoE 1b).
Hydroureteronephrosis and renal func-
tion deterioration gradually occur as a
sequel of lower ureteric obstruction.
6. DIAGNOSIS OF SCHISTOSOMIASIS
6.1 Clinical manifestations
Following a localised itching caused
by skin penetration by the cercaria, a
rash and fever may occur. Symptomatic
disease starts few months later by
active stage of acute cystitis symptoms
associated with fever and haematu-
ria. After some years, egg deposition
and excretion continue at a lower rate
and symptoms cease. Over 30% of light
infections “resolve” spontaneously in
some endemic areas. Although symp-
toms are absent, silent obstructive
uropathy can develop as fibrosis ensue
and the bladder and ureters undergo
irreversible pathology. Patients finally
enter a chronic inactive phase, in which
viable eggs are no longer detected in
urine or tissues. Signs and symptoms at
951
Chapter | 15 | Special urogenital infections
this stage are caused by complications
rather than by the schistosoma infection
itself. Vesical, ureteral, renal and geni-
tal lesions develop [38–39] (LoE 2a).
6.2 Laboratory tests
6.2.1 Egg detection, diagnosis and
quantitation of infection
The presence of terminally- spiked eggs
in urinary sediment is diagnostic of
active S . haematobium infection. S. hae-
matobium egg excretion peaks between
10 AM and 2 PM; the extent of egg shed-
ding may fluctuate widely, and as many
as three specimens may be required in
some patients. The test may be performed
after the incubation period of last known
contact to fresh water; usually after three
months. Urinary egg excretion measure-
ment accurately estimates infection and
its intensity during the early stages but
is imprecise in late stages and inactive
cases [40–41] (LoE 2a).
6.2.2 Serologic tests
Serologic tests are valuable diagnostic and
epidemiologic tool, but cannot distinguish
active from past infections. Antibody
detection has a limited use because anti-
bodies persist after parasitological cure.
Immunoblast assay is used to detect adult
worm antigens in urine or serum. It has
95% sensitivity and 99% specificity for S.
haematobium. Antigen tests may become
negative as early as 10 days after therapy.
These tests may also be negative in light
infections [37, 42] (LoE 2a).
6.2.3 CBC count and coagulation profile
Eosinophilia is prominent in acute schis-
tosomiasis while thromocytopenia, anemia
and prolonged prothrombin time are
present in severe chronic Schistosomiasis.
6.2.4 Urine cytology
Urine cytology is used for suspected
malignant epithelial cells.
952
6.2.5 Semen analysis
Semen analysis is used for cases of
haemospermia to look for bilharzial
ova to diagnose genital schistosomiasis
[43] (LoE 3).
6.3 Imaging studies
Vesical or ureteric bilharzial calcification
and honey-combed calcification of the
seminal vesicles on plain UT are stigma
of infestation and are not necessarily an
evidence of active disease. Other imaging
studies as ultrasonography and CT of the
abdomen and pelvis can diagnose disease
complications.
6.4 Tissue biopsy
Being a very sensitive test is done for
histological diagnosis from bladder, pros-
tate and seminal vesicle lesions and in
patients with typical clinical picture and
negative urine specimens.
7. TREATMENT OF SCHISTOSOMIASIS
AND ITS COMPLICATIONS
7.1 Medical treatment
Praziquantel is the drug of choice for all
types of schistosomiasis giving a cure
rate of 65–90% after single treatment
[44] (LoE 1a, GoR A). It is given as one
oral dose of 40 mg/ kg BW. By inhibit-
ing egg release, praziquantel reduces
prevalence and parasitic burden [45]
(LoE 1b). Praziquantel resistance to
treatment of S. haematobium infections
has been reported in Egypt and Kenya
20 years after multiple courses of treat-
ment [46] (LoE 2b). Other drug which
is effective against S. haematobium is
an organophosphate called Metrifonate
administered in a dose of 5 mg/kg, orally
in three biweekly administrations [47]
(LoE 3, GoR C) Because of multiple
administrations, Metrifonate is opera-
tionally less convenient in community-
based control programmes [48] (LoE 1a,

GoR A). Evidence on the artemisinin
derivatives is currently inconclusive, and
further research is warranted on combi-
nation therapies [48] (LoE 1a, GoR A).
7.2 Surgical treatment
7.2.1 Bilharzial ulcer
Conservative treatment in the form of
antibilharzial and antibacterial drugs
may be tried in small active ulcers.
Transurethral coagulation of the floor
and edges of the ulcer may give relief of
symptoms for few months, but recurrence
is the rule. Transurethral resection (TUR)
of localized superficial ulcers may give
good results. An alternative treatment for
a chronic deep bilharzial bladder ulcer is
open excision or partial cystectomy [13]
(LoE 2b, GoR B).
7.2.2 Leukoplakia
Treatment is TU Resection [16] (LoE 3,
GoR C)
7.2.3 Bilharzial BNO
Treatment is by TUR incision or resection
of the fibrous scar. This will give only a
temporary relief but further formation of
fibrous tissue and re-contracture usually
occurs (LoE 4, GoR D)
7.2.4 Contracted bladder
Treatment in established cases with blad-
der capacity < 100 ml under anaesthesia
by augmentation entero-cystoplasty [16]
(LoE 3, GoR B)
7.2.5 Bilharzial bladder carcinoma
The tumor is usually low-grade deeply
invasive, consequently transurethral
resection and chemotherapy have little
place in the management [20] (LoE 1b,
GoR A).
Radiotherapy results are generally dis-
appointing as the tumor is mostly a low-
grade SCC, of a considerable bulk and
very frequently associated with fibrosis
and infection. (LoE 4, GoR D)
Genitourinary schistosomiasis | 15.8 |
Radical cystectomy and some form of
urinary diversion is the optimum treat-
ment option to most cases of organ-con-
fined invasive bladder tumors [39–40].
Several orthotopic continent reservoirs
are applicable in nearly half of cases.
The reported overall five-year disease-
free survival after radical cystectomy is
48–55.5% [46] and the 10 year survival is
50% and node positivity has an independ-
ent negative impact on disease-free sur-
vival [49] (LoE 2a, GoR A).
7.2.6 Stricture ureter
Bilharzial ureteric strictures represent
a real surgical challenge. Endourological
treatment is indicated for early cases,
non-tight short-segment strictures. High-
pressure balloon dilatation and endour-
eterotomy have been reported to have a
success rate of 40–87% [50–52] (LoE 2b,
GoR B). Open surgery is usually needed
for the more established cases associ-
ated with periuretritis [53] (LoE 2b, GoR
B). The type of reconstructive surgery
depends on the site of the stricture, its
length, bilaterality, extent of periureteral
fibrosis, condition of the proximal ureter,
and bladder capacity. Excision and spat-
ulated end-to-end anastomosis affords
the best result in properly selected
cases. Most strictures of the lower part
of the ureter need ureterovesical re-
implantation [53] (LoE 2b). However,
tailoring of the markedly dilated ureter
provides better results [53] (LoE 3, GoR
C). For more proximal strictures of the
pelvic ureter, the bladder flap opera-
tion (Boari’s) is recommended [54] (LoE
2b, GoR B). In very extensive strictures
involving a long segment, ileal loop
replacement is the only available option,
although its long-term effects of reflux
and urinary tract infection can compro-
mise the kidney [53] (LoE 2b, GoR B).
Tailoring of the ileal ureter with crea-
tion of an intussuscepted nipple valve
at its distal end may prevent reflux and
provide better functional results [55–56]
(LoE 1a and 2b).
953
Chapter | 15 | Special urogenital infections
8. DISEASE CONTROL
Satisfactory disease control can be
attained by large-scale population-based
antibilharzial treatment, adequate sani-
tation for the proper disposal of urine
and stools, mass eradication of snails and
proper health education. This large scale
prevention strategy is difficult to attain in
many countries for cultural and economic
reasons. Moreover, chemical eradication of
snails cannot be implemented because of
its serious environmental consequences.
The World Health Organization strategy in
schistosomiasis control in Africa is a mor-
bidity control package. This includes pro-
viding praziquantel at an affordable price,
a proper case management and an effec-
tive health education, especially in school
health programs [57] (LoE 2b, GoR B).
Few countries like Puerto Rico, Saudi
Arabia and Morocco have eradicated
the disease. Others like Brazil, China
and Egypt have attained partial control,
largely as a result of mass treatment of
all school children by Praziquantel [1].
Travellers to endemic areas should
be strictly advised to avoid any contact
to canal water in rivers or lakes [58]
(LoE 1a, GoR A). They should boil any
possibly contaminated water to destroy
the parasite. Glycosaminoglycans is given
as bladder instillations or orally for uro-
protection in patients suffering chronic
cystitis [58] (LoE 1a).
9. DISCUSSION
Schistosomiasis is an endemic disease in
many regions of the Middle East, Africa,
South East Asia and South America; ≈
200 million people are infested and 1000
million are at risk of the disease world-
wide [20] (LoE 2b). The most serious
complications of genitourinary schisto-
somiasis are the predisposition to SCC of
the bladder and development of obstruc-
tive uropathy that my lead to end-stage
renal failure. Both bladder cancer and
954
end-stage renal failure are debilitating
diseases which are considered as national
health problems in the endemic areas
consuming a great percentage of the
human resources and increasing the cost
of the health services. Therefore, preven-
tion and early treatment of schistosomia-
sis should be one of the most important
health care targets in endemic areas..
The majority of bilharzial-associated
bladder cancers are SCC, whereas the
majority of non-bilharzial cases in the
Western world are transitional cell cancers
(TCC), suggesting different carcinogenetic
mechanisms. Squamous cell carcinoma of
the bladder is a distinct clinico-pathological
entity different from SCC encountered in
the Western World and also different from
the conventional TCC. Most of the SCC
tumors are detected at an advanced stage
and superficial papillary tumors are very
rare. Therefore, the prediction of prognosis
in this cohort of patients depending upon
the presence of superficial type does not
exist because the vast majority of patients
present in muscle-invasive stage which
requires cystectomy.
Numerous individual molecular mark-
ers have been identified in the tissue,
serum, and urinary specimens that corre-
late to some extent with tumor stage and
possibly with its prognosis. However, the
power of many of these individual mark-
ers in predicting recurrence, progres-
sion or the clinical outcome of individual
tumors is still limited. It is conceivable
that the development of biomarkers that
identify patients, whose tumors are likely
to recur or progress, so that they can
be treated more aggressively, would be
beneficial for patients presenting at all
stages. Patients with superficial disease
represent a group who would greatly
benefit from predictive markers of recur-
rence and progression into invasive dis-
ease. This can be attributed to their high
chance of relapse within the first 5 years
after surgery and the poorer clinical out-
come once muscle invasion is present.
For patients with invasive tumors, tumor

markers are needed to predict response to
chemotherapy and development of meta-
static disease [59] (LoE 2a).
The Food and Drug Administration
(FDA) has already accepted urinary tests
for the monitoring of patients with non-
muscle invasive bladder cancer, including
bladder tumor antigen (BTA) test, the BTA
stat test, the fibrinogen-fibrin degradation
products test, fluorescent in situ hydridi-
zation cell assay and the nuclear matrix
protein 22. In general, each of these mark-
ers has better sensitivities but lower spe-
cificities than cytology, and must still be
used as adjuncts with cystoscopy [60] (LoE
2b). The use of these markers was applied
to TCC of the bladder in the vast majority
of studies. The role of these biomarkers
in the early detection of SCC of bilharzial
bladder is a subject of further research.
Genetic and ultimately protein altera-
tion are primary determinants controlling
neoplastic transformation and protein
changes ultimately determine a tumor’s
phenotype and subsequent clinical behav-
ior. The advent of high-throughput DNA
microarrays is accelerating the identifi-
cation process of these molecular events
characteristics of bladder cancer [61]. The
information provided by these analyses
is resulting not only in the identification
of novel therapeutic targets for bladder
cancer, but also in the development of
diagnostic tools [61] (LoE 2a). Most of the
genomic and proteomic studies were con-
fined to TCC of the bladder. Identification
of genetic and protein alterations in bil-
harzial SCC is a virgin area which needs
further research.
10. FURTHER READING
For more details of genitor-urinary schis-
tosomiasis, the following sites and read-
ings are available.
a. Free Medline search through:
Pubmed.com, Cochrane review, emedi-
cine.com, Medscape.com and other
places.
Genitourinary schistosomiasis | 15.8 |
b. EAU guidelines for the manage-
ment of Urogenital Schistosomiasis,
European Urology 2006, 49: 898–1003.
c. WHO search,www.who.int.
Schistosomiasis: Burden and trends.
Update 25 Jan, 2008.
d. Khalaf I and Koritim M.
Genitourinary Schistosomiasis. In
Textbook of Tropical Surgery by
Kamel R and Lumely J, Westminser
Publishing Ltd; 2004:673–680.
11. CONCLUSIONS
Schistosomiasis is a parasitic infestation;
200 million people are infested and 1000
million are at risk of the disease world-
wide. The bladder and lower ureters are
the most common sites of bilharzial infes-
tation. The bladder lesions are precancer-
ous while the ureteric lesions may cause
obstructive uropathy with subsequent
end-stage renal failure
The best treatment option of geni-
tourinary Schistosomiasis is prevention
through disease control. The disease can
be controlled through mass eradication of
snails, adequate sanitation and popula-
tion-based antibilarzial treatment (GoR
A). Travellers to the endemic regions
would be advised to avoid contact to the
contaminated water in the canals, lakes
and rivers (GoR A).
REFERENCES
1. World Health Organization.
Schistosomiasis: Burden and Trends.
2008; Available from: http://www.who.int/
bulletin/volumes/86/10/08-058669/en/.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
3. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
955
Chapter | 15 | Special urogenital infections
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
4. Jelinek T, von Sonnenburg F, and
Nothdurft HD, [Epidemiology and clinical
aspects of imported schistosomiasis]. Med
Klin (Munich), 1997. 92(1): 7–12.
5. Barsoum RS, Schistosomiasis and the kid-
ney. Semin Nephrol, 2003. 23(1): 34–41.
6. Sorour M, The pathology and morbid
histology of the bilharzial lesions in
various parts of the body. Congr Int Trop
Hyg, Cairo, 1928. 4: 322.
7. Makar N, Urological aspects of bilharzia-
sis in Egypt. 1955, [Cairo,: S. O. P.-Press.
viii, 208 p.
8. El-Bolkainy MNE and Chu EWE,
Detection of bladder cancer: associated
with schistosomiasis. 1981, Cairo, Egypt:
The National Cancer Institute, Cairo
University.
9. Leiper R, Report on the results of the
Bilharzias mission in Egypt, 1915. Part V:
Adults and ova. J Roy Army Med Corps,
1915. 30: 235.
10. El-Badawi A, The clinical and pathologi-
cal aspects of bilharziasis of the bladder.
1962, University of Alexandria.
11. el-Feky HM, Aly MA, Mangoud AM,
Naguib A, Kamel H, Kamhawy M,
Bayomi FA, Younis TA, and Morsy TA,
Histopathological study of the bilharzial
affection on the bladder and ureter.
J Egypt Soc Parasitol, 1992. 22(1): 71–6.
12. Ishak K, Le Golvan P, and I E-S, Malignant
bladder tumours associated with schisto-
somiasis, in Bilharziasis, Mostofi F, Editor.
1959, Springer Verlag: Berlin.
13. Ikinger U, Koraitim M, and Seitz HK,
Schistosomiasis: new aspects of an old dis-
ease. 1994, Berlin: Ullstein Mosby. 212p.
14. Shokeir AA, Ibrahim AM, Hamid MY,
Shalaby MA, Hussein HE, and Badr M,
Urinary bilharziasis in upper Egypt. I. A
clinicopathological study. East Afr Med J,
1972. 49(4): 298–311.
15. Koraitim M and al-Ghorab M, The diag-
nosis of bilharzial bladder neck obstruc-
tion: evaluation of criteria in 140 cases.
J Urol, 1972. 107(3): 381–3.
16. Sayegh ES and Dimmette RM, The
fibrotic contracted urinary bladder asso-
ciated with schistosomiasis and chronic
956
ulceration: a clinicopathological study
including treatment. J Urol, 1956. 75(4):
671–9.
17. Khafagy MM, el-Bolkainy MN, and
Mansour MA, Carcinoma of the bilharzial
urinary bladder. A study of the associated
mucosal lesions in 86 cases. Cancer, 1972.
30(1): 150–9.
18. Yosry A, Schistosomiasis and neoplasia.
Contrib Microbiol, 2006. 13: 81–100.
19. El-Bolkainy MN, Topographic pathology
of cancer. 1998: Cairo University: The
National Cancer Institute.
20. Shokeir AA, Squamous cell carcinoma
of the bladder: pathology, diagnosis and
treatment. BJU Int, 2004. 93(2): 216–20.
21. El-Sebai I, Sherif M, El-Bolkainy M,
Mansour M, and M G, Verrucous squa-
mous carcinoma of the bladder. Urology,
1979. 4: 407.
22. El-Bolkainy M, Tawfik H, and Kamel
I, Histopathologic classification of car-
cinomas in the schistosomal bladder,
in Detection of bladder cancer : associ-
ated with schistosomiasis, El-Bolkainy
MNE and Chu EWE, Editors. 1981,
The National Cancer Institute, Cairo
University: Cairo, Egypt.
23. el-Boulkany MN, Ghoneim MA, and
Mansour MA, Carcinoma of the bilharzial
bladder in Egypt. Clinical and pathological
features. Br J Urol, 1972. 44(5): 561–70.
24. Ghoneim MA, el-Mekresh MM, el-Baz
MA, el-Attar IA, and Ashamallah A,
Radical cystectomy for carcinoma of the
bladder: critical evaluation of the results
in 1,026 cases. J Urol, 1997. 158(2): 393–9.
25. Al-Shukri S, Alwan MH, and Nayef M,
[Ureteral strictures caused by bilharzia-
sis]. Z Urol Nephrol, 1987. 80(11): 615–24.
26. al-Ghorab MM, Radiological manifesta-
tions of genito-urinary bilharziasis. Clin
Radiol, 1968. 19(1): 100–11.
27. Al-Shukri S and Alwan MH, Bilharzial
strictures of the lower third of the ureter:
a critical review of 560 strictures. Br J
Urol, 1983. 55(5): 477–82.
28. Sharfi AR and Rayis AB, The continuing
challenge of bilharzial ureteric stricture.
Scand J Urol Nephrol, 1989. 23(2): 123–6.
29. Fall I, N’Doye M, Wandaogo A, Sankale
AA, and Diop A, [A case report of

epididymo-testicular bilharziasis in a child].
Ann Urol (Paris), 1992. 26(6–7): 360–1.
30. Al-Saeed O, Sheikh M, Kehinde EO,
and Makar R, Seminal vesicle masses
detected incidentally during transrectal
sonographic examination of the prostate. J
Clin Ultrasound, 2003. 31(4): 201–6.
31. Vilana R, Corachan M, Gascon J, Valls E,
and Bru C, Schistosomiasis of the male
genital tract: transrectal sonographic
findings. J Urol, 1997. 158(4): 1491–3.
32. Bacelar A, Castro LG, de Queiroz AC, and
Cafe E, Association between prostate can-
cer and schistosomiasis in young patients:
a case report and literature review. Braz J
Infect Dis, 2007. 11(5): 520–2.
33. Basilio-de-Oliveira CA, Aquino A, Simon
EF, and Eyer-Silva WA, Concomitant
prostatic schistosomiasis and adenocar-
cinoma: case report and review. Braz J
Infect Dis, 2002. 6(1): 45–9.
34. Khalaf IM, Giant urinary calculi in rela-
tion to urinary bilharziasis. 1970, Cairo
University, Egypt.
35. Ibrahim A, The relationship between uri-
nary bilharziasis and urolithiasis in the
Sudan. Br J Urol, 1978. 50(5): 294–7.
36. Simmanowski UA and Seitz H K,
Diagnosis of Schistsomiasis, in
Schistsomiasis, Ikimger U, Koraitim M,
and Seitz H K, Editors. 1994, Ullspein
Mosby: Berlin.
37. Dhawan VK, eMedicine, Schistsomiasis.
The Medscape Journal, May 15, 2008.
38. Bichler KH, Feil G, Zumbragel A, Eipper E,
and Dyballa S, Schistosomiasis: a critical
review. Curr Opin Urol, 2001. 11(1): 97–101.
39. Poggensee G, Feldmeier H, and Krantz
I, Schistosomiasis of the female genital
tract: public health aspects. Parasitol
Today, 1999. 15(9): 378–81.
40. Bradley DJA, Simple and rapid method
for counting Schistosome eggs in urine.
Soc. Trop. Med. Hyg, 1964. 28: 291.
41. Peters PA, Mahmoud AA, Warren KS,
Ouma JH, and Siongok TK, Field studies
of a rapid, accurate means of quantifying
Schistosoma haematobium eggs in urine
samples. Bull World Health Organ, 1976.
54(2): 159–62.
42. Tsang VC and Wilkins PP,
Immunodiagnosis of schistosomiasis.
Genitourinary schistosomiasis | 15.8 |
Screen with FAST-ELISA and confirm
with immunoblot. Clin Lab Med, 1991.
11(4): 1029–39.
43. Feldmeier H, Leutscher P, Poggensee G,
and Harms G, Male genital schistosomia-
sis and haemospermia. Trop Med Int
Health, 1999. 4(12): 791–3.
44. Capron A, Riveau GJ, Bartley PB, and
McManus DP, Prospects for a schisto-
some vaccine. Curr Drug Targets Immune
Endocr Metabol Disord, 2002. 2(3): 281–90.
45. Feldmeier H, Doehring E, Daffala AA,
Omer AH, and Dietrich M, Efficacy of
metrifonate in urinary schistosomiasis:
comparison of reduction of Schistosoma
haematobium and S. mansoni eggs. Am J
Trop Med Hyg, 1982. 31(6): 1188–94.
46. William S, Botros S, Ismail M, Farghally
A, Day TA, and Bennett JL, Praziquantel-
induced tegumental damage in vitro
is diminished in schistosomes derived
from praziquantel-resistant infections.
Parasitology, 2001. 122 Pt 1: 63–6.
47. Saathoff E, Olsen A, Magnussen P,
Kvalsvig JD, Becker W, and Appleton CC,
Patterns of Schistosoma haematobium
infection, impact of praziquantel treat-
ment and re-infection after treatment
in a cohort of schoolchildren from rural
KwaZulu-Natal/South Africa. BMC
Infect Dis, 2004. 4: 40.
48. Danso-Appiah A, Utzinger J, Liu J, and
Olliaro P, Drugs for treating urinary
schistosomiasis. Cochrane Database Syst
Rev, 2008(3): CD000053.
49. Ghoneim MA, Abdel-Latif M, el-Mekresh
M, Abol-Enein H, Mosbah A, Ashamallah
A, and el-Baz MA, Radical cystectomy for
carcinoma of the bladder: 2,720
consecutive cases 5 years later. J Urol,
2008. 180(1): 121–7.
50. Ghoneim MA, Nabeeh A, and El-Kappany
H, Endourologic treatment of ureteric
strictures. J Endourol, 1988. 2: 263–270.
51. ElAbd SA, ElShaer AF, ElMahrouky AS,
ElAshry OM, and Emran MA, Long-term
results of endourologic and percutane-
ous management of ureteral strictures
in bilharzial patients. J Endourol, 1996.
10(1): 35–43.
52. de la Taille A, Ravery V, Hoffmann P,
Hermieu JF, Moulinier F, Delmas V, and
957
Chapter | 15 | Special urogenital infections
Boccon-Gibod L, [Treatment of ureteral
stenosis using high pressure dilatation
catheters]. Prog Urol, 1997. 7(3): 408–14.
53. Bazeed MA, Ashamalla A, Abd-
Alrazek AA, Ghoneim M, and Badr M,
Management of bilharzial strictures of the
lower ureter. Urol Int, 1982. 37(1): 19–25.
54. Ravi G and Motalib MA, Surgical cor-
rection of bilharzial ureteric stricture by
Boari flap technique. Br J Urol, 1993.
71(5): 535–8.
55. Shokeir AA, Gaballah MA, Ashamallah
AA, and Ghoneim MA, Optimization of
replacement of the ureter by ileum. J Urol,
1991. 146(2): 306–10.
56. Khalaf I and Koritim M, Genitourinary
Schistosomiasis, in Textbook of Tropical
Surgery Kamel R and Lumley J, Editors.
2004, Westminster Publishing Ltd. p.
673–80.
57. Chitsulo L, Engels D, Montresor A,
and Savioli L, The global status of
958
schistosomiasis and its control. Acta Trop,
2000. 77(1): 41–51.
58. Bichler KH, Savatovsky I, Naber KG,
Bischop MC, Bjerklund-Johansen TE,
Botto H, Cek M, Grabe M, Lobel B,
Redorta JP, and Tenke P, EAU guide-
lines for the management of urogenital
schistosomiasis. Eur Urol, 2006. 49(6):
998–1003.
59. Sanchez-Carbayo M, Recent advances in
bladder cancer diagnostics. Clin Biochem,
2004. 37(7): 562–71.
60. Lotan Y and Roehrborn CG, Sensitivity
and specificity of commonly available
bladder tumor markers versus cytology:
results of a comprehensive literature
review and meta-analyses. Urology, 2003.
61(1): 109–18; discussion 118.
61. Sanchez-Carbayo M, Use of high-through-
put DNA microarrays to identify biomark-
ers for bladder cancer. Clin Chem, 2003.
49(1): 23–31.
|15.9|

Brucellosis: genitourinary
involvement
Ziad A. Memish1, Georgios Pappas2
1
Director Gulf Cooperation Council (states) Center for Infection Control,
Executive Director Infection Prevention & Control Program, King Abdulaziz Medical City, Riyadh, KSA
Adjunct Professor Department of Medicine, Division of Infectious Diseases, University of Ottawa, Canada
E-mail: zmemish@yahoo.com
2
Institute of Continuing Medical Education of Ioannina, H. Trikoupi 10, 45333, Ioannina, Greece,
E-mail: gpele@otenet.gr

ABSTRACT applying in the latter (recently summa-

Genitourinary involvement in brucello-
sis is common and may be the presenting
symptom of the disease. The most typical
presentation is that of testicular involve-
ment, in the form of orchitis/epididymo-or-
chitis, which can be readily attributed to
brucellosis when the epidemiological back-
ground indicates towards this common
zoonotic infection. In endemic areas in
particular, any testicular pathology should
predominantly orientate towards brucello-
sis, and diagnosis (or exclusion) through
appropriate cultures or serology should
be rapid. The available literature on geni-
tourinary brucellosis does not contain any
data from randomized trials, and mainly
consists of few large historical series of
patients. Yet, since genitourinary brucello-
sis is treated as uncomplicated brucellosis
in general, the rules and recommendations
rized as expert guidelines, termed the
“Ioannina Recommendations”), also apply
to genitourinary localization.
Treatment should be based on a com-
bined regimen of doxycycline, adminis-
tered for 6 weeks, with streptomycin, for
2–3 weeks, or rifampicin, administered for
6 weeks. For alternative regimens, see the
following summary of recommendations.
Clinicians should be aware of the poten-
tial for development of abscess or necrotic
testicular forms that may necessitate sur-
gical excision. Relapses, as in brucellosis
in general, can be observed in a minority
of patients, but can be treated with the
initial regimens or minor modifications.
The effect of brucellosis in male fertility
has not been adequately estimated.
Key words: Brucellosis, orchitis,
epididymo-orchitis, genitourinary, doxy-
cycline, rifampicin, aminoglycosides
Chapter | 15 | Special urogenital infections
SUMMARY OF RECOMMENDATIONS
Principles for choosing antibiotics:
1. Regimens are chosen according to
expert guidelines existing for brucello-
sis in general: a combination regimen
is needed, one that should always con-
tain doxycycline, and one that should
be administered in total for at least
6 weeks. The principles of the sug-
gested combinations are efficacy and
patient compliance. Cost issues are not
raised, since expensive combinations
are less efficacious in the first place.
Orchitis/epididymo-orchitis
2. Antibiotic therapy is recommended,
as follows: Doxycycline for 6 weeks
together with streptomycin for 2–3
weeks (GoR A), or doxycycline with
rifampicin for 6 weeks (GoR A), or
doxycycline with gentamicin for at
least a week (GoR A). There is ade-
quate evidence (GoR A) against the
regular use of fluoroquinolone-contain-
ing regimens.
3. Surgical therapy: Warranted in non-
responding abscess formation or in
cases of necrotic testicular lesions
(GoR C).
1. INTRODUCTION
Brucellosis is a zoonotic infection still
endemic in certain parts of Europe and
often imported to non-endemic European
countries also. Genitourinary involve-
ment is common and may be the present-
ing symptom of the disease; thus urology
specialists may be the first clinicians
to encounter the disease and need to be
aware of its presentation, and diagnostic
and therapeutic principles. Since the lat-
ter principles are significantly different
compared to the commonly encountered
960
genitourinary infections, guidelines
applying to the optimal recognition and
treatment of genitourinary brucellosis are
needed in order to minimize inadequately
treated cases.
2. METHODS
A review of the published literature on
genitourinary involvement in brucel-
losis, using PubMed and Scopus, was
performed by the authors using the
keywords “Brucellosis/brucella” AND
“genitourinary/orchitis/epididymits/
epididymo-orchitis/testicular/pelvic”. We
also evaluated large brucellosis series
available in the literature that contained
adequate information on genito-urinary
complications of the disease. Of the ini-
tially retrieved 272 articles which were
then screened by title and abstract,
154 were excluded as being single-case
reports or reports of unusual localizations
of the disease (not comprising a sum of
cases to be statistically evaluated). Of the
remainder articles evaluated through full
text, only six articles (as summarized in
the relevant table) offered adequate data
for extraction of any valuable conclusions.
It should be stated that there are no ran-
domized control trials or meta-analyses
for genitourinary brucellosis published
in the literature. Genitourinary brucello-
sis is a complication that does not need
alteration of the therapeutic regimen,
compared to uncomplicated brucellosis,
as will be subsequently analyzed. Thus,
level of evidence and strength of recom-
mendation in the case of genitourinary
brucellosis are indirectly applied, accord-
ing to general brucellosis treatment
guidelines.
The studies were rated according
to the level of evidence (LoE) and the
grade of recommendation (GoR) using
ICUD standards (for details see Preface)
[1–2].
 Brucellosis: genitourinary involvement
3. DEFINITION OF THE DISEASE
3.1 Overview
Brucellosis is the commonest zoonotic
infection worldwide, and a significant vet-
erinarian, medical, and public health issue
with socioeconomic and political param-
eters [3]. Being prevalent in a series of
animal species, it can be encountered even
in non-endemic areas, imported through
contaminated products or through world-
wide travel [4]. Brucellosis is still endemic
in certain European countries, includ-
ing Greece, Italy, Spain, and Albania and
has furthermore re-emerged in numerous
countries of the Balkans, including Bosnia,
Bulgaria, and the Former Yugoslav
Republic of Macedonia. Imported cases,
acquired through international travel com-
prise the majority of cases encountered in
non-endemic countries as Germany [5].
Worldwide, brucellosis is endemic in the
Middle East [6], Central Asia, parts of
Latin America, the whole Mediterranean
basin, and probably in sub-Saharan
Africa as well [3]. Brucella is comprised
of numerous species with specific animal
host predilection: of these, B. melitensis is
the commonest cause of human disease,
encountered typically in sheep and goats,
while B. abortus (bovine species), B. suis
(pigs but also wildlife animals), B. canis
(canine species), and possibly the provi-
sionally called B. ceti and B. pinnipedialis
(marine species) may also induce human
disease, particularly B. abortus.
3.2 Epidemiology
Human disease is caused either by direct
contact with contaminated animals,
aborted placenta being a particularly infec-
tious source for domestic animal caretakers
and slaughterhouse workers, or through
contaminated animal products, especially
non-pasteurized milk and fresh cheese.
Transmission though can be attributed to
| 15.9 |
direct inoculation through skin and mucosal
abrasions, or through inhalation, since the
pathogen is volatile and environmentally
resistant. The latter mode of transmission is
implicated in brucellosis being the common-
est laboratory acquired infection [7], and its
potential for use as biological warfare [8].
Human brucellosis is characterized by a
variable clinical presentation [9–10] and a
propensity for relapses and chronicity.
3.3 Classifications
Genitourinary involvement in brucellosis
is considered as the presence of confirmed
Brucella infection that is accompanied by
symptoms or signs related to the geni-
tourinary tract. The clinical characteristics
can be, in descending order of frequency,
orchitis, epididymo-orchitis, epididymi-
tis, testicular abscesses, and prostatitis in
males, various forms of abscesses, pelvic
inflammatory disease, pyelonephritis in
females, or pure dysuria in both genders.
3.4 Characterizations
3.4.1 Orchitis/epididymo-orchitis
By far the most frequent form of genitouri-
nary involvement in brucellosis, it has
been reported in 1.6–20% of male patients
with the disease. Typically presents with
scrotal swelling and pain. It may be accom-
panied by fever and may be complicated by
evolution to necrotizing orchitis or abscess
formation. It may be related to oligosper-
mia or aspermia, transient or protracted,
according to one study [11]. Usually
presents in young adults who are occupa-
tionally exposed to the disease. It is often
reported as presenting a more indolent
course compared to epididymo-orchitis of
other causes. It is typically unilateral.
3.4.2 Prostatitis
Brucellosis is possibly a frequent cause
of prostatitis in endemic areas, but
understudied.
961
 Table 1 Selected recent series of patients with Brucella epididymo-orchitis reporting therapeutic regimens and outcome.

962
Chapter

Country of origin/ Number of Overall incidence

Year [Reference] patients (in brucellosis) Therapeutic regimens used Outcome

Saudi Arabia 2001 [19] 26 1.6% DOX/TET-STR or RIF (numbers of patients Duration of treatment 6 weeks
| 15 |

not specified) No failures

1 relapse (regimen not specified)

Spain 2001 [14] 59 Not available DOX-STR (31 patients) Treatment duration 45 days or more in 85% of the patients
DOX-GENT (6) Failure in 13% of DOX-STR, 37% of DOX-GENT/NET, 0% of
DOX-NET (2) DOX-RIF and TMP-SMX-RIF, 29% of TMP-SMX
DOX-RIF (10) Relapse in 19% of DOX-STR, 25% of DOX-GENT/NET, 40%
TMP-SMX (7) of DOX-RIF, 43% of TMP-SMX, and 0% of TMP-SMX-RIF
TMP-SMX- RIF (3)

Greece 2002 [22] 17 11% DOX-RIF 9all patients) Treatment duration 6 weeks
No failures
No relapses

Turkey 2005 [23] 17 9.1% DOX-STR (5 patients) Treatment duration 6–12 weeks (the latter in cases with other
Special urogenital infections

DOX-RIF (6) complications needing protracted therapy)

DOX-CIP (1) No failures
DOX-STR-RIF (2) No relapses
DOX-STR-TMP-SMX (1)
DOX-CIP-STR (1)
DOX-CIP-CTX (1-neurobrucellosis also)

Turkey 2006 [11] 17 12.7% DOX-STR (4 patients) Treatment duration 6–8 weeks
DOX-RIF (10) 2 failures (regimen not specified)
STR-RIF (1) 1 relapse (DOX-STR)
TMP-SMX-STR (1)
CIP-RIF (1)

Spain 2007 [24] 48 7.6% DOX-STR (32 patients) Treatment duration 2 months
TET-STR (1) 1 failure (DOX-RIF, abscess)
DOX-RIF (13) 3 relapses (2 DOX-STR, 1 DOX-RIF)
TMP-SMX-STR or RIF (2)
 Brucellosis: genitourinary involvement
4. CLINICAL EVALUATION/RISK
ASSESSMENT
4.1 Diagnostic and staging
procedures
The diagnosis of orchitis/epididymo-or-
chitis attributed to brucellosis is based
on clinical grounds (presence of scrotal
swelling and/ or pain) and specific bru-
cellosis diagnostic procedures. The latter
include isolation of the microorganism
in blood cultures, serology (agglutina-
tion tests or ELISA) that is evolving or is
accompanied by other compatible clinical
findings, or molecular techniques (PCR).
Urine cultures have an extremely low
specificity for Brucella. Semen cultures
have rarely been reported as positive
[12], as have vaginal exudates cultures
in females [13]. Isolation of Brucella from
epididymal aspirate has been reported
in one of the large brucellar epididymo-
orchitis series [14]. Urine real time PCR
has been recently shown as a rapid,
extremely reliable method of diagnosing
brucellar involvement of the genitouri-
nary tract [15].
4.2 Diagnostic criteria (testing
procedures)
Bacteremia is present in a significant
percentage of genitourinary brucellosis
patients, according to most large patient
series. A negative blood culture does not
rule out the diagnosis though, and appro-
priate serologic tests should always be
performed. Real time PCR, if available,
should allow for rapid diagnosis, although
cost-effectiveness is an issue. Urine cul-
tures are optional: specific processing for
Brucella is needed, and often other path-
ogens co-exist, depending on the regional
flora [16].
4.3 Other issues related to clinical
assessment
Ultrasonography may prove useful in
discriminating between brucellar and
| 15.9 |
other etiologies in vases of orchitis-
epididymo-orchitis. Characteristics that
orientate towards brucellosis include the
presence of heterogenicity, focal echo-
genicity variation, the presence of gran-
ular pattern or septations in hydrocele
fluid, and specific patterns of maximal
and minimal flow velocity in Doppler
ultrasonography [17]. Laboratory testing
is of limited use: the presence of leucocy-
tosis has been suggested as both a posi-
tive and a negative prognostic factor for
brucellosis in numerous studies; urine
sediment is usually benign in cases of
brucellosis, with non-specific changes
(hematuria, aseptic pyuria, proteinuria)
reported in a limited number of patients,
in contrast to non-brucellar cases, where
the urine sediment typically exhibits
abnormalities.
4.4 Discussion
Essentially the diagnosis is clinical and
requires a high index of clinical suspicion.
This is typical in endemic areas, where
clinicians are aware of this complica-
tion of brucellosis. In non-endemic areas
though, one has to orientate through a
thorough patient history towards predis-
posing factors for the disease, particu-
larly international travel.
5. PRINCIPLES OF MANAGEMENT
5.1 Therapy
Series of patients with genitourinary
complications of brucellosis are limited
in the medical literature and practi-
cally refer only to epididymo-orchitis.
Other complications are present as case
reports or isolated patient series, for
example prostatitis [18], or as a minority
of patients with genitourinary complica-
tions in general, for example pyelonephri-
tis [19]. Furthermore, in the case of
epididymo-orchitis, there are no compar-
ative therapeutic trials in the literature.
Data extraction from series of patients
963
Chapter | 15 | Special urogenital infections
with brucellar epididymo-orchitis is dif-
ficult due to the retrospective nature of
the majority of these studies, the hetero-
genicity of the population included, the
heterogenicity of the therapeutic regi-
mens used, the differences in the dura-
tion of administration of the therapeutic
regimens, and the differences in patient
recruitment. Table 1 summarizes the
therapeutic regimens used, their dura-
tion, and the outcome, in selected recent
patient series with epididymo-orchitis
due to brucellosis.
5.1.1 Medication/drug therapy
The therapeutic principles for uncom-
plicated brucellosis include the admin-
istration of a combination regimen
(monotherapy is historically associated
to an increased percentage of relapses
or treatment failures) and the pro-
tracted administration of antibiotics,
that reaches 6 weeks in uncomplicated
brucellosis, but may extend to more than
3 months in severe complications as
spondylitis. A panel of most of the world
experts on the subject recently reviewed
the available therapeutic data and con-
cluded in a form of evidence-based
guidelines for uncomplicated brucellosis,
termed the “Ioannina recommendations”
[20]. These recommendations apply to
most complicated cases of brucellosis,
with the exception of abscesses, spondyli-
tis, central nervous system involvement,
and endocarditis. Thus, theoretically they
also apply to genitourinary complications
such as epididymo-orchitis (Table 2). The
available literature on specific treatment
of epididymo-orchitis patients contains
data too scarce and diverse to be ana-
lyzed in any possible way. The diversity
of the population studied and the ways it
was recruited plays an important role in
this: For example, in the 2001 Spanish
study, the included patients may have
been the patients with the most seri-
ous cases of epididymo-orchitis, or bru-
cellosis in general, that were referred
964
to the reference hospitals participat-
ing in the study. Thus, severe disease
resulted in the need for surgical inter-
ventions in roughly 9% of the patients.
On the other hand, reports from endemic
areas in Greece and Turkey show excel-
lent results with various regimens,
preferably doxycycline with rifampicin,
with no relapses or failures mentioned.
Nevertheless, the drawbacks of this
combination, compared to the combi-
nation of doxycycline with streptomy-
cin, as outlined in Table 2, should also
apply to genitourinary involvement in
brucellosis.
Duration of treatment is not analyti-
cally reported in some of the relevant
patient series: Most of the patients
were cumulatively treated for six weeks,
similarly to duration recommended
for uncomplicated brucellosis. A sin-
gle study refers to treatment duration
of two months and suggests it as opti-
mal. The presented data in this spe-
cific study do not allow for further
clarification of the rationale behind such
a suggestion. Alternative regimens are
included in the evidence-based guide-
lines, and include the administration of
trimethoprim-sulfamethoxazole as a third
component, and the use of fluoroquinolo-
nes as an alternative regimen when other
combinations cannot be used. Regarding
fluoroquinolones in patients with epidi-
dymo-orchitis, such compounds may be
used as an empirical monotherapy before
the suspicion or confirmation of brucel-
losis: in that case, a transient but inad-
equate response may be observed, and
the patient may be at risk of develop-
ment of necrotizing orchitis or abscess,
unless the proper therapeutic regimen
is administered. Whether the addition of
doxycycline to the already administered
fluoroquinolone is adequate therapeuti-
cally in such cases cannot be answered,
due to the absence of published data on
the efficacy of fluoroquinolone-containing
regimens in brucellar epididymo-orchitis
in general.
 Brucellosis: genitourinary involvement | 15.9 |

Table 2 Therapeutic recommendation for epididymo-orchitis attributed to brucellosis.

Treatment Level of Grade of

regimen Dose evidence* recommendation* Comments

DOX-STR DOX: 100 mg twice 1a A Considered the “gold standard.”

daily orally for
6 weeks; STR:
15 mg/kg daily
intramuscularly for
2–3 weeks

DOX-RIF RIF: 600–900 mg 1a A Convenience of the regimen overco-

daily for 6 weeks, mes slight drawbacks concerning the
one morning dose pharmacokinetics of the combination
and the overall outcome.

DOX-GENT GENT: 5 mg/kg 1b A May be considered the preferred

daily parenterally in alternative regimen. Duration of GENT
1 dose for 7 days administration may need modification
for optimal result (different studies
suggest that it may be shortened to
5 days or extended to 14 days).

TMP-SMX- TMP-SMX: 800 + 2a C Recommendation referring to three-

containing 160 mg twice daily drug regimens containing DOX.
regimens for 6 weeks

Quinolone- Ofloxacin: 400 mg 2b A Ofloxacin or ciprofloxacin may be

containing twice daily for 6 used alternatively as second or third
combination weeks; ciprofloxa- agents in combination regimens con-
regimens cin: 500 mg twice taining DOX.
daily for 6 weeks

*level of evidence and grade of guideline recommendation refer to the treatment of uncomplicated brucellosis in general, and are applied to
epididymo-orchitis treatment, based on level of evidence 4 (expert committee reports or opinions or clinical experience of respected authorities).

Adapted from Ariza J, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations.
PLoS Med. 2007;4:e317[20]
Abbreviations: DOX-doxycycline, GENT-gentamicin, RIF-rifampicin, STR-streptomycin, TMP-SMX-trimethoprim-sulfamethoxazole.

5.1.2 Interventions 5.1.3 Follow-up – monitoring –

Surgical treatment is warranted in
the absence of response to antibacte-
rial therapy, or when there is clinical
suspicion of an alternative diagnosis,
including testicular tumors. Abscess for-
mation can be treated with drainage or
orchiectomy. The latter is warranted in
the case of testicular necrosis or if tes-
ticular tumor is a significant diagnostic
possibility. It should be stressed though
that, in the best interest of the patient,
such an invasive procedure, with
major physical and psychological con-
sequences, should be undertaken only
when appropriate antibacterial therapy
has failed to cover an established diag-
nosis of brucellosis.
quality-of-life aspects
As with all uncomplicated brucellosis, a
clinical follow-up is advised, extending to
6 months, or one year, according to others.
The risk of relapse exists during this
period, and can take the form of recurrent
epididymo-orchitis, sometimes affecting
the other testis [21]. Relapses should be
treated identically to the initial infection.
As already mentioned, a single study has
evaluated the impact of genitourinary
brucellosis on male fertility, showing the
development of oligospermia or azoosper-
mia in a subset of patients with brucel-
lar epididymo-orchitis. In the majority of
patients in this study, the phenomenon
reversed upon completion of treatment; it

965
Chapter | 15 | Special urogenital infections
did persist though in a few cases. Thus,
brucellosis can be included in the differ-
ential diagnosis of male infertility. There
are practically no data on pediatric geni-
tourinary brucellosis, thus one cannot
speculate whether orchitis in this age
group may be correlated to subsequent
infertility issues in adult life. The theo-
retically sound, and isolatedly reported,
possibility of bacterial presence in the
semen, allows for suggestion of avoidance
of intercourse, until treatment comple-
tion: there have only been isolated reports
of possible sexual transmission of bru-
cellosis [13], but the theoretic potential
makes this recommendation reasonable.
The data on treatment of other geni-
tourinary complications of brucellosis
are inadequate. In the case of prostatitis
or abscess formation, it seems reason-
able to propose a protracted therapeutic
regimen, or suitable invasive procedures
(drainage, excision). Other complications
should be treated according to the princi-
ples of uncomplicated brucellosis.
5.2 Special populations/exceptions
5.2.1 Concomitant disorders
In the case of co-existent brucellosis
complications, the therapeutic regimen
should be adjusted accordingly, for exam-
ple in the case of co-existing spondylitis.
As already mentioned, there is limited
information regarding genitourinary com-
plications in childhood.
6. FURTHER RESEARCH
Although the available suggested regi-
mens have an efficacy approaching or
surpassing 90 percent, and since the odd
relapse can be readily treated, progress
in genitor-urinary brucellosis should
focus on the optimization of the available
regimens (a process warranted for brucel-
losis in general); in particular the optimal
duration of gentamicin co-administration
966
should be elucidated, since its combina-
tion with doxycycline may emerge as the
most efficacious and convenient one in
the near future. Further validation of
real time PCR of urine samples as a diag-
nostic tool is also warranted. There is
finally a need for evaluation of the effect
of genitourinary brucellosis in males in
semen production and quality; such a
study is strangely missing from medical
literature.
7. CONCLUSIONS
Although brucellar orchitis/epididymo-
orchitis can raise suspicions of more
severe testicular pathology, the rapid rec-
ognition of its infectious origin is feasible,
particularly when taking into account the
assorted epidemiological background of
each patient. Specific recommendations
for the optimal treatment of brucello-
sis, including genitourinary disease, are
available, and clinicians should adhere
to them in order to minimize therapeutic
failures, relapses, or more serious local-
ized complications.
REFERENCES
1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
2. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
3. Pappas G, Papadimitriou P, Akritidis N,
Christou L, and Tsianos EV, The new
global map of human brucellosis. Lancet
Infect Dis, 2006. 6(2): 91–9.
4. Memish ZA and Balkhy HH, Brucellosis
and international travel. J Travel Med,
2004. 11(1): 49–55.
5. Dahouk SA, Neubauer H, Hensel A,
Schoneberg I, Nockler K, Alpers K,
 Brucellosis: genitourinary involvement
Merzenich H, Stark K, and Jansen A,
Changing epidemiology of human brucel-
losis, Germany, 1962–2005. Emerg Infect
Dis, 2007. 13(12): 1895–900.
6. Pappas G and Memish ZA, Brucellosis
in the middle East: a persistent medical,
socioeconomic and political issue.
J Chemother, 2007. 19(3): 243–8.
7. Bouza E, Sanchez-Carrillo C,
Hernangomez S, and Gonzalez MJ,
Laboratory-acquired brucellosis: a
Spanish national survey. J Hosp Infect,
2005. 61(1): 80–83.
8. Pappas G, Panagopoulou P, Christou
L, and Akritidis N, Brucella as a bio-
logical weapon. Cell Mol Life Sci, 2006.
63(19–20): 2229–36.
9. Almuneef M, Memish ZA, Al Shaalan M,
Al Banyan E, Al-Alola S, and Balkhy
HH, Brucella melitensis bacteremia in
children: review of 62 cases. J Chemother,
2003. 15(1): 76–80.
10. Colmenero JD, Reguera JM, Martos F,
Sanchez-De-Mora D, Delgado M, Causse
M, Martin-Farfan A, and Juarez C,
Complications associated with Brucella
melitensis infection: a study of 530
cases. Medicine (Baltimore), 1996. 75(4):
195–211.
11. Akinci E, Bodur H, Cevik MA, Erbay A,
Eren SS, Ziraman I, Balaban N, Atan A,
and Ergul G, A complication of brucel-
losis: epididymo-orchitis. Int J Infect Dis,
2006. 10(2): 171–7.
12. Sozen EE, Aksoy F, Aydin K, Koksal I,
Yilmaz G, and Aksoy HZ, [Isolation of
Brucella melitensis from ejaculate culture
of a brucellosis patient with epididymoor-
chitis]. Mikrobiyol Bul, 2007. 41(3): 465–8.
13. Ruben B, Band JD, Wong P, and
Colville J, Person-to-person transmis-
sion of Brucella melitensis. Lancet, 1991.
337(8732): 14–5.
14. Navarro-Martinez A, Solera J, Corredoira
J, Beato JL, Martinez-Alfaro E, Atienzar
M, and Ariza J, Epididymo-orchitis due
to Brucella mellitensis: a retrospective
study of 59 patients. Clin Infect Dis, 2001.
33(12): 2017–22.
15. Queipo-Ortuno MI, Colmenero JD, Munoz
N, Baeza G, Clavijo E, and Morata P,
Rapid diagnosis of Brucella epididymo-
| 15.9 |
orchitis by real-time polymerase chain
reaction assay in urine samples. J Urol,
2006. 176(5): 2290–3.
16. Pfischner WC, Jr., Ishak KG, Neptune
EM, Jr., Fox SM, 3rd, Farid Z, and El Din
GN, Brucellosis in Egypt; a review of expe-
rience with 228 patients. Am J Med, 1957.
22(6): 915–29.
17. Ozturk A, Ozturk E, Zeyrek F, Onur K,
Sirmatel O, and Kat N, Comparison of
brucella and non-specific epididymo-
orchitis: gray scale and color Doppler
ultrasonographic features. Eur J Radiol,
2005. 56(2): 256–62.
18. Rosales Leal JL, Tallada Bunuel M,
Espejo Maldonado E, Cozar Olmo JM,
Vicente Prados FJ, Martinez Morcillo A,
Buitrago Sivianes S, Rodriguez Herrera
F, and Ortiz Gorraiz M, [Acute prostatitis
as the 1st symptom of brucellosis]. Arch
Esp Urol, 2003. 56(5): 527–9.
19. Akritidis N, Mastora M, and Pappas
G, Genitourinary complications of
Brucellosis. Infect Med, 2002. 19: 384–6.
20. Ariza J, Bosilkovski M, Cascio A,
Colmenero JD, Corbel MJ, Falagas ME,
Memish ZA, Roushan MR, Rubinstein
E, Sipsas NV, Solera J, Young EJ, and
Pappas G, Perspectives for the treatment
of brucellosis in the 21st century: the
Ioannina recommendations. PLoS Med,
2007. 4(12): e317.
21. Akinci E, Bodur H, Erbay CC, and Deveer
M, Brucella abortus epididymo-orchitis
relapsing in the opposite testis 3 months
after antibiotic therapy and development
of aspermia. Int J Infect Dis, 2003. 7(4):
290–1.
22. Papatsoris AG, Mpadra FA, Karamouzis
MV, and Frangides CY, Endemic brucellar
epididymo-orchitis: a 10-year experience.
Int J Infect Dis, 2002. 6(4): 309–13.
23. Yetkin MA, Erdinc FS, Bulut C, and
Tulek N, Epididymo-orchitis due to
brucellosis in central Anatolia, Turkey.
Urol Int, 2005. 75(3): 235–8.
24. Colmenero JD, Munoz-Roca NL,
Bermudez P, Plata A, Villalobos A, and
Reguera JM, Clinical findings, diagnos-
tic approach, and outcome of Brucella
melitensis epididymo-orchitis. Diagn
Microbiol Infect Dis, 2007. 57(4): 367–72.
967
|15.10|

Echinococcus/hydatid disease:
genitourinary involvement
Georgios Pappas, MD1, Ziad A Memish, MD, CIC, FRCPC, FACP, FIDSA2
1
Institute of Continuing Medical Education of Ioannina, H. Trikoupi 10, 45333, Ioannina, Greece
E-mail: gpele@otenet.gr
2
Director Gulf Cooperation Council (states) Center for Infection Control,
Executive Director Infection Prevention & Control Program, King Abdulaziz Medical City, Riyadh, KSA
Adjunct Professor Department of medicine, Division of Infectious Diseases
University of Ottawa, Canada,
E-mail: zmemish@yahoo.com

ABSTRACT be recognized due to it exerting space-

Genitourinary hydatid disease equals
renal infection by Echinococcus granu-
losus, since other localizations are lim-
ited to isolated case reporting. Although
there exist certain series of patients with
renal echinococcosis published in the lit-
erature, many of them are of historical
value and not catching up with recent
advance in the treatment of hydatid dis-
ease in general. Renal echinococcal dis-
ease comprises 0.4 to 4% of the total
hydatid disease burden. Renal hydatid
disease refers to a, typically unilateral,
renal cyst with unique characteristics
that usually allow its rapid and safe rec-
ognition with novel radiologic diagnostic
approaches. Confirmation of the diagno-
sis can be achieved through numerous
serologic approaches. Renal echinococco-
sis can be an accidental finding or it can
occupying pathology, and more rarely
through the, pathognomonic, hydatiduria.
The available therapeutically oriented
series on renal echinococcosis are old
and only surgically oriented. Experience
with medical intervention through the
use of albendazole in renal hydatid dis-
ease is absent, and conclusions can only
be extrapolated through what is known
for hepatic hydatid disease. Depending
on the cyst size and the assorted array of
symptoms, a surgical approach with cys-
tectomy/pericystectomy or, in larger cysts,
with partial or total nephrectomy, is advo-
cated. Smaller asymptomatic cysts can
simply be followed-up. Pre-operative defi-
nite diagnosis is important, in order for
the surgeon to avoid rupture of the cyst,
which may lead to anaphylactic shock
and peritoneal seeding. There are no data
on the use of percutaneous approaches as
 Echinococcus/hydatid disease: genitourinary involvement
PAIR in renal echinococcosis, so its use
cannot be advocated at present.
Key words: hydatid disease, echinococ-
cus granulosus, surgical, albendazole,
PAIR, renal echinococcosis
SUMMARY OF RECOMMENDATIONS
Principles for avoiding surgical
therapy
1. Small, asymptomatic cysts can be
adequately followed up through
sequential ultrasonography.
2. If ultrasonographic characteristics
show a viable cyst that is expanding,
there is theoretical ground for use of
albendazole (GoR C).
Surgical approaches
3. Cystectomy/pericystectomy is advo-
cated for smaller cysts (GoR C).
4. Larger cysts or cases which have
affected the involved kidney’s viability
should be treated with partial or total
nephrectomy (GoR C).
5. The use of percutaneous approaches
such as PAIR, with or without adju-
vant albendazole, in spite of the rel-
evant experience in hepatic hydatid
disease, cannot be advocated at
present in renal echinococcosis due to
the absence of available data (GoR D).
1. INTRODUCTION
Genitourinary hydatid disease practically
refers to renal echinococcal involvement,
since all other localizations of Echinococcus
in the genitourinary tract are limited to
random case reports. Echinococcus granu-
losus accounts for practically all the cases
of renal echinococcosis; Echinococcus mul-
tilocularis, the etiological agent of, the
graver in prognosis, alveolar echinococ-
cosis, has only isolatedly been implicated
| 15.10 |
in genitourinary disease in the available
literature: A Turkish series reported a
case with concomitant hepatic and renal
alveolar echinococcosis [1], (and also a case
of ovarian involvement), while isolated
reports also exist in non-English medical
literature [2]. Indirect renal involvement
in alveolar echinococcosis, in the form of
amyloidosis [3], is beyond the scope of this
review.
The importance of renal hydatid dis-
ease may seem diminished, compared
to past decades, since the nature of a
renal cystic mass can nowadays be read-
ily differentiated through sophisticated
imaging techniques, and the diagnosis
of hydatid disease can be outlined pre-
operatively in most cases. Furthermore,
the progress made in surgical interven-
tions has allowed for minimally amputa-
tion procedures to evolve, augmented by
the appropriate use of chemoprophylaxis.
Nevertheless, eradication of E. granu-
losus remains futile, and international
travel allows for the disease (more pre-
cisely, the patients) to circulate world-
wide: thus the disease, and its potential
mis-diagnosis for tumor-like lesions, is
still relevant today.
2. METHODS
A review of the published literature on
genitourinary involvement in echinococ-
cal disease, using PubMed and Scopus,
was performed by the authors. Keywords
used were “echinococcus or echinococ-
cal or hydatid or hydatidosis” and “geni-
tourinary or urinary or kidney or renal”.
All retrieved articles were evaluated,
although case reports, articles without
abstracts, and articles not describing
explicitly the therapeutic process fol-
lowed, were excluded. Of the 352 articles
screened by abstract, 74 were further
evaluated through their full text, but only
the ones subsequently referenced (seven
in total summarized in the relevant Table)
were considered eligible and inclusive of
969
Chapter | 15 | Special urogenital infections
relevant information. Additional reviews
on the subject of hydatid disease were
evaluated for further information. Data on
treatment were sought in these articles.
It should be stated that there are no ran-
domized control trials or meta-analyses
for renal hydatid disease, the most com-
mon form of genitourinary echinococcal
involvement, published in the literature.
It should also be stated that the majority
of the patient series with renal hydatid
disease include patients that data as back
as the 1960s, when modern imaging and
serologic diagnosis, as well as invasive
therapeutic procedures were not available.
Level of evidence and strength of rec-
ommendation: The studies were rated
according to the level of evidence and the
strength of recommendations. The Oxford
Centre for Evidence Based Medicine
have produced a widely accepted adapta-
tion of the work of the Agency for Health
Care Policy and Research [4].The ICUD
consultations use a modified version of
the Oxford system which can be directly
“mapped” onto the Oxford system [5].
3. DEFINITION OF THE DISEASE
3.1 Overview
Cystic echinococcosis is caused by the
tapeworm E. granulosus. Larvae of the
parasite give rise to the hydatid cysts that
are characteristics of the disease, multi-
layered cysts that grow slowly, predomi-
nantly in the liver or the lungs. Canines,
such as dogs and wolves are the definite
hosts: environmentally stable eggs are
shed after development and maturation in
the canine intestine, and are subsequently
ingested by domestic ungulates, such as
sheep and cattle or camels (or human).
After ingestion, a larva is released by the
egg, enters through the intestinal wall
into the circulation, and is usually cap-
tured by hepatic or pulmonary filters.
Subsequently a multilayered cyst devel-
ops and gradually grows. The majority of
970
the cysts grow at diameter rate <15 mm/
year, needing 3–6 years on average to
reach egg-size [6]. The internal layer is
the germinal one, from which daughter
cysts emerge, and it is surrounded by an
acellular laminated membrane, which
in turn is surrounded by a fibrous layer
derived by the host, the pericyst, that can
be partly, or totally, when the cyst is no
longer viable, calcified. The hydatid cyst is
filled with scoleces and a hyaline fluid [6].
3.2 Epidemiology
Human is an accidental intermediate dead-
end host in the life cycle of E. granularis.
Direct contact with infected hosts (defi-
nite, such as dogs, or intermediate, such as
sheep) or ingestion of food contaminated
with shed eggs (for example non-washed
vegetables) is incriminated for transmis-
sion to humans. Thus, it is not surpris-
ing that the disease is more prevalent
in rural regions and communities heav-
ily involved in sheep raising. The disease
remains a public health problem in the
Mediterranean, North and Northeastern
Africa, Central Asia including China, the
Middle East, Latin America, and Oceania
[7]. The slow growth of the hydatid cysts
though, which may need years to develop
any significant symptoms and be subse-
quently recognized, means that, in case
of immigrants from areas endemic to the
pathogen, the disease may pose a differ-
ential diagnostic problem for clinicians not
familiar with the disease.
3.3 Classifications
Genitourinary involvement in cystic
echinococcosis is considered as the pres-
ence of a hydatid cyst in any part of the
genitourinary tract. The vast majority of
cases refer to renal hydatidosis, which
can develop in any part of the kidney.
Isolated reports of hydatid cysts of the
prostate, bladder [8], testis, seminal vesi-
cles, and the female genitals also exist,
but are too rare for appropriate guidelines
 Echinococcus/hydatid disease: genitourinary involvement
on recognition and treatment to develop.
Renal echinococcal disease comprises 0.4
to 4% of the total hydatid disease burden.
The lowest percentage has been reported
in a Chinese study [9], and the highest in
a Tunisian one [10]. The median percent-
age is around 2% in most studies.
3.4 Characterisations
3.4.1 Renal hydatid cyst
It can be the solitary manifestation of
hydatid disease, or accompanied by other
hydatid cysts in the liver or the lungs. It
almost always presents unilaterally. It
is usually solitary and less often multi-
ple cysts can be detected intrarenally. It
can be located everywhere in the kidney,
although most series report a slight pre-
dominance for the superior pole. It can
grow in size giving the false positive radio-
logical view that it extends extrarenally,
but in most cases remains subcapsular.
Accumulated pressure inside the cyst can
result in rupture, most often into the col-
lecting system, or more rarely retroperi-
toneally or into the peritoneal cavity. If
undetected, progressive growth can lead to
eventual destruction of the involved kidney
due to mechanical pressure. A slight pre-
dominance of male patients can be traced
in the available patient series, although
this may simply reflect the greater per-
centage of males occupationally exposed
to the pathogen. In most series, median
patient age lies in the fourth decade of
life; taking into account that the growth
of the hydatid cyst to a symptom-causing
size requires years, one could specify the
median period of infection in late child-
hood or early adulthood: this though can-
not be ascertained, since growth rates of
each individual cyst do not follow a specific
pattern, but are rather decided by indig-
enous characteristics of the parasite, as
well as anatomical details of the infected
area. Renal hydatidosis in childhood is
rarely reported [11–12]. Hydatid cysts
can be asymptomatic, detected inciden-
tally during imaging for other indications,
| 15.10 |
or can cause symptoms related to their
growth (mass effect): Lumbar pain or a
visible abdominal mass are the two most
common presenting symptoms reported.
Renal colic, usually accompanied by
hydatiduria, is also reported in varying
frequency. More rare symptoms include
digestive complaints, gross hematuria, or
fever, in the case of secondary infection of
the cyst. Hydatiduria: Upon rupture of a
hydatid cyst in the collecting system, pas-
sage of the cyst content, including scoleces
and cystic debris into the urine, gives rise
to a pathognomonic for renal echinococco-
sis state of passage in the urine of a grape-
like material.
4. CLINICAL EVALUATION/RISK
ASSESSMENT
4.1 Diagnostic and staging
procedures
The differential diagnosis of a renal cystic
mass is complex. Whether an incidental
finding or causative of space-occupying
symptoms, imaging studies allow for
the characterization of the cystic lesion
and, modern techniques at least, allow
for orientation towards the diagnosis of
hydatid disease in the proper settings.
The role of imaging techniques is para-
mount in diagnosis: Clinical symptoms
are typically non specific, apart from
the presence of hydatiduria which is
pathognomonic for renal echinococcosis.
Serologic diagnosis has significantly pro-
gressed in recent years; in the case of
renal echinococcal disease, most serologic
studies offer limited information due to
inclusion of patients of previous decades.
Extrapolation of the available experi-
ence for hepatic hydatidosis in this case
though is theoretically sound.
4.2 Diagnostic criteria (testing
procedures)
Of the clinical symptoms, as already
mentioned hydatiduria is pathognomonic
971
Chapter | 15 | Special urogenital infections
of the disease. The Casoni skin test has
been the mainstay of diagnostic orien-
tation in the past, an experience also
reflected in the renal echinococcosis lit-
erature. It is, or should be, abandoned
nowadays. Inspection of urine samples
for the presence of scoleces, hooklets or
fragments of the parasitic membrane has
been performed in a few cases of some of
the relevant studies; the presence of such
elements is obviously pathognomonic
and implies rupture of the cyst into, or
at least communication with the collect-
ing duct [13–14]. Peripheral blood eosi-
nophilia is present in roughly half the
patients: in endemic areas it may be a
strong indicator of the parasitic nature of
a renal cyst, but parasitic disease may be
attributed to a wide array of pathogens.
Positive serology is a strong indicator
for the presence of echinococcal disease.
Various diagnostic serologic techniques
have been developed, none though can
be considered as the gold-standard [7].
ELISA and immunobloting, indirect flu-
orescence, and indirect hemagglutina-
tion tests have been used with varying
sensitivity and specificity. False positive
results can occur in cases of other para-
sitic infections, particularly cysticerco-
sis. Most tests target antigens derived by
the hydatid cyst fluid. Numerous candi-
date antigens, aiming at improving spe-
cificity, are currently under investigation
[15–16]. It should be noted that data on
the specificity and sensitivity of these
assays are practically based on the expe-
rience with hepatic echinococcosis; the
use of these tests in series of renal echi-
nococcosis patients, as reported in the
literature, is scarce. For example, the
utility of counter immunoelectrophoresis
in a large patient series was evaluated
in only 7 patients in a 34-patients series,
and only in 2 out of 20 in another [13,
17]. Similarly, indirect hemagglutination
was tested in 18/23 and 19/178 patients
in other series [10, 18].
Plain abdominal x-rays can show calci-
fications in the renal area, but this finding
972
is non-specific. Most patients series report
on the use of intravenous and retrograde
pyelography, as well as arteriography;
these methods though are of no use in the
era of modern imaging: Ultrasonography
can provide a rapid broad description of
the lesion, and orientate toward hydatid
disease in specific situations [19]: for
example the “waterlily sign”, subsequent
to the detachment of the laminated mem-
brane, is pathognomonic. On experienced
hands, the disease cannot only be con-
firmed but also classified according to the
scheme proposed by WHO/OIE (World
Health Organization/ Office International
des Epizooties) for hepatic cystic echino-
coccosis: Activity and fertility of the cyst
can thus be evaluated [20]. The most
important diagnostic advance though is
the ability of computerized tomography
(CT) to accurately depict details of the
cyst and its surroundings. The increased
density of the hydatid membrane which
enhances after intravenous administra-
tion of contrast agent is also considered
pathognomonic for hydatidosis. The den-
sity of the daughter cysts is also charac-
teristically lower than that of the original
cyst [21]. Magnetic resonance imaging
has only been isolatedly evaluated and
any particular imaging advantages com-
pared to CT have not been shown.
4.3 Discussion
Overall, the diagnostic possibility of renal
hydatid disease should be taken into
account when a cystic lesion of the kidney
is present, particularly in endemic areas.
Ultrasonographic and CT characteristics
can subsequently orientate towards such
a diagnosis, and serology, preferably by
two of the available methods in order to
increase specificity, can further confirm
the diagnosis without the need for inva-
sive procedures. Diagnostic percutaneous
paracentesis of a renal echinococcal cyst
has only been performed in rare cases
when the diagnosis had not been consid-
ered in the first place. It should always be
 Echinococcus/hydatid disease: genitourinary involvement
avoided upon suspicion of hydatid disease,
due to the risk of severe anaphylactic
reactions that may lead do death in case of
spillage of hydatid fluid in the peritoneal
cavity, and the risk for seeding of echinoc-
occal disease in other sites.
5. PRINCIPLES OF MANAGEMENT
5.1 Therapy
Table 1 reviews selected patient series
with renal echinococcal involvement and
the therapeutic approach applied, as well
as potential consequences, when reported.
It should be once more noted that most of
these series include patients diagnosed
prior to the increased differential diagnos-
tic opportunities offered by modern imag-
ing and serology, and thus their results
may be biased, regarding the invasive-
ness of the procedures used.
It should also be noted that the natural
history of renal echinococcal disease has
been inadequately studied. The majority
of the patients included in these series
was symptomatic and was thus subject
to a therapeutic approach. On the other
hand, a “wait and observe” approach,
with imaging follow-up could be advo-
cated in cases where the disease is dis-
covered accidentally.
Finally, regarding medical treatment, it
should be noted that experience with the
use of benzimidazole derivatives in renal
disease is limited to absent. Whether
their use can replace invasive interven-
tions or the “wait and observe” approach
is further discussed on purely theoretical
grounds.
5.1.1 Medication/drug therapy
Albendazole and mebendazole are the
two benzimidazole derivatives that have
been used in cystic echinococcal disease in
general. Of these, the former is the most
extensively studied. It is administered
orally, 10–15 mg.kg of body weight in two
divided doses, for a period extending to 3–6
| 15.10 |
months, and has been suggested as an opti-
mal treatment for inoperable disease or in
cases of systemic involvement (presence of
cysts in two or more organs). It is reported
as inducing 10–30% cure (disappearance
of the lesion) and 50–70% improvement
(smaller size of the cyst or degeneration-
non-viable cyst). The relapses, reported in
14–25% of the cases, can be retreated. A
recent review of the published experience
with albendazole in cystic echinococcosis
[22] concluded that: i. albendazole is supe-
rior to placebo (or for that matter “wait and
observe” approach) in inoperable cases, ii.
is successful as a pre-adjuvant medication
in degenerating hydatid cysts prior to sur-
gery (miminizing thus operational risks),
and iii. when used in conjunction with
the PAIR (Puncture, Aspiration, Injection
of scolicidal agent, and Re-aspiration,
see later) approach it is superior to PAIR
alone or albendazole alone. What is not
know though, according to this review, is
whether albendazole is clearly superior to
mebendazole, whether the combination of
albendazole and PAIR is superior to that
of albendazole and surgery, and whether
the combination of albendazole and prazi-
quantel is superior to albendazole alone
(when efficacy and toxicity are taken into
account). Praziquantel increases by four-
fold the concentrations of albendazole sul-
foxide, which is the scolicidal metabolite.
A recent study compared the co-adminis-
tration of albendazole and praziquantel
alone with their use in conjunction with
surgery and concluded that no significant
differences existed between the two groups
[23]. The major side effects of albendazole
include nausea, hepatotoxicity, potentially
non-reversible neutropenia, and alopecia.
The suggested dose for mebendazole
is 40–50 mg/kg of body weight, in three
divided doses.
5.1.2 Interventions
Surgical interventions are the thera-
peutic mainstay in all renal hydatidosis
series reviewed in Table 1. Conservative
973
Chapter | 15 | Special urogenital infections

Table 1 Selected patient series on renal hydatid disease and therapeutic interventions.

Country/Year Number of
[reference] patients Therapeutic interventions Comments

Morocco 1993 [31] 45 Nephrectomy (7 patients)

Partial cystopericystectomy (38)

Spain 1994 [32] 22 Nephrectomy (10 patients) Co-administration of mebendazole in 2

patients
Partial nephrectomy (5)
Cyst excision (4)
No intervention (3)

Spain 1997 [13] 34 Nephrectomy (21 patients)
Partial nephrectomy (5)
Cyst excision/pericystectomy (7)
Pectunaeous approach for diagnostic
purposes in 4 patients
1 episode of anaphylaxis
2 episodes of seeding
2 secondary nephrectomies (due to
urinary fistula)

Tunisia 2001 [10] 178 Nephrectomy (44 patients) 12 episodes of urinary fistula,
and 5 episodes of infection of
Cyst excision/pericystectomy (134)
remnant cavity, requiring in total
2 secondary nephrectomies
2 episodes of recurrence

Tunisia 2001 [33] 147 Nephrectomy (20 patients) 2 episodes of urinary fistula,
and 1 episode of suppuration of
Partial cystopericystectomy (122)
remnant cavity
Abstention (5)

Morocco 2002 [34] 34 Nephrectomy (6 patients)

Partial cystopericystectomy (23)
Pericystectomy (5)

Turkey 2003 [17] 20 Nephrectomy (13 patients)

Cystectomy and marsupialization (6)
Nothing (1)

Jordan 2004 [14] 8 Nephrectomy (5 patients)

Partial nephrectomy (1)
Cyst excision (2)

approaches include cystectomy and peri-
cystectomy, and require a preoperative def-
inite diagnosis of the hydatid nature of the
cyst, through specific imaging and serology.
This is important in order for the surgeon
to undertake all measures in order to avoid
spillage of the cyst content during surgery:
Serious anaphylactic reactions, resulting
even to death, have been reported in renal
hydatidosis, while the risk of seeding of
Echinococcus into the peritoneal cavity is
also a major concern. Even in large cysts
exerting significant pressure in the kidney,
these procedures have been related to sub-
sequent kidney re-expansion and absence
of sequelae in the future. Partial and total
nephrectomy were the procedures of choice
in most patients from past decades in renal
hydatidosis series, mainly due to the diag-
nostic uncertainty regarding the nature of

974
 Echinococcus/hydatid disease: genitourinary involvement
the cyst, due to the more primitive imag-
ing techniques available. Nowadays, total
nephrectomy should be the optimal thera-
peutic approach in cysts too large to be
handled otherwise, or when the involved
kidney is considered non-viable. The avail-
able data for a percutaneous approach in
echinococcal disease of the kidney are lim-
ited [24–26]: In one of these series, focus-
ing on univesicular cysts, an approach
similar to PAIR was used. In general, the
risks of percutaneous aspiration are simi-
lar to these of cyst rupture during open
surgery, i.e. spillage and anaphylaxis
or secondary seeding. PAIR (Puncture,
Aspiration, Injection of scolicidal agent,
and Re-aspiration) has emerged as the
optimal therapeutic approach in many
cases of hepatic hydatidosis, offering clini-
cal efficacy and fewer complications, as
well as minimizing the hospitalization
duration and patient sequelae compared
with more invasive procedures. Typically
PAIR is accompanied by pre- and post-
intervention use of albendazole, starting
usually 24 hours prior to PAIR and con-
tinuing for 15–30 days. A meta-analysis
showed that the combination of PAIR and
albendazole or mebendazole was superior
and associated with less morbidity, mor-
tality, and hospitalization duration than
surgical intervention in liver hydatid cysts
[27]. A significant risk with PAIR in liver
hydatidosis is the existence of communica-
tion between the biliary tree and the cyst,
which may lead to sclerosing cholangiitis
after instillation of the scolicidal agent.
There is no information on the potential
effect of the scolicidal agent in the collect-
ing duct in cases of communicating renal
cysts.
In conclusion, there is insufficient evi-
dence regarding the optimal treatment of
renal hydatid disease, due to the relative
rarity of the disorder and the fact that a
significant percentage of literature data is
derived from past decades, when sophis-
ticated diagnostic and interventional
procedures were limited. The current
available evidence is mainly extrapolated
| 15.10 |
from the experience with liver echinoc-
occosis. Thus, upon discovery of a renal
cyst with the imaging characteristics of
hydatid disease, and upon serological con-
firmation of the diagnosis, preferably with
two of the available methods, the subse-
quent approach depends on the viability
of the involved kidney and the severity
of symptoms. Interventional procedures,
either cystectomy/pericystectomy or total/
partial nephrectomy should be advocated
in large cysts exerting significant pathol-
ogy. At present, experience with PAIR in
renal hydatidosis is limited to advocate
it in an evidence-based manner in renal
hydatidosis; centers with experience on
the subject though should further experi-
mentally explore its utility. Renal hydatid
cysts that are accidentally discovered and
exert no effect on kidney viability and no
or minor symptoms, can be followed-up by
ultrasound for evaluation of activity and
fertility and the need for potential inter-
vention. These cases can also be treated
with albendazole, particularly when other
localizations are also present, expecting
disappearance, shrinkage, or degeneration
of the cyst in a considerable percentage of
patients. The addition of praziquantel to
enhance albendazole scolicidal effect can-
not be definitely advocated at present. An
albendazole course can be tried in patients
who are candidate for surgery also, if there
is no indication of immediate surgery and
if the kidney is viable, aiming at minimiz-
ing cyst size and achieving a less extensive
surgical procedure in the future.
The therapeutic options in renal hydati-
dosis are summarized in Table 2.
5.1.3 Follow-up – monitoring –
quality-of-life aspects
Although immunological follow-up has
been useful after cyst removal [28],
the mainstay of follow-up for detection
of residual disease, seeding of the dis-
ease during surgery, recurrence, or re-
appearance of hydatid cysts in other
organs, is imaging, and particularly
975
Chapter | 15 | Special urogenital infections
Table 2 Therapeutic options in renal hydatidosis and level of evidence/strength of recommendation.
Therapeutic module
Nephrectomy
Cystectomy/Pericystectomy and
modifications
PAIR (Puncture, Aspiration, Injection of
scolicidal agent, and Re-aspiration)
Albendazole
PAIR and albendazole
ultrasonography in the case of renal
hydatidosis. Preservation of renal anatom-
ical integrity is the major pre-requisite in
treatment planning in cases of renal echi-
nococcal disease, and should be the major
concern in therapeutic planning.
5.2 Special populations/exceptions
5.2.1 Concomitant disorders
Albendazole is potentially teratogenic
and thus its use in pregnancy should be
preferably avoided. Echinococcosis in
pregnancy is an even rarer entity requir-
ing critical decisions applying to mother
and fetal health [29]. A single case of
renal hydatidosis in pregnancy has been
reported in the literature [30].
6. FURTHER RESEARCH
Any further research will predominantly
need large series of patients, who will be
diagnosed readily through the sophis-
ticated radiologic techniques currently
available. Given the disease’s predomi-
nance in the developing world and the
associated administrative difficulties in
optimal medical practice in this area,
one cannot expect further progress in the
near future. What warrants further study
though is whether the use of minimally
invasive procedures, such as PAIR, in con-
junction with albendazole or not, may offer
optimal responses in renal echinococcosis,
as the ones observed in hepatic disease.
976
Level of evidence Grade of recommendation
3 C
3 C
– D
3 C
– D
7. CONCLUSIONS
Prompt recognition of renal hydatid
disease is feasible due to advances in
imaging, and of paramount importance
prior to any therapeutic intervention in
order to avoid intra-operative rupture.
Although experience in renal echinococ-
cosis is mainly historical or extrapolated
from hepatic echinococcosis, an experi-
enced surgeon can guarantee an optimal
outcome, even with preservation of the
involved kidney’s function, if surgical
intervention is needed.
REFERENCES
1. Gundogdu C, Arslan R, Arslan MO, and
Gicik Y, [Evaluation of cystic and alveolar
echinococcosis cases in people in Erzurum
and surrounding cities.]. Turkiye
Parazitol Derg, 2005. 29(3): 163–166.
2. Mikhailichenko VV, Fesenko VN, and
Aletin RR, [Alveolar Echinococcus
(alveococcus) of the kidney]. Vestn Khir
Im I I Grek, 2000. 159(1): 97–9.
3. Ali-Khan Z and Rausch RL,
Demonstration of amyloid and immune
complex deposits in renal and hepatic
parenchyma of Alaskan alveolar hydatid
disease patients. Ann Trop Med Parasitol,
1987. 81(4): 381–92.
4. U.S. Department of Health and Human
Services Public Health Service Agency for
Health Care Policy and Research, 1992:
115–127.
 Echinococcus/hydatid disease: genitourinary involvement
5. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
6. Eckert J and Deplazes P, Biological,
epidemiological, and clinical aspects of
echinococcosis, a zoonosis of increasing
concern. Clin Microbiol Rev, 2004. 17(1):
107–35.
7. McManus DP, Zhang W, Li J, and
Bartley PB, Echinococcosis. Lancet,
2003. 362(9392): 1295–304.
8. Gossios KJ, Kontoyiannis DS,
Dascalogiannaki M, and Gourtsoyiannis
NC, Uncommon locations of hydatid
disease: CT appearances. Eur Radiol,
1997. 7(8): 1303–8.
9. Menghebat L, Jiang L, and Chai J,
A retrospective survey for surgical cases of
cystic echinococcosis in the Xinjiang Uygur
Autonomous Region, PRC (1951–90), in
Compendium on cystic echinococcosis with
special reference to the Xinjiang Uygur
Autonomous Region, the People’s Republic
of China, Andersen FL, Chai J-j, and
Liu F-j, Editors. 1993, Brigham Young
University: Provo, Utah. p. 135–145.
10. Zmerli S, Ayed M, Horchani A, Chami
I, El Ouakdi M, and Ben Slama MR,
Hydatid cyst of the kidney: diagnosis and
treatment. World J Surg, 2001. 25(1):
68–74.
11. Tryfonas GJ, Avtzoglou PP, Chaidos C,
Zioutis J, Gavopoulos S, and Limas C,
Renal hydatid disease: diagnosis and
treatment. J Pediatr Surg, 1993. 28(2):
228–31.
12. Mavridis G, Livaditi E, and
Christopoulos-Geroulanos G,
Management of hydatidosis in children.
Twenty-one year experience. Eur J Pediatr
Surg, 2007. 17(6): 400–3.
13. Angulo JC, Sanchez-Chapado M, Diego A,
Escribano J, Tamayo JC, and Martin L,
Renal echinococcosis: clinical study of 34
cases. J Urol, 1997. 157(3): 787–94.
14. Abu-Qamar AA, Aljader KM, and
Habboub H, Isolated renal hydatid
disease: experience at the queen rania
urology center, the king hussein medical
center. Saudi J Kidney Dis Transpl, 2004.
15(2): 149–54.
| 15.10 |
15. Carmena D, Benito A, and Eraso E,
Antigens for the immunodiagnosis of
Echinococcus granulosus infection: An
update. Acta Trop, 2006. 98(1): 74–86.
16. Zhang W and McManus DP, Recent
advances in the immunology and
diagnosis of echinococcosis. FEMS
Immunol Med Microbiol, 2006.
47(1): 24–41.
17. Gogus C, Safak M, Baltaci S, and
Turkolmez K, Isolated renal hydatidosis:
experience with 20 cases. J Urol, 2003.
169(1): 186–9.
18. Kaya K, Gokce G, Kaya S, Kilicarslan
H, Ayan S, and Gultekin EY, Isolated
renal and retroperitoneal hydatid cysts: a
report of 23 cases. Trop Doct, 2006. 36(4):
243–6.
19. Hasni Bouraoui I, Jemni H, Arifa N, Chebil
M, Ben Sorba N, and Tlili K, [Imaging of
renal hydatid cyst based on a series of 41
cases]. Prog Urol, 2006. 16(2): 139–44.
20. Pawlowski ZS, Eckert J, and DA V,
Echinococcosis in humans: clinical
aspects, diagnosis and treatment. WHO/
OIE Manual on echinococcosis in humans
and animals. 2001, Paris: World Health
Organization.
21. Karabekios S, Gouliamos A, Kalovidouris
A, Vlahos L, Papavasiliou C, and Sakkas
J, Features of computed tomography in
hydatid cysts of the urinary tract. Br J
Urol, 1989. 64(6): 575–8.
22. Falagas ME and Bliziotis IA, Albendazole
for the treatment of human echinococcosis:
a review of comparative clinical trials. Am
J Med Sci, 2007. 334(3): 171–9.
23. Haralabidis S, Diakou A, Frydas S,
Papadopoulos E, Mylonas A, Patsias A,
Roilides E, and Giannoulis E, Long-term
evaluation of patients with hydatidosis
treated with albendazole and praziquan-
tel. Int J Immunopathol Pharmacol, 2008.
21(2): 429–35.
24. Goel MC, Agarwal MR, and Misra A,
Percutaneous drainage of renal hydatid
cyst: early results and follow-up. Br J
Urol, 1995. 75(6): 724–8.
25. Baijal SS, Basarge N, Srinadh ES, Mittal
BR, and Kumar A, Percutaneous manage-
ment of renal hydatidosis: a minimally
invasive therapeutic option. J Urol, 1995.
153(4): 1199–201.
977
Chapter | 15 | Special urogenital infections
26. Akhan O, Ustunsoz B, Somuncu I, Ozmen
M, Oner A, Alemdaroglu A, and Besim
A, Percutaneous renal hydatid cyst treat-
ment: long-term results. Abdom Imaging,
1998. 23(2): 209–13.
27. Smego RA, Jr., Bhatti S, Khaliq AA,
and Beg MA, Percutaneous aspiration-
injection-reaspiration drainage plus
albendazole or mebendazole for hepatic
cystic echinococcosis: a meta-analysis.
Clin Infect Dis, 2003. 37(8): 1073–83.
28. Zhang W, Li J, and McManus DP,
Concepts in immunology and diagnosis of
hydatid disease. Clin Microbiol Rev, 2003.
16(1): 18–36.
29. Rodrigues G and Seetharam P,
Management of hydatid disease
(echinococcosis) in pregnancy. Obstet
Gynecol Surv, 2008. 63(2): 116–23.
30. Manterola C, Espinoza R, Munoz
S, Vial M, Bustos L, Losada H, and
978
Barroso M, Abdominal echinococcosis
during pregnancy: clinical aspects and
management of a series of cases in Chile.
Trop Doct, 2004. 34(3): 171–3.
31. Benjelloun S and Elmrini M, [Hydatid
cyst of the kidney (apropos of 45 cases)].
Prog Urol, 1993. 3(2): 209–15.
32. Rousaud F, Algaba F, Donate T,
Roda M, Barcelo P, and Del Rio
G, Hydatid renal cyst disease:
22 Cases reviewed. Nefrologia, 1994.
14:663–70.
33. Horchani A, Nouira Y, Kbaier I, Attyaoui
F, and Zribi AS, Hydatid cyst of the
kidney. A report of 147 controlled cases.
Eur Urol, 2000. 38(4): 461–7.
34. Ameur A, Lezrek M, Boumdin H,
Touiti D, Abbar M, and Beddouch A,
[Hydatid cyst of the kidney based on
a series of 34 cases]. Prog Urol, 2002.
12(3): 409–14.
 Chapter |16|

Classification of urinary
tract infections
Chair: Truls E. Bjerklund Johansen

CHAPTER OUTLINE
16.1 Critical review of current definitions of urinary
tract infections and proposal of an EAU/ESIU
classification system 980
|16.1|

Critical review of current

definitions of urinary tract
infections and proposal of an
EAU/ESIU classification system
Truls E. Bjerklund Johansen1, Henry Botto2, Mete Cek3, Magnus Grabe4, Peter Tenke5,
Florian M.E. Wagenlehner6, Kurt G. Naber7
1
Urology Department of Urology, Århus University Hospital, Skejby, Århus University, Århus, Denmark
2
Department of Urology, Hopital Foch, Suresnes Cedex, France
3
Department of Urology, Taksim Teaching Hospital Istanbul, Istanbul, Turkey
4
Department of Urology, Malmö General Hospital, University of Lund, Malmö, Sweden
5
Department of Urology, Jahn Ference Del-Pesti Korhaz, Budapest, Hungary
6
Department of Urology, University of Giessen, Giessen, Germany
7
Technical University of Munich, Munich, Germany
Corresponding Author: Truls E. Bjerklund Johansen, MD, PhD
Chairman and Professor, Urology Department, Århus University Hospital, Skejby, Aarhus University
Brendstrupgårdvej 100, DK-8200 Århus N, Denmark
Tel office: (45) 89 49 59 00, tebj@ki.au.dk

ABSTRACT the EAU/ESIU classification system

Classification of urinary tract infec-
tions (UTI) is important for clinical deci-
sions, research, quality measurement
and teaching. Current definitions of UTI
are above all based on the concept of the
two main categories, complicated and
uncomplicated UTI. The category “com-
plicated UTI” especially is very heteroge-
neous and not always clear. We propose
ORENUC based on the clinical presen-
tation of the UTI, categorisation of risk
factors and availability of appropriate
antimicrobial therapy, which finally may
result in the definition of UTI severity
groups.
Key words: classification, urinary tract
infection, cystitis, pyelonephritis, urosep-
sis, risk factors
 Critical review of current definitions of urinary tract infections
1. INTRODUCTION
The objectives of classification of diseases
are
• to organise current knowledge
• to provide a basis for guidelines on
diagnosis and treatment
• to provide a framework for design of
research projects
• to provide a framework for registration
of clinical activity
A classification must be consistent with
prevailing medical rationality and fit
with other frequently used classifications.
Classification categories must be clini-
cally relevant. The number of categories
and grades has to be limited, so that it is
easy to learn and remember. A classifica-
tion has to be tested in studies and prac-
tice. As knowledge increases and clinical
practice changes, classification systems
must be revised.
2. MATERIALS AND METHODS
This paper presents a review of the prin-
ciples for disease classification, a critical
evaluation of current definitions of UTI
and a discussion of key criteria for clas-
sification of UTI. Based on this work we
suggest modifying the classification of
UTI. The method used can be described
as a consensus process involving experts
with clinical, scientific and organisational
experience on a high level (Figure 1).
3. RESULTS
3.1 Principles for disease
classification
Diseases are usually characterised by a
set of categories and described in more
detail by a grading system. For example,
malignant diseases are classified with
| 16.1 |
Development of a new classification of urinary tract infections
Clarifying the purposes
Evaluation of current classifications of UTI (CDC, IDSA, ESCMID)
Defining key features for a good classification system
Good Bad
Defining key criteria for assessment of patients with UTI
Organising criteria into categories of risk factors
Phenotyping risk factors
Identifying clinical types of UTI
Defining UTI severity grades
Figure 1. Development of a new classification of urinary
tract infections.
categories of primary tumour exten-
sion, nodal status and metastases. Each
category is staged according to a simple
numerical scale. In the UPOINT classi-
fication of chronic pelvic pain syndrome,
phenotypes are registered as present
or absent [1]. Results of a primary cat-
egorisation and staging may be further
organised on a secondary level like the
American four letter (A-D) [2] or stage
(I-IV) system [3] and the D`Amico three
figures risk stratification in prostate
cancer [4].
3.2 CLASSIFICATION OF UTI
3.2.1 Evaluation of current
classifications
The most widely used classification of
urinary tract infections (UTI) are those
developed by the Centers for Disease
Control and Prevention in USA (CDC) in
1988 [5] and updated in 2008 [6], IDSA in
1992 [7] and ESCMID in 1993 [8].
981
Chapter | 16 | Classification of urinary tract infections
The purpose of the CDC definitions is
to define and report health care-associ-
ated (nosocomial) UTI. In the 1988 edi-
tion UTI comprised symptomatic UTI,
asymptomatic bacteriuria (ASB) and
other infections of the urinary tract.
Diagnosis of symptomatic UTI is based
on symptoms and evidence for the pres-
ence of a pathogen. The definition pro-
vides several possible types of evidence
such as culture, dipstick, microscopy,
physician’s diagnosis or appropriate anti-
biotic therapy. Repeated cultures are
needed when the urinary culture reveals
colony forming units (CFU) < 102/ml. Two
cultures are needed for diagnosing ASB
in patients without an indwelling cathe-
ter for the last seven days before culture
is taken. In the 2008 update the concept
of health care associated UTI (HA-UTI)
is broadened and nosocomially acquired
UTI (NA-UTI) has become a subtype
of HA-UTI [6]. In both editions it is not
made quite clear, however, whether ASB
is considered an infection or probably
only a risk factor under certain circum-
stances. The CDC definitions of HA-UTI
appear complex to read and to be applied
in clinical practice, but may be useful
for prevalence or incidence studies if
adapted to specific urological needs (see
Chapter 12).
The IDSA [7] and ESCMID [8] guide-
lines were mainly developed for the
evaluation of new anti-infective drugs in
clinical studies. IDSA introduced the con-
cept of complicated and uncomplicated
UTI in order to obtain more homogene-
ous study groups. In “uncomplicated”
UTI mainly UTI due to Escherichia
coli and in “complicated” UTI also UTI
caused by other pathogens than E.coli
can be studied. The term “uncompli-
cated” means that the patient has no
known factors that will render him or
her more susceptible to develop UTI.
Complicated is defined as the presence
of these factors, but the understanding
of “complicating factors” is not always
clear. Some factors are related to the
982
urinary tract like obstruction, stones,
diversion and catheters. Other factors
relate to kidney diseases or co-morbid-
ities like diabetes mellitus, malignan-
cies or immune competence (e.g. immune
compromised patients). In these guide-
lines “complicated” also means a higher
risk for clinical complications if the UTI
is not properly treated as in pregnancy
and childhood. The investigations needed
to diagnose or exclude all the risk fac-
tors are not clearly described. IDSA
also introduced graded criteria for the
amount of bacteria as expressed by col-
ony forming units (CFU) in the diagnosis
of UTI in different groups of patients and
situations.
Most current UTI guidelines and
study protocols are based on the IDSA
[7] and ESCMID [8] guidelines using
the concept of uncomplicated and com-
plicated UTI with some modifications.
However, the term “complicated” some-
times means an increased risk of getting
UTI, sometimes it refers to an increased
risk of treatment failure, and sometimes
an increased risk of loosing nephrons or
even the patient’s life. In complicated
UTI other pathogens than E coli, other
antimicrobials and longer treatment
duration have to be considered. This
mixed understanding of “complicated”
makes the group of complicated UTI
very heterogeneous and results of a clin-
ical study on patients with one criterion
defining “complicated” cannot be trans-
ferred to other patients with complicated
UTI where the diagnosis is based on dif-
ferent criteria. Therefore, more than two
categories are needed for a comprehen-
sive description of patients’ risk factors
related to UTI.
3.2.2 Criteria for classification of UTI
The information needed for assessment
of a patient suspected of having a UTI
is presented in Table 1. The criteria are
organised into five main categories.
Categories I-III and V are important for
 Critical review of current definitions of urinary tract infections | 16.1 |

Table 1 The most important criteria for patient assessment in UTI.

I. Clinical criteria

1. Clinical presentation
a. Urethritis* (UR)
b. Cystitis (CY)
c. Pyelonephritis (PY)
d. Urosepsis (US)
e. Male accessory gland infection (“male adnexitis”)* (MA) (prostatitis, vesiculitis, epididymitis, orchitis)
*need to be considered separately, because the clinical presentations show great diversity (see chapters #13 and #14)
2. Specificity of symptoms
a. UTI specific
i. For lower UTI (cystitis): dysuria, frequency, urgency, suprapubic pain
ii. For upper UTI (pyelonephritis): fever, flank pain, CVA tenderness
b. UTI non-specific symptoms, but relevant in specific clinical situations
i. For catheter associated UTI, e.g. bladder spasm, fever not explained otherwise
ii. For newborn and young children (see chapter #6 on UTI in children)
iii. For elderly patients, e.g. fever not explained otherwise, confusion (see also #10.4)
iv. For patients with neurogenic disorders, e.g. vegetative disorders (see section #8)
3. Severity of symptoms (there is no validated scoring system)
a. Mild
b. Moderate
c. Severe
d. Septic (see definitions of severity of sepsis)
4. Pattern of infection
a. Isolated or sporadic
b. Recurrent
i. Relapse
ii. Reinfection
c. Unresolved or chronic

II. Possible risk factors

1. Patient’s characteristics
a. Gender (male, female)
b. Prematuity, newborn, young child, adolescent
c. Premenopause
d. Pregnancy
e. Postmenopause
f. Elderly (geriatric: physically and/or mentally handicapped)
2. Relevant* diseases outside the urinary tract (*needs to be verified in clinical studies)
a. Immunosupression (not clear at which state it is relevant for which kind of UTI)
i. Innate
ii. Acquired, e.g. AIDS
b. Diabetes mellitus (not clear at which state it is relevant for which kind of UTI)
c. Other diseases (not clear which ones are relevant and for which kind of UTI)

(Continued)

983
Chapter | 16 | Classification of urinary tract infections

Table 1 (Continued)

II. Possible risk factors (Continued)

3. Nephrological risk factors – status of the kidneys
a. Impaired kidney function (not clear which degree of renal insufficiency is relevant for which kind of UTI)
b. Kidney abscess
c. Polycystic renal disease
4. Urological risk factors (functional or morphological disorders (impaired urodynamics) within the urinary tract. (The
degree of impairment is not well defined)
a. Functional disorders e.g. reflux, neurogenic bladder disturbances
b. Obstruction without infectious nidus e.g. tumour, non-infected stone
c. Obstruction with infectious nidus e.g. infective stones, necrotising tumour, stent
5. External catheter
a. Urethral
b. Suprapubic
c. Nephrostomy
d. Others
6. Asymptomatic bacteriuria (ASB): ASB is not considered an infection and is usually not relevant, but in some
situations ASB is a risk factor, e.g in pregnancy and before traumatazing interventions of the urinary tract. In some
situations differentiation between asymptomatic and symptomatic bacteriuria is difficult, e.g. young children,
elderly patients, patients with spinal cord injury

III. Pathogen/etiological agent

1. Bacterial load (colony counts)

2. Pathogens (type, species)
3. Antimicrobial susceptibility/resistance
4. Virulence etc.

IV. Situation – circumstances under which UTI was acquired

1. Community
2. Outpatient service
a. Hospital setting
b. Private practice
3. Inpatient service (Hospital)
4. Long term residential accommodation, nursing home
5. Health care associated (2–4)

V. Therapeutic options

1. Pathogen(s) is (are) susceptible against commonly used antimicrobials,

a. which are available
b. which are not easily available
2. Pathogen(s) has (have) limited susceptibility against commonly used antimicrobials,
a. but alternative antimicrobials are available
b. but alternative antimicrobials are not easily available
3. Pathogen(s) is (are) multiresistant and appropriate antimicrobials are not (or not easily) available

984
 Critical review of current definitions of urinary tract infections
diagnosis and treatment, while category
IV is important for surveillance of treat-
ment quality and the environment. Not
all criteria are equally relevant for clas-
sification of UTI. In a clinical situation,
however, all criteria have to be consid-
ered. This shows the complexity of clini-
cal decision making in the treatment of
UTI. A more detailed assessment of cer-
tain criteria may be relevant in research
projects.
3.2.3 Presentation of symptomatic UTI
3.2.3.1 Definition of symptomatic UTI
A patient has a symptomatic UTI if there
are clinical symptoms indicative of UTI
and if presence of pathogens can be veri-
fied or suspected by culture, microscopy,
dipstick or PCR-techniques, or if the
diagnosis or an appropriate therapy of
symptomatic UTI is made by a physician
upon clinical evaluation. This is consist-
ent with the CDC definitions [6].
3.2.3.2 Clinical presentation
The clinical situation is classified as cys-
titis (CY), pyelonephritis (PY) and uro-
sepsis (US) as in the CDC definitions
[6]. Asymptomatic bacteriuria (ASB) is
considered not as infection but as a risk
factor for UTI in certain circumstances.
Urethritis (UR) and male accessory gland
infections (“male adnexitis”) (MA, e.g.
prostatitis) need to be discussed sepa-
rately, because the clinical presentations
show great diversity. The clinical pres-
entation of the three UTI entities dis-
cussed here (CY, PN, US) are presented
in Table 2 with the attempt to create
severity grades considering that a PN is
always more severe than a CY and a US
always more severe than the two former
ones. In addition, PN can present as a
mild and moderate infection, which usu-
ally can be treated by oral antimicrobi-
als in an outpatient setting, and as a
severe infection with systemic reactions
like nausea and vomiting, which usu-
ally needs initial parenteral therapy and
| 16.1 |
hospitalization may be recommended. For
urosepsis the severity grading of sepsis in
general use can be adapted: sepsis, severe
sepsis, septic shock [9–10].
3.2.3.3 Risk factors
Ideally all five main categories as out-
lined in Table 1 should be weighted and
graded according to their impact on
prognosis. Unfortunately, our knowledge
about their relative impact is scarce,
and therefore they cannot be just added
together. Furthermore, some criteria are
numerical and continuous i.e. number of
CFU. Some are dichotomous variables
like gender. Others are categorical, like
names of pathogens, and types of accom-
modation. We therefore recommend
that the principle of phenotyping [1]
is applied on risk factors and that they
are organised into groups as suggested
earlier [11].
Risk factors may affect the patient
in different ways and may be grouped
according to knowledge on impact on out-
come and prognosis. Some risk factors e.g.
pregnancy, prematurity, newborn, and
immune deficiency mean an increased
risk of a serious outcome like abortion,
loss of nephrons, or even the patient’s life.
Others mean that a more elaborate treat-
ment regimen is needed e.g. obstruction
of the urinary tract and kidney abscess.
Some risk factors increase the risk that
a UTI will recur, e.g. incomplete blad-
der emptying and indwelling catheter.
In recognition of the characteristics of
risk factors relevant for the three infec-
tions (CY, PN, US) discussed here, we
have re-organised the risk factors into six
groups and propose the ORENUC sys-
tem for phenotyping (Table 3): O – NO
known risk factor; R – risk for Recurrent
UTI, but without risk of more severe out-
come; E – Extraurogenital risk factors;
N – relevant Nephropathic diseases; U
– Urological resolvable (transient) risk
factors; C – permanent external urinary
Cathether and non resolved urological
risk factors.
985
Chapter | 16 | Classification of urinary tract infections

Table 2 Clinical presentation of cystitis (CY), pyelonephritis (PN) and urosepsis (US) and grading of severity.

Clinical Grade of
Acronym diagnosis Clinical symptoms severity

CY-1 Cystitis dysuria, frequency, urgency, suprapubic pain; sometimes 1

unspecific symptoms (see table 1)

PN-2 Mild and moderate fever, flank pain, CVA tenderness; 2

pyelonephritis sometimes unspecific symptoms (see table 1)
with or without symptoms of CY

PN-3 Severe pyelonephritis As PN-2, but in addition nausea and vomiting 3

with or without symptoms of CY

US-4 Urosepsis (simple)* Temperature > 38°C or < 36°C 4

Heart rate > 90 beats min
Respiratory rate > 20 breaths/min or
PaCO2 < 32mmHg (< 4.3kPa)
WBC > 12,000 cells/mm3 or < 4,000 cells/mm3 or
≥10% immature (band) forms
With or without symptoms of CY or PN

US-5 Severe urosepsis* As US-4, but in addition associated with organ dysfunction, 5
hypoperfusion or hypotension.
Hypoperfusion and perfusion abnormalities may include but
are not limited to lactic acidosis, oliguria or an acute altera-
tion of mental status

US-6 Uroseptic shock* AS US-4 or US-5, but in addition with hypotension despite 6
adequate fluid resuscitation along with the
presence of perfusion abnormalities that may include, but are
not limited to lactic acidosis, oliguria, or an acute alteration
in mental status. Patients who are on inotropic or vasopressor
agents may not be hypotensive at the time that perfusion
abnormalities are measured.

X – severity category of the corresponding infection: CY, PN or US.

Note: Hypotension due to urosepsis is defined as a systolic blood pressure of < 90mmHg or a reduction of > 40mmHg from baseline in the
absence of other causes of hypotension.
*Urosepsis is defined as sepsis originating from the urogenital tract. Definition of severity is modified according to [9–10].

3.2.3.4 Antimicrobial treatment options of effective antimicrobials (Table 4).

Antimicrobial treatment is a cornerstone Updating is always needed with time and
in the treatment of UTI. Without anti- as knowledge increases.
biotics (as in developing countries) or
without effective antibiotics (as already 3.2.3.5 Severity assessment
in some countries to-day) the prognosis When assessing a patient the severity
may be very serious. For assessment of of the situation always has to be con-
prognosis and severity of UTI we suggest sidered. As mentioned earlier the clini-
that the chance of effective antimicro- cal presentation outweighs all other
bial treatment is included in the overall categories of information for diagnos-
assessment of severity in a patient with tic workup and treatment, because PN
UTI. We suggest a grading with small let- is always more severe than CY and
ters a-c based on the susceptibility of the US always more severe than the two
causative pathogen(s) and the availability former ones. Therefore assessment of

986
 Critical review of current definitions of urinary tract infections | 16.1 |

Table 3 Host risk factors in urinary tract infections categorized according to the ORENUC system.

Phenotype Category of risk factor Examples of risk factors

O NO known risk factor Otherwise healthy premenopausal women

R Risk factors for Recurrent UTI, but no risk of Sexual behaviour (frequency, spermicide),
more severe outcome
Hormonal deficiency in postmenopause
Secretor type of certain blood groups
Well controlled diabetes mellitus

E Extra-urogenital risk factors with risk of more Prematurity, newborn

severe outcome
Pregnancy
Male gender
Badly controlled diabetes mellitus
Relevant immunosuppression (not well defined)

N Nephropathic dieseases with risk of more Relevant renal insufficiency (not well defined)
severe outcome
Polycystic nephropathy
Interstitial nephritis, e.g. due to analgetics

U Urological risk factors with risk of more
severe outcome, which can be resolved
during therapy
Ureteral obstruction due to a ureteral stone
Well controlled neurogenic bladder disturbances
Transient short-term external urinary catheter
Asymptomatic bacteriuria*

C Permanent urinary Catheter and non resolv-
able urological risk factors with risk of more
severe outcome
Long-term external urinary catheter
Non resolvable urinary obstruction
Badly controlled neurogenic bladder disturbances

*only under certain circumstances in combination with other risk factors, e.g. pregnancy, urological intervention.
X – severity category of the corresponding infection: CY, PN or US.

Table 4 Therapeutic option.

Grade a b c

Situation Pathogen(s) is (are) susceptible Pathogen(s) has (have) reduced Pathogen(s) is (are)
against commonly used susceptibility against commonly multiresistant and/or
antibiotics, which are available used antibiotics, but alternative appropriate antimicrobials
antimicrobials are available are not available

severity always starts with the clinical (Table 3). For example: a cystitis (CY)
presentation and the treatment needed. combined with a risk factor of cate-
The assessment of underlying risk fac- gory “E” or “U” is usually more severe
tors is descriptive and may modify the than of category “O” or “R”. Therefore
severity of each clinical presentation the severity category for CY could be

987
Chapter | 16 | Classification of urinary tract infections
modified accordingly. The same applies
for pyelonephritis (PN) and urosepsis
(US). However, it is difficult to quan-
tify the modification by a certain risk
factor without validation. Therefore,
at this stage it is suggested to add the
category of the risk factor in a descrip-
tive manner only. In addition, the avail-
ability of an appropriate antimicrobial
therapy modifies also the risk of a more
severe outcome in any of the clinical
presentations.
Although not explicitly included, ure-
thritis (UR) could probably be handled as
cystitis, whereas acute prostatitis, epidi-
dymitis or orchitis (MA) could be handled
like pyelonephritis, which also is an acute
parenchymal infection. The severity of an
acute infection of these male accessory
glands (MA) could probably be subclas-
sified in mild and moderate (MA-2) and
severe with systemic reactions (MA-3)
similar to acute pyelonephritis. Sepsis
originating from such infections may also
be classified as urosepsis with the three
grades of severity (US-4, US-5, US-6).
The risk factors mentioned in Table 3
could be used as modifiers in the same
way as for CY, PN or US. Chronic bacte-
rial prostatitis and chronic pelvic pain
syndrome is better described with the
UPOINT system [1].
3.2.4 Description of a UTI episode
A given episode of UTI should be
described with a short sentence indi-
cating the clinical diagnosis, the pres-
ence of risk categories as phenotypes,
the pathogen(s), and the availability of
appropriate antimicrobial therapy (see
Table 4). The following parameters are
described separately: Pattern of infection,
the situation under which the UTI occurs
and the source of culture sample. The
“Situation” has to be described at least
for surveillance or research purposes. If
a pathogen was not identified, the name
of the pathogen is replaced by the word
“anonymous”.
988
The handling of the proposed EAU/
ESIU classification is illustrated by some
examples in Table 5.
4. DISCUSSION
Good and well known definitions make
treatment decisions easier and facilitate
teaching and research in the field of UTI.
No clear definition of the term “com-
plicated” has ever existed, and current
definitions of complicated UTI caused
many controversies. According to the
IDSA [7] and ESCMID [8] guidelines
uncomplicated UTI only occurs in oth-
erwise healthy premenopausal (young)
non pregnant women with susceptible
pathogens and without recurrent UTI.
For drug studies it was even suggested
to include only those women with acute
cystitis who have ”significant” bacteriuria
(cfu >105/ml) [12], although it is known
since decades that also lower counts of
uropathogens can be relevant for an acute
episode of uncomplicated cystitis [13].
In all other situations, e.g. in man
by definition, a UTI had to be classi-
fied as complicated, but uncomplicated
cystitis although rarely also exists in
men, especially in young men [14–15].
This has lead to the strange situation,
that many different patients have been
lumped into studies on complicated UTI.
Unfortunately the results of these stud-
ies were then extrapolated to all patients
with complicated UTI with the conse-
quence that these treatment modalities
failed in patients with severely compli-
cated UTI. This situation underlines that
the concept of complicated and uncompli-
cated may cause confusion rather than
good treatment decisions. The classifica-
tion in complicated and uncomplicated
UTI was intended to be a guide whether
a UTI in a specific patient means an
increased risk for a more seriously out-
come unless additional precautions or
treatment modalities are applied. This
intention will be easier met with the new
 Critical review of current definitions of urinary tract infections | 16.1 |

Table 5 Examples of clinical diagnosis, severity grading, risk factors, uropathogen and antibiotic treatment option according
to the ORENUC classification system (Tables 2–4).

CY-1R: E coli (a)

Premenopausal otherwise healthy women with recurrent cystitis (CY) (severity grade 1, risk factor: R), causative agent
Escherichia coli susceptible to common antimicrobials (a), which are also available in the country. Former: uncomplicated
recurrent cystitis.

CY-1E,U: P. aeruginosa (c)

Cystitis (CY) in a pregnant kidney transplant patient (severity grade 1, risk factor: E) with nephrological (risk factor: E) and
urological risk factors (JJ-stent) (risk factor: U) and no effective antibiotics due to a multiresistant P. aeruginosa (c). Former:
complicated cystitis.

PY-3O: E. coli (b)

Severe febrile acute uncomplicated pyelonephritis (PY) with nausea and vomiting in an otherwise healthy premenopausal
woman with no known risk factors (severity grade 3, risk factor: O), due to E coli with reduced susceptibility
(fluoroquinolone resistance) (b). Former: uncomplicated (severe) pyelonephritis

PY-2E,U: K. pneumoniae (b)

Moderate acute pyelonephritis in a man with urinary obstruction due to ureteral stone and relief of obstruction by
JJ-stent (severity grade 2, risk factor: E and U), causative agent Klebsiella pneumoniae with reduced susceptibility (ESBL)
(b), Former: complicated (moderate) pyelonephritis.

US-4E,C: P. mirabilis (a)

Urosepsis in a diabetic geriatric woman in a nursing home with permanent indwelling urinary catheter due to
incontinence, but without organ failure or shock (severity grade 4, risk factor: E). Uropathogen susceptible to ciprofloxacin
(a), which is available.

MA-3U: E. coli (b)

Acute prostatitis with fever, nausea and vomiting after transrectal prostate biopsy (severity grade 3, risk factor: U) due to a
ciprofloxacin resistant E. coli (b) in a 65 year old man.

classification where each patient will be UTI. It should be replaced by UTI

assessed according to UTI severity grade
and specific risk phenotypes.
Asymptomatic bacteriuria is a key
issue. Since ASB can now longer be con-
sidered as infection, it may better be
described as “colonisation”. In some
situations ASB may even be protective
for recurrent symptomatic UTI [16].
However, under certain circumstances
ASB is recognised as a risk factor to
develop (symptomatic) UTI as seems to be
the fact in pregnancy, early childhood and
during interventions in the urinary tract
[17], and ASB has to be treated appropri-
ately. This double role of ASB has to be
recognised and handled carefully accord-
ing to the clinical situation.
A key ambition of the definitions of UTI
presented here is to abolish the current
concept based on only two UTI classes,
“uncomplicated” versus “complicated”
grades with similar risk factors which
finally may lead to the concept of sever-
ity groups, like in prostate cancer [2, 4].
We are, however, aware that there is
limited scientific evidence to support the
selection of categories and grades at the
present time point. As the first step this
kind of classification needs to be tested
with data from already published stud-
ies and then it has to be evaluated in
specifically designed prospective stud-
ies. Categories and grades should then
be adjusted as more knowledge is gath-
ered about the relative importance of risk
factors. For example, the concept of vir-
ulence may one day outweigh the impor-
tance of colony-forming units. There has
to be a continuous development process
with consensus meetings of thought lead-
ers. This new classification can easily
adopt changes. Severity grades in specific

989
Chapter | 16 | Classification of urinary tract infections
infections of the urinary tract have to be
dealt with in future meetings.
5. CONCLUSIONS
The new classification of UTI presented
in this chapter are based on the best fea-
tures of current definitions and classifica-
tions. In addition, we introduce classical
principles of categories and grades. More
attention is given to urine cultures, the
susceptibility of the pathogen(s) and the
availability of appropriate antimicrobials.
No changes are suggested for the defini-
tion and classification of urosepsis.
The new classification enables us
to describe more precisely when fur-
ther evaluation and treatment shall be
started and when patients shall be hos-
pitalised. Defining groups of patients for
research studies should become easier.
Classification of UTI will become more
consistent with other fields of urology
and make teaching easier about UTI.
However, we recognize that further dis-
cussion is still needed and welcome all
comments.
REFERENCES
1. Shoskes DA, Nickel JC, Dolinga R, and
Prots D, Clinical phenotyping of patients
with chronic prostatitis/chronic pelvic
pain syndrome and correlation with
symptom severity. Urology, 2009. 73(3):
538–42; discussion 542–3.
2. Whitmore WF, Jr., Natural history and
staging of prostate cancer. Urol Clin North
Am, 1984. 11(2): 205–20.
3. Iversen P, Madsen PO, and Corle DK,
Radical prostatectomy versus expectant
treatment for early carcinoma of the
prostate. Twenty-three year follow-up
of a prospective randomized study.
Scand J Urol Nephrol Suppl, 1995. 172:
65–72.
4. D’Amico AV, Whittington R, Malkowicz
SB, Schultz D, Blank K, Broderick GA,
Tomaszewski JE, Renshaw AA, Kaplan I,
990
Beard CJ, and Wein A, Biochemical out-
come after radical prostatectomy, external
beam radiation therapy, or interstitial radi-
ation therapy for clinically localized pros-
tate cancer. Jama, 1998. 280(11): 969–74.
5. Garner JS, Jarvis WR, Emori TG, Horan
TC, and Hughes JM, CDC definitions for
nosocomial infections, 1988. Am J Infect
Control, 1988. 16(3): 128–40.
6. Horan TC, Andrus M, and Dudeck MA,
CDC/NHSN surveillance definition of
health care-associated infection and cri-
teria for specific types of infections in the
acute care setting. Am J Infect Control,
2008. 36(5): 309–32.
7. Rubin USE, Andriole VT, Davis RJ,
Stamm WE, Evaluation of new anti-infec-
tive drugs for the treatment of UTI. Clin
Infect Dis, 1992. 15: 216.
8. Rubin UH SE, Andriole VT, Davis RJ,
Stamm WE, with a modification by a
European Working Party (Norrby SR),
General Guidelines for the evaluation
of new anti-infective drugs for the treat-
ment of urinary tract infection. The
European Society of Clinical Microbiology
and Infectious diseases, Taukirchen,
Germany, 1993: 240–310.
9. Bone RC, Balk RA, Cerra FB, Dellinger
RP, Fein AM, Knaus WA, Schein RM, and
Sibbald WJ, Definitions for sepsis and
organ failure and guidelines for the use of
innovative therapies in sepsis. The ACCP/
SCCM Consensus Conference Committee.
American College of Chest Physicians/
Society of Critical Care Medicine. Chest,
1992. 101(6): 1644–55.
10. Levy MM, Fink MP, Marshall JC,
Abraham E, Angus D, Cook D, Cohen
J, Opal SM, Vincent JL, and Ramsay
G, 2001 SCCM/ESICM/ACCP/ATS/
SIS International Sepsis Definitions
Conference. Crit Care Med, 2003. 31(4):
1250–6.
11. Naber KG, Experience with the new
guidelines on evaluation of new anti-
infective drugs for the treatment of
urinary tract infections. Int J Antimicrob
Agents, 1999. 11(3–4): 189–96; discussion
213–6.
12. Kunin CM, Guidelines for the evaluation
of new anti-infective drugs for the treat-
ment of urinary tract infection: additional
 Critical review of current definitions of urinary tract infections
considerations. Clin Infect Dis, 1992.
15(6): 1041–4.
13. Stamm WE, Counts GW, Running KR,
Fihn S, Turck M, and Holmes KK,
Diagnosis of coliform infection in acutely
dysuric women. N Engl J Med, 1982.
307(8): 463–8.
14. Krieger JN, Ross SO, and Simonsen JM,
Urinary tract infections in healthy univer-
sity men. J Urol, 1993. 149(5): 1046–8.
15. Stamm W, Urinary tract infections in young
men., in Urinary tract infections, Bergan T,
Editor. 1997, Karger: Basel. p. 46–47.
| 16.1 |
16. Sunden F, Hakansson L, Ljunggren E,
and Wullt B, Bacterial interference--is
deliberate colonization with Escherichia
coli 83972 an alternative treatment for
patients with recurrent urinary tract
infection? Int J Antimicrob Agents, 2006.
28 Suppl 1: S26–9.
17. Nicolle LE, Bradley S, Colgan R, Rice JC,
Schaeffer A, and Hooton TM, Infectious
Diseases Society of America guidelines
for the diagnosis and treatment of asymp-
tomatic bacteriuria in adults. Clin Infect
Dis, 2005. 40(5): 643–54.
991
This page intentionally left blank

1. Abarbanel J, Engelstein D, Lask D, and
Livne PM, Urinary tract infection in men
younger than 45 years of age: is there a
need for urologic investigation? Urology,
2003. 62(1): 27–9.
2. Abbott KC, Swanson SJ, Richter ER,
Bohen EM, Agodoa LY, Peters TG,
Barbour G, Lipnick R, and Cruess DF,
Late urinary tract infection after renal
transplantation in the United States. Am
J Kidney Dis, 2004. 44(2): 353–62.
3. Abbou CC, Chopin D, Kouri G, Daloubeix
H, Estève C, Lavarenne V, Bottine H,
and Auvert J, Faut-il opérer les reins
muets tuberculeux? Ann.Urol, 1982. 16(4):
254–56.
4. Abdel-Latif M, Mosbah A, El Bahnasawy
MS, Elsawy E, and Shaaban AA,
Asymptomatic bacteriuria in men with
orthotopic ileal neobladders: possible rela-
tionship to nocturnal enuresis. BJU Int,
2005. 96(3): 391–6.
5. Abdul-Halim H, Kehinde EO, Abdeen S,
Lashin I, Al-Hunayan AA, and Al-Awadi
KA, Severe emphysematous pyelonephritis
in diabetic patients: diagnosis and aspects
of surgical management. Urol Int, 2005.
75(2): 123–8.
6. Abouassaly R, Montague DK, and
Angermeier KW, Antibiotic-coated medi-
cal devices: with an emphasis on inflat-
able penile prosthesis. Asian J Androl,
2004. 6(3): 249–57.
7. Abraham E, Glauser MP, Butler T,
Garbino J, Gelmont D, Laterre PF,
Kudsk K, Bruining HA, Otto C, Tobin
E, Zwingelstein C, Lesslauer W, and
Leighton A, p55 Tumor necrosis factor
receptor fusion protein in the treatment
References
of patients with severe sepsis and septic
shock. A randomized controlled multi-
center trial. Ro 45–2081 Study Group.
JAMA, 1997. 277(19): 1531–8.
8. Abraham E, Laterre PF, Garbino J,
Pingleton S, Butler T, Dugernier T,
Margolis B, Kudsk K, Zimmerli W,
Anderson P, Reynaert M, Lew D,
Lesslauer W, Passe S, Cooper P, Burdeska
A, Modi M, Leighton A, Salgo M, and
Van der Auwera P, Lenercept (p55 tumor
necrosis factor receptor fusion protein) in
severe sepsis and early septic shock: a ran-
domized, double-blind, placebo-controlled,
multicenter phase III trial with 1,342
patients. Crit Care Med, 2001. 29(3):
503–10.
9. Abraham E, Laterre PF, Garg R, Levy
H, Talwar D, Trzaskoma BL, Francois
B, Guy JS, Bruckmann M, Rea-Neto
A, Rossaint R, Perrotin D, Sablotzki A,
Arkins N, Utterback BG, and Macias WL,
Drotrecogin alfa (activated) for adults
with severe sepsis and a low risk of death.
N Engl J Med, 2005. 353(13): 1332–41.
10. Abraham E, Reinhart K, Opal S, Demeyer
I, Doig C, Rodriguez AL, Beale R, Svoboda
P, Laterre PF, Simon S, Light B, Spapen
H, Stone J, Seibert A, Peckelsen C, De
Deyne C, Postier R, Pettila V, Artigas A,
Percell SR, Shu V, Zwingelstein C, Tobias
J, Poole L, Stolzenbach JC, and Creasey
AA, Efficacy and safety of tifacogin
(recombinant tissue factor pathway inhib-
itor) in severe sepsis: a randomized con-
trolled trial. JAMA, 2003. 290(2): 238–47.
11. Abrahams HM and Stoller ML, Infection
and urinary stones. Curr Opin Urol, 2003.
13(1): 63–7.
993
 References
12. Abrams P, Khoury S, and Grant A,
Evidence—based medicine overview of the
main steps for developing and grading
guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
13. Abrutyn E, Mossey J, Berlin JA, Boscia J,
Levison M, Pitsakis P, and Kaye D, Does
asymptomatic bacteriuria predict mor-
tality and does antimicrobial treatment
reduce mortality in elderly ambulatory
women? Ann Intern Med, 1994. 120(10):
827–33.
14. Abu-Qamar AA, Aljader KM, and
Habboub H, Isolated renal hydatid
disease: experience at the queen rania
urology center, the king hussein medical
center. Saudi J Kidney Dis Transpl, 2004.
15(2): 149–54.
15. ACOG educational bulletin. Antimicrobial
therapy for obstetric patients. Number
245, March 1998 (replaces no. 117, June
1988). American College of Obstetricians
and Gynecologists. Int J Gynaecol Obstet,
1998. 61(3): 299–308.
16. ACOG Practice Bulletin No. 74. Antibiotic
prophylaxis for gynecologic procedures.
Obstet Gynecol, 2006. 108(1): 225–34.
17. Adler HS and Steinbrink K, Tolerogenic
dendritic cells in health and disease:
friend and foe! Eur J Dermatol, 2007.
17(6): 476–91.
18. Adot Zurbano JM, Salinas Casado J,
Dambros M, Virseda Chamorro M,
Ramirez Fernandez JC, Silmi Moyano A,
and Marcos Diaz J, [Urodynamics of the
bladder diverticulum in the adult male].
Arch Esp Urol, 2005. 58(7): 641–9.
19. Afshan A, Pelvic tuberculosis mimick-
ing malignant ovarian tumour. J Coll
Physicians Surg Pak, 2006. 16(1): 64–6.
20. Agace WW, Hedges SR, Ceska M, and
Svanborg C, Interleukin-8 and the neu-
trophil response to mucosal gram-negative
infection. J Clin Invest, 1993. 92(2):
780–5.
21. Agarwal A and Saleh RA, Role of oxidants
in male infertility: rationale, significance,
and treatment. Urol Clin North Am, 2002.
29(4): 817–27.
22. Aggarwal VK, Verrier Jones K, Asscher
AW, Evans C, and Williams LA, Covert
994
bacteriuria: long term follow up. Arch Dis
Child, 1991. 66(11): 1284–6.
23. Agot KE, Ndinya-Achola JO, Kreiss JK,
and Weiss NS, Risk of HIV-1 in rural
Kenya: a comparison of circumcised and
uncircumcised men. Epidemiology, 2004.
15(2): 157–63.
24. Agustin J, Lacson S, Raffalli J, Aguero-
Rosenfeld ME, and Wormser GP, Failure
of a lipid amphotericin B preparation to
eradicate candiduria: preliminary find-
ings based on three cases. Clin Infect Dis,
1999. 29(3): 686–7.
25. Agwuh KN and MacGowan A,
Pharmacokinetics and pharmacodynam-
ics of the tetracyclines including glycyl-
cyclines. J Antimicrob Chemother, 2006.
58(2): 256–65.
26. Ahlering TE, Boyd SD, Hamilton CL,
Bragin SD, Chandrasoma PT, Lieskovsky
G, and Skinner DG, Emphysematous
pyelonephritis: a 5-year experience with 13
patients. J Urol, 1985. 134(6): 1086–8.
27. AIA Academy of Architecture for Health.
and United States. Dept. of Health
and Human Services., Guidelines for
design and construction of hospital and
health care facilities. 1996–97. ed. 1996,
Washington, D.C.: American Institute of
Architects Press. xi, 143 p.
28. AIDS Finder. Available from: www.aids-
finder.org/.
29. Aitchison M, Mufti GR, Farrell J,
Paterson PJ, and Scott R, Granulomatous
orchitis. Review of 15 cases. Br J Urol,
1990. 66(3): 312–4.
30. Akerlund S, Campanello M, Kaijser B,
and Jonsson O, Bacteriuria in patients
with a continent ileal reservoir for urinary
diversion does not regularly require anti-
biotic treatment. Br J Urol, 1994. 74(2):
177–81.
31. Akhan O, Ustunsoz B, Somuncu I, Ozmen
M, Oner A, Alemdaroglu A, and Besim
A, Percutaneous renal hydatid cyst treat-
ment: long-term results. Abdom Imaging,
1998. 23(2): 209–13.
32. Akhan SE, Dogan Y, Akhan S, Iyibozkurt
AC, Topuz S, and Yalcin O, Pelvic actino-
mycosis mimicking ovarian malignancy:
three cases. Eur J Gynaecol Oncol, 2008.
29(3): 294–7.

33. Akinci E, Bodur H, Cevik MA, Erbay A,
Eren SS, Ziraman I, Balaban N, Atan A,
and Ergul G, A complication of brucel-
losis: epididymoorchitis. Int J Infect Dis,
2006. 10(2): 171–7.
34. Akinci E, Bodur H, Erbay CC, and Deveer
M, Brucella abortus epididymo-orchitis
relapsing in the opposite testis 3 months
after antibiotic therapy and development
of aspermia. Int J Infect Dis, 2003. 7(4):
290–1.
35. Akira S, Toll-like receptor signaling. J
Biol Chem, 2003. 278(40): 38105–8.
36. Akira S, Uematsu S, and Takeuchi O,
Pathogen recognition and innate immu-
nity. Cell, 2006. 124(4): 783–801.
37. Akram M, Shahid M, and Khan AU,
Etiology and antibiotic resistance pat-
terns of community-acquired urinary tract
infections in J N M C Hospital Aligarh,
India. Ann Clin Microbiol Antimicrob,
2007. 6: 4.
38. Akritidis N, Mastora M, and Pappas
G, Genitourinary complications of
Brucellosis. Infect Med, 2002. 19: 384–6.
39. Akyar I, [Antibiotic resistance rates of
extended spectrum beta-lactamase produc-
ing Escherichia coli and Klebsiella spp.
strains isolated from urinary tract infec-
tions in a private hospital]. Mikrobiyol
Bul, 2008. 42(4): 713–5.
40. Alakomi HL, Skytta E, Saarela M,
Mattila-Sandholm T, Latva-Kala K, and
Helander IM, Lactic acid permeabilizes
gram-negative bacteria by disrupting the
outer membrane. Appl Environ Microbiol,
2000. 66(5): 2001–5.
41. Alamuri P and Mobley HL, A novel
autotransporter of uropathogenic Proteus
mirabilis is both a cytotoxin and an
agglutinin. Mol Microbiol, 2008. 68(4):
997–1017.
42. Alamuri P, Eaton KA, Himpsl SD, Smith
SN, and Mobley HL, Vaccination with
proteus toxic agglutinin, a hemolysin-
independent cytotoxin in vivo, protects
against Proteus mirabilis urinary tract
infection. Infect Immun, 2009. 77(2):
632–41.
43. Alangaden GJ, Thyagarajan R, Gruber
SA, Morawski K, Garnick J, El-Amm JM,
West MS, Sillix DH, Chandrasekar PH,
and Haririan A, Infectious complications
References
after kidney transplantation: current
epidemiology and associated risk factors.
Clin Transplant, 2006. 20(4): 401–9.
44. Ala-Opas M, Talja M, Tiitinen J, Hellstrom
P, Heikkinen A, and Nurmi M, Prostakath
in urinary outflow obstruction. Ann Chir
Gynaecol Suppl, 1993. 206: 14–8.
45. Albert X, Huertas I, Pereiro, II, Sanfelix
J, Gosalbes V, and Perrota C, Antibiotics
for preventing recurrent urinary tract
infection in non-pregnant women.
Cochrane Database Syst Rev, 2004(3):
CD001209.
46. Alberti C, Brun-Buisson C, Burchardi
H, Martin C, Goodman S, Artigas A,
Sicignano A, Palazzo M, Moreno R,
Boulme R, Lepage E, and Le Gall R,
Epidemiology of sepsis and infection in
ICU patients from an international mul-
ticentre cohort study. Intensive Care Med,
2002. 28(2): 108–21.
47. Alderson P, Green S, and Higgins JPT,
eds. Cochrane Reviewers’ Handbook 4.2.2.
[updated March 2004]. 2004, John Wiley
& Sons, Ltd. The Cochrane Library, Issue
1, 2004: Chichester, UK.
48. Alexeyev O, Bergh J, Marklund I,
Thellenberg-Karlsson C, Wiklund F,
Gronberg H, Bergh A, and Elgh F,
Association between the presence of bacte-
rial 16S RNA in prostate specimens taken
during transurethral resection of prostate
and subsequent risk of prostate cancer
(Sweden). Cancer Causes Control, 2006.
17(9): 1127–33.
49. al-Ghorab MM, Radiological manifesta-
tions of genito-urinary bilharziasis. Clin
Radiol, 1968. 19(1): 100–11.
50. Al-Habdan I, Sadat-Ali M, Corea JR,
Al-Othman A, Kamal BA, and Shriyan
DS, Assessment of nosocomial urinary
tract infections in orthopaedic patients: a
prospective and comparative study using
two different catheters. Int Surg, 2003.
88(3): 152–4.
51. Alhambra A, Cuadros JA, Cacho J,
Gomez-Garces JL, and Alos JI, In vitro
susceptibility of recent antibiotic-resist-
ant urinary pathogens to ertapenem
and 12 other antibiotics. J Antimicrob
Chemother, 2004. 53(6): 1090–4.
52. Ali-Khan Z and Rausch RL,
Demonstration of amyloid and immune
995
References
complex deposits in renal and hepatic
parenchyma of Alaskan alveolar hydatid
disease patients. Ann Trop Med Parasitol,
1987. 81(4): 381–92.
53. Allan WR and Kumar A, Prophylactic
mezlocillin for transurethral prostatec-
tomy. Br J Urol, 1985. 57(1): 46–9.
54. Allen D, Mishra V, Pepper W, Shah S, and
Motiwala H, A single-center experience of
symptomatic male urethral diverticula.
Urology, 2007. 70(4): 650–3.
55. Allen NE, Hobbs JN, and Alborn WE, Jr.,
Inhibition of peptidoglycan biosynthesis
in gram-positive bacteria by LY146032.
Antimicrob Agents Chemother, 1987.
31(7): 1093–9.
56. Almallah YZ, Rennie CD, Stone J, and
Lancashire MJ, Urinary tract infection
and patient satisfaction after flexible
cystoscopy and urodynamic evaluation.
Urology, 2000. 56(1): 37–9.
57. Almuneef M, Memish ZA, Al Shaalan
M, Al Banyan E, Al-Alola S, and Balkhy
HH, Brucella melitensis bacteremia in
children: review of 62 cases. J Chemother,
2003. 15(1): 76–80.
58. Al-Orifi F, McGillivray D, Tange S, and
Kramer MS, Urine culture from bag speci-
mens in young children: are the risks too
high? J Pediatr, 2000. 137(2): 221–6.
59. Alos JI, Garcia-Pena P, and Tamayo J,
[Biological cost associated with fosfomy-
cin resistance in Escherichia coli isolates
from urinary tract infections]. Rev Esp
Quimioter, 2007. 20(2): 211–5.
60. Al-Saeed O, Sheikh M, Kehinde EO,
and Makar R, Seminal vesicle masses
detected incidentally during transrectal
sonographic examination of the prostate. J
Clin Ultrasound, 2003. 31(4): 201–6.
61. Al-Sayyad AJ, Pike JG, and Leonard MP,
Can prophylactic antibiotics safely be dis-
continued in children with vesicoureteral
reflux? J Urol, 2005. 174(4 Pt 2): 1587–9;
discussion 1589.
62. Al-Shukri S and Alwan MH, Bilharzial
strictures of the lower third of the ureter: a
critical review of 560 strictures. Br J Urol,
1983. 55(5): 477–82.
63. Al-Shukri S, Alwan MH, and Nayef M,
[Ureteral strictures caused by bilhar-
ziasis]. Z Urol Nephrol, 1987. 80(11):
615–24.
996
64. Altaweel W, Jednack R, Bilodeau C, and
Corcos J, Repeated intradetrusor botuli-
num toxin type A in children with neuro-
genic bladder due to myelomeningocele. J
Urol, 2006. 175(3 Pt 1): 1102–5.
65. Alteri CJ and Mobley HL, Quantitative
profile of the uropathogenic Escherichia
coli outer membrane proteome during
growth in human urine. Infect Immun,
2007. 75(6): 2679–88.
66. Alvarez-Lerma F, Nolla-Salas J, Leon
C, Palomar M, Jorda R, Carrasco N,
and Bobillo F, Candiduria in critically
ill patients admitted to intensive care
medical units. Intensive Care Med, 2003.
29(7): 1069–76.
67. Alwall N, On controversial and open ques-
tions about the course and complications
of non-obstructive urinary tract infection
in adult women. Follow-up for up to 80
months of 707 participants in a population
study and evaluation of a clinical series
of 36 selected women with a history of uri-
nary tract infection for up to 40 years. Acta
Med Scand, 1978. 203(5): 369–77.
68. Ambiru S, Kato A, Kimura F, Shimizu H,
Yoshidome H, Otsuka M, and Miyazaki
M, Poor postoperative blood glucose con-
trol increases surgical site infections after
surgery for hepato-biliary-pancreatic can-
cer: a prospective study in a high-volume
institute in Japan. J Hosp Infect, 2008.
68(3): 230–3.
69. Ambler RP, The structure of beta-lactama-
ses. Philos Trans R Soc Lond B Biol Sci,
1980. 289(1036): 321–31.
70. Ambrose PG, Bhavnani SM, and Owens
RC, Jr., Clinical pharmacodynamics of
quinolones. Infect Dis Clin North Am,
2003. 17(3): 529–43.
71. American Society of Anesthesiologists.
ASA physical Status Classification
System. Available from: http://asahq.org/
clinical/physicalstatus.htm.
72. Amesur P, Castronuovo JJ, and
Chandramouly B, Infected cyst localiza-
tion with gallium SPECT imaging in
polycystic kidney disease. Clin Nucl Med,
1988. 13(1): 35–7.
73. Ameur A, Lezrek M, Boumdin H, Touiti
D, Abbar M, and Beddouch A, [Hydatid
cyst of the kidney based on a series of 34
cases]. Prog Urol, 2002. 12(3): 409–14.

74. Amirkhanian YA, Kelly JA, Kirsanova
AV, DiFranceisco W, Khoursine RA,
Semenov AV, and Rozmanova VN, HIV
risk behaviour patterns, predictors, and
sexually transmitted disease prevalence
in the social networks of young men who
have sex with men in St Petersburg,
Russia. Int J STD AIDS, 2006. 17(1):
50–6.
75. Amis S, Ruddy M, Kibbler CC,
Economides DL, and MacLean AB,
Assessment of condoms as probe cov-
ers for transvaginal sonography. J Clin
Ultrasound, 2000. 28(6): 295–8.
76. Ammon HPT, Arzneimittelneben- und
-wechselwirkungen: ein Handbuch und
Tabellenwerk für Ärzte und Apotheker.
4., neu bearbeitet und erw. Aufl. ed.
2001, Stuttgart: Wissenschaftliche
Verlagsgesellschaft. xiii, 1738 p.
77. Anagrius C, Lore B, and Jensen JS,
Mycoplasma genitalium: prevalence, clini-
cal significance, and transmission. Sex
Transm Infect, 2005. 81(6): 458–62.
78. Anatoliotaki M, Galanakis E, Schinaki
A, Stefanaki S, Mavrokosta M, and
Tsilimigaki A, Antimicrobial resistance
of urinary tract pathogens in children in
Crete, Greece. Scand J Infect Dis, 2007.
39(8): 671–5.
79. Anders HJ and Patole PS, Toll-like recep-
tors recognize uropathogenic Escherichia
coli and trigger inflammation in the
urinary tract. Nephrol Dial Transplant,
2005. 20(8): 1529–32.
80. Andersen BR, Kallehave FL, and
Andersen HK, Antibiotics versus placebo
for prevention of postoperative infection
after appendicectomy. Cochrane Database
Syst Rev, 2005(3): CD001439.
81. Anderson GG, Martin SM, and Hultgren
SJ, Host subversion by formation of intra-
cellular bacterial communities in the uri-
nary tract. Microbes Infect, 2004. 6(12):
1094–101.
82. Anderson GG, Palermo JJ, Schilling
JD, Roth R, Heuser J, and Hultgren SJ,
Intracellular bacterial biofilm-like pods
in urinary tract infections. Science, 2003.
301(5629): 105–7.
83. Anderson MR, Klink K, and Cohrssen A,
Evaluation of vaginal complaints. JAMA,
2004. 291(11): 1368–79.
References
84. Andersson DI, The biological cost of
mutational antibiotic resistance: any prac-
tical conclusions? Curr Opin Microbiol,
2006. 9(5): 461–5.
85. Andersson K, Odlind V, and Rybo G,
Levonorgestrel-releasing and copper-
releasing (Nova T) IUDs during five years
of use: a randomized comparative trial.
Contraception, 1994. 49(1): 56–72.
86. Andersson P, Engberg I, Lidin-Janson G,
Lincoln K, Hull R, Hull S, and Svanborg
C, Persistence of Escherichia coli bacteriu-
ria is not determined by bacterial adher-
ence. Infect Immun, 1991. 59(9): 2915–21.
87. Ando E, Monden K, Mitsuhata R,
Kariyama R, and Kumon H, Biofilm
formation among methicillin-resistant
Staphylococcus aureus isolates from
patients with urinary tract infection. Acta
Med Okayama, 2004. 58(4): 207–14.
88. Andrade SS, Sader HS, Jones RN,
Pereira AS, Pignatari AC, and Gales AC,
Increased resistance to first-line agents
among bacterial pathogens isolated from
urinary tract infections in Latin America:
time for local guidelines? Mem Inst
Oswaldo Cruz, 2006. 101(7): 741–8.
89. Andre M, Vernby A, Odenholt I, Lundborg
CS, Axelsson I, Eriksson M, Runehagen
A, Schwan A, and Molstad S, Diagnosis-
prescribing surveys in 2000, 2002 and
2005 in Swedish general practice:
Consultations, diagnosis, diagnostics and
treatment choices. Scand J Infect Dis,
2008: 1–7.
90. Andres FJ, Parker R, Hosein I, and
Benrubi GI, Clindamycin vaginal cream
versus oral metronidazole in the treat-
ment of bacterial vaginosis: a prospective
double-blind clinical trial. South Med J,
1992. 85(11): 1077–80.
91. Andrews JM, BSAC standardized disc
susceptibility testing method (version 7).
J Antimicrob Chemother, 2008. 62(2):
256–78.
92. Andrews SJ, Brooks PT, Hanbury DC,
King CM, Prendergast CM, Boustead GB,
and McNicholas TA, Ultrasonography
and abdominal radiography versus
intravenous urography in investigation
of urinary tract infection in men: prospec-
tive incident cohort study. BMJ, 2002.
324(7335): 454–6.
997
References
93. Anfora AT and Welch RA, DsdX is the sec-
ond D-serine transporter in uropathogenic
Escherichia coli clinical isolate CFT073. J
Bacteriol, 2006. 188(18): 6622–8.
94. Anfora AT, Halladin DK, Haugen
BJ, and Welch RA, Uropathogenic
Escherichia coli CFT073 is adapted to
acetatogenic growth but does not require
acetate during murine urinary tract
infection. Infect Immun, 2008. 76(12):
5760–7.
95. Anfora AT, Haugen BJ, Roesch P,
Redford P, and Welch RA, Roles of serine
accumulation and catabolism in the colo-
nization of the murine urinary tract by
Escherichia coli CFT073. Infect Immun,
2007. 75(11): 5298–304.
96. Ang BS, Telenti A, King B, Steckelberg
JM, and Wilson WR, Candidemia from
a urinary tract source: microbiological
aspects and clinical significance. Clin
Infect Dis, 1993. 17(4): 662–6.
97. Angulo JC, Sanchez-Chapado M, Diego
A, Escribano J, Tamayo JC, and Martin
L, Renal echinococcosis: clinical study of
34 cases. J Urol, 1997. 157(3): 787–94.
98. Angus DC and Wax RS, Epidemiology of
sepsis: an update. Crit Care Med, 2001.
29(7 Suppl): S109–16.
99. Angus DC, Linde-Zwirble WT, Lidicker
J, Clermont G, Carcillo J, and Pinsky
MR, Epidemiology of severe sepsis in the
United States: analysis of incidence, out-
come, and associated costs of care. Crit
Care Med, 2001. 29(7): 1303–10.
100. Anjuere F, del Hoyo GM, Martin P, and
Ardavin C, Langerhans cells develop
from a lymphoid-committed precursor.
Blood, 2000. 96(5): 1633–7.
101. Annane D, Bellissant E, and Cavaillon
JM, Septic shock. Lancet, 2005.
365(9453): 63–78.
102. Annane D, Bellissant E, Bollaert
PE, Briegel J, Keh D, and Kupfer Y,
Corticosteroids for severe sepsis and sep-
tic shock: a systematic review and meta-
analysis. BMJ, 2004. 329(7464): 480.
103. Annane D, Sebille V, Charpentier C,
Bollaert PE, Francois B, Korach JM,
Capellier G, Cohen Y, Azoulay E, Troche
G, Chaumet-Riffaud P, and Bellissant
E, Effect of treatment with low doses of
hydrocortisone and fludrocortisone on
998
mortality in patients with septic shock.
JAMA, 2002. 288(7): 862–71.
104. Annane D, Vignon P, Renault A,
Bollaert PE, Charpentier C, Martin
C, Troche G, Ricard JD, Nitenberg G,
Papazian L, Azoulay E, and Bellissant
E, Norepinephrine plus dobutamine ver-
sus epinephrine alone for management of
septic shock: a randomised trial. Lancet,
2007. 370(9588): 676–84.
105. Antibiotic prophylaxis for urological
patients with total joint replacements. J
Urol, 2003. 169(5): 1796–7.
106. Antimicrobial prophylaxis for surgery.
Treat Guidel Med Lett, 2006. 4(52):
83–8.
107. Anukam KC, Osazuwa E, Osemene
GI, Ehigiagbe F, Bruce AW, and Reid
G, Clinical study comparing probiotic
Lactobacillus GR-1 and RC-14 with
metronidazole vaginal gel to treat symp-
tomatic bacterial vaginosis. Microbes
Infect, 2006. 8(12–13): 2772–6.
108. Aphinives C, Pacheerat K, Chaiyakum
J, Laopaiboon V, Aphinives P, and
Phuttharak W, Prostatic abscesses: radi-
ographic findings and treatment. J Med
Assoc Thai, 2004. 87(7): 810–5.
109. Aphonin AB, Perezmanas EO,
Toporkova EE, and Khodakovsky EP
Tuberculous infection as sexually trans-
mitted infection. Vestnik poslediplom-
nogo obrazovaniya, 2006. 3–4: 69–71.
110. Apisarnthanarak A, Thongphubeth K,
Sirinvaravong S, Kitkangvan D, Yuekyen
C, Warachan B, Warren DK, and Fraser
VJ, Effectiveness of multifaceted hospi-
talwide quality improvement programs
featuring an intervention to remove unnec-
essary urinary catheters at a tertiary care
center in Thailand. Infect Control Hosp
Epidemiol, 2007. 28(7): 791–8.
111. Arbeit RD, Maki D, Tally FP,
Campanaro E, and Eisenstein BI, The
safety and efficacy of daptomycin for
the treatment of complicated skin and
skin-structure infections. Clin Infect Dis,
2004. 38(12): 1673–81.
112. Arca P, Reguera G, and Hardisson C,
Plasmid-encoded fosfomycin resistance in
bacteria isolated from the urinary tract
in a multicentre survey. J Antimicrob
Chemother, 1997. 40(3): 393–9.

113. Ariza J, Bosilkovski M, Cascio A,
Colmenero JD, Corbel MJ, Falagas ME,
Memish ZA, Roushan MR, Rubinstein
E, Sipsas NV, Solera J, Young EJ, and
Pappas G, Perspectives for the treatment
of brucellosis in the 21st century: the
Ioannina recommendations. PLoS Med,
2007. 4(12): e317.
114. Armenakas NA, Schevchuk MM,
Brodherson M, and Fracchia JA, AIDS
presenting as primary testicular lym-
phoma. Urology, 1992. 40(2): 162–4.
115. Aron M, Rajeev TP, and Gupta NP,
Antibiotic prophylaxis for transrectal
needle biopsy of the prostate: a rand-
omized controlled study. BJU Int, 2000.
85(6): 682–5.
116. Aronoff DM, Hao Y, Chung J, Coleman
N, Lewis C, Peres CM, Serezani CH,
Chen GH, Flamand N, Brock TG, and
Peters-Golden M, Misoprostol impairs
female reproductive tract innate immu-
nity against Clostridium sordellii. J
Immunol, 2008. 180(12): 8222–30.
117. Aronoff GR, Drug prescribing in renal
failure: dosing guidelines for adults. 4th
ed. 1999, Philadelphia, PA.: American
College of Physicians. 176 p.
118. Arreaza L, Vazquez F, Alcala B, Otero L,
Salcedo C, and Vazquez JA, Emergence
of gonococcal strains with resistance to
azithromycin in Spain. J Antimicrob
Chemother, 2003. 51(1): 190–1.
119. Arredondo-Garcia JL, Figueroa-Damian
R, Rosas A, Jauregui A, Corral M,
Costa A, Merlos RM, Rios-Fabra A,
Amabile-Cuevas CF, Hernandez-Oliva
GM, Olguin J, and Cardenosa-Guerra
O, Comparison of short-term treatment
regimen of ciprofloxacin versus long-term
treatment regimens of trimethoprim/
sulfamethoxazole or norfloxacin for
uncomplicated lower urinary tract infec-
tions: a randomized, multicentre, open-
label, prospective study. J Antimicrob
Chemother, 2004. 54(4): 840–3.
120. Arsene S and Leclercq R, Role of a qnr-
like gene in the intrinsic resistance of
Enterococcus faecalis to fluoroquinolo-
nes. Antimicrob Agents Chemother,
2007. 51(9): 3254–8.
121. Arthur RR and Shah KV, Occurrence
and significance of papovaviruses BK
References
and JC in the urine. Prog Med Virol,
1989. 36: 42–61.
122. Arthur RR, Shah KV, Baust SJ, Santos
GW, and Saral R, Association of BK viru-
ria with hemorrhagic cystitis in recipi-
ents of bone marrow transplants. N Engl
J Med, 1986. 315(4): 230–4.
123. Artz L, Macaluso M, Meinzen-Derr J,
Kelaghan J, Austin H, Fleenor M, Hook
EW, 3rd, and Brill I, A randomized trial
of clinician-delivered interventions pro-
moting barrier contraception for sexu-
ally transmitted disease prevention. Sex
Transm Dis, 2005. 32(11): 672–9.
124. Arya OP, Mallinson H, and Goddard AD,
Epidemiological and clinical correlates
of chlamydial infection of the cervix. Br J
Vener Dis, 1981. 57(2): 118–24.
125. Asahara T, Nomoto K, Watanuki M, and
Yokokura T, Antimicrobial activity of
intraurethrally administered probiotic
Lactobacillus casei in a murine model of
Escherichia coli urinary tract infection.
Antimicrob Agents Chemother, 2001.
45(6): 1751–60.
126. Asbach HW, Single dose oral administra-
tion of cefixime 400mg in the treatment of
acute uncomplicated cystitis and gonor-
rhoea. Drugs, 1991. 42 Suppl 4: 10–3.
127. Asher EF, Oliver BG, and Fry DE,
Urinary tract infections in the surgical
patient. Am Surg, 1988. 54(7): 466–9.
128. Asscher AW, Sussman M, Waters WE,
Evans JA, Campbell H, Evans KT, and
Williams JE, Asymptomatic significant
bacteriuria in the non-pregnant woman.
II. Response to treatment and follow-up.
Br Med J, 1969. 1(5647): 804–6.
129. Assicot M, Gendrel D, Carsin H,
Raymond J, Guilbaud J, and Bohuon C,
High serum procalcitonin concentrations
in patients with sepsis and infection.
Lancet, 1993. 341(8844): 515–8.
130. Association of the Scientific Medical
Societies in Germany. Available from:
www.awmf.org/.
131. Atashili J, Poole C, Ndumbe PM,
Adimora AA, and Smith JS, Bacterial
vaginosis and HIV acquisition: a meta-
analysis of published studies. AIDS,
2008. 22(12): 1493–501.
132. Atay Y, Altintas A, Tuncer I, and Cennet
A, Ovarian actinomycosis mimicking
999
References
malignancy. Eur J Gynaecol Oncol,
2005. 26(6): 663–4.
133. Atta MG, Gallant JE, Rahman MH,
Nagajothi N, Racusen LC, Scheel PJ,
and Fine DM, Antiretroviral therapy in
the treatment of HIV-associated neph-
ropathy. Nephrol Dial Transplant, 2006.
21(10): 2809–13.
134. Atta MG, Lucas GM, and Fine DM, HIV-
associated nephropathy: epidemiology,
pathogenesis, diagnosis and manage-
ment. Expert Rev Anti Infect Ther, 2008.
6(3): 365–71.
135. Auerbach JD, Hayes RJ, and Kandathil
SM, Overview of effective and promising
interventions to prevent HIV infection.
World Health Organ Tech Rep Ser, 2006.
938: 43–78; discussion 317–41.
136. Auge BK, Pietrow PK, Lallas CD, Raj
GV, Santa-Cruz RW, and Preminger GM,
Ureteral access sheath provides protec-
tion against elevated renal pressures
during routine flexible ureteroscopic
stone manipulation. J Endourol, 2004.
18(1): 33–6.
137. Auger P and Joly J, Microbial flora
associated with Candida albicans vul-
vovaginitis. Obstet Gynecol, 1980. 55(3):
397–401.
138. Auger P, Dumas C, and Joly J, A study
of 666 strains of Candida albicans: cor-
relation between serotype and suscepti-
bility to 5-fluorocytosine. J Infect Dis,
1979. 139(5): 590–4.
139. Ault KA, Statland BD, King MM,
Dozier DI, Joachims ML, and Gunter J,
Antibodies to the chlamydial 60 kilodal-
ton heat shock protein in women with
tubal factor infertility. Infect Dis Obstet
Gynecol, 1998. 6(4): 163–7.
140. Aune A, Alraek T, LiHua H, and
Baerheim A, Acupuncture in the prophy-
laxis of recurrent lower urinary tract
infection in adult women. Scand J Prim
Health Care, 1998. 16(1): 37–9.
141. Auquer F, Cordon F, Gorina E, Caballero
JC, Adalid C, and Batlle J, Single-dose
ciprofloxacin versus 3 days of norfloxacin
in uncomplicated urinary tract infections
in women. Clin Microbiol Infect, 2002.
8(1): 50–4.
142. Aus G, Ahlgren G, Bergdahl S, and
Hugosson J, Infection after transrectal
1000
core biopsies of the prostate—risk factors
and antibiotic prophylaxis. Br J Urol,
1996. 77(6): 851–5.
143. Austenfeld MS and Snow BW,
Complications of pregnancy in women
after reimplantation for vesicoureteral
reflux. J Urol, 1988. 140(5 Pt 2): 1103–6.
144. Austin BJ, Bollard C, and Gunn TR,
Is urethral catheterization a successful
alternative to suprapubic aspiration in
neonates? J Paediatr Child Health, 1999.
35(1): 34–6.
145. Austin PF, Homsy YL, Masel JL, Cain
MP, Casale AJ, and Rink RC, alpha-
Adrenergic blockade in children with
neuropathic and nonneuropathic voiding
dysfunction. J Urol, 1999. 162(3 Pt 2):
1064–7.
146. Australian Gonococcal Surveillance
Programme A-G. Annual report of the
Australian Gonococcal Surveillance
Program, 2006. 2007; Available from:
http://www.aodgp.gov.au/internet/main/
publishing.nsf/Content/cda-pubs-annl-
rpt-gonoanrep.htm.
147. Australian Gonococcal Surveillance
Programme A-G. Annual report of the
Australian Gonococcal Surveillance
Program, 2007. 2008; Available from:
http://www.aodgp.gov.au/internet/main/
publishing.nsf/Content/cda-pubs-annl-
rpt-gonoanrep.htm.
148. Auvert B, Buve A, Ferry B, Carael M,
Morison L, Lagarde E, Robinson NJ,
Kahindo M, Chege J, Rutenberg N,
Musonda R, Laourou M, and Akam
E, Ecological and individual level
analysis of risk factors for HIV infec-
tion in four urban populations in sub-
Saharan Africa with different levels of
HIV infection. Aids, 2001. 15 Suppl 4:
S15–30.
149. Auvert B, Buve A, Lagarde E, Kahindo
M, Chege J, Rutenberg N, Musonda R,
Laourou M, Akam E, and Weiss HA,
Male circumcision and HIV infection in
four cities in sub-Saharan Africa. Aids,
2001. 15 Suppl 4: S31–40.
150. Auvert B, Taljaard D, Lagarde E,
Sobngwi-Tambekou J, Sitta R, and
Puren A, Randomized, controlled inter-
vention trial of male circumcision for
reduction of HIV infection risk: the

ANRS 1265 Trial. PLoS Med, 2005.
2(11): e298.
151. Avila MM, Pando MA, Carrion G, Peralta
LM, Salomon H, Carrillo MG, Sanchez
J, Maulen S, Hierholzer J, Marinello M,
Negrete M, Russell KL, and Carr JK,
Two HIV-1 epidemics in Argentina: dif-
ferent genetic subtypes associated with
different risk groups. J Acquir Immune
Defic Syndr, 2002. 29(4): 422–6.
152. Avorn J, Monane M, Gurwitz J, Glynn
R, Choodnovskiy I, and Lipsitz L,
Reduction of bacteriuria and pyuria
after ingestion of Cranberry juice. JAMA,
1994. 271(10): 751–4.
153. Avorn J, Monane M, Gurwitz JH, Glynn
RJ, Choodnovskiy I, and Lipsitz LA,
Reduction of bacteriuria and pyuria
after ingestion of cranberry juice. JAMA,
1994. 271(10): 751–4.
154. Aydin D, Kucukbasmaci O, Gonullu N,
and Aktas Z, Susceptibilities of Neisseria
gonorrhoeae and Ureaplasma urealyti-
cum isolates from male patients with
urethritis to several antibiotics includ-
ing telithromycin. Chemotherapy, 2005.
51(2–3): 89–92.
155. Ayliffe GA, Role of the environment of
the operating suite in surgical wound
infection. Rev Infect Dis, 1991. 13 Suppl
10: S800–4.
156. Ayliffe GA, The use of ethylene oxide and
low temperature steam/formaldehyde in
hospitals. Infection, 1989. 17(2): 109–10.
157. Baan AH, Vermeulen H, van der Meulen
J, Bossuyt P, Olszyna D, and Gouma
DJ, The effect of suprapubic catheteriza-
tion versus transurethral catheterization
after abdominal surgery on urinary tract
infection: a randomized controlled trial.
Dig Surg, 2003. 20(4): 290–5.
158. Baba M, Mori S, Shigeta S, and
De Clercq E, Selective inhibi-
tory effect of (S)-9-(3-hydroxy-2-
phosphonylmethoxypropyl)adenine
and 2’-nor-cyclic GMP on adenovirus
replication in vitro. Antimicrob Agents
Chemother, 1987. 31(2): 337–9.
159. Baba-Moussa L, Anani L, Scheftel
JM, Couturier M, Riegel P, Haikou N,
Hounsou F, Monteil H, Sanni A, and
Prevost G, Virulence factors produced by
strains of Staphylococcus aureus isolated
References
from urinary tract infections. J Hosp
Infect, 2008. 68(1): 32–8.
160. Babb JR, Lynam P, and Ayliffe GA, Risk
of airborne transmission in an operat-
ing theatre containing four ultraclean
air units. J Hosp Infect, 1995. 31(3):
159–68.
161. Babula O, Lazdane G, Kroica J,
Linhares IM, Ledger WJ, and Witkin
SS, Frequency of interleukin-4 (IL-4)
-589 gene polymorphism and vaginal
concentrations of IL-4, nitric oxide, and
mannose-binding lectin in women with
recurrent vulvovaginal candidiasis. Clin
Infect Dis, 2005. 40(9): 1258–62.
162. Bacelar A, Castro LG, de Queiroz AC,
and Cafe E, Association between prostate
cancer and schistosomiasis in young
patients: a case report and literature
review. Braz J Infect Dis, 2007. 11(5):
520–2.
163. Bacheller CD and Bernstein JM,
Urinary tract infections. Med Clin North
Am, 1997. 81(3): 719–30.
164. Backhouse CI and Matthews JA, Single-
dose enoxacin compared with 3-day
treatment for urinary tract infection.
Antimicrob Agents Chemother, 1989.
33(6): 877–80.
165. Bae KT, Zhu F, Chapman AB, Torres
VE, Grantham JJ, Guay-Woodford LM,
Baumgarten DA, King BF, Jr., Wetzel
LH, Kenney PJ, Brummer ME, Bennett
WM, Klahr S, Meyers CM, Zhang X,
Thompson PA, and Miller JP, Magnetic
resonance imaging evaluation of hepatic
cysts in early autosomal-dominant poly-
cystic kidney disease: the Consortium for
Radiologic Imaging Studies of Polycystic
Kidney Disease cohort. Clin J Am Soc
Nephrol, 2006. 1(1): 64–9.
166. Baert L, Leonard A, D’Hoedt M, and
Vandeursen R, Seminal vesiculography
in chronic bacterial prostatitis. J Urol,
1986. 136(4): 844–5.
167. Baetz-Greenwalt B, Debaz B, and
Kumar ML, Bladder fungus ball: a
reversible cause of neonatal obstructive
uropathy. Pediatrics, 1988. 81(6): 826–9.
168. Bag urine specimens still not appropri-
ate in diagnosing urinary tract infec-
tions in infants. Can J Infect Dis Med
Microbiol, 2004. 15(4): 210–1.
1001
References
169. Baggiolini M, Dewald B, and Moser B,
Interleukin-8 and related chemotactic
cytokines-CXC and CC chemokines. Adv
in Immunol, 1994. 55: 97–179.
170. Bagshaw SM and Laupland KB,
Epidemiology of intensive care unit-
acquired urinary tract infections. Curr
Opin Infect Dis, 2006. 19(1): 67–71.
171. Bahrani-Mougeot FK, Buckles EL,
Lockatell CV, Hebel JR, Johnson DE,
Tang CM, and Donnenberg MS, Type
1 fimbriae and extracellular polysac-
charides are preeminent uropathogenic
Escherichia coli virulence determi-
nants in the murine urinary tract. Mol
Microbiol, 2002. 45(4): 1079–93.
172. Baier W, Sedelmeier EA, and Bessler
WG, Studies on the immunogenicity of an
Escherichia coli extract after oral appli-
cation in mice. Arzneimittelforschung,
1997. 47(8): 980–5.
173. Baijal SS, Basarge N, Srinadh ES,
Mittal BR, and Kumar A, Percutaneous
management of renal hydatidosis: a
minimally invasive therapeutic option. J
Urol, 1995. 153(4): 1199–201.
174. Bailey RC, Moses S, Parker CB, Agot
K, Maclean I, Krieger JN, Williams CF,
Campbell RT, and Ndinya-Achola JO,
Male circumcision for HIV prevention
in young men in Kisumu, Kenya: a ran-
domised controlled trial. Lancet, 2007.
369(9562): 643–56.
175. Bakke A and Digranes A, Bacteriuria in
patients treated with clean intermittent
catheterization. Scand J Infect Dis, 1991.
23(5): 577–82.
176. Bakke A and Malt UF, Psychological
predictors of symptoms of urinary tract
infection and bacteriuria in patients
treated with clean intermittent catheteri-
zation: a prospective 7-year study. Eur
Urol, 1998. 34(1): 30–6.
177. Bakke A, Digranes A, and Hoisaeter
PA, Physical predictors of infection in
patients treated with clean intermittent
catheterization: a prospective 7-year
study. Br J Urol, 1997. 79(1): 85–90.
178. Bakke A, Irgens LM, Malt UF, and
Hoisaeter PA, Clean intermittent cathe-
terisation-performing abilities, aversive
experiences and distress. Paraplegia,
1993. 31(5): 288–97.
1002
179. Ball AJ, Carr TW, Gillespie WA, Kelly
M, Simpson RA, and Smith PJ, Bladder
irrigation with chlorhexidine for the
prevention of urinary infection after
transurethral operations: a prospective
controlled study. J Urol, 1987. 138(3):
491–4.
180. Ball P, Mandell L, Niki Y, and Tillotson
G, Comparative tolerability of the newer
fluoroquinolone antibacterials. Drug Saf,
1999. 21(5): 407–21.
181. Balsalobre C, Silvan JM, Berglund
S, Mizunoe Y, Uhlin BE, and Wai SN,
Release of the type I secreted alpha-
haemolysin via outer membrane vesicles
from Escherichia coli. Mol Microbiol,
2006. 59(1): 99–112.
182. Bamberger DM, Outcome of medical
treatment of bacterial abscesses without
therapeutic drainage: review of cases
reported in the literature. Clin Infect
Dis, 1996. 23(3): 592–603.
183. Banovac K, Wade N, Gonzalez F, Walsh
B, and Rhamy RK, Decreased incidence
of urinary tract infections in patients
with spinal cord injury: effect of meth-
enamine. J Am Paraplegia Soc, 1991.
14(2): 52–4.
184. Bantar C, Fernandez Canigia L, Diaz
C, Ibanez C, Soto M, Smayevsky J,
Rovegno A, Fernandez H, and Bianchi
H, [Clinical, epidemiologic, and micro-
biologic study of urinary infection in
patients with renal transplant at a spe-
cialized center in Argentina]. Arch Esp
Urol, 1993. 46(6): 473–7; discussion
477–8.
185. Barabas G and Molstad S, No associa-
tion between elevated post-void residual
volume and bacteriuria in residents of
nursing homes. Scand J Prim Health
Care, 2005. 23(1): 52–6.
186. Barbut F, Richard A, Hamadi K,
Chomette V, Burghoffer B, and Petit JC,
Epidemiology of recurrences or reinfec-
tions of Clostridium difficile-associated
diarrhea. J Clin Microbiol, 2000. 38(6):
2386–8.
187. Barisic Z, Vrsalovic-Carevic N, Milostic
K, Alfirevic D, Babic-Erceg A, Borzic E,
Zoranic V, Kaliterna V, and Carev M,
Tuberculous orchiepididymitis diagnosed
by nucleic acid amplification test: a case

report. Int Urol Nephrol, 2003. 35(2):
203–5.
188. Barry HC, Hickner J, Ebell MH, and
Ettenhofer T, A randomized controlled
trial of telephone management of sus-
pected urinary tract infections in women.
J Fam Pract, 2001. 50(7): 589–94.
189. Barsoum RS, Schistosomiasis and the
kidney. Semin Nephrol, 2003. 23(1):
34–41.
190. Bartlett BL, Tyring SK, Fife K, Gnann
JW, Jr., Hadala JT, Kianifard F, and
Berber E, Famciclovir treatment options
for patients with frequent outbreaks of
recurrent genital herpes: the RELIEF
trial. J Clin Virol, 2008. 43(2): 190–5.
191. Barton GM and Medzhitov R, Toll-like
receptor signaling pathways. Science,
2003. 300(5625): 1524–5.
192. Bartone FF, Hurwitz RS, Rojas EL,
Steinberg E, and Franceschini R, The
role of percutaneous nephrostomy in the
management of obstructing candidiasis
of the urinary tract in infants. J Urol,
1988. 140(2): 338–41.
193. Barutcu O, Erel HE, Saygili E, Yildirim
T, and Torun D, Abdominopelvic tuber-
culosis simulating disseminated ovarian
carcinoma with elevated CA-125 level:
report of two cases. Abdom Imaging,
2002. 27(4): 465–70.
194. Basilio-de-Oliveira CA, Aquino A, Simon
EF, and Eyer-Silva WA, Concomitant
prostatic schistosomiasis and adenocar-
cinoma: case report and review. Braz J
Infect Dis, 2002. 6(1): 45–9.
195. Basquiera AL, Calafat P, Parodi JM, De
Diller AB, Zlocowski JC, and Caeiro JP,
Cytomegalovirus-induced haemorrhagic
cystitis in a patient with neurogenic
bladder. Scand J Infect Dis, 2003. 35(11–
12): 902–4.
196. Bauer HW, Alloussi S, Egger G,
Blumlein HM, Cozma G, and Schulman
CC, A long-term, multicenter, double-
blind study of an Escherichia coli extract
(OM-89) in female patients with recur-
rent urinary tract infections. Eur Urol,
2005. 47(4): 542–8; discussion 548.
197. Bauer HW, Rahlfs VW, Lauener PA, and
Blessmann GS, Prevention of recurrent
urinary tract infections with immuno-
active E. coli fractions: a meta-analysis
References
of five placebo-controlled double-blind
studies. Int J Antimicrob Agents, 2002.
19(6): 451–6.
198. Bauer SB, Hendren WH, Kozakewich
H, Maloney S, Colodny AH, Mandell J,
and Retik AB, Perforation of the aug-
mented bladder. J Urol, 1992. 148(2 Pt
2): 699–703.
199. Baumer JH and Jones RW, Urinary tract
infection in children, National Institute
for Health and Clinical Excellence. Arch
Dis Child Educ Pract Ed, 2007. 92(6):
189–92.
200. Baumgarten DA and Baumgartner BR,
Imaging and radiologic management of
upper urinary tract infections. Urol Clin
North Am, 1997. 24(3): 545–69.
201. Bautista OM, Kusek JW, Nyberg LM,
McConnell JD, Bain RP, Miller G,
Crawford ED, Kaplan SA, Sihelnik SA,
Brawer MK, and Lepor H, Study design
of the Medical Therapy of Prostatic
Symptoms (MTOPS) trial. Control Clin
Trials, 2003. 24(2): 224–43.
202. Bax L, Yu LM, Ikeda N, Tsuruta H, and
Moons KG, Development and validation
of MIX: comprehensive free software for
meta-analysis of causal research data.
BMC Med Res Methodol, 2006. 6: 50.
203. Baynham SA, Katner HP, and Cleveland
KB, Increased prevalence of renal cell
carcinoma in patients with HIV infec-
tion. AIDS Patient Care STDS, 1997.
11(3): 161–5.
204. Bazeed MA, Ashamalla A, Abd-
Alrazek AA, Ghoneim M, and Badr M,
Management of bilharzial strictures of
the lower ureter. Urol Int, 1982. 37(1):
19–25.
205. Bebear CM, de Barbeyrac B, Pereyre
S, Renaudin H, Clerc M, and Bebear C,
Activity of moxifloxacin against the uro-
genital mycoplasmas Ureaplasma spp.,
Mycoplasma hominis and Mycoplasma
genitalium and Chlamydia trachomatis.
Clin Microbiol Infect, 2008. 14(8): 801–5.
206. Beck EM and Riehle RA, Jr., The fate of
residual fragments after extracorporeal
shock wave lithotripsy monotherapy of
infection stones. J Urol, 1991. 145(1):
6–9; discussion 9–10.
207. Becker GJ, Ihle BU, Fairley KF, Bastos
M, and Kincaid-Smith P, Effect of
1003
References
pregnancy on moderate renal failure in
reflux nephropathy. Br Med J (Clin Res
Ed), 1986. 292(6523): 796–8.
208. Becopoulos T, Tsagatakis E,
Constantinides C, Paniara O, Mouka N,
and Psaras L, Ureaplasma urealyticum
and infected renal calculi. J Chemother,
1991. 3(1): 39–41.
209. Beekmann SE, Gilbert DN, and
Polgreen PM, Toxicity of extended
courses of linezolid: results of an
Infectious Diseases Society of America
Emerging Infections Network survey.
Diagn Microbiol Infect Dis, 2008. 62(4):
407–410.
210. Beerepoot MAJ and et al, Lactobacillus
rhamnosus GR-1 and L. reuteri RC-14
versus trimethoprim-sulfamethoxazole
(TMP/SMX) in the prevention of recur-
rent urinary tract infections (rUTIs) in
postmenopausal women: a randomized
double-blind non-inferiority trial.
ICAAC, 2009: Abstract L1–1656a.
211. Beeson PB and Guze LB, Experimental
pyelonephritis. I. Effect of ureteral liga-
tion on the course of bacterial infection
in the kidney of the rat. J Exp Med,
1956. 104(6): 803–15.
212. Beetz R, Bachmann H, Gatermann
S, Keller H, Kuwertz-Broking E,
Misselwitz J, Naber KG, Rascher W,
Scholz H, Thuroff JW, Vahlensieck W,
and Westenfelder M, [Urinary tract
infections in infants and children — a
consensus on diagnostic, therapy and
prophylaxis]. Urologe A, 2007. 46(2):
112, 114–8, 120–3.
213. Beetz R, Mannhardt W, Fisch M, Stein
R, and Thuroff JW, Long-term followup
of 158 young adults surgically treated
for vesicoureteral reflux in childhood: the
ongoing risk of urinary tract infections. J
Urol, 2002. 168(2): 704–7; discussion 707.
214. Beetz R, Schulte-Wissermann H, Troger
J, Riedmiller H, Mannhardt W, Schofer
O, and Hohenfellner R, Long-term
follow-up of children with surgically
treated vesicorenal reflux: postoperative
incidence of urinary tract infections,
renal scars and arterial hypertension.
Eur Urol, 1989. 16(5): 366–71.
215. Beigi RH, Meyn LA, Moore DM, Krohn
MA, and Hillier SL, Vaginal yeast
1004
colonization in nonpregnant women:
a longitudinal study. Obstet Gynecol,
2004. 104(5 Pt 1): 926–30.
216. Belda Junior W, Velho PE, Fagundes
LJ, and Arnone M, Evaluation of the in
vitro activity of six antimicrobial agents
against Neisseria gonorrhoeae. Rev Inst
Med Trop Sao Paulo, 2007. 49(1): 55–8.
217. Bellan C, De Falco G, Lazzi S, and
Leoncini L, Pathologic aspects of AIDS
malignancies. Oncogene, 2003. 22(42):
6639–45.
218. Bellomo R, Chapman M, Finfer S,
Hickling K, and Myburgh J, Low-
dose dopamine in patients with early
renal dysfunction: a placebo-controlled
randomised trial. Australian and
New Zealand Intensive Care Society
(ANZICS) Clinical Trials Group. Lancet,
2000. 356(9248): 2139–43.
219. Ben David S, Einarson T, Ben David Y,
Nulman I, Pastuszak A, and Koren G,
The safety of nitrofurantoin during the
first trimester of pregnancy: meta-analy-
sis. Fundam Clin Pharmacol, 1995. 9(5):
503–7.
220. Benador D, Benador N, Slosman D,
Mermillod B, and Girardin E, Are
younger children at highest risk of renal
sequelae after pyelonephritis? Lancet,
1997. 349(9044): 17–9.
221. Bengtsson C, Bengtsson U, Bjorkelund
C, Lincoln K, and Sigurdsson JA,
Bacteriuria in a population sample of
women: 24-year follow-up study. Results
from the prospective population-based
study of women in Gothenburg, Sweden.
Scand J Urol Nephrol, 1998. 32(4): 284–9.
222. Benjelloun S and Elmrini M, [Hydatid
cyst of the kidney (apropos of 45 cases)].
Prog Urol, 1993. 3(2): 209–15.
223. Benn PD, Rooney G, Carder C, Brown
M, Stevenson SR, Copas A, Robinson AJ,
and Ridgway GL, Chlamydia trachoma-
tis and Neisseria gonorrhoeae infection
and the sexual behaviour of men who
have sex with men. Sex Transm Infect,
2007. 83(2): 106–12.
224. Bennani S, Aboutaieb R, el Mrini M, and
Benjelloun S, [The role of corticotherapy
and endoscopy in the treatment of uro-
genital tuberculosis]. Ann Urol (Paris),
1994. 28(5): 243–9.

225. Bennett WM, Elzinga L, Pulliam JP,
Rashad AL, and Barry JM, Cyst fluid
antibiotic concentrations in autosomal-
dominant polycystic kidney disease. Am
J Kidney Dis, 1985. 6(6): 400–4.
226. Bennett WM, Plamp CE, Gilbert DN,
Parker RA, and Porter GA, The influ-
ence of dosage regimen on experimental
gentamicin nephrotoxicity: dissociation
of peak serum levels from renal failure. J
Infect Dis, 1979. 140(4): 576–80.
227. Benoit RM, Peele PB, and Docimo SG,
The cost-effectiveness of dextranomer/
hyaluronic acid copolymer for the man-
agement of vesicoureteral reflux. 1: sub-
stitution for surgical management. J
Urol, 2006. 176(4 Pt 1): 1588–92; discus-
sion 1592.
228. Benson M, Jodal U, Agace W,
Andreasson A, Mårild S, Stokland
E, Wettergren B, and Svanborg C,
Interleukin-6 and interleukin-8 in chil-
dren with febrile urinary tract infection
and asymptomatic bacteriuria. J Infect
Dis, 1996. 174: 1080–1084.
229. Benson MC and Olsson CA, Continent
urinary diversion, in Campbell’s urology,
Campbell MF and Walsh PC, Editors.
1998, W.B. Saunders Co.: Philadelphia.
p. 3190–3245.
230. Bent S, Nallamothu BK, Simel DL,
Fihn SD, and Saint S, Does this woman
have an acute uncomplicated urinary
tract infection? JAMA, 2002. 287(20):
2701–10.
231. Benveniste R and Davies J, Structure-
activity relationships among the
aminoglycoside antibiotics: role
of hydroxyl and amino groups.
Antimicrob Agents Chemother, 1973.
4(4): 402–9.
232. Benway BM and Moon TD, Bacterial
prostatitis. Urol Clin North Am, 2008.
35(1): 23–32; v.
233. Bergogne-Berezin E, Structure-
activity relationship of ceftazidime.
Consequences on the bacterial spectrum.
Presse Med., 1988. 17: 1878–1882.
234. Bergqvist D, Bronnestam R, Hedelin H,
and Stahl A, The relevance of urinary
sampling methods in patients with ind-
welling Foley catheters. Br J Urol, 1980.
52(2): 92–5.
References
235. Bergqvist D, Hedelin H, Stenstrom G,
and Stahl A, [Clinical evaluation of
Foley catheters]. Lakartidningen, 1979.
76(15): 1416–8.
236. Bergsten G, Samuelsson M, Wullt B,
Leijonhufvud I, Fischer H, and Svanborg
C, PapG-dependent adherence breaks
mucosal inertia and triggers the innate
host response. J Infect Dis, 2004. 189(9):
1734–42.
237. Bergsten G, Wullt B, Schembri MA,
Leijonhufvud I, and Svanborg C, Do type
1 fimbriae promote inflammation in the
human urinary tract? Cell Microbiol,
2007. 9(7): 1766–81.
238. Bernard GR, Vincent JL, Laterre
PF, LaRosa SP, Dhainaut JF, Lopez-
Rodriguez A, Steingrub JS, Garber GE,
Helterbrand JD, Ely EW, and Fisher CJ,
Jr., Efficacy and safety of recombinant
human activated protein C for severe
sepsis. N Engl J Med, 2001. 344(10):
699–709.
239. Bernardis Fd, Boccabera M, and Casone
A, The role of immunity against vaginal
candida infection, in Fungal immunol-
ogy: from an organ perspective, Fidel
PL and Huffnagle GB, Editors. 2005,
Springer: New York. p. xv, 492 p.
240. Bernd Sebastian Kamps. Available from:
www.hiv.net.
241. Berrouane YF, Herwaldt LA, and Pfaller
MA, Trends in antifungal use and epide-
miology of nosocomial yeast infections in
a university hospital. J Clin Microbiol,
1999. 37(3): 531–7.
242. Berry A and Barratt A, Prophylactic
antibiotic use in transurethral prostatic
resection: a meta-analysis. J Urol, 2002.
167(2 Pt 1): 571–7.
243. Bertapelle P, Bodo G, and Carone R,
Detrusor acontractility in urinary reten-
tion: detrusor contractility test as exclu-
sion criteria for sacral neurostimulation.
J Urol, 2008. 180(1): 215–6.
244. Bessler WG, Antibodies against OM-89,
Proteus mirabilis, and Klebsiella
pneumoniae in sera of OM-89 treated
patients from the clinical study
UV-1996/1 PROJECT UV 1999/03.
2002, Institut für Molekulare Medizin
und Zellforschung, Arbeitsbereich
Tumorimmunologie / Vakzine.
1005
References
Universitätsklinikum Freiburg:
Freiburg.
245. Best CD, Terris MK, Tacker JR, and
Reese JH, Clinical and radiological find-
ings in patients with gas forming renal
abscess treated conservatively. J Urol,
1999. 162(4): 1273–6.
246. Bettocchi C, Ditonno P, Palumbo F,
Lucarelli G, Garaffa G, Giammusso B,
and Battaglia M, Penile Prosthesis: What
Should We Do about Complications? Adv
Urol, 2008: 573560.
247. Beuerle JR and Barrueto F, Jr.,
Neurogenic bladder and chronic urinary
retention associated with MDMA abuse.
J Med Toxicol, 2008. 4(2): 106–8.
248. Beutler B and Moresco EM, The for-
ward genetic dissection of afferent innate
immunity. Curr Top Microbiol Immunol,
2008. 321: 3–26.
249. Bezold G, Politch JA, Kiviat NB,
Kuypers JM, Wolff H, and Anderson
DJ, Prevalence of sexually transmissible
pathogens in semen from asymptomatic
male infertility patients with and with-
out leukocytospermia. Fertil Steril, 2007.
87(5): 1087–97.
250. Bhakdi S, Mackman N, Menestrina G,
Gray L, Hugo F, Seeger W, and Holland
IB, The hemolysin of Escherichia coli.
Eur J Epidemiol, 1988. 4(2): 135–43.
251. Bhalla P, Baveja UK, Chawla R, Saini
S, Khaki P, Bhalla K, Mahajan S, and
Reddy BS, Simultaneous detection of
Neisseria gonorrhoeae and Chlamydia
trachomatis by PCR in genitourinary
specimens from men and women attend-
ing an STD clinic. J Commun Dis, 2007.
39(1): 1–6.
252. Bhushan S, Schuppe HC, Fijak M,
and Meinhardt A, Testicular infection:
microorganisms, clinical implications
and host-pathogen interaction. J Reprod
Immunol, 2009. 83(1–2): 164–7.
253. Bhushan S, Tchatalbachev S, Klug J,
Fijak M, Pineau C, Chakraborty T, and
Meinhardt A, Uropathogenic Escherichia
coli block MyD88-dependent and activate
MyD88-independent signaling pathways
in rat testicular cells. J Immunol, 2008.
180(8): 5537–47.
254. Bichler KH, Behrendt WA, Haussmann
A, Schulze HS, and Harzmann R,
1006
[Detection of ureolytic bacteria in the
urine of stone patients (author’s transl)].
Urol Int, 1980. 35(6): 421–6.
255. Bichler KH, Eipper E, Naber K,
Braun V, Zimmermann R, and Lahme
S, Urinary infection stones. Int J
Antimicrob Agents, 2002. 19(6): 488–98.
256. Bichler KH, Feil G, Zumbragel A, Eipper
E, and Dyballa S, Schistosomiasis: a
critical review. Curr Opin Urol, 2001.
11(1): 97–101.
257. Bichler KH, Savatovsky I, Naber KG,
Bischop MC, Bjerklund-Johansen TE,
Botto H, Cek M, Grabe M, Lobel B,
Redorta JP, and Tenke P, EAU guide-
lines for the management of urogenital
schistosomiasis. Eur Urol, 2006. 49(6):
998–1003.
258. Bidet P, Mahjoub-Messai F, Blanco J,
Blanco J, Dehem M, Aujard Y, Bingen
E, and Bonacorsi S, Combined multilo-
cus sequence typing and O serogrouping
distinguishes Escherichia coli subtypes
associated with infant urosepsis and/
or meningitis. J Infect Dis, 2007. 196(2):
297–303.
259. Bielorai B, Shulman LM, Rechavi G,
and Toren A, CMV reactivation induced
BK virus-associated late onset hemor-
rhagic cystitis after peripheral blood
stem cell transplantation. Bone Marrow
Transplant, 2001. 28(6): 613–4.
260. Biering-Sorensen F, Bagi P, and Hoiby
N, Urinary tract infections in patients
with spinal cord lesions: treatment and
prevention. Drugs, 2001. 61(9): 1275–87.
261. Biering-Sorensen F, Urinary tract infec-
tion in individuals with spinal cord
lesion. Curr Opin Urol, 2002. 12(1): 45–9.
262. Bierkens AF, Hendrikx AJ, Ezz el Din
KE, de la Rosette JJ, Horrevorts A,
Doesburg W, and Debruyne FM, The
value of antibiotic prophylaxis during
extracorporeal shock wave lithotripsy in
the prevention of urinary tract infections
in patients with urine proven sterile prior
to treatment. Eur Urol, 1997. 31(1): 30–5.
263. Billips BK, Forrestal SG, Rycyk MT,
Johnson JR, Klumpp DJ, and Schaeffer
AJ, Modulation of host innate immune
response in the bladder by uropathogenic
Escherichia coli. Infect Immun, 2007.
75(11): 5353–60.

264. Billips BK, Schaeffer AJ, and Klumpp
DJ, Molecular basis of uropathogenic
Escherichia coli evasion of the innate
immune response in the bladder. Infect
Immun, 2008. 76(9): 3891–900.
265. Bin C, Hui W, Renyuan Z, Yongzhong
N, Xiuli X, Yingchun X, Yuanjue Z, and
Minjun C, Outcome of cephalosporin
treatment of bacteremia due to CTX-M-
type extended-spectrum beta-lactamase-
producing Escherichia coli. Diagn
Microbiol Infect Dis, 2006. 56(4): 351–7.
266. Binelli CA, Moretti ML, Assis RS,
Sauaia N, Menezes PR, Ribeiro E,
Geiger DC, Mikami Y, Miyaji M,
Oliveira MS, Barone AA, and Levin AS,
Investigation of the possible association
between nosocomial candiduria and can-
didaemia. Clin Microbiol Infect, 2006.
12(6): 538–43.
267. Binsaleh S, Al-Assiri M, Aronson S, and
Steinberg A, Septic shock after transrec-
tal ultrasound guided prostate biopsy. Is
ciprofloxacin prophylaxis always protect-
ing? Can J Urol, 2004. 11(4): 2352–3.
268. Bircan ZE, Buyan N, Hasanoglu E,
Ozturk E, Bayhan H, and Isik S,
Radiologic evaluation of urinary tract
infection. Int Urol Nephrol, 1995. 27(1):
27–32.
269. Birkner V, Essers M, Bühring M,
Koldovsky U, and Mendling W,
Randomisierte 3-armige, offene, kon-
trollierte, klinische Therapiestudie
zur Behandlung der chronisch-rez-
idivierenden vaginalen Kandidose
mit einer systematischen apparativen
Heliotherapie im Vergleich zu einer
antimykotischen Standardtherapie
und einer Vakzinationsbehandlung mit
Gynatren. Mycoses, 2005. 48(5): 310.
270. Bishop BL, Duncan MJ, Song J, Li G,
Zaas D, and Abraham SN, Cyclic AMP-
regulated exocytosis of Escherichia coli
from infected bladder epithelial cells.
Nat Med, 2007. 13(5): 625–30.
271. Bishop-Townsend V, STDs: Screening,
therapy, and long-term implications
for the adolescent patient. Int J Fertil
Menopausal Stud, 1996. 41(2): 109–14.
272. Bisschop MP, Merkus JM, Scheygrond
H, and van Cutsem J, Co-treatment of
the male partner in vaginal candidosis:
References
a double-blind randomized control
study. Br J Obstet Gynaecol, 1986. 93(1):
79–81.
273. Bitz H, Darmon D, Goldfarb M, Shina A,
Block C, Rosen S, Brezis M, and Heyman
SN, Transient urethral obstruction pre-
disposes to ascending pyelonephritis and
tubulo-interstitial disease: studies in
rats. Urol Res, 2001. 29(1): 67–73.
274. Bitzer EM and et al., preliminary data,
personal communication.
275. Bjartling C, Osser S, and Persson K,
The frequency of salpingitis and ectopic
pregnancy as epidemiologic markers of
Chlamydia trachomatis. Acta Obstet
Gynecol Scand, 2000. 79(2): 123–8.
276. Bjerklund Johansen TE, Cek M, Naber
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
urinary tract infections in urology
departments. Eur Urol, 2007. 51(4):
1100–11; discussion 1112.
277. Bjerklund-Johansen TE, Cek M, Naber
KG, Stratchounski L, Svenden MV, and
P T, Hospital acquired urinary tract
infections in urology departments: patho-
gens, susceptibility and use of antibiot-
ics. Data from PEP and PEAP-studies.
Int J Antimicr Agents, 2006. 28(Suppl):
S91-S107.
278. Bjork DT, Pelletier LL, and Tight RR,
Urinary tract infections with antibiotic
resistant organisms in catheterized nurs-
ing home patients. Infect Control, 1984.
5(4): 173–6.
279. Bjornelius E, Anagrius C, Bojs G,
Carlberg H, Johannisson G, Johansson
E, Moi H, Jensen JS, and Lidbrink P,
Antibiotic treatment of symptomatic
Mycoplasma genitalium infection in
Scandinavia: a controlled clinical trial.
Sex Transm Infect, 2008. 84(1): 72–6.
280. Blacklock AR, Geddes JR, and Shaw RE,
The treatment of large bladder diver-
ticula. Br J Urol, 1983. 55(1): 17–20.
281. Blahna MT, Zalewski CA, Reuer J,
Kahlmeter G, Foxman B, and Marrs CF,
The role of horizontal gene transfer in
the spread of trimethoprim-sulfameth-
oxazole resistance among uropathogenic
Escherichia coli in Europe and Canada.
J Antimicrob Chemother, 2006. 57(4):
666–72.
1007
References
282. Blaschke-Hellmessen R,
[Epidemiological studies of the occur-
rence of yeasts in children and their
mothers]. Mykosen, 1968. 11(9): 611–6.
283. Blaschke-Hellmessen R, [Vertical
transmission of Candida and its conse-
quences]. Mycoses, 1998. 41 Suppl 2:
31–6.
284. Blaser J, Stone BB, Groner MC, and
Zinner SH, Comparative study with
enoxacin and netilmicin in a pharmaco-
dynamic model to determine importance
of ratio of antibiotic peak concentration
to MIC for bactericidal activity and
emergence of resistance. Antimicrob
Agents Chemother, 1987. 31(7):
1054–60.
285. Blattner WA, Human retroviruses: their
role in cancer. Proc Assoc Am Physicians,
1999. 111(6): 563–72.
286. Block JM, Walstad RA, Bjertnaes
A, Hafstad PE, Holte M, Ottemo I,
Svarva PL, Rolstad T, and Peterson LE,
Ofloxacin versus trimethoprim-sulpham-
ethoxazole in acute cystitis. Drugs, 1987.
34 Suppl 1: 100–6.
287. Bloom S, Wechsler H, and Lattimer
JK, Results of a long-term study of non-
functioning tuberculous kidneys. J Urol,
1970. 104(5): 654–7.
288. Bloomfield P, Hodson EM, and Craig JC,
Antibiotics for acute pyelonephritis in
children. Cochrane Database Syst Rev,
2005(1): CD003772.
289. Blossom DB and McDonald LC,
The challenges posed by reemerging
Clostridium difficile infection. Clin
Infect Dis, 2007. 45(2): 222–7.
290. Bodel P, Cotran R, and Kass E,
Cranberry juice and the antibacterial
action of hippuric acid. J Lab Clin Med,
1959. 54(Dec): 881–8.
291. Boerema JB and Willems FT,
Fosfomycin trometamol in a single dose
versus norfloxacin for seven days in the
treatment of uncomplicated urinary
infections in general practice. Infection,
1990. 18 Suppl 2: S80–8.
292. Boggess KA, Benedetti TJ, and Raghu
G, Nitrofurantoin-induced pulmonary
toxicity during pregnancy: a report of a
case and review of the literature. Obstet
Gynecol Surv, 1996. 51(6): 367–70.
1008
293. Bohannon NJ, Treatment of vulvovagi-
nal candidiasis in patients with diabe-
tes. Diabetes Care, 1998. 21(3): 451–6.
294. Boldorini R, Brustia M, Veggiani C,
Barco D, Andorno S, and Monga G,
Periodic assessment of urine and serum
by cytology and molecular biology as a
diagnostic tool for BK virus nephropathy
in renal transplant patients. Acta Cytol,
2005. 49(3): 235–43.
295. Boldorini R, Veggiani C, Barco D, and
Monga G, Kidney and urinary tract
polyomavirus infection and distribution:
molecular biology investigation of 10
consecutive autopsies. Arch Pathol Lab
Med, 2005. 129(1): 69–73.
296. Bollgren I, Antibacterial prophylaxis in
children with urinary tract infection. Acta
Paediatr Suppl, 1999. 88(431): 48–52.
297. Bollgren I, Engstrom CF, Hammarlind
M, Kallenius G, Ringertz H, and
Svenson SB, Low urinary counts of
P-fimbriated Escherichia coli in pre-
sumed acute pyelonephritis. Arch Dis
Child, 1984. 59(2): 102–6.
298. Bond CM and Watson MC, The develop-
ment of evidence-based guidelines for
over-the-counter treatment of vulvovagi-
nal candidiasis. Pharm World Sci, 2003.
25(4): 177–81.
299. Bone RC, Balk RA, Cerra FB, Dellinger
RP, Fein AM, Knaus WA, Schein RM,
and Sibbald WJ, Definitions for sepsis
and organ failure and guidelines for the
use of innovative therapies in sepsis. The
ACCP/SCCM Consensus Conference
Committee. American College of Chest
Physicians/Society of Critical Care
Medicine. Chest, 1992. 101(6): 1644–55.
300. Bone RC, Balk RA, Fein AM, Perl TM,
Wenzel RP, Reines HD, Quenzer RW,
Iberti TJ, Macintyre N, and Schein
RM, A second large controlled clinical
study of E5, a monoclonal antibody to
endotoxin: results of a prospective, multi-
center, randomized, controlled trial. The
E5 Sepsis Study Group. Crit Care Med,
1995. 23(6): 994–1006.
301. Bone RC, Sprung CL, and Sibbald WJ,
Definitions for sepsis and organ failure.
Crit Care Med, 1992. 20(6): 724–6.
302. Bonfiglio G, Mattina R, Lanzafame
A, Cammarata E, and Tempera G,

Fosfomycin tromethamine in uncompli-
cated urinary tract infections: a clinical
study. Chemotherapy, 2005. 51(2–3):
162–6.
303. Bonvoisin C, Weekers L, Xhignesse P,
Grosch S, Milicevic M, and Krzesinski
JM, Polyomavirus in renal transplanta-
tion: a hot problem. Transplantation,
2008. 85(7 Suppl): S42–8.
304. Bonza E, San Juan R, Mu˜noz P, Voss
A, and Kluytmans J, Co-operative
Group of the European Study Group
on Nosocomial Infections. A European
perspective on nosocomial urinary tract
infections II. Report on incidence, clini-
cal characteristics and outcome (ESGNI-
004 study). European Study Group on
Nosocomial Infection. Clin Microbiol
Infect, 2001. 7: 532–42.
305. Book M, Lehmann LE, Schewe JC,
Weber S, and Stuber F, [Urosepsis.
Current therapy and diagnosis]. Urologe
A, 2005. 44(4): 413–22; quiz 423–4.
306. Boon ME, van Keep JP, and Kok LP,
Polyomavirus infection versus high-
grade bladder carcinoma. The impor-
tance of cytologic and comparative
morphometric studies of plastic-embed-
ded voided urine sediments. Acta Cytol,
1989. 33(6): 887–93.
307. Bootsma AM, Laguna Pes MP, Geerlings
SE, and Goossens A, Antibiotic prophy-
laxis in urologic procedures: a systematic
review. Eur Urol, 2008. 54(6): 1270–86.
308. Borras-Blasco J, Conesa-Garcia V,
Navarro-Ruiz A, Marin-Jimenez F,
Gonzalez-Delgado M, and Gomez-
Corrons A, Ciprofloxacin, but not levo-
floxacin, affects cyclosporine blood levels
in a patient with pure red blood cell
aplasia. Am J Med Sci, 2005. 330(3):
144–6.
309. Boruchov AM, Heller G, Veri MC,
Bonvini E, Ravetch JV, and Young JW,
Activating and inhibitory IgG Fc recep-
tors on human DCs mediate opposing
functions. J Clin Invest, 2005. 115(10):
2914–23.
310. Bosch A, Benedi VJ, Pares R,
and Jofre J, Enhancement of the
humoral immune response and
resistance to bacterial infection in
mice by the oral administration of a
References
bacterial immunomodulator (OM-89).
Immunopharmacol Immunotoxicol,
1988. 10(3): 333–43.
311. Botto H, Naber K, Bishop M, Jarlier
V, Lim V, and Norby R, Antimicrobial
policy in prophylaxis and treatment of
nosocomial urinary tract infections, in
Nosocomial and health care associated
infections in urology, Naber KG, Editor.
2001, Health Publication Ltd: Plymouth.
p. 207 p.
312. Bouchon A, Facchetti F, Weigand MA,
and Colonna M, TREM-1 amplifies
inflammation and is a crucial mediator
of septic shock. Nature, 2001. 410(6832):
1103–7.
313. Bougnoux ME, Kac G, Aegerter P,
d’Enfert C, and Fagon JY, Candidemia
and candiduria in critically ill patients
admitted to intensive care units in
France: incidence, molecular diversity,
management and outcome. Intensive
Care Med, 2008. 34(2): 292–9.
314. Bouissou F, Munzer C, Decramer S,
Roussel B, Novo R, Morin D, Lavocat
MP, Guyot C, Taque S, Fischbach M,
Ouhayoun E, and Loirat C, Prospective,
randomized trial comparing short and
long intravenous antibiotic treatment
of acute pyelonephritis in children:
dimercaptosuccinic acid scintigraphic
evaluation at 9 months. Pediatrics, 2008.
121(3): e553–60.
315. Bouvier d`Yvoire MJY and Maire PH,
Dosage regimens of antibacterials. Clin
Drug Invest, 1996. 11: 229–239.
316. Bouza E, San Juan R, Munoz P, Voss A,
and Kluytmans J, A European perspec-
tive on nosocomial urinary tract infec-
tions II. Report on incidence, clinical
characteristics and outcome (ESGNI-
004 study). European Study Group on
Nosocomial Infection. Clin Microbiol
Infect, 2001. 7(10): 532–42.
317. Bouza E, San Juan R, Munoz P, Voss
A, and Kluytmans J, A European per-
spective on nosocomial urinary tract
infections I. Report on the microbiol-
ogy workload, etiology and antimicro-
bial susceptibility (ESGNI-003 study).
European Study Group on Nosocomial
Infections. Clin Microbiol Infect, 2001.
7(10): 523–31.
1009
References
318. Bouza E, Sanchez-Carrillo C,
Hernangomez S, and Gonzalez MJ,
Laboratory-acquired brucellosis: a
Spanish national survey. J Hosp Infect,
2005. 61(1): 80–83.
319. Bower M, Palmieri C, and Dhillon T,
AIDS-related malignancies: changing
epidemiology and the impact of highly
active antiretroviral therapy. Curr Opin
Infect Dis, 2006. 19(1): 14–9.
320. Boyce JM and Pittet D, Guideline for
Hand Hygiene in Health-Care Settings.
Recommendations of the Healthcare
Infection Control Practices Advisory
Committee and the HICPAC/SHEA/
APIC/IDSA Hand Hygiene Task Force.
Society for Healthcare Epidemiology of
America/Association for Professionals
in Infection Control/Infectious Diseases
Society of America. MMWR Recomm
Rep, 2002. 51(RR-16): 1–45, quiz CE1–4.
321. Boyko EJ, Fihn SD, Scholes D, Abraham
L, and Monsey B, Risk of urinary tract
infection and asymptomatic bacteriuria
among diabetic and nondiabetic post-
menopausal women. Am J Epidemiol,
2005. 161(6): 557–64.
322. Boyko EJ, Fihn SD, Scholes D, Chen CL,
Normand EH, and Yarbro P, Diabetes
and the risk of acute urinary tract infec-
tion among postmenopausal women.
Diabetes Care, 2002. 25(10): 1778–83.
323. Bradbury SM, Collection of urine speci-
mens in general practice: to clean or
not to clean? J R Coll Gen Pract, 1988.
38(313): 363–5.
324. Braddom RL and et al, Physical
Medicine & Rehabilitation. 2007:
Saunders Elsevier.
325. Bradley DJA, Simple and rapid method
for counting Schistosome eggs in urine.
Soc. Trop. Med. Hyg, 1964. 28: 291.
326. Bradshaw CS, Chen MY, and Fairley
CK, Persistence of Mycoplasma geni-
talium following azithromycin therapy.
PLoS One, 2008. 3(11): e3618.
327. Bradshaw CS, Jensen JS, Tabrizi SN,
Read TR, Garland SM, Hopkins CA, Moss
LM, and Fairley CK, Azithromycin fail-
ure in Mycoplasma genitalium urethritis.
Emerg Infect Dis, 2006. 12(7): 1149–52.
328. Bradshaw CS, Tabrizi SN, Read TR,
Garland SM, Hopkins CA, Moss LM,
1010
and Fairley CK, Etiologies of nongono-
coccal urethritis: bacteria, viruses, and
the association with orogenital exposure.
J Infect Dis, 2006. 193(3): 336–45.
329. Brändlein S, Tumorimmunity:
Specificity, Genetics and Function of
natural IgM antibodies (http://www.
opus-bayern.de/uni-wuerzburg/voll-
texte/2003/666/), in Pathologisches
Institut, Fakultät für Biologie. 2003,
Universität Würzburg: Würzburg.
330. Branigan EF and Muller CH, Efficacy of
treatment and recurrence rate of leuko-
cytospermia in infertile men with prosta-
titis. Fertil Steril, 1994. 62(3): 580–4.
331. Branson BM, State of the art for diag-
nosis of HIV infection. Clin Infect Dis,
2007. 45 Suppl 4: S221–5.
332. Brant MD, Ludlow JK, and Mulcahy JJ,
The prosthesis salvage operation: imme-
diate replacement of the infected penile
prosthesis. J Urol, 1996. 155(1): 155–7.
333. Bratu S, Landman D, Alam M, Tolentino
E, and Quale J, Detection of KPC
carbapenem-hydrolyzing enzymes in
Enterobacter spp. from Brooklyn, New
York. Antimicrob Agents Chemother,
2005. 49(2): 776–8.
334. Bratzler DW and Houck PM,
Antimicrobial prophylaxis for surgery:
an advisory statement from the National
Surgical Infection Prevention Project.
Am J Surg, 2005. 189(4): 395–404.
335. Bratzler DW, Houck PM, Richards
C, Steele L, Dellinger EP, Fry DE,
Wright C, Ma A, Carr K, and Red L,
Use of antimicrobial prophylaxis for
major surgery: baseline results from the
National Surgical Infection Prevention
Project. Arch Surg, 2005. 140(2):
174–82.
336. Brazda E, Ofner D, Riedmann B,
Spechtenhauser B, and Margreiter R,
The effect of nephrectomy on the outcome
of renal transplantation in patients
with polycystic kidney disease. Ann
Transplant, 1996. 1(2): 15–8.
337. Bregenzer T, Frei R, Widmer AF, Seiler
W, Probst W, Mattarelli G, and Zimmerli
W, Low risk of bacteremia during cath-
eter replacement in patients with long-
term urinary catheters. Arch Intern Med,
1997. 157(5): 521–5.

338. Brendstrup L, Hjelt K, Petersen KE,
Petersen S, Andersen EA, Daugbjerg PS,
Stagegaard BR, Nielsen OH, Vejlsgaard
R, Schou G, and et al., Nitrofurantoin
versus trimethoprim prophylaxis in
recurrent urinary tract infection in chil-
dren. A randomized, double-blind study.
Acta Paediatr Scand, 1990. 79(12):
1225–34.
339. Bretan PN, Jr., Price DC, and McClure
RD, Localization of abscess in adult
polycystic kidney by indium-111 leuko-
cyte scan. Urology, 1988. 32(2): 169–71.
340. Bricker EM, Bladder substitution after
pelvic evisceration. Surg Clin North Am,
1950. 30(5): 1511–21.
341. Bridges B, Donegan S, and Badros A,
Cidofovir bladder instillation for the
treatment of BK hemorrhagic cystitis
after allogeneic stem cell transplanta-
tion. Am J Hematol, 2006. 81(7): 535–7.
342. Briffaux R, Merlet B, Normand G,
Coloby P, Leremboure H, Bruyere F,
Pires C, Ouaki F, Dore B, and Irani
J, [Short or long schemes of antibiotic
prophylaxis for prostate biopsy. A mul-
ticentre prospective randomised study].
Prog Urol, 2009. 19(1): 39–46.
343. Briggs GG, Freeman RK, and Yaffe
SJ, Drugs in lactation. 2nd ed. 2002,
Baltimore: Williams & Wilkins.
344. Brilot F, Strowig T, Roberts SM, Arrey
F, and Munz C, NK cell survival medi-
ated through the regulatory synapse with
human DCs requires IL-15Ralpha. J
Clin Invest, 2007. 117(11): 3316–29.
345. British Association for Sexual health
and HIV B. 2006 UK National guide-
line for the management of genital tract
infection with Chlamydia trachomatis.
2006; Available from: http://www.bashh.
org/documents/61/61.pdf.
346. British Association for Sexual health
and HIV B. 2008 National guideline on
the management of non-gonococcal ure-
thritis. 2008; Available from: http://www.
bashh.org/documents/89/89.pdf.
347. British Association for Sexual health
and HIV B. National guideline on
the diagnosis and treatment of gonor-
rhoea in adults 2005. 2005; Available
from: http://www.bashh.org/docu-
ments/116/116.pdf.
References
348. British Association for Sexual Health
and HIV. Available from: www.bashh.
org/guidelines.
349. Britton KE, Renal radionuclide studies,
in Textbook of genitourinary surgery,
Whitfield HN, Hendry WF, and Kirby
RS, Editors. 1998, Blackwell Science:
Oxford. p. 76–103.
350. Brogard JM, Jehl F, Willemin B,
Lamalle AM, Blickle JF, and Monteil
H, Clinical pharmacokinetics of cefo-
tiam. Clin Pharmacokinet, 1989. 17(3):
163–74.
351. Brogden RN and Ward A, Ceftriaxone. A
reappraisal of its antibacterial activity
and pharmacokinetic properties, and an
update on its therapeutic use with par-
ticular reference to once-daily adminis-
tration. Drugs, 1988. 35(6): 604–45.
352. Brooks D, Garrett G, and Hollihead R,
Sulphadimidine, co-trimoxazole, and
a placebo in the management of symp-
tomatic urinary tract infection in gen-
eral practice. J R Coll Gen Pract, 1972.
22(123): 695–703.
353. Brosnahan J, Jull A, and Tracy C, Types
of urethral catheters for management of
short-term voiding problems in hospi-
talised adults. Cochrane Database Syst
Rev, 2004(1): CD004013.
354. Brough RJ, O’Flynn KJ, Fishwick J, and
Gough DC, Bladder washout and stone
formation in paediatric enterocysto-
plasty. Eur Urol, 1998. 33(5): 500–2.
355. Brown AJ, Odds FC, and Gow NA,
Infection-related gene expression in
Candida albicans. Curr Opin Microbiol,
2007. 10(4): 307–13.
356. Brown HJ, Sacks SH, and Robson MG,
Toll-like receptor 2 agonists exacerbate
accelerated nephrotoxic nephritis. J Am
Soc Nephrol, 2006. 17(7): 1931–9.
357. Brown JS, Vittinghoff E, Kanaya AM,
Agarwal SK, Hulley S, and Foxman B,
Urinary tract infections in postmeno-
pausal women: effect of hormone therapy
and risk factors. Obstet Gynecol, 2001.
98(6): 1045–52.
358. Brown MR, Allison DG, and Gilbert P,
Resistance of bacterial biofilms to anti-
biotics: a growth-rate related effect? J
Antimicrob Chemother, 1988. 22(6):
777–80.
1011
References
359. Brown MR, Collier PJ, and Gilbert P,
Influence of growth rate on susceptibility
to antimicrobial agents: modification of
the cell envelope and batch and continu-
ous culture studies. Antimicrob Agents
Chemother, 1990. 34(9): 1623–8.
360. Brown PD, Freeman A, and Foxman B,
Prevalence and predictors of trimetho-
prim-sulfamethoxazole resistance among
uropathogenic Escherichia coli isolates
in Michigan. Clin Infect Dis, 2002. 34(8):
1061–6.
361. Brown PD, Urinary Tract Infections in
Renal Transplant Recipients. Curr Infect
Dis Rep, 2002. 4(6): 525–528.
362. Browne RF, Zwirewich C, and
Torreggiani WC, Imaging of urinary
tract infection in the adult. Eur Radiol,
2004. 14 Suppl 3: E168–83.
363. Bruce AW and Reid G, Intravaginal
instillation of lactobacilli for prevention
of recurrent urinary tract infections. Can
J Microbiol, 1988. 34(3): 339–43.
364. Bruce AW, Reid G, McGroarty JA, Taylor
M, and Preston C, Preliminary study
on the prevention of recurrent urinary
tract infections in ten adult women
using intravaginal lactobacilli. Int.
Urogynecol. J, 1992. 3: 22–25.
365. Bruce RG, Munch LC, Hoven AD,
Jerauld RS, Greenburg R, Porter WH,
and Rutter PW, Urolithiasis associated
with the protease inhibitor indinavir.
Urology, 1997. 50(4): 513–8.
366. Brumfitt W and Hamilton-Miller JM,
A comparative trial of low dose cefaclor
and macrocrystalline nitrofurantoin in
the prevention of recurrent urinary tract
infection. Infection, 1995. 23(2): 98–102.
367. Brumfitt W and Hamilton-Miller JM,
Efficacy and safety profile of long-term
nitrofurantoin in urinary infections:
18 years’ experience. J Antimicrob
Chemother, 1998. 42(3): 363–71.
368. Brumfitt W and Hamilton-Miller JM,
Prophylactic antibiotics for recurrent
urinary tract infections. J Antimicrob
Chemother, 1990. 25(4): 505–12.
369. Brumfitt W, Hamilton-Miller JM,
Gargan RA, Cooper J, and Smith GW,
Long-term prophylaxis of urinary infec-
tions in women: comparative trial of tri-
methoprim, methenamine hippurate and
1012
topical povidone-iodine. J Urol, 1983.
130(6): 1110–4.
370. Brun-Buisson C, Meshaka P, Pinton
P, and Vallet B, EPISEPSIS: a reap-
praisal of the epidemiology and outcome
of severe sepsis in French intensive care
units. Intensive Care Med, 2004. 30(4):
580–8.
371. Brun-Buisson C, The epidemiology of
the systemic inflammatory response.
Intensive Care Med, 2000. 26 Suppl 1:
S64–74.
372. Brunkhorst FM, [Epidemiology, economy
and practice — results of the German
study on prevalence by the competence
network sepsis (SepNet)]. Anasthesiol
Intensivmed Notfallmed Schmerzther,
2006. 41(1): 43–4.
373. Brunkhorst FM, Engel C, Bloos F,
Meier-Hellmann A, Ragaller M, Weiler
N, Moerer O, Gruendling M, Oppert M,
Grond S, Olthoff D, Jaschinski U, John
S, Rossaint R, Welte T, Schaefer M,
Kern P, Kuhnt E, Kiehntopf M, Hartog
C, Natanson C, Loeffler M, and Reinhart
K, Intensive insulin therapy and pentas-
tarch resuscitation in severe sepsis. N
Engl J Med, 2008. 358(2): 125–39.
374. Brunkhorst FM, Kuhnt E, Engel C,
Meier-Hellmann A, Raggaler M, Quintel
M, Weiler N, Grundling M, Oppert
M, and Deufel T, Intensive insulin in
patients with severe sepsis and septic
shock is associated with an increased
rate of hypoglycemia – results from a
randomized multicenter study (VISEP).
Infection, 2005. 33: 19–20.
375. Brunkhorst FM, Wegscheider K, Forycki
ZF, and Brunkhorst R, Procalcitonin for
early diagnosis and differentiation of
SIRS, sepsis, severe sepsis, and septic
shock. Intensive Care Med, 2000. 26
Suppl 2: S148–52.
376. Bruskewitz RC, Iversen P, and Madsen
PO, Value of postvoid residual urine
determination in evaluation of pros-
tatism. Urology, 1982. 20(6): 602–4.
377. Bryan DE, Mulcahy JJ, and Simmons
GR, Salvage procedure for infected non-
eroded artificial urinary sphincters. J
Urol, 2002. 168(6): 2464–6.
378. Brzuszkiewicz E, Brüggemann H,
Liesegang H, Emmerth M, Ölschläger

T, Nagy G, Albermann K, Wagner C,
Buchrieser C, Emödy L, Gottschalk
G, Hacker J, and Dobrindt U, How to
become a uropathogen: comparative
genomic analysis of extraintestinal
pathogenic Escherichia coli strains. Proc
Natl Acad Sci U S A, 2006. 103(34):
12879–84.
379. Buch A and Skytte Christensen E,
Treatment of vaginal candidosis with
natamycin and effect of treating the
partner at the same time. Acta Obstet
Gynecol Scand, 1982. 61(5): 393–6.
380. Buchbinder SP, Vittinghoff E, Heagerty
PJ, Celum CL, Seage GR, 3rd, Judson
FN, McKirnan D, Mayer KH, and Koblin
BA, Sexual risk, nitrite inhalant use,
and lack of circumcision associated with
HIV seroconversion in men who have sex
with men in the United States. J Acquir
Immune Defic Syndr, 2005. 39(1): 82–9.
381. Buijk SE, Mouton JW, Gyssens IC,
Verbrugh HA, and Bruining HA,
Experience with a once-daily dosing
program of aminoglycosides in critically
ill patients. Intensive Care Med, 2002.
28(7): 936–42.
382. Bukowski TP, Betrus GG, Aquilina JW,
and Perlmutter AD, Urinary tract infec-
tions and pregnancy in women who
underwent antireflux surgery in child-
hood. J Urol, 1998. 159(4): 1286–9.
383. Bull E, Chilton CP, Gould CA, and
Sutton TM, Single-blind, randomised,
parallel group study of the Bard Biocath
catheter and a silicone elastomer coated
catheter. Br J Urol, 1991. 68(4): 394–9.
384. Bundrick W, Heron SP, Ray P, Schiff
WM, Tennenberg AM, Wiesinger BA,
Wright PA, Wu SC, Zadeikis N, and
Kahn JB, Levofloxacin versus cipro-
floxacin in the treatment of chronic
bacterial prostatitis: a randomized
double-blind multicenter study. Urology,
2003. 62(3): 537–41.
385. Buonaguro L, Tagliamonte M, Tornesello
M, and Buonaguro FM, Evolution of the
HIV-1 V3 region in the Italian epidemic.
New Microbiol, 2007. 30(1): 1–11.
386. Buonaguro L, Tagliamonte M, Tornesello
ML, and Buonaguro FM, Genetic and
phylogenetic evolution of HIV-1 in a
low subtype heterogeneity epidemic: the
References
Italian example. Retrovirology, 2007. 4:
34.
387. Buonaguro L, Tornesello ML, and
Buonaguro FM, Human immunodefi-
ciency virus type 1 subtype distribution
in the worldwide epidemic: pathogenetic
and therapeutic implications. J Virol,
2007. 81(19): 10209–19.
388. Burall LS, Harro JM, Li X, Lockatell
CV, Himpsl SD, Hebel JR, Johnson DE,
and Mobley HL, Proteus mirabilis genes
that contribute to pathogenesis of uri-
nary tract infection: identification of 25
signature-tagged mutants attenuated
at least 100-fold. Infect Immun, 2004.
72(5): 2922–38.
389. Burke DM, Shackley DC, and O’Reilly
PH, The community-based morbidity of
flexible cystoscopy. BJU Int, 2002. 89(4):
347–9.
390. Burke JP, Infection control – a problem
for patient safety. N Engl J Med, 2003.
348(7): 651–6.
391. Burkhardt H, Hahn T, Gretz N, and
Gladisch R, Bedside estimation of the
glomerular filtration rate in hospitalized
elderly patients. Nephron Clin Pract,
2005. 101(1): c1–8.
392. Burman WJ, Breese PE, Murray BE,
Singh KV, Batal HA, MacKenzie TD,
Ogle JW, Wilson ML, Reves RR, and
Mehler PS, Conventional and molecular
epidemiology of trimethoprim-sulfam-
ethoxazole resistance among urinary
Escherichia coli isolates. Am J Med,
2003. 115(5): 358–64.
393. Burmolle M, Bahl MI, Jensen LB,
Sorensen SJ, and Hansen LH, Type
3 fimbriae, encoded by the conjuga-
tive plasmid pOLA52, enhance biofilm
formation and transfer frequencies in
Enterobacteriaceae strains. Microbiology,
2008. 154(Pt 1): 187–95.
394. Burns MW, Burns JL, and Krieger
JN, Pediatric urinary tract infection.
Diagnosis, classification, and signifi-
cance. Pediatr Clin North Am, 1987.
34(5): 1111–20.
395. Burr RG and Nuseibeh I, The blocking
urinary catheter: the role of variation in
urine flow. Br J Urol, 1995. 76(1): 61–5.
396. Burstein GR and Workowski KA,
Sexually transmitted diseases treatment
1013
References
guidelines. Curr Opin Pediatr, 2003.
15(4): 391–7.
397. Busscher HJ and Weerkamp AH,
Specific and non-specific interactions in
bacterial adhesion to solid substrata.
FEMS Microbiol Rev, 1987(46): 165–173.
398. Busscher HJ, Bos R, and van der Mei
HC, Initial microbial adhesion is a
determinant for the strength of biofilm
adhesion. FEMS Microbiol Lett, 1995.
128(3): 229–34.
399. Busscher HJ, Stokoos I, and
Schakenraad JM, Two-dimensional spa-
tial arrangement of fibronectin adsorbed
to biomaterials with different wettabili-
ties. Cells Mater, 1991. 1: 19–57.
400. Butler CC, Hillier S, Roberts Z, Dunstan
F, Howard A, and Palmer S, Antibiotic-
resistant infections in primary care are
symptomatic for longer and increase
workload: outcomes for patients with E.
coli UTIs. Br J Gen Pract, 2006. 56(530):
686–92.
401. Buys H, Pead L, Hallett R, and Maskell
R, Suprapubic aspiration under ultra-
sound guidance in children with fever
of undiagnosed cause. BMJ, 1994.
308(6930): 690–2.
402. Byl B, Clevenbergh P, Kentos A, Jacobs
F, Marchant A, Vincent JL, and Thys
JP, Ceftazidime- and imipenem-induced
endotoxin release during treatment of
gram-negative infections. Eur J Clin
Microbiol Infect Dis, 2001. 20(11):
804–7.
403. Cadeddu JA, Chen R, Bishoff J, Micali
S, Kumar A, Moore RG, and Kavoussi
LR, Clinical significance of fever after
percutaneous nephrolithotomy. Urology,
1998. 52(1): 48–50.
404. Cadieux P, Burton J, Gardiner G,
Braunstein I, Bruce AW, Kang CY,
and Reid G, Lactobacillus strains and
vaginal ecology. JAMA, 2002. 287(15):
1940–1.
405. Cadieux PA, Burton J, Devillard E, and
Reid G, Lactobacillus by-products inhibit
the growth and virulence of uropatho-
genic Escherichia coli. Pharmacol, 2009.
Accepted.
406. Cafferkey MT, Falkiner FR, Gillespie
WA, and Murphy DM, Antibiotics for
the prevention of septicaemia in urology.
1014
J Antimicrob Chemother, 1982. 9(6):
471–7.
407. Caillot JL, Cote C, Abidi H, and Fabry
J, Electronic evaluation of the value of
double gloving. Br J Surg, 1999. 86(11):
1387–90.
408. Cain MP, Wu SD, Austin PF, Herndon
CD, and Rink RC, Alpha blocker therapy
for children with dysfunctional void-
ing and urinary retention. J Urol, 2003.
170(4 Pt 2): 1514–5; discussion 1516–7.
409. Cakan M, Demirel F, Karabacak O,
Yalcinkaya F, and Altug U, Risk factors
for penile prosthetic infection. Int Urol
Nephrol, 2003. 35(2): 209–13.
410. Calandra T and Cohen J, The interna-
tional sepsis forum consensus conference
on definitions of infection in the intensive
care unit. Crit Care Med, 2005. 33(7):
1538–48.
411. Calderone RA and Fonzi WA, Virulence
factors of Candida albicans. Trends
Microbiol, 2001. 9(7): 327–35.
412. Caldwell DE, Cultivation and study
of biofilm communities, in Microbial
Biofilms, Lappin-Scott HM and
Costerton JW, Editors, Cambridge
University Press: Cambridge. p. 1195:
4–69.
413. Calhoun EA MR, O’Keeffe-Rosetti M,
Gao S, Brown S, Clemens JQ. Prevalence
of prostatitis-like symptoms in a man-
aged care population. in American
Urological Association Annual Meeting.
2005. San Antonio: J Urol.
414. Camargo RP, Simoes JA, Cecatti JG,
Alves VM, and Faro S, Impact of treat-
ment for bacterial vaginosis on prematu-
rity among Brazilian pregnant women:
a retrospective cohort study. Sao Paulo
Med J, 2005. 123(3): 108–12.
415. Cameron DW, Simonsen JN, D’Costa
LJ, Ronald AR, Maitha GM, Gakinya
MN, Cheang M, Ndinya-Achola JO, Piot
P, Brunham RC, and et al., Female to
male transmission of human immuno-
deficiency virus type 1: risk factors for
seroconversion in men. Lancet, 1989.
2(8660): 403–7.
416. Campbell SJ, Cropsey KL, and
Matthews CA, Intrauterine device use in
a high-risk population: experience from
an urban university clinic. Am J Obstet

Gynecol, 2007. 197(2): 193 e1–6; discus-
sion 193 e6–7.
417. Canales B and Monga M, Surgical man-
agement of the calyceal diverticulum.
Curr Opin Urol, 2003. 13(3): 255–60.
418. Canton R, Novais A, Valverde A,
Machado E, Peixe L, Baquero F, and
Coque TM, Prevalence and spread of
extended-spectrum beta-lactamase-
producing Enterobacteriaceae in Europe.
Clin Microbiol Infect, 2008. 14 Suppl 1:
144–53.
419. Cao V, Ratsima E, Van Tri D, Bercion
R, Fonkoua MC, Richard V, and
Talarmin A, Antimicrobial susceptibil-
ity of Neisseria gonorrhoeae strains iso-
lated in 2004–2006 in Bangui, Central
African Republic; Yaounde, Cameroon;
Antananarivo, Madagascar; and Ho Chi
Minh Ville and Nha Trang, Vietnam. Sex
Transm Dis, 2008. 35(11): 941–5.
420. Capozza N and Caione P, Dextranomer/
hyaluronic acid copolymer implantation
for vesico-ureteral reflux: a randomized
comparison with antibiotic prophylaxis.
J Pediatr, 2002. 140(2): 230–4.
421. Capozza N, Lais A, Matarazzo E, Nappo
S, Patricolo M, and Caione P, Treatment
of vesico-ureteric reflux: a new algorithm
based on parental preference. BJU Int,
2003. 92(3): 285–8.
422. Capron A, Riveau GJ, Bartley PB, and
McManus DP, Prospects for a schis-
tosome vaccine. Curr Drug Targets
Immune Endocr Metabol Disord, 2002.
2(3): 281–90.
423. Carapeti EA, Andrews SM, and Bentley
PG, Randomized study of sterile versus
non-sterile urethral catheterization. Ann
R Coll Surg Engl, 1994. 78: 59–60.
424. Cardenas DD and Hooton TM, Urinary
tract infection in persons with spinal
cord injury. Arch Phys Med Rehabil,
1995. 76(3): 272–80.
425. Carey JM and Korman HJ, Transrectal
ultrasound guided biopsy of the prostate.
Do enemas decrease clinically significant
complications? J Urol, 2001. 166(1):
82–5.
426. Carl P and Stark L, Indications for
surgical management of genitourinary
tuberculosis. World J Surg, 1997. 21(5):
505–10.
References
427. Carmena D, Benito A, and Eraso E,
Antigens for the immunodiagnosis of
Echinococcus granulosus infection: An
update. Acta Trop, 2006. 98(1): 74–86.
428. Caron F, [Bacteriologic diagnosis and
antibiotic therapy of urinary tract infec-
tions]. Rev Prat, 2003. 53(16): 1760–9.
429. Carr MC, Fetal myelomeningocele
repair: urologic aspects. Curr Opin Urol,
2007. 17(4): 257–62.
430. Carrie AG, Metge CJ, Collins DM,
Harding GK, and Zhanel GG, Use
of administrative healthcare claims
to examine the effectiveness of tri-
methoprim-sulfamethoxazole versus
fluoroquinolones in the treatment of com-
munity-acquired acute pyelonephritis in
women. J Antimicrob Chemother, 2004.
53(3): 512–7.
431. Cars O, Hogberg LD, Murray M,
Nordberg O, Sivaraman S, Lundborg
CS, So AD, and Tomson G, Meeting the
challenge of antibiotic resistance. BMJ,
2008. 337: a1438.
432. Carson C and Naber KG, Role of fluo-
roquinolones in the treatment of serious
bacterial urinary tract infections. Drugs,
2004. 64(12): 1359–73.
433. Carson C, Antibiotic impregnation of
inflatable penile prostheses: effect on
perioperative infection. Expert Rev Med
Devices, 2004. 1(2): 165–7.
434. Carson CC and Robertson CN, Late
hematogenous infection of penile prosthe-
ses. J Urol, 1988. 139(1): 50–2.
435. Carson CC, 3rd, Efficacy of antibiotic
impregnation of inflatable penile pros-
theses in decreasing infection in original
implants. J Urol, 2004. 171(4): 1611–4.
436. Carson CC, 3rd, Management of prosthe-
sis infections in urologic surgery. Urol
Clin North Am, 1999. 26(4): 829–39, x.
437. Carson CC, Diagnosis, treatment and
prevention of penile prosthesis infec-
tion. Int J Impot Res, 2003. 15 Suppl 5:
S139–46.
438. Carson CC, Infections in genitourinary
prostheses. Urol Clin North Am, 1989.
16(1): 139–47.
439. Carson CC, Mulcahy JJ, and Govier
FE, Efficacy, safety and patient satis-
faction outcomes of the AMS 700CX
inflatable penile prosthesis: results of
1015
References
a long-term multicenter study. AMS
700CX Study Group. J Urol, 2000.
164(2): 376–80.
440. Carson J, Cerda J, Chae JH, Hirano M,
and Maggiore P, Severe lactic acidosis
associated with linezolid use in a patient
with the mitochondrial DNA A2706G
polymorphism. Pharmacotherapy, 2007.
27(5): 771–4.
441. Carton JA, Maradona JA, Nuno FJ,
Fernandez-Alvarez R, Perez-Gonzalez
F, and Asensi V, Diabetes mellitus
and bacteraemia: a comparative study
between diabetic and non-diabetic
patients. Eur J Med, 1992. 1(5): 281–7.
442. Casaz P, Garrity-Ryan LK, McKenney
D, Jackson C, Levy SB, Tanaka SK,
and Alekshun MN, MarA, SoxS and
Rob function as virulence factors in an
Escherichia coli murine model of ascend-
ing pyelonephritis. Microbiology, 2006.
152(Pt 12): 3643–50.
443. Casewell M and Phillips I, Hands as
route of transmission for Klebsiella spe-
cies. Br Med J, 1977. 2(6098): 1315–7.
444. Casey JT, Erickson BA, Navai N, Zhao
LC, Meeks JJ, and Gonzalez CM,
Urethral reconstruction in patients with
neurogenic bladder dysfunction. J Urol,
2008. 180(1): 197–200.
445. Casola G, vanSonnenberg E, D’Agostino
HB, Harker CP, Varney RR, and Smith
D, Percutaneous drainage of tubo-ovar-
ian abscesses. Radiology, 1992. 182(2):
399–402.
446. Casper C, Krantz EM, Corey L, Kuntz
SR, Wang J, Selke S, Hamilton S,
Huang ML, and Wald A, Valganciclovir
for suppression of human herpesvirus-8
replication: a randomized, double-blind,
placebo-controlled, crossover trial. J
Infect Dis, 2008. 198(1): 23–30.
447. Cassone A, De Bernardis F, and
Torososantucci A, An outline of the role
of anti-Candida antibodies within the
context of passive immunization and pro-
tection from candidiasis. Curr Mol Med,
2005. 5(4): 377–82.
448. Cassone A, De Bernardis F, Mondello F,
Ceddia T, and Agatensi L, Evidence for a
correlation between proteinase secretion
and vulvovaginal candidosis. J Infect
Dis, 1987. 156(5): 777–83.
1016
449. Catarci M, Mancini S, Gentileschi P,
Camplone C, Sileri P, and Grassi GB,
Antibiotic prophylaxis in elective laparo-
scopic cholecystectomy. Lack of need or
lack of evidence? Surg Endosc, 2004.
18(4): 638–41.
450. Cattoir V, Lesprit P, Lascols C, Denamur
E, Legrand P, Soussy CJ, and Cambau
E, In vivo selection during ofloxacin
therapy of Escherichia coli with com-
bined topoisomerase mutations that
confer high resistance to ofloxacin
but susceptibility to nalidixic acid. J
Antimicrob Chemother, 2006. 58(5):
1054–7.
451. Cauwenberg G, International experience
with Ketoconazole in vaginal candido-
sis, in Oral therapy in vaginal candi-
dosis, Eliot BW, Editor. 1984, Medicine
Publishing Foundation: Oxford.
452. Cavagnaro F, [Urinary tract infection in
childhood]. Rev Chilena Infectol, 2005.
22(2): 161–8.
453. Cek M, Lenk S, Naber KG, Bishop MC,
Johansen TE, Botto H, Grabe M, Lobel
B, Redorta JP, and Tenke P, EAU guide-
lines for the management of genitouri-
nary tuberculosis. Eur Urol, 2005. 48(3):
353–62.
454. Centers for Disease Control and
Prevention (CDC), Revised recommenda-
tions for HIV testing of adults, adoles-
cents, and pregnant women in the health
care setting. MMWR Recom R, 2006.
455. Centers for Disease Control and
Prevention (CDC), Twenty five years of
HIV/AIDS-United States 1981–2006.
MMWR Morb Mortal Wkly Rep, 2006.
55: 585–589.
456. Centers for Disease Control and
Prevention (CDC). Estimates of
Healthcare-Associated Infections. [cited
2010 08.01.2010]; Available from: http://
www.cdc.gov/ncidod/dhqp/hai.html.
457. Centers for Disease Control and
Prevention (CDC). Incorporating
HIV Prevention into the Medical Care
of Persons Living with HIV. CDC
Morbidity & Mortality Weekly Report
(MMWR) July 18, 2003/ 52, RR 12;
1–24. Available from: http://www.
cdc.gov/mmwr/preview/mmwrhtml/
rr5212a1.htm.

458. Centers For Disease Control And
Prevention. Available from: www.cdc.gov/
std/default.htm.
459. Cetin M, Ocak S, Gungoren A, and
Hakverdi AU, Distribution of Candida
species in women with vulvovaginal
symptoms and their association with dif-
ferent ages and contraceptive methods.
Scand J Infect Dis, 2007. 39(6–7): 584–8.
460. Cetti RJ, Venn S, and Woodhouse CR,
The risks of long-term nitrofurantoin
prophylaxis in patients with recurrent
urinary tract infection: a recent medico-
legal case. BJU Int, 2009. 103(5): 567–9.
461. Chaim W, Foxman B, and Sobel JD,
Association of recurrent vaginal candidia-
sis and secretory ABO and Lewis pheno-
type. J Infect Dis, 1997. 176(3): 828–30.
462. Chakrabarti S, Mautner V, Osman H,
Collingham KE, Fegan CD, Klapper PE,
Moss PA, and Milligan DW, Adenovirus
infections following allogeneic stem cell
transplantation: incidence and outcome
in relation to graft manipulation, immu-
nosuppression, and immune recovery.
Blood, 2002. 100(5): 1619–27.
463. Chakraborty H, Helms RW, Sen PK,
and Cohen MS, Estimating correlation
by using a general linear mixed model:
evaluation of the relationship between
the concentration of HIV-1 RNA in
blood and semen. Stat Med, 2003. 22(9):
1457–64.
464. Chakraborty H, Sen PK, Helms RW,
Vernazza PL, Fiscus SA, Eron JJ,
Patterson BK, Coombs RW, Krieger JN,
and Cohen MS, Viral burden in genital
secretions determines male-to-female
sexual transmission of HIV-1: a probabi-
listic empiric model. AIDS, 2001. 15(5):
621–7.
465. Champion JD, Piper J, Holden A, Korte
J, and Shain RN, Abused women and
risk for pelvic inflammatory disease.
West J Nurs Res, 2004. 26(2): 176–91;
discussion 192–5.
466. Chan DJ, Fatal attraction: sex, sexually
transmitted infections and HIV-1. Int J
STD AIDS, 2006. 17(10): 643–51.
467. Chan PT and Schlegel PN, Inflammatory
conditions of the male excurrent ductal
system. Part I. J Androl, 2002. 23(4):
453–60.
References
468. Chan RC, Bruce AW, and Reid G,
Adherence of cervical, vaginal and dis-
tal urethral normal microbial flora to
human uroepithelial cells and the inhi-
bition of adherence of gram-negative
uropathogens by competitive exclusion. J
Urol, 1984. 131(3): 596–601.
469. Chan RC, Reid G, Irvin RT, Bruce AW,
and Costerton JW, Competitive exclusion
of uropathogens from human uroepi-
thelial cells by Lactobacillus whole cells
and cell wall fragments. Infect Immun,
1985. 47(1): 84–9.
470. Chan RK, Lye WC, Lee EJ, and
Kumarasinghe G, Nosocomial urinary
tract infection: a microbiological study.
Ann Acad Med Singapore, 1993. 22(6):
873–7.
471. Chan TM, Preventing renal failure in
patients with severe lupus nephritis.
Kidney Int Suppl, 2005(94): S116–9.
472. Chandra M and Maddix H, Urodynamic
dysfunction in infants with vesi-
coureteral reflux. J Pediatr, 2000. 136(6):
754–9.
473. Chang WC, Hung YC, Li TC, Yang TC,
Chen HY, and Lin CC, Short course of
prophylactic antibiotics in laparoscopi-
cally assisted vaginal hysterectomy. J
Reprod Med, 2005. 50(7): 524–8.
474. Chapman AB, Thickman D, and Gabow
PA, Percutaneous cyst puncture in the
treatment of cyst infection in autosomal
dominant polycystic kidney disease. Am
J Kidney Dis, 1990. 16(3): 252–5.
475. Charalabopoulos K, Karachalios G,
Baltogiannis D, Charalabopoulos A,
Giannakopoulos X, and Sofikitis N,
Penetration of antimicrobial agents into
the prostate. Chemotherapy, 2003. 49(6):
269–79.
476. Charton M, Vallancien G, Veillon B, and
Brisset JM, Urinary tract infection in
percutaneous surgery for renal calculi. J
Urol, 1986. 135(1): 15–7.
477. Charton M, Vallancien G, Veillon B,
Prapotnich D, Mombet A, and Brisset
JM, Use of antibiotics in the conjunction
with extracorporeal lithotripsy. Eur Urol,
1990. 17(2): 134–8.
478. Chatwani A, Nyirjesy P, and Amin-
Hanjani S, Chronic endometritis and
positive Mycoplasma cultures: is there a
1017
References
correlation? Infect Dis Obstet Gynecol,
1995. 3(1): 3–6.
479. Chaudhry A, Stone WJ, and Breyer JA,
Occurrence of pyuria and bacteriuria in
asymptomatic hemodialysis patients. Am
J Kidney Dis, 1993. 21(2): 180–3.
480. Chaudhry R, Thakur R, Talwar V, and
Aggarwal N, Anaerobic and aerobic
microflora of pouch of Douglas aspirate
v/s high vaginal swab in cases of pelvic
inflammatory disease. Indian J Pathol
Microbiol, 1996. 39(2): 115–20.
481. Cheadle WG, Risk factors for surgical
site infection. Surg Infect (Larchmt),
2006. 7 Suppl 1: S7–11.
482. Chen FE, Liang RH, Lo JY, Yuen KY,
Chan TK, and Peiris M, Treatment of
adenovirus-associated haemorrhagic
cystitis with ganciclovir. Bone Marrow
Transplant, 1997. 20(11): 997–9.
483. Chen MT, Huang CN, Chou YH,
Huang CH, Chiang CP, and Liu GC,
Percutaneous drainage in the treat-
ment of emphysematous pyelonephritis:
10-year experience. J Urol, 1997. 157(5):
1569–73.
484. Chen SC, Tong ZS, Lee OC, Halliday C,
Playford EG, Widmer F, Kong FR, Wu
C, and Sorrell TC, Clinician response
to Candida organisms in the urine of
patients attending hospital. Eur J Clin
Microbiol Infect Dis, 2008. 27(3): 201–8.
485. Chen SL, Hung CS, Xu J, Reigstad CS,
Magrini V, Sabo A, Blasiar D, Bieri
T, Meyer RR, Ozersky P, Armstrong
JR, Fulton RS, Latreille JP, Spieth J,
Hooton TM, Mardis ER, Hultgren SJ,
and Gordon JI, Identification of genes
subject to positive selection in uropatho-
genic strains of Escherichia coli: a
comparative genomics approach. Proc
Natl Acad Sci U S A, 2006. 103(15):
5977–82.
486. Chen SS, Chen KK, Lin AT, Chang YH,
Wu HH, Hsu TH, Chiu AW, and Chang
LS, Complicated urinary tract infection:
analysis of 179 patients. Zhonghua Yi
Xue Za Zhi (Taipei), 1998. 61(11): 651–6.
487. Chen WM, Yang CR, Ou YC, Ho HC,
Su CK, Chiu KY, and Cheng CL,
Combination regimen in the treatment
of chronic prostatitis. Arch Androl, 2006.
52(2): 117–21.
1018
488. Chen XS, Yin YP, Gong XD, Liang
GJ, Zhang WY, Poumerol G, Shi MQ,
Wu SQ, and Zhang GC, Prevalence of
sexually transmitted infections among
long-distance truck drivers in Tongling,
China. Int J STD AIDS, 2006. 17(5):
304–8.
489. Chen Y, Nitzan O, Saliba W, Chazan B,
Colodner R, and Raz R, Are blood cul-
tures necessary in the management of
women with complicated pyelonephritis?
J Infect, 2006. 53(4): 235–40.
490. Chene G, Boulard G, and Gachie JP,
[A controlled trial of a new material for
coating urinary catheters]. Agressologie,
1990. 31(8 Spec No): 499–501.
491. Cheng CH, Tsau YK, and Lin TY,
Effective duration of antimicrobial
therapy for the treatment of acute lobar
nephronia. Pediatrics, 2006. 117(1):
e84–9.
492. Cheriachan D, Arianayagam M, and
Rashid P, Symptomatic urinary stone
disease in pregnancy. Aust N Z J Obstet
Gynaecol, 2008. 48(1): 34–9.
493. Cherpes TL, Hillier SL, Meyn LA,
Busch JL, and Krohn MA, A delicate
balance: risk factors for acquisition
of bacterial vaginosis include sexual
activity, absence of hydrogen peroxide-
producing lactobacilli, black race, and
positive herpes simplex virus type 2
serology. Sex Transm Dis, 2008. 35(1):
78–83.
494. Chesney RW, Carpenter MA, Moxey-
Mims M, Nyberg L, Greenfield SP,
Hoberman A, Keren R, Matthews R, and
Matoo TK, Randomized Intervention
for Children With Vesicoureteral Reflux
(RIVUR): background commentary of
RIVUR investigators. Pediatrics, 2008.
122 Suppl 5: S233–9.
495. Chew LD and Fihn SD, Recurrent cysti-
tis in nonpregnant women. West J Med,
1999. 170(5): 274–7.
496. Chin J and Bennett A, Heterosexual HIV
transmission dynamics: implications for
prevention and control. Int J STD AIDS,
2007. 18(8): 509–13.
497. Chitale SV, Shaida N, Burtt G, and
Burgess N, Endoscopic management
of renal candidiasis. J Endourol, 2004.
18(9): 865–6.

498. Chitsulo L, Engels D, Montresor A, and
Savioli L, The global status of schis-
tosomiasis and its control. Acta Trop,
2000. 77(1): 41–51.
499. Cho IR, Keener TS, Nghiem HV, Winter
T, and Krieger JN, Prostate blood flow
characteristics in the chronic prostati-
tis/pelvic pain syndrome. J Urol, 2000.
163(4): 1130–3.
500. Chocas EC, Paap CM, and Godley PJ,
Cefpodoxime proxetil: a new, broad-
spectrum, oral cephalosporin. Ann
Pharmacother, 1993. 27(11): 1369–77.
501. Chodak GW and Plaut ME, Systemic
antibiotics for prophylaxis in urologic
surgery: a critical review. J Urol, 1979.
121(6): 695–9.
502. Chong LY, Cheung WM, Leung CS, Yu
CW, and Chan LY, Clinical evaluation
of ceftibuten in gonorrhea. A pilot study
in Hong Kong. Sex Transm Dis, 1998.
25(9): 464–7.
503. Chong TW, Bui MH, and Fuchs GJ,
Calyceal diverticula. Ureteroscopic man-
agement. Urol Clin North Am, 2000.
27(4): 647–54.
504. Choong KK, Gruenewald SM, Hodson
EM, Antico VF, Farlow DC, and Cohen
RC, Volume expanded diuretic renog-
raphy in the postnatal assessment of
suspected uretero-pelvic junction obstruc-
tion. J Nucl Med, 1992. 33(12): 2094–8.
505. Choong S and Whitfield H, Biofilms and
their role in infections in urology. BJU
Int, 2000. 86(8): 935–41.
506. Choong S, Wood S, Fry C, and Whitfield
H, Catheter associated urinary tract
infection and encrustation. Int J
Antimicrob Agents, 2001. 17(4): 305–10.
507. Chou YH, Tiu CM, Liu JY, Chen JD,
Chiou HJ, Chiou SY, Wang JH, and
Yu C, Prostatic abscess: transrectal
color Doppler ultrasonic diagnosis and
minimally invasive therapeutic manage-
ment. Ultrasound Med Biol, 2004. 30(6):
719–24.
508. Chou YY, Lin TY, Lin JC, Wang NC,
Peng MY, and Chang FY, Vancomycin-
resistant enterococcal bacteremia:
comparison of clinical features and
outcome between Enterococcus faecium
and Enterococcus faecalis. J Microbiol
Immunol Infect, 2008. 41(2): 124–9.
References
509. Chow JW, Fine MJ, Shlaes DM, Quinn
JP, Hooper DC, Johnson MP, Ramphal
R, Wagener MM, Miyashiro DK, and
Yu VL, Enterobacter bacteremia: clini-
cal features and emergence of antibiotic
resistance during therapy. Ann Intern
Med, 1991. 115(8): 585–90.
510. Chow TW, Lim BK, and Vallipuram
S, The masquerades of female pelvic
tuberculosis: case reports and review of
literature on clinical presentations and
diagnosis. J Obstet Gynaecol Res, 2002.
28(4): 203–10.
511. Christensen B, Which antibiotics are
appropriate for treating bacteriuria in
pregnancy? J Antimicrob Chemother,
2000. 46 Suppl A: 29–34.
512. Christiaens TC, De Meyere M,
Verschraegen G, Peersman W, Heytens
S, and De Maeseneer JM, Randomised
controlled trial of nitrofurantoin versus
placebo in the treatment of uncomplicated
urinary tract infection in adult women.
Br J Gen Pract, 2002. 52(482): 729–34.
513. Christiaens TH, Heytens S,
Verschraegen G, De Meyere M, and De
Maeseneer J, Which bacteria are found
in Belgian women with uncomplicated
urinary tract infections in primary
health care, and what is their suscep-
tibility pattern anno 95–96? Acta Clin
Belg, 1998. 53(3): 184–8.
514. Christoph F, Weikert S, Muller M,
Miller K, and Schrader M, How septic
is urosepsis? Clinical course of infected
hydronephrosis and therapeutic strate-
gies. World J Urol, 2005. 23(4): 243–7.
515. Christophe JL, van Ypersele de Strihou
C, and Pirson Y, Complications of
autosomal dominant polycystic kidney
disease in 50 haemodialysed patients.
A case-control study. The U.C.L.
Collaborative Group. Nephrol Dial
Transplant, 1996. 11(7): 1271–6.
516. Chromek M, Slamova Z, Bergman
P, Kovacs L, Podracka L, Ehren I,
Hokfelt T, Gudmundsson GH, Gallo RL,
Agerberth B, and Brauner A, The antimi-
crobial peptide cathelicidin protects the
urinary tract against invasive bacterial
infection. Nat Med, 2006. 12(6): 636–41.
517. Chuang P, Parikh CR, and Langone
A, Urinary tract infections after renal
1019
References
transplantation: a retrospective review
at two US transplant centers. Clin
Transplant, 2005. 19(2): 230–5.
518. Chugh K and Agrawal S, Cefpodoxime:
pharmacokinetics and therapeutic uses.
Indian J Pediatr, 2003. 70(3): 227–31.
519. Chung BH, Chang SY, Kim SI, and Choi
HS, Successfully treated renal fungal
ball with continuous irrigation of fluco-
nazole. J Urol, 2001. 166(5): 1835–6.
520. Cibert J, La tuberculose rénale sous
l’angle de la thérapeutique. 1946, Paris,:
Masson. 533 p.
521. Cicerello E, Merlo F, Gambaro G,
Maccatrozzo L, Fandella A, Baggio B,
and Anselmo G, Effect of alkaline citrate
therapy on clearance of residual renal
stone fragments after extracorporeal
shock wave lithotripsy in sterile calcium
and infection nephrolithiasis patients. J
Urol, 1994. 151(1): 5–9.
522. Ciftcioglu N, Miller-Hjelle MA, Hjelle
JT, and Kajander EO, Inhibition of
nanobacteria by antimicrobial drugs as
measured by a modified microdilution
method. Antimicrob Agents Chemother,
2002. 46(7): 2077–86.
523. Cirl C, Wieser A, Yadav M, Duerr S,
Schubert S, Fischer H, Stappert D,
Wantia N, Rodriguez N, Wagner H,
Svanborg C, and Miethke T, Subversion
of Toll-like receptor signaling by a
unique family of bacterial Toll/inter-
leukin-1 receptor domain-containing pro-
teins. Nat Med, 2008. 14(4): 399–406.
524. Cisar JO, Xu DQ, Thompson J, Swaim
W, Hu L, and Kopecko DJ, An alterna-
tive interpretation of nanobacteria-
induced biomineralization. Proc Natl
Acad Sci U S A, 2000. 97(21): 11511–5.
525. Claes H, Vandeursen R, and Baert L,
Amoxycillin/clavulanate prophylaxis for
extracorporeal shock wave lithotripsy—
a comparative study. J Antimicrob
Chemother, 1989. 24 Suppl B: 217–20.
526. Clark KR and Higgs MJ, Urinary infec-
tion following out-patient flexible cystos-
copy. Br J Urol, 1990. 66(5): 503–5.
527. Clark PA, Eisenman J, and Szapor S,
Mandatory neonatal male circumcision
in Sub-Saharan Africa: medical and
ethical analysis. Med Sci Monit, 2007.
13(12): RA205–13.
1020
528. Clark S, Male circumcision could help
protect against HIV infection. Lancet,
2000. 356(9225): 225.
529. Classen DC, Evans RS, Pestotnik SL,
Horn SD, Menlove RL, and Burke JP,
The timing of prophylactic adminis-
tration of antibiotics and the risk of
surgical-wound infection. N Engl J Med,
1992. 326: 281–286.
530. Cleavenger RL, Juckett RG, and Hobbs
GR, Trends in chlamydia and other sexu-
ally transmitted diseases in a university
health service. J Am Coll Health, 1996.
44(6): 263–5.
531. Cleghorn AG and Wilkinson RG,
The IUCD-associated incidence of
Actinomyces israelii in the female genital
tract. Aust N Z J Obstet Gynaecol, 1989.
29(4): 445–9.
532. Clemens JQ MR, O’Keeffe-Rosetti M,
Gao SY, Calhoun EA. Incidence and clin-
ical characteristics of NIH type III pros-
tatitis in a managed care population. in
American Urological Association Annual
Meeting. 2005. San Antonio: J Urol.
533. Clinical and Laboratory Standards
Institute, Performance standards for
antimicrobial susceptibility testing.
Seventeenth informational supplement
M100-S18, 2008. 27(1): 98–163.
534. Clot J, In vitro experiments with
OM-8930. Experimental report 1983.
535. Coelho GM, Bouzada MC, Lemos GS,
Pereira AK, Lima BP, and Oliveira EA,
Risk factors for urinary tract infection in
children with prenatal renal pelvic dila-
tation. J Urol, 2008. 179(1): 284–9.
536. Coelho RF, Schneider-Monteiro ED,
Mesquita JL, Mazzucchi E, Marmo Lucon
A, and Srougi M, Renal and perinephric
abscesses: analysis of 65 consecutive
cases. World J Surg, 2007. 31(2): 431–6.
537. Cohen C, Emphysematous pyelonephri-
tis. A report of 2 cases. S Afr Med J,
1983. 63(5): 166–7.
538. Cohen CR, Manhart LE, Bukusi EA,
Astete S, Brunham RC, Holmes KK,
Sinei SK, Bwayo JJ, and Totten PA,
Association between Mycoplasma geni-
talium and acute endometritis. Lancet,
2002. 359(9308): 765–6.
539. Cohen CR, Mugo NR, Astete SG, Odondo
R, Manhart LE, Kiehlbauch JA, Stamm

WE, Waiyaki PG, and Totten PA,
Detection of Mycoplasma genitalium in
women with laparoscopically diagnosed
acute salpingitis. Sex Transm Infect,
2005. 81(6): 463–6.
540. Cohen D, Timsit MO, Chretien Y,
Thiounn N, Vassiliu V, Mamzer MF,
Legendre C, and Mejean A, [Place of
nephrectomy in patients with autosomal
dominant polycystic kidney disease wait-
ing for renal transplantation]. Prog Urol,
2008. 18(10): 642–9.
541. Cohen J and Carlet J, INTERSEPT:
an international, multicenter, placebo-
controlled trial of monoclonal antibody
to human tumor necrosis factor-alpha in
patients with sepsis. International Sepsis
Trial Study Group. Crit Care Med, 1996.
24(9): 1431–40.
542. Cohen L, Is more than one application
of an antifungal necessary in the treat-
ment of acute vaginal candidiasis? Am
J Obstet Gynecol, 1985. 152(7 Pt 2):
961–4.
543. Cohen MS, Hellmann N, Levy JA,
DeCock K, and Lange J, The spread,
treatment, and prevention of HIV-1:
evolution of a global pandemic. J Clin
Invest, 2008. 118(4): 1244–54.
544. Cohen MS, Hoffman IF, Royce RA,
Kazembe P, Dyer JR, Daly CC, Zimba
D, Vernazza PL, Maida M, Fiscus SA,
and Eron JJ, Jr., Reduction of concentra-
tion of HIV-1 in semen after treatment of
urethritis: implications for prevention of
sexual transmission of HIV-1. AIDSCAP
Malawi Research Group. Lancet, 1997.
349(9069): 1868–73.
545. Cohen TD, Streem SB, and Lammert G,
Long-term incidence and risks for recur-
rent stones following contemporary man-
agement of upper tract calculi in patients
with a urinary diversion. J Urol, 1996.
155(1): 62–5.
546. Cohn EB and Schaeffer AJ,
Urinary tract infections in adults.
ScientificWorldJournal, 2004. 4 Suppl
1: 76–88.
547. Colau A, Lucet JC, Rufat P, Botto H,
Benoit G, and Jardin A, Incidence and
risk factors of bacteriuria after transure-
thral resection of the prostate. Eur Urol,
2001. 39(3): 272–6.
References
548. Colgan R, Johnson JR, Kuskowski M,
and Gupta K, Risk factors for trimeth-
oprim-sulfamethoxazole resistance in
patients with acute uncomplicated cysti-
tis. Antimicrob Agents Chemother, 2008.
52(3): 846–51.
549. Collins MM, Stafford RS, O’Leary MP,
and Barry MJ, How common is prostati-
tis? A national survey of physician visits.
J Urol, 1998. 159(4): 1224–8.
550. Colmenero JD, Munoz-Roca NL,
Bermudez P, Plata A, Villalobos A, and
Reguera JM, Clinical findings, diagnos-
tic approach, and outcome of Brucella
melitensis epididymo-orchitis. Diagn
Microbiol Infect Dis, 2007. 57(4): 367–72.
551. Colmenero JD, Reguera JM, Martos F,
Sanchez-De-Mora D, Delgado M, Causse
M, Martin-Farfan A, and Juarez C,
Complications associated with Brucella
melitensis infection: a study of 530
cases. Medicine (Baltimore), 1996. 75(4):
195–211.
552. Colodner R, Ken-Dror S, Kavenshtock
B, Chazan B, and Raz R, Epidemiology
and clinical characteristics of patients
with Staphylococcus saprophyticus bac-
teriuria in Israel. Infection, 2006. 34(5):
278–81.
553. Colodner R, Nuri Y, Chazan B, and Raz
R, Community-acquired and hospital-
acquired candiduria: comparison of
prevalence and clinical characteristics.
Eur J Clin Microbiol Infect Dis, 2008.
27(4): 301–5.
554. Cone RW, Hobson AC, Palmer J,
Remington M, and Corey L, Extended
duration of herpes simplex virus DNA in
genital lesions detected by the polymer-
ase chain reaction. J Infect Dis, 1991.
164(4): 757–60.
555. Conklin JD, The pharmacokinetics of
nitrofurantoin and its related bioavail-
ability. Antibiot Chemother, 1978. 25:
233–52.
556. Connell I, Agace W, Klemm P, Schembri
M, Marild S, and Svanborg C, Type 1
fimbrial expression enhances Escherichia
coli virulence for the urinary tract.
Proc Natl Acad Sci U S A, 1996. 93(18):
9827–32.
557. Consortium for Spinal Cord Medicine,
Clinical Practice Guidelines – Bladder
1021
References
Management in Adults with Spinal Cord
Injury. 2006(Aug): 21,32,33,37.
558. Conte F, [Treatment of urinary tract
infection in the course of autosomal
dominant polycystic kidney disease: new
advances]. Minerva Urol Nefrol, 1987.
39(3): 291–5.
559. Conte JE, Jr., Golden JA, Kipps J, and
Zurlinden E, Intrapulmonary pharma-
cokinetics of linezolid. Antimicrob Agents
Chemother, 2002. 46(5): 1475–80.
560. Conte Visus A, Grases Freixedas F,
Costa-Bauza A, and Piza Reus P,
[Microinfections and kidney lithiasis].
Arch Esp Urol, 2001. 54(9): 855–60.
561. Contopoulos-Ioannidis DG, Giotis ND,
Baliatsa DV, and Ioannidis JP, Extended-
interval aminoglycoside administration
for children: a meta-analysis. Pediatrics,
2004. 114(1): e111–8.
562. Conway PH, Cnaan A, Zaoutis T, Henry
BV, Grundmeier RW, and Keren R,
Recurrent urinary tract infections in
children: risk factors and association
with prophylactic antimicrobials. Jama,
2007. 298(2): 179–86.
563. Cook DJ, Witt LG, Cook RJ, and Guyatt
GH, Stress ulcer prophylaxis in the criti-
cally ill: a meta-analysis. Am J Med,
1991. 91(5): 519–27.
564. Cook RJ and Sackett DL, The number
needed to treat: a clinically useful
measure of treatment effect. BMJ, 1995.
310(6977): 452–4.
565. Coombs RW, Reichelderfer PS, and
Landay AL, Recent observations on HIV
type-1 infection in the genital tract of
men and women. AIDS, 2003. 17(4):
455–80.
566. Coombs RW, Speck CE, Hughes JP, Lee
W, Sampoleo R, Ross SO, Dragavon J,
Peterson G, Hooton TM, Collier AC,
Corey L, Koutsky L, and Krieger JN,
Association between culturable human
immunodeficiency virus type 1 (HIV-1) in
semen and HIV-1 RNA levels in semen
and blood: evidence for compartmen-
talization of HIV-1 between semen and
blood. J Infect Dis, 1998. 177(2): 320–30.
567. Cooper CS, Chung BI, Kirsch AJ,
Canning DA, and Snyder HM, 3rd,
The outcome of stopping prophylac-
tic antibiotics in older children with
1022
vesicoureteral reflux. J Urol, 2000.
163(1): 269–72; discussion 272–3.
568. Cooper DE, White AA, Werkema AN,
and Auge BK, Anaphylaxis following
cystoscopy with equipment sterilized
with Cidex OPA (ortho-phthalaldehyde):
a review of two cases. J Endourol, 2008.
22(9): 2181–4.
569. Cooper TG, Weidner W, and Nieschlag
E, The influence of inflammation of the
human male genital tract on secretion of
the seminal markers alpha-glucosidase,
glycerophosphocholine, carnitine, fruc-
tose and citric acid. Int J Androl, 1990.
13(5): 329–36.
570. Copper IUDs, infection and infertility.
Drug Ther Bull, 2002. 40(9): 67–9.
571. Coque TM, Baquero F, and Canton
R, Increasing prevalence of ESBL-
producing Enterobacteriaceae in Europe.
Euro Surveill, 2008. 13(47).
572. Coraggio MJ, Gross TP, and Roscelli
JD, Nitrofurantoin toxicity in children.
Pediatr Infect Dis J, 1989. 8(3): 163–6.
573. Corey L, Adams HG, Brown ZA, and
Holmes KK, Genital herpes simplex
virus infections: clinical manifestations,
course, and complications. Ann Intern
Med, 1983. 98(6): 958–72.
574. Cormio L, Berardi B, Callea A,
Fiorentino N, Sblendorio D, Zizzi V, and
Traficante A, Antimicrobial prophylaxis
for transrectal prostatic biopsy: a pro-
spective study of ciprofloxacin vs pipera-
cillin/tazobactam. BJU Int, 2002. 90(7):
700–2.
575. Cornaglia G, Hryniewicz W, Jarlier
V, Kahlmeter G, Mittermayer H,
Stratchounski L, and Baquero F,
European recommendations for anti-
microbial resistance surveillance. Clin
Microbiol Infect, 2004. 10(4): 349–83.
576. Cornia PB, Takahashi TA, and Lipsky
BA, The microbiology of bacteriuria in
men: a 5-year study at a Veterans’ Affairs
hospital. Diagn Microbiol Infect Dis,
2006. 56(1): 25–30.
577. Corr SC, Li Y, Riedel CU, O’Toole PW,
Hill C, and Gahan CG, Bacteriocin
production as a mechanism for the anti-
infective activity of Lactobacillus salivar-
ius UCC118. Proc Natl Acad Sci U S A,
2007. 104(18): 7617–21.

578. Corrado ML, Grad C, and Sabbaj J,
Norfloxacin in the treatment of urinary
tract infections in men with and without
identifiable urologic complications. Am J
Med, 1987. 82(6B): 70–4.
579. Corrao G, Zambon A, Bertu L, Mauri
A, Paleari V, Rossi C, and Venegoni M,
Evidence of tendinitis provoked by fluo-
roquinolone treatment: a case-control
study. Drug Saf, 2006. 29(10): 889–96.
580. Correas JM, Claudon M, Tranquart F,
and Helenon AO, The kidney: imag-
ing with microbubble contrast agents.
Ultrasound Q, 2006. 22(1): 53–66.
581. Corsello S, Spinillo A, Osnengo G, Penna
C, Guaschino S, Beltrame A, Blasi N,
and Festa A, An epidemiological survey
of vulvovaginal candidiasis in Italy. Eur
J Obstet Gynecol Reprod Biol, 2003.
110(1): 66–72.
582. Costa RJ and Krauss-Silva L,
[Systematic review and meta-analysis of
antibiotic prophylaxis in abdominal hys-
terectomy]. Cad Saude Publica, 2004. 20
Suppl 2: S175–89.
583. Costantine MM, Rahman M, Ghulmiyah
L, Byers BD, Longo M, Wen T, Hankins
GD, and Saade GR, Timing of periopera-
tive antibiotics for cesarean delivery:
a metaanalysis. Am J Obstet Gynecol,
2008. 199(3): 301 e1–6.
584. Costantino G, Condorelli S, and
Costanzo V, The antibacterial che-
moprophylaxis in ureteroscopy: the
employment of the levofloxacin used as
switch-therapy versus oral treatment
with a single 500mg once a day. Gazz
Med Ital – Arch Sci Med, 2005. 164:
43–6.
585. Costerton JW, Introduction to biofilm.
Int J Antimicrob Agents, 1999. 11(3–4):
217–21; discussion 237–9.
586. Costerton JW, Lewandowski Z, Caldwell
DE, Korber DR, and Lappin-Scott HM,
Microbial biofilms. Annu Rev Microbiol,
1995. 49: 711–45.
587. Cottell E, Harrison RF, McCaffrey M,
Walsh T, Mallon E, and Barry-Kinsella
C, Are seminal fluid microorganisms of
significance or merely contaminants?
Fertil Steril, 2000. 74(3): 465–70.
588. Couillard DR, Vapnek JM, Rentzepis
MJ, and Stone AR, Fatal perforation of
References
augmentation cystoplasty in an adult.
Urology, 1993. 42(5): 585–8.
589. Coulthard MG, Flecknell P, Orr H,
Manas D, and O’Donnell M, Renal scar-
ring caused by vesicoureteric reflux
and urinary infection: a study in pigs.
Pediatr Nephrol, 2002. 17(7): 481–4.
590. Cox CE and Hinman F, Jr., Experiments
with induced bacteriuria, vesical empty-
ing and bacterial growth on the mecha-
nism of bladder defense to infection. J
Urol, 1961. 86: 739–48.
591. Cox JT, The development of cervical can-
cer and its precursors: what is the role of
human papillomavirus infection? Curr
Opin Obstet Gynecol, 2006. 18 Suppl 1:
s5-s13.
592. Cox SM, Shelburne P, Mason R, Guss
S, and Cunningham FG, Mechanisms of
hemolysis and anemia associated with
acute antepartum pyelonephritis. Am J
Obstet Gynecol, 1991. 164(2): 587–90.
593. Craig JC, Knight JF, Sureshkumar
P, Lam A, Onikul E, and Roy LP,
Vesicoureteric reflux and timing of
micturating cystourethrography after
urinary tract infection. Arch Dis Child,
1997. 76(3): 275–7.
594. Craig JC, Knight JF, Sureshkumar P,
Mantz E, and Roy LP, Effect of circumci-
sion on incidence of urinary tract infec-
tion in preschool boys. J Pediatr, 1996.
128(1): 23–7.
595. Craig JC, Simpson JM, Williams GJ,
Lowe A, Reynolds GJ, McTaggart SJ,
Hodson EM, Carapetis JR, Cranswick
NE, Smith G, Irwig LM, Caldwell PH,
Hamilton S, and Roy LP, Antibiotic
prophylaxis and recurrent urinary tract
infection in children. N Engl J Med,
2009. 361(18): 1748–59.
596. Craig WA, Basic pharmacodynamics of
antibacterials with clinical applications
to the use of beta-lactams, glycopeptides,
and linezolid. Infect Dis Clin North Am,
2003. 17(3): 479–501.
597. Crawford ED, Haynes AL, Jr., Story
MW, and Borden TA, Prevention of uri-
nary tract infection and sepsis follow-
ing transrectal prostatic biopsy. J Urol,
1982. 127(3): 449–51.
598. Crider KS, Cleves MA, Reefhuis J, Berry
RJ, Hobbs CA, and Hu DJ, Antibacterial
1023
References
medication use during pregnancy and
risk of birth defects: National Birth
Defects Prevention Study. Arch Pediatr
Adolesc Med, 2009. 163(11): 978–85.
599. Cronberg S, Banke S, Bergman B,
Boman H, Eilard T, Elbel E, Hugo-
Persson M, Johansson E, Kuylenstierna
N, Lanbeck P, Lindblom A, Paulsen O,
Schonbeck C, Walder M, and Wieslander
P, Fewer bacterial relapses after oral
treatment with norfloxacin than with
ceftibuten in acute pyelonephritis ini-
tially treated with intravenous cefuro-
xime. Scand J Infect Dis, 2001. 33(5):
339–43.
600. Cronin L, Cook DJ, Carlet J, Heyland
DK, King D, Lansang MA, and Fisher
CJ, Jr., Corticosteroid treatment for
sepsis: a critical appraisal and meta-
analysis of the literature. Crit Care Med,
1995. 23(8): 1430–9.
601. Croom KF and Goa KL, Levofloxacin:
a review of its use in the treatment of
bacterial infections in the United States.
Drugs, 2003. 63(24): 2769–802.
602. Cross NA, Kellock DJ, Kinghorn GR,
Taraktchoglou M, Bataki E, Oxley KM,
Hawkey PM, and Eley A, Antimicrobial
susceptibility testing of Chlamydia tra-
chomatis using a reverse transcriptase
PCR-based method. Antimicrob Agents
Chemother, 1999. 43(9): 2311–3.
603. Cruse PJ and Foord R, The epidemiology
of wound infection. A 10-year prospective
study of 62,939 wounds. Surg Clin North
Am, 1980. 60(1): 27–40.
604. Cucarella C, Solano C, Valle J, Amorena
B, Lasa I, and Penades JR, Bap, a
Staphylococcus aureus surface pro-
tein involved in biofilm formation. J
Bacteriol, 2001. 183(9): 2888–96.
605. Culver DH, Horan TC, Gaynes RP,
Martone WJ, Jarvis WR, Emori TG,
Banerjee SN, Edwards JR, Tolson JS,
Henderson TS, and et al., Surgical
wound infection rates by wound class,
operative procedure, and patient risk
index. National Nosocomial Infections
Surveillance System. Am J Med, 1991.
91(3B): 152S-157S.
606. Cundiff GW, McLennan MT, and Bent
AE, Randomized trial of antibiotic
prophylaxis for combined urodynamics
1024
and cystourethroscopy. Obstet Gynecol,
1999. 93(5 Pt 1): 749–52.
607. Cunha BA, Nitrofurantoin—current con-
cepts. Urology, 1988. 32(1): 67–71.
608. Cunningham D, Analysis and standardi-
zation of Cranberry products. American
Chemical Society, 2002(803): 151–6.
609. Cunningham FG, Lucas MJ, and
Hankins GD, Pulmonary injury compli-
cating antepartum pyelonephritis. Am J
Obstet Gynecol, 1987. 156(4): 797–807.
610. Czaja CA, Stapleton AE, Yarova-
Yarovaya Y, and Stamm WE, Phase I
trial of a Lactobacillus crispatus vagi-
nal suppository for prevention of recur-
rent urinary tract infection in women.
Infect Dis Obstet Gynecol, 2007. 2007:
35387.
611. Czeizel AE, Fladung B, and Vargha P,
Preterm birth reduction after clotrima-
zole treatment during pregnancy. Eur
J Obstet Gynecol Reprod Biol, 2004.
116(2): 157–63.
612. Czeizel AE, Rockenbauer M, Sorensen
HT, and Olsen J, Use of cephalosporins
during pregnancy and in the presence of
congenital abnormalities: a population-
based, case-control study. Am J Obstet
Gynecol, 2001. 184(6): 1289–96.
613. Czeizel AE, Toth M, and Rockenbauer
M, No teratogenic effect after clot-
rimazole therapy during pregnancy.
Epidemiology, 1999. 10(4): 437–40.
614. Dahlberg A, Perttila I, Wuokko E, and
Ala-Opas M, Bladder management in
persons with spinal cord lesion. Spinal
Cord, 2004. 42(12): 694–8.
615. Dahn A, Saunders S, Hammond JA,
Carter D, Kirjavainen P, Anukam K,
and Reid G, Effect of bacterial vaginosis,
Lactobacillus and Premarin estrogen
replacement therapy on vaginal gene
expression changes. Microbes Infect,
2008. 10(6): 620–7.
616. Dahouk SA, Neubauer H, Hensel A,
Schoneberg I, Nockler K, Alpers K,
Merzenich H, Stark K, and Jansen A,
Changing epidemiology of human bru-
cellosis, Germany, 1962–2005. Emerg
Infect Dis, 2007. 13(12): 1895–900.
617. Dajani AM and O’Flynn JD, Prostatic
abscess. A report of 25 cases. Br J Urol,
1968. 40(6): 736–9.

618. Dal Maso L, Serraino D, and Franceschi
S, Epidemiology of AIDS-related
tumours in developed and developing
countries. Eur J Cancer, 2001. 37(10):
1188–201.
619. Dale SE, Doherty-Kirby A, Lajoie G, and
Heinrichs DE, Role of siderophore bio-
synthesis in virulence of Staphylococcus
aureus: identification and characteriza-
tion of genes involved in production of a
siderophore. Infect Immun, 2004. 72(1):
29–37.
620. Dalkin BL, Wessells H, and Cui H, A
national survey of urinary and health
related quality of life outcomes in men
with an artificial urinary sphincter for
post-radical prostatectomy incontinence.
J Urol, 2003. 169(1): 237–9.
621. Dalla Palma L, Pozzi-Mucelli F, and
Ene V, Medical treatment of renal and
perirenal abscesses: CT evaluation. Clin
Radiol, 1999. 54(12): 792–7.
622. D’Amico AV, Whittington R, Malkowicz
SB, Schultz D, Blank K, Broderick GA,
Tomaszewski JE, Renshaw AA, Kaplan
I, Beard CJ, and Wein A, Biochemical
outcome after radical prostatectomy,
external beam radiation therapy, or
interstitial radiation therapy for clini-
cally localized prostate cancer. Jama,
1998. 280(11): 969–74.
623. Dancer SJ, Mopping up hospital infec-
tion. J Hosp Infect, 1999. 43(2): 85–100.
624. Danese PN, Pratt LA, Dove SL, and
Kolter R, The outer membrane protein,
antigen 43, mediates cell-to-cell interac-
tions within Escherichia coli biofilms.
Mol Microbiol, 2000. 37(2): 424–32.
625. Daneshgari F, Zimmern PE, and
Jacomides L, Magnetic resonance imag-
ing detection of symptomatic noncommu-
nicating intraurethral wall diverticula
in women. J Urol, 1999. 161(4): 1259–61;
discussion 1261–2.
626. Dani C, Biadaioli R, Bertini G, Martelli
E, and Rubaltelli FF, Probiotics feeding
in prevention of urinary tract infection,
bacterial sepsis and necrotizing entero-
colitis in preterm infants. A prospective
double-blind study. Biol Neonate, 2002.
82(2): 103–8.
627. Danso-Appiah A, Utzinger J, Liu J, and
Olliaro P, Drugs for treating urinary
References
schistosomiasis. Cochrane Database
Syst Rev, 2008(3): CD000053.
628. Dantas SR, Kuboyama RH, Mazzali M,
and Moretti ML, Nosocomial infections
in renal transplant patients: risk factors
and treatment implications associated
with urinary tract and surgical site infec-
tions. J Hosp Infect, 2006. 63(2): 117–23.
629. Danzig LA, Resnick D, and Akeson WH,
The treatment of cervical spine metasta-
sis from the prostate with a Halo cast.
Spine (Phila Pa 1976), 1980. 5(5): 395–8.
630. Darenkov AF, Derevianko, II, Martov
AG, Kotliarova GA, Kondrat’eva EM,
and Siniukhin VN, [The prevention of
infectious-inflammatory complications
in the postoperative period in percutane-
ous surgical interventions in patients
with urolithiasis]. Urol Nefrol (Mosk),
1994(2): 24–6.
631. Darge K, Moeller RT, Trusen A, Butter
F, Gordjani N, and Riedmiller H,
Diagnosis of vesicoureteric reflux with
low-dose contrast-enhanced harmonic
ultrasound imaging. Pediatr Radiol,
2005. 35(1): 73–8.
632. Darge K, Voiding urosonography with
US contrast agents for the diagnosis
of vesicoureteric reflux in children. II.
Comparison with radiological examina-
tions. Pediatr Radiol, 2008. 38(1): 54–63;
quiz 126–7.
633. Darouiche RO and Hull RA, Bacterial
interference for prevention of urinary
tract infection: an overview. J Spinal
Cord Med, 2000. 23(2): 136–41.
634. Darouiche RO, Donovan WH, Del Terzo
M, Thornby JI, Rudy DC, and Hull
RA, Pilot trial of bacterial interference
for preventing urinary tract infection.
Urology, 2001. 58(3): 339–44.
635. Darouiche RO, Smith JA, Jr., Hanna H,
Dhabuwala CB, Steiner MS, Babaian
RJ, Boone TB, Scardino PT, Thornby JI,
and Raad, II, Efficacy of antimicrobial-
impregnated bladder catheters in reduc-
ing catheter-associated bacteriuria: a
prospective, randomized, multicenter
clinical trial. Urology, 1999. 54(6):
976–81.
636. Darouiche RO, Thornby JI, Cerra-
Stewart C, Donovan WH, and Hull RA,
Bacterial interference for prevention of
1025
References
urinary tract infection: a prospective,
randomized, placebo-controlled, double-
blind pilot trial. Clin Infect Dis, 2005.
41(10): 1531–4.
637. Das P, Vaginal vaccine for recurrent uri-
nary-tract infections. Lancet Infect Dis,
2002. 2(2): 68.
638. Daschner F and Marget W, Treatment
of recurrent urinary tract infection in
children. II. Compliance of parents and
children with antibiotic therapy regimen.
Acta Paediatr Scand, 1975. 64(1): 105–8.
639. Dashe JS and Gilstrap LC, 3rd,
Antibiotic use in pregnancy. Obstet
Gynecol Clin North Am, 1997. 24(3):
617–29.
640. Daskalakis G, Papapanagiotou
A, Mesogitis S, Papantoniou N,
Mavromatis K, and Antsaklis A,
Bacterial vaginosis and group B strepto-
coccal colonization and preterm delivery
in a low-risk population. Fetal Diagn
Ther, 2006. 21(2): 172–6.
641. Datta N and Kontomichalou P,
Penicillinase synthesis control-
led by infectious R factors in
Enterobacteriaceae. Nature, 1965.
208(5007): 239–41.
642. Daudon M, Dore JC, Jungers P, and
Lacour B, Changes in stone composition
according to age and gender of patients:
a multivariate epidemiological approach.
Urol Res, 2004. 32(3): 241–7.
643. Daudon M, Estepa L, Viard JP, Joly D,
and Jungers P, Urinary stones in HIV-1-
positive patients treated with indinavir.
Lancet, 1997. 349(9061): 1294–5.
644. Davey P, Brown E, Fenelon L, Finch R,
Gould I, Hartman G, Holmes A, Ramsay
C, Taylor E, Wilcox M, and Wiffen P,
Interventions to improve antibiotic pre-
scribing practices for hospital inpatients.
Cochrane Database Syst Rev, 2005(4):
CD003543.
645. David J and Terhorst C, Organs and
cells of the immune system, in Scientific
American Medicine; Ch. 6. Immunology.
1999, WebMD Corp.
646. David RD, DeBlieux PM, and Press R,
Rational antibiotic treatment of outpa-
tient genitourinary infections in a chang-
ing environment. Am J Med, 2005. 118
Suppl 7A: 7S-13S.
1026
647. Davidson F and Mould RF, Recurrent
genital candidosis in women and the
effect of intermittent prophylactic treat-
ment. Br J Vener Dis, 1978. 54(3):
176–83.
648. Davidson F and Oates JK, The pill does
not cause ‘thrush’. Br J Obstet Gynaecol,
1985. 92(12): 1265–6.
649. Davies AJ, Desai HN, Turton S, and
Dyas A, Does instillation of chlorhexi-
dine into the bladder of catheterized geri-
atric patients help reduce bacteriuria? J
Hosp Infect, 1987. 9(1): 72–5.
650. Davies SC, Madjid B, Pardohudoyo S,
Wiraguna AA, Patten JH, and Upadisari
LP, Prevalence of sexually transmissible
infections (STI) among male patients
with STI in Denpasar and Makassar,
Indonesia: are symptoms of urethritis
sufficient to guide syndromic treatment?
Sex Health, 2007. 4(3): 213–5.
651. Davis BL and Robinson DG, Diverticula
of the female urethra: assay of 120 cases.
J Urol, 1970. 104(6): 850–3.
652. Davis JM, Carvalho HM, Rasmussen
SB, and O’Brien AD, Cytotoxic necro-
tizing factor type 1 delivered by outer
membrane vesicles of uropathogenic
Escherichia coli attenuates polymorpho-
nuclear leukocyte antimicrobial activity
and chemotaxis. Infect Immun, 2006.
74(8): 4401–8.
653. de Allori MC, Jure MA, Romero C, and
de Castillo ME, Antimicrobial resist-
ance and production of biofilms in
clinical isolates of coagulase-negative
Staphylococcus strains. Biol Pharm Bull,
2006. 29(8): 1592–6.
654. De Backer D, Christiaens T, Heytens
S, De Sutter A, Stobberingh EE, and
Verschraegen G, Evolution of bacterial
susceptibility pattern of Escherichia coli
in uncomplicated urinary tract infections
in a country with high antibiotic con-
sumption: a comparison of two surveys
with a 10 year interval. J Antimicrob
Chemother, 2008. 62(2): 364–8.
655. De Backer D, Creteur J, Silva E, and
Vincent JL, Effects of dopamine, nore-
pinephrine, and epinephrine on the
splanchnic circulation in septic shock:
which is best? Crit Care Med, 2003.
31(6): 1659–67.

656. De Bernardis F, Agatensi L, Ross IK,
Emerson GW, Lorenzini R, Sullivan PA,
and Cassone A, Evidence for a role for
secreted aspartate proteinase of Candida
albicans in vulvovaginal candidiasis. J
Infect Dis, 1990. 161(6): 1276–83.
657. de Jong TP, Chrzan R, Klijn AJ, and Dik
P, Treatment of the neurogenic bladder
in spina bifida. Pediatr Nephrol, 2008.
23(6): 889–96.
658. de Jong Z, Pontonnier F, and Plante
P, Single-dose fosfomycin trometamol
(Monuril) versus multiple-dose nor-
floxacin: results of a multicenter study
in females with uncomplicated lower
urinary tract infections. Urol Int, 1991.
46(4): 344–8.
659. De Jongh M, Dangor Y, Adam A, and
Hoosen AA, Gonococcal resistance: evolv-
ing from penicillin, tetracycline to the
quinolones in South Africa — implica-
tions for treatment guidelines. Int J STD
AIDS, 2007. 18(10): 697–9.
660. de la Taille A, Ravery V, Hoffmann P,
Hermieu JF, Moulinier F, Delmas V, and
Boccon-Gibod L, [Treatment of ureteral
stenosis using high pressure dilatation
catheters]. Prog Urol, 1997. 7(3): 408–14.
661. de Leon EM, Jacober SJ, Sobel JD, and
Foxman B, Prevalence and risk factors
for vaginal Candida colonization in
women with type 1 and type 2 diabetes.
BMC Infect Dis, 2002. 2: 1.
662. de Man P, Claeson I, Johanson IM, Jodal
U, and Svanborg Eden C, Bacterial
attachment as a predictor of renal abnor-
malities in boys with urinary tract infec-
tion. J Pediatr, 1989. 115(6): 915–22.
663. de Oliveira AC, Ciosak SI, Ferraz EM,
and Grinbaum RS, Surgical site infec-
tion in patients submitted to digestive
surgery: risk prediction and the NNIS
risk index. Am J Infect Control, 2006.
34(4): 201–7.
664. De Paepe H, Hoebeke P, Renson C, Van
Laecke E, Raes A, Van Hoecke E, Van
Daele J, and Vande Walle J, Pelvic-floor
therapy in girls with recurrent urinary
tract infections and dysfunctional void-
ing. Br J Urol, 1998. 81 Suppl 3: 109–13.
665. De Paepe H, Renson C, Hoebeke P, Raes
A, Van Laecke E, and Vande Walle J,
The role of pelvic-floor therapy in the
References
treatment of lower urinary tract dysfunc-
tions in children. Scand J Urol Nephrol,
2002. 36(4): 260–7.
666. De Paepe H, Renson C, Van Laecke E,
Raes A, Vande Walle J, and Hoebeke P,
Pelvic-floor therapy and toilet training
in young children with dysfunctional
voiding and obstipation. BJU Int, 2000.
85(7): 889–93.
667. De Paepe ME and Waxman M, Testicular
atrophy in AIDS: a study of 57 autopsy
cases. Hum Pathol, 1989. 20(3): 210–4.
668. De Ridder DJ, Everaert K, Fernandez
LG, Valero JV, Duran AB, Abrisqueta
ML, Ventura MG, and Sotillo
AR, Intermittent catheterisation
with hydrophilic-coated catheters
(SpeediCath) reduces the risk of clini-
cal urinary tract infection in spinal
cord injured patients: a prospective ran-
domised parallel comparative trial. Eur
Urol, 2005. 48(6): 991–5.
669. De Sadeleer C, De Boe V, Keuppens F,
Desprechins B, Verboven M, and Piepsz
A, How good is technetium-99m mercap-
toacetyltriglycine indirect cystography?
Eur J Nucl Med, 1994. 21(3): 223–7.
670. de Sanjose S, Diaz M, Castellsague X,
Clifford G, Bruni L, Munoz N, and Bosch
FX, Worldwide prevalence and genotype
distribution of cervical human papil-
lomavirus DNA in women with normal
cytology: a meta-analysis. Lancet Infect
Dis, 2007. 7(7): 453–9.
671. de Vincenzi I, A longitudinal study
of human immunodeficiency virus
transmission by heterosexual partners.
European Study Group on Heterosexual
Transmission of HIV. N Engl J Med,
1994. 331(6): 341–6.
672. Deeks SG, Smith M, Holodniy M, and
Kahn JO, HIV-1 protease inhibitors.
A review for clinicians. JAMA, 1997.
277(2): 145–53.
673. Deguchi T, Yoshida T, Miyazawa T,
Yasuda M, Tamaki M, Ishiko H, and
Maeda S, Association of Ureaplasma
urealyticum (biovar 2) with nongonococ-
cal urethritis. Sex Transm Dis, 2004.
31(3): 192–5.
674. Delavierre D, Huiban B, Fournier G,
Le Gall G, Tande D, and Mangin P,
[The value of antibiotic prophylaxis
1027
References
in transurethral resection of bladder
tumors. Apropos of 61 cases]. Prog Urol,
1993. 3(4): 577–82.
675. Deliveliotis C, Giftopoulos A,
Koutsokalis G, Raptidis G, and
Kostakopoulos A, The necessity of pro-
phylactic antibiotics during extracor-
poreal shock wave lithotripsy. Int Urol
Nephrol, 1997. 29(5): 517–21.
676. Dellinger RP, Carlet JM, Masur H,
Gerlach H, Calandra T, Cohen J, Gea-
Banacloche J, Keh D, Marshall JC,
Parker MM, Ramsay G, Zimmerman JL,
Vincent JL, and Levy MM, Surviving
Sepsis Campaign guidelines for manage-
ment of severe sepsis and septic shock.
Intensive Care Med, 2004. 30(4): 536–55.
677. Dellinger RP, Levy MM, Carlet JM, Bion
J, Parker MM, Jaeschke R, Reinhart
K, Angus DC, Brun-Buisson C, Beale
R, Calandra T, Dhainaut JF, Gerlach
H, Harvey M, Marini JJ, Marshall J,
Ranieri M, Ramsay G, Sevransky J,
Thompson BT, Townsend S, Vender
JS, Zimmerman JL, and Vincent JL,
Surviving Sepsis Campaign: interna-
tional guidelines for management of
severe sepsis and septic shock: 2008. Crit
Care Med, 2008. 36(1): 296–327.
678. Dellit TH, Owens RC, McGowan JE, Jr.,
Gerding DN, Weinstein RA, Burke JP,
Huskins WC, Paterson DL, Fishman
NO, Carpenter CF, Brennan PJ, Billeter
M, and Hooton TM, Infectious Diseases
Society of America and the Society for
Healthcare Epidemiology of America
guidelines for developing an institu-
tional program to enhance antimicrobial
stewardship. Clin Infect Dis, 2007. 44(2):
159–77.
679. Delves PJ and Roitt IM, The immune
system. First of two parts. N Engl J Med,
2000. 343(1): 37–49.
680. DeMaoi J, Urinary Tract Infection,
Complicated (UTI). Antibiotic guide –
Johns Hopkins. http://prod.hopkins-
abxguide.org.
681. Dembry LM and Andriole VT, Renal
and perirenal abscesses. Infect Dis Clin
North Am, 1997. 11(3): 663–80.
682. Demertzis J and Menias CO, State of the
art: imaging of renal infections. Emerg
Radiol, 2007. 14(1): 13–22.
1028
683. Dennemark N, Meyer-Wilmes M, and R
S, Screening and treatment of bacterial
vaginosis in the early second trimester of
pregnancy: a sufficient measure for pre-
vention of preterm deliveries?. Intern J
STD AIDS, 1997(8): 38–40.
684. Dennerstein GJ and Ellis DH,
Oestrogen, glycogen and vaginal can-
didiasis. Aust N Z J Obstet Gynaecol,
2001. 41(3): 326–8.
685. Denstedt JD, Reid G, and Sofer M,
Advances in ureteral stent technology.
World J Urol, 2000. 18(4): 237–42.
686. Denstedt JD, Wollin TA, and Reid G,
Biomaterials used in urology: current
issues of biocompatibility, infection, and
encrustation. J Endourol, 1998. 12(6):
493–500.
687. Department of Health and Human
Services, Public Health Service,. 1992,
Agency for Health Care Policy and
Research. p. 115–127.
688. Deresinski SC and Perkash I, Urinary
tract infections in male spinal cord
injured patients. Part one: Bacteriologic
diagnosis. J Am Paraplegia Soc, 1985.
8(1): 4–6.
689. Desai K, Boily MC, Garnett GP, Masse
BR, Moses S, and Bailey RC, The role of
sexually transmitted infections in male
circumcision effectiveness against HIV—
insights from clinical trial simulation.
Emerg Themes Epidemiol, 2006. 3: 19.
690. Desai PJ, Castle EP, Daley SM,
Swanson SK, Ferrigni RG, Humphreys
MR, and Andrews PE, Bilateral laparo-
scopic nephrectomy for significantly
enlarged polycystic kidneys: a tech-
nique to optimize outcome in the largest
of specimens. BJU Int, 2008. 101(8):
1019–23.
691. Desir G, Helman D, Herlich M, Turka L,
and Bia MJ, Haemophilus parainfluen-
zae liver abscess in a recipient of a renal
transplant who had polycystic disease.
JAMA, 1986. 255(14): 1878.
692. Dessus-Babus S, Bebear CM, Charron
A, Bebear C, and de Barbeyrac B,
Sequencing of gyrase and topoisomerase
IV quinolone-resistance-determining
regions of Chlamydia trachomatis and
characterization of quinolone-resistant
mutants obtained In vitro. Antimicrob

Agents Chemother, 1998. 42(10):
2474–81.
693. Deville WL, Yzermans JC, van Duijn
NP, Bezemer PD, van der Windt DA, and
Bouter LM, The urine dipstick test use-
ful to rule out infections. A meta-analysis
of the accuracy. BMC Urol, 2004. 4: 4.
694. Dewan B, Sharma M, Nayak N, and
Sharma SK, Upper urinary tract stones
& Ureaplasma urealyticum. Indian J
Med Res, 1997. 105: 15–21.
695. Dhainaut JF, Laterre PF, LaRosa
SP, Levy H, Garber GE, Heiselman
D, Kinasewitz GT, Light RB, Morris
P, Schein R, Sollet JP, Bates BM,
Utterback BG, and Maki D, The clini-
cal evaluation committee in a large
multicenter phase 3 trial of drotrecogin
alfa (activated) in patients with severe
sepsis (PROWESS): role, methodology,
and results. Crit Care Med, 2003. 31(9):
2291–301.
696. Dharnidharka VR, Agodoa LY, and
Abbott KC, Effects of urinary tract infec-
tion on outcomes after renal transplanta-
tion in children. Clin J Am Soc Nephrol,
2007. 2(1): 100–6.
697. Dhawan VK, eMedicine, Schistsomiasis.
The Medscape Journal, May 15, 2008.
698. Di Bartolomeo S, Mirta DH, Janer
M, Rodriguez Fermepin MR, Sauka
D, Magarinos F, and de Torres RA,
Incidence of Chlamydia trachomatis and
other potential pathogens in neonatal
conjunctivitis. Int J Infect Dis, 2001.
5(3): 139–43.
699. Di Martino P, Agniel R, David K,
Templer C, Gaillard JL, Denys P, and
Botto H, Reduction of Escherichia coli
adherence to uroepithelial bladder cells
after consumption of cranberry juice:
a double-blind randomized placebo-
controlled cross-over trial. World J Urol,
2006. 24(1): 21–7.
700. Diehl JL and Borgel D, Sepsis and
coagulation. Curr Opin Crit Care, 2005.
11(5): 454–60.
701. Diemer T, Hales DB, and Weidner W,
Immune-endocrine interactions and
Leydig cell function: the role of cytokines.
Andrologia, 2003. 35(1): 55–63.
702. Diemer T, Huwe P, Ludwig M, Hauck
EW, and W W, Urogenital infections and
References
sperm motility. Andrologia, 2003. 35:
283–287.
703. Diemer T, Huwe P, Michelmann HW,
Mayer F, Schiefer HG, and Weidner W,
Escherichia coli-induced alterations of
human spermatozoa. An electron micros-
copy analysis. Int J Androl, 2000. 23(3):
178–86.
704. Diemer T, Ludwig M, Huwe P, Hales DB,
and Weidner W, Influence of urogenital
infection on sperm function. Curr Opin
Urol, 2000. 10(1): 39–44.
705. Dik P, Klijn AJ, van Gool JD, de Jong-de
Vos van Steenwijk CC, and de Jong TP,
Early start to therapy preserves kidney
function in spina bifida patients. Eur
Urol, 2006. 49(5): 908–13.
706. DiMartino P, Agniel R, David
K, Templer C, Botto H, and al e,
Reduction of Escherichia coli adherence
to uroepithelial bladder cells after con-
sumption of cranberry juice: a double-
blind randomized placebo-controlled
cross-over trial. World J Urol, 2006.
24(1): 21–7.
707. Dimitrova D, Kalaydjiev S, Hristov L,
Nikolov K, Boyadjiev T, and Nakov L,
Antichlamydial and antisperm antibod-
ies in patients with chlamydial infec-
tions. Am J Reprod Immunol, 2004.
52(5): 330–6.
708. Dincel C, Ozdiler E, Ozenci H, Tazici N,
and Kosar A, Incidence of urinary tract
infection in patients without bacteriuria
undergoing SWL: comparison of stone
types. J Endourol, 1998. 12(1): 1–3.
709. Dineen P and Drusin L, Epidemics of
postoperative wound infections associ-
ated with hair carriers. Lancet, 1973.
2(7839): 1157–9.
710. Dineen P, The role of impervious drapes
and gowns preventing surgical infection.
Clin Orthop Relat Res, 1973(96): 210–2.
711. Diokno AC, Sonda LP, Hollander JB,
and Lapides J, Fate of patients started
on clean intermittent self-catheterization
therapy 10 years ago. J Urol, 1983.
129(6): 1120–2.
712. Dionisio F, Conceicao IC, Marques AC,
Fernandes L, and Gordo I, The evolution
of a conjugative plasmid and its ability
to increase bacterial fitness. Biol Lett,
2005. 1(2): 250–2.
1029
References
713. Do Chau Giang, The current situa-
tion of Tuberculosis in the World and
in Vietnam. Seminar on the National
Antituberculous Program, 2004: 1–11.
714. Doberneck RC, Pelvic actinomycosis
associated with use of intrauterine
device: a new challenge for the surgeon.
Am Surg, 1982. 48(1): 25–7.
715. Dodds RD, Guy PJ, Peacock AM, Duffy
SR, Barker SG, and Thomas MH,
Surgical glove perforation. Br J Surg,
1988. 75(10): 966–8.
716. Doehn C, Fornara P, Kausch I, Buttner
H, Friedrich HJ, and Jocham D, Value of
acute-phase proteins in the differential
diagnosis of acute scrotum. Eur Urol,
2001. 39(2): 215–21.
717. Dogan HS, Sahin A, Cetinkaya Y,
Akdogan B, Ozden E, and Kendi S,
Antibiotic prophylaxis in percutaneous
nephrolithotomy: prospective study in
81 patients. J Endourol, 2002. 16(9):
649–53.
718. Doganis D, Mavrikou M, Delis D,
Stamoyannou L, Siafas K, and
Sinaniotis K, Timing of voiding cystoure-
thrography in infants with first time
urinary infection. Pediatr Nephrol, 2009.
24(2): 319–22.
719. Doganis D, Siafas K, Mavrikou M,
Issaris G, Martirosova A, Perperidis
G, Konstantopoulos A, and Sinaniotis
K, Does early treatment of urinary
tract infection prevent renal damage?
Pediatrics, 2007. 120(4): e922–8.
720. Dohle GR, Colpi GM, Hargreave TB,
Papp GK, Jungwirth A, and Weidner W,
EAU guidelines on male infertility. Eur
Urol, 2005. 48(5): 703–11.
721. Dolapci I, Tekeli A, Ozsan M, Yaman
O, Ergin S, and Elhan A, Detecting of
Mycoplasma genitalium in male patients
with urethritis symptoms in Turkey by
polymerase chain reaction. Saudi Med J,
2005. 26(1): 64–8.
722. Domingue GJ, Sr. and Hellstrom WJ,
Prostatitis. Clin Microbiol Rev, 1998.
11(4): 604–13.
723. Domsky MF and Wilson RF,
Hemodynamic resuscitation. Crit Care
Clin, 1993. 9(4): 715–26.
724. Donders G, Bellen G, Byttebier G,
Verguts L, Hinoul P, Walckiers R,
1030
Stalpaert M, Vereecken A, and Van
Eldere J, Individualized decreasing-
dose maintenance fluconazole regimen
for recurrent vulvovaginal candidiasis
(ReCiDiF trial). Am J Obstet Gynecol,
2008. 199(6): 613 e1–9.
725. Donders G, De Wet HG, Hooft P,
and Desmyter J, Lactobacilli in
Papanicolaou smears, genital infections,
and pregnancy. Am J Perinatol, 1993.
10(5): 358–61.
726. Donders G, We, specialists in vul-
vovaginitis. Am J Obstet Gynecol, 2001.
184(2): 248–9.
727. Donders GG, Babula O, Bellen G,
Linhares IM, and Witkin SS, Mannose-
binding lectin gene polymorphism and
resistance to therapy in women with
recurrent vulvovaginal candidiasis.
BJOG, 2008. 115(10): 1225–31.
728. Donders GG, Definition and classifica-
tion of abnormal vaginal flora. Best
Pract Res Clin Obstet Gynaecol, 2007.
21(3): 355–73.
729. Donders GG, Management of genital
infections in pregnant women. Curr Opin
Infect Dis, 2006. 19(1): 55–61.
730. Donders GG, Microscopy of the bacterial
flora on fresh vaginal smears. Infect Dis
Obstet Gynecol, 1999. 7(4): 177–9.
731. Donders GG, Prenen H, Verbeke G, and
Reybrouck R, Impaired tolerance for
glucose in women with recurrent vaginal
candidiasis. Am J Obstet Gynecol, 2002.
187(4): 989–93.
732. Donders GG, Treatment of sexually
transmitted bacterial diseases in preg-
nant women. Drugs, 2000. 59(3): 477–85.
733. Donders GG, Vereecken A, Bosmans E,
Dekeersmaecker A, Salembier G, and
Spitz B, Definition of a type of abnormal
vaginal flora that is distinct from bacte-
rial vaginosis: aerobic vaginitis. BJOG,
2002. 109(1): 34–43.
734. Donders GGG, Bacterial vaginosis dur-
ing pregnancy: screen and treat? Europ J
Obst Gynecol Reprod Biol, 1999(3): 1–4.
735. Donegan EA, Wirawan DN, Muliawan
P, Schachter J, Moncada J, Parekh
M, and Knapp JS, Fluoroquinolone-
resistant Neisseria gonorrhoeae in Bali,
Indonesia: 2004. Sex Transm Dis, 2006.
33(10): 625–9.

736. Donnan PT, Wei L, Steinke DT, Phillips
G, Clarke R, Noone A, Sullivan FM,
MacDonald TM, and Davey PG, Presence
of bacteriuria caused by trimethoprim
resistant bacteria in patients prescribed
antibiotics: multilevel model with prac-
tice and individual patient data. BMJ,
2004. 328(7451): 1297.
737. Donowitz GR and Mandell GL, Beta-
Lactam antibiotics (1). N Engl J Med,
1988. 318(7): 419–26.
738. Dontas AS, Kasviki-Charvati P,
Papanayiotou PC, and Marketos SG,
Bacteriuria and survival in old age. N
Engl J Med, 1981. 304(16): 939–43.
739. Dontas AS, Tzonou A, Kasviki-Charvati
P, Georgiades GL, Christakis G, and
Trichopoulos D, Survival in a
residential home: an eleven-year longi-
tudinal study. J Am Geriatr Soc, 1991.
39(7): 641–9.
740. Double-blind comparison of 3-day ver-
sus 7-day treatment with norfloxacin in
symptomatic urinary tract infections.
The Inter-Nordic Urinary Tract Infection
Study Group. Scand J Infect Dis, 1988.
20(6): 619–24.
741. Douenias R, Rich M, Badlani G, Mazor
D, and Smith A, Predisposing factors
in bladder calculi. Review of 100 cases.
Urology, 1991. 37(3): 240–3.
742. Dowling KJ, Roberts JA, and Kaack MB,
P-fimbriated Escherichia coli urinary
tract infection: a clinical correlation.
South Med J, 1987. 80(12): 1533–6.
743. Drach GW, Urinary lithiasis: etiology,
diagnosis, and medical management,
in Campbell’s urology, Campbell MF
and Walsh PC, Editors. 1992, Saunders:
Philadelphia. p. 2085–2156.
744. Drain PK, Halperin DT, Hughes JP,
Klausner JD, and Bailey RC, Male
circumcision, religion, and infectious
diseases: an ecologic analysis of 118
developing countries. BMC Infect Dis,
2006. 6: 172.
745. Drechsel H, Thieken A, Reissbrodt R,
Jung G, and Winkelmann G, Alpha-
keto acids are novel siderophores in
the genera Proteus, Providencia, and
Morganella and are produced by amino
acid deaminases. J Bacteriol, 1993.
175(9): 2727–33.
References
746. Drenth JP and van der Meer JW, The
inflammasome—a linebacker of innate
defense. N Engl J Med, 2006. 355(7):
730–2.
747. Dretler SP and Pfister RC, Primary dis-
solution therapy of struvite calculi. J
Urol, 1984. 131(5): 861–3.
748. Dromerick AW and Edwards DF,
Relation of postvoid residual to urinary
tract infection during stroke rehabili-
tation. Arch Phys Med Rehabil, 2003.
84(9): 1369–72.
749. Dronge AS, Perkal MF, Kancir S,
Concato J, Aslan M, and Rosenthal RA,
Long-term glycemic control and postop-
erative infectious complications. Arch
Surg, 2006. 141(4): 375–80; discussion
380.
750. Dropulic LK and Jones RJ,
Polyomavirus BK infection in blood and
marrow transplant recipients. Bone
Marrow Transplant, 2008. 41(1): 11–8.
751. Drury NE, Dyer JP, Breitenfeldt
N, Adamson AS, and Harrison GS,
Management of acute epididymitis: are
European guidelines being followed?
Eur Urol, 2004. 46(4): 522–4; discussion
524–5.
752. Drusano GL, Johnson DE, Rosen M, and
Standiford HC, Pharmacodynamics of a
fluoroquinolone antimicrobial agent in a
neutropenic rat model of Pseudomonas
sepsis. Antimicrob Agents Chemother,
1993. 37(3): 483–90.
753. Drusano GL, Preston SL, Hardalo C,
Hare R, Banfield C, Andes D, Vesga O,
and Craig WA, Use of preclinical data
for selection of a phase II/III dose for
evernimicin and identification of a pre-
clinical MIC breakpoint. Antimicrob
Agents Chemother, 2001. 45(1): 13–22.
754. Drusano GL, Preston SL, Van Guilder
M, North D, Gombert M, Oefelein M,
Boccumini L, Weisinger B, Corrado M,
and Kahn J, A population pharmacoki-
netic analysis of the penetration of the
prostate by levofloxacin. Antimicrob
Agents Chemother, 2000. 44(8):
2046–51.
755. Dubi J, Chappuis P, and Darioli R,
[Treatment of urinary infection with a
single dose of co-trimoxazole compared
with a single dose of amoxicillin and
1031
References
a placebo]. Schweiz Med Wochenschr,
1982. 112(3): 90–2.
756. Ducel G, Fabry J, Nicolle LE, and World
Health Organization, Prevention of
hospital-acquired infections: a practi-
cal guide. 2nd ed. 2002, Geneva: World
Health Organization. vi, 64 p.
757. Dudley MN and Barriere SL,
Cefotaxime: microbiology, pharmacology,
and clinical use. Clin Pharm, 1982. 1(2):
114–24.
758. Duenas-Garcia OF, Rico H, Gorbea-
Sanchez V, and Herrerias-Canedo T,
Bladder rupture caused by postpartum
urinary retention. Obstet Gynecol, 2008.
112(2 Pt 2): 481–2.
759. Duff P and Park RC, Antibiotic prophy-
laxis in vaginal hysterectomy: a review.
Obstet Gynecol, 1980. 55(5 Suppl): 193S-
202S.
760. Duffy LM, Cleary J, Ahern S, Kuskowski
MA, West M, Wheeler L, and Mortimer
JA, Clean intermittent catheterization:
safe, cost-effective bladder management
for male residents of VA nursing homes.
J Am Geriatr Soc, 1995. 43(8): 865–70.
761. Dulin JD and Akers MC, Pelvic inflam-
matory disease and sepsis. Crit Care
Nurs Clin North Am, 2003. 15(1): 63–70.
762. Duncan ME, Perine PL, and Krause DW,
Pelvic infection caused by Salmonella
typhi. Two unusual cases. East Afr Med
J, 1981. 58(9): 703–7.
763. Dunnick NR, Ford K, Osborne D, Carson
CC, 3rd, and Paulson DF, Seminal vesic-
ulography: limited value in vesiculitis.
Urology, 1982. 20(4): 454–7.
764. Dunser MW, Mayr AJ, Tur A, Pajk W,
Barbara F, Knotzer H, Ulmer H, and
Hasibeder WR, Ischemic skin lesions as
a complication of continuous vasopressin
infusion in catecholamine-resistant
vasodilatory shock: incidence and risk fac-
tors. Crit Care Med, 2003. 31(5): 1394–8.
765. Dupin N, Bijaoui G, Schwarzinger M,
Ernault P, Gerhardt P, Jdid R, Hilab S,
Pantoja C, Buffet M, Escande JP, and
Costa JM, Detection and quantifica-
tion of Mycoplasma genitalium in male
patients with urethritis. Clin Infect Dis,
2003. 37(4): 602–5.
766. Dwivedi US, Goyal NK, Saxena V,
Acharya RL, Trivedi S, Singh PB,
1032
Vyas N, Datta B, Kumar A, and Das S,
Xanthogranulomatous pyelonephritis:
our experience with review of published
reports. ANZ J Surg, 2006. 76(11):
1007–9.
767. Dyer JR, Gilliam BL, Eron JJ, Jr.,
Cohen MS, Fiscus SA, and Vernazza
PL, Shedding of HIV-1 in semen during
primary infection. AIDS, 1997. 11(4):
543–5.
768. Dyer JR, Gilliam BL, Eron JJ, Jr.,
Grosso L, Cohen MS, and Fiscus SA,
Quantitation of human immunode-
ficiency virus type 1 RNA in cell free
seminal plasma: comparison of NASBA
with Amplicor reverse transcription-PCR
amplification and correlation with quan-
titative culture. J Virol Methods, 1996.
60(2): 161–70.
769. e.V. DIfN, Medizinische Mikrobiologie
– Empfindlichkeitsprüfung von
mikrobiellen Krankheitserregern
gegen Chemotherapeutika – Teil 4:
Bewertungsstufen für die minimalen
Hemmkonzentrationen – MHK-
Grenzwerte – von antibakteriel-
len Wirkstoffen., in Beiblatt zu DIN
58940–1., e.V. DIfN, Editor. August
2005: Beuth, Berlin.
770. EARSS. 2007.
771. EAU Professional Resources. Available
from: www.uroweb.org/nc/professional-
resources/guidelines/online.
772. Eckert J and Deplazes P, Biological,
epidemiological, and clinical aspects of
echinococcosis, a zoonosis of increasing
concern. Clin Microbiol Rev, 2004. 17(1):
107–35.
773. Eckert LO, Hawes SE, Stevens CE,
Koutsky LA, Eschenbach DA, and
Holmes KK, Vulvovaginal candidiasis:
clinical manifestations, risk factors,
management algorithm. Obstet Gynecol,
1998. 92(5): 757–65.
774. Eckert LO, Thwin SS, Hillier SL, Kiviat
NB, and Eschenbach DA, The antimicro-
bial treatment of subacute endometritis:
a proof of concept study. Am J Obstet
Gynecol, 2004. 190(2): 305–13.
775. Edelstein H and McCabe RE,
Perinephric abscess. Modern diagnosis
and treatment in 47 cases. Medicine
(Baltimore), 1988. 67(2): 118–31.

776. Edgardh K, [Strong increase of
Chlamydia trachomatis. A new mutant
and current sexual habits have had
“favourable” effects for the transmission].
Lakartidningen, 2007. 104(47): 3539–42.
777. Edin-Liljegren A, Grenabo L, Hedelin H,
Jonsson O, Akerlund S, and Pettersson
S, Concrement formation and urease-
induced crystallization in urine from
patients with continent ileal reservoirs.
Br J Urol, 1996. 78(1): 57–63.
778. Edin-Liljegren A, Grenabo L, Hedelin H,
Larsson P, and Pettersson S, Influence of
Escherichia coli on urease-induced crys-
tallisation in human urine. Scand J Urol
Nephrol, 1993. 27(2): 163–7.
779. Edin-Liljegren A, Rodin L, Grenabo L,
and Hedelin H, The importance of glu-
cose for the Escherichia coli mediated
citrate depletion in synthetic and human
urine. Scand J Urol Nephrol, 2001.
35(2): 106–11.
780. Edlund C and Nord CE, Effect on the
human normal microflora of oral antibi-
otics for treatment of urinary tract infec-
tions. J Antimicrob Chemother, 2000. 46
Suppl A: 41–48.
781. Edwards D, Normand IC, Prescod N, and
Smellie JM, Disappearance of vesicouret-
eric reflux during long-term prophylaxis
of urinary tract infection in children. Br
Med J, 1977. 2(6082): 285–8.
782. Efstathiou SP, Pefanis AV, Tsioulos DI,
Zacharos ID, Tsiakou AG, Mitromaras
AG, Mastorantonakis SE, Kanavaki SN,
and Mountokalakis TD, Acute pyelone-
phritis in adults: prediction of mortality
and failure of treatment. Arch Intern
Med, 2003. 163(10): 1206–12.
783. Eggimann P, Sax H, and Pittet D,
Catheter-related infections. Microbes
Infect, 2004. 6(11): 1033–42.
784. Eggli DF and Tulchinsky M,
Scintigraphic evaluation of pediatric
urinary tract infection. Semin Nucl Med,
1993. 23(3): 199–218.
785. Ehrenkranz NJ and Alfonso BC, Failure
of bland soap handwash to prevent
hand transfer of patient bacteria to
urethral catheters. Infect Control Hosp
Epidemiol, 1991. 12(11): 654–62.
786. Ehrstrom SM, Kornfeld D, Thuresson J,
and Rylander E, Signs of chronic stress
References
in women with recurrent candida vul-
vovaginitis. Am J Obstet Gynecol, 2005.
193(4): 1376–81.
787. Eickhoff JH, Frimodt-Moller N, Walter
S, and Frimodt-Moller C, A double-
blind, randomized, controlled multi-
centre study to compare the efficacy of
ciprofloxacin with pivampicillin as oral
therapy for epididymitis in men over
40 years of age. BJU Int, 1999. 84(7):
827–34.
788. Eisenbarth SC, Piggott DA, Huleatt JW,
Visintin I, Herrick CA, and Bottomly K,
Lipopolysaccharide-enhanced, toll-like
receptor 4-dependent T helper cell type 2
responses to inhaled antigen. J Exp Med,
2002. 196(12): 1645–51.
789. Eissinger RP, Asghar F, Kolasa C, and
Weinstein MP, Does pyuria indicate
infection in asymptomatic dialysis
patients? Clin Neph, 1997. 47: 50–51.
790. Eknoyan G, Qunibi WY, Grissom RT,
Tuma SN, and Ayus JC, Renal papil-
lary necrosis: an update. Medicine
(Baltimore), 1982. 61(2): 55–73.
791. el Khader K, Lrhorfi MH, el Fassi J,
Tazi K, Hachimi M, and Lakrissa A,
[Urogenital tuberculosis. Experience in
10 years]. Prog Urol, 2001. 11(1): 62–7.
792. ElAbd SA, ElShaer AF, ElMahrouky AS,
ElAshry OM, and Emran MA, Long-term
results of endourologic and percutane-
ous management of ureteral strictures
in bilharzial patients. J Endourol, 1996.
10(1): 35–43.
793. El-Badawi A, The clinical and pathologi-
cal aspects of bilharziasis of the bladder.
1962, University of Alexandria.
794. Elbasha EH, Dasbach EJ, and Insinga
RP, A multi-type HPV transmission
model. Bull Math Biol, 2008. 70(8):
2126–76.
795. El-Bolkainy M, Tawfik H, and Kamel
I, Histopathologic classification of car-
cinomas in the schistosomal bladder,
in Detection of bladder cancer: associ-
ated with schistosomiasis, El-Bolkainy
MNE and Chu EWE, Editors. 1981,
The National Cancer Institute, Cairo
University: Cairo, Egypt.
796. El-Bolkainy MN, Topographic pathology
of cancer. 1998: Cairo University: The
National Cancer Institute.
1033
References
797. El-Bolkainy MNE and Chu EWE,
Detection of bladder cancer: associated
with schistosomiasis. 1981, Cairo, Egypt:
The National Cancer Institute, Cairo
University.
798. el-Boulkany MN, Ghoneim MA, and
Mansour MA, Carcinoma of the bilhar-
zial bladder in Egypt. Clinical and path-
ological features. Br J Urol, 1972. 44(5):
561–70.
799. Elder HA, Santamarina BA, Smith
S, and Kass EH, The natural history
of asymptomatic bacteriuria during
pregnancy: the effect of tetracycline on
the clinical course and the outcome of
pregnancy. Am J Obstet Gynecol, 1971.
111(3): 441–62.
800. Elder JS, Diaz M, Caldamone AA,
Cendron M, Greenfield S, Hurwitz
R, Kirsch A, Koyle MA, Pope J, and
Shapiro E, Endoscopic therapy for vesi-
coureteral reflux: a meta-analysis. I.
Reflux resolution and urinary tract infec-
tion. J Urol, 2006. 175(2): 716–22.
801. Elder JS, Peters CA, Arant BS, Jr.,
Ewalt DH, Hawtrey CE, Hurwitz RS,
Parrott TS, Snyder HM, 3rd, Weiss RA,
Woolf SH, and Hasselblad V, Pediatric
Vesicoureteral Reflux Guidelines Panel
summary report on the management of
primary vesicoureteral reflux in children.
J Urol, 1997. 157(5): 1846–51.
802. Elder JS, Shah MB, Batiste LR, and
Eaddy M, Part 3: Endoscopic injection
versus antibiotic prophylaxis in the
reduction of urinary tract infections
in patients with vesicoureteral reflux.
Curr Med Res Opin, 2007. 23 Suppl 4:
S15–20.
803. Elder JS, Snyder HM, Hulbert WC,
and Duckett JW, Perforation of the aug-
mented bladder in patients undergoing
clean intermittent catheterization. J
Urol, 1988. 140(5 Pt 2): 1159–62.
804. Eley A, Oxley KM, Spencer RC,
Kinghorn GR, Ben-Ahmeida ET, and
Potter CW, Detection of Chlamydia
trachomatis by the polymerase chain
reaction in young patients with acute
epididymitis. Eur J Clin Microbiol Infect
Dis, 1992. 11(7): 620–3.
805. el-Feky HM, Aly MA, Mangoud AM,
Naguib A, Kamel H, Kamhawy M,
1034
Bayomi FA, Younis TA, and Morsy TA,
Histopathological study of the bilharzial
affection on the bladder and ureter. J
Egypt Soc Parasitol, 1992. 22(1): 71–6.
806. Elhanan G, Sarhat M, and Raz R,
Empiric antibiotic treatment and the
misuse of culture results and antibiotic
sensitivities in patients with community-
acquired bacteraemia due to urinary tract
infection. J Infect, 1997. 35(3): 283–8.
807. Elison BS, Taylor D, Van der Wall
H, Pereira JK, Cahill S, Rosenberg
AR, Farnsworth RH, and Murray IP,
Comparison of DMSA scintigraphy with
intravenous urography for the detection
of renal scarring and its correlation with
vesicoureteric reflux. Br J Urol, 1992.
69(3): 294–302.
808. Elkahwaji JE, Prevention of Recurrent
Lower Urinary Tract Infections by 4
Bacterial Lysates in Female Mice (OM
PHARMA PROJECT: BL 2007/01
FINAL REPORT «Preclinical». 2007,
Department of Surgery-Division of
Urological Surgery, University of
Nebraska Medical Center: Omaha.
809. Elliott SP, Villar R, and Duncan B,
Bacteriuria management and urological
evaluation of patients with spina bifida
and neurogenic bladder: a multicenter
survey. J Urol, 2005. 173(1): 217–20.
810. Ellis-Grosse EJ, Babinchak T, Dartois
N, Rose G, and Loh E, The efficacy and
safety of tigecycline in the treatment
of skin and skin-structure infections:
results of 2 double-blind phase 3 com-
parison studies with vancomycin-aztre-
onam. Clin Infect Dis, 2005. 41 Suppl 5:
S341–53.
811. Elmore JM, Kirsch AJ, Heiss EA,
Gilchrist A, and Scherz HC, Incidence of
urinary tract infections in children after
successful ureteral reimplantation ver-
sus endoscopic dextranomer/hyaluronic
acid implantation. J Urol, 2008. 179(6):
2364–7; discussion 2367–8.
812. El-Sebai I, Sherif M, El-Bolkainy M,
Mansour M, and M G, Verrucous squa-
mous carcinoma of the bladder. Urology,
1979. 4: 407.
813. Elzinga LW, Barry JM, Torres VE,
Zincke H, Wahner HW, Swan S, and
Bennett WM, Cyst decompression

surgery for autosomal dominant poly-
cystic kidney disease. J Am Soc Nephrol,
1992. 2(7): 1219–26.
814. Ena J, Arjona F, Martinez-Peinado C,
Lopez-Perezagua Mdel M, and Amador
C, Epidemiology of urinary tract infec-
tions caused by extended-spectrum beta-
lactamase-producing Escherichia coli.
Urology, 2006. 68(6): 1169–74.
815. Enders M, Turnwald-Maschler A, and
Regnath T, Antimicrobial resistance
of Neisseria gonorrhoeae isolates from
the Stuttgart and Heidelberg areas of
southern Germany. Eur J Clin Microbiol
Infect Dis, 2006.
816. Engeler DS, Hauri D, and John H,
Impact of prostatitis NIH IIIB (prosta-
todynia) on ejaculate parameters. Eur
Urol, 2003. 44(5): 546–8.
817. Engin G, Acunas B, Acunas G, and
Tunaci M, Imaging of extrapulmonary
tuberculosis. Radiographics, 2000. 20(2):
471–88; quiz 529–30, 532.
818. Enjalbert B, MacCallum DM, Odds FC,
and Brown AJ, Niche-specific activation
of the oxidative stress response by the
pathogenic fungus Candida albicans.
Infect Immun, 2007. 75(5): 2143–51.
819. Enlund AL and Varenhorst E, Morbidity
of ultrasound-guided transrectal core
biopsy of the prostate without prophylac-
tic antibiotic therapy. A prospective study
in 415 cases. Br J Urol, 1997. 79(5):
777–80.
820. Eriksen B, A randomized, open, parallel-
group study on the preventive effect of an
estradiol-releasing vaginal ring (Estring)
on recurrent urinary tract infections in
postmenopausal women. Am J Obstet
Gynecol, 1999. 180(5): 1072–9.
821. Esbjorner E, Hansson S, and Jakobsson
B, Management of children with dilat-
ing vesico-ureteric reflux in Sweden. Acta
Paediatr, 2004. 93(1): 37–42.
822. Eschenbach DA, Gravett MG, Hoyme
UB, and Holmes KK, An association
with prematurity and postpartum
complication, in Bacterial vaginosis.
WHO workshop on anaerobic curved
rods and bacterial vaginosis, Mardh
PA and Taylor-Robinson D, Editors.
1984, Almqvist & Wiksell: Stockholm. p.
213–218.
References
823. Eschenbach DA, Hillier S, Critchlow
C, Stevens C, DeRouen T, and Holmes
KK, Diagnosis and clinical manifesta-
tions of bacterial vaginosis. Am J Obstet
Gynecol, 1988. 158(4): 819–28.
824. Esclarin De Ruz A, Garcia Leoni E, and
Herruzo Cabrera R, Epidemiology and
risk factors for urinary tract infection in
patients with spinal cord injury. J Urol,
2000. 164(4): 1285–9.
825. Estores IM, Olsen D, and Gomez-Marin
O, Silver hydrogel urinary catheters:
evaluation of safety and efficacy in single
patient with chronic spinal cord injury. J
Rehabil Res Dev, 2008. 45(1): 135–9.
826. Ethans KD, Nance PW, Bard RJ, Casey
AR, and Schryvers OI, Efficacy and
safety of tolterodine in people with neu-
rogenic detrusor overactivity. J Spinal
Cord Med, 2004. 27(3): 214–8.
827. Ethel S, Bhat GK, and Hegde BM,
Bacterial adherence and humoral
immune response in women with symp-
tomatic and asymptomatic urinary tract
infection. Indian J Med Microbiol, 2006.
24(1): 30–3.
828. Etienne M, Chavanet P, Sibert L, Michel
F, Levesque H, Lorcerie B, Doucet J,
Pfitzenmeyer P, and Caron F, Acute
bacterial prostatitis: heterogeneity in
diagnostic criteria and management.
Retrospective multicentric analysis of
371 patients diagnosed with acute pros-
tatitis. BMC Infect Dis, 2008. 8: 12.
829. Eto DS, Jones TA, Sundsbak JL, and
Mulvey MA, Integrin-mediated host cell
invasion by type 1-piliated uropatho-
genic Escherichia coli. PLoS Pathog,
2007. 3(7): e100.
830. EUCAST technical note on fluconazole.
Clin Microbiol Infect, 2008. 14(2): 193–5.
831. Europe Gonococcal Antimicrobial
Surveillance Programme E-G. Euro-
GASP Anual report No.2, 2007. 2008;
Available from: http://www.essti.org/
microbiology.php#micro_gasp.
832. Evanoff GV, Thompson CS, Foley R, and
Weinman EJ, Spectrum of gas within the
kidney. Emphysematous pyelonephritis
and emphysematous pyelitis. Am J Med,
1987. 83(1): 149–54.
833. Evans DA, Kass EH, Hennekens CH,
Rosner B, Miao L, Kendrick MI, Miall
1035
References
WE, and Stuart KL, Bacteriuria and
subsequent mortality in women. Lancet,
1982. 1(8264): 156–8.
834. Evans JP, Smart JG, and Bagshaw PF,
Bacterial content of enucleated prostate
glands. Urology, 1981. 17(4): 328–31.
835. Evans RS, Pestotnik SL, Classen DC,
Clemmer TP, Weaver LK, Orme JF,
Lloyd JF, and Burke JP, A computer-
assisted management program for anti-
biotics and other anti-infective agents. N
Engl J Med, 1998. 338: 232–238.
836. Eyong ME, Ikepeme EE, and Ekanem
EE, Relationship between Schistosoma
haematobium infection and urinary
tract infection among children in South
Eastern, Nigeria. Niger Postgrad Med J,
2008. 15(2): 89–93.
837. Fadda G, Nicoletti G, Schito GC, and
Tempera G, Antimicrobial susceptibil-
ity patterns of contemporary pathogens
from uncomplicated urinary tract infec-
tions isolated in a multicenter Italian
survey: possible impact on guidelines. J
Chemother, 2005. 17(3): 251–7.
838. Fahmy NW, Honore LH, and Cumming
DC, Subacute focal endometritis.
Association with cervical colonization
with ureaplasma urealyticum, pelvic
pathology and endometrial maturation.
J Reprod Med, 1987. 32(9): 685–7.
839. Falagas ME and Bliziotis IA,
Albendazole for the treatment of human
echinococcosis: a review of compara-
tive clinical trials. Am J Med Sci, 2007.
334(3): 171–9.
840. Falagas ME and Vergidis PI, Urinary
tract infections in patients with urinary
diversion. Am J Kidney Dis, 2005. 46(6):
1030–7.
841. Falagas ME, Alexiou VG, Giannopoulou
KP, and Siempos, II, Risk factors for mor-
tality in patients with emphysematous
pyelonephritis: a meta-analysis. J Urol,
2007. 178(3 Pt 1): 880–5; quiz 1129.
842. Falagas ME, Betsi GI, and Athanasiou
S, Probiotics for prevention of recurrent
vulvovaginal candidiasis: a review. J
Antimicrob Chemother, 2006. 58(2):
266–72.
843. Falagas ME, Giannopoulou KP,
Kokolakis GN, and Rafailidis PI,
Fosfomycin: use beyond urinary tract
1036
and gastrointestinal infections. Clin
Infect Dis, 2008. 46(7): 1069–77.
844. Falagas ME, Kotsantis IK, Vouloumanou
EK, and Rafailidis PI, Antibiotics versus
placebo in the treatment of women with
uncomplicated cystitis: a meta-analysis
of randomized controlled trials. J Infect,
2009. 58(2): 91–102.
845. Falagas ME, Makris GC, Matthaiou
DK, and Rafailidis PI, Statins for infec-
tion and sepsis: a systematic review
of the clinical evidence. J Antimicrob
Chemother, 2008. 61(4): 774–85.
846. Falagas ME, Rafailidis PI, and Makris
GC, Bacterial interference for the preven-
tion and treatment of infections. Int J
Antimicrob Agents, 2008. 31(6): 518–22.
847. Falagas ME, Rafailidis PI, Matthaiou
DK, Virtzili S, Nikita D, and
Michalopoulos A, Pandrug-resistant
Klebsiella pneumoniae, Pseudomonas
aeruginosa and Acinetobacter bau-
mannii infections: characteristics and
outcome in a series of 28 patients. Int J
Antimicrob Agents, 2008. 32(5): 450–4.
848. Falk L, Fredlund H, and Jensen JS,
Tetracycline treatment does not eradicate
Mycoplasma genitalium. Sex Transm
Infect, 2003. 79(4): 318–9.
849. Fall I, N’Doye M, Wandaogo A, Sankale
AA, and Diop A, [A case report of epidi-
dymo-testicular bilharziasis in a child].
Ann Urol (Paris), 1992. 26(6–7): 360–1.
850. Farajnia S, Alikhani MY, Ghotaslou R,
Naghili B, and Nakhlband A, Causative
agents and antimicrobial susceptibilities
of urinary tract infections in the north-
west of Iran. Int J Infect Dis, 2009.
13(2): 140–4.
851. Faro S and Fenner DE, Urinary tract
infections. Clin Obstet Gynecol, 1998.
41(3): 744–54.
852. Farrell SM, Hawkins DF, and Ryder
TA, Scanning electron microscope study
of Candida albicans invasion of cul-
tured human cervical epithelial cells.
Sabouraudia, 1983. 21(3): 251–4.
853. Farriol VG, Comella XP, Agromayor EG,
Creixams XS, and Martinez De La Torre
IB, Gray-scale and power doppler sono-
graphic appearances of acute inflam-
matory diseases of the scrotum. J Clin
Ultrasound, 2000. 28(2): 67–72.

854. Farsi HM, Mosli HA, Al-Zemaity
MF, Bahnassy AA, and Alvarez M,
Bacteriuria and colonization of double-
pigtail ureteral stents: long-term expe-
rience with 237 patients. J Endourol,
1995. 9(6): 469–72.
855. Faust WC, Diaz M, and Pohl HG,
Incidence of post-pyelonephritic renal
scarring: a meta-analysis of the dimer-
capto-succinic acid literature. J Urol,
2009. 181(1): 290–7; discussion 297–8.
856. Febre N, Silva V, Medeiros EA, Wey
SB, Colombo AL, and Fischman O,
Microbiological characteristics of yeasts
isolated from urinary tracts of intensive
care unit patients undergoing urinary
catheterization. J Clin Microbiol, 1999.
37(5): 1584–6.
857. Feldmann F, Sorsa LJ, Hildinger K, and
Schubert S, The salmochelin siderophore
receptor IroN contributes to invasion of
urothelial cells by extraintestinal patho-
genic Escherichia coli in vitro. Infect
Immun, 2007. 75(6): 3183–7.
858. Feldmeier H, Doehring E, Daffala AA,
Omer AH, and Dietrich M, Efficacy of
metrifonate in urinary schistosomiasis:
comparison of reduction of Schistosoma
haematobium and S. mansoni eggs. Am
J Trop Med Hyg, 1982. 31(6): 1188–94.
859. Feldmeier H, Leutscher P, Poggensee
G, and Harms G, Male genital schisto-
somiasis and haemospermia. Trop Med
Int Health, 1999. 4(12): 791–3.
860. Ferrie BG and Rundle JS, Genito-
urinary tuberculosis in Glasgow 1970 to
1979: a review of 230 patients. Scott Med
J, 1985. 30(1): 30–4.
861. Ferris DG, Nyirjesy P, Sobel JD, Soper
D, Pavletic A, and Litaker MS, Over-
the-counter antifungal drug misuse
associated with patient-diagnosed vul-
vovaginal candidiasis. Obstet Gynecol,
2002. 99(3): 419–25.
862. Ferry SA, Holm SE, Stenlund H,
Lundholm R, and Monsen TJ, Clinical
and bacteriological outcome of differ-
ent doses and duration of pivmecil-
linam compared with placebo therapy
of uncomplicated lower urinary tract
infection in women: the LUTIW project.
Scand J Prim Health Care, 2007. 25(1):
49–57.
References
863. Ferry SA, Holm SE, Stenlund H,
Lundholm R, and Monsen TJ, The natu-
ral course of uncomplicated lower urinary
tract infection in women illustrated by
a randomized placebo controlled study.
Scand J Infect Dis, 2004. 36(4): 296–301.
864. Ferry T, Perpoint T, Vandenesch F, and
Etienne J, Virulence determinants in
Staphylococcus aureus and their involve-
ment in clinical syndromes. Curr Infect
Dis Rep, 2005. 7(6): 420–8.
865. Fexby S, Bjarnsholt T, Jensen PO, Roos
V, Hoiby N, Givskov M, and Klemm
P, Biological Trojan horse: Antigen 43
provides specific bacterial uptake and
survival in human neutrophils. Infect
Immun, 2007. 75(1): 30–4.
866. Fidel PL, Jr., Immunity in vaginal can-
didiasis. Curr Opin Infect Dis, 2005.
18(2): 107–11.
867. Fidel PL, Jr., Vazquez JA, and Sobel JD,
Candida glabrata: review of epidemiol-
ogy, pathogenesis, and clinical disease
with comparison to C. albicans. Clin
Microbiol Rev, 1999. 12(1): 80–96.
868. Fieno JV, Costing adult male circumci-
sion in high HIV prevalence, low circum-
cision rate countries. AIDS Care, 2008.
20(5): 515–20.
869. Figueiredo AA, Lucon AM, Junior RF,
and Srougi M, Epidemiology of urogeni-
tal tuberculosis worldwide. Int J Urol,
2008. 15(9): 827–32.
870. Fihn SD, Clinical practice. Acute uncom-
plicated urinary tract infection in women.
N Engl J Med, 2003. 349(3): 259–66.
871. Finer G and Landau D, Pathogenesis
of urinary tract infections with normal
female anatomy. Lancet Infect Dis, 2004.
4(10): 631–5.
872. Finer LB, Darroch JE, and Singh S,
Sexual partnership patterns as a behav-
ioral risk factor for sexually transmitted
diseases. Fam Plann Perspect, 1999.
31(5): 228–36.
873. Finfer S, Bellomo R, Boyce N, French J,
Myburgh J, and Norton R, A comparison
of albumin and saline for fluid resuscita-
tion in the intensive care unit. N Engl J
Med, 2004. 350(22): 2247–56.
874. Fink AJ, A possible explanation for het-
erosexual male infection with AIDS. N
Engl J Med, 1986. 315: 1167.
1037
References
875. Finkelstein R, Kassis E, Reinhertz
G, Gorenstein S, and Herman P,
Community-acquired urinary tract infec-
tion in adults: a hospital viewpoint. J
Hosp Infect, 1998. 38(3): 193–202.
876. Fischer H, Ellstrom P, Ekstrom K,
Gustafsson L, Gustafsson M, and
Svanborg C, Ceramide as a TLR4 ago-
nist; a putative signalling intermediate
between sphingolipid receptors for micro-
bial ligands and TLR4. Cell Microbiol,
2007.
877. Fischer H, Yamamoto M, Akira S,
Beutler B, and Svanborg C, Mechanism
of pathogen-specific TLR4 activation in
the mucosa: fimbriae, recognition recep-
tors and adaptor protein selection. Eur J
Immunol, 2006. 36(2): 267–77.
878. Fischer M, Bhatnagar J, Guarner J,
Reagan S, Hacker JK, Van Meter SH,
Poukens V, Whiteman DB, Iton A,
Cheung M, Dassey DE, Shieh WJ, and
Zaki SR, Fatal toxic shock syndrome
associated with Clostridium sordellii
after medical abortion. N Engl J Med,
2005. 353(22): 2352–60.
879. Fish DN, Levofloxacin: update and per-
spectives on one of the original ‘respira-
tory quinolones’. Expert Rev Anti Infect
Ther, 2003. 1(3): 371–87.
880. Fisher J, Mayhall G, Duma R, Shadomy
S, Shadomy J, and Watlington C,
Fungus balls of the urinary tract. South
Med J, 1979. 72(10): 1281–4, 1287.
881. Fisher JF, Woeltje K, Espinel-Ingroff A,
Stanfield J, and DiPiro JT, Efficacy of
a single intravenous dose of amphoter-
icin B for Candida urinary tract infec-
tions: further favorable experience. Clin
Microbiol Infect, 2003. 9(10): 1024–7.
882. Fishman IJ, Scott FB, and Selam IN,
Rescue procedure: an alternative to com-
plete removal for treatment of infected
penile prosthesis. J Urol, 1987. 137:
202A.
883. Fitzpatrick PM, Torres VE, Charboneau
JW, Offord KP, Holley KE, and Zincke H,
Long-term outcome of renal transplanta-
tion in autosomal dominant polycystic
kidney disease. Am J Kidney Dis, 1990.
15(6): 535–43.
884. Flanigan RC, Reda DJ, Wasson JH,
Anderson RJ, Abdellatif M, and
1038
Bruskewitz RC, 5-year outcome of
surgical resection and watchful wait-
ing for men with moderately sympto-
matic benign prostatic hyperplasia: a
Department of Veterans Affairs coopera-
tive study. J Urol, 1998. 160(1): 12–6;
discussion 16–7.
885. Flechner SM and Gow JG, Role of
nephrectomy in the treatment of non-
functioning or very poorly functioning
unilateral tuberculous kidney. J Urol,
1980. 123(6): 822–5.
886. Fleming DT and Wasserheit JN, From
epidemiological synergy to public health
policy and practice: the contribution of
other sexually transmitted diseases to
sexual transmission of HIV infection.
Sex Transm Infect, 1999. 75(1): 3–17.
887. Fletcher M, Bacterial adhesion: molecu-
lar and ecological diversity. Wiley series
in ecological and applied microbiology.
1996, New York: Wiley-Liss. xi, 361 p.
888. Fluit AC, Jones ME, Schmitz FJ, Acar J,
Gupta R, and Verhoef J, Antimicrobial
resistance among urinary tract infec-
tion (UTI) isolates in Europe: results
from the SENTRY Antimicrobial
Surveillance Program 1997. Antonie Van
Leeuwenhoek, 2000. 77(2): 147–52.
889. Flynn P, Havens P, Brady M, Emmanuel
P, Read J, Hoyt L, Henry-Reid L, Van
Dyke R, and Mofenson L, Male circumci-
sion for prevention of HIV and other sex-
ually transmitted diseases. Pediatrics,
2007. 119(4): 821–2.
890. Foda MM, Middlebrook PF, Gatfield CT,
Potvin G, Wells G, and Schillinger JF,
Efficacy of cranberry in prevention of
urinary tract infection in a susceptible
pediatric population. Can J Urol, 1995.
2(1): 98–102.
891. Foglia G, Sateren WB, Renzullo PO,
Bautista CT, Langat L, Wasunna MK,
Singer DE, Scott PT, Robb ML, and Birx
DL, High prevalence of HIV infection
among rural tea plantation residents in
Kericho, Kenya. Epidemiol Infect, 2008.
136(5): 694–702.
892. Fong IW, The value of chronic suppres-
sive therapy with itraconazole versus
clotrimazole in women with recurrent
vaginal candidiasis. Genitourin Med,
1992. 68(6): 374–7.

893. Fong T, Akriviadis EA, Runyon BA, and
Reynolds TB, Polymorphonuclear cell
count response and duration of antibiotic
therapy in spontaneous bacterial perito-
nitis. Hepatology, 1989. 9: 423–426.
894. Fontaine E, Barthelemy Y, Houlgatte
A, Chartier E, and Beurton D, Twenty-
year experience with jejunal conduits.
Urology, 1997. 50(2): 207–13.
895. Fontaine E, Leaver R, and Woodhouse
CR, The effect of intestinal urinary
reservoirs on renal function: a 10-year
follow-up. BJU Int, 2000. 86(3): 195–8.
896. Fontanges R, Study in mice of the pro-
tective and immunostimulating capac-
ity of LFC (OM-89) given enterally.
Experimental report. 1979.
897. Foo L, Lu Y, Howell A, and Vorsa N, The
structure of Cranberry proanthocyani-
dins which inhibit adherence of uropath-
ogenic P-fimbriated Escherichia coli
in vitro. Phytochemistry, 2000. 54(2):
173–81
898. Food and Drug Administration (FDA).
CIPRO (ciprofloxacin) use by pregnant
and lactating Women. Available from:
www.fda.gov/cder/drug/infopage/cipro/
ciprogreg.htm.
899. Forssbohm M, Zwahlen M,
Loddenkemper R, and Rieder HL,
Demographic characteristics of patients
with extrapulmonary tuberculosis in
Germany. Eur Respir J, 2008. 31(1):
99–105.
900. Fourcade RO, Antibiotic prophylaxis
with cefotaxime in endoscopic extrac-
tion of upper urinary tract stones: a
randomized study. The Cefotaxime
Cooperative Group. J Antimicrob
Chemother, 1990. 26 Suppl A: 77–83.
901. Fourcroy JL, Berner B, Chiang YK,
Cramer M, Rowe L, and Shore N,
Efficacy and safety of a novel once-daily
extended-release ciprofloxacin tablet
formulation for treatment of uncompli-
cated urinary tract infection in women.
Antimicrob Agents Chemother, 2005.
49(10): 4137–43.
902. Fowler JE, Jr. and Pulaski ET, Excretory
urography, cystography, and cystoscopy
in the evaluation of women with urinary-
tract infection: a prospective study. N
Engl J Med, 1981. 304(8): 462–5.
References
903. Fowler JE, Jr., Antimicrobial therapy
for bacterial and nonbacterial prosta-
titis. Urology, 2002. 60(6 Suppl): 24–6;
discussion 26.
904. Fox BC, Sollinger HW, Belzer FO, and
Maki DG, A prospective, randomized,
double-blind study of trimethoprim-sul-
famethoxazole for prophylaxis of infec-
tion in renal transplantation: clinical
efficacy, absorption of trimethoprim-sul-
famethoxazole, effects on the microflora,
and the cost-benefit of prophylaxis. Am J
Med, 1990. 89(3): 255–74.
905. Foxman B and Brown P, Epidemiology
of urinary tract infections: transmission
and risk factors, incidence, and costs.
Infect Dis Clin North Am, 2003. 17(2):
227–41.
906. Foxman B, Epidemiology of urinary
tract infections: incidence, morbidity,
and economic costs. Am J Med, 2002.
113 Suppl 1A: 5S-13S.
907. Foxman B, Gillespie B, Koopman J,
Zhang L, Palin K, Tallman P, Marsh JV,
Spear S, Sobel JD, Marty MJ, and Marrs
CF, Risk factors for second urinary tract
infection among college women. Am J
Epidemiol, 2000. 151(12): 1194–205.
908. Foxman B, Recurring urinary tract
infection: incidence and risk factors. Am
J Public Health, 1990. 80(3): 331–3.
909. Foxman B, Somsel P, Tallman P,
Gillespie B, Raz R, Colodner R,
Kandula D, and Sobel JD, Urinary
tract infection among women aged 40
to 65: behavioral and sexual risk fac-
tors. J Clin Epidemiol, 2001. 54(7):
710–8.
910. Foxman B, The epidemiology of vul-
vovaginal candidiasis: risk factors. Am J
Public Health, 1990. 80(3): 329–31.
911. France AM, Kugeler KM, Freeman A,
Zalewski CA, Blahna M, Zhang L, Marrs
CF, and Foxman B, Clonal groups and
the spread of resistance to trimethoprim-
sulfamethoxazole in uropathogenic
Escherichia coli. Clin Infect Dis, 2005.
40(8): 1101–7.
912. Franco EL, Villa LL, Sobrinho JP,
Prado JM, Rousseau MC, Desy M, and
Rohan TE, Epidemiology of acquisi-
tion and clearance of cervical human
papillomavirus infection in women from
1039
References
a high-risk area for cervical cancer. J
Infect Dis, 1999. 180(5): 1415–23.
913. Franco I, Overactive bladder in children.
Part 1: Pathophysiology. J Urol, 2007.
178(3 Pt 1): 761–8; discussion 768.
914. Frazer IH, Cox JT, Mayeaux EJ, Jr.,
Franco EL, Moscicki AB, Palefsky JM,
Ferris DG, Ferenczy AS, and Villa LL,
Advances in prevention of cervical cancer
and other human papillomavirus-related
diseases. Pediatr Infect Dis J, 2006. 25(2
Suppl): S65–81, quiz S82.
915. Freedman LR, Natural history of uri-
nary infection in adults. Kidney Int
Suppl, 1975. 4: S96–100.
916. Frei U and Schober-Halstenberg H-J,
Nierenersatztherapie in Deutschland.
Bericht über Dialysebehandlung und
Nierentransplantation in Deutschland
2000 und 2004. Quasi-Niere GmbH..
2001; 38 & 2006; 11.
917. Frendeus B, Godaly G, Hang L,
Karpman D, and Svanborg C,
Interleukin-8 receptor deficiency confers
susceptibility to acute pyelonephritis. J
Infect Dis, 2001. 183 Suppl 1: S56–60.
918. Frendeus B, Godaly G, Hang L,
Karpman D, Lundstedt AC, and
Svanborg C, Interleukin 8 receptor defi-
ciency confers susceptibility to acute
experimental pyelonephritis and may
have a human counterpart. J Exp Med,
2000. 192(6): 881–90.
919. Frendeus B, Wachtler C, Hedlund M,
Fischer H, Samuelsson P, Svensson M,
and Svanborg C, Escherichia coli P fim-
briae utilize the Toll-like receptor 4 path-
way for cell activation. Mol Microbiol,
2001. 40(1): 37–51.
920. Frey C, Obolensky W, and Wyss H,
Treatment of recurrent urinary tract
infections: efficacy of an orally adminis-
tered biological response modifier. Urol
Int, 1986. 41(6): 444–6.
921. Friedman S, Reif S, Assia A, Mishaal
R, and Levy I, Clinical and laboratory
characteristics of non-E. coli urinary
tract infections. Arch Dis Child, 2006.
91(10): 845–6.
922. Frimodt-Moller N, Espersen F, Jacobsen
B, Schlundt J, Meyling A, and Wegener
H, Problems with antibiotic resistance in
Spain and their relation to antibiotic use
1040
in humans elsewhere. Clin Infect Dis,
1997. 25: 939–941.
923. Fujimoto Y, Ueno K, Yamada S, Isogai K,
Komeda H, and Ban Y, [Clinical inves-
tigation of clean intermittent catheteri-
zation]. Hinyokika Kiyo, 1994. 40(4):
309–13.
924. Fujita K, Murayama K, Ida T,
Sumiyoshi Y, Yoshida K, Takaha M,
Kaji S, and Kitagawa M, [A cooperative
study on the incidence of bacteriuria in
patients with benign prostatic hypertro-
phy]. Nippon Hinyokika Gakkai Zasshi,
1994. 85(9): 1348–52.
925. Fujita K, Tanaka T, Kono S, Narai H,
Omori N, Manabe Y, and Abe K, Urinary
retention secondary to Listeria meningi-
tis. Intern Med, 2008. 47(12): 1129–31.
926. Funfstuck R, Straube E, Schildbach O,
and Tietz U, [Prevention of reinfection
by L-methionine in patients with recur-
rent urinary tract infection]. Med Klin
(Munich), 1997. 92(10): 574–81.
927. Funk-Bretano JL, Vantelon J, and
Lopez-Alvarez R, Les accidents evolitifs
de la maladie polykystique des reins: 154
observations personelles. Presse Med,
1964. 72: 1583.
928. Gabow PA, Chapman AB, Johnson
AM, Tangel DJ, Duley IT, Kaehny WD,
Manco-Johnson M, and Schrier RW,
Renal structure and hypertension in
autosomal dominant polycystic kidney
disease. Kidney Int, 1990. 38(6): 1177–80.
929. Gaither K, Ardite A, and Mason TC,
Pregnancy complicated by emphysema-
tous pyonephrosis. J Natl Med Assoc,
2005. 97(10): 1411–3.
930. Gales AC, Sader HS, and Jones RN,
Urinary tract infection trends in Latin
American hospitals: report from the
SENTRY antimicrobial surveillance
program (1997–2000). Diagn Microbiol
Infect Dis, 2002. 44(3): 289–99.
931. Galvin SR and Cohen MS, The role of
sexually transmitted diseases in HIV
transmission. Nat Rev Microbiol, 2004.
2(1): 33–42.
932. Gambaro G, Favaro S, and D’Angelo A,
Risk for renal failure in nephrolithiasis.
Am J Kidney Dis, 2001. 37(2): 233–43.
933. Game X, Castel-Lacanal E, Bentaleb
Y, Thiry-Escudie I, De Boissezon X,

Malavaud B, Marque P, and Rischmann
P, Botulinum toxin A detrusor injections
in patients with neurogenic detrusor
overactivity significantly decrease the
incidence of symptomatic urinary tract
infections. Eur Urol, 2008. 53(3): 613–8.
934. Game X, Vincendeau S, Palascak R,
Milcent S, Fournier R, and Houlgatte
A, Total and free serum prostate specific
antigen levels during the first month of
acute prostatitis. Eur Urol, 2003. 43(6):
702–5.
935. Ganabathi K, Leach GE, Zimmern PE,
and Dmochowski R, Experience with the
management of urethral diverticulum
in 63 women. J Urol, 1994. 152(5 Pt 1):
1445–52.
936. Ganderton L, Chawla J, Winters C,
Wimpenny J, and Stickler D, Scanning
electron microscopy of bacterial biofilms
on indwelling bladder catheters. Eur J
Clin Microbiol Infect Dis, 1992. 11(9):
789–96.
937. Gao F, Linhartova L, Johnston AM, and
Thickett DR, Statins and sepsis. Br J
Anaesth, 2008. 100(3): 288–98.
938. Gao F, Robertson DL, Morrison SG, Hui
H, Craig S, Decker J, Fultz PN, Girard
M, Shaw GM, Hahn BH, and Sharp PM,
The heterosexual human immunodefi-
ciency virus type 1 epidemic in Thailand
is caused by an intersubtype (A/E)
recombinant of African origin. J Virol,
1996. 70(10): 7013–29.
939. Garcia Leoni ME and Esclarin De Ruz
A, Management of urinary tract infec-
tion in patients with spinal cord injuries.
Clin Microbiol Infect, 2003. 9(8): 780–5.
940. Garcia S, Casco R, Perazzi B, De Mier C,
Vay C, and Famiglietti A, [Ciprofloxacin
resistance of Neisseria gonorrhoeae
according to sexual habits]. Medicina (B
Aires), 2008. 68(5): 358–62.
941. Gardiner GE, Heinemann C, Bruce AW,
Beuerman D, and Reid G, Persistence
of Lactobacillus fermentum RC-14 and
Lactobacillus rhamnosus GR-1 but not
L. rhamnosus GG in the human vagina
as demonstrated by randomly ampli-
fied polymorphic DNA. Clin Diagn Lab
Immunol, 2002. 9(1): 92–6.
942. Gargollo PC and Diamond DA, Therapy
insight: What nephrologists need to know
References
about primary vesicoureteral reflux. Nat
Clin Pract Nephrol, 2007. 3(10): 551–63.
943. Garibaldi RA, Burke JP, Britt MR,
Miller MA, and Smith CB, Meatal colo-
nization and catheter-associated bacteri-
uria. N Engl J Med, 1980. 303(6): 316–8.
944. Garibaldi RA, Burke JP, Dickman ML,
and Smith CB, Factors predisposing to
bacteriuria during indwelling urethral
catheterization. N Engl J Med, 1974.
291(5): 215–9.
945. Garibaldi RA, Skolnick D, Lerer T,
Poirot A, Graham J, Krisuinas E, and
Lyons R, The impact of preoperative skin
disinfection on preventing intraoperative
wound contamination. Infect Control
Hosp Epidemiol, 1988. 9(3): 109–13.
946. Garin EH, Campos A, and Homsy Y,
Primary vesicoureteral reflux: review of
current concepts. Pediatr Nephrol, 1998.
12(3): 249–56.
947. Garin EH, Olavarria F, Araya C,
Broussain M, Barrera C, and Young L,
Diagnostic significance of clinical and
laboratory findings to localize site of uri-
nary infection. Pediatr Nephrol, 2007.
22(7): 1002–6.
948. Garin EH, Olavarria F, Garcia Nieto
V, Valenciano B, Campos A, and Young
L, Clinical significance of primary vesi-
coureteral reflux and urinary antibiotic
prophylaxis after acute pyelonephritis:
a multicenter, randomized, controlled
study. Pediatrics, 2006. 117(3): 626–32.
949. Garner JS and Favero MS, CDC
Guideline for Handwashing and
Hospital Environmental Control, 1985.
Infect Control, 1986. 7(4): 231–43.
950. Garner JS, Guideline for isolation
precautions in hospitals. The Hospital
Infection Control Practices Advisory
Committee. Infect Control Hosp
Epidemiol, 1996. 17(1): 53–80.
951. Garner JS, Jarvis WR, Emori TG, Horan
TC, and Hughes JM, CDC definitions for
nosocomial infections, 1988. Am J Infect
Control, 1988. 16(3): 128–40.
952. Gaspard U, Scheen A, Endrikat J,
Buicu C, Lefebvre P, Gerlinger C, and
Heithecker R, A randomized study over
13 cycles to assess the influence of oral
contraceptives containing ethinylestra-
diol combined with drospirenone or
1041
References
desogestrel on carbohydrate metabolism.
Contraception, 2003. 67(6): 423–9.
953. Gaspari RJ, Dickson E, Karlowsky
J, and Doern G, Antibiotic resistance
trends in paediatric uropathogens. Int J
Antimicrob Agents, 2005. 26(4): 267–71.
954. Gastmeier P, Kampf G, Wischnewski N,
Hauer T, Schulgen G, Schumacher M,
Daschner F, and Ruden H, Prevalence of
nosocomial infections in representative
German hospitals. J Hosp Infect, 1998.
38(1): 37–49.
955. Gattegno B, Sicard F, Alcaidinho
D, Arnaud E, and Thibault P,
[Extracorporeal lithotripsy and pro-
phylactic antibiotic therapy]. Ann Urol
(Paris), 1988. 22(2): 101–2.
956. Gault MH, Longerich LL, Crane G,
Cooper R, Dow D, Best L, Stockall
E, and Brown W, Bacteriology of uri-
nary tract stones. J Urol, 1995. 153(4):
1164–70.
957. Gauthier M, Chevalier I, Sterescu A,
Bergeron S, Brunet S, and Taddeo D,
Treatment of urinary tract infections
among febrile young children with daily
intravenous antibiotic therapy at a
day treatment center. Pediatrics, 2004.
114(4): e469–76.
958. Gaydos CA, Kent CK, Rietmeijer CA,
Willard NJ, Marrazzo JM, Chapin JB,
Dunne EF, Markowitz LE, Klausner JD,
Ellen JM, and Schillinger JA, Prevalence
of Neisseria Gonorrhoeae among men
screened for Chlamydia Trachomatis in
four United States cities, 1999–2003. Sex
Transm Dis, 2006. 33(5): 314–9.
959. Gdoura R, Kchaou W, Ammar-Keskes
L, Chakroun N, Sellemi A, Znazen A,
Rebai T, and Hammami A, Assessment
of Chlamydia trachomatis, Ureaplasma
urealyticum, Ureaplasma parvum,
Mycoplasma hominis, and Mycoplasma
genitalium in semen and first void urine
specimens of asymptomatic male part-
ners of infertile couples. J Androl, 2008.
29(2): 198–206.
960. Gdoura R, Kchaou W, Znazen A,
Chakroun N, Fourati M, Ammar-Keskes
L, and Hammami A, Screening for bacte-
rial pathogens in semen samples from
infertile men with and without leukocyt-
ospermia. Andrologia, 2008. 40(4): 209–18.
1042
961. Geerlings SE, Brouwer EC, Gaastra W,
and Hoepelman AI, Is a second urine
specimen necessary for the diagnosis of
asymptomatic bacteriuria? Clin Infect
Dis, 2000. 31(3): E3–4.
962. Geerlings SE, Brouwer EC, Gaastra W,
Stolk R, Diepersloot RJ, and Hoepelman
AI, Virulence factors of Escherichia coli
isolated from urine of diabetic women
with asymptomatic bacteriuria: cor-
relation with clinical characteristics.
Antonie Van Leeuwenhoek, 2001. 80(2):
119–27.
963. Geerlings SE, Brouwer EC, Gaastra W,
Verhoef J, and Hoepelman AI, Effect
of glucose and pH on uropathogenic
and non-uropathogenic Escherichia
coli: studies with urine from diabetic
and non-diabetic individuals. J Med
Microbiol, 1999. 48(6): 535–9.
964. Geerlings SE, Brouwer EC, Van
Kessel KC, Gaastra W, Stolk RP, and
Hoepelman AI, Cytokine secretion is
impaired in women with diabetes mel-
litus. Eur J Clin Invest, 2000. 30(11):
995–1001.
965. Geerlings SE, Meiland R, van Lith
EC, Brouwer EC, Gaastra W, and
Hoepelman AI, Adherence of type 1-fim-
briated Escherichia coli to uroepithelial
cells: more in diabetic women than in
control subjects. Diabetes Care, 2002.
25(8): 1405–9.
966. Geerlings SE, Stolk RP, Camps MJ,
Netten PM, Collet JT, Schneeberger
PM, and Hoepelman AI, Consequences
of asymptomatic bacteriuria in women
with diabetes mellitus. Arch Intern Med,
2001. 161(11): 1421–7.
967. Geerlings SE, Stolk RP, Camps MJ,
Netten PM, Collet TJ, and Hoepelman
AI, Risk factors for symptomatic urinary
tract infection in women with diabetes.
Diabetes Care, 2000. 23(12): 1737–41.
968. Geerlings SE, Stolk RP, Camps MJ,
Netten PM, Hoekstra JB, Bouter KP,
Bravenboer B, Collet JT, Jansz AR, and
Hoepelman AI, Asymptomatic bacteriu-
ria may be considered a complication in
women with diabetes. Diabetes Mellitus
Women Asymptomatic Bacteriuria
Utrecht Study Group. Diabetes Care,
2000. 23(6): 744–9.

969. Geerlings SE, Urinary tract infections in
patients with diabetes mellitus: epidemi-
ology, pathogenesis and treatment. Int J
Antimicrob Agents, 2008. 31 Suppl 1:
S54–7.
970. Geerts W, Cook D, Selby R, and Etchells
E, Venous thromboembolism and its
prevention in critical care. J Crit Care,
2002. 17(2): 95–104.
971. Geetha D, Tong BC, Racusen L,
Markowitz JS, and Westra WH, Bladder
carcinoma in a transplant recipient: evi-
dence to implicate the BK human polyo-
mavirus as a causal transforming agent.
Transplantation, 2002. 73(12): 1933–6.
972. Geisler WM, Yu S, and Hook EW, 3rd,
Chlamydial and gonococcal infection
in men without polymorphonuclear leu-
kocytes on gram stain: implications for
diagnostic approach and management.
Sex Transm Dis, 2005. 32(10): 630–4.
973. Gemmell CG, Edwards DI, Fraise AP,
Gould FK, Ridgway GL, and Warren
RE, Guidelines for the prophylaxis
and treatment of methicillin-resist-
ant Staphylococcus aureus (MRSA)
infections in the UK. J Antimicrob
Chemother, 2006. 57(4): 589–608.
974. Generao SE, Dall’era JP, Stone AR, and
Kurzrock EA, Spinal cord injury in
children: long-term urodynamic and uro-
logical outcomes. J Urol, 2004. 172(3):
1092–4, discussion 1094.
975. Gentilini M, Tuberculose, in Médecine
tropicale. 1993, Médecine-Sciences:
Flammarion, Paris. p. 1157–78.
976. Gentle DL, Stoller ML, Jarrett TW,
Ward JF, Geib KS, and Wood AF,
Protease inhibitor-induced urolithiasis.
Urology, 1997. 50(4): 508–11.
977. Georgaki-Angelaki H, Kostaridou S,
Daikos GL, Kapoyiannis A, Veletzas
Z, Michos AG, and Syriopoulou VP,
Long-term follow-up of children with
vesicoureteral reflux with and without
antibiotic prophylaxis. Scand J Infect
Dis, 2005. 37(11–12): 842–5.
978. German “Zentralkommitee zur
Bekämpfung der Tuberkulose”: 31st
Information Report 2008, Berlin.
979. German “Zentralkommitee zur
Bekämpfung der Tuberkulose”: 30th
Information Report 2007, Berlin.
References
980. Gesu GP and Marchetti F, Increasing
resistance according to patient’s age and
sex in Escherichia coli isolated from urine
in Italy. J Chemother, 2007. 19(2): 161–5.
981. Ghalayini IF, Pathological spectrum
of nephrectomies in a general hospital.
Asian J Surg, 2002. 25(2): 163–9.
982. Ghannoum MA and Abu-Elteen KH,
Pathogenicity determinants of Candida.
Mycoses, 1990. 33(6): 265–82.
983. Ghannoum MA, Potential role of phos-
pholipases in virulence and fungal
pathogenesis. Clin Microbiol Rev, 2000.
13(1): 122–43, table of contents.
984. Ghoneim MA, Abdel-Latif M, el-
Mekresh M, Abol-Enein H, Mosbah A,
Ashamallah A, and el-Baz MA, Radical
cystectomy for carcinoma of the bladder:
2,720 consecutive cases 5 years later. J
Urol, 2008. 180(1): 121–7.
985. Ghoneim MA, el-Mekresh MM, el-Baz
MA, el-Attar IA, and Ashamallah A,
Radical cystectomy for carcinoma of the
bladder: critical evaluation of the results
in 1,026 cases. J Urol, 1997. 158(2):
393–9.
986. Ghoneim MA, Nabeeh A, and
El-Kappany H, Endourologic treatment
of ureteric strictures. J Endourol, 1988.
2: 263–270.
987. Ghys PD, Fransen K, Diallo MO,
Ettiegne-Traore V, Coulibaly IM, Yeboue
KM, Kalish ML, Maurice C, Whitaker
JP, Greenberg AE, and Laga M, The
associations between cervicovaginal HIV
shedding, sexually transmitted diseases
and immunosuppression in female sex
workers in Abidjan, Cote d’Ivoire. AIDS,
1997. 11(12): F85–93.
988. Giakoupi P, Maltezou H, Polemis M,
Pappa O, Saroglou G, and Vatopoulos A,
KPC-2-producing Klebsiella pneumoniae
infections in Greek hospitals are mainly
due to a hyperepidemic clone. Euro
Surveill, 2009. 14(21).
989. Giamarellos-Bourboulis EJ, Pechere
JC, Routsi C, Plachouras D, Kollias S,
Raftogiannis M, Zervakis D, Baziaka F,
Koronaios A, Antonopoulou A, Markaki
V, Koutoukas P, Papadomichelakis E,
Tsaganos T, Armaganidis A, Koussoulas
V, Kotanidou A, Roussos C, and
Giamarellou H, Effect of clarithromycin
1043
References
in patients with sepsis and ventilator-
associated pneumonia. Clin Infect Dis,
2008. 46(8): 1157–64.
990. Giamarellos-Bourboulis EJ, Routsi C,
Plachouras D, Markaki V, Raftogiannis
M, Zervakis D, Koussoulas V, Orfanos S,
Kotanidou A, Armaganidis A, Roussos C,
and Giamarellou H, Early apoptosis of
blood monocytes in the septic host: is it a
mechanism of protection in the event of
septic shock? Crit Care, 2006. 10(3): R76.
991. Giamarellos-Bourboulis EJ, Zakynthinos
S, Baziaka F, Papadomichelakis E,
Virtzili S, Koutoukas P, Armaganidis A,
Giamarellou H, and Roussos C, Soluble
triggering receptor expressed on myeloid
cells 1 as an anti-inflammatory media-
tor in sepsis. Intensive Care Med, 2006.
32(2): 237–43.
992. Giamarellou H, Antoniadou A, and
Kanellakopoulou K, Acinetobacter bau-
mannii: a universal threat to public
health? Int J Antimicrob Agents, 2008.
32(2): 106–19.
993. Giamarellou H, Kolokythas E, Petrikkos
G, Gazis J, Aravantinos D, and Sfikakis
P, Pharmacokinetics of three newer
quinolones in pregnant and lactating
women. Am J Med, 1989. 87(5A): 49S-
51S.
994. Giamarellou H, Low-dosage cefepime
as treatment for serious bacterial infec-
tions. J Antimicrob Chemother, 1993. 32
Suppl B: 123–32.
995. Giannantoni A, Mearini E, Del Zingaro
M, Santaniello F, and Porena M,
Botulinum A toxin in the treatment of
neurogenic detrusor overactivity: a con-
solidated field of application. BJU Int,
2008. 102 Suppl 1: 2–6.
996. Giannarini G, Mogorovich A, Valent F,
Morelli G, De Maria M, Manassero F,
Barbone F, and Selli C, Prulifloxacin
versus levofloxacin in the treatment of
chronic bacterial prostatitis: a prospec-
tive, randomized, double-blind trial. J
Chemother, 2007. 19(3): 304–8.
997. Giannopoulos A, Koratzanis G,
Giamarellos-Bourboulis EJ, Stinios
I, Chrisofos M, Giannopoulou M, and
Giamarellou H, Pharmacokinetics of
intravenously administered pefloxacin in
the prostate; perspectives for its
1044
application in surgical prophylaxis. Int
J Antimicrob Agents, 2001. 17(3): 221–4.
998. Gibbs RS, O’Dell TN, MacGregor RR,
Schwarz RH, and Morton H, Puerperal
endometritis: a prospective microbio-
logic study. Am J Obstet Gynecol, 1975.
121(7): 919–25.
999. Gift TL and Owens CJ, The direct
medical cost of epididymitis and orchi-
tis: evidence from a study of insurance
claims. Sex Transm Dis, 2006. 33(10
Suppl): S84–8.
1000. Gilad J, Borer A, Maimon N,
Riesenberg K, Klein M, and Schlaeffer
F, Failure of ciprofloxacin prophylaxis
for ultrasound guided transrectal pro-
static biopsy in the era of multiresist-
ant enterobacteriaceae. J Urol, 1999.
161(1): 222.
1001. Gilbert DN, The Sanford guide to anti-
microbial therapy. 37th ed. ed. 2007,
Sperryville: Antimicrobial Therapy Inc.
1002. Gill IS, Kaouk JH, Hobart MG, Sung
GT, Schweizer DK, and Braun WE,
Laparoscopic bilateral synchronous
nephrectomy for autosomal dominant
polycystic kidney disease: the ini-
tial experience. J Urol, 2001. 165(4):
1093–8.
1003. Gillespie JL, Arnold KE, Noble-Wang J,
Jensen B, Arduino M, Hageman J, and
Srinivasan A, Outbreak of Pseudomonas
aeruginosa infections after transrectal
ultrasound-guided prostate biopsy.
Urology, 2007. 69(5): 912–4.
1004. Gillespie WA, Simpson RA, Jones JE,
Nashef L, Teasdale C, and Speller DC,
Does the addition of disinfectant to
urine drainage bags prevent infection
in catheterised patients? Lancet, 1983.
1(8332): 1037–9.
1005. Gillon G, Nissenkorn I, and Servadio C,
Bladder diverticula in elderly females
with urgency, dysuria and incontinence.
Eur Urol, 1988. 14(1): 34–6.
1006. Gilstrap LC, 3rd and Ramin SM,
Urinary tract infections during preg-
nancy. Obstet Gynecol Clin North Am,
2001. 28(3): 581–91.
1007. Gilstrap LC, 3rd, Cunningham FG,
and Whalley PJ, Acute pyelonephritis
in pregnancy: an anterospective study.
Obstet Gynecol, 1981. 57(4): 409–13.

1008. Gilstrap LG, 3rd, Hankins GD, Snyder
RR, and Greenberg RT, Acute pyelone-
phritis in pregnancy. Compr Ther,
1986. 12(12): 38–42.
1009. Giorgi LJ, Jr., Bratslavsky G, and Kogan
BA, Febrile urinary tract infections in
infants: renal ultrasound remains neces-
sary. J Urol, 2005. 173(2): 568–70.
1010. Giraldo P, Neuer A, Korneeva IL,
Ribeiro-Filho A, Simoes JA, and Witkin
SS, Vaginal heat shock protein expression
in symptom-free women with a history
of recurrent vulvovaginitis. Am J Obstet
Gynecol, 1999. 180(3 Pt 1): 524–9.
1011. Giramonti KM, Kogan BA, Agboola
OO, Ribons L, and Dangman B, The
association of constipation with child-
hood urinary tract infections. J Pediatr
Urol, 2005. 1(4): 273–8.
1012. Giske CG, Buaro L, Sundsfjord A,
and Wretlind B, Alterations of porin,
pumps, and penicillin-binding pro-
teins in carbapenem resistant clinical
isolates of Pseudomonas aeruginosa.
Microb Drug Resist, 2008. 14(1): 23–30.
1013. Gisselquist D, Potterat JJ, and Brody
S, Running on empty: sexual co-factors
are insufficient to fuel Africa’s tur-
bocharged HIV epidemic. Int J STD
AIDS, 2004. 15(7): 442–52.
1014. Glauser MP, Meylan P, and Bille J,
The inflammatory response and tissue
damage. The example of renal scars
following acute renal infection. Pediatr
Nephrol, 1987. 1(4): 615–22.
1015. Glazier DB, Jacobs MG, Lyman NW,
Whang MI, Manor E, and Mulgaonkar
SP, Urinary tract infection associated
with ureteral stents in renal transplan-
tation. Can J Urol, 1998. 5(1): 462–466.
1016. Gleckman R, Bradley P, Roth R, Hibert
D, and Pelletier C, Therapy of sympto-
matic pyelonephritis in women. J Urol,
1985. 133(2): 176–8.
1017. Gleckman R, Esposito A, Crowley M,
and Natsios GA, Reliability of a single
urine culture in establishing diagnosis
of asymptomatic bacteriuria in adult
males. J Clin Microbiol, 1979. 9(5):
596–7.
1018. Gleckman R, The controversy of treat-
ment of asymptomatic bacteriuria in
References
non-pregnant women—resolved. J Urol,
1976. 116(6): 776–7.
1019. Goel MC, Agarwal MR, and Misra A,
Percutaneous drainage of renal hydatid
cyst: early results and follow-up. Br J
Urol, 1995. 75(6): 724–8.
1020. Goettsch WG, Janknegt R, and Herings
RM, Increased treatment failure after
3-days’ courses of nitrofurantoin and
trimethoprim for urinary tract infec-
tions in women: a population-based
retrospective cohort study using
the PHARMO database. Br J Clin
Pharmacol, 2004. 58(2): 184–9.
1021. Gogus C, Ozden E, Karaboga R, and
Yagci C, The value of transrectal ultra-
sound guided needle aspiration in
treatment of prostatic abscess. Eur J
Radiol, 2004. 52(1): 94–8.
1022. Gogus C, Safak M, Baltaci S, and
Turkolmez K, Isolated renal hydatido-
sis: experience with 20 cases. J Urol,
2003. 169(1): 186–9.
1023. Goharkhay N, Verma U, and
Maggiorotto F, Comparison of CT- or
ultrasound-guided drainage with con-
comitant intravenous antibiotics vs.
intravenous antibiotics alone in the
management of tubo-ovarian abscesses.
Ultrasound Obstet Gynecol, 2007.
29(1): 65–9.
1024. Gokce G, Kilicarslan H, Ayan S, Tas
F, Akar R, Kaya K, and Gultekin EY,
Genitourinary tuberculosis: a review
of 174 cases. Scand J Infect Dis, 2002.
34(5): 338–40.
1025. Gokce I, Alpay H, Biyikli N, and
Ozdemir N, Urinary tract pathogens
and their antimicrobial resistance
patterns in Turkish children. Pediatr
Nephrol, 2006. 21(9): 1327–8.
1026. Goldblum RM, Schanler RJ, Garza C,
and Goldman AS, Human milk feed-
ing enhances the urinary excretion
of immunologic factors in low birth
weight infants. Pediatr Res, 1989.
25(2): 184–8.
1027. Goldstein DP, deCholnoky C, Leventhal
JM, and Emans SJ, New insights into
the old problem of chronic pelvic pain. J
Pediatr Surg, 1979. 14(6): 675–80.
1028. Golubovic Z, Milanovic D, Vukadinovic
V, Rakic I, and Perovic S, The
1045
References
conservative treatment of phimosis in
boys. Br J Urol, 1996. 78(5): 786–8.
1029. Golz R and Mendling W, Candidosis of
the prostate: a rare form of endomyco-
sis. Mycoses, 1991. 34(9–10): 381–4.
1030. Gomelsky A and Dmochowski RR,
Antibiotic prophylaxis in urologic pros-
thetic surgery. Curr Pharm Des, 2003.
9(12): 989–96.
1031. Gomes CM, Trigo-Rocha F, Arap MA,
Gabriel AJ, Alaor de Figueiredo J, and
Arap S, Schistosomal myelopathy: uro-
logic manifestations and urodynamic
findings. Urology, 2002. 59(2): 195–200.
1032. Gomha MA and Boone TB, Artificial
urinary sphincter for post-prostate-
ctomy incontinence in men who had
prior radiotherapy: a risk and outcome
analysis. J Urol, 2002. 167(2 Pt 1):
591–6.
1033. Gomolin IH, Siami PF, Reuning-
Scherer J, Haverstock DC, and Heyd
A, Efficacy and safety of ciprofloxacin
oral suspension versus trimethoprim-
sulfamethoxazole oral suspension for
treatment of older women with acute
urinary tract infection. J Am Geriatr
Soc, 2001. 49(12): 1606–13.
1034. Gonococcal Isolate Surveillance Project
G. Sexually Transmitted Diseases
Surveillance 2005 Supplement, GISP
Annual report 2005. 2006; Available
from: http://www.cdc.gov/std/gisp/.
1035. Gonococcal Isolate Surveillance Project
G. Sexually Transmitted Diseases
Surveillance 2005 Supplement, GISP
Annual report 2006. 2007; Available
from: http://www.cdc.gov/std/gisp/.
1036. Gontero P, Masood S, Sogni F, Fontana
F, Mufti G, and Frea B, Upper urinary
tract complications in pregnant women
with an ileal conduit. Lessons learned
from two cases. Scand J Urol Nephrol,
2004. 38(6): 523–4.
1037. Gonzales GT, Munoz G, Sanchez R,
Henkel R, Gallegos-Avila G, Diaz-
Gutierrez O, Vigil P, Vasquez F,
Kartebani G, Mazzoli A, and Bustor-
Obregon E, Update on the impact of C.
trachomatis infection on male infertil-
ity. Andrologia, 2004. 36: 1–12.
1038. González Pedraza Avilés A, Sánchez
Hernández G, and Ponce Rosas RE,
1046
Frequency, risk factors and vaginal
colonization due to Escherichia coli.
Ginecol Obstet Mex, 2004(72): 68–75.
1039. Gonzalez R and Reinberg Y,
Localization of bacteriuria in patients
with enterocystoplasty and nonreflux-
ing conduits. J Urol, 1987. 138(4 Pt 2):
1104–5.
1040. Goossens H, Coenen S, Costers M, De
Corte S, De Sutter A, Gordts B, Laurier
L, and Struelens M, Achievements
of the Belgian Antibiotic Policy
Coordination Committee (BAPCOC).
Euro Surveill, 2008. 13(46).
1041. Goossens H, Ferech M, Vander Stichele
R, and Elseviers M, Outpatient anti-
biotic use in Europe and association
with resistance: a cross-national data-
base study. Lancet, 2005. 365(9459):
579–87.
1042. Goplerud CP, Ohm MJ, and Galask
RP, Aerobic and anaerobic flora of the
cervix during pregnancy and the puer-
perium. Am J Obstet Gynecol, 1976.
126(7): 858–68.
1043. Goppert-Kattewitz F, Uber die eitri-
gen Erkrankungen der Harnwege im
Kindersalter.. Ergebinesse uber innern
Medizin und Kinderheilkund, 1908. 2:
30–73.
1044. Gorczynska E, Turkiewicz D, Rybka
K, Toporski J, Kalwak K, Dyla A,
Szczyra Z, and Chybicka A, Incidence,
clinical outcome, and management of
virus-induced hemorrhagic cystitis in
children and adolescents after alloge-
neic hematopoietic cell transplantation.
Biol Blood Marrow Transplant, 2005.
11(10): 797–804.
1045. Gordon KA and Jones RN,
Susceptibility patterns of orally admin-
istered antimicrobials among urinary
tract infection pathogens from hos-
pitalized patients in North America:
comparison report to Europe and Latin
America. Results from the SENTRY
Antimicrobial Surveillance Program
(2000). Diagn Microbiol Infect Dis,
2003. 45(4): 295–301.
1046. Gordon RJ and Lowy FD, Pathogenesis
of methicillin-resistant Staphylococcus
aureus infection. Clin Infect Dis, 2008.
46 Suppl 5: S350–9.

1047. Gorelick JI, Senterfit LB, and Vaughan
ED, Jr., Quantitative bacterial tis-
sue cultures from 209 prostatectomy
specimens: findings and implications. J
Urol, 1988. 139(1): 57–60.
1048. Gorelov S, Zedan F, and Startsev V,
The choice of urinary drainage in
patients with ureteral calculi of solitary
kidneys. Arch Ital Urol Androl, 2004.
76(2): 56–8.
1049. Gorlero F, Macciavello S, Paccagnella
F, Ferraiolo A, Gianrosso G, de Gecco L,
and Schito GC, Clindamycin phosphate
vaginal cream – a local approach to the
treatment of bacterial vaginosis. Report
of the 3rd International Symposium
on Vaginitis/Vaginosis. Clin Commun
(Oxf), 1994.
1050. Gorse GJ and Belshe RB, Male genital
tuberculosis: a review of the literature
with instructive case reports. Rev Infect
Dis, 1985. 7(4): 511–24.
1051. Gossios KJ, Kontoyiannis
DS, Dascalogiannaki M, and
Gourtsoyiannis NC, Uncommon loca-
tions of hydatid disease: CT appear-
ances. Eur Radiol, 1997. 7(8): 1303–8.
1052. Gossius G and Vorland L, A ran-
domised comparison of single-dose vs.
three-day and ten-day therapy with tri-
methoprim-sulfamethoxazole for acute
cystitis in women. Scand J Infect Dis,
1984. 16(4): 373–9.
1053. Gossius G VL, The treatment of acute
dysuria-frequency syndrome in adult
women: double-blind, randomized com-
parison of three-day vs ten-day trimeth-
oprim therapy. Curr Ther Res, 1985.
37: 34–42.
1054. Goswami D, Goswami R, Banerjee U,
Dadhwal V, Miglani S, Lattif AA, and
Kochupillai N, Pattern of Candida spe-
cies isolated from patients with diabetes
mellitus and vulvovaginal candidiasis
and their response to single dose oral
fluconazole therapy. J Infect, 2006.
52(2): 111–7.
1055. Goswami R, Dadhwal V, Tejaswi S,
Datta K, Paul A, Haricharan RN,
Banerjee U, and Kochupillai NP,
Species-specific prevalence of vaginal
candidiasis among patients with dia-
betes mellitus and its relation to their
References
glycaemic status. J Infect, 2000. 41(2):
162–6.
1056. Gothefors L, Olling S, and Winberg J,
Breast feeding and biological properties
of faecal E. coli strains. Acta Paediatr
Scand, 1975. 64(6): 807–12.
1057. Goto T, Kitagawa T, Kawahara M,
Hayami H, and Ohi Y, Comparative
study of single-dose and three-day ther-
apy for acute uncomplicated cystitis.
Hinyokika Kiyo, 1999. 45(2): 85–9.
1058. Goto T, Nakame Y, Nishida M, and Ohi
Y, Bacterial biofilms and catheters in
experimental urinary tract infection.
Int J Antimicrob Agents, 1999. 11(3–4):
227–31; discussion 237–9.
1059. Goto T, Nakame Y, Nishida M, and
Ohi Y, In vitro bactericidal activities of
beta-lactamases, amikacin, and fluo-
roquinolones against Pseudomonas
aeruginosa biofilm in artificial urine.
Urology, 1999. 53(5): 1058–62.
1060. Gottfried HW, Schlmers HP, Gschwend
J, Brandle E, and Hautmann RE,
Thermosensitive stent (Memotherm) for
the treatment of benign prostatic hyper-
plasia. Arch Esp Urol, 1994. 47(9):
933–43; discussion 943–6.
1061. Gotz H, Lindback J, Ripa T, Arneborn
M, Ramsted K, and Ekdahl K, Is the
increase in notifications of Chlamydia
trachomatis infections in Sweden the
result of changes in prevalence, sam-
pling frequency or diagnostic methods?
Scand J Infect Dis, 2002. 34(1): 28–34.
1062. Gow JG, Genitourinary tuberculosis: a
study of short course regimes. J Urol,
1997. 115: 707–711.
1063. Gower PE, The use of small doses of
cephalexin (125 mg) in the management
of recurrent urinary tract infection in
women. J Antimicrob Chemother, 1975.
1(3 Suppl): 93–8.
1064. Goya N, Tanabe K, Iguchi Y, Oshima
T, Yagisawa T, Toma H, Agishi T, Ota
K, and Takahashi K, Prevalence of uri-
nary tract infection during outpatient
follow-up after renal transplantation.
Infection, 1997. 25(2): 101–5.
1065. Grabe M (chairman) BM, Bjerklund-
Johansen TE, Botto H, Cek M, Lobel
B, Naber KG, Palou J, Tenke P.,
Guidelines on the management of
1047
References
urinary and male genital tract infec-
tions., in European Association of
Urology Guidelines, Urology EAo,
Editor. 2008, European Association of
Urology Arnhem, The Netherlands. p.
1–116.
1066. Grabe M (chairman) BM, Bjerklund-
Johansen TE, Botto H, Cek M, Lobel
B, Naber KG, Palou J, Tenke P,
Wagenlehner F, Guidelines on urologi-
cal infections., in European Association
of Urology Guidelines, Urology EAo,
Editor. 2009, European Association of
Urology Arnhem, The Netherlands. p.
1–110.
1067. Grabe M and Hellsten S, Bacteriuria a
risk factor in men with bladder outlet
obstruction, in Host Parasite interac-
tions in urinary tract infection, Kass
EH and Svanborg Eden C, Editors.
1986, University of Chicago Press
Chicago. p. 303–306.
1068. Grabe M, Antimicrobial agents in
transurethral prostatic resection. J
Urol, 1987. 138(2): 245–52.
1069. Grabe M, Bishop MC, T.E. Bjerklund-
Johansen, Botto H, Çek M, Lobel
B, Naber KG, Palou J, and Tenke
P. Guideline on the management of
urinary and male genital tract infec-
tions. 2008; Available from: http://
www.uroweb.org/fileadmin/tx_eau-
guidelines/The%20Management%20
of%20Male%20Urinary%20and%20
Genital%20Tract%20Infections.pdf.
1070. Grabe M, C BM, Bkerklund-Johansen,
H B, and et al, Guidelines on
Urological Infections. 2009: European
Association of Urology
1071. Grabe M, Controversies in antibi-
otic prophylaxis in urology. Int J
Antimicrob Agents, 2004. 23 Suppl 1:
S17–23.
1072. Grabe M, Forsgren A, and Hellsten S,
The effect of a short antibiotic course in
transurethral prostatic resection. Scand
J Urol Nephrol, 1984. 18(1): 37–42.
1073. Grabe M, Forsgren A, Bjork T, and
Hellsten S, Controlled trial of a
short and a prolonged course with
ciprofloxacin in patients undergoing
transurethral prostatic surgery. Eur J
Clin Microbiol, 1987. 6(1): 11–7.
1048
1074. Grabe M, Perioperative antibiotic
prophylaxis in urology. Curr Opin Urol,
2001. 11(1): 81–5.
1075. Grabe M, Risk Factors at TURP.
Discussion of RA Janknegt’s presen-
tation. Infection, 1992. 20(Suppl 3):
S217–220.
1076. Grabe M, Shortliffe L, Arakawa S,
Kitamura T, and et al., Risk Factors,
in Nosocomial and Health Care
Associated Infections in Urology.
1st International Consultations
on Nosocomial and Health Care
Associated Infections in Urology
2000, Paris., Naber K, Pechère J.C,
Kumazawa J, Khoury S, and et al.,
Editors. 2001: Plymbridge Distributors
Ltd
1077. Gradwohl SE (Team Leader) and
University of Michigan Health System
(Agency for Healthcare Research
and Quality (AHRQ)), Urinary tract
infection. May 2005, Ann Arbor (MI):
University of Michigan Health System.
1078. Granados EA, Riley G, Salvador J, and
Vincente J, Prostatic abscess: diagnosis
and treatment. J Urol, 1992. 148(1):
80–2.
1079. Graninger W, Pivmecillinam—therapy
of choice for lower urinary tract infec-
tion. Int J Antimicrob Agents, 2003. 22
Suppl 2: 73–8.
1080. Graves N, Tong E, Morton AP, Halton
K, Curtis M, Lairson D, and Whitby
M, Factors associated with health care-
acquired urinary tract infection. Am J
Infect Control, 2007. 35(6): 387–92.
1081. Gray R, Azire J, Serwadda D,
Kiwanuka N, Kigozi G, Kiddugavu
M, Nalugoda F, Li X, and Wawer M,
Male circumcision and the risk of sexu-
ally transmitted infections and HIV
in Rakai, Uganda. Aids, 2004. 18(18):
2428–30.
1082. Gray RH, Kigozi G, Serwadda D,
Makumbi F, Watya S, Nalugoda F,
Kiwanuka N, Moulton LH, Chaudhary
MA, Chen MZ, Sewankambo NK,
Wabwire-Mangen F, Bacon MC,
Williams CF, Opendi P, Reynolds
SJ, Laeyendecker O, Quinn TC, and
Wawer MJ, Male circumcision for HIV
prevention in men in Rakai, Uganda:

a randomised trial. Lancet, 2007.
369(9562): 657–66.
1083. Gray RH, Li X, Kigozi G, Serwadda
D, Nalugoda F, Watya S, Reynolds SJ,
and Wawer M, The impact of male cir-
cumcision on HIV incidence and cost
per infection prevented: a stochastic
simulation model from Rakai, Uganda.
Aids, 2007. 21(7): 845–50.
1084. Gray RH, Wabwire-Mangen F, Kigozi
G, Sewankambo NK, Serwadda D,
Moulton LH, Quinn TC, O’Brien KL,
Meehan M, Abramowsky C, Robb M,
and Wawer MJ, Randomized trial
of presumptive sexually transmitted
disease therapy during pregnancy in
Rakai, Uganda. Am J Obstet Gynecol,
2001. 185(5): 1209–17.
1085. Gray RH, Wawer MJ, Brookmeyer
R, Sewankambo NK, Serwadda D,
Wabwire-Mangen F, Lutalo T, Li X,
vanCott T, and Quinn TC, Probability
of HIV-1 transmission per coital act
in monogamous, heterosexual, HIV-1-
discordant couples in Rakai, Uganda.
Lancet, 2001. 357(9263): 1149–53.
1086. Gray RH, Wawer MJ, Polis CB, Kigozi
G, and Serwadda D, Male Circumcision
and Prevention of HIV and Sexually
Transmitted Infections. Curr Infect Dis
Rep, 2008. 10(2): 121–7.
1087. Great Britain. Expert Advisory
Group on AIDS., Guidance for clini-
cal health care workers: protection
against infection with HIV and hepa-
titis viruses: recommendations of the
Expert Advisory Group on AIDS. 1990,
London: HMSO. 52 p.
1088. Green EC, Male circumcision and HIV
infection. Lancet, 2000. 355(9207): 927.
1089. Greenfield SP and Wan J,
Vesicoureteral reflux: practical aspects
of evaluation and management. Pediatr
Nephrol, 1996. 10(6): 789–94.
1090. Greenfield SP, Chesney RW, Carpenter
M, Moxey-Mims M, Nyberg L,
Hoberman A, Keren R, Matthews R,
and Mattoo T, Vesicoureteral reflux: the
RIVUR study and the way forward. J
Urol, 2008. 179(2): 405–7.
1091. Greenwell TJ, Venn SN, and Mundy
AR, Augmentation cystoplasty. BJU
Int, 2001. 88(6): 511–25.
References
1092. Greenwell TJ, Venn SN, Creighton
S, Leaver RB, and Woodhouse CR,
Pregnancy after lower urinary tract
reconstruction for congenital abnormal-
ities. BJU Int, 2003. 92(7): 773–7.
1093. Gregory E, Simmons D, and Weinberg
JJ, Care and sterilization of endouro-
logic instruments. Urol Clin North Am,
1988. 15: 541–546.
1094. Greif R, Akca O, Horn EP, Kurz A, and
Sessler DI, Supplemental periopera-
tive oxygen to reduce the incidence of
surgical-wound infection. Outcomes
Research Group. N Engl J Med, 2000.
342(3): 161–7.
1095. Grenabo L, Brorson JE, Hedelin H, and
Pettersson S, Concrement formation in
the urinary bladder in rats inoculated
with Ureaplasma urealyticum. Urol
Res, 1985. 13(4): 195–8.
1096. Grenabo L, Brorson JE, Hedelin H, and
Pettersson S, Ureaplasma urealyticum-
induced crystallization of magnesium
ammonium phosphate and calcium
phosphates in synthetic urine. J Urol,
1984. 132(4): 795–9.
1097. Grenabo L, Claes G, Hedelin H, and
Pettersson S, Rapidly recurrent renal
calculi caused by Ureaplasma urealyti-
cum: a case report. J Urol, 1986. 135(5):
995–7.
1098. Grenabo L, Hedelin H, Hugosson J,
and Pettersson S, Adherence of urease-
induced crystals to rat bladder epi-
thelium following acute infection with
different uropathogenic microorgan-
isms. J Urol, 1988. 140(2): 428–30.
1099. Gribble MJ and Puterman ML,
Prophylaxis of urinary tract infec-
tion in persons with recent spinal cord
injury: a prospective, randomized,
double-blind, placebo-controlled study
of trimethoprim-sulfamethoxazole. Am
J Med, 1993. 95(2): 141–52.
1100. Gribble MJ, McCallum NM, and
Schechter MT, Evaluation of diagnos-
tic criteria for bacteriuria in acutely
spinal cord injured patients under-
going intermittent catheterization.
Diagn Microbiol Infect Dis, 1988. 9(4):
197–206.
1101. Griffin MD, Bergstralhn EJ, and
Larson TS, Renal papillary necrosis—a
1049
References
sixteen-year clinical experience. J Am
Soc Nephrol, 1995. 6(2): 248–56.
1102. Griffith BC, Morey AF, Ali-Khan
MM, Canby-Hagino E, Foley JP, and
Rozanski TA, Single dose levofloxacin
prophylaxis for prostate biopsy in
patients at low risk. J Urol, 2002.
168(3): 1021–3.
1103. Griffith DP and Osborne CA, Infection
(urease) stones. Miner Electrolyte
Metab, 1987. 13(4): 278–85.
1104. Griffith DP, Gleeson MJ, Lee H,
Longuet R, Deman E, and Earle N,
Randomized, double-blind trial of
Lithostat (acetohydroxamic acid) in
the palliative treatment of infection-in-
duced urinary calculi. Eur Urol, 1991.
20(3): 243–7.
1105. Griffiths DM and Malone PS, The
Malone antegrade continence enema. J
Pediatr Surg, 1995. 30(1): 68–71.
1106. Griffiths R and Fernandez R, Policies
for the removal of short-term indwelling
urethral catheters. Cochrane Database
Syst Rev, 2005(1): CD004011.
1107. Grimes DA, Intrauterine device and
upper-genital-tract infection. Lancet,
2000. 356(9234): 1013–9.
1108. Grocott MP, Mythen MG, and Gan TJ,
Perioperative fluid management and
clinical outcomes in adults. Anesth
Analg, 2005. 100(4): 1093–106.
1109. Gross AJ and Herrmann TR,
Management of stones in calyceal diver-
ticulum. Curr Opin Urol, 2007. 17(2):
136–40.
1110. Grossfeld GD and Coakley FV, Benign
prostatic hyperplasia: clinical overview
and value of diagnostic imaging. Radiol
Clin North Am, 2000. 38(1): 31–47.
1111. Grosskurth H, Mosha F, Todd J,
Mwijarubi E, Klokke A, Senkoro K,
Mayaud P, Changalucha J, Nicoll
A, ka-Gina G, and et al., Impact of
improved treatment of sexually trans-
mitted diseases on HIV infection in
rural Tanzania: randomised control-
led trial. Lancet, 1995. 346(8974):
530–6.
1112. Grude N, Tveten Y, Jenkins A, and
Kristiansen BE, Uncomplicated uri-
nary tract infections. Bacterial findings
and efficacy of empirical antibacterial
1050
treatment. Scand J Prim Health Care,
2005. 23(2): 115–9.
1113. Grulich AE, Li Y, McDonald AM,
Correll PK, Law MG, and Kaldor JM,
Decreasing rates of Kaposi’s sarcoma
and non-Hodgkin’s lymphoma in the
era of potent combination anti-retrovi-
ral therapy. AIDS, 2001. 15(5): 629–33.
1114. Grupper M, Kravtsov A, and Potasman
I, Emphysematous cystitis: illustrative
case report and review of the literature.
Medicine (Baltimore), 2007. 86(1):
47–53.
1115. Gubbins PO, McConnell SA, and
Penzak SR, Current management of
funguria. Am J Health Syst Pharm,
1999. 56(19): 1929–35; quiz 1936.
1116. Gubelin HW, Martinez TM, Cespedes
PP, Fich SF, Fuenzalida CH, Parra
CRL, Valderrama KL, and Zapata MS,
[Molecular detection of Mycoplasma
genitalium in men and pregnant
women.]. Rev Chilena Infectol, 2006.
23(1): 15–9.
1117. Guercini F, Pajoncini C, Bard R,
Fiorentino F, Bini V, Costantini E, and
Porena M, Echoguided drug infiltration
in chronic prostatitis: results of a multi-
centre study. Arch Ital Urol Androl,
2005. 77(2): 87–92.
1118. Guideline for the use of high-level disin-
fectants and sterilants for reprocessing
of flexible gastrointestinal endoscopes.
Society of Gastroenterology Nurses and
Associates, Inc. Gastroenterol Nurs,
1999. 22(3): 127–34.
1119. Guidelines for the management of
acute urinary tract infection in child-
hood. Report of a Working Group of
the Research Unit, Royal College of
Physicians. J R Coll Physicians Lond,
1991. 25(1): 36–42.
1120. Guidet B, Aegerter P, Gauzit R,
Meshaka P, and Dreyfuss D, Incidence
and impact of organ dysfunctions asso-
ciated with sepsis. Chest, 2005. 127(3):
942–51.
1121. Guillou ML, Pariente J-L, and et
Guege S-M, Tuberculose urogénitale, in
Encycl.Med.Chir. 1993, Néphrologie-
Urologie, 18–078-A-10. p. 11p.
1122. Gundogdu C, Arslan R, Arslan MO,
and Gicik Y, [Evaluation of cystic and

alveolar echinococcosis cases in people
in Erzurum and surrounding cities.].
Turkiye Parazitol Derg, 2005. 29(3):
163–166.
1123. Gunn RA, O’Brien CJ, Lee MA, and
Gilchick RA, Gonorrhea screening
among men who have sex with men:
value of multiple anatomic site testing,
San Diego, California, 1997–2003. Sex
Transm Dis, 2008. 35(10): 845–8.
1124. Gupta K and Stamm WE, Outcomes
associated with trimethoprim/sul-
phamethoxazole (TMP/SMX) therapy
in TMP/SMX resistant community-
acquired UTI. Int J Antimicrob Agents,
2002. 19(6): 554–6.
1125. Gupta K and Stamm WE, Pathogenesis
and management of recurrent urinary
tract infections in women. World J Urol,
1999. 17(6): 415–20.
1126. Gupta K, Chou M, Howell A, Wobbe C,
Grady R, and Stapteton A, Cranberry
products inhibit adherence of
P-fimbriated Escherichia coli to primary
cultured bladder and vaginal epithelial
cells. J Urol, 2007. 177(6): 2357–60.
1127. Gupta K, Hooton TM, and Stamm WE,
Increasing antimicrobial resistance and
the management of uncomplicated com-
munity-acquired urinary tract infec-
tions. Ann Intern Med, 2001. 135(1):
41–50.
1128. Gupta K, Hooton TM, Roberts PL, and
Stamm WE, Patient-initiated treatment
of uncomplicated recurrent urinary
tract infections in young women. Ann
Intern Med, 2001. 135(1): 9–16.
1129. Gupta K, Hooton TM, Roberts PL, and
Stamm WE, Short-course nitrofuran-
toin for the treatment of acute uncom-
plicated cystitis in women. Arch Intern
Med, 2007. 167(20): 2207–12.
1130. Gupta K, Sahm DF, Mayfield D, and
Stamm WE, Antimicrobial resistance
among uropathogens that cause com-
munity-acquired urinary tract infec-
tions in women: a nationwide analysis.
Clin Infect Dis, 2001. 33(1): 89–94.
1131. Gupta N, Rajwanshi A, Srinivasan R,
and Nijhawan R, Fine needle aspiration
of epididymal nodules in Chandigarh,
north India: an audit of 228 cases.
Cytopathology, 2006. 17(4): 195–8.
References
1132. Gupta P, Mellors J, Kingsley L, Riddler
S, Singh MK, Schreiber S, Cronin M,
and Rinaldo CR, High viral load in
semen of human immunodeficiency
virus type 1-infected men at all stages
of disease and its reduction by therapy
with protease and nonnucleoside
reverse transcriptase inhibitors. J Virol,
1997. 71(8): 6271–5.
1133. Gupta S, Seith A, Sud K, Kohli HS,
Singh SK, Sakhuja V, and Suri S, CT
in the evaluation of complicated auto-
somal dominant polycystic kidney dis-
ease. Acta Radiol, 2000. 41(3): 280–4.
1134. Gupta V, Yadav A, and Joshi RM,
Antibiotic resistance pattern in
uropathogens. Indian J Med Microbiol,
2002. 20(2): 96–8.
1135. Guralnick ML, Miller E, Toh KL, and
Webster GD, Transcorporal artificial
urinary sphincter cuff placement in
cases requiring revision for erosion and
urethral atrophy. J Urol, 2002. 167(5):
2075–8; discussion 2079.
1136. Gutierrez J, Carlos S, Martinez JL,
Liebana JL, Soto MJ, Luna Jde D,
and Piedrola G, [A study of clinical
response to antibiotic treatment in
subjects with chronic bacterial prosta-
titis]. Rev Esp Quimioter, 2004. 17(2):
189–92.
1137. Guttmann L and Frankel H, The value
of intermittent catheterisation in the
early management of traumatic para-
plegia and tetraplegia. Paraplegia,
1966. 4(2): 63–84.
1138. Guyer DM, Radulovic S, Jones FE,
and Mobley HL, Sat, the secreted
autotransporter toxin of uropathogenic
Escherichia coli, is a vacuolating cyto-
toxin for bladder and kidney epithe-
lial cells. Infect Immun, 2002. 70(8):
4539–46.
1139. Gyssens IC and Kullberg BJ,
Improving the quality of antimicrobial
drug use can result in cost containment.
Pharm World Sci, 1995. 17(5): 163–7.
1140. Gyssens IC, All EU hands to the EU
pumps: the Science Academies of
Europe (EASAC) recommend strong
support of research to tackle antibacte-
rial resistance. Clin Microbiol Infect,
2008. 14(10): 889–91.
1051
References
1141. Gyssens IC, Blok WL, van den Broek
PJ, Hekster YA, and van der Meer JW,
Implementation of an educational pro-
gram and an antibiotic order form to
optimize quality of antimicrobial drug
use in a department of internal medi-
cine. Eur J Clin Microbiol Infect Dis,
1997. 16(12): 904–12.
1142. Gyssens IC, Geerligs IE, Dony JM, van
der Vliet JA, van Kampen A, van den
Broek PJ, Hekster YA, and van der
Meer JW, Optimising antimicrobial
drug use in surgery: an intervention
study in a Dutch university hospital.
J Antimicrob Chemother, 1996. 38(6):
1001–12.
1143. Gyssens IC, International guidelines
for infectious diseases: a practical
guide. Neth J Med, 2005. 63(8): 291–9.
1144. Gyssens IC, Smits-Caris C, Stolk-
Engelaar MV, Slooff TJ, and
Hoogkamp-Korstanje JA, An audit of
microbiology laboratory utilization: the
diagnosis of infection in orthopedic sur-
gery. Clin Microbiol Infect, 1997. 3(5):
518–522.
1145. Ha US, Kim ME, Kim CS, Shim BS,
Han CH, Lee SD, and Cho YH, Acute
bacterial prostatitis in Korea: clinical
outcome, including symptoms, manage-
ment, microbiology and course of dis-
ease. Int J Antimicrob Agents, 2008. 31
Suppl 1: S96–101.
1146. Haaren van K.Visser HS, Vliet van S,
Timmermans AE, Yadava R, Geerlings
SE, Rietter G, and B Pv, NHG-
Standaard Urineweginfecties (tweede
herziening). Huisarts & Wetenschap,
2005. 48: 341–352.
1147. Habash M and Reid G, Microbial
biofilms: their development and sig-
nificance for medical device-related
infections. J Clin Pharmacol, 1999.
39(9): 887–98.
1148. Habib AR and Fernando R, Efficacy of
azithromycin 1g single dose in the man-
agement of uncomplicated gonorrhoea.
Int J STD AIDS, 2004. 15(4): 240–2.
1149. Hachen HJ, Oral immunotherapy in
paraplegic patients with chronic uri-
nary tract infections: a double-blind,
placebo-controlled trial. J Urol, 1990.
143(4): 759–62; discussion 762–3.
1052
1150. Hackel H, Hartmann AA, Elsner P, and
Burg G, Prevalence of Ureaplasma ure-
alyticum in the urethra of men without
urethritis in relation to clinical diagno-
sis. Dermatologica, 1990. 180(2): 76–8.
1151. Hadgu A, Koch G, and Westrom L,
Analysis of ectopic pregnancy data
using marginal and conditional mod-
els. Stat Med, 1997. 16(21): 2403–17.
1152. Ha’eri GB and Wiley AM, The efficacy of
standard surgical face masks: an inves-
tigation using “tracer particles”. Clin
Orthop Relat Res, 1980(148): 160–2.
1153. Hagan EC and Mobley HL, Haem
acquisition is facilitated by a novel
receptor Hma and required by uropath-
ogenic Escherichia coli for kidney infec-
tion. Mol Microbiol, 2009. 71(1): 79–91.
1154. Hagberg L, Briles DE, and Eden CS,
Evidence for separate genetic defects in
C3H/HeJ and C3HeB/FeJ mice, that
affect susceptibility to gram-negative
infections. J Immunol, 1985. 134(6):
4118–22.
1155. Hagerty J, Maizels M, Kirsch A, Liu
D, Afshar K, Bukowski T, Caione P,
Homsy Y, Meyer T, and Kaplan W,
Treatment of occult reflux lowers the
incidence rate of pediatric febrile uri-
nary tract infection. Urology, 2008.
72(1): 72–6.
1156. Haggerty CL and Ness RB,
Epidemiology, pathogenesis and treat-
ment of pelvic inflammatory disease.
Expert Rev Anti Infect Ther, 2006. 4(2):
235–47.
1157. Haggerty CL and Ness RB, Newest
approaches to treatment of pelvic
inflammatory disease: a review of recent
randomized clinical trials. Clin Infect
Dis, 2007. 44(7): 953–60.
1158. Haggerty CL, Evidence for a role of
Mycoplasma genitalium in pelvic
inflammatory disease. Curr Opin Infect
Dis, 2008. 21(1): 65–9.
1159. Haggerty CL, Totten PA, Astete SG,
Lee S, Hoferka SL, Kelsey SF, and
Ness RB, Failure of cefoxitin and
doxycycline to eradicate endometrial
Mycoplasma genitalium and the conse-
quence for clinical cure of pelvic inflam-
matory disease. Sex Transm Infect,
2008. 84(5): 338–42.

1160. Haidl G and Opper C, Changes in lipids
and membrane anisotropy in human
spermatozoa during epididymal matura-
tion. Hum Reprod, 1997. 12(12): 2720–3.
1161. Haidl G, Allam JP, and Schuppe HC,
Chronic epididymitis: impact on semen
parameters and therapeutic options.
Andrologia, 2008. 40(2): 92–6.
1162. Hales DB, Diemer T, and Hales KH,
Role of cytokines in testicular function.
Endocrine, 1999. 10(3): 201–17.
1163. Halevy R, Smolkin V, Bykov S,
Chervinsky L, Sakran W, and Koren A,
Power Doppler ultrasonography in the
diagnosis of acute childhood pyelone-
phritis. Pediatr Nephrol, 2004. 19(9):
987–91.
1164. Haley RW, Culver DH, White JW,
Morgan WM, and Emori TG, The
nationwide nosocomial infection rate.
A new need for vital statistics. Am J
Epidemiol, 1985. 121(2): 159–67.
1165. Haley RW, Hooton TM, Culver DH,
Stanley RC, Emori TG, Hardison CD,
Quade D, Shachtman RH, Schaberg
DR, Shah BV, and Schatz GD,
Nosocomial infections in U.S. hospitals,
1975–1976: estimated frequency by
selected characteristics of patients. Am
J Med, 1981. 70(4): 947–59.
1166. Hall BG, Salipante SJ, and Barlow M,
The metallo-beta-lactamases fall into
two distinct phylogenetic groups. J Mol
Evol, 2003. 57(3): 249–54.
1167. Hallander HO, Kallner A, Lundin A,
and Osterberg E, Evaluation of rapid
methods for the detection of bacteriuria
(screening) in primary health care. Acta
Pathol Microbiol Immunol Scand B,
1986. 94(1): 39–49.
1168. Haller M, Brandis M, and Berner R,
Antibiotic resistance of urinary tract
pathogens and rationale for empirical
intravenous therapy. Pediatr Nephrol,
2004. 19(9): 982–6.
1169. Hallett TB, Singh K, Smith JA, White
RG, Abu-Raddad LJ, and Garnett GP,
Understanding the impact of male cir-
cumcision interventions on the spread
of HIV in southern Africa. PLoS ONE,
2008. 3(5): e2212.
1170. Halls GA, The management of
infections and antibiotic therapy:
References
a European survey. J Antimicrob
Chemother, 1993. 31: 985–1000.
1171. Halperin DT and Bailey RC, Male cir-
cumcision and HIV infection: 10 years
and counting. Lancet, 1999. 354(9192):
1813–5.
1172. Halperin DT, Fritz K, McFarland W,
and Woelk G, Acceptability of adult
male circumcision for sexually trans-
mitted disease and HIV prevention
in Zimbabwe. Sex Transm Dis, 2005.
32(4): 238–9.
1173. Hamasuna R, Betsunoh H, Sueyoshi
T, Yakushiji K, Tsukino H, Nagano M,
Takehara T, and Osada Y, Bacteria of
preoperative urinary tract infections
contaminate the surgical fields and
develop surgical site infections in uro-
logical operations. Int J Urol, 2004.
11(11): 941–7.
1174. Hamasuna R, Nose K, Osada Y, and
Muscarella LF, Correction: high-level
disinfection of cystoscopic equipment
with ortho-phthalaldehyde solution. J
Hosp Infect, 2005. 61(4): 363–4.
1175. Hamasuna R, Osada Y, and Jensen
JS, Antibiotic susceptibility testing of
Mycoplasma genitalium by TaqMan
5’ nuclease real-time PCR. Antimicrob
Agents Chemother, 2005. 49(12): 4993–8.
1176. Hambraeus A, Aerobiology in the oper-
ating room—a review. J Hosp Infect,
1988. 11 Suppl A: 68–76.
1177. Hamburger J, Renal tuberculosis, in
Nephrology, Saunders C, Editor. 1969:
Philadelphia. p. 1157–78.
1178. Hamdi M, Mohan P, Little DM, and
Hickey DP, Successful renal transplan-
tation in children with spina bifida:
long term single center experience.
Pediatr Transplant, 2004. 8(2): 167–70.
1179. Hamid R, Arya M, Patel HR, and Shah
PJ, The mesh wallstent in the treatment
of detrusor external sphincter dyssyn-
ergia in men with spinal cord injury: a
12-year follow-up. BJU Int, 2003. 91(1):
51–3.
1180. Hamid R, Robertson WG, and
Woodhouse CR, Comparison of bio-
chemistry and diet in patients with
enterocystoplasty who do and do not
form stones. BJU Int, 2008. 101(11):
1427–32.
1053
References
1181. Hammer SM, Eron JJ, Jr., Reiss P,
Schooley RT, Thompson MA, Walmsley
S, Cahn P, Fischl MA, Gatell JM,
Hirsch MS, Jacobsen DM, Montaner
JS, Richman DD, Yeni PG, and
Volberding PA, Antiretroviral treat-
ment of adult HIV infection: 2008
recommendations of the International
AIDS Society-USA panel. JAMA, 2008.
300(5): 555–70.
1182. Hammer SM, Katzenstein DA, Hughes
MD, Gundacker H, Schooley RT,
Haubrich RH, Henry WK, Lederman
MM, Phair JP, Niu M, Hirsch MS, and
Merigan TC, A trial comparing nucle-
oside monotherapy with combination
therapy in HIV-infected adults with
CD4 cell counts from 200 to 500 per
cubic millimeter. AIDS Clinical Trials
Group Study 175 Study Team. N Engl J
Med, 1996. 335(15): 1081–90.
1183. Hammond ML, Ertapenem: a Group
1 carbapenem with distinct antibacte-
rial and pharmacological properties.
J Antimicrob Chemother, 2004. 53
Suppl 2: ii7–9.
1184. Hamory BH and Wenzel RP, Hospital-
associated candiduria: predisposing
factors and review of the literature. J
Urol, 1978. 120(4): 444–8.
1185. Hampel C, Gillitzer R, Pahernik S,
Hohenfellner M, and Thuroff JW,
[Epidemiology and etiology of overac-
tive bladder]. Urologe A, 2003. 42(6):
776–86.
1186. Han CH, Yang CH, Sohn DW, Kim SW,
Kang SH, and Cho YH, Synergistic
effect between lycopene and cipro-
floxacin on a chronic bacterial prostati-
tis rat model. Int J Antimicrob Agents,
2008. 31 Suppl 1: S102–7.
1187. Hancock V, Ferrieres L, and Klemm P,
The ferric yersiniabactin uptake recep-
tor FyuA is required for efficient biofilm
formation by urinary tract infectious
Escherichia coli in human urine.
Microbiology, 2008. 154(Pt 1): 167–75.
1188. Hang L, Frendeus B, Godaly G, and
Svanborg C, Interleukin-8 receptor
knockout mice have subepithelial neu-
trophil entrapment and renal scarring
following acute pyelonephritis. J Infect
Dis, 2000. 182(6): 1738–48.
1054
1189. Hankeln K, Radel C, Beez M, Laniewski
P, and Bohmert F, Comparison of
hydroxyethyl starch and lactated
Ringer’s solution on hemodynamics and
oxygen transport of critically ill patients
in prospective crossover studies. Crit
Care Med, 1989. 17(2): 133–5.
1190. Hansson S, Caugant D, Jodal U, and
Svanborg-Eden C, Untreated asympto-
matic bacteriuria in girls: I—Stability
of urinary isolates. Bmj, 1989.
298(6677): 853–5.
1191. Hansson S, Jodal U, Lincoln K, and
Svanborg-Eden C, Untreated asympto-
matic bacteriuria in girls: II—Effect of
phenoxymethylpenicillin and erythro-
mycin given for intercurrent infections.
Bmj, 1989. 298(6677): 856–9.
1192. Hansson S, Jodal U, Noren L, and
Bjure J, Untreated bacteriuria in
asymptomatic girls with renal scarring.
Pediatrics, 1989. 84(6): 964–8.
1193. Hara N, Kitamura Y, Saito T,
Komatsubara S, Nishiyama T, and
Takahashi K, Perioperative antibiotics
in radical cystectomy with ileal conduit
urinary diversion: efficacy and risk of
antimicrobial prophylaxis on the opera-
tion day alone. Int J Urol, 2008. 15(6):
511–5.
1194. Hara N, Koike H, Ogino S, Okuizumi M,
and Kawaguchi M, Application of serum
PSA to identify acute bacterial prostati-
tis in patients with fever of unknown ori-
gin or symptoms of acute pyelonephritis.
Prostate, 2004. 60(4): 282–8.
1195. Haralabidis S, Diakou A, Frydas S,
Papadopoulos E, Mylonas A, Patsias
A, Roilides E, and Giannoulis E,
Long-term evaluation of patients with
hydatidosis treated with albendazole
and praziquantel. Int J Immunopathol
Pharmacol, 2008. 21(2): 429–35.
1196. Harbarth S, Holeckova K, Froidevaux
C, Pittet D, Ricou B, Grau GE, Vadas
L, and Pugin J, Diagnostic value of
procalcitonin, interleukin-6, and inter-
leukin-8 in critically ill patients admit-
ted with suspected sepsis. Am J Respir
Crit Care Med, 2001. 164(3): 396–402.
1197. Harding GK, Nicolle LE, Ronald AR,
Preiksaitis JK, Forward KR, Low
DE, and Cheang M, How long should

catheter-acquired urinary tract infec-
tion in women be treated? A rand-
omized controlled study. Ann Intern
Med, 1991. 114(9): 713–9.
1198. Harding GK, Ronald AR, Nicolle LE,
Thomson MJ, and Gray GJ, Long-term
antimicrobial prophylaxis for recurrent
urinary tract infection in women. Rev
Infect Dis, 1982. 4(2): 438–43.
1199. Harding GK, Zhanel GG, Nicolle LE,
and Cheang M, Antimicrobial treat-
ment in diabetic women with asympto-
matic bacteriuria. N Engl J Med, 2002.
347(20): 1576–83.
1200. Haridas M and Malangoni MA,
Predictive factors for surgical site infec-
tion in general surgery. Surgery, 2008.
144(4): 496–501; discussion 501–3.
1201. Harisinghani MG, McLoud TC,
Shepard JA, Ko JP, Shroff MM, and
Mueller PR, Tuberculosis from head to
toe. Radiographics, 2000. 20(2): 449–70;
quiz 528–9, 532.
1202. Harries AD, Robert Koch and the dis-
covery of the tubercle bacillus: the chal-
lenge of HIV and tuberculosis 125 years
later. Int J Tuberc Lung Dis, 2008.
12(3): 241–9.
1203. Harris RE and Gilstrap LC, 3rd,
Cystitis during pregnancy: a distinct
clinical entity. Obstet Gynecol, 1981.
57(5): 578–80.
1204. Harris RE, Gilstrap LC, 3rd, and
Pretty A, Single-dose antimicrobial
therapy for asymptomatic bacteriuria
during pregnancy. Obstet Gynecol,
1982. 59(5): 546–9.
1205. Harris RE, The significance of eradica-
tion of bacteriuria during pregnancy.
Obstet Gynecol, 1979. 53(1): 71–3.
1206. Hart CE, Lennox JL, Pratt-Palmore
M, Wright TC, Schinazi RF, Evans-
Strickfaden T, Bush TJ, Schnell C,
Conley LJ, Clancy KA, and Ellerbrock
TV, Correlation of human immunodefi-
ciency virus type 1 RNA levels in blood
and the female genital tract. J Infect
Dis, 1999. 179(4): 871–82.
1207. Hasni Bouraoui I, Jemni H, Arifa N,
Chebil M, Ben Sorba N, and Tlili K,
[Imaging of renal hydatid cyst based on
a series of 41 cases]. Prog Urol, 2006.
16(2): 139–44.
References
1208. Haspels AA, Bennink HJ, and Schreurs
WH, Disturbance of tryptophan metabo-
lism and its correction during oestrogen
treatment in postmenopausal women.
Maturitas, 1978. 1(1): 15–20.
1209. Hasui Y, Marutsuka K, Asada Y, Ide
H, Nishi S, and Osada Y, Relationship
between serum prostate specific antigen
and histological prostatitis in patients
with benign prostatic hyperplasia.
Prostate, 1994. 25(2): 91–6.
1210. Haverkorn M and Mandigers J,
Reduction of bacteriuria and pyuria
using Cranberry juice (letter). JAMA,
1994. 272(8): 590.
1211. Hay P and Czeizel AE, Asymptomatic
trichomonas and candida colonization
and pregnancy outcome. Best Pract
Res Clin Obstet Gynaecol, 2007. 21(3):
403–9.
1212. Hay P, HIV transmission and sexually
transmitted infections. Clin Med, 2008.
8(3): 323–6.
1213. Hayashi K, Other antibiotics. Clin
Orthop Relat Res, 1984(190): 109–13.
1214. Haycock GB, A practical approach to
evaluating urinary tract infection in
children. Pediatr Nephrol, 1991. 5(4):
401–2; discussion 403.
1215. Health Canada. Available from: www.
hc-sc.gc.ca.
1216. Heaton KW, Radvan J, Cripps H,
Mountford RA, Braddon FE, and
Hughes AO, Defecation frequency and
timing, and stool form in the general
population: a prospective study. Gut,
1992. 33(6): 818–24.
1217. Heaton ND, Hogan B, Michell M,
Thompson P, and Yates-Bell AJ,
Tuberculous epididymo-orchitis: clini-
cal and ultrasound observations. Br J
Urol, 1989. 64(3): 305–9.
1218. Hedelin H, Brorson JE, Grenabo L, and
Pettersson S, Ureaplasma urealyticum
and upper urinary tract stones. Br J
Urol, 1984. 56(3): 244–9.
1219. Hedelin H, Uropathogens and urinary
tract concretion formation and catheter
encrustations. Int J Antimicrob Agents,
2002. 19(6): 484–7.
1220. Hedges S, Anderson P, Lindin-
Janson G, deMan P, and Svanborg C,
Interleukin-6 response to deliberate
1055
References
colonization of the human urinary tract
with gram-negative bacteria. Infection
and Immunity, 1991. 59: 421–427.
1221. Hedin K, Petersson C, Wideback
K, Kahlmeter G, and Molstad S,
Asymptomatic bacteriuria in a popu-
lation of elderly in municipal institu-
tional care. Scand J Prim Health Care,
2002. 20(3): 166–8.
1222. Hedlund M, Frendeus B, Wachtler C,
Hang L, Fischer H, and Svanborg C,
Type 1 fimbriae deliver an LPS- and
TLR4-dependent activation signal to
CD14-negative cells. Mol Microbiol,
2001. 39(3): 542–52.
1223. Hedlund M, Svensson M, Nilsson A,
Duan RD, and Svanborg C, Role of the
ceramide-signaling pathway in cytokine
responses to P-fimbriated Escherichia
coli. J Exp Med, 1996. 183(3): 1037–44.
1224. Heilmann C, Niemann S, Sinha B,
Herrmann M, Kehrel BE, and Peters G,
Staphylococcus aureus fibronectin-bind-
ing protein (FnBP)-mediated adherence
to platelets, and aggregation of platelets
induced by FnBPA but not by FnBPB. J
Infect Dis, 2004. 190(2): 321–9.
1225. Heilmann C, Schweitzer O, Gerke
C, Vanittanakom N, Mack D, and
Götz F, Molecular basis of intercel-
lular adhesion in the biofilm-forming
Staphylococcus epidermidis. Mol
Microbiol, 1996. 20(5): 1083–91.
1226. Heinamaki P, Haavisto M, Hakulinen
T, Mattila K, and Rajala S, Mortality
in relation to urinary characteristics in
the very aged. Gerontology, 1986. 32(3):
167–71.
1227. Hell W, Meyer HG, and Gatermann
SG, Cloning of aas, a gene encoding a
Staphylococcus saprophyticus surface
protein with adhesive and autolytic
properties. Mol Microbiol, 1998. 29(3):
871–81.
1228. Hellerstein S, Long-term consequences
of urinary tract infections. Curr Opin
Pediatr, 2000. 12(2): 125–8.
1229. Hellerstein S, Urinary tract infection in
children: pathophysiology,risk factors
and management. Infect Med, 2002. 19:
554–560.
1230. Hellinger WC and Brewer NS,
Carbapenems and monobactams:
1056
imipenem, meropenem, and aztreonam.
Mayo Clin Proc, 1999. 74(4): 420–34.
1231. Hellstrom WJ, Hyun JS, Human L,
Sanabria JA, Bivalacqua TJ, and
Leungwattanakij S, Antimicrobial
activity of antibiotic-soaked, Resist-
coated Bioflex. Int J Impot Res, 2003.
15(1): 18–21.
1232. Helmholz HF, Sr., Determination of the
bacterial content of the urethra: a new
method, with results of a study of 82
men. J Urol, 1950. 64(1): 158–66.
1233. Hemal AK, Gupta NP, Rajeev
TP, Kumar R, Dar L, and Seth P,
Polymerase chain reaction in clinically
suspected genitourinary tuberculosis:
comparison with intravenous urogra-
phy, bladder biopsy, and urine acid fast
bacilli culture. Urology, 2000. 56(4):
570–4.
1234. Hemila M, Henriksson L, and
Ylikorkala O, Serum CRP in the diag-
nosis and treatment of pelvic inflam-
matory disease. Arch Gynecol Obstet,
1987. 241(3): 177–82.
1235. Henderson IR, Meehan M, and Owen P,
Antigen 43, a phase-variable bipartite
outer membrane protein, determines
colony morphology and autoaggrega-
tion in Escherichia coli K-12. FEMS
Microbiol Lett, 1997. 149(1): 115–20.
1236. Henderson IR, Navarro-Garcia F,
Desvaux M, Fernandez RC, and
Ala’Aldeen D, Type V protein secretion
pathway: the autotransporter story.
Microbiol Mol Biol Rev, 2004. 68(4):
692–744.
1237. Hendler I, Andrews WW, Carey CJ,
Klebanoff MA, Noble WD, Sibai BM,
Hillier SL, Dudley D, Ernest JM,
Leveno KJ, Wapner R, Iams JD,
Varner M, Moawad A, Miodovnik M,
O’Sullivan MJ, and Van Dorsten PJ,
The relationship between resolution
of asymptomatic bacterial vaginosis
and spontaneous preterm birth in
fetal fibronectin-positive women. Am J
Obstet Gynecol, 2007. 197(5): 488 e1–5.
1238. Hendrikx AJ, Strijbos WE, de Knijff
DW, Kums JJ, Doesburg WH, and
Lemmens WA, Treatment for extended-
mid and distal ureteral stones: SWL or
ureteroscopy? Results of a multicenter

study. J Endourol, 1999. 13(10):
727–33.
1239. Hendry WF, Levison DA, Parkinson
MC, Parslow JM, and Royle MG,
Testicular obstruction: clinicopatho-
logical studies. Ann R Coll Surg Engl,
1990. 72(6): 396–407.
1240. Henkel R, Ludwig M, Schuppe HC,
Diemer T, Schill WB, and Weidner W,
Chronic pelvic pain syndrome/chronic
prostatitis affect the acrosome reaction
in human spermatozoa. World J Urol,
2006. 24(1): 39–44.
1241. Henry D, Ellison W, Sullivan J,
Mansfield DL, Magner DJ, Dorr MB,
and Talbot GH, Treatment of commu-
nity-acquired acute uncomplicated uri-
nary tract infection with sparfloxacin
versus ofloxacin. The Sparfloxacin
Multi Center UUTI Study Group.
Antimicrob Agents Chemother, 1998.
42(9): 2262–6.
1242. Henry DC, Jr., Bettis RB, Riffer E,
Haverstock DC, Kowalsky SF, Manning
K, Hamed KA, and Church DA,
Comparison of once-daily extended-
release ciprofloxacin and conventional
twice-daily ciprofloxacin for the treat-
ment of uncomplicated urinary tract
infection in women. Clin Ther, 2002.
24(12): 2088–104.
1243. Henry DC, Nenad RC, Iravani A, Tice
AD, Mansfield DL, Magner DJ, Dorr
MB, and Talbot GH, Comparison of
sparfloxacin and ciprofloxacin in the
treatment of community-acquired acute
uncomplicated urinary tract infection
in women. Sparfloxacin Multicenter
Uncomplicated Urinary Tract Infection
Study Group. Clin Ther, 1999. 21(6):
966–81.
1244. Henry GD, Wilson SK, Delk JR, 2nd,
Carson CC, Silverstein A, Cleves MA,
and Donatucci CF, Penile prosthesis cul-
tures during revision surgery: a multi-
center study. J Urol, 2004. 172(1): 153–6.
1245. Henry K and Campbell S, Needlestick/
sharps injuries and HIV exposure
among health care workers. National
estimates based on a survey of U.S. hos-
pitals. Minn Med, 1995. 78(11): 41–4.
1246. Henry-Suchet J and Tesquier L, Role
of laparoscopy in the management of
References
pelvic adhesions and pelvic sepsis.
Baillieres Clin Obstet Gynaecol, 1994.
8(4): 759–72.
1247. Henry-Suchet J, PID: clinical and
laparoscopic aspects. Ann N Y Acad Sci,
2000. 900: 301–8.
1248. Hensle TW, Bingham J, Lam J, and
Shabsigh A, Preventing reservoir cal-
culi after augmentation cystoplasty and
continent urinary diversion: the influ-
ence of an irrigation protocol. BJU Int,
2004. 93(4): 585–7.
1249. Hensle TW, Bingham JB, Reiley EA,
Cleary-Goldman JE, Malone FD, and
Robinson JN, The urological care and
outcome of pregnancy after urinary
tract reconstruction. BJU Int, 2004.
93(4): 588–90.
1250. Hensle TW, Hyun G, Grogg AL, and
Eaddy M, Part 2: Examining pediat-
ric vesicoureteral reflux: a real-world
evaluation of treatment patterns and
outcomes. Curr Med Res Opin, 2007. 23
Suppl 4: S7–13.
1251. Herieka E and Fisk P, Methicillin
resistant Staphylococcus aureus
(MRSA) balanoposthitis in an insulin
dependent diabetic male. Sex Transm
Infect, 2001. 77(3): 223.
1252. Hermanides HS, Hulscher ME,
Schouten JA, Prins JM, and Geerlings
SE, Development of quality indicators
for the antibiotic treatment of compli-
cated urinary tract infections: a first
step to measure and improve care. Clin
Infect Dis, 2008. 46(5): 703–11.
1253. Hermans PE and Wilhelm MP,
Vancomycin. Mayo Clin Proc, 1987.
62(10): 901–5.
1254. Hermieu JF, Delmas V, and Boccon-
Gibod L, Micturition disturbances and
human immunodeficiency virus infec-
tion. J Urol, 1996. 156(1): 157–9.
1255. Hernandez Gonzalez E, Zamora
Perez F, Martinez Arroyo M, Valdez
Fernandez M, and Alberti Amador E,
[Epidemiologic, clinical and microbio-
logical characteristics of nosocomial
urinary infection in the spinal cord
lesioned patient]. Actas Urol Esp, 2007.
31(7): 764–70.
1256. Hernandez-Diaz S, Werler MM, Walker
AM, and Mitchell AA, Folic acid
1057
References
antagonists during pregnancy and the
risk of birth defects. N Engl J Med,
2000. 343(22): 1608–14.
1257. Herndon CD, DeCambre M, and
McKenna PH, Changing concepts
concerning the management of vesi-
coureteral reflux. J Urol, 2001. 166(4):
1439–43.
1258. Heron M, Deaths: leading causes for
2004. Natl Vital Stat Rep, 2007. 56(5):
1–95.
1259. Herzog LW, Urinary tract infections
and circumcision. A case-control study.
Am J Dis Child, 1989. 143(3): 348–50.
1260. Hess B and Ackermann D, [Preventive
measures in stones due to infection, uric
acid and cystine]. Ther Umsch, 1992.
49(1): 44–8.
1261. Hess M, Hess P, Sullivan M, Nee M,
and Yalla S, Evaluation of cranberry
tablets for the presentation of urinary
tract infections in spinal cord injured
patients with neurogenic bladder.
Spinal Cord, 2008. 46: 622–6.
1262. Hess MJ, Hess PE, Sullivan MR,
Nee M, and Yalla SV, Evaluation of
cranberry tablets for the prevention of
urinary tract infections in spinal cord
injured patients with neurogenic blad-
der. Spinal Cord, 2008. 46(9): 622–6.
1263. Hesse A and Heimbach D, Causes of
phosphate stone formation and the
importance of metaphylaxis by urinary
acidification: a review. World J Urol,
1999. 17(5): 308–15.
1264. Hewitt IK, Zucchetta P, Rigon L,
Maschio F, Molinari PP, Tomasi L,
Toffolo A, Pavanello L, Crivellaro C,
Bellato S, and Montini G, Early treat-
ment of acute pyelonephritis in children
fails to reduce renal scarring: data
from the Italian Renal Infection Study
Trials. Pediatrics, 2008. 122(3): 486–90.
1265. Heyns CF and Fisher M, The urologi-
cal management of the patient with
acquired immunodeficiency syndrome.
BJU Int, 2005. 95(5): 709–16.
1266. Heystek MJ, Tellarini M, Schmitz H,
and Krasemann C, Efficacy and safety
of moxifloxacine vs ciprofloxacine plus
doxycycline plus metronidazole for
the treatment of uncomplicated pelvic
inflammatory disease. abstract.
1058
1267. Higashide M, Kuroda M, Ohkawa S,
and Ohta T, Evaluation of a cefoxitin
disk diffusion test for the detection of
mecA-positive methicillin-resistant
Staphylococcus saprophyticus. Int J
Antimicrob Agents, 2006. 27(6): 500–4.
1268. High KP, Bradley S, Loeb M, Palmer
R, Quagliarello V, and Yoshikawa T, A
new paradigm for clinical investigation
of infectious syndromes in older adults:
assessment of functional status as a
risk factor and outcome measure. Clin
Infect Dis, 2005. 40(1): 114–22.
1269. High KP, Bradley SF, Gravenstein S,
Mehr DR, Quagliarello VJ, Richards
C, and Yoshikawa TT, Clinical practice
guideline for the evaluation of fever
and infection in older adult residents of
long-term care facilities: 2008 update
by the Infectious Diseases Society of
America. Clin Infect Dis, 2009. 48(2):
149–71.
1270. Hilbert DW, Pascal KE, Libby EK,
Mordechai E, Adelson ME, and
Trama JP, Uropathogenic Escherichia
coli dominantly suppress the innate
immune response of bladder epithelial
cells by a lipopolysaccharide- and Toll-
like receptor 4-independent pathway.
Microbes Infect, 2008. 10(2): 114–21.
1271. Hildebrand WL, Schreiner RL, Stevens
DC, Gosling CG, and Sternecker CL,
Suprapubic bladder aspiration in
infants. Am Fam Physician, 1981.
23(5): 115–8.
1272. Hill DE and Kramer SA, Management
of pregnancy after augmentation cysto-
plasty. J Urol, 1990. 144(2 Pt 2): 457–9;
discussion 460.
1273. Hill GB, Preterm birth: associations
with genital and possibly oral micro-
flora. Ann Periodontol, 1998. 3(1):
222–32.
1274. Hill JB, Sheffield JS, McIntire DD, and
Wendel GD, Jr., Acute pyelonephritis
in pregnancy. Obstet Gynecol, 2005.
105(1): 18–23.
1275. Hill MJ and Drasar BS, The normal
colonic bacterial flora. Gut, 1975. 16(4):
318–23.
1276. Hill MJ, Hudson MJ, and Stewart M,
The urinary bacterial flora in patients
with three types of urinary tract

diversion. J Med Microbiol, 1983. 16(2):
221–6.
1277. Hillebrand L, Harmanli OH, Whiteman
V, and Khandelwal M, Urinary tract
infections in pregnant women with bac-
terial vaginosis. Am J Obstet Gynecol,
2002. 186(5): 916–7.
1278. Hillier S, Watts DH, Lee MF, and
Eschenbach DA, Etiology and
treatment of post-cesarean-section
endometritis after cephalosporin
prophylaxis. J Reprod Med, 1990. 35(3
Suppl): 322–8.
1279. Hillier SL, Krohn MA, Watts H,
Wolner-Hanssen P, and DA E,
Microbiologic efficacy of intravaginal
clindamycin cream for the treatment
of bacterial vaginosis. Obstet Gynecol,
1990(76): 407–413.
1280. Hillier SL, Nugent RP, Eschenbach
DA, Krohn MA, Gibbs RS, Martin DH,
Cotch MF, Edelman R, Pastorek JG,
2nd, Rao AV, and et al., Association
between bacterial vaginosis and pre-
term delivery of a low-birth-weight
infant. The Vaginal Infections and
Prematurity Study Group. N Engl J
Med, 1995. 333(26): 1737–42.
1281. Hillis SD, Joesoef R, Marchbanks
PA, Wasserheit JN, Cates W, Jr., and
Westrom L, Delayed care of pelvic
inflammatory disease as a risk fac-
tor for impaired fertility. Am J Obstet
Gynecol, 1993. 168(5): 1503–9.
1282. Hillman LJ, Burns SP, and Kraft GH,
Neurological worsening due to infection
from renal stones in a multiple sclerosis
patient. Mult Scler, 2000. 6(6): 403–6.
1283. Hilton E, Isenberg HD, Alperstein
P, France K, and Borenstein MT,
Ingestion of yogurt containing
Lactobacillus acidophilus as prophy-
laxis for candidal vaginitis. Ann Intern
Med, 1992. 116(5): 353–7.
1284. Himpsl SD, Lockatell CV, Hebel
JR, Johnson DE, and Mobley HL,
Identification of virulence determinants
in uropathogenic Proteus mirabilis
using signature-tagged mutagen-
esis. J Med Microbiol, 2008. 57(Pt 9):
1068–78.
1285. Hinman F, Ileocystoplasty, in Atlas of
urologic surgery, Hinman F, Editor.
References
1998, W.B. Saunders: Philadelphia;
London. p. xxviii,1172p.
1286. Hinman F, Jr., Directional growth of
renal calculi. J Urol, 1979. 121(6):
700–5.
1287. Hinting A, Soebadi DM, and Santoso
RI, Evaluation of the immunological
cause of male infertility. Andrologia,
1996. 28(2): 123–6.
1288. Hiraoka M, Hashimoto G, Tsuchida S,
Tsukahara H, Ohshima Y, and Mayumi
M, Early treatment of urinary infection
prevents renal damage on cortical scin-
tigraphy. Pediatr Nephrol, 2003. 18(2):
115–8.
1289. Hiraoka M, Tsukahara H, Ohshima Y,
and Mayumi M, Meatus tightly covered
by the prepuce is associated with uri-
nary infection. Pediatr Int, 2002. 44(6):
658–62.
1290. Hirsch HH, Brennan DC, Drachenberg
CB, Ginevri F, Gordon J, Limaye AP,
Mihatsch MJ, Nickeleit V, Ramos
E, Randhawa P, Shapiro R, Steiger
J, Suthanthiran M, and Trofe J,
Polyomavirus-associated nephropathy
in renal transplantation: interdisci-
plinary analyses and recommenda-
tions. Transplantation, 2005. 79(10):
1277–86.
1291. Hirsch M: AFSSA – Saisine n° 2003-
SA-0352.
1292. Hirsh DD, Fainstein V, and Musher
DM, Do condom catheter collecting
systems cause urinary tract infection?
JAMA, 1979. 242(4): 340–1.
1293. Hitti J and Watts DH, Bacterial
Sexually Transmitted Infections in
Pregnancy, in Sexually transmitted
diseases, Holmes KK, Editor. 2008,
McGraw-Hill, Medical: New York. p.
1529–1561.
1294. Hiyama L, Tang A, and Miller LG,
Levofloxacin penetration into a renal
cyst in a patient with autosomal domi-
nant polycystic kidney disease. Am J
Kidney Dis, 2006. 47(1): e9–13.
1295. Ho PL, Chan WM, Tsang KW, Wong
SS, and Young K, Bacteremia caused
by Escherichia coli producing extended-
spectrum beta-lactamase: a case-control
study of risk factors and outcomes.
Scand J Infect Dis, 2002. 34(8): 567–73.
1059
References
1296. Ho PL, Yip KS, Chow KH, Lo JY, Que
TL, and Yuen KY, Antimicrobial resist-
ance among uropathogens that cause
acute uncomplicated cystitis in women
in Hong Kong: a prospective multi-
center study in 2006 to 2008. Diagn
Microbiol Infect Dis, 2009.
1297. Hoberman A and Wald ER, Urinary
tract infections in young febrile children.
Pediatr Infect Dis J, 1997. 16(1): 11–7.
1298. Hoberman A, Chao HP, Keller DM,
Hickey R, Davis HW, and Ellis D,
Prevalence of urinary tract infection in
febrile infants. J Pediatr, 1993. 123(1):
17–23.
1299. Hoberman A, Charron M, Hickey RW,
Baskin M, Kearney DH, and Wald ER,
Imaging studies after a first febrile uri-
nary tract infection in young children.
N Engl J Med, 2003. 348(3): 195–202.
1300. Hoberman A, Wald ER, Hickey RW,
Baskin M, Charron M, Majd M,
Kearney DH, Reynolds EA, Ruley J,
and Janosky JE, Oral versus initial
intravenous therapy for urinary tract
infections in young febrile children.
Pediatrics, 1999. 104(1 Pt 1): 79–86.
1301. Hoberman A, Wald ER, Reynolds EA,
Penchansky L, and Charron M, Is urine
culture necessary to rule out urinary
tract infection in young febrile chil-
dren? Pediatr Infect Dis J, 1996. 15(4):
304–9.
1302. Hochreiter WW, The issue of prostate
cancer evaluation in men with elevated
prostate-specific antigen and chronic
prostatitis. Andrologia, 2008. 40(2):
130–3.
1303. Hoddick W, Jeffrey RB, Goldberg HI,
Federle MP, and Laing FC, CT and
sonography of severe renal and perire-
nal infections. AJR Am J Roentgenol,
1983. 140(3): 517–20.
1304. Hodgin KE and Moss M, The epidemi-
ology of sepsis. Curr Pharm Des, 2008.
14(19): 1833–9.
1305. Hodson EM, Wheeler DM,
Vimalchandra D, Smith GH, and Craig
JC, Interventions for primary vesi-
coureteric reflux. Cochrane Database
Syst Rev, 2007(3): CD001532.
1306. Hodson EM, Willis NS, and Craig JC,
Antibiotics for acute pyelonephritis in
1060
children. Cochrane Database Syst Rev,
2007(4): CD003772.
1307. Hoepelman AI, van Buren M, van den
Broek J, and Borleffs JC, Bacteriuria
in men infected with HIV-1 is related to
their immune status (CD4+ cell count).
AIDS, 1992. 6(2): 179–84.
1308. Hoeprich PD, Culture of the urine. J
Lab Clin Med, 1960. 56: 899–907.
1309. Hof H, [Antimicrobial therapy with
nitroheterocyclic compounds, for
example, metronidazole and nitro-
furantoin]. Immun Infekt, 1988. 16(6):
220–5.
1310. Hoffman M, Molpus K, Roberts
WS, Lyman GH, and Cavanagh D,
Tuboovarian abscess in postmenopau-
sal women. J Reprod Med, 1990. 35(5):
525–8.
1311. Hoffman MJ and Adams WE,
Recognition and Repair of Urethral
Diverticula: A Report of 60 Cases. Am J
Obstet Gynecol, 1965. 92: 106–11.
1312. Hoffstetter SE, Barr S, LeFevre C,
Leong FC, and Leet T, Self-reported
yeast symptoms compared with clinical
wet mount analysis and vaginal yeast
culture in a specialty clinic setting. J
Reprod Med, 2008. 53(6): 402–6.
1313. Hofland CA, Eron LJ, and Washecka
RM, Hemorrhagic adenovirus cystitis
after renal transplantation. Transplant
Proc, 2004. 36(10): 3025–7.
1314. Hofmann W, [Urosepsis and uroseptic
shock]. Z Urol Nephrol, 1990. 83(6):
317–24.
1315. Hofstetter A, Friesen A, Bishop-
Freudling GB, and Vergin H,
[Co-trimoxazole concentration in the
prostatic fluid of patients with subacute
and chronic prostatitis]. Fortschr Med,
1984. 102(9): 244–6.
1316. Hogan TF, Padgett BL, Walker DL,
Borden EC, and McBain JA, Rapid
detection and identification of JC virus
and BK virus in human urine by using
immunofluorescence microscopy. J Clin
Microbiol, 1980. 11(2): 178–83.
1317. Holmang S, Grenabo L, Hedelin H,
Wang YH, and Pettersson S, Influence
of indomethacin on the adherence of
urease-induced crystals to rat bladder
epithelium. J Urol, 1991. 145(1): 176–8.

1318. Holmberg L, Boman G, Bottiger LE,
Eriksson B, Spross R, and Wessling
A, Adverse reactions to nitrofurantoin.
Analysis of 921 reports. Am J Med,
1980. 69(5): 733–8.
1319. Holmes KK, Eschenbach DA, and
Knapp JS, Salpingitis: overview of eti-
ology and epidemiology. Am J Obstet
Gynecol, 1980. 138(7 Pt 2): 893–900.
1320. Holtgrewe HL, Mebust WK, Dowd JB,
Cockett AT, Peters PC, and Proctor C,
Transurethral prostatectomy: practice
aspects of the dominant operation in
American urology. J Urol, 1989. 141(2):
248–53.
1321. Hood HM, Allman RM, Burgess PA,
Farmer R, and Xu W, Effects of timely
antibiotic administration and culture
acquisition on the treatment of urinary
tract infection. Am J Med Qual, 1998.
13(4): 195–202.
1322. Hooton TM and Stam WE,
Management of acute uncomplicated
urinary tract infection in adults. Med
Clin North Am, 1991. 75(2): 339–57.
1323. Hooton TM and Stamm WE, Diagnosis
and treatment of uncomplicated uri-
nary tract infection. Infect Dis Clin
North Am, 1997. 11(3): 551–81.
1324. Hooton TM, Bradley SF, Cardenas DD,
Colgan R, Geerling SE, Rice JC, Saint
S, Schaeffer AJ, Tam byah PA, Tenke
P, and LE N, International clinical
practice guidelines for the diagnosis,
prevention and treatment of catheter-
associated urinary tract infection in
adults. 2010 (in press).
1325. Hooton TM, Carlet, J.M., Duse, A.G.,
Krieger, J.N., Steele, L., Sunakawa,
K., Definitions and epidemiology,
in Nosocomial and Health Care
Associated Infections in Urology, Naber
KG, Pechere, J.C., Kumazawa, J.,
Khoury, S., Gerberding, J.L., Schaeffer,
A.J., Editor. 2001, Health Publication
Ltd.: Plymouth, UK.
1326. Hooton TM, Johnson C, Winter C,
Kuwamura L, Rogers ME, Roberts PL,
and Stamm WE, Single-dose and three-
day regimens of ofloxacin versus tri-
methoprim-sulfamethoxazole for acute
cystitis in women. Antimicrob Agents
Chemother, 1991. 35(7): 1479–83.
References
1327. Hooton TM, Latham RH, Wong ES,
Johnson C, Roberts PL, and Stamm
WE, Ofloxacin versus trimethoprim-
sulfamethoxazole for treatment of acute
cystitis. Antimicrob Agents Chemother,
1989. 33(8): 1308–12.
1328. Hooton TM, Practice guidelines for uri-
nary tract infection in the era of man-
aged care. Int J Antimicrob Agents,
1999. 11(3–4): 241–5; discussion 261–4.
1329. Hooton TM, Recurrent urinary tract
infection in women. Int J Antimicrob
Agents, 2001. 17(4): 259–68.
1330. Hooton TM, Scholes D, Gupta K,
Stapleton AE, Roberts PL, and Stamm
WE, Amoxicillin-clavulanate vs cipro-
floxacin for the treatment of uncompli-
cated cystitis in women: a randomized
trial. Jama, 2005. 293(8): 949–55.
1331. Hooton TM, Scholes D, Hughes JP,
Winter C, Roberts PL, Stapleton AE,
Stergachis A, and Stamm WE, A pro-
spective study of risk factors for symp-
tomatic urinary tract infection in young
women. N Engl J Med, 1996. 335(7):
468–74.
1332. Hooton TM, Scholes D, Stapleton
AE, Roberts PL, Winter C, Gupta K,
Samadpour M, and Stamm WE, A pro-
spective study of asymptomatic bacte-
riuria in sexually active young women.
N Engl J Med, 2000. 343(14): 992–7.
1333. Hooton TM, Stapleton AE, Roberts PL,
and Stamm WE, Comparison of micro-
biologic findings in paired midstream
and catheter urine specimens from
women with acute uncomplicated cysti-
tis. Abstract L-609 48th Annual ICAAC
Washington DC, 2008.
1334. Hooton TM, The current management
strategies for community-acquired
urinary tract infection. Infect Dis Clin
North Am, 2003. 17(2): 303–32.
1335. Hopkins WJ, Elkahwaji J, Beierle LM,
Leverson GE, and Uehling DT, Vaginal
mucosal vaccine for recurrent urinary
tract infections in women: results of
a phase 2 clinical trial. J Urol, 2007.
177(4): 1349–53; quiz 1591.
1336. Horan TC, Andrus M, and Dudeck MA,
CDC/NHSN surveillance definition of
health care-associated infection and
criteria for specific types of infections
1061
References
in the acute care setting. Am J Infect
Control, 2008. 36(5): 309–32.
1337. Horcajada JP, Moreno I, Velasco M,
Martinez JA, Moreno-Martinez A,
Barranco M, Vila J, and Mensa J,
Community-acquired febrile urinary
tract infection in diabetics could
deserve a different management: a
case-control study. J Intern Med, 2003.
254(3): 280–6.
1338. Horcajada JP, Vila J, Moreno-Martinez
A, Ruiz J, Martinez JA, Sanchez M,
Soriano E, and Mensa J, Molecular epi-
demiology and evolution of resistance to
quinolones in Escherichia coli after pro-
longed administration of ciprofloxacin
in patients with prostatitis. J Antimicrob
Chemother, 2002. 49(1): 55–9.
1339. Horcajada JP, Vilana R, Moreno-
Martinez A, Alvarez-Vijande R, Bru
C, Bargallo X, Bunesch L, Martinez
JA, and Mensa J, Transrectal prostatic
ultrasonography in acute bacterial
prostatitis: findings and clinical impli-
cations. Scand J Infect Dis, 2003. 35(2):
114–20.
1340. Horchani A, Nouira Y, Kbaier I,
Attyaoui F, and Zribi AS, Hydatid cyst
of the kidney. A report of 147 controlled
cases. Eur Urol, 2000. 38(4): 461–7.
1341. Horner PJ, European guideline for the
management of epididymo-orchitis and
syndromic management of acute scro-
tal swelling. Int J STD AIDS, 2001. 12
Suppl 3: 88–93.
1342. Hornick DB, Allen BL, Horn MA, and
Clegg S, Adherence to respiratory epi-
thelia by recombinant Escherichia coli
expressing Klebsiella pneumoniae type
3 fimbrial gene products. Infect Immun,
1992. 60(4): 1577–88.
1343. Hossain A, Ferraro MJ, Pino RM, Dew
RB, 3rd, Moland ES, Lockhart TJ,
Thomson KS, Goering RV, and Hanson
ND, Plasmid-mediated carbapenem-
hydrolyzing enzyme KPC-2 in an
Enterobacter sp. Antimicrob Agents
Chemother, 2004. 48(11): 4438–40.
1344. Hotchkiss RS and Karl IE, The patho-
physiology and treatment of sepsis. N
Engl J Med, 2003. 348(2): 138–50.
1345. Hovelius B and Mardh PA,
Staphylococcus saprophyticus as a
1062
common cause of urinary tract infec-
tions. Rev Infect Dis, 1984. 6(3):
328–37.
1346. Hovelius B, Mardh PA, Nygaard-
Pedersen L, and Wathne B, Nalidixic
acid and pivmecillinam for treatment
of acute lower urinary tract infections.
Scand J Prim Health Care, 1985. 3(4):
227–32.
1347. Hovhannisyan G, von Schoen-Angerer
T, Babayan K, Fenichiu O, and
Gaboulaud V, Antimicrobial suscepti-
bility of Neisseria gonorrheae strains in
three regions of Armenia. Sex Transm
Dis, 2007. 34(9): 686–8.
1348. Howe RA and Spencer RC,
Cotrimoxazole. Rationale for re-exam-
ining its indications for use. Drug Saf,
1996. 14(4): 213–8.
1349. Howell A, Bioactive compounds in
cranberries and their role in prevention
of urinary tract infections. Mol. Nutr.
Food Res, 2007. 51(6): 732–7.
1350. Howell A, Vorsa N, Marderosian AD,
and Foo L, Inhibition of adherence of
P-fimbriated Eschericha coli to uroepi-
thelial-cell surfaces by proanthocyani-
din extracts from Cranberries. N Engl J
Med, 1998. 339(19): 1085–6.
1351. Hoyme UB and Saling E, Efficient
prematurity prevention is possible by
pH-self measurement and immediate
therapy of threatening ascending infec-
tion. Eur J Obstet Gynecol Reprod Biol,
2004. 115(2): 148–53.
1352. Hoyme UB, [Prenatal guidelines and
Chlamydia screening]. Z Geburtshilfe
Neonatol, 1997. 201(4): 113–4.
1353. Hsu CY, Fang HC, Chou KJ, Chen CL,
Lee PT, and Chung HM, The clinical
impact of bacteremia in complicated
acute pyelonephritis. Am J Med Sci,
2006. 332(4): 175–80.
1354. Hsu JM, Chen M, Lin WC, Chang HK,
and Yang S, Ureteroscopic management
of sepsis associated with ureteral stone
impaction: is it still contraindicated?
Urol Int, 2005. 74(4): 319–22.
1355. Hu WL, Zhong SZ, and He HX,
Treatment of chronic bacterial prostati-
tis with amikacin through anal submu-
cosal injection. Asian J Androl, 2002.
4(3): 163–7.

1356. Huang HP, Lai YC, Tsai IJ, Chen SY,
and Tsau YK, Renal ultrasonography
should be done routinely in children
with first urinary tract infections.
Urology, 2008. 71(3): 439–43.
1357. Huang HS, Chen J, Teng LJ, and Lai
MK, Use of polymerase chain reac-
tion to detect Proteus mirabilis and
Ureaplasma urealyticum in urinary
calculi. J Formos Med Assoc, 1999.
98(12): 844–50.
1358. Huang JJ and Tseng CC,
Emphysematous pyelonephritis:
clinicoradiological classification, man-
agement, prognosis, and pathogen-
esis. Arch Intern Med, 2000. 160(6):
797–805.
1359. Huang JJ, Chen KW, and Ruaan MK,
Mixed acid fermentation of glucose as a
mechanism of emphysematous urinary
tract infection. J Urol, 1991. 146(1):
148–51.
1360. Huang JJ, Sung JM, Chen KW, Ruaan
MK, Shu GH, and Chuang YC, Acute
bacterial nephritis: a clinicoradiologic
correlation based on computed tomog-
raphy. Am J Med, 1992. 93(3): 289–98.
1361. Huber M, Ayoub M, Pfannes SD,
Mittenbuhler K, Weis K, Bessler WG,
and Baier W, Immunostimulatory activ-
ity of the bacterial extract OM-8. Eur J
Med Res, 2000. 5(3): 101–9.
1362. Huber M, Baier W, Serr A, and Bessler
WG, Immunogenicity of an E. coli
extract after oral or intraperitoneal
administration: induction of antibodies
against pathogenic bacterial strains.
Int J Immunopharmacol, 2000. 22(1):
57–68.
1363. Hugosson J, Grenabo L, Hedelin H,
and Pettersson S, Effects of serum,
albumin and immunoglobulins on
urease-induced crystallization in urine.
Urol Res, 1990. 18(6): 407–11.
1364. Hugosson J, Grenabo L, Hedelin
H, Pettersson S, and Seeberg S,
Bacteriology of upper urinary tract
stones. J Urol, 1990. 143(5): 965–8.
1365. Hugosson J, Grenabo L, Hedelin H,
Pettersson S, and Tarfusser I, How
variations in the composition of urine
influence urease-induced crystalliza-
tion. Urol Res, 1990. 18(6): 413–7.
References
1366. Hull R, Rudy D, Donovan W, Svanborg
C, Wieser I, Stewart C, and Darouiche
R, Urinary tract infection prophylaxis
using Escherichia coli 83972 in spinal
cord injured patients. J Urol, 2000.
163(3): 872–7.
1367. Hull RA, Rudy DC, Donovan WH,
Wieser IE, Stewart C, and Darouiche
RO, Virulence properties of Escherichia
coli 83972, a prototype strain associated
with asymptomatic bacteriuria. Infect
Immun, 1999. 67(1): 429–32.
1368. Hummers-Pradier E and Kochen MM,
Urinary tract infections in adult gen-
eral practice patients. Br J Gen Pract,
2002. 52(482): 752–61.
1369. Humphreys H, Marshall RJ, Ricketts
VE, Russell AJ, and Reeves DS,
Theatre over-shoes do not reduce oper-
ating theatre floor bacterial counts. J
Hosp Infect, 1991. 17(2): 117–23.
1370. Hung CS, Bouckaert J, Hung D,
Pinkner J, Widberg C, DeFusco A,
Auguste CG, Strouse R, Langermann
S, Waksman G, and Hultgren
SJ, Structural basis of tropism of
Escherichia coli to the bladder during
urinary tract infection. Mol Microbiol,
2002. 44(4): 903–15.
1371. Hung TH, Jeng CJ, Su SC, and
Wang KG, Pelvic abscess caused by
Salmonella: a case report. Zhonghua Yi
Xue Za Zhi (Taipei), 1996. 57(6): 457–9.
1372. Hunstad DA, Justice SS, Hung
CS, Lauer SR, and Hultgren SJ,
Suppression of bladder epithelial
cytokine responses by uropathogenic
Escherichia coli. Infect Immun, 2005.
73(7): 3999–4006.
1373. Hunter DJ, Berra-Unamuno A, and
Martin-Gordo A, Prevalence of uri-
nary symptoms and other urological
conditions in Spanish men 50 years
old or older. J Urol, 1996. 155(6):
1965–70.
1374. Huovinen P, Huovinen S, and Jacoby
GA, Sequence of PSE-2 beta-lactamase.
Antimicrob Agents Chemother, 1988.
32(1): 134–6.
1375. Huppert JS and Adams Hillard PJ,
Sexually transmitted disease screening
in teens. Curr Womens Health Rep,
2003. 3(6): 451–8.
1063
References
1376. Hurlbut TA, 3rd and Littenberg B, The
diagnostic accuracy of rapid dipstick
tests to predict urinary tract infection.
Am J Clin Pathol, 1991. 96(5): 582–8.
1377. Hussain M, Greenwell TJ, Venn SN,
and Mundy AR, The current role of the
artificial urinary sphincter for the treat-
ment of urinary incontinence. J Urol,
2005. 174(2): 418–24.
1378. Hussain M, Heilmann C, Peters G, and
Herrmann M, Teichoic acid enhances
adhesion of Staphylococcus epidermidis
to immobilized fibronectin. Microb
Pathog, 2001. 31(6): 261–70.
1379. Huth TS, Burke JP, Larsen RA, Classen
DC, and Stevens LE, Clinical trial of
junction seals for the prevention of uri-
nary catheter-associated bacteriuria.
Arch Intern Med, 1992. 152(4): 807–12.
1380. Hutt P, Shchepetova J, Loivukene
K, Kullisaar T, and Mikelsaar M,
Antagonistic activity of probiotic
lactobacilli and bifidobacteria against
entero- and uropathogens. J Appl
Microbiol, 2006. 100(6): 1324–32.
1381. Huwe P, Menkveld R, Ludwig M, and
Weidner W, Effect of epididymitis on
semen biochemical and sperm mor-
phology parameters. Urologe A, 2004.
43(Suppl 1): S81.
1382. Hyodo T, Yoshida K, Sakai T, and Baba
S, Asymptomatic hyperleukocyturia in
hemodialysis patients analyzed by the
automated urinary flow cytometer. Ther
Apher Dial, 2005. 9(5): 402–6.
1383. Hyun G and Lowe FC, AIDS and the
urologist. Urol Clin North Am, 2003.
30(1): 101–9.
1384. Iakovlev SV, [Lemofloxacin: antimi-
crobial ability and clinico-pharma-
cokinetic basis for use in urogenital
infections]. Urologiia, 2002(1): 11–4.
1385. Ibrahim A, The relationship between uri-
nary bilharziasis and urolithiasis in the
Sudan. Br J Urol, 1978. 50(5): 294–7.
1386. Ibrahim AI, Bilal NE, Shetty SD, Patil
KP, and Gommaa H, The source of
organisms in the post-prostatectomy
bacteriuria of patients with pre-opera-
tive sterile urine. Br J Urol, 1993. 72(5
Pt 2): 770–4.
1387. Ibrahim EH, Sherman G, Ward
S, Fraser VJ, and Kollef MH, The
1064
influence of inadequate antimicrobial
treatment of bloodstream infections on
patient outcomes in the ICU setting.
Chest, 2000. 118(1): 146–55.
1388. Ikaheimo R, Siitonen A, Heiskanen
T, Karkkainen U, Kuosmanen
P, Lipponen P, and Makela PH,
Recurrence of urinary tract infection
in a primary care setting: analysis of
a 1-year follow-up of 179 women. Clin
Infect Dis, 1996. 22(1): 91–9.
1389. Ikinger U, Koraitim M, and Seitz HK,
Schistosomiasis: new aspects of an old
disease. 1994, Berlin: Ullstein Mosby.
212p.
1390. Ikonen S, Kivisaari L, Tervahartiala P,
Vehmas T, Taari K, and Rannikko S,
Prostatic MR imaging. Accuracy in dif-
ferentiating cancer from other prostatic
disorders. Acta Radiol, 2001. 42(4):
348–54.
1391. Ilina EN, Vereshchagin VA, Borovskaya
AD, Malakhova MV, Sidorenko SV,
Al-Khafaji NC, Kubanova AA, and
Govorun VM, Relation between genetic
markers of drug resistance and sus-
ceptibility profile of clinical Neisseria
gonorrhoeae strains. Antimicrob Agents
Chemother, 2008. 52(6): 2175–82.
1392. Imirzalioglu C, Hain T, Chakraborty
T, and Domann E, Hidden pathogens
uncovered: metagenomic analysis of
urinary tract infections. Andrologia,
2008. 40(2): 66–71.
1393. Infertility and sexually transmitted dis-
ease: a public health challenge. Popul
Rep L, 1983(4): L114–51.
1394. Ingerslev HJ, Moller BR, and Mardh
PA, Chlamydia trachomatis in acute
and chronic endometritis. Scand J
Infect Dis Suppl, 1982. 32: 59–63.
1395. Inglis JA and Tolley DA, Antibiotic
prophylaxis at the time of percutane-
ous stone surgery. J Endourol, 1988. 2:
59–62.
1396. Institute of Medicine, Preterm birth:
Causes, consequences and preven-
tion. 2006, Washington, DC: National
Academic.
1397. Institute. CaLS, Methods for dilution
antimicrobial susceptibility testing.,
in 17th Informational supplement,
Institute. CaLS, Editor. 2007, Clinical

and Laboratory Standards Institute.:
PA, USA.
1398. International Agency for Reasearch
on Cancer (IARC). IARC classi-
fies formaldehyde as carcinogenic to
humans. Available from: http://www.
iarc.fr/en/Media-Centre/IARC-Press-
Releases/Archives-2006–2004/2004/
IARC-classifies-formaldehyde-as-
carcinogenic-to-humans.
1399. International AIDS Society. Available
from: www.iasociety.org.
1400. Inungu J, MaloneBeach E, and Betts
J, Male circumcision and the risk of
HIV infection. AIDS Read, 2005. 15(3):
130–1, 135, 138.
1401. Iosif CS and Bekassy Z, Prevalence
of genito-urinary symptoms in the
late menopause. Acta Obstet Gynecol
Scand, 1984. 63(3): 257–60.
1402. Ip WK and Lau YL, Role of mannose-
binding lectin in the innate defense
against Candida albicans: enhance-
ment of complement activation, but lack
of opsonic function, in phagocytosis by
human dendritic cells. J Infect Dis,
2004. 190(3): 632–40.
1403. Iravani A CP, Maladorno D. Fleroxacin
in the treatment of uncomplicated
urinary tract infections in women. in
7th European Congress of Clinical
Microbiology and Infectious Diseases
(ECCMID). 1995. Vienna, Austria.
1404. Iravani A, Klimberg I, Briefer C,
Munera C, Kowalsky SF, and Echols
RM, A trial comparing low-dose, short-
course ciprofloxacin and standard 7
day therapy with co-trimoxazole or
nitrofurantoin in the treatment of
uncomplicated urinary tract infection.
J Antimicrob Chemother, 1999. 43
Suppl A: 67–75.
1405. Iravani A, Multicenter study of single-
dose and multiple-dose fleroxacin ver-
sus ciprofloxacin in the treatment of
uncomplicated urinary tract infections.
Am J Med, 1993. 94(3A): 89S-96S.
1406. Iravani A, Tice AD, McCarty J, Sikes
DH, Nolen T, Gallis HA, Whalen EP,
Tosiello RL, Heyd A, Kowalsky SF, and
et al., Short-course ciprofloxacin treat-
ment of acute uncomplicated urinary
tract infection in women. The minimum
References
effective dose. The Urinary Tract
Infection Study Group [corrected]. Arch
Intern Med, 1995. 155(5): 485–94.
1407. Isen K, Kupeli B, Sinik Z, Sozen S,
and Bozkirli I, Antibiotic prophylaxis
for transrectal biopsy of the prostate:
a prospective randomized study of the
prophylactic use of single dose oral
fluoroquinolone versus trimethoprim-
sulfamethoxazole. Int Urol Nephrol,
1999. 31(4): 491–5.
1408. Iser P, Read TH, Tabrizi S, Bradshaw
C, Lee D, Horvarth L, Garland S,
Denham I, and Fairley CK, Symptoms
of non-gonococcal urethritis in hetero-
sexual men: a case control study. Sex
Transm Infect, 2005. 81(2): 163–5.
1409. Ishak K, Le Golvan P, and I E-S,
Malignant bladder tumours associated
with schistosomiasis, in Bilharziasis,
Mostofi F, Editor. 1959, Springer
Verlag: Berlin.
1410. Ishitoya S, Yamamoto S, Mitsumori K,
Ogawa O, and Terai A, Non-secretor
status is associated with female acute
uncomplicated pyelonephritis. BJU Int,
2002. 89(9): 851–4.
1411. Isiugo-Abanihe UC, Sociocultural
aspects of HIV/AIDS infection in
Nigeria. Afr J Med Med Sci, 2006. 35
Suppl: 45–55.
1412. Ismail A and Lupan DM, Utilization
of siderophores by Candida albicans.
Mycopathologia, 1986. 96(2): 109–13.
1413. Ison CA, Martin IM, Lowndes CM,
and Fenton KA, Comparability of
laboratory diagnosis and antimicro-
bial susceptibility testing of Neisseria
gonorrhoeae from reference laborato-
ries in Western Europe. J Antimicrob
Chemother, 2006. 58(3): 580–6.
1414. Ison MG, Adenovirus infections in
transplant recipients. Clin Infect Dis,
2006. 43(3): 331–9.
1415. Israele V, Darabi A, and McCracken
GH, Jr., The role of bacterial virulence
factors and Tamm-Horsfall protein in
the pathogenesis of Escherichia coli
urinary tract infection in infants. Am J
Dis Child, 1987. 141(11): 1230–4.
1416. Ito M, Deguchi T, Mizutani KS,
Yasuda M, Yokoi S, Ito S, Takahashi
Y, Ishihara S, Kawamura Y, and Ezaki
1065
References
T, Emergence and spread of Neisseria
gonorrhoeae clinical isolates harbor-
ing mosaic-like structure of penicillin-
binding protein 2 in Central Japan.
Antimicrob Agents Chemother, 2005.
49(1): 137–43.
1417. Itokazu GS, Quinn JP, Bell-Dixon
C, Kahan FM, and Weinstein RA,
Antimicrobial resistance rates among
aerobic gram-negative bacilli recovered
from patients in intensive care units:
evaluation of a national postmarketing
surveillance program. Clin Infect Dis,
1996. 23(4): 779–84.
1418. Iversen P, Madsen PO, and Corle DK,
Radical prostatectomy versus expectant
treatment for early carcinoma of the
prostate. Twenty-three year follow-up of
a prospective randomized study. Scand
J Urol Nephrol Suppl, 1995. 172:
65–72.
1419. Iwakiri J, Freiha FS, and Shortliffe
LM, Prospective study of urinary tract
infections and urinary antibodies after
radical prostatectomy and cystopros-
tatectomy. Urol Clin North Am, 2002.
29(1): 251–8, xii.
1420. Iwasaki A and Medzhitov R, Toll-like
receptor control of the adaptive immune
responses. Nat Immunol, 2004. 5(10):
987–95.
1421. Jackson SL, Boyko EJ, Scholes D,
Abraham L, Gupta K, and Fihn SD,
Predictors of urinary tract infection
after menopause: a prospective study.
Am J Med, 2004. 117(12): 903–11.
1422. Jacob JT, Nguyen TM, and Ray SM,
Male genital tuberculosis. Lancet Infect
Dis, 2008. 8(5): 335–42.
1423. Jacobs B, Whitworth J, Kambugu F,
and Pool R, Sexually transmitted dis-
ease management in Uganda’s private-
for-profit formal and informal sector
and compliance with treatment. Sex
Transm Dis, 2004. 31(11): 650–4.
1424. Jacobs LG, Fungal urinary tract infec-
tions in the elderly: treatment guide-
lines. Drugs Aging, 1996. 8(2): 89–96.
1425. Jacobs LG, Skidmore EA, Cardoso
LA, and Ziv F, Bladder irrigation with
amphotericin B for treatment of fungal
urinary tract infections. Clin Infect Dis,
1994. 18(3): 313–8.
1066
1426. Jacobs LG, Skidmore EA, Freeman K,
Lipschultz D, and Fox N, Oral fluco-
nazole compared with bladder irriga-
tion with amphotericin B for treatment
of fungal urinary tract infections in
elderly patients. Clin Infect Dis, 1996.
22(1): 30–5.
1427. Jacobson L and Westrom L,
Objectivized diagnosis of acute pelvic
inflammatory disease. Diagnostic and
prognostic value of routine laparoscopy.
Am J Obstet Gynecol, 1969. 105(7):
1088–98.
1428. Jacoby G and Bush K. Amino Acid
Sequences for TEM, SHV and OXA
Extended-Spectrum and Inhibitor
Resistant ß-Lactamases. Available
from: Lahey Clinic website. http://www.
lahey.org/Studies/.
1429. Jagger J, Hunt EH, Brand-Elnaggar J,
and Pearson RD, Rates of needlestick
injury caused by various devices in
a university hospital. N Engl J Med,
1988. 319: 284–8.
1430. Jahnukainen T, Honkinen O,
Ruuskanen O, and Mertsola J,
Ultrasonography after the first febrile
urinary tract infection in children. Eur
J Pediatr, 2006. 165(8): 556–9.
1431. Jakob SM, Prevention of acute renal
failure—fluid repletion and colloids. Int
J Artif Organs, 2004. 27(12): 1043–8.
1432. Jakobsson B and Svensson L, Transient
pyelonephritic changes on 99mTechne-
tium-dimercaptosuccinic acid scan for
at least five months after infection. Acta
Paediatr, 1997. 86(8): 803–7.
1433. Jakobsson B, Esbjorner E, and
Hansson S, Minimum incidence and
diagnostic rate of first urinary tract
infection. Pediatrics, 1999. 104(2 Pt 1):
222–6.
1434. Jakobsson B, Jacobson SH, and
Hjalmas K, Vesico-ureteric reflux and
other risk factors for renal damage:
identification of high- and low-risk
children. Acta Paediatr Suppl, 1999.
88(431): 31–9.
1435. Jakobsson B, Soderlundh S, and Berg
U, Diagnostic significance of 99mTc-
dimercaptosuccinic acid (DMSA) scin-
tigraphy in urinary tract infection. Arch
Dis Child, 1992. 67(11): 1338–42.

1436. James-Ellison MY, Roberts R, Verrier-
Jones K, Williams JD, and Topley N,
Mucosal immunity in the urinary tract:
changes in sIgA, FSC and total IgA
with age and in urinary tract infection.
Clin Nephrol, 1997. 48(2): 69–78.
1437. Jameson RM and Heal MR, The surgi-
cal management of acute renal papil-
lary necrosis. Br J Surg, 1973. 60(6):
428–30.
1438. Jantunen ME, Saxen H, Lukinmaa
S, Ala-Houhala M, and Siitonen A,
Genomic identity of pyelonephritogenic
Escherichia coli isolated from blood,
urine and faeces of children with urosep-
sis. J Med Microbiol, 2001. 50(7): 650–2.
1439. Jantunen ME, Siitonen A, Koskimies
O, Wikstrom S, Karkkainen U, Salo E,
and Saxen H, Predominance of class
II papG allele of Escherichia coli in
pyelonephritis in infants with normal
urinary tract anatomy. J Infect Dis,
2000. 181(5): 1822–4.
1440. Jardin A and Cesana M, Randomized,
double-blind comparison of single-dose
regimens of rufloxacin and pefloxacin
for acute uncomplicated cystitis in
women. French Multicenter Urinary
Tract Infection-Rufloxacin Group.
Antimicrob Agents Chemother, 1995.
39(1): 215–20.
1441. Jardin A, A general practitioner mul-
ticenter study: fosfomycin trometamol
single dose versus pipemidic acid mul-
tiple dose. Infection, 1990. 18 Suppl 2:
S89–93.
1442. Jarow JP, Risk factors for penile pros-
thetic infection. J Urol, 1996. 156(2 Pt
1): 402–4.
1443. Jaurin B and Grundstrom T, ampC
cephalosporinase of Escherichia coli
K-12 has a different evolutionary ori-
gin from that of beta-lactamases of the
penicillinase type. Proc Natl Acad Sci U
S A, 1981. 78(8): 4897–901.
1444. Javaid B and Quigg RJ, Treatment of
glomerulonephritis: will we ever have
options other than steroids and cytotox-
ics? Kidney Int, 2005. 67(5): 1692–703.
1445. Jayasuriya A, Robertson C, and Allan
PS, Twenty-five years of HIV man-
agement. J R Soc Med, 2007. 100(8):
363–6.
References
1446. Jeavons HS, Prevention and treatment
of vulvovaginal candidiasis using exog-
enous Lactobacillus. J Obstet Gynecol
Neonatal Nurs, 2003. 32(3): 287–96.
1447. Jelinek T, von Sonnenburg F, and
Nothdurft HD, [Epidemiology and clini-
cal aspects of imported schistosomiasis].
Med Klin (Munich), 1997. 92(1): 7–12.
1448. Jellheden B, Norrby RS, and Sandberg
T, Symptomatic urinary tract infec-
tion in women in primary health care.
Bacteriological, clinical and diagnostic
aspects in relation to host response to
infection. Scand J Prim Health Care,
1996. 14(2): 122–8.
1449. Jemni L, Mdimagh L, Jemni-Gharbi
H, Jemni M, Kraiem C, and Allegue M,
[Kidney carbuncle: diagnostic, bacterio-
logical and therapeutic considerations.
Apropos of 11 cases]. J Urol (Paris),
1992. 98(4): 228–31.
1450. Jeng DK and Severin JE, Povidone
iodine gel alcohol: a 30-second, onetime
application preoperative skin prepara-
tion. Am J Infect Control, 1998. 26(5):
488–94.
1451. Jenkin GA, Choo M, Hosking P, and
Johnson PD, Candidal epididymo-
orchitis: case report and review. Clin
Infect Dis, 1998. 26(4): 942–5.
1452. Jenkins PR, Jenkins RA, Nannis ED,
McKee KT, Jr., and Temoshok LR,
Reducing risk of sexually transmitted
disease (STD) and human immuno-
deficiency virus infection in a military
STD clinic: evaluation of a randomized
preventive intervention trial. Clin Infect
Dis, 2000. 30(4): 730–5.
1453. Jenks P, Brown J, Warnock D, and
Barnes N, Candida glabrata epidi-
dymo-orchitis: an unusual infection
rapidly cured with surgical and anti-
fungal treatment. J Infect, 1995. 31(1):
71–2.
1454. Jensen JS, Bjornelius E, Dohn B, and
Lidbrink P, Comparison of first void
urine and urogenital swab specimens
for detection of Mycoplasma genital-
ium and Chlamydia trachomatis by
polymerase chain reaction in patients
attending a sexually transmitted dis-
ease clinic. Sex Transm Dis, 2004.
31(8): 499–507.
1067
References
1455. Jensen JS, Bradshaw CS, Tabrizi
SN, Fairley CK, and Hamasuna R,
Azithromycin Treatment Failure in
Mycoplasma genitalium-Positive
Patients with Nongonococcal Urethritis
Is Associated with Induced Macrolide
Resistance. Clin Infect Dis, 2008.
1456. Jensen JS, Mycoplasma genitalium
infections. Dan Med Bull, 2006. 53(1):
1–27.
1457. Jepson R and Craig J, Cranberries for
preventing urinary tract infections.
Cochrane Database Syst Rev, 2008:
CD001321.
1458. Jepson R, Mihaljevic L, and Craig J,
Cranberries for preventing urinary
tract infections. Cochrane Database
Syst Rev, 2004. 23(1): CD001321.
1459. Jepson RG and Craig JC, Cranberries
for preventing urinary tract infections.
Cochrane Database Syst Rev, 2008(1):
CD001321.
1460. Jernberg E, Moghaddam A, and Moi
H, Azithromycin and moxifloxacin for
microbiological cure of Mycoplasma
genitalium infection: an open study. Int
J STD AIDS, 2008. 19(10): 676–9.
1461. Jernelius H, Zbornik J, and Bauer CA,
One or three weeks’ treatment of acute
pyelonephritis? A double-blind com-
parison, using a fixed combination of
pivampicillin plus pivmecillinam. Acta
Med Scand, 1988. 223(5): 469–77.
1462. Jerome KR and Corey L, The Danger
Within. N Engl J Med, 2004. 350:
411–2.
1463. Jevons MP, “Celbenin”-resistant staphy-
lococci. Br Med J, 1961. 1: 124–125.
1464. Jevons MP, Coe AW, and Parker MT,
Methicillin resistance in staphylococci.
Lancet, 1963. 1(7287): 904–7.
1465. Jewes LA, Gillespie WA, Leadbetter A,
Myers B, Simpson RA, Stower MJ, and
Viant AC, Bacteriuria and bacteraemia
in patients with long-term indwelling
catheters—a domiciliary study. J Med
Microbiol, 1988. 26(1): 61–5.
1466. Jewkes R, Dunkle K, Nduna M, Levin
J, Jama N, Khuzwayo N, Koss M,
Puren A, and Duvvury N, Factors
associated with HIV sero-positivity in
young, rural South African men. Int J
Epidemiol, 2006. 35(6): 1455–60.
1068
1467. Jick SS, Jick H, Walker AM, and
Hunter JR, Hospitalizations for pulmo-
nary reactions following nitrofurantoin
use. Chest, 1989. 96(3): 512–5.
1468. Jimenez Cruz JF, Sanz Chinesta S,
Otero G, Diaz Gonzalez R, Alvarez
Ruiz F, Flores N, Virseda J, Rioja
LA, Zuluaga A, Tallada M, and et al.,
[Antimicrobial prophylaxis in urethro-
cystoscopy. Comparative study]. Actas
Urol Esp, 1993. 17(3): 172–5.
1469. Jimenez MF and Marshall JC, Source
control in the management of sepsis.
Intensive Care Med, 2001. 27 Suppl 1:
S49–62.
1470. Jodal U and Hansson S, Urinary tract
infection, in Pediatric Nephrology,
Holliday MA, Barratt TM, and Avner
ED, Editors. 1994, Williams & Wilkins:
Baltimore. p. 950 – 962.
1471. Jodal U and Lindberg U, Guidelines
for management of children with uri-
nary tract infection and vesico-ureteric
reflux. Recommendations from a
Swedish state-of-the-art conference.
Swedish Medical Research Council.
Acta Paediatr Suppl, 1999. 88(431):
87–9.
1472. Jodal U, Koskimies O, Hanson E, Lohr
G, Olbing H, Smellie J, and Tamminen-
Mobius T, Infection pattern in children
with vesicoureteral reflux randomly
allocated to operation or long-term
antibacterial prophylaxis. The
International Reflux Study in Children.
J Urol, 1992. 148(5 Pt 2): 1650–2.
1473. Jodal U, Smellie JM, Lax H, and Hoyer
PF, Ten-year results of randomized
treatment of children with severe vesi-
coureteral reflux. Final report of the
International Reflux Study in Children.
Pediatr Nephrol, 2006. 21(6): 785–92.
1474. Johannisson G, Enstrom Y, Lowhagen
GB, Nagy V, Ryberg K, Seeberg S, and
Welinder-Olsson C, Occurrence and
treatment of Mycoplasma genitalium in
patients visiting STD clinics in Sweden.
Int J STD AIDS, 2000. 11(5): 324–6.
1475. Johansen TE, Cek M, Naber KG,
Stratchounski L, Svendsen MV, and
Tenke P, Hospital acquired urinary
tract infections in urology departments:
pathogens, susceptibility and use of

antibiotics. Data from the PEP and
PEAP-studies. Int J Antimicrob Agents,
2006. 28 Suppl 1: S91–107.
1476. Johansen TE, The role of imaging in
urinary tract infections. World J Urol,
2004. 22(5): 392–8.
1477. John U, Everding AS, Kuwertz-
Broking E, Bulla M, Muller-Wiefel DE,
Misselwitz J, and Kemper MJ, High
prevalence of febrile urinary tract infec-
tions after paediatric renal transplan-
tation. Nephrol Dial Transplant, 2006.
21(11): 3269–74.
1478. Johnson DE, Bahrani FK, Lockatell
CV, Drachenberg CB, Hebel JR, Belas
R, Warren JW, and Mobley HL, Serum
immunoglobulin response and protec-
tion from homologous challenge by
Proteus mirabilis in a mouse model of
ascending urinary tract infection. Infect
Immun, 1999. 67(12): 6683–7.
1479. Johnson DE, Russell RG, Lockatell CV,
Zulty JC, and Warren JW, Urethral
obstruction of 6 hours or less causes
bacteriuria, bacteremia, and pyelone-
phritis in mice challenged with “non-
uropathogenic” Escherichia coli. Infect
Immun, 1993. 61(8): 3422–8.
1480. Johnson JR, Clabots C, and Rosen
H, Effect of inactivation of the global
oxidative stress regulator oxyR on the
colonization ability of Escherichia coli
O1:K1:H7 in a mouse model of ascend-
ing urinary tract infection. Infect
Immun, 2006. 74(1): 461–8.
1481. Johnson JR, Jelacic S, Schoening LM,
Clabots C, Shaikh N, Mobley HL, and
Tarr PI, The IrgA homologue adhesin
Iha is an Escherichia coli virulence fac-
tor in murine urinary tract infection.
Infect Immun, 2005. 73(2): 965–71.
1482. Johnson JR, Kuskowski MA, Gajewski
A, Soto S, Horcajada JP, Jimenez de
Anta MT, and Vila J, Extended viru-
lence genotypes and phylogenetic back-
ground of Escherichia coli isolates from
patients with cystitis, pyelonephritis, or
prostatitis. J Infect Dis, 2005. 191(1):
46–50.
1483. Johnson JR, Lyons MF, 2nd, Pearce
W, Gorman P, Roberts PL, White N,
Brust P, Olsen R, Gnann JW, Jr.,
and Stamm WE, Therapy for women
References
hospitalized with acute pyelonephri-
tis: a randomized trial of ampicillin
versus trimethoprim-sulfamethoxazole
for 14 days. J Infect Dis, 1991. 163(2):
325–30.
1484. Johnson JR, O’Bryan TT, Delavari P,
Kuskowski M, Stapleton A, Carlino
U, and Russo TA, Clonal relation-
ships and extended virulence genotypes
among Escherichia coli isolates from
women with a first or recurrent episode
of cystitis. J Infect Dis, 2001. 183(10):
1508–17.
1485. Johnson JR, Roberts PL, Olsen RJ,
Moyer KA, and Stamm WE, Prevention
of catheter-associated urinary tract
infection with a silver oxide-coated
urinary catheter: clinical and micro-
biologic correlates. J Infect Dis, 1990.
162(5): 1145–50.
1486. Johnson JR, Weissman SJ, Stell AL,
Trintchina E, Dykhuizen DE, and
Sokurenko EV, Clonal and pathotypic
analysis of archetypal Escherichia
coli cystitis isolate NU14. J Infect Dis,
2001. 184(12): 1556–65.
1487. Johnson K and Way A, Risk factors for
HIV infection in a national adult popu-
lation: evidence from the 2003 Kenya
Demographic and Health Survey. J
Acquir Immune Defic Syndr, 2006.
42(5): 627–36.
1488. Johnson MI, Merrilees D, Robson
WA, Lennon T, Masters J, Orr KE,
Matthews JN, and Neal DE, Oral cip-
rofloxacin or trimethoprim reduces bac-
teriuria after flexible cystoscopy. BJU
Int, 2007. 100(4): 826–9.
1489. Joint United Nations Programme
on HIV/AIDS (UNAIDS) and World
Health Organization (WHO). 2008
Report on the global AIDS epidemic. [10
January 2009]; Available from: http://
www.unaids.org/en/KnowledgeCentre/
HIVData/GlobalReport/2008/2008_
Global_report.asp.
1490. Jombo GT, Egah DZ, Banwat EB, and
Ayeni JA, Nosocomial and community
acquired urinary tract infections at
a teaching hospital in north central
Nigeria: findings from a study of 12,458
urine samples. Niger J Med, 2006.
15(3): 230–6.
1069
References
1491. Jones R, Gazzard B, and Halima Y,
Preventing HIV infection. Bmj, 2005.
331(7528): 1285–6.
1492. Jones RN and Masterton R,
Determining the value of antimicrobial
surveillance programs. Diagn Microbiol
Infect Dis, 2001. 41(4): 171–5.
1493. Jones RN and Preston DA, The anti-
microbial activity of cephalexin against
old and new pathogens. Postgrad Med
J, 1983. 59 Suppl 5: 9–15.
1494. Jones RN, Kugler KC, Pfaller MA, and
Winokur PL, Characteristics of patho-
gens causing urinary tract infections
in hospitals in North America: results
from the SENTRY Antimicrobial
Surveillance Program, 1997. Diagn
Microbiol Infect Dis, 1999. 35(1):
55–63.
1495. Jones RN, Sader HS, and Fritsche TR,
Comparative activity of doripenem and
three other carbapenems tested against
Gram-negative bacilli with various
beta-lactamase resistance mechanisms.
Diagn Microbiol Infect Dis, 2005. 52(1):
71–4.
1496. Jones SM, Morgan M, Humphrey TJ,
and Lappin-Scott H, Effect of vancomy-
cin and rifampicin on meticillin-resist-
ant Staphylococcus aureus biofilms.
Lancet, 2001. 357(9249): 40–1.
1497. Jorgensen ET and Svensson A, The
treatment of phimosis in boys, with
a potent topical steroid (clobetasol
propionate 0.05%) cream. Acta Derm
Venereol, 1993. 73(1): 55–6.
1498. Josephson MA, Gillen D, Javaid
B, Kadambi P, Meehan S, Foster
P, Harland R, Thistlethwaite RJ,
Garfinkel M, Atwood W, Jordan J,
Sadhu M, Millis MJ, and Williams J,
Treatment of renal allograft polyoma
BK virus infection with leflunomide.
Transplantation, 2006. 81(5): 704–10.
1499. Joshi N, Caputo GM, Weitekamp
MR, and Karchmer AW, Infections in
patients with diabetes mellitus. N Engl
J Med, 1999. 341(25): 1906–12.
1500. Jung K, Meyer A, Lein M, Rudolph B,
Schnorr D, and Loening SA, Ratio of
free-to-total prostate specific antigen in
serum cannot distinguish patients with
prostate cancer from those with chronic
1070
inflammation of the prostate. J Urol,
1998. 159(5): 1595–8.
1501. Jurstrand M, Jensen JS, Magnuson
A, Kamwendo F, and Fredlund H,
A serological study of the role of
Mycoplasma genitalium in pelvic
inflammatory disease and ectopic
pregnancy. Sex Transm Infect, 2007.
83(4): 319–23.
1502. Justice SS, Hung C, Theriot JA,
Fletcher DA, Anderson GG, Footer MJ,
and Hultgren SJ, Differentiation and
developmental pathways of uropatho-
genic Escherichia coli in urinary tract
pathogenesis. Proc Natl Acad Sci U S A,
2004. 101(5): 1333–8.
1503. Justice SS, Hunstad DA, Seed PC,
and Hultgren SJ, Filamentation
by Escherichia coli subverts innate
defenses during urinary tract infec-
tion. Proc Natl Acad Sci U S A, 2006.
103(52): 19884–9.
1504. Juthani-Mehta M, Tinetti M, Perrelli
E, Towle V, and Quagliarello V, Role
of dipstick testing in the evaluation
of urinary tract infection in nursing
home residents. Infect Control Hosp
Epidemiol, 2007. 28(7): 889–91.
1505. K/DOQI clinical practice guidelines
for chronic kidney disease: evalua-
tion, classification, and stratification.
Am J Kidney Dis, 2002. 39(2 Suppl 1):
S1–266.
1506. Kabaalioglu A, Bahat E, and Boneval
C, Renal candidiasis in a 2-month-old
infant: treatment of fungus balls with
streptokinase. AJR Am J Roentgenol,
2001. 176(2): 511–2.
1507. Kabay SC, Yucel M, and Kabay S,
Acute effect of posterior tibial nerve
stimulation on neurogenic detrusor
overactivity in patients with multiple
sclerosis: urodynamic study. Urology,
2008. 71(4): 641–5.
1508. Kachar B, Liang F, Lins U, Ding M,
Wu XR, Stoffler D, Aebi U, and Sun TT,
Three-dimensional analysis of the 16
nm urothelial plaque particle: luminal
surface exposure, preferential head-to-
head interaction, and hinge formation.
J Mol Biol, 1999. 285(2): 595–608.
1509. Kadiri S, Ajayi SO, and Toki RA,
Quinolones for short-term treatment of

uncomplicated urinary tract infection.
East Afr Med J, 1999. 76(10): 587–9.
1510. Kadow C, Feneley RC, and Abrams
PH, Prostatectomy or conservative
management in the treatment of benign
prostatic hypertrophy? Br J Urol, 1988.
61(5): 432–4.
1511. Kaefer M, Hendren WH, Bauer SB,
Goldenblatt P, Peters CA, Atala A, and
Retik AB, Reservoir calculi: a compari-
son of reservoirs constructed from stom-
ach and other enteric segments. J Urol,
1998. 160(6 Pt 1): 2187–90.
1512. Kahlmeter G and Menday P, Cross-
resistance and associated resistance
in 2478 Escherichia coli isolates from
the Pan-European ECO.SENS Project
surveying the antimicrobial susceptibil-
ity of pathogens from uncomplicated
urinary tract infections. J Antimicrob
Chemother, 2003. 52(1): 128–31.
1513. Kahlmeter G, An international survey
of the antimicrobial susceptibility of
pathogens from uncomplicated urinary
tract infections: the ECO.SENS Project.
J Antimicrob Chemother, 2003. 51(1):
69–76.
1514. Kahlmeter G, Prevalence and antimi-
crobial susceptibility of pathogens in
uncomplicated cystitis in Europe. The
ECO.SENS study. Int J Antimicrob
Agents, 2003. 22 Suppl 2: 49–52.
1515. Kahlmeter G, The ECO*SENS Project:
a prospective, multinational, multicen-
tre epidemiological survey of the preva-
lence and antimicrobial susceptibility of
urinary tract pathogens-interim report.
J Antimicrob Chemother, 2000. 46
Suppl A: 15–22.
1516. Kahlmeter G, The ECO.SENS Project:
a prospective, multinational, multicen-
tre epidemiological survey of the preva-
lence and antimicrobial susceptibility
of urinary tract pathogens—interim
report. J Antimicrob Chemother, 2000.
46 Suppl 1: 15–22; discussion 63–5.
1517. Kahn JG, Marseille E, and Auvert B,
Cost-effectiveness of male circumcision
for HIV prevention in a South African
setting. PLoS Med, 2006. 3(12): e517.
1518. Kahn RH, Mosure DJ, Blank S, Kent
CK, Chow JM, Boudov MR, Brock J,
and Tulloch S, Chlamydia trachomatis
References
and Neisseria gonorrhoeae prevalence
and coinfection in adolescents entering
selected US juvenile detention cent-
ers, 1997–2002. Sex Transm Dis, 2005.
32(4): 255–9.
1519. Kaimal AJ, Zlatnik MG, Cheng YW,
Thiet MP, Connatty E, Creedy P, and
Caughey AB, Effect of a change in pol-
icy regarding the timing of prophylactic
antibiotics on the rate of postcesarean
delivery surgical-site infections. Am J
Obstet Gynecol, 2008. 199(3): 310 e1–5.
1520. Kaiser E and Fournier R,
[Emphysematous pyelonephritis: diag-
nosis and treatment]. Ann Urol (Paris),
2005. 39(2): 49–60.
1521. Kaitz AL and Hodder EW, Bacteriuria
and pyelonephritis of pregnancy. A pro-
spective study of 616 pregnant women.
N Engl J Med, 1961. 265: 667–72.
1522. Kajander EO and Ciftcioglu N,
Nanobacteria: an alternative mecha-
nism for pathogenic intra- and extracel-
lular calcification and stone formation.
Proc Natl Acad Sci U S A, 1998. 95(14):
8274–9.
1523. Kajander EO, Tahvanainen E, Kuronen
I, and Cíftçíoglu N, Comparison of
Staphylococci and novel bacteria-like
particles from blood. Zentralblatt
Bakteriol, 1994. Suppl(26): 147–9.
1524. Kajbafzadeh AM, Moosavi S, Tajik P,
Arshadi H, Payabvash S, Salmasi AH,
Akbari HR, and Nejat F, Intravesical
injection of botulinum toxin type A:
management of neuropathic bladder
and bowel dysfunction in children with
myelomeningocele. Urology, 2006. 68(5):
1091–6; discussion 1096–7.
1525. Kalaitzis C, Passadakis P,
Giannakopoulos S, Panagoutsos
S, Mpantis E, Triantafyllidis A,
Touloupidis S, and Vargemezis V,
Urological management of indinavir-
associated acute renal failure in HIV-
positive patients. Int Urol Nephrol,
2007. 39(3): 743–6.
1526. Kalambaheti K, Siliconized Foley cath-
eters. Am J Surg, 1965. 110(6): 935–6.
1527. Kalil AC, Levitsky J, Lyden E, Stoner
J, and Freifeld AG, Meta-analysis: the
efficacy of strategies to prevent organ
disease by cytomegalovirus in solid
1071
References
organ transplant recipients. Ann Intern
Med, 2005. 143(12): 870–80.
1528. Kallenius G, Mollby R, Svenson
SB, Winberg J, and Hultberg H,
Identification of a carbohydrate recep-
tor recognized by uropathogenic
Escherichia coli. Infection, 1980. 8
Suppl 3: 288–93.
1529. Kamali A, Quigley M, Nakiyingi
J, Kinsman J, Kengeya-Kayondo
J, Gopal R, Ojwiya A, Hughes P,
Carpenter LM, and Whitworth J,
Syndromic management of sexually-
transmitted infections and behaviour
change interventions on transmission
of HIV-1 in rural Uganda: a commu-
nity randomised trial. Lancet, 2003.
361(9358): 645–52.
1530. Kaminska W, Patzer J, and
Dzierzanowska D, Urinary tract infec-
tions caused by endemic multi-resistant
Enterobacter cloacae in a dialysis and
transplantation unit. J Hosp Infect,
2002. 51(3): 215–20.
1531. Kandirali E, Boran C, Serin E,
Semercioz A, and Metin A, Association
of extent and aggressiveness of inflam-
mation with serum PSA levels and
PSA density in asymptomatic patients.
Urology, 2007. 70(4): 743–7.
1532. Kane CJ, Bolton DM, Connolly JA, and
Tanagho EA, Voiding dysfunction in
human immunodeficiency virus infec-
tions. J Urol, 1996. 155(2): 523–6.
1533. Kaneko K, Ohtomo Y, Shimizu T,
Yamashiro Y, Yamataka A, and Miyano
T, Antibiotic prophylaxis by low-dose
cefaclor in children with vesicoureteral
reflux. Pediatr Nephrol, 2003. 18(5):
468–70.
1534. Kang CI, Kim SH, Park WB, Lee KD,
Kim HB, Kim EC, Oh MD, and Choe
KW, Bloodstream infections due to
extended-spectrum beta-lactamase-pro-
ducing Escherichia coli and Klebsiella
pneumoniae: risk factors for mortality
and treatment outcome, with special
emphasis on antimicrobial therapy.
Antimicrob Agents Chemother, 2004.
48(12): 4574–81.
1535. Kangarloo H, Gold RH, Fine RN,
Diament MJ, and Boechat MI, Urinary
tract infection in infants and children
1072
evaluated by ultrasound. Radiology,
1985. 154(2): 367–73.
1536. Kantele A, Mottonen T, Ala-Kaila K,
and Arvilommi HS, P fimbria-specific
B cell responses in patients with uri-
nary tract infection. J Infect Dis, 2003.
188(12): 1885–91.
1537. Kapiga SH, Sam NE, Mlay J, Aboud
S, Ballard RC, Shao JF, and Larsen U,
The epidemiology of HIV-1 infection in
northern Tanzania: results from a com-
munity-based study. AIDS Care, 2006.
18(4): 379–87.
1538. Kaplan MS, Wechsler M, and Benson
MC, Urologic manifestations of AIDS.
Urology, 1987. 30(5): 441–3.
1539. Kaplan W and Laing R, Priority
Medicines for Europe and the World “A
Public Health Approach to Innovation.”
2004, World Health Organisation:
Geneva.
1540. Kapoor DA, Klimberg IW, Malek GH,
Wegenke JD, Cox CE, Patterson AL,
Graham E, Echols RM, Whalen E, and
Kowalsky SF, Single-dose oral cipro-
floxacin versus placebo for prophylaxis
during transrectal prostate biopsy.
Urology, 1998. 52(4): 552–8.
1541. Karabekios S, Gouliamos A,
Kalovidouris A, Vlahos L, Papavasiliou
C, and Sakkas J, Features of computed
tomography in hydatid cysts of the uri-
nary tract. Br J Urol, 1989. 64(6): 575–8.
1542. Karam G, Maillet F, Parant S, Soulillou
JP, and Giral-Classe M, Ureteral necro-
sis after kidney transplantation: risk
factors and impact on graft and patient
survival. Transplantation, 2004. 78(5):
725–9.
1543. Karchmer TB, Giannetta ET, Muto CA,
Strain BA, and Farr BM, A randomized
crossover study of silver-coated urinary
catheters in hospitalized patients. Arch
Intern Med, 2000. 160(21): 3294–8.
1544. Karlowsky JA, Jones ME, Thornsberry
C, Critchley I, Kelly LJ, and Sahm DF,
Prevalence of antimicrobial resistance
among urinary tract pathogens isolated
from female outpatients across the US
in 1999. Int J Antimicrob Agents, 2001.
18(2): 121–7.
1545. Karlowsky JA, Kelly LJ, Thornsberry
C, Jones ME, and Sahm DF, Trends in

antimicrobial resistance among urinary
tract infection isolates of Escherichia
coli from female outpatients in the
United States. Antimicrob Agents
Chemother, 2002. 46(8): 2540–5.
1546. Karlowsky JA, Kelly LJ, Thornsberry
C, Jones ME, Evangelista AT, Critchley
IA, and Sahm DF, Susceptibility to
fluoroquinolones among commonly
isolated Gram-negative bacilli in 2000:
TRUST and TSN data for the United
States. Tracking Resistance in the
United States Today. The Surveillance
Network. Int J Antimicrob Agents,
2002. 19(1): 21–31.
1547. Karmazyn B, Steinberg R, Kornreich
L, Freud E, Grozovski S, Schwarz M,
Ziv N, and Livne P, Clinical and sono-
graphic criteria of acute scrotum in chil-
dren: a retrospective study of 172 boys.
Pediatr Radiol, 2005. 35(3): 302–10.
1548. Karmouni T, Bensalah K, Alva A,
Patard JJ, Lobel B, and Guille F, [Role
of antibiotic prophylaxis in ambula-
tory cystoscopy]. Prog Urol, 2001. 11(6):
1239–41.
1549. Karou SD, Ilboudo IP, Nadembega WM,
Ameyapoh Y, Ouermi D, Pignatelli S,
Pietra V, Traore AS, de Souza C, and
Simpore J, Antibiotic resistance in uri-
nary tract bacteria in Ouagadougou.
Pak J Biol Sci, 2009. 12(9): 712–6.
1550. Karr JF, Nowicki BJ, Truong LD, Hull
RA, Moulds JJ, and Hull SI, pap-2-
encoded fimbriae adhere to the P blood
group-related glycosphingolipid stage-
specific embryonic antigen 4 in the
human kidney. Infect Immun, 1990.
58(12): 4055–62.
1551. Kartal ED, Yenilmez A, Kiremitci
A, Meric H, Kale M, and Usluer G,
Effectiveness of ciprofloxacin prophy-
laxis in preventing bacteriuria caused
by urodynamic study: a blind, rand-
omized study of 192 patients. Urology,
2006. 67(6): 1149–53.
1552. Kasanen A, Sundquist H, Elo J, Anttila
M, and Kangas L, Secondary preven-
tion of urinary tract infections. The role
of trimethoprim alone. Ann Clin Res,
1983. 15(Suppl 36): 1–36.
1553. Kashanian J, Hakimian P, Blute M,
Jr., Wong J, Khanna H, Wise G, and
References
Shabsigh R, Nitrofurantoin: the return
of an old friend in the wake of grow-
ing resistance. BJU Int, 2008. 102(11):
1634–7.
1554. Kashuba AD, Nafziger AN, Drusano
GL, and Bertino JSJ, Optimizing
aminoglycoside therapy for nosoco-
mial pneumonia caused by gram-
negative bacteria. Antimicrob Agents
Chemother, 1999. 43: 623–629.
1555. Kasiakou SK, Lawrence KR, Choulis
N, and Falagas ME, Continuous versus
intermittent intravenous administra-
tion of antibacterials with time-de-
pendent action: a systematic review
of pharmacokinetic and pharmacody-
namic parameters. Drugs, 2005. 65(17):
2499–511.
1556. Kass EH and Finland M, Asymptomatic
infections of the urinary tract. J Urol,
2002. 168(2): 420–4.
1557. Kass EH, Asymptomatic infections
of the urinary tract. Trans Assoc Am
Physicians, 1956. 69: 56–64.
1558. Kass EH, Bacteriuria and pyelone-
phritis of pregnancy. Arch Intern Med,
1960. 105: 194–8.
1559. Kass EH, Chemotherapeutic and anti-
biotic drugs in the management of
infections of the urinary tract. Am J
Med, 1955. 18(5): 764–81.
1560. Kass EH, Pyelonephritis and bacteriu-
ria. A major problem in preventive med-
icine. Ann Intern Med, 1962. 56: 46–53.
1561. Kass EJ, Fink-Bennett D, Cacciarelli
AA, Balon H, and Pavlock S, The sensi-
tivity of renal scintigraphy and sonog-
raphy in detecting nonobstructive acute
pyelonephritis. J Urol, 1992. 148(2 Pt
2): 606–8.
1562. Kass EJ, Imaging in acute pyelonephri-
tis. Curr Opin Urol, 1994. 4(1): 39–44.
1563. Kass EJ, Kernen KM, and Carey JM,
Paediatric urinary tract infection and
the necessity of complete urological
imaging. BJU Int, 2000. 86(1): 94–6.
1564. Katchman EA, Milo G, Paul M,
Christiaens T, Baerheim A, and Leibovici
L, Three-day vs longer duration of anti-
biotic treatment for cystitis in women:
systematic review and meta-analysis. Am
J Med, 2005. 118(11): 1196–207.
1073
References
1565. Katz BP, Blythe MJ, Van der Pol B,
and Jones RB, Declining prevalence of
chlamydial infection among adolescent
girls. Sex Transm Dis, 1996. 23(3):
226–9.
1566. Katz IT and Wright AA,
Circumcision—a surgical strategy for
HIV prevention in Africa. N Engl J
Med, 2008. 359(23): 2412–5.
1567. Kauffman CA, Candiduria. Clin Infect
Dis, 2005. 41 Suppl 6: S371–6.
1568. Kauffman CA, Vazquez JA, Sobel JD,
Gallis HA, McKinsey DS, Karchmer
AW, Sugar AM, Sharkey PK, Wise
GJ, Mangi R, Mosher A, Lee JY, and
Dismukes WE, Prospective multicenter
surveillance study of funguria in hospi-
talized patients. The National Institute
for Allergy and Infectious Diseases
(NIAID) Mycoses Study Group. Clin
Infect Dis, 2000. 30(1): 14–8.
1569. Kaul R, Pettengell C, Sheth PM,
Sunderji S, Biringer A, MacDonald K,
Walmsley S, and Rebbapragada A, The
genital tract immune milieu: an impor-
tant determinant of HIV susceptibility
and secondary transmission. J Reprod
Immunol, 2008. 77(1): 32–40.
1570. Kavatha D, Giamarellou H, Alexiou Z,
Vlachogiannis N, Pentea S, Gozadinos
T, Poulakou G, Hatzipapas A, and
Koratzanis G, Cefpodoxime-proxetil
versus trimethoprim-sulfamethoxazole
for short-term therapy of uncomplicated
acute cystitis in women. Antimicrob
Agents Chemother, 2003. 47(3): 897–900.
1571. Kawashima A and LeRoy AJ,
Radiologic evaluation of patients with
renal infections. Infect Dis Clin North
Am, 2003. 17(2): 433–56.
1572. Kaya K, Gokce G, Kaya S, Kilicarslan
H, Ayan S, and Gultekin EY, Isolated
renal and retroperitoneal hydatid cysts:
a report of 23 cases. Trop Doct, 2006.
36(4): 243–6.
1573. Kayabas U, Bayraktar M, Otlu
B, Ugras M, Ersoy Y, Bayindir
Y, and Durmaz R, An outbreak of
Pseudomonas aeruginosa because of
inadequate disinfection procedures in a
urology unit: a pulsed-field gel electro-
phoresis-based epidemiologic study. Am
J Infect Control, 2008. 36(1): 33–8.
1074
1574. Keegan KA, Nanigian DK, and Stone
AR, Female urethral stricture disease.
Curr Urol Rep, 2008. 9(5): 419–23.
1575. Keenan C, Prevention of neonatal
group B streptococcal infection. Am
Fam Physician, 1998. 57(11): 2713–20,
2725.
1576. Kellum JA and J MD, Use of dopamine
in acute renal failure: a meta-analysis.
Crit Care Med, 2001. 29(8): 1526–31.
1577. Kelly R, Kiwanuka N, Wawer MJ,
Serwadda D, Sewankambo NK,
Wabwire-Mangen F, Li C, Konde-Lule
JK, Lutalo T, Makumbi F, and Gray
RH, Age of male circumcision and risk
of prevalent HIV infection in rural
Uganda. Aids, 1999. 13(3): 399–405.
1578. Kennelly MJ and Oesterling JE,
Conservative management of a seminal
vesicle abscess. J Urol, 1989. 141(6):
1432–3.
1579. Keren R and Chan E, A meta-analysis of
randomized, controlled trials comparing
short- and long-course antibiotic therapy
for urinary tract infections in children.
Pediatrics, 2002. 109(5): E70–0.
1580. Keren R, Carpenter MA, Hoberman
A, Shaikh N, Matoo TK, Chesney RW,
Matthews R, Gerson AC, Greenfield SP,
Fivush B, McLurie GA, Rushton HG,
Canning D, Nelson CP, Greenbaum L,
Bukowski T, Primack W, Sutherland
R, Hosking J, Stewart D, Elder
J, Moxey-Mims M, and Nyberg L,
Rationale and design issues of the
Randomized Intervention for Children
With Vesicoureteral Reflux (RIVUR)
study. Pediatrics, 2008. 122 Suppl 5:
S240–50.
1581. Keren R, Imaging and treatment strate-
gies for children after first urinary tract
infection. Curr Opin Pediatr, 2007.
19(6): 705–10.
1582. Kerschbaum HH, Singh SK, and
Hermann A, Lymphoid tissue in the
kidney of the musk shrew, Suncus
murinus. Tissue Cell, 1995. 27(4):
421–4.
1583. Khafagy MM, el-Bolkainy MN, and
Mansour MA, Carcinoma of the bil-
harzial urinary bladder. A study of the
associated mucosal lesions in 86 cases.
Cancer, 1972. 30(1): 150–9.

1584. Khaki P, Bhalla P, Sharma A, and
Kumar V, Correlation between In vitro
susceptibility and treatment outcome
with azithromycin in gonorrhoea: a pro-
spective study. Indian J Med Microbiol,
2007. 25(4): 354–7.
1585. Khalaf I and Koritim M, Genitourinary
Schistosomiasis, in Textbook of Tropical
Surgery Kamel R and Lumley J,
Editors. 2004, Westminster Publishing
Ltd. p. 673–80.
1586. Khalaf IM, Giant urinary calculi in
relation to urinary bilharziasis. 1970,
Cairo University, Egypt.
1587. Khalturin K, Becker M, Rinkevich B,
and Bosch TC, Urochordates and the
origin of natural killer cells: identifica-
tion of a CD94/NKR-P1-related recep-
tor in blood cells of Botryllus. Proc Natl
Acad Sci U S A, 2003. 100(2): 622–7.
1588. Khameneh ZR and Afshar AT,
Antimicrobial susceptibility pattern
of urinary tract pathogens. Saudi J
Kidney Dis Transpl, 2009. 20(2): 251–3.
1589. Khen-Dunlop N, Van Egroo A,
Bouteiller C, Biserte J, and Besson R,
Biofeedback therapy in the treatment
of bladder overactivity, vesico-ureteral
reflux and urinary tract infection. J
Pediatr Urol, 2006. 2(5): 424–9.
1590. Khosroshahi HT, Mogaddam AN,
and Shoja MM, Efficacy of high-dose
trimethoprim-sulfamethoxazol prophy-
laxis on early urinary tract infection
after renal transplantation. Transplant
Proc, 2006. 38(7): 2062–4.
1591. Khoury AE, Dave S, Peralta-Del Valle
MH, Braga LH, Lorenzo AJ, and Bagli
D, Severe bladder trabeculation obvi-
ates the need for bladder outlet proce-
dures during augmentation cystoplasty
in incontinent patients with neurogenic
bladder. BJU Int, 2008. 101(2): 223–6.
1592. Kibar Y, Ors O, Demir E, Kalman S,
Sakallioglu O, and Dayanc M, Results
of biofeedback treatment on reflux reso-
lution rates in children with dysfunc-
tional voiding and vesicoureteral reflux.
Urology, 2007. 70(3): 563–6; discussion
566–7.
1593. Kicovic PM, Cortes-Prieto J, Milojevic
S, Haspels AA, and Aljinovic A, The
treatment of postmenopausal vaginal
References
atrophy with Ovestin vaginal cream or
suppositories: clinical, endocrinological
and safety aspects. Maturitas, 1980.
2(4): 275–82.
1594. Kiddoo DA, Wollin TA, and Mador DR,
A population based assessment of com-
plications following outpatient hydroce-
lectomy and spermatocelectomy. J Urol,
2004. 171(2 Pt 1): 746–8.
1595. Kiernan SC, Pinckert TL, and Keszler
M, Ultrasound guidance of suprapu-
bic bladder aspiration in neonates. J
Pediatr, 1993. 123(5): 789–91.
1596. Kikuchi T, Hagiwara K, Honda Y,
Gomi K, Kobayashi T, Takahashi H,
Tokue Y, Watanabe A, and Nukiwa T,
Clarithromycin suppresses lipopolysac-
charide-induced interleukin-8 produc-
tion by human monocytes through AP-1
and NF-kappa B transcription factors.
J Antimicrob Chemother, 2002. 49(5):
745–55.
1597. Kim B, Lim HK, Choi MH, Woo JY,
Ryu J, Kim S, and Peck KR, Detection
of parenchymal abnormalities in acute
pyelonephritis by pulse inversion har-
monic imaging with or without micro-
bubble ultrasonographic contrast agent:
correlation with computed tomography.
J Ultrasound Med, 2001. 20(1): 5–14.
1598. Kim FY and Goldstein M, Antibacterial
skin preparation decreases the inci-
dence of false-positive semen culture
results. J Urol, 1999. 161(3): 819–21.
1599. Kim HH, Lee KS, Park K, and Ahn H,
Laparoscopic nephrectomy for nonfunc-
tioning tuberculous kidney. J Endourol,
2000. 14(5): 433–7.
1600. Kim JH, Rivas DA, Shenot PJ, Green
B, Kennelly M, Erickson JR, O’Leary
M, Yoshimura N, and Chancellor
MB, Intravesical resiniferatoxin for
refractory detrusor hyperreflexia: a
multicenter, blinded, randomized,
placebo-controlled trial. J Spinal Cord
Med, 2003. 26(4): 358–63.
1601. Kincaid-Smith PS, Bastos MG, and
Becker GJ, Reflux nephropathy in
the adult. Contrib Nephrol, 1984. 39:
94–101.
1602. King CH, Keating CE, Muruka JF,
Ouma JH, Houser H, Siongok TK, and
Mahmoud AA, Urinary tract morbidity
1075
References
in schistosomiasis haematobia: associa-
tions with age and intensity of infection
in an endemic area of Coast Province,
Kenya. Am J Trop Med Hyg, 1988.
39(4): 361–8.
1603. Kirjavainen PK, Laine RM, Carter D,
Hammond J-A, and Reid G, Expression
of anti-microbial defense factors in
vaginal mucosa following exposure to
Lactobacillus rhamnosus GR-1. Int J
Probiotics, 2008. 3: 99–106.
1604. Kirkland KB, Briggs JP, Trivette SL,
Wilkinson WE, and Sexton DJ, The
impact of surgical-site infections in the
1990s: attributable mortality, excess
length of hospitalization, and extra
costs. Infect Control Hosp Epidemiol,
1999. 20(11): 725–30.
1605. Kiss H, Petricevic L, and Husslein P,
Prospective randomised controlled trial
of an infection screening programme
to reduce the rate of preterm delivery.
BMJ, 2004. 329(7462): 371.
1606. Kiwamoto T, Endo T, and Sekizawa K,
[A case of septic pulmonary embolism
induced by urinary tract infection].
Nihon Kokyuki Gakkai Zasshi, 2004.
42(1): 89–93.
1607. Kizirgil A, Demirdag K, Ozden M,
Bulut Y, Yakupogullari Y, and Toraman
ZA, In vitro activity of three differ-
ent antimicrobial agents against
ESBL producing Escherichia coli and
Klebsiella pneumoniae blood isolates.
Microbiol Res, 2005. 160(2): 135–40.
1608. Klar A, Hurvitz H, Berkun Y, Nadjari
M, Blinder G, Israeli T, Halamish A,
Katz A, Shazberg G, and Branski D,
Focal bacterial nephritis (lobar neph-
ronia) in children. J Pediatr, 1996.
128(6): 850–3.
1609. Klausner HA, Brown P, Peterson J,
Kaul S, Khashab M, Fisher AC, and
Kahn JB, A trial of levofloxacin 750
mg once daily for 5 days versus cipro-
floxacin 400 mg and/or 500 mg twice
daily for 10 days in the treatment of
acute pyelonephritis. Curr Med Res
Opin, 2007. 23(11): 2637–45.
1610. Klavs I and Hamers FF, Male cir-
cumcision in Slovenia: results from a
national probability sample survey. Sex
Transm Infect, 2008. 84(1): 49–50.
1076
1611. Klebe JG, Espersen T, and Allen J,
Diabetes mellitus and pregnancy. A
seven-year material of pregnant diabet-
ics, where control during pregnancy
was based on a centralized ambulant
regime. Acta Obstet Gynecol Scand,
1986. 65(3): 235–40.
1612. Klein FA, Smith MJ, and Vick CW,
Emphysematous pyelonephritis: diag-
nosis and treatment. South Med J,
1986. 79: 41–46.
1613. Kleinman PK, Diamond DA, Karellas
A, Spevak MR, Nimkin K, and
Belanger P, Tailored low-dose fluoro-
scopic voiding cystourethrography for
the reevaluation of vesicoureteral reflux
in girls. AJR Am J Roentgenol, 1994.
162(5): 1151–4; discussion 1155–6.
1614. Klemm P, Roos V, Ulett GC, Svanborg
C, and Schembri MA, Molecular
characterization of the Escherichia
coli asymptomatic bacteriuria strain
83972: the taming of a pathogen. Infect
Immun, 2006. 74(1): 781–5.
1615. Klemm P, Roos V, Ulett GC, Svanborg
C, and Schembri MA, Molecular
Characterization of the Escherichia
coli 83972 Asymptomatic Bacteriuria
Strain: the Taming of a Pathogen.
Infection and Immunity, 2006. Jan:
781–785.
1616. Klevens RM, Edwards JR, Tenover FC,
McDonald LC, Horan T, and Gaynes R,
Changes in the epidemiology of methi-
cillin-resistant Staphylococcus aureus
in intensive care units in US hospitals,
1992–2003. Clin Infect Dis, 2006. 42(3):
389–91.
1617. Kliebe C, Nies BA, Meyer JF, Tolxdorff-
Neutzling RM, and Wiedemann B,
Evolution of plasmid-coded resistance
to broad-spectrum cephalosporins.
Antimicrob Agents Chemother, 1985.
28(2): 302–7.
1618. Klumpp DJ, Rycyk MT, Chen
MC, Thumbikat P, Sengupta S,
and Schaeffer AJ, Uropathogenic
Escherichia coli induces extrinsic and
intrinsic cascades to initiate urothelial
apoptosis. Infect Immun, 2006. 74(9):
5106–13.
1619. Klumpp DJ, Weiser AC, Sengupta S,
Forrestal SG, Batler RA, and Schaeffer

AJ, Uropathogenic Escherichia coli
potentiates type 1 pilus-induced apop-
tosis by suppressing NF-kappaB. Infect
Immun, 2001. 69(11): 6689–95.
1620. Klumpp DJ, Wieser AC, Sengupta S,
Forrestal SG, Batler RA, and Schaeffer
AJ, Uropathogenic E. coli potentiate
type 1 pili-induced apoptosis by sup-
pressing NFkB. Infect Immun, 2001.
69: 6689–6695.
1621. Knaus WA, Sun X, Nystrom O, and
Wagner DP, Evaluation of defini-
tions for sepsis. Chest, 1992. 101(6):
1656–62.
1622. Knipper A, Bohle A, Pensel J, and
Hofstetter AG, [Antibiotic prophylaxis
with enoxacin in extracorporeal shock-
wave lithotripsy]. Infection, 1989. 17
Suppl 1: S37–8.
1623. Knochel JQ, Koehler PR, Lee TG, and
Welch DM, Diagnosis of abdominal
abscesses with computed tomography,
ultrasound, and 111In leukocyte scans.
Radiology, 1980. 137(2): 425–32.
1624. Knoll LD, Penile prosthetic infection:
management by delayed and immedi-
ate salvage techniques. Urology, 1998.
52(2): 287–90.
1625. Knopf HJ, Graff HJ, and Schulze H,
Perioperative antibiotic prophylaxis in
ureteroscopic stone removal. Eur Urol,
2003. 44(1): 115–8.
1626. Knothe H, Schafer V, Sammann A, and
Shah PM, Influence of fosfomycin on
the intestinal and pharyngeal flora of
man. Infection, 1991. 19(1): 18–20.
1627. Knothe H, Shah P, Krcmery V, Antal M,
and Mitsuhashi S, Transferable resist-
ance to cefotaxime, cefoxitin, cefaman-
dole and cefuroxime in clinical isolates
of Klebsiella pneumoniae and Serratia
marcescens. Infection, 1983. 11(6):
315–7.
1628. Ko TL, Li YT, Chu YC, Chen TH, Chen
CS, Chen FM, and Kuo TC, An uncom-
mon case of pelvic and abdominal wall
mass: presumed pelvic actinomycosis.
Taiwan J Obstet Gynecol, 2007. 46(3):
299–303.
1629. Kobashi K, Hase J, and Uehara
K, Specific inhibition of urease by
hydroxamic acids. Biochim Biophys
Acta, 1962. 65: 380–3.
References
1630. Kobashi K, Kumaki K, and Hase JI,
Effect of acyl residues of hydroxamic
acids on urease inhibition. Biochim
Biophys Acta, 1971. 227(2): 429–41.
1631. Kobashi K, Takebe S, and Numata
A, Specific inhibition of urease
by N-acylphosphoric triamides. J
Biochem, 1985. 98(6): 1681–8.
1632. Kobayashi CC, de Fernandes OF,
Miranda KC, de Sousa ED, and
Silva Mdo R, Candiduria in hos-
pital patients: a study prospective.
Mycopathologia, 2004. 158(1): 49–52.
1633. Koch VH and Zuccolotto SM, [Urinary
tract infection: a search for evidence].
J Pediatr (Rio J), 2003. 79 Suppl 1:
S97–106.
1634. Koff SA and Murtagh DS, The uninhib-
ited bladder in children: effect of treat-
ment on recurrence of urinary infection
and on vesicoureteral reflux resolution.
J Urol, 1983. 130(6): 1138–41.
1635. Koff SA, Wagner TT, and Jayanthi
VR, The relationship among dysfunc-
tional elimination syndromes, primary
vesicoureteral reflux and urinary tract
infections in children. J Urol, 1998.
160(3 Pt 2): 1019–22.
1636. Kohl KS, Sternberg MR, Markowitz
LE, Blythe MJ, Kissinger P, Lafferty
WE, Groseclose SL, and Levine WC,
Screening of males for Chlamydia tra-
chomatis and Neisseria gonorrhoeae
infections at STD clinics in three US
cities — Indianapolis, New Orleans,
Seattle. Int J STD AIDS, 2004. 15(12):
822–8.
1637. Kohnen PW and Drach GW, Patterns of
inflammation in prostatic hyperplasia:
a histologic and bacteriologic study. J
Urol, 1979. 121(6): 755–60.
1638. Kojima M, Masuda K, Yada Y, Hayase
Y, Muratani T, and Matsumoto T,
Single-dose treatment of male patients
with gonococcal urethritis using 2g
spectinomycin: microbiological and
clinical evaluations. Int J Antimicrob
Agents, 2008. 32(1): 50–4.
1639. Koldowsky H, Kariger U, and Mendling
W, Herstellung eines autologen mem-
brangebundenen Candida-Antigens
und in-vitro-Untersuchungen zu
seinen immunologischen Reaktionen,
1077
References
in Candida-Infektionen des weibli-
chen Genitaltraktes, Metzner G and
Weissenbacher ER, Editors. 1999,
Medifact: München. p. 25–32.
1640. Kollef MH and Ward S, The influence of
mini-BAL cultures on patient outcomes:
implications for the antibiotic manage-
ment of ventilator-associated pneumo-
nia. Chest, 1998. 113(2): 412–20.
1641. Kondo T, Okuda H, Suzuki M,
Okumura T, and Toma H, [A case
of emphysematous pyelonephritis
improved with conservative therapy—
indication for conservative therapy].
Hinyokika Kiyo, 2000. 46(5): 335–8.
1642. Konig JE, Senge T, Allhoff EP, and
Konig W, Analysis of the inflammatory
network in benign prostate hyperplasia
and prostate cancer. Prostate, 2004.
58(2): 121–9.
1643. Kontiokari T, Sundqvist K, Nuutinen
M, Pokka T, Koskela M, and Uhari
M, Randomised trial of cranberry-
lingonberry juice and Lactobacillus
GG drink for the prevention of urinary
tract infections in women. BMJ, 2001.
322(7302): 1571.
1644. Kontiokari T, Sundqvist K, Nuutinen
M, Pokla T, Koskela M, and Uhari
M, Randomised trial of Cranberry-
lingonberry juice and Lactobacillus
GG drink for the prevention of urinary
tract infection in women. BMJ, 2001.
322(7302): 1751–3.
1645. Koraitim M and al-Ghorab M, The
diagnosis of bilharzial bladder neck
obstruction: evaluation of criteria in
140 cases. J Urol, 1972. 107(3): 381–3.
1646. Korkes F, Favoretto RL, Broglio M,
Silva CA, Castro MG, and Perez MD,
Xanthogranulomatous pyelonephri-
tis: clinical experience with 41 cases.
Urology, 2008. 71(2): 178–80.
1647. Korn AP, Hessol NA, Padian NS, Bolan
GA, Donegan E, Landers DV, and
Schachter J, Risk factors for plasma
cell endometritis among women with
cervical Neisseria gonorrhoeae, cervical
Chlamydia trachomatis, or bacterial
vaginosis. Am J Obstet Gynecol, 1998.
178(5): 987–90.
1648. Korniewicz DM, Laughon BE, Butz A,
and Larson E, Integrity of vinyl and
1078
latex procedure gloves. Nurs Res, 1989.
38(3): 144–6.
1649. Korvick JA, Bryan CS, Farber B,
Beam TR, Jr., Schenfeld L, Muder RR,
Weinbaum D, Lumish R, Gerding DN,
Wagener MM, and et al., Prospective
observational study of Klebsiella bac-
teremia in 230 patients: outcome for
antibiotic combinations versus mono-
therapy. Antimicrob Agents Chemother,
1992. 36(12): 2639–44.
1650. Koschinski A, Repp H, Unver B, Dreyer
F, Brockmeier D, Valeva A, Bhakdi
S, and Walev I, Why Escherichia coli
alpha-hemolysin induces calcium oscil-
lations in mammalian cells – the pore is
on its own. Faseb J, 2006. 20(7): 973–5.
1651. Koseoglu RD, Erdemir F, Parlaktas
BS, Filiz NO, Uluocak N, and Etikan
I, Effect of chronic prostatitis on ang-
iogenic activity and serum prostate
specific antigen level in benign prostatic
hyperplasia. Kaohsiung J Med Sci,
2007. 23(8): 387–94.
1652. Kostiala AA and Ranta T, Pelvic
inflammatory disease caused by
Salmonella panama and its treatment
with ciprofloxacin. Case report. Br J
Obstet Gynaecol, 1989. 96(1): 120–2.
1653. Kotoula A, Gardikis S, Tsalkidis
A, Mantadakis E, Zissimopoulos A,
Kambouri K, Deftereos S, Tripsianis G,
Manolas K, Chatzimichael A, and Vaos
G, Procalcitonin for the early predic-
tion of renal parenchymal involvement
in children with UTI: preliminary
results. Int Urol Nephrol, 2009. 41(2):
393–9.
1654. Kotton CN and Fishman JA, Viral
infection in the renal transplant recipi-
ent. J Am Soc Nephrol, 2005. 16(6):
1758–74.
1655. Koulaouzidis A, Bhat S, Moschos J, Tan
C, and De Ramon A, Nitrofurantoin-
induced lung- and hepatotoxicity. Ann
Hepatol, 2007. 6(2): 119–21.
1656. Kouokam JC, Wai SN, Fällman M,
Dobrindt U, Hacker J, and Uhlin BE,
Active cytotoxic necrotizing factor 1
associated with outer membrane vesi-
cles from uropathogenic Escherichia
coli. Infect Immun, 2006. 74(4):
2022–30.

1657. Kowalczyk JJ, Spicer DL, and Mulcahy
JJ, Long-term experience with the
double-cuff AMS 800 artificial urinary
sphincter. Urology, 1996. 47(6): 895–7.
1658. Kraft JK and Stamey TA, The natural
history of symptomatic recurrent bacte-
riuria in women. Medicine (Baltimore),
1977. 56(1): 55–60.
1659. Kramer A, Sausville J, Haririan A,
Bartlett S, Cooper M, and Phelan
M, Simultaneous bilateral native
nephrectomy and living donor renal
transplantation are successful for poly-
cystic kidney disease: the University
of Maryland experience. J Urol, 2009.
181(2): 724–8.
1660. Kramer G and Marberger M, Could
inflammation be a key component in the
progression of benign prostatic hyper-
plasia? Curr Opin Urol, 2006. 16(1):
25–9.
1661. Kramer G, Mitteregger D, and
Marberger M, Is benign prostatic
hyperplasia (BPH) an immune inflam-
matory disease? Eur Urol, 2007. 51(5):
1202–16.
1662. Kramer G, Steiner GE, Handisurya
A, Stix U, Haitel A, Knerer B, Gessl
A, Lee C, and Marberger M, Increased
expression of lymphocyte-derived
cytokines in benign hyperplastic pros-
tate tissue, identification of the produc-
ing cell types, and effect of differentially
expressed cytokines on stromal cell pro-
liferation. Prostate, 2002. 52(1): 43–58.
1663. Kramer SA, Rathbun SR, Elkins D,
Karnes RJ, and Husmann DA, Double-
blind placebo controlled study of
alpha-adrenergic receptor antagonists
(doxazosin) for treatment of voiding
dysfunction in the pediatric population.
J Urol, 2005. 173(6): 2121–4; discus-
sion 2124.
1664. Krantz I, Lowhagen GB, Ahlberg BM,
and Nilstun T, Ethics of screening for
asymptomatic herpes virus type 2 infec-
tion. BMJ, 2004. 329(7466): 618–21.
1665. Kravchick S, Cytron S, Agulansky L,
and Ben-Dor D, Acute prostatitis in
middle-aged men: a prospective study.
BJU Int, 2004. 93(1): 93–6.
1666. Krcmery S, Dubrava M, and Krcmery
V, Jr., Fungal urinary tract infections
References
in patients at risk. Int J Antimicrob
Agents, 1999. 11(3–4): 289–91.
1667. Kreger BE, Craven DE, and McCabe
WR, Gram-negative bacteremia. IV.
Re-evaluation of clinical features and
treatment in 612 patients. Am J Med,
1980. 68(3): 344–55.
1668. Kreger BE, Craven DE, Carling PC,
and McCabe WR, Gram-negative
bacteremia. III. Reassessment of eti-
ology, epidemiology and ecology in
612 patients. Am J Med, 1980. 68(3):
332–43.
1669. Kreymann KG, de Heer G, Nierhaus A,
and Kluge S, Use of polyclonal immu-
noglobulins as adjunctive therapy for
sepsis or septic shock. Crit Care Med,
2007. 35(12): 2677–85.
1670. Krieger JN and McGonagle LA,
Diagnostic considerations and interpre-
tation of microbiological findings for
evaluation of chronic prostatitis. J Clin
Microbiol, 1989. 27(10): 2240–4.
1671. Krieger JN, Bailey RC, Opeya J, Ayieko
B, Opiyo F, Agot K, Parker C, Ndinya-
Achola JO, Magoha GA, and Moses
S, Adult male circumcision: results of
a standardized procedure in Kisumu
District, Kenya. BJU Int, 2005. 96(7):
1109–13.
1672. Krieger JN, Bailey RC, Opeya JC,
Ayieko BO, Opiyo FA, Omondi D, Agot
K, Parker C, Ndinya-Achola JO, and
Moses S, Adult male circumcision out-
comes: experience in a developing coun-
try setting. Urol Int, 2007. 78(3): 235–40.
1673. Krieger JN, Kaiser DL, and Wenzel RP,
Urinary tract etiology of bloodstream
infections in hospitalized patients. J
Infect Dis, 1983. 148(1): 57–62.
1674. Krieger JN, Nyberg L, Jr., and Nickel
JC, NIH consensus definition and clas-
sification of prostatitis. JAMA, 1999.
282(3): 236–7.
1675. Krieger JN, Ross SO, and Simonsen
JM, Urinary tract infections in healthy
university men. J Urol, 1993. 149(5):
1046–8.
1676. Kronner KM, Casale AJ, Cain MP,
Zerin MJ, Keating MA, and Rink RC,
Bladder calculi in the pediatric aug-
mented bladder. J Urol, 1998. 160(3 Pt
2): 1096–8; discussion 1103.
1079
References
1677. Krzeski T, Witeska A, Borowka A, and
Pypno W, Diverticula of renal calyces.
Int Urol Nephrol, 1981. 13(3): 231–5.
1678. Ku JH, Kim YH, Jeon YS, and Lee NK,
The preventive effect of systemic treat-
ment with interferon-alpha2B for infer-
tility from mumps orchitis. BJU Int,
1999. 84(7): 839–42.
1679. Kubanova A, Frigo N, Kubanov A,
Sidorenko S, Priputnevich T, Vachnina
T, Al-Khafaji N, Polevshikova S,
Solomka V, Domeika M, and Unemo
M, National surveillance of antimi-
crobial susceptibility in Neisseria
gonorrhoeae in 2005–2006 and recom-
mendations of first-line antimicro-
bial drugs for gonorrhoea treatment
in Russia. Sex Transm Infect, 2008.
84(4): 285–9.
1680. Kuehn MJ and Kesty NC, Bacterial
outer membrane vesicles and the host-
pathogen interaction. Genes Dev, 2005.
19(22): 2645–55.
1681. Kuehnert MJ, Hill HA, Kupronis
BA, Tokars JI, Solomon SL, and
Jernigan DB, Methicillin-resistant-
Staphylococcus aureus hospitalizations,
United States. Emerg Infect Dis, 2005.
11(6): 868–72.
1682. Kul’chavenia EV and Muzyko LV, [Two
cases of tuberculosis after transplanta-
tion of the kidney]. Urologiia, 2007(6):
80–2.
1683. Kul’chavenia EV, [Ex juvantibus
therapy in the differential diagnosis of
urogenital tuberculosis]. Probl Tuberk,
2001(2): 29–31.
1684. Kul’chavenia EV, [Extrapulmonary
tuberculosis control in Siberia and the
Far East]. Probl Tuberk Bolezn Legk,
2008(9): 16–9.
1685. Kul’chavenia EV, [Low-intensity laser
irradiation in the treatment of patients
with tuberculosis of the urinary sys-
tem]. Probl Tuberk, 2002(6): 39–41.
1686. Kul’chavenia EV, [Polychemotherapy
combined with low-intensity laser
therapy in treating patients with renal
tuberculosis]. Urologiia, 2002(2): 34–7.
1687. Kul’chavenia EV, Khomiakov VT, and
Zhukova, II, [Male genital tuberculosis
in West Siberia]. Urologiia, 2004(4):
34–7.
1080
1688. Kulchavenya E, Filimonov P, and
Shvetsova O, An Atlas of a Urogenital
tuberculosis and other extrapulmo-
nary localizations (monograph). 2007:
Novosibirsk: «Tirazh-Sibir».
1689. Kulchavenya E, Tuberculosis of uro-
genital system in Urology: National
Manual Lopatkin N, Editor. 2009,
Geotar-Media: Moscow. p. p.584–601.
1690. Kumagai T, Tamai, S, Abe, T, Hikida,
M, Current status of oral carbapenem
development. Current Medicinal
Chemistry – Anti-Infective Agents,
2002. 1: 1–14.
1691. Kumamoto CA and Vinces MD,
Contributions of hyphae and hypha-co-
regulated genes to Candida albicans
virulence. Cell Microbiol, 2005. 7(11):
1546–54.
1692. Kumar A, Roberts D, Wood KE, Light
B, Parrillo JE, Sharma S, Suppes R,
Feinstein D, Zanotti S, Taiberg L,
Gurka D, and Cheang M, Duration of
hypotension before initiation of effec-
tive antimicrobial therapy is the critical
determinant of survival in human sep-
tic shock. Crit Care Med, 2006. 34(6):
1589–96.
1693. Kumar PV, Owji SM, and Khezri AA,
Tuberculous orchitis diagnosed by fine
needle aspiration cytology. Acta Cytol,
1996. 40(6): 1253–6.
1694. Kumon H, Management of biofilm
infections in the urinary tract. World J
Surg, 2000. 24(10): 1193–6.
1695. Kumon H, Pathogenesis and manage-
ment of bacterial biofilms in the uri-
nary tract. J Infect Chemother, 1996. 2:
18–28.
1696. Kunin CM, Bacteriuria, pyuria, pro-
teinuria, hematuria, and pneumaturia,
in Urinary tract infections: detection,
prevention, and management, Kunin
CM, Editor. 1997, Williams & Wilkins:
Baltimore; London. p. ix, 419p.
1697. Kunin CM, Chin QF, and Chambers S,
Formation of encrustations on indwell-
ing urinary catheters in the elderly: a
comparison of different types of catheter
materials in “blockers” and “nonblock-
ers”. J Urol, 1987. 138(4): 899–902.
1698. Kunin CM, Chin QF, and Chambers
S, Morbidity and mortality associated

with indwelling urinary catheters in
elderly patients in a nursing home—
confounding due to the presence of asso-
ciated diseases. J Am Geriatr Soc, 1987.
35(11): 1001–6.
1699. Kunin CM, Detection, prevention and
management of UTIs. 5th ed. 1997,
Philadephia, PA, USA: Lea & Febiger.
1700. Kunin CM, Deutscher R, and Paquin
A, Jr., URINARY TRACT INFECTION
IN SCHOOL CHILDREN: AN
EPIDEMIOLOGIC, CLINICAL AND
LABORATORY STUDY. Medicine
(Baltimore), 1964. 43: 91–130.
1701. Kunin CM, Does kidney infection cause
renal failure? Annu Rev Med, 1985. 36:
165–76.
1702. Kunin CM, Douthitt S, Dancing J,
Anderson J, and Moeschberger M, The
association between the use of urinary
catheters and morbidity and mortal-
ity among elderly patients in nursing
homes. Am J Epidemiol, 1992. 135(3):
291–301.
1703. Kunin CM, Evans C, Bartholomew
D, and Bates DG, The antimicrobial
defense mechanism of the female ure-
thra: a reassessment. J Urol, 2002.
168(2): 413–9.
1704. Kunin CM, Guidelines for the evalua-
tion of new anti-infective drugs for the
treatment of urinary tract infection:
additional considerations. Clin Infect
Dis, 1992. 15(6): 1041–4.
1705. Kunin CM, Kunin CMDp, and man-
agement of urinary tract i, Urinary
tract infections: detection, preven-
tion, and management. 5th ed. ed.
1997, Baltimore; London: Williams &
Wilkins. ix, 419p.
1706. Kunin CM, Urinary Tract Infections.
Detection, Prevention and Management.
5th ed. 1997, Baltimore: Williams and
Wilkins.
1707. Kunin CM, White LV, and Hua TH, A
reassessment of the importance of “low-
count” bacteriuria in young women
with acute urinary symptoms. Ann
Intern Med, 1993. 119(6): 454–60.
1708. Kunishima Y, Takeyama K, Takahashi
S, Matsukawa M, Koroku M, Tanda
H, Tanaka T, Hirose T, Iwasawa A,
Nishimura M, Takeda K, Suzuki N,
References
Horita H, Yokoo A, and Tsukamoto
T, Gatifloxacin treatment for chronic
prostatitis: a prospective multicenter
clinical trial. J Infect Chemother, 2008.
14(2): 137–40.
1709. Kunzelmann V, Tietz HJ, Roßner D,
Czaika V, Hopp M, Schmalreck A, and
Sterry W, Voraussetzungen für eine
effektive Therapie chronisch rezidi-
vierender Vaginalkandidosen. Mycoses,
1996. 39(Suppl 1): 65–72.
1710. Kuo BI, Fung CP, and Liu CY,
Meropenem versus imipenem/cilastatin
in the treatment of sepsis in Chinese
patients. Zhonghua Yi Xue Za Zhi
(Taipei), 2000. 63(5): 361–7.
1711. Kuo YT, Chen MT, Liu GC, Huang
CN, Huang CL, and Huang CH,
Emphysematous pyelonephritis: imag-
ing diagnosis and follow-up. Kaohsiung
J Med Sci, 1999. 15(3): 159–70.
1712. Kuroda M, Yamashita A, Hirakawa H,
Kumano M, Morikawa K, Higashide
M, Maruyama A, Inose Y, Matoba
K, Toh H, Kuhara S, Hattori M, and
Ohta T, Whole genome sequence of
Staphylococcus saprophyticus reveals
the pathogenesis of uncomplicated uri-
nary tract infection. Proc Natl Acad Sci
U S A, 2005. 102(37): 13272–7.
1713. Kurup A, Chlebicki MP, Ling ML, Koh
TH, Tan KY, Lee LC, and Howe KB,
Control of a hospital-wide vancomycin-
resistant Enterococci outbreak. Am J
Infect Control, 2008. 36(3): 206–11.
1714. Kurzer E and Kaplan S, Cost effective-
ness model comparing trimethoprim
sulfamethoxazole and ciprofloxacin
for the treatment of chronic bacterial
prostatitis. Eur Urol, 2002. 42(2):
163–6.
1715. Kutzenberger J, Domurath B, and
Sauerwein D, Spastic bladder and spi-
nal cord injury: seventeen years of expe-
rience with sacral deafferentation and
implantation of an anterior root stimu-
lator. Artif Organs, 2005. 29(3): 239–41.
1716. Kwak C, Oh SJ, Lee A, and Choi H,
Effect of circumcision on urinary tract
infection after successful antireflux sur-
gery. BJU Int, 2004. 94(4): 627–9.
1717. Kwan DJ and Lowe FC, Acquired
immunodeficiency syndrome. A venereal
1081
References
disease. Urol Clin North Am, 1992.
19(1): 13–24.
1718. Kwok L, Stapleton AE, Stamm WE,
Hillier SL, Wobbe CL, and Gupta K,
Adherence of Lactobacillus crispatus
to vaginal epithelial cells from women
with or without a history of recurrent
urinary tract infection. J Urol, 2006.
176(5): 2050–4; discussion 2054.
1719. Laboratory Service in Programmes
on Fight with Tuberculosis. Culture
Investigation: World Health
Organization/TB, 2008. 258: 48.
1720. Lackner J, Schatzl G, Horvath S,
Kratzik C, and Marberger M, Value of
counting white blood cells (WBC) in
semen samples to predict the presence of
bacteria. Eur Urol, 2006. 49(1): 148–52;
discussion 152–3.
1721. Ladhani S and Gransden W, Increasing
antibiotic resistance among urinary
tract isolates. Arch Dis Child, 2003.
88(5): 444–5.
1722. Laga M, Manoka A, Kivuvu M, Malele
B, Tuliza M, Nzila N, Goeman J,
Behets F, Batter V, Alary M, and et al.,
Non-ulcerative sexually transmitted
diseases as risk factors for HIV-1 trans-
mission in women: results from a cohort
study. AIDS, 1993. 7(1): 95–102.
1723. Lagrotteria D, Rotstein C, and Lee CH,
Treatment of candiduria with micafun-
gin: A case series. Can J Infect Dis Med
Microbiol, 2007. 18(2): 149–50.
1724. (Läkemedelsverket) SMPA,
Guidelines for treatment of uncom-
plicated female UTI (Swedish title:
Behandlingsrekommendationer
vid nedre okomplicerad UVI).
Läkemedelsverket, 2007. 18(2): 8–15.
1725. Lallemand F, Salhi Y, Linard F, Giami A,
and Rozenbaum W, Sexual dysfunction
in 156 ambulatory HIV-infected men
receiving highly active antiretroviral
therapy combinations with and without
protease inhibitors. J Acquir Immune
Defic Syndr, 2002. 30(2): 187–90.
1726. Lamba H, Goldmeier D, Mackie NE,
and Scullard G, Antiretroviral therapy
is associated with sexual dysfunction
and with increased serum oestradiol
levels in men. Int J STD AIDS, 2004.
15(4): 234–7.
1082
1727. Land MH, Rouster-Stevens K, Woods
CR, Cannon ML, Cnota J, and Shetty
AK, Lactobacillus sepsis associated
with probiotic therapy. Pediatrics,
2005. 115(1): 178–81.
1728. Landau D, Turner ME, Brennan J, and
Majd M, The value of urinalysis in dif-
ferentiating acute pyelonephritis from
lower urinary tract infection in febrile
infants. Pediatr Infect Dis J, 1994.
13(9): 777–81.
1729. Lande RE, Health care providers can
prevent and treat PID. Indian Med
Trib, 1994: 11.
1730. Landovitz RJ, Recent efforts in biomed-
ical prevention of HIV. Top HIV Med,
2007. 15(3): 99–103.
1731. Lane MC and Mobley HL, Role of
P-fimbrial-mediated adherence in
pyelonephritis and persistence of
uropathogenic Escherichia coli (UPEC)
in the mammalian kidney. Kidney Int,
2007. 72(1): 19–25.
1732. Lane MC, Alteri CJ, Smith SN, and
Mobley HL, Expression of flagella
is coincident with uropathogenic
Escherichia coli ascension to the upper
urinary tract. Proc Natl Acad Sci U S A,
2007. 104(42): 16669–74.
1733. Lane MC, Lockatell V, Monterosso
G, Lamphier D, Weinert J, Hebel JR,
Johnson DE, and Mobley HL, Role of
motility in the colonization of uropatho-
genic Escherichia coli in the urinary
tract. Infect Immun, 2005. 73(11):
7644–56.
1734. Lane MC, Simms AN, and Mobley
HL, Complex interplay between type
1 fimbrial expression and flagellum-
mediated motility of uropathogenic
Escherichia coli. J Bacteriol, 2007.
189(15): 5523–33.
1735. Langermann S, Mollby R, Burlein
JE, Palaszynski SR, Auguste CG,
DeFusco A, Strouse R, Schenerman
MA, Hultgren SJ, Pinkner JS,
Winberg J, Guldevall L, Soderhall M,
Ishikawa K, Normark S, and Koenig
S, Vaccination with FimH adhesin
protects cynomolgus monkeys from
colonization and infection by uropath-
ogenic Escherichia coli. J Infect Dis,
2000. 181(2): 774–8.

1736. Lansang MC, Ma L, Schold JD, Meier-
Kriesche HU, and Kaplan B, The
relationship between diabetes and infec-
tious hospitalizations in renal trans-
plant recipients. Diabetes Care, 2006.
29(7): 1659–60.
1737. Lapides J, Diokno AC, Silber SJ, and
Lowe BS, Clean, intermittent self cath-
eterisation in the treatment of urinary
tract disease. J Urol, 1972. 108(1):
79–81.
1738. Larcombe J, Urinary tract infection
in children. BMJ, 1999. 319(7218):
1173–5.
1739. Larson EL, APIC guideline for hand-
washing and hand antisepsis in health
care settings. Am J Infect Control,
1995. 23(4): 251–69.
1740. Larsson P, Norming U, Tornblom M,
and Gustafsson O, Antibiotic prophy-
laxis for prostate biopsy: benefits and
costs. Prostate Cancer Prostatic Dis,
1999. 2(2): 88–90.
1741. Larsson PG, Fahraeus L, Carlsson B,
Jakobsson T, and Forsum U, Late mis-
carriage and preterm birth after treat-
ment with clindamycin: a randomised
consent design study according to
Zelen. BJOG, 2006. 113(6): 629–37.
1742. Larsson PG, Platz-Christensen JJ,
Thejls H, Forsum U, and Pahlson C,
Incidence of pelvic inflammatory dis-
ease after first-trimester legal abortion
in women with bacterial vaginosis after
treatment with metronidazole: a double-
blind, randomized study. Am J Obstet
Gynecol, 1992. 166(1 Pt 1): 100–3.
1743. Latthe PM, Foon R, and Toozs-Hobson
P, Prophylactic antibiotics in urody-
namics: a systematic review of effective-
ness and safety. Neurourol Urodyn,
2008. 27(3): 167–73.
1744. Lattif AA, Prasad R, Banerjee U, Gupta
N, Mohammad S, and Baquer NZ, The
glyoxylate cycle enzyme activities in the
pathogenic isolates of Candida albicans
obtained from HIV/AIDS, diabetic and
burn patients. Mycoses, 2006. 49(2):
85–90.
1745. Lau CS and Sant GR, Urethritis,
Prostatitis, Epididymitis, and Orchitis,
in Infectious diseases, Gorbach SL,
Bartlett JG, and Blacklow NR, Editors.
References
2004, Lippincott Williams & Wilkins:
Philadelphia; London. p. xxix, 2515 p.,
[2] p. of plates.
1746. Lau CY and Qureshi AK, Azithromycin
versus doxycycline for genital chlamy-
dial infections: a meta-analysis of rand-
omized clinical trials. Sex Transm Dis,
2002. 29(9): 497–502.
1747. Laufman H, The operating room, in
Hospital infections, Bennett JV and
Brachman PS, Editors. 1986, Little,
Brown: Boston. p. 315–23.
1748. Laughton JM, Devillard E, Heinrichs
DE, Reid G, and McCormick JK,
Inhibition of expression of a staphyloco-
ccal superantigen-like protein by a solu-
ble factor from Lactobacillus reuteri.
Microbiology, 2006. 152(Pt 4): 1155–67.
1749. Laupland KB, Zygun DA, Davies HD,
Church DL, Louie TJ, and Doig CJ,
Incidence and risk factors for acquir-
ing nosocomial urinary tract infection
in the critically ill. J Crit Care, 2002.
17(1): 50–7.
1750. Lautenbach E, Weiner MG, Nachamkin
I, Bilker WB, Sheridan A, and Fishman
NO, Imipenem resistance among pseu-
domonas aeruginosa isolates: risk
factors for infection and impact of
resistance on clinical and economic out-
comes. Infect Control Hosp Epidemiol,
2006. 27(9): 893–900.
1751. Lauzier F, Levy B, Lamarre P, and
Lesur O, Vasopressin or norepinephrine
in early hyperdynamic septic shock: a
randomized clinical trial. Intensive
Care Med, 2006. 32(11): 1782–9.
1752. Lavigne J, Bourg G, Combescure C,
Botto H, and Sotto A, In-vitro and
in-vivo evidence of dose-dependent
decrease of uropathogenic Escherichia
coli virulence after consumption of
commercial Vaccinium macrocarpon
(Cranberry) capsules. Clin Microbiol
Infect, 2008. 14(4): 350–5.
1753. Lawrence JR and Caldwell DE,
Behaviour of bacterial stream popu-
lations within the hydrodynamic
boundary layers of surface microen-
vironments. Microbial Ecol, 1987. 14:
15–27.
1754. Lawrenson RA and Logie JW,
Antibiotic failure in the treatment
1083
References
of urinary tract infections in young
women. J Antimicrob Chemother, 2001.
48(6): 895–901.
1755. Lawrentschuk N, Ooi J, Pang A, Naidu
KS, and Bolton DM, Cystoscopy in
women with recurrent urinary tract
infection. Int J Urol, 2006. 13(4):
350–3.
1756. Lazar JD and Hilligoss DM, The clini-
cal pharmacology of fluconazole. Semin
Oncol, 1990. 17(3 Suppl 6): 14–8.
1757. Lazzeri M, Spinelli M, Zanollo A, and
Turini D, Intravesical vanilloids and
neurogenic incontinence: ten years expe-
rience. Urol Int, 2004. 72(2): 145–9.
1758. Le J, Briggs GG, McKeown A, and
Bustillo G, Urinary tract infections
during pregnancy. Ann Pharmacother,
2004. 38(10): 1692–701.
1759. Le Lin B, Pastore R, Liassine N,
Aramburu C, and Sudre P, A new
sexually transmitted infection (STI)
in Geneva? Ciprofloxacin-resistant
Neisseria gonorrhoeae, 2002–2005.
Swiss Med Wkly, 2008. 138(15–16):
243–6.
1760. Le Saux N, Pham B, and Moher D,
Evaluating the benefits of antimicrobial
prophylaxis to prevent urinary tract
infections in children: a systematic
review. CMAJ, 2000. 163(5): 523–9.
1761. Leach GE and Bavendam TG, Female
urethral diverticula. Urology, 1987.
30(5): 407–15.
1762. Leach GE, Schmidbauer CP, Hadley
HR, Staskin DR, Zimmern P, and Raz
S, Surgical treatment of female ure-
thral diverticulum. Semin Urol, 1986.
4(1): 33–42.
1763. Leblanc MM, When to refer an
infertile mare to a theriogenologist.
Theriogenology, 2008. 70(3): 421–9.
1764. Leblebicioglu H and Esen S, Hospital-
acquired urinary tract infections in
Turkey: a nationwide multicenter point
prevalence study. J Hosp Infect, 2003.
53(3): 207–10.
1765. Lecomte F, Allaert, FA., Le traitement
monodose de la cystite par fosfomycin
trometamol. Analyse de 15 essais com-
paratifs portant sur 2048 malades.
Médecine et Maladies infectieuses,
1996. 26: 338–343.
1084
1766. Lecomte F, Allaert, FA., Single-dose
treatment of cystitis with fosfomycin
trometamol (Monuril): Analysis of 15
comparative trials on 2.048 patients.
Giorn. It. Ost. Gin., 1997. 19: 399–404.
1767. Ledger WJ, Polaseczky MM, Yih MC,
Jeremias J, Tolbert V, and Witkin SS,
Difficulties in the diagnosis of candida
vaginitis. Inf Dis Clin Bact, 2000. 9:
66–69.
1768. Ledger WJ, Prophylactic antibiotics in
obstetrics-gynecology: a current asset, a
future liability? Expert Rev Anti Infect
Ther, 2006. 4(6): 957–64.
1769. Lee BB, Haran MJ, Hunt LM,
Simpson JM, Marial O, Rutkowski SB,
Middleton JW, Kotsiou G, Tudehope M,
and Cameron ID, Spinal-injured neu-
ropathic bladder antisepsis (SINBA)
trial. Spinal Cord, 2007. 45(8): 542–50.
1770. Lee BB, Simpson JM, Craig JC, and
Bhuta T, Methenamine hippurate for
preventing urinary tract infections.
Cochrane Database Syst Rev, 2007(4):
CD003265.
1771. Lee BE, Seol HY, Kim TK, Seong EY,
Song SH, Lee DW, Lee SB, and Kwak
IS, Recent clinical overview of renal
and perirenal abscesses in 56 consecu-
tive cases. Korean J Intern Med, 2008.
23(3): 140–8.
1772. Lee CC, Chen SY, Chang IJ, Chen SC,
and Wu SC, Comparison of clinical
manifestations and outcome of commu-
nity-acquired bloodstream infections
among the oldest old, elderly, and adult
patients. Medicine (Baltimore), 2007.
86(3): 138–44.
1773. Lee JH, Choi HS, Kim JK, Won HS,
Kim KS, Moon DH, Cho KS, and Park
YS, Nonrefluxing neonatal hydroneph-
rosis and the risk of urinary tract infec-
tion. J Urol, 2008. 179(4): 1524–8.
1774. Lee JH, Son CH, Lee MS, and Park
YS, Vesicoureteral reflux increases the
risk of renal scars: a study of unilateral
reflux. Pediatr Nephrol, 2006. 21(9):
1281–4.
1775. Lee JW, Cho SJ, Park EA, and Lee
SJ, Topical hydrocortisone and physi-
otherapy for nonretractile physiologic
phimosis in infants. Pediatr Nephrol,
2006. 21(8): 1127–30.

1776. Lee LK, Dinneen MD, and Ahmad S,
The urologist and the patient infected
with human immunodeficiency virus or
with acquired immunodeficiency syn-
drome. BJU Int, 2001. 88(6): 500–10.
1777. Lee NC, Rubin GL, and Grimes DA,
Measures of sexual behavior and the
risk of pelvic inflammatory disease.
Obstet Gynecol, 1991. 77(3): 425–30.
1778. Lee SE, Romero R, Kim EC, and Yoon
BH, A high Nugent score but not a posi-
tive culture for genital mycoplasmas is
a risk factor for spontaneous preterm
birth. J Matern Fetal Neonatal Med,
2009. 22(3): 212–7.
1779. Lee SH, Vigliotti VS, and Pappu
S, DNA sequencing validation of
Chlamydia trachomatis and Neisseria
gonorrhoeae nucleic acid tests. Am J
Clin Pathol, 2008. 129(6): 852–9.
1780. Lee SJ, Cho YH, Ha US, Kim SW, Yoon
MS, and Bae K, Sexual behavior survey
and screening for chlamydia and gon-
orrhea in university students in South
Korea. Int J Urol, 2005. 12(2): 187–93.
1781. Lee SJ, Kim SW, Cho YH, and Yoon
MS, Anti-inflammatory effect of an
Escherichia coli extract in a mouse
model of lipopolysaccharide-induced
cystitis. World J Urol, 2006. 24(1): 33–8.
1782. Lee SJ, Kim SW, Cho YH, Shin WS,
Lee SE, Kim CS, Hong SJ, Chung BH,
Kim JJ, and Yoon MS, A comparative
multicentre study on the incidence of
catheter-associated urinary tract infec-
tion between nitrofurazone-coated and
silicone catheters. Int J Antimicrob
Agents, 2004. 24 Suppl 1: S65–9.
1783. Lee SJ, Shim YH, Cho SJ, and Lee JW,
Probiotics prophylaxis in children with
persistent primary vesicoureteral reflux.
Pediatr Nephrol, 2007. 22(9): 1315–20.
1784. Lee SR, Chung JM, and Kim YG,
Rapid one step detection of patho-
genic bacteria in urine with sexually
transmitted disease (STD) and pros-
tatitis patient by multiplex PCR assay
(mPCR). J Microbiol, 2007. 45(5):
453–9.
1785. Lee YS, Han CH, Kang SH, Lee SJ,
Kim SW, Shin OR, Sim YC, Lee SJ,
and Cho YH, Synergistic effect between
catechin and ciprofloxacin on chronic
References
bacterial prostatitis rat model. Int J
Urol, 2005. 12(4): 383–9.
1786. Leffler H and Svanborg-Edén C,
Chemical identification of a glycosphin-
golipid receptor for Escherichia coli
attaching to human urinary tract epi-
thelial cells and agglutinating human
erythrocytes. FEMS Microbiol Lett,
1980. 8: 127–134.
1787. Legrand F, Berrebi D, Houhou N,
Freymuth F, Faye A, Duval M,
Mougenot JF, Peuchmaur M, and
Vilmer E, Early diagnosis of adenovi-
rus infection and treatment with cidofo-
vir after bone marrow transplantation
in children. Bone Marrow Transplant,
2001. 27(6): 621–6.
1788. Leigh AP, Nemeth MA, Keyserling CH,
Hotary LH, and Tack KJ, Cefdinir ver-
sus cefaclor in the treatment of uncom-
plicated urinary tract infection. Clin
Ther, 2000. 22(7): 818–25.
1789. Leiper R, Report on the results of the
Bilharzias mission in Egypt, 1915. Part
V: Adults and ova. J Roy Army Med
Corps, 1915. 30: 235.
1790. Lemonnier M, Landraud L, and
Lemichez E, Rho GTPase-activating bac-
terial toxins: from bacterial virulence reg-
ulation to eukaryotic cell biology. FEMS
Microbiol Rev, 2007. 31(5): 515–34.
1791. Lenaghan D, Cass AS, Cussen LJ, and
Stephens FD, Long-term effect of vesi-
coureteral reflux on the upper urinary
tract of dogs. 1. Without urinary infec-
tion. J Urol, 1972. 107(5): 755–7.
1792. Lendvay TS, Sorensen M, Cowan CA,
Joyner BD, Mitchell MM, and Grady
RW, The evolution of vesicoureteral
reflux management in the era of dex-
tranomer/hyaluronic acid copolymer:
a pediatric health information system
database study. J Urol, 2006. 176(4 Pt
2): 1864–7.
1793. Lenk S and Schroeder J, Genitourinary
tuberculosis. Curr Opin Urol, 2001. 11:
93–96.
1794. Lenk S, Detection of mycobacterica in
specimens of genitourinary tract. J Urol
Urogynäkologie, 2000. 7: 7–13.
1795. Lenk S, Epidemiology of genitourinary
tuberculosis in Germany. Eur Urol,
2004. Suppl 3(2): 206.
1085
References
1796. Lenke RR, VanDorsten JP, and Schifrin
BS, Pyelonephritis in pregnancy: a
prospective randomized trial to pre-
vent recurrent disease evaluating sup-
pressive therapy with nitrofurantoin
and close surveillance. Am J Obstet
Gynecol, 1983. 146(8): 953–7.
1797. Leon CG, Tory R, Jia J, Sivak O, and
Wasan KM, Discovery and development
of toll-like receptor 4 (TLR4) antago-
nists: a new paradigm for treating
sepsis and other diseases. Pharm Res,
2008. 25(8): 1751–61.
1798. Leone M, Albanese J, Garnier F,
Sapin C, Barrau K, Bimar MC, and
Martin C, Risk factors of nosocomial
catheter-associated urinary tract infec-
tion in a polyvalent intensive care
unit. Intensive Care Med, 2003. 29(7):
1077–80.
1799. Leone M, Garnier F, Avidan M, and
Martin C, Catheter-associated urinary
tract infections in intensive care units.
Microbes Infect, 2004. 6(11): 1026–32.
1800. Leone M, Perrin AS, Granier I,
Visintini P, Blasco V, Antonini F,
Albanese J, and Martin C, A rand-
omized trial of catheter change and
short course of antibiotics for asympto-
matic bacteriuria in catheterized ICU
patients. Intensive Care Med, 2007.
33(4): 726–9.
1801. Leport C, Rousseau F, Perronne C,
Salmon D, Joerg A, and Vilde JL,
Bacterial prostatitis in patients infected
with the human immunodeficiency
virus. J Urol, 1989. 141(2): 334–6.
1802. Lerman SE and Liao JC, Neonatal
circumcision. Pediatr Clin North Am,
2001. 48(6): 1539–57.
1803. Lescure FX, Biendo M, Douadi Y,
Schmit JL, and Eveillard M, Changing
epidemiology of methicillin-resistant
Staphylococcus aureus and effects on
cross-transmission in a teaching hos-
pital. Eur J Clin Microbiol Infect Dis,
2006. 25(3): 205–7.
1804. Lettgen B, Prophylaxe rezidivierender
Harnwegsinfektionen bei Mädchen.
Curr Ther Res, 1996. 27: 463 – 475.
1805. Leung A, Eastick K, Haddon LE,
Horn CK, Ahuja D, and Horner PJ,
Mycoplasma genitalium is associated
1086
with symptomatic urethritis. Int J STD
AIDS, 2006. 17(5): 285–8.
1806. Leung AY, Chan MT, Yuen KY, Cheng
VC, Chan KH, Wong CL, Liang R,
Lie AK, and Kwong YL, Ciprofloxacin
decreased polyoma BK virus load in
patients who underwent allogeneic
hematopoietic stem cell transplanta-
tion. Clin Infect Dis, 2005. 40(4):
528–37.
1807. Leutscher PD, Pedersen M, Raharisolo
C, Jensen JS, Hoffmann S, Lisse I,
Ostrowski SR, Reimert CM, Mauclere
P, and Ullum H, Increased prevalence
of leukocytes and elevated cytokine
levels in semen from Schistosoma hae-
matobium-infected individuals. J Infect
Dis, 2005. 191(10): 1639–47.
1808. Léveillé S, Caza M, Johnson JR,
Clabots C, Sabri M, and Dozois CM,
Iha from an Escherichia coli urinary
tract infection outbreak clonal group A
strain is expressed in vivo in the mouse
urinary tract and functions as a cat-
echolate siderophore receptor. Infect
Immun, 2006. 74(6): 3427–36.
1809. Levi M and van der Poll T,
Recombinant human activated protein
C: current insights into its mechanism
of action. Crit Care, 2007. 11 Suppl 5:
S3.
1810. Levi M, Levy M, Williams MD, Douglas
I, Artigas A, Antonelli M, Wyncoll D,
Janes J, Booth FV, Wang D, Sundin DP,
and Macias WL, Prophylactic heparin
in patients with severe sepsis treated
with drotrecogin alfa (activated). Am
J Respir Crit Care Med, 2007. 176(5):
483–90.
1811. Levy B, Bollaert PE, Charpentier C,
Nace L, Audibert G, Bauer P, Nabet P,
and Larcan A, Comparison of norepine-
phrine and dobutamine to epinephrine
for hemodynamics, lactate metabolism,
and gastric tonometric variables in
septic shock: a prospective, randomized
study. Intensive Care Med, 1997. 23(3):
282–7.
1812. Levy J, Morgan J, and Brown EA,
Oxford handbook of dialysis. 2nd ed.
Oxford handbooks. 2004, Oxford; New
York: Oxford University Press. xxx,
903 p.

1813. Levy MM, Fink MP, Marshall JC,
Abraham E, Angus D, Cook D, Cohen
J, Opal SM, Vincent JL, and Ramsay
G, 2001 SCCM/ESICM/ACCP/ATS/
SIS International Sepsis Definitions
Conference. Intensive Care Med, 2003.
29(4): 530–8.
1814. Levy SB and Marshall B, Antibacterial
resistance worldwide: causes, chal-
lenges and responses. Nat Med, 2004.
10(12 Suppl): S122–9.
1815. Lewis CM and Zervos MJ, Clinical
manifestations of enterococcal infection.
Eur J Clin Microbiol Infect Dis, 1990.
9(2): 111–7.
1816. Lewis DA, Pillay C, Mohlamonyane O,
Vezi A, Mbabela S, Mzaidume Y, and
Radebe F, The burden of asymptomatic
sexually transmitted infections among
men in Carletonville, South Africa:
implications for syndromic manage-
ment. Sex Transm Infect, 2008. 84(5):
371–6.
1817. Lewis DA, Scott L, Slabbert M,
Mhlongo S, van Zijl A, Sello M, du
Plessis N, Radebe F, and Wasserman
E, Escalation in the relative prevalence
of ciprofloxacin-resistant gonorrhoea
among men with urethral discharge in
two South African cities: association
with HIV seropositivity. Sex Transm
Infect, 2008. 84(5): 352–5.
1818. Lewis E, Tuberculosis of the penis: a
report of 5 new cases and a complete
review of the literature. J Urol, 1946.
56: 737–45.
1819. Lewis RI, Carrion HM, Lockhart
JL, and Politano VA, Significance of
asymptomatic bacteriuria in neurogenic
bladder disease. Urology, 1984. 23(4):
343–7.
1820. Li J, Fan SR, Liu XP, Li DM, Nie ZH,
Li F, Lin H, Huang WM, Zong LL, Jin
JG, Lei H, and Bai FY, Biased geno-
type distributions of Candida albicans
strains associated with vulvovaginal
candidosis and candidal balanopost-
hitis in China. Clin Infect Dis, 2008.
47(9): 1119–25.
1821. Li J, Nation RL, Turnidge JD, Milne
RW, Coulthard K, Rayner CR, and
Paterson DL, Colistin: the re-emerging
antibiotic for multidrug-resistant
References
Gram-negative bacterial infections.
Lancet Infect Dis, 2006. 6(9):
589–601.
1822. Li X, Lockatell CV, Johnson DE, Lane
MC, Warren JW, and Mobley HL,
Development of an intranasal vaccine
to prevent urinary tract infection by
Proteus mirabilis. Infect Immun, 2004.
72(1): 66–75.
1823. Li X, Zhao H, Lockatell CV,
Drachenberg CB, Johnson DE, and
Mobley HL, Visualization of Proteus
mirabilis within the matrix of urease-
induced bladder stones during experi-
mental urinary tract infection. Infect
Immun, 2002. 70(1): 389–94.
1824. Licht MR, Montague DK, Angermeier
KW, and Lakin MM, Cultures from
genitourinary prostheses at reoperation:
questioning the role of Staphylococcus
epidermidis in periprosthetic infection.
J Urol, 1995. 154(2 Pt 1): 387–90.
1825. Liddle AD and Davies AH, Pelvic con-
gestion syndrome: chronic pelvic pain
caused by ovarian and internal iliac
varices. Phlebology, 2007. 22(3): 100–4.
1826. Lidwell OM, Clean air at operation
and subsequent sepsis in the joint. Clin
Orthop Relat Res, 1986(211): 91–102.
1827. Liedberg H and Lundeberg T, Silver
alloy coated catheters reduce catheter-
associated bacteriuria. Br J Urol, 1990.
65(4): 379–81.
1828. Liedberg H, Lundeberg T, and Ekman
P, Refinements in the coating of ure-
thral catheters reduces the incidence
of catheter-associated bacteriuria. An
experimental and clinical study. Eur
Urol, 1990. 17(3): 236–40.
1829. Liedl B, Catheter-associated urinary
tract infections. Curr Opin Urol, 2001.
11(1): 75–9.
1830. Lifshitz E and Kramer L, Outpatient
urine culture: does collection tech-
nique matter? Arch Intern Med, 2000.
160(16): 2537–40.
1831. Lin DS, Huang SH, Lin CC, Tung YC,
Huang TT, Chiu NC, Koa HA, Hung
HY, Hsu CH, Hsieh WS, Yang DI, and
Huang FY, Urinary tract infection
in febrile infants younger than eight
weeks of Age. Pediatrics, 2000. 105(2):
E20.
1087
References
1832. Lin H, Hou CL, Zhong G, Xie Q, and
Wang S, Reconstruction of reflex path-
ways to the atonic bladder after conus
medullaris injury: preliminary clini-
cal results. Microsurgery, 2008. 28(6):
429–35.
1833. Linares L, Cervera C, Cofan F,
Ricart MJ, Esforzado N, Torregrosa
V, Oppenheimer F, Campistol JM,
Marco F, and Moreno A, Epidemiology
and outcomes of multiple antibiotic-
resistant bacterial infection in renal
transplantation. Transplant Proc, 2007.
39(7): 2222–4.
1834. Lindberg R, Fredlund H, Nicholas R,
and Unemo M, Neisseria gonorrhoeae
isolates with reduced susceptibility to
cefixime and ceftriaxone: association
with genetic polymorphisms in penA,
mtrR, porB1b, and ponA. Antimicrob
Agents Chemother, 2007. 51(6):
2117–22.
1835. Lindberg U, Asymptomatic bacte-
riuria in schoolgirls. V. The clinical
course and response to treatment. Acta
Paediatr. Scand., 1975. 64: 718–724.
1836. Lindberg U, Hansson LÅ, Jodal U,
Lidin-Janson G, Lincoln K, and Olling
S, Asymptomatic bacteriuria in school-
girls. II. Differences in Escherichia coli
causing asymptomatic and sympto-
matic bacteriuria. Acta Paediatr Scand,
1975. 64: 432–436.
1837. Lindblad B, Ekengren, K,. The long-
term prognosis of non-obstructive
urinary tract infection in infancy and
childhood after the advent of sulphona-
mides. Acta Pediatrica Scandinavica,
1969. 58: 25–32.
1838. Lindert KA, Kabalin JN, and Terris
MK, Bacteremia and bacteriuria after
transrectal ultrasound guided prostate
biopsy. J Urol, 2000. 164(1): 76–80.
1839. Lindstedt S, Lindstrom U, Ljunggren
E, Wullt B, and Grabe M, Single-dose
antibiotic prophylaxis in core prostate
biopsy: Impact of timing and identifi-
cation of risk factors. Eur Urol, 2006.
50(4): 832–7.
1840. Linsenmeyer T, Harrison B, Oakley
A, Kirshblum S, Stock J, and Millis S,
Evaluation of cranberry supplement for
reduction of urinary tract infections in
1088
individuals with neurogenic bladders
secondary to spinal cord injury. A pro-
spective, double-blinded, placebo-con-
trolled, crossover study. J Spinal Cord
Med, 2004. 27(1): 29–34.
1841. Linsenmeyer TA and Oakley A,
Accuracy of individuals with spinal
cord injury at predicting urinary tract
infections based on their symptoms. J
Spinal Cord Med, 2003. 26(4): 352–7.
1842. Linsenmeyer TA, Harrison B, Oakley
A, Kirshblum S, Stock JA, and Millis
SR, Evaluation of cranberry supple-
ment for reduction of urinary tract
infections in individuals with neuro-
genic bladders secondary to spinal cord
injury. A prospective, double-blinded,
placebo-controlled, crossover study. J
Spinal Cord Med, 2004. 27(1): 29–34.
1843. Linshaw M, Asymptomatic bacteriuria
and vesicoureteral reflux in children.
Kidney Int, 1996. 50(1): 312–29.
1844. Linshaw MA, Controversies in child-
hood urinary tract infections. World J
Urol, 1999. 17(6): 383–95.
1845. Lipovac M, Kurz C, Reithmayr F,
Verhoeven HC, Huber JC, and Imhof
M, Prevention of recurrent bacterial
urinary tract infections by intravesical
instillation of hyaluronic acid. Int J
Gynaecol Obstet, 2007. 96(3): 192–5.
1846. Lipp A and Lusardi G, Systemic anti-
microbial prophylaxis for percutane-
ous endoscopic gastrostomy. Cochrane
Database Syst Rev, 2006(4): CD005571.
1847. Lipsky BA, Ireton RC, Fihn SD,
Hackett R, and Berger RE, Diagnosis
of bacteriuria in men: specimen collec-
tion and culture interpretation. J Infect
Dis, 1987. 155(5): 847–54.
1848. Lipsky BA, Prostatitis and urinary
tract infection in men: what’s new;
what’s true? Am J Med, 1999. 106(3):
327–34.
1849. Lipsky BA, Urinary tract infections in
men. Epidemiology, pathophysiology,
diagnosis, and treatment. Ann Intern
Med, 1989. 110(2): 138–50.
1850. LiPuma JJ, Stull TL, Dasen SE, Pidcock
KA, Kaye D, and Korzeniowski OM,
DNA polymorphisms among Escherichia
coli isolated from bacteriuric women. J
Infect Dis, 1989. 159(3): 526–32.

1851. Little JW and Rhodus NL, The need for
antibiotic prophylaxis of patients with
penile implants during invasive dental
procedures: a national survey of urolo-
gists. J Urol, 1992. 148(6): 1801–4.
1852. Littrup PJ, Lee F, McLeary RD, Wu D,
Lee A, and Kumasaka GH, Transrectal
US of the seminal vesicles and ejacu-
latory ducts: clinical correlation.
Radiology, 1988. 168(3): 625–8.
1853. Litwin MS, McNaughton-Collins M,
Fowler FJ, Jr., Nickel JC, Calhoun EA,
Pontari MA, Alexander RB, Farrar
JT, and O’Leary MP, The National
Institutes of Health chronic prostati-
tis symptom index: development and
validation of a new outcome measure.
Chronic Prostatitis Collaborative
Research Network. J Urol, 1999. 162(2):
369–75.
1854. Liu CC, Huang SP, Chou YH, Li CC,
Wu MT, Huang CH, and Wu WJ,
Clinical presentation of acute scrotum
in young males. Kaohsiung J Med Sci,
2007. 23(6): 281–6.
1855. Liu H and Mulholland SG, Appropriate
antibiotic treatment of genitourinary
infections in hospitalized patients. Am
J Med, 2005. 118 Suppl 7A: 14S-20S.
1856. Liu KJ, Dendritic Cell, Toll-Like
Receptor, and The Immune System.
Journal of Cancer Molecules, 2006.
2(6): 213–5.
1857. Livornese LL, Jr., Benz RL, Ingerman
MJ, and Santoro J, Antibacterial
agents in renal failure. Infect Dis Clin
North Am, 1995. 9(3): 591–614.
1858. Llanes R, Sosa J, Guzman D, Llop A,
Valdes EA, Martinez I, Palma S, and
Lantero MI, Antimicrobial susceptibil-
ity of Neisseria gonorrhoeae in Cuba
(1995–1999): implications for treatment
of gonorrhea. Sex Transm Dis, 2003.
30(1): 10–4.
1859. Lloyd AL, Henderson TA, Vigil PD,
and Mobley HL, Genomic Islands
of Uropathogenic Escherichia coli
Contribute to Virulence. J Bacteriol,
2009.
1860. Lode H, Von der Hoh N, Ziege S,
Borner K, and Nord CE, Ecological
effects of linezolid versus amoxicil-
lin/clavulanic acid on the normal
References
intestinal microflora. Scand J Infect
Dis, 2001. 33(12): 899–903.
1861. Loeb M, Bentley DW, Bradley S,
Crossley K, Garibaldi R, Gantz N,
McGeer A, Muder RR, Mylotte J,
Nicolle LE, Nurse B, Paton S, Simor
AE, Smith P, and Strausbaugh L,
Development of minimum criteria for
the initiation of antibiotics in residents
of long-term-care facilities: results of
a consensus conference. Infect Control
Hosp Epidemiol, 2001. 22(2): 120–4.
1862. Loeb M, Brazil K, Lohfeld L, McGeer
A, Simor A, Stevenson K, Zoutman
D, Smith S, Liu X, and Walter SD,
Effect of a multifaceted intervention on
number of antimicrobial prescriptions
for suspected urinary tract infections in
residents of nursing homes: cluster ran-
domised controlled trial. BMJ, 2005.
331(7518): 669.
1863. Loebstein R, Addis A, Ho E, Andreou
R, Sage S, Donnenfeld AE, Schick
B, Bonati M, Moretti M, Lalkin A,
Pastuszak A, and Koren G, Pregnancy
outcome following gestational exposure
to fluoroquinolones: a multicenter pro-
spective controlled study. Antimicrob
Agents Chemother, 1998. 42(6):
1336–9.
1864. Loeffler W, Terminology of human
mycoses. Nomenclature of mycotic dis-
eases of man. List of accepted German
terms translated, arranged and pub-
lished, together with comments, for the
International Society for Human and
Animal Mycology (ISHAM). Mykosen,
1983. 26(7): 346–84.
1865. Loening-Baucke V, Urinary incon-
tinence and urinary tract infection
and their resolution with treatment
of chronic constipation of childhood.
Pediatrics, 1997. 100(2 Pt 1): 228–32.
1866. Logadottir Y, Dahlstrand C, Fall M,
Knutson T, and Peeker R, Invasive uro-
dynamic studies are well tolerated by
the patients and associated with a low
risk of urinary tract infection. Scand J
Urol Nephrol, 2001. 35(6): 459–62.
1867. Lohr JA, Nunley DH, Howards SS, and
Ford RF, Prevention of recurrent uri-
nary tract infections in girls. Pediatrics,
1977. 59(4): 562–5.
1089
References
1868. Lohr JA, Use of routine urinalysis in
making a presumptive diagnosis of uri-
nary tract infection in children. Pediatr
Infect Dis J, 1991. 10(9): 646–50.
1869. Londish GJ and Murray JM,
Significant reduction in HIV prevalence
according to male circumcision inter-
vention in sub-Saharan Africa. Int J
Epidemiol, 2008.
1870. Lopez-Corona E, Garcia-Gonzalez VM,
and Gabilondo F, [Results of nephrec-
tomy in patients with autosomal domi-
nant polycystic kidney disease]. Rev
Invest Clin, 2004. 56(4): 437–42.
1871. L’opez-Plaza L and Bostwick DG,
Prostatitis. Pathology of the prostate,
ed. Bostwick DG. 1990, New York:
Churchill Livingstone.
1872. Lorente JA, Arango O, Bielsa O,
Cortadellas R, and Gelabert-Mas A,
Effect of antibiotic treatment on serum
PSA and percent free PSA levels in
patients with biochemical criteria for
prostate biopsy and previous lower
urinary tract infections. Int J Biol
Markers, 2002. 17(2): 84–9.
1873. Lotan Y and Roehrborn CG, Sensitivity
and specificity of commonly available
bladder tumor markers versus cytology:
results of a comprehensive literature
review and meta-analyses. Urology,
2003. 61(1): 109–18; discussion 118.
1874. Louie A, Kaw P, Liu W, Jumbe
N, Miller MH, and Drusano GL,
Pharmacodynamics of daptomycin in a
murine thigh model of Staphylococcus
aureus infection. Antimicrob Agents
Chemother, 2001. 45(3): 845–51.
1875. Lowder JL, Burrows LJ, Howden NL,
and Weber AM, Prophylactic antibiotics
after urodynamics in women: a decision
analysis. Int Urogynecol J Pelvic Floor
Dysfunct, 2007. 18(2): 159–64.
1876. Lowe FC and Fagelman E, Cranberry
juice and urinary tract infections: what
is the evidence? Urology, 2001. 57(3):
407–13.
1877. Lowe FC, Lattimer DG, and Metroka
CE, Kaposi’s sarcoma of the penis in
patients with acquired immunodeficiency
syndrome. J Urol, 1989. 142(6): 1475–7.
1878. Lowe NK, Neal JL, and Ryan-Wenger
NA, Accuracy of the clinical diagnosis
1090
of vaginitis compared with a DNA
probe laboratory standard. Obstet
Gynecol, 2009. 113(1): 89–95.
1879. Lucas MJ, Cox SM, Roark ML, and
Cunningham FG, Ticarcillin/clavu-
lanate in the treatment of pelvic infec-
tions. J Reprod Med, 1990. 35(3 Suppl):
343–7.
1880. Luchi M, Morrison DC, Opal S, Yoneda
K, Slotman G, Chambers H, Wiesenfeld
H, Lemke J, Ryan JL, and Horn D,
A comparative trial of imipenem
versus ceftazidime in the release of
endotoxin and cytokine generation in
patients with gram-negative urosepsis.
Urosepsis Study Group. J Endotoxin
Res, 2000. 6(1): 25–31.
1881. Ludwig M, Diagnosis and therapy of
acute prostatitis, epididymitis and
orchitis. Andrologia, 2008. 40(2): 76–80.
1882. Ludwig M, Hoyme U, and Weidner W,
[Recurrent urinary tract infection in
women. Long-term antibiotic prophy-
laxis]. Urologe A, 2006. 45(4): 436–42.
1883. Ludwig M, Schroeder-Printzen I,
Schiefer HG, and Weidner W, Diagnosis
and therapeutic management of 18
patients with prostatic abscess. Urology,
1999. 53(2): 340–5.
1884. Ludwig M, Velcovsky HG, and Weidner
W, Tuberculous epididymo-orchitis and
prostatitis: a case report. Andrologia,
2008. 40(2): 81–3.
1885. Ludwig M, Vidal A, Diemer T, Pabst
W, Failing K, and Weidner W, Seminal
secretory capacity of the male acces-
sory sex glands in chronic pelvic pain
syndrome (CPPS)/chronic prostatitis
with special focus on the new prostati-
tis classification. Eur Urol, 2002. 42(1):
24–8.
1886. Lujan J, de Onate WA, Delva W,
Claeys P, Sambola F, Temmerman M,
Fernando J, and Folgosa E, Prevalence
of sexually transmitted infections in
women attending antenatal care in Tete
province, Mozambique. S Afr Med J,
2008. 98(1): 49–51.
1887. Luk WH, Woo YH, Au-Yeung AW, and
Chan JC, Imaging in pediatric urinary
tract infection: a 9-year local experi-
ence. AJR Am J Roentgenol, 2009.
192(5): 1253–60.

1888. Lumbiganon P, Villar J, Laopaiboon
M, Widmer M, Thinkhamrop J,
Carroli G, Duc Vy N, Mignini L,
Festin M, Prasertcharoensuk W,
Limpongsanurak S, Liabsuetrakul
T, and Sirivatanapa P, One-day com-
pared with 7-day nitrofurantoin for
asymptomatic bacteriuria in preg-
nancy: a randomized controlled trial.
Obstet Gynecol, 2009. 113(2 Pt 1):
339–45.
1889. Luna CM, Vujacich P, Niederman MS,
Vay C, Gherardi C, Matera J, and Jolly
EC, Impact of BAL data on the therapy
and outcome of ventilator-associated
pneumonia. Chest, 1997. 111(3):
676–85.
1890. Lundback D, Fredlund H, Berglund T,
Wretlind B, and Unemo M, Molecular
epidemiology of Neisseria gonorrhoeae-
identification of the first presumed
Swedish transmission chain of an
azithromycin-resistant strain. Apmis,
2006. 114(1): 67–71.
1891. Lundeberg T, Prevention of catheter-as-
sociated urinary-tract infections by use
of silver-impregnated catheters. Lancet,
1986. 2(8514): 1031.
1892. Lundstedt AC, Leijonhufvud I,
Ragnarsdottir B, Karpman D,
Andersson B, and Svanborg C,
Inherited susceptibility to acute
pyelonephritis: a family study of uri-
nary tract infection. J Infect Dis, 2007.
195(8): 1227–34.
1893. Lundstedt AC, McCarthy S, Gustafsson
MC, Godaly G, Jodal U, Karpman D,
Leijonhufvud I, Linden C, Martinell
J, Ragnarsdottir B, Samuelsson
M, Truedsson L, Andersson B, and
Svanborg C, A genetic basis of suscep-
tibility to acute pyelonephritis. PLoS
ONE, 2007. 2(9): e825.
1894. Lunevicius R and Morkevicius M,
Systematic review comparing laparo-
scopic and open repair for perforated
peptic ulcer. Br J Surg, 2005. 92(10):
1195–207.
1895. Lutter SA, Currie ML, Mitz LB, and
Greenbaum LA, Antibiotic resistance
patterns in children hospitalized for
urinary tract infections. Arch Pediatr
Adolesc Med, 2005. 159(10): 924–8.
References
1896. Lutters M and Vogt N, Antibiotic dura-
tion for treating uncomplicated, symp-
tomatic lower urinary tract infections
in elderly women. Cochrane Database
Syst Rev, 2002(3): CD001535.
1897. Lutters M and Vogt-Ferrier NB,
Antibiotic duration for treating uncom-
plicated, symptomatic lower urinary
tract infections in elderly women.
Cochrane Database Syst Rev, 2008(3):
CD001535.
1898. Luzzi GA and O’Brien TS, Acute epidi-
dymitis. BJU Int, 2001. 87(8): 747–55.
1899. Lyerova L, Lacha J, Skibova J, Teplan
V, Vitko S, and Schuck O, Urinary tract
infection in patients with urological
complications after renal transplanta-
tion with respect to long-term function
and allograft survival. Ann Transplant,
2001. 6(2): 19–20.
1900. Lyss SB, Kamb ML, Peterman TA,
Moran JS, Newman DR, Bolan G,
Douglas JM, Jr., Iatesta M, Malotte
CK, Zenilman JM, Ehret J, Gaydos C,
and Newhall WJ, Chlamydia tracho-
matis among patients infected with
and treated for Neisseria gonorrhoeae
in sexually transmitted disease clinics
in the United States. Ann Intern Med,
2003. 139(3): 178–85.
1901. Ma JF and Shortliffe LM, Urinary tract
infection in children: etiology and epi-
demiology. Urol Clin North Am, 2004.
31(3): 517–26, ix-x.
1902. MacDermott JP, Ewing RE, Somerville
JF, and Gray BK, Cephradine prophy-
laxis in transurethral procedures for
carcinoma of the bladder. Br J Urol,
1988. 62(2): 136–9.
1903. MacDonald KS, Malonza I, Chen DK,
Nagelkerke NJ, Nasio JM, Ndinya-
Achola J, Bwayo JJ, Sitar DS, Aoki FY,
and Plummer FA, Vitamin A and risk
of HIV-1 seroconversion among Kenyan
men with genital ulcers. Aids, 2001.
15(5): 635–9.
1904. MacDonald R, Fink HA, Huckabay
C, Monga M, and Wilt TJ, Botulinum
toxin for treatment of urinary incon-
tinence due to detrusor overactivity: a
systematic review of effectiveness and
adverse effects. Spinal Cord, 2007.
45(8): 535–41.
1091
References
1905. MacDonald R, Monga M, Fink HA,
and Wilt TJ, Neurotoxin treatments for
urinary incontinence in subjects with
spinal cord injury or multiple sclerosis:
a systematic review of effectiveness and
adverse effects. J Spinal Cord Med,
2008. 31(2): 157–65.
1906. MacDougall C and Polk RE,
Antimicrobial stewardship programs in
healthcare systems. Clin Microbiol Rev,
2005. 18: 638–656.
1907. MacGowan AP, Pharmacokinetic and
pharmacodynamic profile of linezolid
in healthy volunteers and patients with
Gram-positive infections. J Antimicrob
Chemother, 2003. 51 Suppl 2: ii17–25.
1908. MacKenzie JR, Fowler K, Hollman AS,
Tappin D, Murphy AV, Beattie TJ, and
Azmy AF, The value of ultrasound in
the child with an acute urinary tract
infection. Br J Urol, 1994. 74(2): 240–4.
1909. Madeb R, Marshall J, Nativ O, and
Erturk E, Epididymal tuberculosis:
case report and review of the literature.
Urology, 2005. 65(4): 798.
1910. Maeda S, Deguchi T, Ishiko H,
Matsumoto T, Naito S, Kumon
H, Tsukamoto T, Onodera S, and
Kamidono S, Detection of Mycoplasma
genitalium, Mycoplasma hominis,
Ureaplasma parvum (biovar 1) and
Ureaplasma urealyticum (biovar 2) in
patients with non-gonococcal urethritis
using polymerase chain reaction-micro-
titer plate hybridization. Int J Urol,
2004. 11(9): 750–4.
1911. Maeda SI, Tamaki M, Kojima K,
Yoshida T, Ishiko H, Yasuda M, and
Deguchi T, Association of Mycoplasma
genitalium persistence in the urethra
with recurrence of nongonococcal ure-
thritis. Sex Transm Dis, 2001. 28(8):
472–6.
1912. Maenpaa J, Taina E, Gronroos M,
Soderstrom KO, Ristimaki T, and
Narhinen L, Abdominopelvic actino-
mycosis associated with intrauterine
devices. Two case reports. Arch Gynecol
Obstet, 1988. 243(4): 237–41.
1913. Magasi P, Panovics J, Illes A, and Nagy
M, Uro-Vaxom and the management
of recurrent urinary tract infection
in adults: a randomized multicenter
1092
double-blind trial. Eur Urol, 1994.
26(2): 137–40.
1914. Magbanua JP, Goh BT, Michel CE,
Aguirre-Andreasen A, Alexander S,
Ushiro-Lumb I, Ison C, and Lee H,
Chlamydia trachomatis variant not
detected by plasmid based nucleic acid
amplification tests: molecular char-
acterisation and failure of single dose
azithromycin. Sex Transm Infect, 2007.
83(4): 339–43.
1915. Magill SS, Swoboda SM, Johnson EA,
Merz WG, Pelz RK, Lipsett PA, and
Hendrix CW, The association between
anatomic site of Candida colonization,
invasive candidiasis, and mortality in
critically ill surgical patients. Diagn
Microbiol Infect Dis, 2006. 55(4):
293–301.
1916. Magri V, Trinchieri A, Ceriani I,
Marras E, and Perletti G, Eradication
of unusual pathogens by combination
pharmacological therapy is paralleled
by improvement of signs and symptoms
of chronic prostatitis syndrome. Arch
Ital Urol Androl, 2007. 79(2): 93–8.
1917. Magri V, Trinchieri A, Pozzi G, Restelli
A, Garlaschi MC, Torresani E, Zirpoli
P, Marras E, and Perletti G, Efficacy of
repeated cycles of combination therapy
for the eradication of infecting organ-
isms in chronic bacterial prostatitis.
Int J Antimicrob Agents, 2007. 29(5):
549–56.
1918. Mahant S, To T, and Friedman J,
Timing of voiding cystourethrogram
in the investigation of urinary tract
infections in children. J Pediatr, 2001.
139(4): 568–71.
1919. Mahbub Hasan AK, Ou Z, Sakakibara
K, Hirahara S, Iwasaki T, Sato K, and
Fukami Y, Characterization of Xenopus
egg membrane microdomains contain-
ing uroplakin Ib/III complex: roles of
their molecular interactions for subcel-
lular localization and signal transduc-
tion. Genes Cells, 2007. 12(2): 251–67.
1920. Mahbub Hasan AK, Sato K, Sakakibara
K, Ou Z, Iwasaki T, Ueda Y, and
Fukami Y, Uroplakin III, a novel Src
substrate in Xenopus egg rafts, is a tar-
get for sperm protease essential for ferti-
lization. Dev Biol, 2005. 286(2): 483–92.

1921. Mahmoud KM, Sobh MA, El-Agroudy
AE, Mostafa FE, Baz ME, Shokeir AA,
and Ghoneim MA, Impact of schisto-
somiasis on patient and graft outcome
after renal transplantation: 10 years’
follow-up. Nephrol Dial Transplant,
2001. 16(11): 2214–21.
1922. Majd M, Rushton HG, Jantausch B,
and Wiedermann BL, Relationship
among vesicoureteral reflux,
P-fimbriated Escherichia coli, and
acute pyelonephritis in children
with febrile urinary tract infection. J
Pediatr, 1991. 119(4): 578–85.
1923. Mak RH and Kuo HJ, Pathogenesis of
urinary tract infection: an update. Curr
Opin Pediatr, 2006. 18(2): 148–52.
1924. Mak RH and Wong JH, Are oral antibi-
otics alone efficacious for the treatment
of a first episode of acute pyelonephritis
in children? Nat Clin Pract Nephrol,
2008. 4(1): 10–1.
1925. Makar N, Urological aspects of bilhar-
ziasis in Egypt. 1955, [Cairo,: S. O.
P.-Press. viii, 208 p.
1926. Maki DG and Tambyah PA,
Engineering out the risk for infection
with urinary catheters. Emerg Infect
Dis, 2001. 7(2): 342–7.
1927. Maki DG, Fox BC, Kuntz J, Sollinger
HW, and Belzer FO, A prospective, ran-
domized, double-blind study of trimeth-
oprim-sulfamethoxazole for prophylaxis
of infection in renal transplantation.
Side effects of trimethoprim-sulfameth-
oxazole, interaction with cyclosporine. J
Lab Clin Med, 1992. 119(1): 11–24.
1928. Maki DG, Hennekens CG, Phillips CW,
Shaw WV, and Bennett JV, Nosocomial
urinary tract infection with Serratia
marcescens: an epidemiologic study. J
Infect Dis, 1973. 128(5): 579–87.
1929. Maki DG, Knasinski V, Halvorson K,
and Tambyah PA, A novel silver-hydro-
gel-impregnated indwelling urinary
catheter reduces CAUTIs: A prospective
double-blind trial. Infection Control &
Hospital Epidemiology, 1998. 1992(19):
682.
1930. Malik AI, Papagrigoriadis S, Leather
AJ, Rennie JA, Salisbury JR, and
Beese RC, Abdominopelvic mass
secondary to Actinomyces israelii
References
mimicking cancer: report of two cases.
Tech Coloproctol, 2005. 9(2): 170–1.
1931. Malone PS, Circumcision for prevent-
ing urinary tract infection in boys:
European view. Arch Dis Child, 2005.
90(8): 773–4.
1932. Maloney C and Oliver ML, Effect of
local conjugated estrogens on vaginal
pH in elderly women. J Am Med Dir
Assoc, 2001. 2(2): 51–5.
1933. Manges AR, Dietrich PS, and Riley
LW, Multidrug-resistant Escherichia
coli clonal groups causing community-
acquired pyelonephritis. Clin Infect
Dis, 2004. 38(3): 329–34.
1934. Manges AR, Johnson JR, Foxman B,
O’Bryan TT, Fullerton KE, and Riley
LW, Widespread distribution of urinary
tract infections caused by a multidrug-
resistant Escherichia coli clonal group.
N Engl J Med, 2001. 345(14): 1007–13.
1935. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline
for prevention of surgical site infec-
tion, 1999. Hospital Infection Control
Practices Advisory Committee. Infect
Control Hosp Epidemiol, 1999. 20(4):
250–78; quiz 279–80.
1936. Mangram AJ, Horan TC, Pearson ML,
Silver LC, and Jarvis WR, Guideline
for Prevention of Surgical Site
Infection, 1999. Centers for Disease
Control and Prevention (CDC) Hospital
Infection Control Practices Advisory
Committee. Am J Infect Control, 1999.
27(2): 97–132; quiz 133–4; discussion
96.
1937. Mansfield JT, Snow BW, Cartwright
PC, and Wadsworth K, Complications
of pregnancy in women after childhood
reimplantation for vesicoureteral reflux:
an update with 25 years of followup. J
Urol, 1995. 154(2 Pt 2): 787–90.
1938. Manson AL, Is antibiotic administra-
tion indicated after outpatient cystos-
copy. J Urol, 1988. 140(2): 316–7.
1939. Månsson LE, Kjäll P, Pellett S, Nagy
G, Welch RA, Bäckhed F, Frisan T, and
Richter-Dahlfors A, Role of the lipopoly-
saccharide-CD14 complex for the activ-
ity of hemolysin from uropathogenic
Escherichia coli. Infect Immun, 2007.
75(2): 997–1004.
1093
References
1940. Mansson W, Colleen S, Low K, Mardh
PA, and Lundblad A, Immunoglobulins
in urine from patients with ileal and
colonic conduits and reservoirs. J Urol,
1985. 133(4): 713–6.
1941. Mantel N and Haenszel W, Statistical
aspects of the analysis of data from
retrospective studies of disease. J Natl
Cancer Inst, 1959. 22(4): 719–48.
1942. Manterola C, Espinoza R, Munoz
S, Vial M, Bustos L, Losada H, and
Barroso M, Abdominal echinococco-
sis during pregnancy: clinical aspects
and management of a series of cases in
Chile. Trop Doct, 2004. 34(3): 171–3.
1943. Marcel JP, Alfa M, Baquero F, Etienne
J, Goossens H, Harbarth S, Hryniewicz
W, Jarvis W, Kaku M, Leclercq R, Levy
S, Mazel D, Nercelles P, Perl T, Pittet
D, Vandenbroucke-Grauls C, Woodford
N, and Jarlier V, Healthcare-associated
infections: think globally, act locally.
Clin Microbiol Infect, 2008. 14(10):
895–907.
1944. Marchand M, Kuffer F, and Tonz M,
Long-term outcome in women who
underwent anti-reflux surgery in
childhood. J Pediatr Urol, 2007. 3(3):
178–83.
1945. Marconi M, Pilatz A, Wagenlehner
F, Diemer T, and Weidner W, Are
antisperm antibodies really associated
with proven inflammatory, infectious
diseases of the male reproductive tract.
Eur Urol, in press.
1946. Marcus N, Ashkenazi S, Yaari A, Samra
Z, and Livni G, Non-Escherichia coli
versus Escherichia coli community-
acquired urinary tract infections in
children hospitalized in a tertiary
center: relative frequency, risk factors,
antimicrobial resistance and outcome.
Pediatr Infect Dis J, 2005. 24(7): 581–5.
1947. Marcus RJ, Post JC, Stoodley P, Hall-
Stoodley L, McGill RL, Sureshkumar
KK, and Gahlot V, Biofilms in nephrol-
ogy. Expert Opin Biol Ther, 2008. 8(8):
1159–66.
1948. Mardh PA and Westrom L, Antibodies
to Mycoplasma hominis in patients
with genital infections and in healthy
controls. Br J Vener Dis, 1970. 46(5):
390–7.
1094
1949. Mardh PA, Increased serum levels of
IgM in acute salpingitis related to the
occurrence of Mycoplasma hominis. Acta
Pathol Microbiol Scand B Microbiol
Immunol, 1970. 78(6): 726–32.
1950. Mardh PA, Lind I, Svensson
L, Westrom L, and Moller BR,
Antibodies to Chlamydia trachomatis,
Mycoplasma hominis, and Neisseria
gonorrhoeae in sera from patients with
acute salpingitis. Br J Vener Dis, 1981.
57(2): 125–9.
1951. Mardis HK and Kroeger RM, Ureteral
stents. Materials. Urol Clin North Am,
1988. 15(3): 471–9.
1952. Marenzi G, Marana I, Lauri G,
Assanelli E, Grazi M, Campodonico J,
Trabattoni D, Fabbiocchi F, Montorsi
P, and Bartorelli AL, The prevention of
radiocontrast-agent-induced nephropa-
thy by hemofiltration. N Engl J Med,
2003. 349(14): 1333–40.
1953. Maresso AW and Schneewind O,
Iron acquisition and transport in
Staphylococcus aureus. Biometals,
2006. 19(2): 193–203.
1954. Margel D, Ehrlich Y, Brown N, Lask
D, Livne PM, and Lifshitz DA, Clinical
implication of routine stone culture
in percutaneous nephrolithotomy—a
prospective study. Urology, 2006. 67(1):
26–9.
1955. Mariappan P and Loong CW,
Midstream urine culture and sensitivity
test is a poor predictor of infected urine
proximal to the obstructing ureteral
stone or infected stones: a prospective
clinical study. J Urol, 2004. 171(6 Pt 1):
2142–5.
1956. Mariappan P, Smith G, Bariol SV,
Moussa SA, and Tolley DA, Stone and
pelvic urine culture and sensitivity are
better than bladder urine as predictors
of urosepsis following percutaneous
nephrolithotomy: a prospective clinical
study. J Urol, 2005. 173(5): 1610–4.
1957. Mariappan P, Smith G, Moussa SA,
and Tolley DA, One week of cipro-
floxacin before percutaneous nephro-
lithotomy significantly reduces upper
tract infection and urosepsis: a prospec-
tive controlled study. BJU Int, 2006.
98(5): 1075–9.

1958. Marik PE, Pastores SM, Annane D,
Meduri GU, Sprung CL, Arlt W, Keh D,
Briegel J, Beishuizen A, Dimopoulou I,
Tsagarakis S, Singer M, Chrousos GP,
Zaloga G, Bokhari F, and Vogeser M,
Recommendations for the diagnosis and
management of corticosteroid insuf-
ficiency in critically ill adult patients:
consensus statements from an inter-
national task force by the American
College of Critical Care Medicine. Crit
Care Med, 2008. 36(6): 1937–49.
1959. Marild S, Hansson S, Jodal U, Oden
A, and Svedberg K, Protective effect of
breastfeeding against urinary tract infec-
tion. Acta Paediatr, 2004. 93(2): 164–8.
1960. Marild S, Jodal U, and Mangelus L,
Medical histories of children with acute
pyelonephritis compared with controls.
Pediatr Infect Dis J, 1989. 8(8): 511–5.
1961. Marild S, Jodal U, and Sandberg T,
Ceftibuten versus trimethoprim-sulfam-
ethoxazole for oral treatment of febrile
urinary tract infection in children.
Pediatr Nephrol, 2009. 24(3): 521–6.
1962. Marion E, McMurdo M, Argo I, Phillips
G, Daly F, and Davey P, Cranberry
or trimethoprim for the prevention of
recurrent urinary tract infections? A
randomised controlled trial in older
women. J Antimicrob Chemother, 2008.
63(2): 1000–8.
1963. Marks G, Crepaz N, Senterfitt JW, and
Janssen RS, Meta-analysis of high-risk
sexual behavior in persons aware and
unaware they are infected with HIV in
the United States: implications for HIV
prevention programs. J Acquir Immune
Defic Syndr, 2005. 39(4): 446–53.
1964. Maroncle NM, Sivick KE, Brady R,
Stokes FE, and Mobley HL, Protease
activity, secretion, cell entry, cytotox-
icity, and cellular targets of secreted
autotransporter toxin of uropathogenic
Escherichia coli. Infect Immun, 2006.
74(11): 6124–34.
1965. Marple CD, The frequency and char-
acter of urinary tract infections in an
unselected group of women. Ann Intern
Med, 1941. 14: 2220–39.
1966. Marrazzo J, Syphilis and other sexually
transmitted diseases in HIV infection.
Top HIV Med, 2007. 15(1): 11–6.
References
1967. Marrs CF, Zhang L, and Foxman B,
Escherichia coli mediated urinary tract
infections: are there distinct uropatho-
genic E. coli (UPEC) pathotypes?
FEMS Microbiol Lett, 2005. 252(2):
183–90.
1968. Marshall WF and Blair JE, The cepha-
losporins. Mayo Clin Proc, 1999. 74(2):
187–95.
1969. Marszalek WW and Dhai A, Genito-
urinary tuberculosis. A 4-year review. S
Afr Med J, 1982. 62(6): 158–9.
1970. Martens MG, Faro S, Hammill
H, Phillips LE, and Riddle GD,
Comparison of two endometrial sam-
pling devices. Cotton-tipped swab and
double-lumen catheter with a brush. J
Reprod Med, 1989. 34(11): 875–9.
1971. Martens MG, Faro S, Maccato M,
Hammill HA, and Riddle G, Prevalence
of beta-lactamase enzyme production
in bacteria isolated from women with
postpartum endometritis. J Reprod
Med, 1993. 38(10): 795–8.
1972. Martin C, Papazian L, Perrin G, Saux
P, and Gouin F, Norepinephrine or
dopamine for the treatment of hyper-
dynamic septic shock? Chest, 1993.
103(6): 1826–31.
1973. Martin C, Saux P, Eon B, Aknin P, and
Gouin F, Septic shock: a goal-directed
therapy using volume loading, dob-
utamine and/or norepinephrine. Acta
Anaesthesiol Scand, 1990. 34(5): 413–7.
1974. Martin DH, Jones RB, and Johnson
RB, A phase-II study of trovafloxacin
for the treatment of Chlamydia tracho-
matis infections. Sex Transm Dis, 1999.
26(7): 369–73.
1975. Martin GS, Mannino DM, Eaton S, and
Moss M, The epidemiology of sepsis in
the United States from 1979 through
2000. N Engl J Med, 2003. 348(16):
1546–54.
1976. Martin HL, Richardson BA, Nyange
PM, Lavreys L, Hillier SL, Chohan
B, Mandaliya K, Ndinya-Achola JO,
Bwayo J, and Kreiss J, Vaginal lacto-
bacilli, microbial flora, and risk of
human immunodeficiency virus type
1 and sexually transmitted disease
acquisition. J Infect Dis, 1999. 180(6):
1863–8.
1095
References
1977. Martin IM, Hoffmann S, and Ison CA,
European Surveillance of Sexually
Transmitted Infections (ESSTI): the
first combined antimicrobial suscepti-
bility data for Neisseria gonorrhoeae
in Western Europe. J Antimicrob
Chemother, 2006. 58(3): 587–93.
1978. Martinell J, Claesson I, Lidin-Janson
G, and Jodal U, Urinary infection,
reflux and renal scarring in females
continuously followed for 13–38 years.
Pediatr Nephrol, 1995. 9(2): 131–6.
1979. Martinell J, Jodal U, and Lidin-Janson
G, Pregnancies in women with and
without renal scarring after urinary
infections in childhood. BMJ, 1990.
300(6728): 840–4.
1980. Martinez JJ and Hultgren SJ,
Requirement of Rho-family GTPases in
the invasion of Type 1-piliated uropath-
ogenic Escherichia coli. Cell Microbiol,
2002. 4(1): 19–28.
1981. Martinez JJ, Mulvey MA, Schilling JD,
Pinkner JS, and Hultgren SJ, Type 1
pilus-mediated bacterial invasion of
bladder epithelial cells. Embo J, 2000.
19(12): 2803–12.
1982. Martinez JR and Grantham JJ,
Polycystic kidney disease: etiology,
pathogenesis, and treatment. Dis Mon,
1995. 41(11): 693–765.
1983. Martinez-Martinez L, Hernandez-Alles
S, Alberti S, Tomas JM, Benedi VJ,
and Jacoby GA, In vivo selection of
porin-deficient mutants of Klebsiella
pneumoniae with increased resistance
to cefoxitin and expanded-spectrum-
cephalosporins. Antimicrob Agents
Chemother, 1996. 40(2): 342–8.
1984. Martinez-Pineiro JA, de Iriarte EG,
and Armero AH, The problem of recur-
rences and infection after surgical
removal of staghorn calculi. Eur Urol,
1982. 8(2): 94–101.
1985. Martins AC and Krauss-Silva L,
[Systematic reviews of antibiotic
prophylaxis in cesareans]. Cad Saude
Publica, 2006. 22(12): 2513–26.
1986. Martius JAH, Über die Bedeutung
der Bakteriellen Vaginose und
anderer Urogenitalinfektionen
in der Schwangerschaft für die
Frühgeburtlichkeit und die mütterliche
1096
peripartale Infektmorbidität. 1986,
Universität Würzburg.
1987. Marty R, Hysteroscopy necessary before
IUD? Acta Eur Fertil, 1986. 17(6):
449–50.
1988. Marx M, Weber M, Schafranek D,
Wandel E, Meyer zum Buschenfelde
KH, and Kohler H, Secretory immu-
noglobulin A in urinary tract infec-
tion, chronic glomerulonephritis, and
renal transplantation. Clin Immunol
Immunopathol, 1989. 53(2 Pt 1):
181–91.
1989. Masago T, Watanabe T, Isoyama T,
Kobayashi N, Hikita K, Morizane S,
Taji S, Matsumoto M, and Miyagawa I,
Experiences of emphysematous pyelone-
phritis 2 cases. Jpn J Urol Surg, 2007.
20: 1323–1326.
1990. Masood J, Voulgaris S, Awogu O,
Younis C, Ball AJ, and Carr TW,
Condom perforation during transrectal
ultrasound guided (TRUS) prostate
biopsies: a potential infection risk. Int
Urol Nephrol, 2007. 39(4): 1121–4.
1991. Massari V, Dorleans Y, and Flahault
A, Persistent increase in the incidence
of acute male urethritis diagnosed in
general practices in France. Br J Gen
Pract, 2006. 56(523): 110–4.
1992. Mastro TD and Kitayaporn D, HIV type
1 transmission probabilities: estimates
from epidemiological studies. AIDS Res
Hum Retroviruses, 1998. 14 Suppl 3:
S223–7.
1993. Mastro TD, Farley TA, Elliott JA,
Facklam RR, Perks JR, Hadler JL,
Good RC, and Spika JS, An outbreak of
surgical-wound infections due to group
A streptococcus carried on the scalp. N
Engl J Med, 1990. 323(14): 968–72.
1994. Mastroiacovo P, Mazzone T, Botto LD,
Serafini MA, Finardi A, Caramelli
L, and Fusco D, Prospective assess-
ment of pregnancy outcomes after
first-trimester exposure to fluconazole.
Am J Obstet Gynecol, 1996. 175(6):
1645–50.
1995. Mateos JJ, Velasco M, Lomena F,
Horcajada JP, Setoain FJ, Martin F,
Ortega M, Fuster D, Piera C, Pons F,
and Mensa J, 111Indium labelled leu-
kocyte scintigraphy in the detection of

acute prostatitis. Nucl Med Commun,
2002. 23(11): 1137–42.
1996. Mathai D, Jones RN, and Pfaller MA,
Epidemiology and frequency of resist-
ance among pathogens causing urinary
tract infections in 1,510 hospitalized
patients: a report from the SENTRY
Antimicrobial Surveillance Program
(North America). Diagn Microbiol
Infect Dis, 2001. 40(3): 129–36.
1997. Mathema B, Cross E, Dun E, Park
S, Bedell J, Slade B, Williams M,
Riley L, Chaturvedi V, and Perlin DS,
Prevalence of vaginal colonization by
drug-resistant Candida species in col-
lege-age women with previous exposure
to over-the-counter azole antifungals.
Clin Infect Dis, 2001. 33(5): E23–7.
1998. Matlaga BR, Hodges SJ, Shah OD,
Passmore L, Hart LJ, and Assimos DG,
Percutaneous nephrostolithotomy: pre-
dictors of length of stay. J Urol, 2004.
172(4 Pt 1): 1351–4.
1999. Matsukawa M, Kunishima Y,
Takahashi S, Takeyama K, and
Tsukamoto T, Staphylococcus aureus
bacteriuria and surgical site infections
by methicillin-resistant Staphylococcus
aureus. Int J Antimicrob Agents, 2001.
17(4): 327–9, discussion 329–30.
2000. Matsumoto T, Muratani T, Takahashi
K, Ando Y, Sato Y, Kurashima M, Yokoo
D, Ikuyama T, Shimokawa H, and
Yanai S, Single dose of cefodizime com-
pletely eradicated multidrug-resistant
strain of Neisseria gonorrhoeae in ure-
thritis and uterine cervicitis. J Infect
Chemother, 2006. 12(2): 97–9.
2001. Matsumoto T, Muratani T, Takahashi
K, Ikuyama T, Yokoo D, Ando Y, Sato
Y, Kurashima M, Shimokawa H, and
Yanai S, Multiple doses of cefodiz-
ime are necessary for the treatment
of Neisseria gonorrhoeae pharyngeal
infection. J Infect Chemother, 2006.
12(3): 145–7.
2002. Matsumoto T, Takahashi K, Manabe N,
Iwatsubo E, and Kawakami Y, Urinary
tract infection in neurogenic bladder. Int
J Antimicrob Agents, 2001. 17(4): 293–7.
2003. Mavridis G, Livaditi E, and
Christopoulos-Geroulanos G,
Management of hydatidosis in children.
References
Twenty-one year experience. Eur J
Pediatr Surg, 2007. 17(6): 400–3.
2004. Mavromanolakis E, Maraki S, Samonis
G, Tselentis Y, and Cranidis A, Effect of
norfloxacin, trimethoprim-sulfamethox-
azole and nitrofurantoin on fecal flora
of women with recurrent urinary tract
infections. J Chemother, 1997. 9(3):
203–7.
2005. Maynard FM and Diokno AC, Urinary
infection and complications during
clean intermittent catheterization fol-
lowing spinal cord injury. J Urol, 1984.
132(5): 943–6.
2006. Mazumdar S and Levine AS, Antisperm
antibodies: etiology, pathogenesis,
diagnosis, and treatment. Fertil Steril,
1998. 70(5): 799–810.
2007. Mazzei T, Cassetta MI, Fallani
S, Arrigucci S, and Novelli A,
Pharmacokinetic and pharmacody-
namic aspects of antimicrobial agents
for the treatment of uncomplicated uri-
nary tract infections. Int J Antimicrob
Agents, 2006. 28 Suppl 1: S35–41.
2008. Mazzola BL, von Vigier RO, Marchand
S, Tonz M, and Bianchetti MG,
Behavioral and functional abnormali-
ties linked with recurrent urinary tract
infections in girls. J Nephrol, 2003.
16(1): 133–8.
2009. Mazzoli S, Cai T, Rupealta V, Gavazzi
A, Castricchi Pagliai R, Mondaini N,
and Bartoletti R, Interleukin 8 and
anti-chlamydia trachomatis mucosal
IgA as urogenital immunologic markers
in patients with C. trachomatis pros-
tatic infection. Eur Urol, 2007. 51(5):
1385–93.
2010. Mazzulli T, Skulnick M, Small G,
Marshall W, Hoban DJ, Zhanel GG,
Finn S, and Low DE, Susceptibility
of community Gram-negative urinary
tract isolates to mecillinam and other
oral agents. Can J Infect Dis, 2001.
12(5): 289–92.
2011. Mboto CI, Davies A, Fielder M, and
Jewell AP, Human immunodeficiency
virus and hepatitis C co-infection in
sub-Saharan West Africa. Br J Biomed
Sci, 2006. 63(1): 29–37.
2012. McAleer IM, Kaplan GW, Bradley JS,
and Carroll SF, Staghorn calculus
1097
References
endotoxin expression in sepsis. Urology,
2002. 59(4): 601.
2013. McAleer IM, Kaplan GW, Bradley JS,
Carroll SF, and Griffith DP, Endotoxin
content in renal calculi. J Urol, 2003.
169(5): 1813–4.
2014. McAleer SJ and Loughlin KR,
Nephrolithiasis and pregnancy. Curr
Opin Urol, 2004. 14(2): 123–7.
2015. McAleer SJ, Johnson CW, and Johnson
Jr. WD, Genitourinary Tuberculosis,
in Campbell-Walsh urology: ninth
edition, Wein AJ, Editor. 2007,
Elsevier Saunders: Philadelphia, Pa.;
Edinburgh. p. xxviii, 528 p.
2016. McCarter YS and Sharp SE,
Laboratory diagnosis of urinary tract
infections. 2009, Washington, D.C.:
ASM Press. 25 p.
2017. McCarty JM, Richard G, Huck W,
Tucker RM, Tosiello RL, Shan M,
Heyd A, and Echols RM, A rand-
omized trial of short-course cipro-
floxacin, ofloxacin, or trimethoprim/
sulfamethoxazole for the treatment
of acute urinary tract infection in
women. Ciprofloxacin Urinary Tract
Infection Group. Am J Med, 1999.
106(3): 292–9.
2018. McClanahan C, Grimes MM, Callaghan
E, and Stewart J, Hemorrhagic cystitis
associated with herpes simplex virus. J
Urol, 1994. 151(1): 152–3.
2019. McConnell JD, Barry MJ, and
Bruskewitz RC, Benign prostatic
hyperplasia: diagnosis and treatment.
Agency for Health Care Policy and
Research. Clin Pract Guidel Quick Ref
Guide Clin, 1994(8): 1–17.
2020. McConnell JD, Roehrborn CG,
Bautista OM, Andriole GL, Jr., Dixon
CM, Kusek JW, Lepor H, McVary KT,
Nyberg LM, Jr., Clarke HS, Crawford
ED, Diokno A, Foley JP, Foster HE,
Jacobs SC, Kaplan SA, Kreder KJ,
Lieber MM, Lucia MS, Miller GJ,
Menon M, Milam DF, Ramsdell JW,
Schenkman NS, Slawin KM, and Smith
JA, The long-term effect of doxazosin,
finasteride, and combination therapy
on the clinical progression of benign
prostatic hyperplasia. N Engl J Med,
2003. 349(25): 2387–98.
1098
2021. McCoombe SG and Short RV, Potential
HIV-1 target cells in the human penis.
Aids, 2006. 20(11): 1491–5.
2022. McCormack WM, Dalu ZA, Martin
DH, Hook EW, 3rd, Laisi R, Kell P,
Pluck ND, and Johnson RB, Double-
blind comparison of trovafloxacin and
doxycycline in the treatment of uncom-
plicated Chlamydial urethritis and
cervicitis. Trovafloxacin Chlamydial
Urethritis/Cervicitis Study Group. Sex
Transm Dis, 1999. 26(9): 531–6.
2023. McCormick RD, Meisch MG, Ircink FG,
and Maki DG, Epidemiology of hospital
sharps injuries: a 14-year prospective
study in the pre-AIDS and AIDS eras.
Am J Med, 1991. 91(3B): 301S-307S.
2024. McCracken GH, Jr., Recurrent urinary
tract infections in children. Pediatr
Infect Dis, 1984. 3(3 Suppl): S28–30.
2025. McDonald A, Scranton M, Gillespie R,
Mahajan V, and Edwards GA, Voiding
cystourethrograms and urinary tract
infections: how long to wait? Pediatrics,
2000. 105(4): E50.
2026. McDougal WS, Use of intestinal
segments and urinary diversion,
in Campbell’s urology, Campbell
MF and Walsh PC, Editors. 1998,
W.B. Saunders Co.: Philadelphia. p.
3121–3161.
2027. McGeer A, Campbell B, Emori
TG, Hierholzer WJ, Jackson MM,
Nicolle LE, Peppler C, Rivera A,
Schollenberger DG, Simor AE, and et
al., Definitions of infection for surveil-
lance in long-term care facilities. Am J
Infect Control, 1991. 19(1): 1–7.
2028. McGregor JA, French JI, and Seo K,
Adjunctive clindamycin therapy for
preterm labor: results of a double-blind,
placebo-controlled trial. Am J Obstet
Gynecol, 1991. 165(4 Pt 1): 867–75.
2029. McGroarty JA and Reid G, Detection of
a Lactobacillus substance that inhibits
Escherichia coli. Can J Microbiol, 1988.
34(8): 974–8.
2030. McGroarty JA and Reid G, Inhibition of
enterococci by Lactobacillus species in
vitro. Microbial Ecol. Health Dis, 1988.
1: 215–219.
2031. McGroarty JA, Faguy D, Bruce
AW, and Reid G, Influence of the

spermicidal compound nonoxynol-9 on
adhesion of E. coli. Int. Urogynecol. J,
1993. 4(4): 194–198.
2032. McHugh TP, Albanna SE, and Stewart
NJ, Bilateral emphysematous pyelone-
phritis. Am J Emerg Med, 1998. 16(2):
166–9.
2033. McIsaac WJ, Moineddin R, and Ross
S, Validation of a decision aid to assist
physicians in reducing unnecessary
antibiotic drug use for acute cysti-
tis. Arch Intern Med, 2007. 167(20):
2201–6.
2034. McKinnon PS, Paladino JA, and
Schentag JJ, Evaluation of area under
the inhibitory curve (AUIC) and time
above the minimum inhibitory con-
centration (T>MIC) as predictors of
outcome for cefepime and ceftazidime
in serious bacterial infections. Int
J Antimicrob Agents, 2008. 31(4):
345–51.
2035. McLean RJ, Lawrence JR, Korber DR,
and Caldwell DE, Proteus mirabilis
biofilm protection against struvite
crystal dissolution and its implications
in struvite urolithiasis. J Urol, 1991.
146(4): 1138–42.
2036. McLuskey K, Cameron S,
Hammerschmidt F, and Hunter WN,
Structure and reactivity of hydroxy-
propylphosphonic acid epoxidase in
fosfomycin biosynthesis by a cation-
and flavin-dependent mechanism. Proc
Natl Acad Sci U S A, 2005. 102(40):
14221–6.
2037. McMahon MJ, Ananth CV, and Liston
RM, Gestational diabetes mellitus. Risk
factors, obstetric complications and
infant outcomes. J Reprod Med, 1998.
43(4): 372–8.
2038. McManus DP, Zhang W, Li J, and
Bartley PB, Echinococcosis. Lancet,
2003. 362(9392): 1295–304.
2039. McMurdo M, Bissett L, Price R,
Phillips G, and Crombie I, Does inges-
tion of cranberry juice reduce sympto-
matic urinary tract infections in older
people in hospital? A double-blind, pla-
cebo-controlled trial. Age Ageing, 2005.
34(3): 256–61.
2040. McMurdo ME and Gillespie ND,
Urinary tract infection in old age:
References
over-diagnosed and over-treated. Age
Ageing, 2000. 29(4): 297–8.
2041. McMurdo ME, Argo I, Phillips G, Daly F,
and Davey P, Cranberry or trimethoprim
for the prevention of recurrent urinary
tract infections? A randomized control-
led trial in older women. J Antimicrob
Chemother, 2009. 63(2): 389–95.
2042. McNair RD, MacDonald SR, Dooley
SL, and Peterson LR, Evaluation of the
centrifuged and Gram-stained smear,
urinalysis, and reagent strip testing
to detect asymptomatic bacteriuria
in obstetric patients. Am J Obstet
Gynecol, 2000. 182(5): 1076–9.
2043. McPhail MJ, Abu-Hilal M, and Johnson
CD, A meta-analysis comparing
suprapubic and transurethral cath-
eterization for bladder drainage after
abdominal surgery. Br J Surg, 2006.
93(9): 1038–44.
2044. Meares EM and Stamey TA,
Bacteriologic localization patterns in
bacterial prostatitis and urethritis.
Invest Urol, 1968. 5(5): 492–518.
2045. Meares EM, Jr., Prostatitis. Med Clin
North Am, 1991. 75(2): 405–24.
2046. Meares EM, Jr., Prostatitis: review of
pharmacokinetics and therapy. Rev
Infect Dis, 1982. 4(2): 475–83.
2047. Mebust WK, Holtgrewe HL, Cockett
AT, and Peters PC, Transurethral pros-
tatectomy: immediate and postoperative
complications. Cooperative study of 13
participating institutions evaluating
3,885 patients. J Urol, 141: 243–247,
1989. J Urol, 2002. 167(1): 5–9.
2048. Medellin-Pena MJ, Wang H, Johnson
R, Anand S, and Griffiths MW,
Probiotics affect virulence-related gene
expression in Escherichia coli O157:H7.
Appl Environ Microbiol, 2007. 73(13):
4259–67.
2049. Medical Devices Agency, Latex medical
gloves (surgeons and examination) pow-
dered latex medical gloves (surgeons
and examination). SN(98)25 1998,
London: HMSO.
2050. Medlar EM, Spain DM, and Holliday
RW, Post-mortem compared with clini-
cal diagnosis of genito-urinary tuber-
culosis in adult males. J Urol, 1949.
61(6): 1078–88.
1099
References
2051. Meier AS, Bukusi EA, Cohen CR, and
Holmes KK, Independent association
of hygiene, socioeconomic status, and
circumcision with reduced risk of HIV
infection among Kenyan men. J Acquir
Immune Defic Syndr, 2006. 43(1):
117–8.
2052. Meiland R, Geerlings SE, and
Hoepelman AI, Management of bacte-
rial urinary tract infections in adult
patients with diabetes mellitus. Drugs,
2002. 62(13): 1859–68.
2053. Meiland R, Geerlings SE, De Neeling
AJ, and Hoepelman AI, Diabetes mel-
litus in itself is not a risk factor for
antibiotic resistance in Escherichia coli
isolated from patients with bacteriuria.
Diabet Med, 2004. 21(9): 1032–4.
2054. Meiland R, Geerlings SE, Stolk RP,
Netten PM, Schneeberger PM, and
Hoepelman AI, Asymptomatic bacteriu-
ria in women with diabetes mellitus:
effect on renal function after 6 years
of follow-up. Arch Intern Med, 2006.
166(20): 2222–7.
2055. Meinhof W, [Hydrochloric acid toler-
ance of Candida albicans]. Mykosen,
1974. 17(12): 339–47.
2056. Meisner M, Brunkhorst FM, Reith HB,
Schmidt J, Lestin HG, and Reinhart K,
Clinical experiences with a new semi-
quantitative solid phase immunoassay
for rapid measurement of procalcitonin.
Clin Chem Lab Med, 2000. 38(10):
989–95.
2057. Melekos MD and Asbach HW,
Epididymitis: aspects concerning eti-
ology and treatment. J Urol, 1987.
138(1): 83–6.
2058. Melekos MD, Asbach HW, Gerharz E,
Zarakovitis IE, Weingaertner K, and
Naber KG, Post-intercourse versus
daily ciprofloxacin prophylaxis for
recurrent urinary tract infections in
premenopausal women. J Urol, 1997.
157(3): 935–9.
2059. Melekos MD, Efficacy of prophylactic
antimicrobial regimens in preventing
infectious complications after tran-
srectal biopsy of the prostate. Int Urol
Nephrol, 1990. 22(3): 257–62.
2060. Melis K, Vandevivere J, Hoskens C,
Vervaet A, Sand A, and Van Acker KJ,
1100
Involvement of the renal parenchyma
in acute urinary tract infection: the con-
tribution of 99mTc dimercaptosuccinic
acid scan. Eur J Pediatr, 1992. 151(7):
536–9.
2061. Memish ZA and Balkhy HH,
Brucellosis and international travel. J
Travel Med, 2004. 11(1): 49–55.
2062. Menday AP, Comparison of pivmecil-
linam and cephalexin in acute uncom-
plicated urinary tract infection. Int J
Antimicrob Agents, 2000. 13(3): 183–7.
2063. Menday AP, Symptomatic vaginal
candidiasis after pivmecillinam and
norfloxacin treatment of acute uncom-
plicated lower urinary tract infection.
Int J Antimicrob Agents, 2002. 20(4):
297–300.
2064. Mendling W and Koldovsky U,
Investigations by cell-mediated immu-
nologic tests and therapeutic trials with
thymopentin in vaginal mycoses. Infect
Dis Obstet Gynecol, 1996. 4(4): 225–31.
2065. Mendling W and Seebacher C,
Vulvovaginalkandidose. AWMF-
Guideline 013/004 (S1), 2008.
2066. Mendling W and Spitzbart H,
Antimykotische Therapie der vaginalen
Hefepilz-Kolonisation von Schwangeren
zur Verhütung von Kandidamykosen
beim Neugeborenen. AMWF, Guideline
015/042 (S1), 2008.
2067. Mendling W, [Torulopsis in gynecol-
ogy]. Geburtshilfe Frauenheilkd, 1984.
44(9): 583–6.
2068. Mendling W, Azoles in the therapy of
vaginal candidosis, in Sterol biosyn-
thesis inhibitors, Berg D and Plempel
M, Editors. 1988, Ellis Horwood:
Chichester. p. 480–506.
2069. Mendling W, Gutschmidt J,
Gantenberg R, Andrade P,
and Schönian G, Vergleich der
Stammspezifität von Hefepilzen ver-
schiedener Lokalisationen bei Frauen
mit Vaginalcandidosen. Mykosen, 1998.
41(Suppl 2): 22–5.
2070. Mendling W, Krauss C, and Fladung
B, A clinical multicenter study compar-
ing efficacy and tolerability of topical
combination therapy with clotrima-
zole (Canesten, two formats) with oral
single dose fluconazole (Diflucan) in

vulvovaginal mycoses. Mycoses, 2004.
47(3–4): 136–42.
2071. Mendling W, Niemann D, and Tintelnot
K, Vaginal Colonisation with Candida
Species with Special Focus on Candida
dubliniensis. A Prospective Study.
Geburtshilfe Frauenheilkd, 2007. 67:
1132–7.
2072. Meng MV, Mario LA, and McAninch
JW, Current treatment and outcomes
of perinephric abscesses. J Urol, 2002.
168(4 Pt 1): 1337–40.
2073. Menghebat L, Jiang L, and Chai J, A
retrospective survey for surgical cases
of cystic echinococcosis in the Xinjiang
Uygur Autonomous Region, PRC
(1951–90), in Compendium on cystic
echinococcosis with special reference
to the Xinjiang Uygur Autonomous
Region, the People’s Republic of
China, Andersen FL, Chai J-j, and
Liu F-j, Editors. 1993, Brigham Young
University: Provo, Utah. p. 135–145.
2074. Mengoli C, Cusinato R, Biasolo MA,
Cesaro S, Parolin C, and Palu G,
Assessment of CMV load in solid organ
transplant recipients by pp65 antigen-
emia and real-time quantitative DNA
PCR assay: correlation with pp67 RNA
detection. J Med Virol, 2004. 74(1):
78–84.
2075. Menif E, Nouira K, Baccar S, Nouira
Y, Mouelhi M, Horchani A, and Slim R,
[Emphysematous pyelonephritis: report
of 3 cases]. Ann Urol (Paris), 2001.
35(2): 97–100.
2076. Menkveld R, Huwe P, Ludwig M, and
Weidner W, Morphological sperm alter-
nations in different types of prostatitis.
Andrologia, 2003. 35(5): 288–93.
2077. Menninger M, Urosepsis, Klinik,
Diagnostik und Therapie, in
Urogenitale Infektionen, Hofstetter
A, Editor. 1998, Springer: Berlin
Heidelberg New York. p. 521–528.
2078. Mentler PA, Kuhn BR, and Gandhi G,
Risk stratification for trimethoprim-sul-
famethoxazole resistance in community-
acquired, uncomplicated urinary tract
infections. Am J Health Syst Pharm,
2006. 63(17): 1588, 1590.
2079. Meretyk S, Gofrit ON, Gafni O, Pode
D, Shapiro A, Verstandig A, Sasson
References
T, Katz G, and Landau EH, Complete
staghorn calculi: random prospective
comparison between extracorporeal
shock wave lithotripsy monotherapy
and combined with percutaneous neph-
rostolithotomy. J Urol, 1997. 157(3):
780–6.
2080. Meria P, Desgrippes A, Fournier R, Arfi
C, Antoine C, Martinat L, Teillac P,
and Le Duc A, The conservative man-
agement of corynebacterium group D2
encrusted pyelitis. BJU Int, 1999. 84(3):
270–5.
2081. Merimsky E and Feldman C,
Perinephric abscess: report of 19 cases.
Int Surg, 1981. 66(1): 79–80.
2082. Mermin J, Musinguzi J, Opio A,
Kirungi W, Ekwaru J, Hladik W,
Kaharuza F, Downing R, and Bunnell
R, Risk Factors for Recent HIV
Infection in Uganda. JAMA, 2008.
300(5): 540–49.
2083. Merrick MV, Notghi A, Chalmers N,
Wilkinson AG, and Uttley WS, Long-
term follow up to determine the prog-
nostic value of imaging after urinary
tract infections. Part 2: Scarring. Arch
Dis Child, 1995. 72(5): 393–6.
2084. Merry C, Barry MG, Ryan M, Tjia JF,
Hennessy M, Eagling VA, Mulcahy F,
and Back DJ, Interaction of sildenafil
and indinavir when co-administered
to HIV-positive patients. AIDS, 1999.
13(15): F101–7.
2085. Mestecky J and Fultz PN, Mucosal
immune system of the human genital
tract. J Infect Dis, 1999. 179 Suppl 3:
S470–4.
2086. Mesurolle B, Mignon F, and Gagnon
JH, Fitz-Hugh-Curtis syndrome caused
by Chlamydia trachomatis: atypical CT
findings. AJR Am J Roentgenol, 2004.
182(3): 822–4; author reply 824.
2087. Metlay JP, Strom BL, and Asch DA,
Prior antimicrobial drug exposure: a
risk factor for trimethoprim-sulfame-
thoxazole-resistant urinary tract infec-
tions. J Antimicrob Chemother, 2003.
51(4): 963–70.
2088. Meyer H, Goettlicher S, and Mendling
W, Stress as a cause of chronic recur-
rent vulvovaginal candidosis and
the effectiveness of the conventional
1101
References
antimycotic therapy. Mycoses, 2006.
49(3): 202–9.
2089. Meyer NL, Hosier KV, Scott K, and
Lipscomb GH, Cefazolin versus cefazo-
lin plus metronidazole for antibiotic
prophylaxis at cesarean section. South
Med J, 2003. 96(10): 992–5.
2090. Meyer-Bahlburg A, Khim S, and
Rawlings DJ, B cell intrinsic TLR sig-
nals amplify but are not required for
humoral immunity. J Exp Med, 2007.
204(13): 3095–101.
2091. Miano R, Germani S, and Vespasiani
G, Stones and urinary tract infections.
Urol Int, 2007. 79 Suppl 1: 32–6.
2092. Michael M, Hodson EM, Craig JC,
Martin S, and Moyer VA, Short com-
pared with standard duration of
antibiotic treatment for urinary tract
infection: a systematic review of ran-
domised controlled trials. Arch Dis
Child, 2002. 87(2): 118–23.
2093. Michael M, Hodson EM, Craig JC,
Martin S, and Moyer VA, Short versus
standard duration oral antibiotic ther-
apy for acute urinary tract infection in
children. Cochrane Database Syst Rev,
2003(1): CD003966.
2094. Michaeli J, Mogle P, Perlberg
S, Heiman S, and Caine M,
Emphysematous pyelonephritis. J Urol,
1984. 131(2): 203–8.
2095. Michels TC, Chronic endometritis. Am
Fam Physician, 1995. 52(1): 217–22.
2096. Michielsen WJ, Geurs FJ,
Verschraegen GL, Claeys GW, and
Afschrift MB, A simple and efficient
urine sampling method for bacteriologi-
cal examination in elderly women. Age
Ageing, 1997. 26(6): 493–5.
2097. Miettinen A, Laine S, Teisala K, and
Heinonen PK, The effect of cipro-
floxacin and doxycycline plus metro-
nidazole on lower genital tract flora
in patients with proven pelvic inflam-
matory disease. Arch Gynecol Obstet,
1991. 249(2): 95–101.
2098. Migliori GB, Loddenkemper R, Blasi
F, and Raviglione MC, 125 years after
Robert Koch’s discovery of the tubercle
bacillus: the new XDR-TB threat. Is
“science” enough to tackle the epidemic?
Eur Respir J, 2007. 29(3): 423–7.
1102
2099. Mikhailichenko VV, Fesenko VN, and
Aletin RR, [Alveolar Echinococcus
(alveococcus) of the kidney]. Vestn Khir
Im I I Grek, 2000. 159(1): 97–9.
2100. Miles BJ, Melser M, Farah R,
Markowitz N, and Fisher E, The uro-
logical manifestations of the acquired
immunodeficiency syndrome. J Urol,
1989. 142(3): 771–3.
2101. Millan Rodriguez F, Orsola de los
Santos A, Vayreda Martija JM, and
Chechile Toniolo G, [Management of
acute prostatitis: experience with 84
patients]. Arch Esp Urol, 1995. 48(2):
129–36.
2102. Millan-Rodriguez F, Palou J, Bujons-
Tur A, Musquera-Felip M, Sevilla-
Cecilia C, Serrallach-Orejas M,
Baez-Angles C, and Villavicencio-
Mavrich H, Acute bacterial prostatitis:
two different sub-categories according
to a previous manipulation of the lower
urinary tract. World J Urol, 2006.
24(1): 45–50.
2103. Millar L, DeBuque L, Leialoha C,
Grandinetti A, and Killeen J, Rapid
enzymatic urine screening test to detect
bacteriuria in pregnancy. Obstet
Gynecol, 2000. 95(4): 601–4.
2104. Millar LK and Cox SM, Urinary tract
infections complicating pregnancy. Infect
Dis Clin North Am, 1997. 11(1): 13–26.
2105. Millar LK, Wing DA, Paul RH, and
Grimes DA, Outpatient treatment of
pyelonephritis in pregnancy: a rand-
omized controlled trial. Obstet Gynecol,
1995. 86(4 Pt 1): 560–4.
2106. Miller J, Ludwig M, Schroeder-
Printzen I, Schiefer HG, and Weidner
W, Transurethral laser therapy and uri-
nary tract infections. Ann Urol (Paris),
1996. 30(3): 131–8.
2107. Miller JL and Krieger JN, Urinary
tract infections cranberry juice, under-
wear, and probiotics in the 21st cen-
tury. Urol Clin North Am, 2002. 29(3):
695–9.
2108. Miller T and Phillips S, Pyelonephritis:
the relationship between infection, renal
scarring, and antimicrobial therapy.
Kidney Int, 1981. 19(5): 654–62.
2109. Millett GA, Ding H, Lauby J, Flores S,
Stueve A, Bingham T, Carballo-Dieguez

A, Murrill C, Liu KL, Wheeler D, Liau
A, and Marks G, Circumcision status
and HIV infection among Black and
Latino men who have sex with men in
3 US cities. J Acquir Immune Defic
Syndr, 2007. 46(5): 643–50.
2110. Mills M, Meysick KC, and O’Brien AD,
Cytotoxic necrotizing factor type 1 of
uropathogenic Escherichia coli kills
cultured human uroepithelial 5637
cells by an apoptotic mechanism. Infect
Immun, 2000. 68(10): 5869–80.
2111. Milutinovic J, Fialkow PJ, Agodoa LY,
Phillips LA, Rudd TG, and Sutherland
S, Clinical manifestations of autosomal
dominant polycystic kidney disease
in patients older than 50 years. Am J
Kidney Dis, 1990. 15(3): 237–43.
2112. Mims AD, Norman DC, Yamamura RH,
and Yoshikawa TT, Clinically inap-
parent (asymptomatic) bacteriuria in
ambulatory elderly men: epidemiologi-
cal, clinical, and microbiological find-
ings. J Am Geriatr Soc, 1990. 38(11):
1209–14.
2113. Minassian MA, Lewis DA,
Chattopadhyay D, Bovill B, Duckworth
GJ, and Williams JD, A compari-
son between single-dose fosfomycin
trometamol (Monuril) and a 5-day
course of trimethoprim in the treatment
of uncomplicated lower urinary tract
infection in women. Int J Antimicrob
Agents, 1998. 10(1): 39–47.
2114. Minervini A, Ralph DJ, and Pryor JP,
Outcome of penile prosthesis implanta-
tion for treating erectile dysfunction:
experience with 504 procedures. BJU
Int, 2006. 97(1): 129–33.
2115. Mingeot-Leclercq MP and Tulkens
PM, Aminoglycosides: nephrotoxicity.
Antimicrob Agents Chemother, 1999.
43(5): 1003–12.
2116. Mingeot-Leclercq MP, Glupczynski
Y, and Tulkens PM, Aminoglycosides:
activity and resistance. Antimicrob
Agents Chemother, 1999. 43(4):
727–37.
2117. Miriagou V, Tzouvelekis LS, Rossiter
S, Tzelepi E, Angulo FJ, and Whichard
JM, Imipenem resistance in a
Salmonella clinical strain due to plas-
mid-mediated class A carbapenemase
References
KPC-2. Antimicrob Agents Chemother,
2003. 47(4): 1297–300.
2118. Miron D, Daas A, Sakran W, Lumelsky
D, Koren A, and Horovitz Y, Is omit-
ting post urinary-tract-infection renal
ultrasound safe after normal antenatal
ultrasound? An observational study.
Arch Dis Child, 2007. 92(6): 502–4.
2119. Mishra V, Assche SB, Greener R,
Vaessen M, Hong R, Ghys PD, Boerma
JT, Van Assche A, Khan S, and Rutstein
S, HIV infection does not disproportion-
ately affect the poorer in sub-Saharan
Africa. Aids, 2007. 21 Suppl 7: S17–28.
2120. Mishra VC, Allen DJ, Nicolaou
C, Sharif H, Hudd C, Karim OM,
Motiwala HG, and Laniado ME, Does
intraprostatic inflammation have a role
in the pathogenesis and progression of
benign prostatic hyperplasia? BJU Int,
2007. 100(2): 327–31.
2121. Mitsumori K, Terai A, Yamamoto
S, and Yoshida O, Virulence char-
acteristics and DNA fingerprints of
Escherichia coli isolated from women
with acute uncomplicated pyelonephri-
tis. J Urol, 1997. 158(6): 2329–32.
2122. Mittal R, Khandwaha RK, Gupta V,
Mittal PK, and Harjai K, Phenotypic
characters of urinary isolates of
Pseudomonas aeruginosa & their asso-
ciation with mouse renal colonization.
Indian J Med Res, 2006. 123(1): 67–72.
2123. Mitterberger M, Pinggera GM,
Colleselli D, Bartsch G, Strasser
H, Steppan I, Pallwein L, Friedrich
A, Gradl J, and Frauscher F, Acute
pyelonephritis: comparison of diagnosis
with computed tomography and con-
trast-enhanced ultrasonography. BJU
Int, 2008. 101(3): 341–4.
2124. Miyake K, Roles for accessory molecules
in microbial recognition by Toll-like
receptors. J Endotoxin Res, 2006. 12(4):
195–204.
2125. Mobley HL and Belas R, Swarming
and pathogenicity of Proteus mirabilis
in the urinary tract. Trends Microbiol,
1995. 3(7): 280–4.
2126. Mobley HL and Hausinger RP,
Microbial ureases: significance, regula-
tion, and molecular characterization.
Microbiol Rev, 1989. 53(1): 85–108.
1103
References
2127. Mobley HL, Chippendale GR, Swihart
KG, and Welch RA, Cytotoxicity of the
HpmA hemolysin and urease of Proteus
mirabilis and Proteus vulgaris against
cultured human renal proximal tubular
epithelial cells. Infect Immun, 1991.
59(6): 2036–42.
2128. Moerer O, Schmid A, Hofmann M,
Herklotz A, Reinhart K, Werdan K,
Schneider H, and Burchardi H, Direct
costs of severe sepsis in three German
intensive care units based on retrospec-
tive electronic patient record analysis of
resource use. Intensive Care Med, 2002.
28(10): 1440–6.
2129. Mohanty NK and Jolly BB, Prevalence
of bacterial prostatitis in benign pro-
static hyperplasia. Indian J Pathol
Microbiol, 1996. 39(2): 111–4.
2130. Mohler JL, Cowen DL, and Flanigan
RC, Suppression and treatment of uri-
nary tract infection in patients with an
intermittently catheterized neurogenic
bladder. J Urol, 1987. 138(2): 336–40.
2131. Mohllajee AP, Curtis KM, and Peterson
HB, Does insertion and use of an intra-
uterine device increase the risk of pelvic
inflammatory disease among women
with sexually transmitted infection? A
systematic review. Contraception, 2006.
73(2): 145–53.
2132. Mohllajee AP, Curtis KM, Martins SL,
and Peterson HB, Hormonal contra-
ceptive use and risk of sexually trans-
mitted infections: a systematic review.
Contraception, 2006. 73(2): 154–65.
2133. Molander P, Cacciatore B, Sjoberg J,
and Paavonen J, Laparoscopic manage-
ment of suspected acute pelvic inflam-
matory disease. J Am Assoc Gynecol
Laparosc, 2000. 7(1): 107–10.
2134. Molander U, Arvidsson L, Milsom I,
and Sandberg T, A longitudinal cohort
study of elderly women with urinary
tract infections. Maturitas, 2000. 34(2):
127–31.
2135. Molavi A, Cephalosporins. Rational for
clinical use-review article. American
family physician, 1991. March 1991.
2136. Moller BR, Taylor-Robinson D, Furr
PM, and Freundt EA, Acute upper geni-
tal-tract disease in female monkeys pro-
voked experimentally by Mycoplasma
1104
genitalium. Br J Exp Pathol, 1985.
66(4): 417–26.
2137. Montague DK, Periprosthetic infec-
tions. J Urol, 1987. 138(1): 68–9.
2138. Montgomery JS, Johnston WK, 3rd,
and Wolf JS, Jr., Wound complications
after hand assisted laparoscopic sur-
gery. J Urol, 2005. 174(6): 2226–30.
2139. Montini G and Hewitt I, Urinary tract
infections: to prophylaxis or not to
prophylaxis? Pediatr Nephrol, 2009.
2140. Montini G, Rigon L, Zucchetta P,
Fregonese F, Toffolo A, Gobber D,
Cecchin D, Pavanello L, Molinari PP,
Maschio F, Zanchetta S, Cassar W,
Casadio L, Crivellaro C, Fortunati
P, Corsini A, Calderan A, Comacchio
S, Tommasi L, Hewitt IK, Da Dalt
L, Zacchello G, and Dall’Amico R,
Prophylaxis after first febrile urinary
tract infection in children? A multi-
center, randomized, controlled, nonin-
feriority trial. Pediatrics, 2008. 122(5):
1064–71.
2141. Montini G, Toffolo A, Zucchetta P,
Dall’Amico R, Gobber D, Calderan
A, Maschio F, Pavanello L, Molinari
PP, Scorrano D, Zanchetta S, Cassar
W, Brisotto P, Corsini A, Sartori S,
Da Dalt L, Murer L, and Zacchello G,
Antibiotic treatment for pyelonephritis
in children: multicentre randomised
controlled non-inferiority trial. BMJ,
2007. 335(7616): 386.
2142. Moodley P, Martin IM, Pillay K, Ison
CA, and Sturm AW, Molecular epidemi-
ology of recently emergent ciprofloxacin-
resistant Neisseria gonorrhoeae in
South Africa. Sex Transm Dis, 2006.
33(6): 357–60.
2143. Moodley P, Pillay C, Nzimande G,
Coovadia YM, and Sturm AW, Lower
dose of ciprofloxacin is adequate for
the treatment of Neisseria gonorrhoeae
in KwaZulu Natal, South Africa. Int
J Antimicrob Agents, 2002. 20(4):
248–52.
2144. Moody FG, Lithotripsy in the treat-
ment of biliary stones. Am J Surg, 1993.
165(4): 479–82.
2145. Moonen WA, Stricture of the ureter and
contracture of the bladder and bladder
neck due to tuberculosis: their diagnosis

and treatment. J Urol, 1958. 80(4):
218–28.
2146. Moore EE, Hawes SE, Scholes D,
Boyko EJ, Hughes JP, and Fihn SD,
Sexual intercourse and risk of sympto-
matic urinary tract infection in post-
menopausal women. J Gen Intern Med,
2008. 23(5): 595–9.
2147. Moore KN, Fader M, and Getliffe K,
Long-term bladder management by
intermittent catheterisation in adults
and children. Cochrane Database Syst
Rev, 2007(4): CD006008.
2148. Moore RA, Inflammation of the prostate
gland. J Urol, 1937. 38: 173–82.
2149. Mor Z, Kent CK, Kohn RP, and
Klausner JD, Declining rates in male
circumcision amidst increasing evi-
dence of its public health benefit. PLoS
ONE, 2007. 2(9): e861.
2150. Moradi M, Abbasi M, Moradi A,
Boskabadi A, and Jalali A, Effect of
antibiotic therapy on asymptomatic
bacteriuria in kidney transplant recipi-
ents. Urol J, 2005. 2(1): 32–5.
2151. Moraes PS, de Lima Goiaba S, and
Taketomi EA, Candida albicans
allergen immunotherapy in recurrent
vaginal candidiasis. J Investig Allergol
Clin Immunol, 2000. 10(5): 305–9.
2152. Morelli L, Zonenenschain D, Del
Piano M, and Cognein P, Utilization
of the intestinal tract as a delivery
system for urogenital probiotics. J
Clin Gastroenterol, 2004. 38(6 Suppl):
S107–10.
2153. Morello FA, Jr., Mansilla AV, and
Wallace MJ, Removal of renal fungus
balls using a mechanical thrombectomy
device. AJR Am J Roentgenol, 2002.
178(5): 1191–3.
2154. Moreno E, Planells I, Prats G,
Planes AM, Moreno G, and Andreu
A, Comparative study of Escherichia
coli virulence determinants in strains
causing urinary tract bacteremia ver-
sus strains causing pyelonephritis and
other sources of bacteremia. Diagn
Microbiol Infect Dis, 2005. 53(2):
93–9.
2155. Mori R, Lakhanpaul M, and Verrier-
Jones K, Diagnosis and management
of urinary tract infection in children:
References
summary of NICE guidance. BMJ,
2007. 335(7616): 395–7.
2156. Moritz RL and Welch RA, The
Escherichia coli argW-dsdCXA genetic
island is highly variable, and E. coli K1
strains commonly possess two copies of
dsdCXA. J Clin Microbiol, 2006. 44(11):
4038–48.
2157. Morote J, Lopez M, Encabo G, and de
Torres IM, Effect of inflammation and
benign prostatic enlargement on total
and percent free serum prostatic specific
antigen. Eur Urol, 2000. 37(5): 537–40.
2158. Morris BJ, Why circumcision is a bio-
medical imperative for the 21(st) cen-
tury. Bioessays, 2007. 29(11): 1147–58.
2159. Morris SR, Knapp JS, Moore DF, Trees
DL, Wang SA, Bolan G, and Bauer HM,
Using strain typing to characterise a
fluoroquinolone-resistant Neisseria
gonorrhoeae transmission network in
southern California. Sex Transm Infect,
2008. 84(4): 290–1.
2160. Morton SC, Shekelle PG, Adams JL,
Bennett C, Dobkin BH, Montgomerie J,
and Vickrey BG, Antimicrobial prophy-
laxis for urinary tract infection in
persons with spinal cord dysfunction.
Arch Phys Med Rehabil, 2002. 83(1):
129–38.
2161. Moser C, Kriegbaum NJ, Larsen SO,
Hoiby N, and Biering-Sorensen F,
Antibodies to urinary tract pathogens
in patients with spinal cord lesions.
Spinal Cord, 1998. 36(9): 613–6.
2162. Moses S, Nagelkerke NJ, and
Blanchard J, Analysis of the scientific
literature on male circumcision and
risk for HIV infection. Int J STD AIDS,
1999. 10(9): 626–8.
2163. Mosetti MA, Leonardou P, Motohara T,
Kanematsu M, Armao D, and Semelka
RC, Autosomal dominant polycystic
kidney disease: MR imaging evalua-
tion using current techniques. J Magn
Reson Imaging, 2003. 18(2): 210–5.
2164. Mould JW and Carson CC, Infectious
complications of penile prostheses.
Infections in Urology, 1989. 139: 50–52.
2165. Moussa OM, Eraky I, El-Far MA,
Osman HG, and Ghoneim MA, Rapid
diagnosis of genitourinary tuberculosis
by polymerase chain reaction and non-
1105
References
radioactive DNA hybridization. J Urol,
2000. 164(2): 584–8.
2166. Mouton JW and Vinks AA, Continuous
infusion of beta-lactams. Curr Opin
Crit Care, 2007. 13(5): 598–606.
2167. Mouton JW, Dudley MN, Cars O,
Derendorf H, and Drusano GL,
Standardization of pharmacokinetic/
pharmacodynamic (PK/PD) terminol-
ogy for anti-infective drugs: an update.
J Antimicrob Chemother, 2005. 55(5):
601–7.
2168. Mouton YJ and Beuscart C, Empirical
monotherapy with meropenem in seri-
ous bacterial infections. Meropenem
Study Group. J Antimicrob Chemother,
1995. 36 Suppl A: 145–56.
2169. Moylan JA, Fitzpatrick KT, and
Davenport KE, Reducing wound infec-
tions. Improved gown and drape bar-
rier performance. Arch Surg, 1987.
122(2): 152–7.
2170. Mucci B and Maguire B, Does routine
ultrasound have a role in the investi-
gation of children with urinary tract
infection? Clin Radiol, 1994. 49(5):
324–5.
2171. Muder RR, Brennen C, Drenning SD,
Stout JE, and Wagener MM, Multiply
antibiotic-resistant gram-negative
bacilli in a long-term-care facility: a
case-control study of patient risk fac-
tors and prior antibiotic use. Infect
Control Hosp Epidemiol, 1997. 18(12):
809–13.
2172. Muder RR, Brennen C, Rihs JD,
Wagener MM, Obman A, Stout JE,
and Yu VL, Isolation of Staphylococcus
aureus from the urinary tract: asso-
ciation of isolation with symptomatic
urinary tract infection and subsequent
staphylococcal bacteremia. Clin Infect
Dis, 2006. 42(1): 46–50.
2173. Mueller BU, MacKay K, Cheshire LB,
Choyke PL, Kitchen B, Widemann B,
and Pizzo PA, Cytomegalovirus uret-
eritis as a cause of renal failure in a
child infected with the human immuno-
deficiency virus. Clin Infect Dis, 1995.
20(4): 1040–3.
2174. Mulcahy JJ, Brant MD, and Ludlow
JK, Management of infected penile
implants. Tech Urol, 1995. 1(3): 115–9.
1106
2175. Mulcahy JJ, Management of the
infected penile implant—concepts on
salvage techniques. Int J Impot Res,
1999. 11 Suppl 1: S58–9.
2176. Mulcahy JJ, Treatment alternatives for
the infected penile implant. Int J Impot
Res, 2003. 15 Suppl 5: S147–9.
2177. Muller B, Becker KL, Schachinger H,
Rickenbacher PR, Huber PR, Zimmerli
W, and Ritz R, Calcitonin precursors
are reliable markers of sepsis in a medi-
cal intensive care unit. Crit Care Med,
2000. 28(4): 977–83.
2178. Muller J, Wold B, Kubitta D, and
Baument J, Quantitative inter-
suchangen uber die doderlein-flora
gesunder sowie mykosekranker
probandinnen unter lokaler isconatol-
nitrat therapie, in Mongraphic excerpta
medica, Seelinger HPR, Editor. 1981:
Amsterdam, Oxford, Princeton. p.
81–93.
2179. Muller LM, Gorter KJ, Hak E,
Goudzwaard WL, Schellevis FG,
Hoepelman AI, and Rutten GE,
Increased risk of common infections in
patients with type 1 and type 2 diabetes
mellitus. Clin Infect Dis, 2005. 41(3):
281–8.
2180. Mulvaney WP, A new solvent for certain
urinary calculi: a preliminary report. J
Urol, 1959. 82: 546–8.
2181. Mulvaney WP, The clinical use of rena-
cidin in urinary calcifications. J Urol,
1960. 84: 206–12.
2182. Mulvey M, Lopez-Boado Y, Wilson
C, Roth R, Parks W, Heuser J, and
Hultgren S, Induction and evasion
of host defenses by type 1-piliated
uropathogenic Escherichia coli.
Science, 1998. 282: 494–497.
2183. Mulvey MA, Adhesion and entry of
uropathogenic Escherichia coli. Cell
Microbiol, 2002. 4(5): 257–71.
2184. Mulvey MA, Lopez-Boado YS, Wilson
CL, Roth R, Parks WC, Heuser J,
and Hultgren SJ, Induction and eva-
sion of host defenses by type 1-piliated
uropathogenic Escherichia coli.
Science, 1998. 282(5393): 1494–7.
2185. Mulvey MA, Schilling JD, and
Hultgren SJ, Establishment of a per-
sistent Escherichia coli reservoir during

the acute phase of a bladder infection.
Infect Immun, 2001. 69(7): 4572–9.
2186. Mulvey MA, Schilling JD, Martinez JJ,
and Hultgren SJ, Bad bugs and belea-
guered bladders: interplay between
uropathogenic Escherichia coli and
innate host defenses. Proc Natl Acad Sci
U S A, 2000. 97(16): 8829–35.
2187. Munar MY and Singh H, Drug dosing
adjustments in patients with chronic
kidney disease. Am Fam Physician,
2007. 75(10): 1487–96.
2188. Mungadi IA and Ntia IO, Management
of “watering-can” perineum. East Afr
Med J, 2007. 84(6): 283–6.
2189. Munoz P, Management of urinary tract
infections and lymphocele in renal
transplant recipients. Clin Infect Dis,
2001. 33 Suppl 1: S53–7.
2190. Muratani T and Matsumoto T,
Bacterial resistance to antimicrobials
in urinary isolates. Int J Antimicrob
Agents, 2004. 24 Suppl 1: S28–31.
2191. Muratani T, Iihara K, Nishimura T,
Inatomi H, Fujimoto N, Kobayashi
T, Yamada Y, Takahashi K, and
Matsumoto T, [Faropenem 300 mg
3 times daily versus levofloxacin
100 mg 3 times daily in the treat-
ment of urinary tract infections in
patients with neurogenic bladder
and/or benign prostatic hypertrophy].
Kansenshogaku Zasshi, 2002. 76(11):
928–38.
2192. Muratani T, Inatomi H, Ando Y, Kawai
S, Akasaka S, and Matsumoto T,
Single dose 1 g ceftriaxone for urogeni-
tal and pharyngeal infection caused
by Neisseria gonorrhoeae. Int J Urol,
2008. 15(9): 837–42.
2193. Muratani T, Kobayashi T, and
Matsumoto T, Emergence and preva-
lence of beta-lactamase-producing
Klebsiella pneumoniae resistant to
cephems in Japan. Int J Antimicrob
Agents, 2006. 27(6): 491–9.
2194. Murphy DM, Fallon B, Lane V, and
O’Flynn JD, Tuberculous stricture of
ureter. Urology, 1982. 20(4): 382–4.
2195. Murray S and Wooltorton E, Septic
shock after medical abortions with
mifepristone (Mifeprex, RU 486) and
misoprostol. CMAJ, 2005. 173(5): 485.
References
2196. Murthy B and Schmitt-Hoffmann
A, Pharmacokinetics and
Pharmacodynamics of Ceftobiprole, an
Anti-MRSA Cephalosporin with Broad-
Spectrum Activity. Clin Pharmacokinet,
2008. 47(1): 21–33.
2197. Muto CA, Blank MK, Marsh JW, Vergis
EN, O’Leary MM, Shutt KA, Pasculle
AW, Pokrywka M, Garcia JG, Posey
K, Roberts TL, Potoski BA, Blank GE,
Simmons RL, Veldkamp P, Harrison
LH, and Paterson DL, Control of an
outbreak of infection with the hyper-
virulent Clostridium difficile BI strain
in a university hospital using a compre-
hensive “bundle” approach. Clin Infect
Dis, 2007. 45(10): 1266–73.
2198. Muto CA, Jernigan JA, Ostrowsky BE,
Richet HM, Jarvis WR, Boyce JM, and
Farr BM, SHEA guideline for prevent-
ing nosocomial transmission of multid-
rug-resistant strains of Staphylococcus
aureus and enterococcus. Infect Control
Hosp Epidemiol, 2003. 24(5): 362–86.
2199. Muttarak M, Peh WC, Lojanapiwat
B, and Chaiwun B, Tuberculous
epididymitis and epididymo-orchitis:
sonographic appearances. AJR Am J
Roentgenol, 2001. 176(6): 1459–66.
2200. Myer L, Denny L, Telerant R, Souza M,
Wright TC, Jr., and Kuhn L, Bacterial
vaginosis and susceptibility to HIV
infection in South African women: a
nested case-control study. J Infect Dis,
2005. 192(8): 1372–80.
2201. Mysorekar IU and Hultgren SJ,
Mechanisms of uropathogenic
Escherichia coli persistence and eradi-
cation from the urinary tract. Proc Natl
Acad Sci U S A, 2006. 103(38): 14170–5.
2202. Mysorekar IU, Isaacson-Schmid M,
Walker JN, Mills JC, and Hultgren SJ,
Bone morphogenetic protein 4 signaling
regulates epithelial renewal in the uri-
nary tract in response to uropathogenic
infection. Cell Host Microbe, 2009. 5(5):
463–75.
2203. Mysorekar IU, Mulvey MA, Hultgren
SJ, and Gordon JI, Molecular regula-
tion of urothelial renewal and host
defenses during infection with uropath-
ogenic Escherichia coli. J Biol Chem,
2002. 277(9): 7412–9.
1107
References
2204. Naas T, Nordmann P, Vedel G, and
Poyart C, Plasmid-mediated carbapen-
em-hydrolyzing beta-lactamase KPC in
a Klebsiella pneumoniae isolate from
France. Antimicrob Agents Chemother,
2005. 49(10): 4423–4.
2205. Naber CK, Steghafner M, Kinzig-
Schippers M, Sauber C, Sorgel
F, Stahlberg HJ, and Naber KG,
Concentrations of gatifloxacin in
plasma and urine and penetration into
prostatic and seminal fluid, ejaculate,
and sperm cells after single oral admin-
istrations of 400 milligrams to volun-
teers. Antimicrob Agents Chemother,
2001. 45(1): 293–7.
2206. Naber K, Schito G, Botto H, Palou
J, and Mazzei T, Surveillance Study
in Europe and Brazil on Clinical
Aspects and Antimicrobial Resistance
Epidemiology in Females with Cystitits
(ARESC): Implications for Empiric
Therapy. Eur Urol, 2008. 54(5):
1164–78.
2207. Naber KG and Adam D, Classification
of fluoroquinolones. Int J Antimicrob
Agents, 1998. 10(4): 255–7.
2208. Naber KG and Giamarellou H,
Proposed study design in prostatitis.
Infection, 1994. 22 Suppl 1: S59–60.
2209. Naber KG and Koch EM, Cefuroxime
axetil versus ofloxacin for short-term
therapy of acute uncomplicated lower
urinary tract infections in women.
Infection, 1993. 21(1): 34–9.
2210. Naber KG and Sorgel F, Antibiotic
therapy—rationale and evidence for
optimal drug concentrations in pros-
tatic and seminal fluid and in prostatic
tissue. Andrologia, 2003. 35(5): 331–5.
2211. Naber KG BW, Fischer M, Kresken M,
Pefloxacin single-dose in the treatment
of acute uncomplicated lower urinary
tract infections in women: a meta-
analysis of seven clinical trials. Int J
Antimicrob Agents, 1994. 4: 197–202.
2212. Naber KG SS, Hauke W, Cefpodoxime
proxetil in patients with acute uncom-
plicated pyelonephritis. International,
prospective, randomized comparative
study versus ciprofloxacin in general
practice. Chemotherapie Journal, 2001.
10: 29–34.
1108
2213. Naber KG, Allin DM, Clarysse L,
Haworth DA, James IG, Raini C,
Schneider H, Wall A, Weitz P, Hopkins
G, and Ankel-Fuchs D, Gatifloxacin
400 mg as a single shot or 200 mg
once daily for 3 days is as effective as
ciprofloxacin 250 mg twice daily for
the treatment of patients with uncom-
plicated urinary tract infections. Int
J Antimicrob Agents, 2004. 23(6):
596–605.
2214. Naber KG, Bartnicki A, Bischoff W,
Hanus M, Milutinovic S, van Belle F,
Schonwald S, Weitz P, and Ankel-Fuchs
D, Gatifloxacin 200 mg or 400 mg once
daily is as effective as ciprofloxacin
500 mg twice daily for the treatment of
patients with acute pyelonephritis or
complicated urinary tract infections.
Int J Antimicrob Agents, 2004. 23
Suppl 1: S41–53.
2215. Naber KG, Bergman B, Bishop MC,
Bjerklund-Johansen TE, Botto H,
Lobel B, Jinenez Cruz F, and Selvaggi
FP, EAU guidelines for the manage-
ment of urinary and male genital tract
infections. Urinary Tract Infection
(UTI) Working Group of the Health
Care Office (HCO) of the European
Association of Urology (EAU). Eur
Urol, 2001. 40(5): 576–88.
2216. Naber KG, Bishop MC, and Bjerklund-
Johansen TE, The management of uri-
nary and male genital tract infections,
in European Association of Urology
Guidelines, Office EG, Editor. 2006,
Drukkerij Gelderland: Arnhem, The
Netherlands. p. 1–126.
2217. Naber KG, Bishop MC, Bjerklund-
Johansen TE, Botto H, Cek M,
Grabe M, Lobel B, Palou J, and P
T, Guidelines on the Management
of Urinary and Male Genital Tract
Infections. EU Guidelines, 2006.
2218. Naber KG, Busch W, and Focht J,
Ciprofloxacin in the treatment of
chronic bacterial prostatitis: a prospec-
tive, non-comparative multicentre clini-
cal trial with long-term follow-up. The
German Prostatitis Study Group. Int J
Antimicrob Agents, 2000. 14(2): 143–9.
2219. Naber KG, Cho YH, Matsumoto T,
and Schaeffer AJ, Immunoactive

prophylaxis of recurrent urinary tract
infections: a meta-analysis. Int J
Antimicrob Agents, 2009. 33(2): 111–9.
2220. Naber KG, Eisenstein, B.I., Tally, F.P.,
Daptomycin versus ciprofloxacin in the
treatment of complicated urinary tract
infection due to Gram-positive bacte-
ria. Infect Dis Clin Pract, 2004. 12:
322–327.
2221. Naber KG, Experience with the new
guidelines on evaluation of new anti-
infective drugs for the treatment of uri-
nary tract infections. Int J Antimicrob
Agents, 1999. 11(3–4): 189–96; discus-
sion 213–6.
2222. Naber KG, Hofstetter AG, Bruhl P,
Bichler K, and Lebert C, Guidelines for
the perioperative prophylaxis in uro-
logical interventions of the urinary and
male genital tract. Int J Antimicrob
Agents, 2001. 17(4): 321–6.
2223. Naber KG, Llorens, L., Kaniga, K.,
Kotey, P., Redman, R., Intravenous
therapy with doripenem versus levo-
floxacin with an option to switch to
oral therapy for the treatment of com-
plicated lower urinary tract infection
and pyelonephritis. Antimicr Agents
Chemotherapy, submitted.
2224. Naber KG, Lomefloxacin versus cip-
rofloxacin in the treatment of chronic
bacterial prostatitis. Int J Antimicrob
Agents, 2002. 20(1): 18–27.
2225. Naber KG, Management of bacterial
prostatitis: what’s new? BJU Int, 2008.
101 Suppl 3: 7–10.
2226. Naber KG, Prostatitis. Nephrol Dial
Transplant, 2001. 16 Suppl 6: 132–4.
2227. Naber KG, Roscher K, Botto H, and
Schaefer V, Oral levofloxacin 500 mg
once daily in the treatment of chronic
bacterial prostatitis. Int J Antimicrob
Agents, 2008. 32(2): 145–53.
2228. Naber KG, Savov O, and Salmen HC,
Piperacillin 2 g/tazobactam 0.5 g is
as effective as imipenem 0.5 g/cilas-
tatin 0.5 g for the treatment of acute
uncomplicated pyelonephritis and
complicated urinary tract infections.
Int J Antimicrob Agents, 2002. 19(2):
95–103.
2229. Naber KG, Schito G, Botto H, Palou
J, and Mazzei T, Surveillance study
References
in Europe and Brazil on clinical
aspects and Antimicrobial Resistance
Epidemiology in Females with Cystitis
(ARESC): implications for empiric ther-
apy. Eur Urol, 2008. 54(5): 1164–75.
2230. Naber KG, Schito, G.C., Botto, H.,
Palou, J., Mazzei, T., Surveillance
study in Europe and Brazil on clinical
aspects and antimicrobial resistance
epidemiology in females with cystitis
(ARESC): Implications for empiric ther-
apy. European Urology, 2008. in press.
2231. Naber KG, Schito, G.C., Gualco,L. on
behalf of the ARESC working group.
An international survey on etiology
and susceptibility of uropathogens iso-
lated from women with uncomplicated
UTI: the ARESC study. in Interscience
Conference on Antimicrobial Agents
and Chemotherapy (ICAAC). 2007.
Chicago, Ilinois, USA.
2232. Naber KG, Short-term therapy of acute
uncomplicated cystitis. Curr Opin Urol,
1999. 9(1): 57–64.
2233. Naber KG, Urogenital infections: The
pivotal role of the urologist. Eur Urol,
2006. 50(4): 657–9.
2234. Naber KG, Which fluoroquinolones
are suitable for the treatment of uri-
nary tract infections? Int J Antimicrob
Agents, 2001. 17(4): 331–41.
2235. Naber KG, Witte W, Bauernfeind A,
Wiedemann B, Wagenlehner F, Klare
I, and Heisig P, Clinical significance
and spread of fluoroquinolone resistant
uropathogens in hospitalised urological
patients. Infection, 1994. 22 Suppl 2:
S122–7.
2236. Nacey JN, Tulloch AG, and Ferguson
AF, Catheter-induced urethritis: a com-
parison between latex and silicone cath-
eters in a prospective clinical trial. Br J
Urol, 1985. 57(3): 325–8.
2237. Nadkarni AS, Schliep T, Khan L, and
Zeana CB, Cluster of bloodstream infec-
tions caused by KPC-2 carbapenemase-
producing Klebsiella pneumoniae in
Manhattan. Am J Infect Control, 2009.
37(2): 121–6.
2238. Naglik J, Albrecht A, Bader O, and
Hube B, Candida albicans proteinases
and host/pathogen interactions. Cell
Microbiol, 2004. 6(10): 915–26.
1109
References
2239. Nagot N, Ouedraogo A, Foulongne V,
Konate I, Weiss HA, Vergne L, Defer
MC, Djagbare D, Sanon A, Andonaba
JB, Becquart P, Segondy M, Vallo
R, Sawadogo A, Van de Perre P, and
Mayaud P, Reduction of HIV-1 RNA
levels with therapy to suppress herpes
simplex virus. N Engl J Med, 2007.
356(8): 790–9.
2240. Najmaldin A, Burge DM, and Atwell
JD, Reflux nephropathy secondary to
intrauterine vesicoureteric reflux. J
Pediatr Surg, 1990. 25(4): 387–90.
2241. Nakada J, Kawahara M, Onodera S,
and Oishi Y, [Clinical study of Silver
Lubricath Foley catheter]. Hinyokika
Kiyo, 1996. 42(6): 433–8.
2242. Nakai H, Asanuma H, Shishido S,
Kitahara S, and Yasuda K, Changing
concepts in urological management of
the congenital anomalies of kidney and
urinary tract, CAKUT. Pediatr Int,
2003. 45(5): 634–41.
2243. Nakanishi K and Yoshikawa N, Genetic
disorders of human congenital anoma-
lies of the kidney and urinary tract
(CAKUT). Pediatr Int, 2003. 45(5):
610–6.
2244. Narayana AS, Kelly DG, and Duff FA,
Tuberculosis of the penis. Br J Urol,
1976. 48(4): 274.
2245. Nassoura Z, Ivatury RR, Simon RJ,
Jabbour N, and Stahl WM, Candiduria
as an early marker of disseminated
infection in critically ill surgical
patients: the role of fluconazole therapy.
J Trauma, 1993. 35(2): 290–4; discus-
sion 294–5.
2246. Nathwani D and Wood MJ, Penicillins.
A current review of their clinical phar-
macology and therapeutic use. Drugs,
1993. 45(6): 866–94.
2247. Nathwani D, Morgan M, Masterton
RG, Dryden M, Cookson BD, French G,
and Lewis D, Guidelines for UK prac-
tice for the diagnosis and management
of methicillin-resistant Staphylococcus
aureus (MRSA) infections present-
ing in the community. J Antimicrob
Chemother, 2008. 61(5): 976–94.
2248. National guideline clearinghouse,
Guideline for treatment of urinary tract
infections. http://www.guideline.gov.
1110
2249. National Nosocomial Infections
Surveillance (NNIS) report, data
summary from October 1986-April
1996, issued May 1996. A report from
the National Nosocomial Infections
Surveillance (NNIS) System. Am J
Infect Control, 1996. 24(5): 380–8.
2250. National Nosocomial Infections
Surveillance (NNIS) System Report,
data summary from January 1992
through June 2004, issued October
2004. Am J Infect Control, 2004. 32(8):
470–85.
2251. Navarro-Martinez A, Solera J,
Corredoira J, Beato JL, Martinez-
Alfaro E, Atienzar M, and Ariza J,
Epididymoorchitis due to Brucella
mellitensis: a retrospective study of 59
patients. Clin Infect Dis, 2001. 33(12):
2017–22.
2252. Navon-Venezia S, Chmelnitsky I,
Leavitt A, Schwaber MJ, Schwartz
D, and Carmeli Y, Plasmid-mediated
imipenem-hydrolyzing enzyme KPC-2
among multiple carbapenem-resistant
Escherichia coli clones in Israel.
Antimicrob Agents Chemother, 2006.
50(9): 3098–101.
2253. Nayir A, Emre S, Sirin A, Bulut A,
Alpay H, and Tanman F, The effects of
vaccination with inactivated uropatho-
genic bacteria in recurrent urinary tract
infections of children. Vaccine, 1995.
13(11): 987–90.
2254. Neal DE, Acute bacterial prostatitis,
in Textbook of prostatitis, Nickel JC,
Editor. 1999, Isis Medical Media:
Oxford. p. 115–122.
2255. Neal DE, Jr., Clejan S, Sarma D, and
Moon TD, Prostate specific antigen and
prostatitis. I. Effect of prostatitis on
serum PSA in the human and nonhu-
man primate. Prostate, 1992. 20(2):
105–11.
2256. Nejad VM and Shafaie S, The associa-
tion of bacterial vaginosis and preterm
labor. J Pak Med Assoc, 2008. 58(3):
104–6.
2257. Nelson DB, Jarvis WR, Rutala WA,
Foxx-Orenstein AE, Isenberg G, Dash
GR, Alvarado CJ, Ball M, Griffin-Sobel
J, Petersen C, Ball KA, Henderson J,
and Stricof RL, Multi-society guideline

for reprocessing flexible gastrointesti-
nal endoscopes. Society for Healthcare
Epidemiology of America. Infect
Control Hosp Epidemiol, 2003. 24(7):
532–7.
2258. Nemoy NJ and Staney TA, Surgical,
bacteriological, and biochemical man-
agement of “infection stones”. JAMA,
1971. 215(9): 1470–6.
2259. Neringer R, Forsgren A, Hansson C,
and Ode B, Lomefloxacin versus nor-
floxacin in the treatment of uncompli-
cated urinary tract infections: three-day
versus seven-day treatment. The South
Swedish Lolex Study Group. Scand J
Infect Dis, 1992. 24(6): 773–80.
2260. Ness RB, Hillier SL, Richter HE, Soper
DE, Stamm C, McGregor J, Bass DC,
Sweet RL, and Rice P, Douching in
relation to bacterial vaginosis, lacto-
bacilli, and facultative bacteria in the
vagina. Obstet Gynecol, 2002. 100(4):
765.
2261. Ness RB, Kip KE, Hillier SL, Soper
DE, Stamm CA, Sweet RL, Rice P, and
Richter HE, A cluster analysis of bac-
terial vaginosis-associated microflora
and pelvic inflammatory disease. Am J
Epidemiol, 2005. 162(6): 585–90.
2262. Nethercliffe J, Trewick A, Samuell C,
Leaver R, and Woodhouse CR, False-
positive pregnancy tests in patients
with enterocystoplasties. BJU Int, 2001.
87(9): 780–2.
2263. NethMap, Consumption of antimi-
crobial agents and antimicrobial
resistance among medically impor-
tant bacteria in the Netherlands,
SWAB DWPoAP, Editor. 2009: The
Netherlands.
2264. Neuhaus TJ, Berger C, Buechner K,
Parvex P, Bischoff G, Goetschel P,
Husarik D, Willi U, Molinari L, Rudin
C, Gervaix A, Hunziker U, Stocker S,
Girardin E, and Nadal D, Randomised
trial of oral versus sequential intrave-
nous/oral cephalosporins in children
with pyelonephritis. Eur J Pediatr,
2008. 167(9): 1037–47.
2265. Neves NA, Carvalho LP, De Oliveira
MA, Giraldo PC, Bacellar O, Cruz
AA, and Carvalho EM, Association
between atopy and recurrent vaginal
References
candidiasis. Clin Exp Immunol, 2005.
142(1): 167–71.
2266. Neveus T, von Gontard A, Hoebeke
P, Hjalmas K, Bauer S, Bower W,
Jorgensen TM, Rittig S, Walle JV,
Yeung CK, and Djurhuus JC, The
standardization of terminology of
lower urinary tract function in chil-
dren and adolescents: report from the
Standardisation Committee of the
International Children’s Continence
Society. J Urol, 2006. 176(1): 314–24.
2267. New Nutrition Business, 2004. 9(8).
2268. Newman LM, Moran JS, and
Workowski KA, Update on the man-
agement of gonorrhea in adults in the
United States. Clin Infect Dis, 2007. 44
Suppl 3: S84–101.
2269. Newman LM, Warner L, and Weinstock
HS, Predicting subsequent infection in
patients attending sexually transmitted
disease clinics. Sex Transm Dis, 2006.
33(12): 737–42.
2270. Nggada HA, Eni UE, and Nwankwo
EA, Histopathological findings in
nephrectomy specimens—A review of
42 cases. Niger Postgrad Med J, 2006.
13(3): 244–6.
2271. Ngo Gia Hy, Overview on Genitourinary
tuberculosis. Ho Chi Minh city’s
Medico-pharmacology Actualities,
2000: 68–72.
2272. Ngo Gia Hy, Pham Van Bui, Vo Thi
Hong Lien, and Nguyen Phuc Cam
Hoang, Some particular clinical aspects
of Genitourinary Tuberculosis and
Reconstructive Surgeries. Ho Chi Minh
city’s Medico-pharmacology Actualities,
1995. 5: 33–35.
2273. Nguyen HB, Corbett SW, Steele
R, Banta J, Clark RT, Hayes SR,
Edwards J, Cho TW, and Wittlake WA,
Implementation of a bundle of quality
indicators for the early management of
severe sepsis and septic shock is asso-
ciated with decreased mortality. Crit
Care Med, 2007. 35(4): 1105–12.
2274. Nguyen LH, Hsu DI, Ganapathy V,
Shriner K, and Wong-Beringer A,
Reducing empirical use of fluoroquinolo-
nes for Pseudomonas aeruginosa infec-
tions improves outcome. J Antimicrob
Chemother, 2008. 61(3): 714–20.
1111
References
2275. Nguyen Phuc Cam Hoang, Le Van
Hieu Nhan, and Vu Le Chuyen,
Genitourinary tuberculosis: diagnosis
and treatment. (Abstract), Urology 74
(Supplement 4A), 30th Congress of the
Société Internationale d’Urologie, Nov.
2009, 2009: S241.
2276. Nguyen Phuc Cam Hoang, Le Van Hieu
Nhan, Phan Van Hoang, Tran Ngoc
Khac Linh, and Vu Le Chuyen, Are
tuberculosis nonfunctioning kidneys
amenable to laparoscopic nephrectomy?
Abstract), Urology 74 (Supplement
4A), 30th Congress of the Société
Internationale d’Urologie, Nov. 2009,
2009: S189.
2277. Nguyen Phuc Cam Hoang, Le Van
Hieu Nhan, Tran Ngoc Khac Linh,
Nguyen Viet Cuong, and Vu Le
Chuyen, Laparoscopic augmentation
ileocystoplasty for TB contracted blad-
der: Our initial case report. (Abstract).
20th World Congress Video Urology,
Jul.2009. Program Book, 2009: 83.
2278. Nguyen Phuc Cam Hoang, Ngo Gia Hy,
Pham Van Bui, and Vo Thi Hong Lien,
A propos of 167 cases of Genitourinary
Tuberculosis treated at Binh Dan hos-
pital in 5 years (1990–1994). Binh Dan
hospital’s Science and Technology actu-
alities, 1994. 7: 293–305.
2279. Nguyen Phuc Cam Hoang, Tuberculosis
ureteric strictures: diagnosis and
outcome of treatment. Vietnamese
National Thesis for PhD Degree 2008.
(Abstract), Urology 74 (Supplement
4A), 30th Congress of the Société
Internationale d’Urologie, 2009: S90.
2280. Nguyen-Van-Tam SE, Nguyen-Van-
Tam JS, Myint S, and Pearson JC,
Risk factors for hospital-acquired uri-
nary tract infection in a large English
teaching hospital: a case-control study.
Infection, 1999. 27(3): 192–7.
2281. Nichols RL, The operating room, in
Hospital infections, Bennett JV and
Brachman PS, Editors. 1992, Little,
Brown: Boston. p. 461–73.
2282. Nickel JC and Moon T, Chronic bacte-
rial prostatitis: an evolving clinical
enigma. Urology, 2005. 66(1): 2–8.
2283. Nickel JC and Xiang J, Clinical sig-
nificance of nontraditional bacterial
1112
uropathogens in the management
of chronic prostatitis. J Urol, 2008.
179(4): 1391–5.
2284. Nickel JC ZN, Spivey M, Wu SC.
Clinical significance of antimicrobial
therapy in chronic prostatitis associated
with non-traditional uropathogens. in
American Urological Association Annual
Meeting. 2005. San Antonio: J Urol.
2285. Nickel JC, Catheter-associated urinary
tract infection: new perspectives on old
problems. Can J Infect Control, 1991.
6(2): 38–42.
2286. Nickel JC, Costerton JW, McLean RJ,
and Olson M, Bacterial biofilms: influ-
ence on the pathogenesis, diagnosis and
treatment of urinary tract infections.
J Antimicrob Chemother, 1994. 33
Suppl A: 31–41.
2287. Nickel JC, Downey J, and Costerton
JW, Movement of pseudomonas aeru-
ginosa along catheter surfaces. A
mechanism in pathogenesis of catheter-
associated infection. Urology, 1992.
39(1): 93–8.
2288. Nickel JC, Downey J, Johnston B, and
Clark J, Predictors of patient response
to antibiotic therapy for the chronic
prostatitis/chronic pelvic pain syn-
drome: a prospective multicenter clini-
cal trial. J Urol, 2001. 165(5): 1539–44.
2289. Nickel JC, Downey J, Young I, and Boag
S, Asymptomatic inflammation and/or
infection in benign prostatic hyperpla-
sia. BJU Int, 1999. 84(9): 976–81.
2290. Nickel JC, Feero P, Costerton JW, and
Wilson E, Incidence and importance of
bacteriuria in postoperative, short-term
urinary catheterization. Can J Surg,
1989. 32(2): 131–2.
2291. Nickel JC, Lower urinary tract evalu-
ation. Prostatitis and related condi-
tions, in Campbell’s urology, Walsh PC,
Editor. 2002, Saunders: Philadelphia;
London. p. 4 v. (xl, 3954 p.).
2292. Nickel JC, Olson M, McLean RJ, Grant
SK, and Costerton JW, An ecological
study of infected urinary stone genesis
in an animal model. Br J Urol, 1987.
59(1): 21–30.
2293. Nickel JC, Olson ME, and Ceri
H Experimental prostatitis., in
Prostatitis., Weidner W, Madsen

PO, and Schiefer HG, Editors. 1993,
Springer-Verlag: Berlin; New York. p.
xiii, 276 p.
2294. Nickel JC, Olson ME, and Costerton
JW, Rat model of experimental bacte-
rial prostatitis. Infection, 1991. 19
Suppl 3: S126–30.
2295. Nickel JC, Olson ME, Barabas A,
Benediktsson H, Dasgupta MK, and
Costerton JW, Pathogenesis of chronic
bacterial prostatitis in an animal
model. Br J Urol, 1990. 66(1): 47–54.
2296. Nickel JC, Patel M, and Cameron M,
Chronic prostatitis/chronic pelvic pain
syndrome: finding a way forward in the
United kingdom: report from the first
United kingdom symposium on chronic
prostatitis, january 30, 2008, london,
United kingdom. Rev Urol, 2008. 10(2):
160–3.
2297. Nickel JC, Prostatitis: evolving man-
agement strategies. Urol Clin North
Am, 1999. 26(4): 737–51.
2298. Nickel JC, Shoskes D, Wang Y,
Alexander RB, Fowler JE, Jr., Zeitlin
S, O’Leary MP, Pontari MA, Schaeffer
AJ, Landis JR, Nyberg L, Kusek JW,
and Propert KJ, How does the pre-
massage and post-massage 2-glass test
compare to the Meares-Stamey 4-glass
test in men with chronic prostatitis/
chronic pelvic pain syndrome? J Urol,
2006. 176(1): 119–24.
2299. Nickel JC, Teichman JM, Gregoire M,
Clark J, and Downey J, Prevalence,
diagnosis, characterization, and treat-
ment of prostatitis, interstitial cystitis,
and epididymitis in outpatient urologi-
cal practice: the Canadian PIE Study.
Urology, 2005. 66(5): 935–40.
2300. Nickel JC, The bottle of the bladder: the
pathogenesis and treatment of uncom-
plicated cystitis Int Urogynecol J,
1990(1): 218–222.
2301. Nickel JC, Wilson J, Morales A, and
Heaton J, Value of urologic investiga-
tion in a targeted group of women with
recurrent urinary tract infections. Can
J Surg, 1991. 34(6): 591–4.
2302. Nickel JC, Wright JB, Ruseska
I, Marrie TJ, Whitfield C, and
Costerton JW, Antibiotic resistance of
Pseudomonas aeruginosa colonizing
References
a urinary catheter in vitro. Eur J Clin
Microbiol, 1985. 4(2): 213–8.
2303. Nicolas-Chanoine MH, Blanco
J, Leflon-Guibout V, Demarty R,
Alonso MP, Canica MM, Park YJ,
Lavigne JP, Pitout J, and Johnson
JR, Intercontinental emergence of
Escherichia coli clone O25:H4-ST131
producing CTX-M-15. J Antimicrob
Chemother, 2008. 61(2): 273–81.
2304. Nicolle L, Best pharmacological prac-
tice: urinary tract infections. Expert
Opin Pharmacother, 2003. 4(5):
693–704.
2305. Nicolle LE and Ronald AR, Recurrent
urinary tract infection in adult women:
diagnosis and treatment. Infect Dis
Clin North Am, 1987. 1(4): 793–806.
2306. Nicolle LE, A practical guide to antimi-
crobial management of complicated uri-
nary tract infection. Drugs Aging, 2001.
18(4): 243–54.
2307. Nicolle LE, A practical guide to the
management of complicated urinary
tract infection. Drugs, 1997. 53(4):
583–92.
2308. Nicolle LE, Asymptomatic bacteriuria
in diabetic women. Diabetes Care,
2000. 23(6): 722–3.
2309. Nicolle LE, Asymptomatic bacteriuria
in the elderly. Infect Dis Clin North
Am, 1997. 11(3): 647–62.
2310. Nicolle LE, Asymptomatic bacteriu-
ria: review and discussion of the IDSA
guidelines. Int J Antimicrob Agents,
2006. 28 Suppl 1: S42–8.
2311. Nicolle LE, Bjornson J, Harding GK,
and MacDonell JA, Bacteriuria in eld-
erly institutionalized men. N Engl J
Med, 1983. 309(23): 1420–5.
2312. Nicolle LE, Bradley S, Colgan R, Rice
JC, Schaeffer A, and Hooton TM,
Infectious Diseases Society of America
guidelines for the diagnosis and treat-
ment of asymptomatic bacteriuria in
adults. Clin Infect Dis, 2005. 40(5):
643–54.
2313. Nicolle LE, Catheter-related urinary
tract infection. Drugs Aging, 2005.
22(8): 627–39.
2314. Nicolle LE, Consequences of asympto-
matic bacteriuria in the elderly. Int J
Antimicrob Agents, 1994. 4(2): 107–11.
1113
References
2315. Nicolle LE, DuBois J, Martel AY,
Harding GK, Shafran SD, and Conly
JM, Treatment of acute uncomplicated
urinary tract infections with 3 days of
lomefloxacin compared with treatment
with 3 days of norfloxacin. Antimicrob
Agents Chemother, 1993. 37(3): 574–9.
2316. Nicolle LE, Harding GK, Kennedy J,
McIntyre M, Aoki F, and Murray D,
Urine specimen collection with exter-
nal devices for diagnosis of bacteriu-
ria in elderly incontinent men. J Clin
Microbiol, 1988. 26(6): 1115–9.
2317. Nicolle LE, Harding GK, Thompson
M, Kennedy J, Urias B, and Ronald
AR, Prospective, randomized, placebo-
controlled trial of norfloxacin for the
prophylaxis of recurrent urinary tract
infection in women. Antimicrob Agents
Chemother, 1989. 33(7): 1032–5.
2318. Nicolle LE, Harding GK, Thomson M,
Kennedy J, Urias B, and Ronald AR,
Efficacy of five years of continuous, low-
dose trimethoprim-sulfamethoxazole
prophylaxis for urinary tract infection.
J Infect Dis, 1988. 157(6): 1239–42.
2319. Nicolle LE, Henderson E, Bjornson
J, McIntyre M, Harding GK, and
MacDonell JA, The association of bac-
teriuria with resident characteristics
and survival in elderly institutionalized
men. Ann Intern Med, 1987. 106(5):
682–6.
2320. Nicolle LE, Hoepelman AI, Floor M,
Verhoef J, and Norgard K, Comparison
of three days’ therapy with cefcanel or
amoxicillin for the treatment of acute
uncomplicated urinary tract infection.
Scand J Infect Dis, 1993. 25(5): 631–7.
2321. Nicolle LE, Madsen KS, Debeeck GO,
Blochlinger E, Borrild N, Bru JP,
McKinnon C, O’Doherty B, Spiegel W,
Van Balen FA, and Menday P, Three
days of pivmecillinam or norfloxacin for
treatment of acute uncomplicated uri-
nary infection in women. Scand J Infect
Dis, 2002. 34(7): 487–92.
2322. Nicolle LE, Managing recurrent
urinary tract infections in women.
Womens Health (Lond Engl), 2005.
1(1): 39–50.
2323. Nicolle LE, Mayhew WJ, and Bryan L,
Prospective randomized comparison of
1114
therapy and no therapy for asympto-
matic bacteriuria in institutionalized
elderly women. Am J Med, 1987. 83(1):
27–33.
2324. Nicolle LE, Pivmecillinam in the
treatment of urinary tract infections.
J Antimicrob Chemother, 2000. 46
Suppl 1: 35–9; discussion 63–5.
2325. Nicolle LE, Prophylaxis: recurrent
urinary tract infection in women.
Infection, 1992. 20 Suppl 3: S203–5;
discussion S206–10.
2326. Nicolle LE, Strausbaugh LJ, and
Garibaldi RA, Infections and antibi-
otic resistance in nursing homes. Clin
Microbiol Rev, 1996. 9(1): 1–17.
2327. Nicolle LE, The chronic indwelling cath-
eter and urinary infection in long-term-
care facility residents. Infect Control
Hosp Epidemiol, 2001. 22(5): 316–21.
2328. Nicolle LE, Urinary tract infection in
diabetes. Curr Opin Infect Dis, 2005.
18(1): 49–53.
2329. Nicolle LE, Urinary tract infections in
long-term-care facilities. Infect Control
Hosp Epidemiol, 2001. 22(3): 167–75.
2330. Nicolle LE, Zhanel GG, and Harding
GK, Microbiological outcomes in
women with diabetes and untreated
asymptomatic bacteriuria. World J
Urol, 2006. 24(1): 61–5.
2331. Nicolosi A, Correa Leite ML, Musicco
M, Arici C, Gavazzeni G, and Lazzarin
A, The efficiency of male-to-female and
female-to-male sexual transmission of
the human immunodeficiency virus:
a study of 730 stable couples. Italian
Study Group on HIV Heterosexual
Transmission. Epidemiology, 1994.
5(6): 570–5.
2332. Niebyl JR, Antibiotics and other anti-
infective agents in pregnancy and
lactation. Am J Perinatol, 2003. 20(8):
405–14.
2333. Nielsen JB, Djurhuus JC, and
Jorgensen TM, Lower urinary tract
dysfunction in vesicoureteral reflux.
Urol Int, 1984. 39(1): 29–31.
2334. Niel-Weise BS and van den Broek
PJ, Antibiotic policies for short-term
catheter bladder drainage in adults.
Cochrane Database Syst Rev, 2005(3):
CD005428.

2335. Niel-Weise BS and van den Broek PJ,
Urinary catheter policies for long-term
bladder drainage. Cochrane Database
Syst Rev, 2005(1): CD004201.
2336. Nieschlag E, Nosologie andrologischer
Krankheitsbilder, in Andrologie.
Grundlagen und Klinik der reproduk-
tiven Gesundheit des Mannes.,
Nieschlag E and Behre H, Editors.
2002, Springer: Berlin. p. 91–95.
2337. Niewerth M, Kunze D, Seibold M,
Schaller M, Korting HC, and Hube B,
Ciclopirox olamine treatment affects
the expression pattern of Candida
albicans genes encoding virulence fac-
tors, iron metabolism proteins, and
drug resistance factors. Antimicrob
Agents Chemother, 2003. 47(6):
1805–17.
2338. Nijman RJ, Borgstein NG, Ellsworth P,
and Siggaard C, Long-term tolerability
of tolterodine extended release in chil-
dren 5–11 years of age: results from a
12-month, open-label study. Eur Urol,
2007. 52(5): 1511–6.
2339. Nilsen FS, Karlsen SJ, and Gjertsen
O, Gas-containing renal stones treated
with percutaneous nephrolithotomy:
case report. J Endourol, 2001. 15(9):
915–7.
2340. Nishino M, Hayakawa K, Iwasaku K,
and Takasu K, Magnetic resonance
imaging findings in gynecologic emer-
gencies. J Comput Assist Tomogr, 2003.
27(4): 564–70.
2341. Nissenkorn I and Slutzker D, The
intraurethral catheter: long-term fol-
low-up in patients with urinary reten-
tion due to infravesical obstruction. Br
J Urol, 1991. 68(3): 277–9.
2342. Nistal M and Paniagua R, Testicular
and epididymal pathology. 1984, New
York: Thieme-Stratton. 358p.
2343. Nmorsi O, Ukwandu N, Egwungenya
O, and Obhiemi N, Evaluation of
CD4(+)/CD8(+) status and urinary
tract infections associated with urinary
schistosomiasis among some rural
Nigerians. Afr Health Sci, 2005. 5(2):
126–30.
2344. Nmorsi OP, Kwandu UN, and
Ebiaguanye LM, Schistosoma haema-
tobium and urinary tract pathogens
References
co-infections in a rural community of
Edo State, Nigeria. J Commun Dis,
2007. 39(2): 85–90.
2345. Nmorsi OP, Ukwandu NC, Ogoinja S,
Blackie HO, and Odike MA, Urinary
tract pathology in Schistosoma hae-
matobium infected rural Nigerians.
Southeast Asian J Trop Med Public
Health, 2007. 38(1): 32–7.
2346. Norden CW and Kass EH, Bacteriuria
of pregnancy—a critical appraisal.
Annu Rev Med, 1968. 19: 431–70.
2347. Nordenstam G, Sundh V, Lincoln K,
Svanborg A, and Eden CS, Bacteriuria
in representative population samples
of persons aged 72–79 years. Am J
Epidemiol, 1989. 130(6): 1176–86.
2348. Nordenstam GR, Brandberg CA, Oden
AS, Svanborg Eden CM, and Svanborg
A, Bacteriuria and mortality in an eld-
erly population. N Engl J Med, 1986.
314(18): 1152–6.
2349. Norinder BS, Norrby R, Palmgren
AC, Hollenberg S, Eriksson U, and
Nord CE, Microflora changes with nor-
floxacin and pivmecillinam in women
with recurrent urinary tract infection.
Antimicrob Agents Chemother, 2006.
50(4): 1528–30.
2350. Norrby SR, Design of clinical trials in
patients with urinary tract infections.
Infection, 1992. 20 Suppl 3: S181–8;
discussion S189–92.
2351. Nougayrède JP, Taieb F, De Rycke J,
and Oswald E, Cyclomodulins: bacte-
rial effectors that modulate the eukary-
otic cell cycle. Trends Microbiol, 2005.
13(3): 103–10.
2352. Novara G, Editorial comment on:
Botulinum toxin A detrusor injections
in patients with neurogenic detru-
sor overactivity significantly decrease
the incidence of symptomatic urinary
tract infections. Eur Urol, 2008. 53(3):
618–9.
2353. Nurbhai M, Grimshaw J, Watson M,
Bond C, Mollison J, and Ludbrook A,
Oral versus intra-vaginal imidazole
and triazole anti-fungal treatment of
uncomplicated vulvovaginal candidia-
sis (thrush). Cochrane Database Syst
Rev, 2007(4): CD002845.
1115
References
2354. Nurse DE, McInerney PD, Thomas PJ,
and Mundy AR, Stones in enterocysto-
plasties. Br J Urol, 1996. 77(5):
684–7.
2355. Nuutinen M and Uhari M, Recurrence
and follow-up after urinary tract infec-
tion under the age of 1 year. Pediatr
Nephrol, 2001. 16(1): 69–72.
2356. Nuutinen M, Uhari M, Murphy MF,
and Hey K, Clinical guidelines and
hospital discharges of children with
acute urinary tract infections. Pediatr
Nephrol, 1999. 13(1): 45–9.
2357. Nwadiaro HC, Nnamonu MI, Ramyil
VM, and Igun GO, Comparative analy-
sis of urethral catheterization versus
suprapubic cystostomy in management
of neurogenic bladder in spinal injured
patients. Niger J Med, 2007. 16(4):
318–21.
2358. Nyindo M, Complementary factors con-
tributing to the rapid spread of HIV-I
in sub-Saharan Africa: a review. East
Afr Med J, 2005. 82(1): 40–6.
2359. Nyirjesy P, Alexander AB, and Weitz
MV, Vaginal Candida parapsilosis:
pathogen or bystander? Infect Dis
Obstet Gynecol, 2005. 13(1): 37–41.
2360. Nyirjesy P, Seeney SM, Grody MH,
Jordan CA, and Buckley HR, Chronic
fungal vaginitis: the value of cultures.
Am J Obstet Gynecol, 1995. 173(3 Pt
1): 820–3.
2361. Oben FT, Wright RD, and Ahaghotu
CA, Tuberculous epididymitis with
extensive retroperitoneal and mediasti-
nal involvement. Urology, 2004. 64(1):
156–8.
2362. Ochiai S, Ishiko H, Yasuda M, and
Deguchi T, Rapid detection of the
mosaic structure of the Neisseria gonor-
rhoeae penA Gene, which is associated
with decreased susceptibilities to oral
cephalosporins. J Clin Microbiol, 2008.
46(5): 1804–10.
2363. Ochsendorf FR, Sexually transmitted
infections: impact on male fertility.
Andrologia, 2008. 40(2): 72–5.
2364. O’Connor RC, Gerber GS, Avila D,
Chen AA, and Bales GT, Comparison
of outcomes after single or DOUBLE-
CUFF artificial urinary sphincter
insertion. Urology, 2003. 62(4): 723–6.
1116
2365. O’Connor RC, Laven BA, Bales GT, and
Gerber GS, Nonsurgical management
of benign prostatic hyperplasia in men
with bladder calculi. Urology, 2002.
60(2): 288–91.
2366. Odds FC, Arai T, Disalvo AF, Evans
EG, Hay RJ, Randhawa HS, Rinaldi
MG, and Walsh TJ, Nomenclature of
fungal diseases: a report and recom-
mendations from a Sub-Committee of
the International Society for Human
and Animal Mycology (ISHAM). J Med
Vet Mycol, 1992. 30(1): 1–10.
2367. Odds FC, Candida and Candidosis.
2nd Edition ed. 1988, England: W B
Saunders.
2368. Ode B, Broms M, Walder M, and
Cronberg S, Failure of excessive
doses of ampicillin to prevent bacte-
rial relapse in the treatment of acute
pyelonephritis. Acta Med Scand, 1980.
207(4): 305–7.
2369. Odejinmi F, Annan HG, and Hussein
SY, Tuberculosis, the great mimic
again? A report of two cases of pelvic
tuberculosis initially suspected to be
advanced ovarian carcinoma. J Obstet
Gynaecol, 2000. 20(5): 544–5.
2370. Oesterling JE, A permanent, epithelial-
izing stent for the treatment of benign
prostatic hyperplasia. Preliminary
results. J Androl, 1991. 12(6): 423–8.
2371. O’Farrell N and Egger M, Circumcision
in men and the prevention of HIV infec-
tion: a ‘meta-analysis’ revisited. Int J
STD AIDS, 2000. 11(3): 137–42.
2372. Oh MM, Jin MH, Bae JH, Park HS,
Lee JG, and Moon du G, The role of
vesicoureteral reflux in acute renal cor-
tical scintigraphic lesion and ultimate
scar formation. J Urol, 2008. 180(5):
2167–70.
2373. Ohkawa M, Shimamura M, Tokunaga
S, Nakashima T, and Orito M,
Bacteremia resulting from prostatic
surgery in patients with or without
preoperative bacteriuria under periop-
erative antibiotic use. Chemotherapy,
1993. 39(2): 140–6.
2374. Okhamafe AO, Akerele JO, and
Chukuka CS, Pharmacokinetic interac-
tions of norfloxacin with some metal-
lic medicinal agents. International

Journal of Pharmaceutics, 1991. 68(1–
3): 11–18.
2375. Okishio N, Hanai S, Ishiguro K,
Yanaoka M, Tamai H, and Naide Y,
[Urinary tract infection associated
with benign prostatic hypertrophy and
related diseases and transurethral sur-
gery]. Hinyokika Kiyo, 1986. 32(11):
1610–6.
2376. Olbing H, Claesson I, Ebel KD,
Seppanen U, Smellie JM, Tamminen-
Mobius T, and Wikstad I, Renal scars
and parenchymal thinning in children
with vesicoureteral reflux: a 5-year
report of the International Reflux Study
in Children (European branch). J Urol,
1992. 148(5 Pt 2): 1653–6.
2377. Oliveira P, Andrade JA, Porto HC,
Filho JE, and Vinhaes AF, Diagnosis
and treatment of prostatic abscess. Int
Braz J Urol, 2003. 29(1): 30–4.
2378. Oliviereo L, Perdiz M, and Bourlioux
P, Role direct de la nitroxiline dans
l’inhibtion e l’adherence bacterienne
sur sonde urinaire. Pathol Biol (Paris),
1990. 38: 455 – 458.
2379. Olsen B, Hadad R, Fredlund H, and
Unemo M, The Neisseria gonorrhoeae
population in Sweden during 2005-
phenotypes, genotypes and antibiotic
resistance. Apmis, 2008. 116(3): 181–9.
2380. Olsen JH, Friis-Moller A, Jensen SK,
Korner B, and Hvidt V, Cefotaxime
for prevention of infectious complica-
tions in bacteriuric men undergoing
transurethral prostatic resection. A con-
trolled comparison with methenamine.
Scand J Urol Nephrol, 1983. 17(3):
299–301.
2381. Olson RP, Harrell LJ, and Kaye KS,
Antibiotic resistance in urinary iso-
lates of Escherichia coli from college
women with urinary tract infections.
Antimicrob Agents Chemother, 2009.
53(3): 1285–6.
2382. Olszyna DP, Opal SM, Prins JM, Horn
DL, Speelman P, van Deventer SJ, and
van der Poll T, Chemotactic activity of
CXC chemokines interleukin-8, growth-
related oncogene-alpha, and epithelial
cell-derived neutrophil-activating pro-
tein-78 in urine of patients with urosep-
sis. J Infect Dis, 2000. 182(6): 1731–7.
References
2383. Omli R, Skotnes LH, Mykletun A,
Bakke AM, and Kuhry E, Residual
urine as a risk factor for lower urinary
tract infection: a 1-year follow-up study
in nursing homes. J Am Geriatr Soc,
2008. 56(5): 871–4.
2384. Ong CL, Ulett GC, Mabbett AN,
Beatson SA, Webb RI, Monaghan
W, Nimmo GR, Looke DF, McEwan
AG, and Schembri MA, Identification
of type 3 fimbriae in uropathogenic
Escherichia coli reveals a role in biofilm
formation. J Bacteriol, 2008. 190(3):
1054–63.
2385. Onrust SV, Lamb HM, and Balfour JA,
Ofloxacin. A reappraisal of its use in
the management of genitourinary tract
infections. Drugs, 1998. 56(5): 895–928.
2386. Ooe K and Udagawa H, A new type of
fulminant group A streptococcal infec-
tion in obstetric patients: report of
two cases. Hum Pathol, 1997. 28(4):
509–12.
2387. O’Regan S and Yazbeck S,
Constipation: a cause of enuresis, uri-
nary tract infection and vesico-ureteral
reflux in children. Med Hypotheses,
1985. 17(4): 409–13.
2388. O’Regan S, Russo P, Lapointe N, and
Rousseau E, AIDS and the urinary
tract. J Acquir Immune Defic Syndr,
1990. 3(3): 244–51.
2389. O’Regan S, Yazbeck S, and Schick E,
Constipation, bladder instability, uri-
nary tract infection syndrome. Clin
Nephrol, 1985. 23(3): 152–4.
2390. O’Reilly P, Aurell M, Britton K, Kletter
K, Rosenthal L, and Testa T, Consensus
on diuresis renography for investigat-
ing the dilated upper urinary tract.
Radionuclides in Nephrourology Group.
Consensus Committee on Diuresis
Renography. J Nucl Med, 1996. 37(11):
1872–6.
2391. Orenstein R and Wong ES, Urinary
tract infections in adults. Am Fam
Physician, 1999. 59(5): 1225–34, 1237.
2392. Orr NW, Is a mask necessary in the
operating theatre? Ann R Coll Surg
Engl, 1981. 63(6): 390–2.
2393. Orroth KK, Freeman EE, Bakker R,
Buve A, Glynn JR, Boily MC, White
RG, Habbema JD, and Hayes RJ,
1117
References
Understanding the differences between
contrasting HIV epidemics in east and
west Africa: results from a simulation
model of the Four Cities Study. Sex
Transm Infect, 2007. 83 Suppl 1: i5–16.
2394. Orsola A, Caffaratti J, and Garat JM,
Conservative treatment of phimosis
in children using a topical steroid.
Urology, 2000. 56(2): 307–10.
2395. Ortega M, Marco F, Soriano A, Almela
M, Martinez JA, Munoz A, and Mensa
J, Analysis of 4758 Escherichia coli
bacteraemia episodes: predictive factors
for isolation of an antibiotic-resistant
strain and their impact on the outcome.
J Antimicrob Chemother, 2009. 63(3):
568–74.
2396. Orth K, Palmer LE, Bao ZQ, Stewart
S, Rudolph AE, Bliska JB, and Dixon
JE, Inhibition of the mitogen-activated
protein kinase kinase superfamily
by a Yersinia effector. Science, 1999.
285(5435): 1920–3.
2397. Ortiz R and Lee K, Nosocomial infec-
tions in neurocritical care. Curr Neurol
Neurosci Rep, 2006. 6(6): 525–30.
2398. Osaka K, Takakura T, Narukawa K,
Takahata M, Endo K, Kiyota H, and
Onodera S, Analysis of amino acid
sequences of penicillin-binding protein
2 in clinical isolates of Neisseria gon-
orrhoeae with reduced susceptibility
to cefixime and ceftriaxone. J Infect
Chemother, 2008. 14(3): 195–203.
2399. Osegbe DN, Testicular function after
unilateral bacterial epididymo-orchitis.
Eur Urol, 1991. 19(3): 204–8.
2400. Osman M, Wendt-Nordahl G, Heger
K, Michel MS, Alken P, and Knoll T,
Percutaneous nephrolithotomy with
ultrasonography-guided renal access:
experience from over 300 cases. BJU
Int, 2005. 96(6): 875–8.
2401. Ostolaza H, Soloaga A, and Goni FM,
The binding of divalent cations to
Escherichia coli alpha-haemolysin. Eur
J Biochem, 1995. 228(1): 39–44.
2402. Otnes B, Correlation between causes
and composition of urinary stones.
Scand J Urol Nephrol, 1983. 17(1):
93–8.
2403. Ott M, Hacker J, Schmoll T, Jarchau T,
Korhonen TK, and Goebel W, Analysis
1118
of the genetic determinants coding for
the S-fimbrial adhesin (sfa) in different
Escherichia coli strains causing menin-
gitis or urinary tract infections. Infect
Immun, 1986. 54(3): 646–53.
2404. Otto G, Braconier J, Andreasson A, and
Svanborg C, Interleukin-6 and disease
severity in patients with bacteremic
and nonbacteremic febrile urinary tract
infection. J Infect Dis, 1999. 179(1):
172–9.
2405. Ottolini MC, Shaer CM, Rushton HG,
Majd M, Gonzales EC, and Patel KM,
Relationship of asymptomatic bacteriu-
ria and renal scarring in children with
neuropathic bladders who are practic-
ing clean intermittent catheterization. J
Pediatr, 1995. 127(3): 368–72.
2406. Ouslander JG, Greendale GA, Uman G,
Lee C, Paul W, and Schnelle J, Effects
of oral estrogen and progestin on the
lower urinary tract among female nurs-
ing home residents. J Am Geriatr Soc,
2001. 49(6): 803–7.
2407. Ouslander JG, Greengold B, and Chen
S, External catheter use and urinary
tract infections among incontinent male
nursing home patients. J Am Geriatr
Soc, 1987. 35(12): 1063–70.
2408. Ouslander JG, Greengold BA,
Silverblatt FJ, and Garcia JP, An accu-
rate method to obtain urine for culture
in men with external catheters. Arch
Intern Med, 1987. 147(2): 286–8.
2409. Ouslander JG, Schapira M, Schnelle
JF, Uman G, Fingold S, Tuico E, and
Nigam JG, Does eradicating bacteriu-
ria affect the severity of chronic urinary
incontinence in nursing home resi-
dents? Ann Intern Med, 1995. 122(10):
749–54.
2410. Owens RC, Jr. and Ambrose PG,
Torsades de pointes associated with
fluoroquinolones. Pharmacotherapy,
2002. 22(5): 663–8; discussion 668–72.
2411. Owens RC, Jr., Nightingale CH, and
Nicolau DP, Ceftibuten: an overview.
Pharmacotherapy, 1997. 17(4): 707–20.
2412. Ozalp S, Yalcin OT, Tanir HM,
Kabukcuoglu S, and Akcay A, Pelvic
tuberculosis mimicking signs of abdom-
inopelvic malignancy. Gynecol Obstet
Invest, 2001. 52(1): 71–2.

2413. Ozden C, Ozdal OL, Guzel O, Han O,
Seckin S, and Memis A, The correlation
between serum prostate specific antigen
levels and asymptomatic inflammatory
prostatitis. Int Urol Nephrol, 2007.
39(3): 859–63.
2414. Ozen S, Alikasifoglu M, Saatci U,
Bakkaloglu A, Besbas N, Kara N,
Kocak H, Erbas B, Unsal I, and
Tuncbilek E, Implications of certain
genetic polymorphisms in scarring in
vesicoureteric reflux: importance of ACE
polymorphism. Am J Kidney Dis, 1999.
34(1): 140–5.
2415. Ozturk A, Ozturk E, Zeyrek F, Onur
K, Sirmatel O, and Kat N, Comparison
of brucella and non-specific epididy-
morchitis: gray scale and color Doppler
ultrasonographic features. Eur J
Radiol, 2005. 56(2): 256–62.
2416. P. Abrams SK, A. Grant, Evidence-
based medicine overview of the main
steps for developing and grading guide-
line recommendations. Progress in
Urology, 2007. 17(3): 681–4.
2417. Pabich WL, Fihn SD, Stamm WE,
Scholes D, Boyko EJ, and Gupta K,
Prevalence and determinants of vaginal
flora alterations in postmenopausal
women. J Infect Dis, 2003. 188(7):
1054–8.
2418. Padian NS, Shiboski SC, Glass SO, and
Vittinghoff E, Heterosexual transmis-
sion of human immunodeficiency virus
(HIV) in northern California: results
from a ten-year study. Am J Epidemiol,
1997. 146(4): 350–7.
2419. Padmore DE, Norman RW, and Millard
OH, Analyses of indications for and
outcomes of epididymectomy. J Urol,
1996. 156(1): 95–6.
2420. Paduch DA, Viral lower urinary tract
infections. Curr Urol Rep, 2007. 8(4):
324–35.
2421. Pagano M and Gauvreau K, Principles
of biostatistics. 2nd ed. 2000, Australia;
Pacific Grove, CA: Duxbury. 1 v. (vari-
ous pagings).
2422. Pai MG and Bhat HS, Prostatic
abscess. J Urol, 1972. 108(4):
599–600.
2423. Pakarinen P, Toivonen J, and
Luukkainen T, Randomized
References
comparison of levonorgestrel- and
copper-releasing intrauterine systems
immediately after abortion, with 5
years’ follow-up. Contraception, 2003.
68(1): 31–4.
2424. Palasubramaniam S, Subramaniam
G, Muniandy S, and Parasakthi N,
Extended-spectrum beta-lactam resist-
ance due to AmpC hyperproduction
and CMY-2 coupled with the loss of
OMPK35 in Malaysian strains of
Escherichia coli and Klebsiella pneu-
moniae. Microb Drug Resist, 2007.
13(3): 186–90.
2425. Palmer HM, Young H, Winter A, and
Dave J, Emergence and spread of
azithromycin-resistant Neisseria gon-
orrhoeae in Scotland. J Antimicrob
Chemother, 2008. 62(3): 490–4.
2426. Palmer LS, Franco I, Kogan SJ, Reda
E, Gill B, and Levitt SB, Urolithiasis in
children following augmentation cysto-
plasty. J Urol, 1993. 150(2 Pt 2): 726–9.
2427. Panaretto K, Craig J, Knight J,
Howman-Giles R, Sureshkumar P,
and Roy L, Risk factors for recurrent
urinary tract infection in preschool chil-
dren. J Paediatr Child Health, 1999.
35(5): 454–9.
2428. Pansadoro V, Emiliozzi P, Defidio L,
Scarpone P, Sabatini G, Brisciani A,
and Lauretti S, Prostate-specific anti-
gen and prostatitis in men under fifty.
Eur Urol, 1996. 30(1): 24–7.
2429. Papatsoris AG, Mpadra FA,
Karamouzis MV, and Frangides CY,
Endemic brucellar epididymo-orchitis:
a 10-year experience. Int J Infect Dis,
2002. 6(4): 309–13.
2430. Pape L, Gunzer F, Ziesing S, Pape A,
Offner G, and Ehrich JH, [Bacterial
pathogens, resistance patterns and
treatment options in community
acquired pediatric urinary tract infec-
tion]. Klin Padiatr, 2004. 216(2): 83–6.
2431. Pappas G and Memish ZA, Brucellosis
in the middle East: a persistent medi-
cal, socioeconomic and political issue. J
Chemother, 2007. 19(3): 243–8.
2432. Pappas G, Panagopoulou P, Christou L,
and Akritidis N, Brucella as a biologi-
cal weapon. Cell Mol Life Sci, 2006.
63(19–20): 2229–36.
1119
References
2433. Pappas G, Papadimitriou P, Akritidis
N, Christou L, and Tsianos EV, The
new global map of human brucellosis.
Lancet Infect Dis, 2006. 6(2): 91–9.
2434. Pappas PG, Kauffman CA, Andes
D, Benjamin DK, Jr., Calandra TF,
Edwards JE, Jr., Filler SG, Fisher
JF, Kullberg BJ, Ostrosky-Zeichner
L, Reboli AC, Rex JH, Walsh TJ, and
Sobel JD, Clinical practice guidelines
for the management of candidiasis:
2009 update by the Infectious Diseases
Society of America. Clin Infect Dis,
2009. 48(5): 503–35.
2435. Parienti JJ, Thibon P, Heller R, Le
Roux Y, von Theobald P, Bensadoun
H, Bouvet A, Lemarchand F, and Le
Coutour X, Hand-rubbing with an
aqueous alcoholic solution vs tradi-
tional surgical hand-scrubbing and
30-day surgical site infection rates: a
randomized equivalence study. JAMA,
2002. 288(6): 722–7.
2436. Parker WR, Wheat J, Montgomery JS,
and Latini JM, Urethral diverticulum
after endoscopic urethrotomy: case
report. Urology, 2007. 70(5): 1008 e5–7.
2437. Park-Wyllie LY, Juurlink DN, Kopp
A, Shah BR, Stukel TA, Stumpo C,
Dresser L, Low DE, and Mamdani MM,
Outpatient gatifloxacin therapy and
dysglycemia in older adults. N Engl J
Med, 2006. 354(13): 1352–61.
2438. Parsons CL, Greenspan C, Moore
SW, and Mulholland SG, Role of sur-
face mucin in primary antibacterial
defense of bladder. Urology, 1977. 9(1):
48–52.
2439. Parsons CL, Interstitial cystitis and
lower urinary tract symptoms in males
and females-the combined role of potas-
sium and epithelial dysfunction. Rev
Urol, 2002. 4 Suppl 1: S49–55.
2440. Parsons CL, Stein PC, Dobke MK,
Virden CP, and Frank DH, Diagnosis
and therapy of subclinically infected
prostheses. Surg Gynecol Obstet, 1993.
177(5): 504–6.
2441. Pasqualotto FF, Sharma RK, Potts JM,
Nelson DR, Thomas AJ, and Agarwal
A, Seminal oxidative stress in patients
with chronic prostatitis. Urology, 2000.
55(6): 881–5.
1120
2442. Patel PS and Wilbur AC, Cystic semi-
nal vesiculitis: CT demonstration. J
Comput Assist Tomogr, 1987. 11(6):
1103–4.
2443. Patel SS, Balfour JA, and Bryson HM,
Fosfomycin tromethamine. A review
of its antibacterial activity, pharma-
cokinetic properties and therapeutic
efficacy as a single-dose oral treatment
for acute uncomplicated lower urinary
tract infections. Drugs, 1997. 53(4):
637–56.
2444. Paterson DL, Ko WC, Von Gottberg A,
Casellas JM, Mulazimoglu L, Klugman
KP, Bonomo RA, Rice LB, McCormack
JG, and Yu VL, Outcome of cepha-
losporin treatment for serious infections
due to apparently susceptible organ-
isms producing extended-spectrum
beta-lactamases: implications for the
clinical microbiology laboratory. J Clin
Microbiol, 2001. 39(6): 2206–12.
2445. Patterson BK, Landay A, Siegel JN,
Flener Z, Pessis D, Chaviano A, and
Bailey RC, Susceptibility to human
immunodeficiency virus-1 infection
of human foreskin and cervical tissue
grown in explant culture. Am J Pathol,
2002. 161(3): 867–73.
2446. Patterson JE and Andriole VT,
Bacterial urinary tract infections in
diabetes. Infect Dis Clin North Am,
1997. 11(3): 735–50.
2447. Patterson TF and Andriole VT,
Detection, significance, and therapy of
bacteriuria in pregnancy. Update in
the managed health care era. Infect Dis
Clin North Am, 1997. 11(3): 593–608.
2448. Patton JP, Nash DB, and Abrutyn E,
Urinary tract infection: economic con-
siderations. Med Clin North Am, 1991.
75(2): 495–513.
2449. Paul WE, Th1 fate determination in
CD4+ T cells: notice is served of the
importance of IL-12! J Immunol, 2008.
181(7): 4435–6.
2450. Paulitsch A, Weger W, Ginter-
Hanselmayer G, Marth E, and Buzina
W, A 5-year (2000–2004) epidemiologi-
cal survey of Candida and non-Cand-
ida yeast species causing vulvovaginal
candidiasis in Graz, Austria. Mycoses,
2006. 49(6): 471–5.

2451. Pawlowski ZS, Eckert J, and DA V,
Echinococcosis in humans: clinical
aspects, diagnosis and treatment.
WHO/OIE Manual on echinococcosis
in humans and animals. 2001, Paris:
World Health Organization.
2452. Payne SR, Timoney AG, McKenning
ST, den Hollander D, Pead LJ, and
Maskell RM, Microbiological look at
urodynamic studies. Lancet, 1988.
2(8620): 1123–6.
2453. Pea F, Pavan F, Di Qual E, Brollo L,
Nascimben E, Baldassarre M, and
Furlanut M, Urinary pharmacokinet-
ics and theoretical pharmacodynamics
of intravenous levofloxacin in intensive
care unit patients treated with 500 mg
b.i.d. for ventilator-associated pneumo-
nia. J Chemother, 2003. 15(6): 563–7.
2454. Pea F, Viale P, and Furlanut M,
Antimicrobial therapy in critically ill
patients: a review of pathophysiological
conditions responsible for altered dispo-
sition and pharmacokinetic variability.
Clin Pharmacokinet, 2005. 44(10):
1009–34.
2455. Pead L, Maskell R, and Morris J,
Staphylococcus saprophyticus as a uri-
nary pathogen: a six year prospective
survey. Br Med J (Clin Res Ed), 1985.
291(6503): 1157–9.
2456. Pearle MS and Roehrborn CG,
Antimicrobial prophylaxis prior to
shock wave lithotripsy in patients with
sterile urine before treatment: a meta-
analysis and cost-effectiveness analysis.
Urology, 1997. 49(5): 679–86.
2457. Pearman JW, Urological follow-up of
99 spinal cord injured patients initially
managed by intermittent catheterisa-
tion. Br J Urol, 1976. 48(5): 297–310.
2458. Pearson MM, Sebaihia M, Churcher C,
Quail MA, Seshasayee AS, Luscombe
NM, Abdellah Z, Arrosmith C, Atkin B,
Chillingworth T, Hauser H, Jagels K,
Moule S, Mungall K, Norbertczak H,
Rabbinowitsch E, Walker D, Whithead
S, Thomson NR, Rather PN, Parkhill
J, and Mobley HL, Complete genome
sequence of uropathogenic Proteus
mirabilis, a master of both adherence
and motility. J Bacteriol, 2008. 190(11):
4027–37.
References
2459. Pecile P and Romanello C,
Procalcitonin and pyelonephritis in
children. Curr Opin Infect Dis, 2007.
20(1): 83–7.
2460. Pedler SJ and Bint AJ, Comparative
study of amoxicillin-clavulanic acid
and cephalexin in the treatment of bac-
teriuria during pregnancy. Antimicrob
Agents Chemother, 1985. 27(4): 508–10.
2461. Peipert JF, Boardman L, Hogan JW,
Sung J, and Mayer KH, Laboratory
evaluation of acute upper genital tract
infection. Obstet Gynecol, 1996. 87(5 Pt
1): 730–6.
2462. Peipert JF, Ness RB, Blume J, Soper
DE, Holley R, Randall H, Sweet
RL, Sondheimer SJ, Hendrix SL,
Amortegui A, Trucco G, and Bass DC,
Clinical predictors of endometritis in
women with symptoms and signs of pel-
vic inflammatory disease. Am J Obstet
Gynecol, 2001. 184(5): 856–63; discus-
sion 863–4.
2463. Peipert JF, Ness RB, Soper DE, and
Bass D, Association of lower genital
tract inflammation with objective evi-
dence of endometritis. Infect Dis Obstet
Gynecol, 2000. 8(2): 83–7.
2464. Pelle G, Vimont S, Levy PP, Hertig A,
Ouali N, Chassin C, Arlet G, Rondeau
E, and Vandewalle A, Acute pyelone-
phritis represents a risk factor impair-
ing long-term kidney graft function. Am
J Transplant, 2007. 7(4): 899–907.
2465. Pellegrino R, Galvalisi U, Scavone P,
Sosa V, and Zunino P, Evaluation of
Proteus mirabilis structural fimbrial
proteins as antigens against urinary
tract infections. FEMS Immunol Med
Microbiol, 2003. 36(1–2): 103–10.
2466. Pelletier C, Prognon P, and Bourlioux
P, Roles of divalent cations and pH
in mechanism of action of nitroxo-
line against Escherichia coli strains.
Antimicrob Agents Chemother, 1995.
39(3): 707–13.
2467. Peloquin CA, Cumbo TJ, and Schentag
JJ, Kinetics and dynamics of tobramy-
cin action in patients with bacteriuria
given single doses. Antimicrob Agents
Chemother, 1991. 35(6): 1191–5.
2468. Pena C, Dominguez MA, Pujol M,
Verdaguer R, Gudiol F, and Ariza J,
1121
References
An outbreak of carbapenem-resistant
Pseudomonas aeruginosa in a urology
ward. Clin Microbiol Infect, 2003. 9(9):
938–43.
2469. Penna G, Mondaini N, Amuchastegui
S, Degli Innocenti S, Carini M, Giubilei
G, Fibbi B, Colli E, Maggi M, and
Adorini L, Seminal plasma cytokines
and chemokines in prostate inflam-
mation: interleukin 8 as a predictive
biomarker in chronic prostatitis/
chronic pelvic pain syndrome and
benign prostatic hyperplasia. Eur Urol,
2007. 51(2): 524–33; discussion 533.
2470. Pennesi M, Travan L, Peratoner L,
Bordugo A, Cattaneo A, Ronfani L,
Minisini S, and Ventura A, Is antibi-
otic prophylaxis in children with vesi-
coureteral reflux effective in preventing
pyelonephritis and renal scars? A ran-
domized, controlled trial. Pediatrics,
2008. 121(6): e1489–94.
2471. Pereira DA, Barroso U, Jr., Machado
P, Pestana JO, Rosito TE, Pires J,
Almeida C, Ortiz V, and Macedo A,
Jr., Effects of urinary tract infection in
patients with bladder augmentation
and kidney transplantation. J Urol,
2008. 180(6): 2607–10; discussion 2610.
2472. Perkash I and Giroux J, Prevention,
treatment, and management of urinary
tract infections in neuropathic blad-
ders. J Am Paraplegia Soc, 1985. 8(1):
15–7.
2473. Perletti G, Vral, A., Patrosso, M.C.,
Marras, E., Ceriani, I., Willems, P.,
Magri, V., Prevention and modulation
of aminoglycoside ototoxicity. Molecular
Medicine Reports, 2008. 1: 3–13.
2474. Perrone RD, Ruthazer R, and Terrin
NC, Survival after end-stage renal dis-
ease in autosomal dominant polycystic
kidney disease: contribution of extra-
renal complications to mortality. Am J
Kidney Dis, 2001. 38(4): 777–84.
2475. Perrotta C, Aznar M, Mejia R, Albert
X, and Ng CW, Oestrogens for prevent-
ing recurrent urinary tract infection
in postmenopausal women. Cochrane
Database Syst Rev, 2008(2): CD005131.
2476. Perry CM and Brogden RN, Cefuroxime
axetil. A review of its antibacterial
activity, pharmacokinetic properties
1122
and therapeutic efficacy. Drugs, 1996.
52(1): 125–58.
2477. Persson K, Mansson A, Jonsson E, and
Nordenfelt E, Decline of herpes simplex
virus type 2 and Chlamydia trachoma-
tis infections from 1970 to 1993 indi-
cated by a similar change in antibody
pattern. Scand J Infect Dis, 1995. 27(3):
195–9.
2478. Persson PB, Hansell P, and Liss P,
Pathophysiology of contrast medium-
induced nephropathy. Kidney Int, 2005.
68(1): 14–22.
2479. Peschers UM, Kempf V, Jundt K,
Autenrieth I, and Dimpfl T, Antibiotic
treatment to prevent urinary tract infec-
tions after urodynamic evaluation. Int
Urogynecol J Pelvic Floor Dysfunct,
2001. 12(4): 254–7.
2480. Pessaux P, Atallah D, Lermite E, Msika
S, Hay JM, Flamant Y, and Arnaud JP,
Risk factors for prediction of surgical
site infections in “clean surgery”. Am J
Infect Control, 2005. 33(5): 292–8.
2481. Pestalozzi DM, Boss HP, and Knonagel
H, [Infectious complications after
transurethral resection]. Helv Chir
Acta, 1992. 59(3): 497–500.
2482. Petas A, Talja M, Tammela TL, Taari
K, Valimaa T, and Tormala P, The
biodegradable self-reinforced poly-DL-
lactic acid spiral stent compared with
a suprapubic catheter in the treatment
of post-operative urinary retention after
visual laser ablation of the prostate. Br
J Urol, 1997. 80(3): 439–43.
2483. Peters PA, Mahmoud AA, Warren KS,
Ouma JH, and Siongok TK, Field stud-
ies of a rapid, accurate means of quan-
tifying Schistosoma haematobium eggs
in urine samples. Bull World Health
Organ, 1976. 54(2): 159–62.
2484. Peterson J, Kaul S, Khashab M, Fisher
A, and Kahn JB, Identification and
pretherapy susceptibility of pathogens
in patients with complicated urinary
tract infection or acute pyelonephri-
tis enrolled in a clinical study in the
United States from November 2004
through April 2006. Clin Ther, 2007.
29(10): 2215–21.
2485. Peterson J, Kaul S, Khashab M, Fisher
AC, and Kahn JB, A double-blind,

randomized comparison of levofloxacin
750 mg once-daily for five days with
ciprofloxacin 400/500 mg twice-daily
for 10 days for the treatment of compli-
cated urinary tract infections and acute
pyelonephritis. Urology, 2008. 71(1):
17–22.
2486. Petersson C, Hedges S, Stenqvist K,
Sandberg T, Connell H, and Svanborg
C, Suppressed antibody and inter-
leukin-6 responses to acute pyelone-
phritis in pregnancy. Kidney Int, 1994.
45(2): 571–7.
2487. Petraitis V, Petraitiene R, Groll AH,
Roussillon K, Hemmings M, Lyman
CA, Sein T, Bacher J, Bekersky I, and
Walsh TJ, Comparative antifungal
activities and plasma pharmacokinet-
ics of micafungin (FK463) against dis-
seminated candidiasis and invasive
pulmonary aspergillosis in persistently
neutropenic rabbits. Antimicrob Agents
Chemother, 2002. 46(6): 1857–69.
2488. Pettersson B and Tiselius HG, Are pro-
phylactic antibiotics necessary during
extracorporeal shockwave lithotripsy?
Br J Urol, 1989. 63(5): 449–52.
2489. Pettersson L, Klingstrom J, Hardestam
J, Lundkvist A, Ahlm C, and Evander
M, Hantavirus RNA in saliva from
patients with hemorrhagic fever with
renal syndrome. Emerg Infect Dis,
2008. 14(3): 406–11.
2490. Peyromaure M, Ravery V, and Boccon-
Gibod L, The management of stress
urinary incontinence after radical
prostatectomy. BJU Int, 2002. 90(2):
155–61.
2491. Pfau A and Sacks TG, Effective postcoi-
tal quinolone prophylaxis of recurrent
urinary tract infections in women. J
Urol, 1994. 152(1): 136–8.
2492. Pfau A and Sacks TG, Effective prophy-
laxis for recurrent urinary tract infec-
tions during pregnancy. Clin Infect Dis,
1992. 14(4): 810–4.
2493. Pfau A and Sacks TG, Effective prophy-
laxis of recurrent urinary tract infec-
tions in premenopausal women by
postcoital administration of cephalexin.
J Urol, 1989. 142(5): 1276–8.
2494. Pfau A, Sacks T, and Engelstein D,
Recurrent urinary tract infections in
References
premenopausal women: prophylaxis
based on an understanding of the
pathogenesis. J Urol, 1983. 129(6):
1153–7.
2495. Pfefferkorn U, Lea S, Moldenhauer J,
Peterli R, von Flue M, and Ackermann
C, Antibiotic prophylaxis at urinary
catheter removal prevents urinary tract
infections: a prospective randomized
trial. Ann Surg, 2009. 249(4): 573–5.
2496. Pfischner WC, Jr., Ishak KG, Neptune
EM, Jr., Fox SM, 3rd, Farid Z, and El
Din GN, Brucellosis in Egypt; a review
of experience with 228 patients. Am J
Med, 1957. 22(6): 915–29.
2497. Phalipon A, Cardona A, Kraehenbuhl
JP, Edelman L, Sansonetti PJ, and
Corthesy B, Secretory component: a
new role in secretory IgA-mediated
immune exclusion in vivo. Immunity,
2002. 17(1): 107–15.
2498. Phillips AJ, Treatment of non-albicans
Candida vaginitis with amphotericin
B vaginal suppositories. Am J Obstet
Gynecol, 2005. 192(6): 2009–12; discus-
sion 2012–3.
2499. Phillips JR and Karlowicz MG,
Prevalence of Candida species in hospi-
tal-acquired urinary tract infections in
a neonatal intensive care unit. Pediatr
Infect Dis J, 1997. 16(2): 190–4.
2500. Phipps S, Lim YN, McClinton S, Barry
C, Rane A, and N’Dow J, Short term
urinary catheter policies following
urogenital surgery in adults. Cochrane
Database Syst Rev, 2006(2): CD004374.
2501. Piaggio G, Degl’ Innocenti ML,
Toma P, Calevo MG, and Perfumo F,
Cystosonography and voiding cys-
tourethrography in the diagnosis of
vesicoureteral reflux. Pediatr Nephrol,
2003. 18(1): 18–22.
2502. Pichon C, Hechard C, du Merle L,
Chaudray C, Bonne I, Guadagnini S,
Vandewalle A, and Le Bouguenec C,
Uropathogenic Escherichia coli AL511
requires flagellum to enter renal col-
lecting duct cells. Cell Microbiol, 2009.
11(4): 616–28.
2503. Pickworth FE, Carlin JB, Ditchfield
MR, de Campo MP, de Campo JF,
Cook DJ, Nolan T, Powell HR, Sloane
R, and Grimwood K, Sonographic
1123
References
measurement of renal enlargement in
children with acute pyelonephritis and
time needed for resolution: implications
for renal growth assessment. AJR Am J
Roentgenol, 1995. 165(2): 405–8.
2504. Piepsz A, Tamminen-Mobius T, Reiners
C, Heikkila J, Kivisaari A, Nilsson NJ,
Sixt R, Risdon RA, Smellie JM, and
Soderborg B, Five-year study of medical
or surgical treatment in children with
severe vesico-ureteral reflux dimercap-
tosuccinic acid findings. International
Reflux Study Group in Europe. Eur J
Pediatr, 1998. 157(9): 753–8.
2505. Piercey KR, Khoury AE, McLorie GA,
and Churchill BM, Diagnosis and man-
agement of urinary tract infections.
Curr Opin Urol, 1993. 3: 25–29.
2506. Pieretti RV and Pieretti-Vanmarcke
RV, Congenital bladder diverticula in
children. J Pediatr Surg, 1999. 34(3):
468–73.
2507. Piipo T PT, Salo SA, Three-day versus
seven-day treatment with norfloxacin in
acute cystitis. Curr Ther Res, 1990. 47:
644–653.
2508. Pimentel FL, Dolgner A, Guimaraes J,
Quintas M, and Mario-Reis J, Efficacy
and safety of norfloxacin 800 mg once-
daily versus norfloxacin 400 mg twice-
daily in the treatment of uncomplicated
urinary tract infections in women: a
double-blind, randomized clinical trial.
J Chemother, 1998. 10(2): 122–7.
2509. Pinson AG, Philbrick JT, Lindbeck GH,
and Schorling JB, ED management of
acute pyelonephritis in women: a cohort
study. Am J Emerg Med, 1994. 12(3):
271–8.
2510. Pirotta M, Gunn J, Chondros P, Grover
S, O’Malley P, Hurley S, and Garland
S, Effect of lactobacillus in preventing
post-antibiotic vulvovaginal candidia-
sis: a randomised controlled trial. BMJ,
2004. 329(7465): 548.
2511. Pirotta MV and Garland SM, Genital
Candida species detected in samples
from women in Melbourne, Australia,
before and after treatment with anti-
biotics. J Clin Microbiol, 2006. 44(9):
3213–7.
2512. Pirotta MV, Gunn JM, and Chondros P,
“Not thrush again!” Women’s experience
1124
of post-antibiotic vulvovaginitis. Med J
Aust, 2003. 179(1): 43–6.
2513. Pisani E, Palla R, and Bono AV, Double-
blind randomised clinical study of
OM-8930 vs placebo in patients suf-
fering from recurrent urinary tract
infections. 1992. Quoted in Chiavaroli
C Moore A. An Hypothesis to Link
the Opposing Immunological Effects
Induced by the Bacterial Lysate
OM-89 in Urinary Tract Infection and
Rheumatoid Arthritis. Biodrugs 2006;
20: 141–149: Geneva: OM Pharma.
2514. Pitout JD and Laupland KB, Extended-
spectrum beta-lactamase-producing
Enterobacteriaceae: an emerging pub-
lic-health concern. Lancet Infect Dis,
2008. 8(3): 159–66.
2515. Pitsouni E, Iavazzo C, and Falagas
ME, Itraconazole vs fluconazole for
the treatment of uncomplicated acute
vaginal and vulvovaginal candidiasis
in nonpregnant women: a metaanalysis
of randomized controlled trials. Am J
Obstet Gynecol, 2008. 198(2): 153–60.
2516. Pittet D and Ducel G, Infectious risk
factors related to operating rooms.
Infect Control Hosp Epidemiol, 1994.
15(7): 456–62.
2517. Pittet D, Mourouga P, and Perneger
TV, Compliance with handwashing in
a teaching hospital. Infection Control
Program. Ann Intern Med, 1999.
130(2): 126–30.
2518. Platt R, Polk BF, Murdock B, and
Rosner B, Mortality associated with
nosocomial urinary-tract infection. N
Engl J Med, 1982. 307(11): 637–42.
2519. Platt R, Polk BF, Murdock B, and
Rosner B, Reduction of mortality asso-
ciated with nosocomial urinary tract
infection. Lancet, 1983. 1(8330): 893–7.
2520. Platt R, Polk BF, Murdock B, and
Rosner B, Risk factors for nosoco-
mial urinary tract infection. Am J
Epidemiol, 1986. 124(6): 977–85.
2521. Platt R, Quantitative definition of bacte-
riuria. Am J Med, 1983. 75(1B): 44–52.
2522. Plempel M, [Pharmacokinetics of imi-
dazole-antimycotics (author’s transl)].
Mykosen, 1980. 23(1): 16–27.
2523. Plos K, Lomberg H, Hull S, Johansson
I, and Svanborg C, Escherichia coli in

patients with renal scarring: genotype
and phenotype of Gal alpha 1–4Gal
beta-, Forssman- and mannose-specific
adhesins. Pediatr Infect Dis J, 1991.
10(1): 15–9.
2524. Plummer DC, Garland SM, and Gilbert
GL, Bacteraemia and pelvic infection in
women due to Ureaplasma urealyticum
and Mycoplasma hominis. Med J Aust,
1987. 146(3): 135–7.
2525. Plummer FA, Simonsen JN, Cameron
DW, Ndinya-Achola JO, Kreiss JK,
Gakinya MN, Waiyaki P, Cheang M,
Piot P, Ronald AR, and et al., Cofactors
in male-female sexual transmission of
human immunodeficiency virus type 1.
J Infect Dis, 1991. 163(2): 233–9.
2526. Poggensee G, Feldmeier H, and Krantz
I, Schistosomiasis of the female genital
tract: public health aspects. Parasitol
Today, 1999. 15(9): 378–81.
2527. Poggio ED, Wang X, Greene T, Van
Lente F, and Hall PM, Performance of
the modification of diet in renal dis-
ease and Cockcroft-Gault equations in
the estimation of GFR in health and
in chronic kidney disease. J Am Soc
Nephrol, 2005. 16(2): 459–66.
2528. Poirel L, Heritier C, Spicq C, and
Nordmann P, In vivo acquisition of
high-level resistance to imipenem in
Escherichia coli. J Clin Microbiol, 2004.
42(8): 3831–3.
2529. Polito C, Rambaldi PF, Mansi L, Di
Toro R, and La Manna A, Unilateral
vesicoureteric reflux: Low prevalence of
contralateral renal damage. J Pediatr,
2001. 138(6): 875–9.
2530. Pollok RC, Francis N, Cliff S, Nelson
N, and Gazzard B, Kaposi’s sarcoma in
the kidney. Int J STD AIDS, 1995. 6(4):
289–90.
2531. Pontin AR, Barnes RD, Joffe J, and
Kahn D, Emphysematous pyelonephri-
tis in diabetic patients. Br J Urol, 1995.
75(1): 71–4.
2532. Poretsky L and Moses AC,
Hypoglycemia associated with tri-
methoprim/sulfamethoxazole therapy.
Diabetes Care, 1984. 7(5): 508–9.
2533. Porter MF, III. Uro-Genital
Tuberculosis in the Male. Ann Surg,
1894. 20(4): 396–405.
References
2534. Potts M, Halperin DT, Kirby D, Swidler
A, Marseille E, Klausner JD, Hearst
N, Wamai RG, Kahn JG, and Walsh J,
Public health. Reassessing HIV preven-
tion. Science, 2008. 320(5877): 749–50.
2535. Poulsen AL, Schou J, Ovesen H, and
Nordling J, Memokath: a second gen-
eration of intraprostatic spirals. Br J
Urol, 1993. 72(3): 331–4.
2536. Powell BL and Drutz DJ, Identification
of a high-affinity binder for estradiol
and a low-affinity binder for testoster-
one in Coccidioides immitis. Infect
Immun, 1984. 45(3): 784–6.
2537. Powell PH, Smith PJ, and Feneley RC,
The identification of patients at risk
from acute retention. Br J Urol, 1980.
52(6): 520–2.
2538. Powers KA, Poole C, Pettifor AE, and
Cohen MS, Rethinking the heterosexual
infectivity of HIV-1: a systematic review
and meta-analysis. Lancet Infect Dis,
2008. 8(9): 553–63.
2539. Powers RD, New directions in the
diagnosis and therapy of urinary tract
infections. Am J Obstet Gynecol, 1991.
164(5 Pt 2): 1387–9.
2540. Practice parameter: the diagnosis,
treatment, and evaluation of the ini-
tial urinary tract infection in febrile
infants and young children. American
Academy of Pediatrics. Committee on
Quality Improvement. Subcommittee
on Urinary Tract Infection. Pediatrics,
1999. 103(4 Pt 1): 843–52.
2541. Prasad A, Cevallos ME, Riosa S,
Darouiche RO, and Trautner BW, A
bacterial interference strategy for pre-
vention of UTI in persons practicing
intermittent catheterization. Spinal
Cord, 2009. 47(7): 565–9.
2542. Prat V, Horcickova M, Matousovic K,
Hatala M, and Liska M, Urinary tract
infection in renal transplant patients.
Infection, 1985. 13(5): 207–10.
2543. Pratikaki M, Platsouka E, Sotiropoulou
C, Douka E, Paramythiotou E, Kaltsas
P, Kotanidou A, Paniara O, Roussos C,
and Routsi C, Epidemiology, risk fac-
tors for and outcome of candidaemia
among non-neutropenic patients in a
Greek intensive care unit. Mycoses,
2009.
1125
References
2544. Pratt LA and Kolter R, Genetic analysis
of Escherichia coli biofilm formation:
roles of flagella, motility, chemotaxis
and type I pili. Mol Microbiol, 1998.
30(2): 285–93.
2545. Pratt RJ, Pellowe C, Loveday HP,
Robinson N, Smith GW, Barrett
S, Davey P, Harper P, Loveday C,
McDougall C, Mulhall A, Privett S,
Smales C, Taylor L, Weller B, and
Wilcox M, The epic project: develop-
ing national evidence-based guidelines
for preventing healthcare associated
infections. Phase I: Guidelines for pre-
venting hospital-acquired infections.
Department of Health (England). J
Hosp Infect, 2001. 47 Suppl: S3–82.
2546. Prelog M, Schiefecker D, Fille
M, Wurzner R, Brunner A, and
Zimmerhackl LB, Febrile urinary tract
infection in children: ampicillin and
trimethoprim insufficient as empirical
mono-therapy. Pediatr Nephrol, 2008.
23(4): 597–602.
2547. Preminger GM, Assimos DG, Lingeman
JE, Nakada SY, Pearle MS, and Wolf
JS, Jr., Chapter 1: AUA guideline on
management of staghorn calculi: diag-
nosis and treatment recommendations.
J Urol, 2005. 173(6): 1991–2000.
2548. Premkumar A and Newhouse JH,
Seminal vesicle tuberculosis: CT
appearance. J Comput Assist Tomogr,
1988. 12(4): 676–7.
2549. Prere MF, Licznar P, Decramer S, and
Fayet O, [E.coli from urinary tract
infections and acute pyelonephritis of
children: 1% of strains are resistant
to a subset of third generation cepha-
losporins]. Pathol Biol (Paris), 2004.
52(8): 497–500.
2550. Prevention CfDCa. Sexually
Transmitted Diseases Treatment
Guidelines 2006, CDC, Editor. 2006,
CDC.
2551. Prieto-Fingerhut T, Banovac K, and
Lynne CM, A study comparing sterile
and nonsterile urethral catheteriza-
tion in patients with spinal cord injury.
Rehabil Nurs, 1997. 22(6): 299–302.
2552. Prigent-Combaret C, Prensier G,
Le Thi TT, Vidal O, Lejeune P, and
Dorel C, Developmental pathway for
1126
biofilm formation in curli-producing
Escherichia coli strains: role of flag-
ella, curli and colanic acid. Environ
Microbiol, 2000. 2(4): 450–64.
2553. Prospective trial of operative versus
non-operative treatment of severe vesi-
coureteric reflux in children: five years’
observation. Birmingham Reflux Study
Group. Br Med J (Clin Res Ed), 1987.
295(6592): 237–41.
2554. Psihramis KE and Donahoe PK,
Primary genitourinary tuberculosis:
rapid progression and tissue destruc-
tion during treatment. J Urol, 1986.
135(5): 1033–6.
2555. Public Health Laboratory Service.
Available from: www.phls.co.uk.
2556. Pudney J and Anderson DJ,
Immunobiology of the human penile
urethra. Am J Pathol, 1995. 147(1):
155–65.
2557. Puig J, Darnell A, Bermudez P, Malet
A, Serrate G, Bare M, and Prats J,
Transrectal ultrasound-guided prostate
biopsy: is antibiotic prophylaxis neces-
sary? Eur Radiol, 2006. 16(4): 939–43.
2558. Pujari SB, Joshi SK, Bhatt RV, and
Patel BC, Complications following
use of Lippes’ Loop. J Obstet Gynaecol
India, 1968. 18(2): 257–61.
2559. Puri P, Pirker M, Mohanan N, Dawrant
M, Dass L, and Colhoun E, Subureteral
dextranomer/hyaluronic acid injec-
tion as first line treatment in the man-
agement of high grade vesicoureteral
reflux. J Urol, 2006. 176(4 Pt 2): 1856–
9; discussion 1859–60.
2560. Puvaneswary M, Bisits A, and Hosken
B, Renal abscess with paranephric
extension in a gravid woman: ultra-
sound and magnetic resonance imaging
findings. Australas Radiol, 2005. 49(3):
230–2.
2561. Qiang W, Jianchen W, MacDonald
R, Monga M, and Wilt TJ, Antibiotic
prophylaxis for transurethral prostatic
resection in men with preoperative
urine containing less than 100,000
bacteria per ml: a systematic review. J
Urol, 2005. 173(4): 1175–81.
2562. Queipo-Ortuno MI, Colmenero JD,
Munoz N, Baeza G, Clavijo E, and
Morata P, Rapid diagnosis of Brucella

epididymo-orchitis by real-time
polymerase chain reaction assay in
urine samples. J Urol, 2006. 176(5):
2290–3.
2563. Quereux C, Gelas B, Chevallier T, Petit
F, and Micheletti MC, [Evaluation of
the efficacity and speed of action of
sertaconazole nitrate suppository and
cream combined treatment for vul-
vovaginal candidiasis]. Gynecol Obstet
Fertil, 2000. 28(3): 238–44.
2564. Quesada ET and Light JK, The AMS
700 inflatable penile prosthesis: long-
term experience with the controlled
expansion cylinders. J Urol, 1993.
149(1): 46–8.
2565. Quigley MA, Weiss HA, and Hayes RJ,
Male circumcision as a measure to con-
trol HIV infection and other sexually
transmitted diseases. Curr Opin Infect
Dis, 2001. 14(1): 71–5.
2566. Quigley R, Diagnosis of urinary tract
infections in children. Curr Opin
Pediatr, 2009. 21(2): 194–8.
2567. Quinn TC, Circumcision and HIV
transmission. Curr Opin Infect Dis,
2007. 20(1): 33–8.
2568. Quinn TC, Wawer MJ, Sewankambo N,
Serwadda D, Li C, Wabwire-Mangen F,
Meehan MO, Lutalo T, and Gray RH,
Viral load and heterosexual transmis-
sion of human immunodeficiency virus
type 1. Rakai Project Study Group. N
Engl J Med, 2000. 342(13): 921–9.
2569. Raad I, Darouiche R, Hachem
R, Sacilowski M, and Bodey GP,
Antibiotics and prevention of microbial
colonization of catheters. Antimicrob
Agents Chemother, 1995. 39(11):
2397–400.
2570. Raad I, Hanna H, Jiang Y, Dvorak T,
Reitzel R, Chaiban G, Sherertz R, and
Hachem R, Comparative activities of
daptomycin, linezolid, and tigecycline
against catheter-related methicillin-re-
sistant Staphylococcus bacteremic iso-
lates embedded in biofilm. Antimicrob
Agents Chemother, 2007. 51(5):
1656–60.
2571. Rabkin DG, Stifelman MD, Birkhoff J,
Richardson KA, Cohen D, Nowygrod R,
Benvenisty AI, and Hardy MA, Early
catheter removal decreases incidence of
References
urinary tract infections in renal trans-
plant recipients. Transplant Proc, 1998.
30(8): 4314–6.
2572. Rachmiel M, Aladjem M, Starinsky R,
Strauss S, Villa Y, and Goldman M,
Symptomatic urinary tract infections
following voiding cystourethrogra-
phy. Pediatr Nephrol, 2005. 20(10):
1449–52.
2573. Radwanski E, Teal M, Affrime M,
Cayen M, and Lin CC, Multiple-
Dose Pharmacokinetics of Ceftibuten
in Healthy Adults and Geriatric
Volunteers. Am J Ther, 1994. 1(1):
42–48.
2574. Rady MY, Rivers EP, and Nowak RM,
Resuscitation of the critically ill in the
ED: responses of blood pressure, heart
rate, shock index, central venous oxygen
saturation, and lactate. Am J Emerg
Med, 1996. 14(2): 218–25.
2575. Rafalsky V, Andreeva I, and Rjabkova
E, Quinolones for uncomplicated acute
cystitis in women. Cochrane Database
Syst Rev, 2006. 3: CD003597.
2576. Rafique M, Nephrectomy: indications,
complications and mortality in 154
consecutive patients. J Pak Med Assoc,
2007. 57(6): 308–11.
2577. Ragnarsdottir B, Fischer H, Godaly
G, Gronberg-Hernandez J, Gustafsson
M, Karpman D, Lundstedt AC, Lutay
N, Ramisch S, Svensson ML, Wullt B,
Yadav M, and Svanborg C, TLR- and
CXCR1-dependent innate immunity:
insights into the genetics of urinary
tract infections. Eur J Clin Invest,
2008. 38 Suppl 2: 12–20.
2578. Ragnarsdottir B, Samuelsson M,
Gustafsson MC, Leijonhufvud I,
Karpman D, and Svanborg C, Reduced
toll-like receptor 4 expression in chil-
dren with asymptomatic bacteriuria. J
Infect Dis, 2007. 196(3): 475–84.
2579. Rahav G, Pinco E, Bachrach G, and
Bercovier H, Molecular epidemiology of
asymptomatic bacteriuria in the elderly.
Age Ageing, 2003. 32(6): 670–3.
2580. Rahav G, Pinco E, Silbaq F, and
Bercovier H, Molecular epidemiology of
catheter-associated bacteriuria in nurs-
ing home patients. J Clin Microbiol,
1994. 32(4): 1031–4.
1127
References
2581. Raj GV, Peterson AC, and Webster GD,
Outcomes following erosions of the arti-
ficial urinary sphincter. J Urol, 2006.
175(6): 2186–90; discussion 2190.
2582. Raj GV, Peterson AC, Toh KL, and
Webster GD, Outcomes following revi-
sions and secondary implantation of
the artificial urinary sphincter. J Urol,
2005. 173(4): 1242–5.
2583. Rajpurkar A, Fairfax M, Li H, and
Dhabuwala CB, Antibiotic soaked
hydrophilic coated bioflex: a new strat-
egy in the prevention of penile prosthe-
sis infection. J Sex Med, 2004. 1(2):
215–20.
2584. Ramage IJ, Chapman JP, Hollman AS,
Elabassi M, McColl JH, and Beattie
TJ, Accuracy of clean-catch urine collec-
tion in infancy. J Pediatr, 1999. 135(6):
765–7.
2585. Ramakrishnan K and Scheid DC,
Diagnosis and management of acute
pyelonephritis in adults. Am Fam
Physician, 2005. 71(5): 933–42.
2586. Ramanathan R, Kumar A, Kapoor R,
and Bhandari M, Relief of urinary tract
obstruction in tuberculosis to improve
renal function. Analysis of predic-
tive factors. Br J Urol, 1998. 81(2):
199–205.
2587. Ramsey AM and Zilberberg MD,
Secular trends of hospitalization with
vancomycin-resistant enterococcus
infection in the United States, 2000–
2006. Infect Control Hosp Epidemiol,
2009. 30(2): 184–6.
2588. Ramsteiner, In vivo study of the immu-
nostimulating activity of OM-89 using
the plaque-forming cells technique in
mice. Experimental report 1990.
2589. Rane A, Cahill D, Saleemi A,
Montgomery B, and Palfrey E, The
issue of prophylactic antibiotics prior
to flexible cystoscopy. Eur Urol, 2001.
39(2): 212–4.
2590. Rangel-Frausto MS, Pittet D, Costigan
M, Hwang T, Davis CS, and Wenzel
RP, The natural history of the systemic
inflammatory response syndrome
(SIRS). A prospective study. JAMA,
1995. 273(2): 117–23.
2591. Ransley PG and Risdon RA, Reflux
nephropathy: effects of antimicrobial
1128
therapy on the evolution of the early
pyelonephritic scar. Kidney Int, 1981.
20(6): 733–42.
2592. Ransley PG, Risdon RA, and Godley
ML, High pressure sterile vesicoureteral
reflux and renal scarring: an experi-
mental study in the pig and minipig.
Contrib Nephrol, 1984. 39: 320–43.
2593. Rao PN, Dube DA, Weightman
NC, Oppenheim BA, and Morris J,
Prediction of septicemia following
endourological manipulation for stones
in the upper urinary tract. J Urol, 1991.
146(4): 955–60.
2594. Rasmussen BA and Bush K,
Carbapenem-hydrolyzing beta-lacta-
mases. Antimicrob Agents Chemother,
1997. 41(2): 223–32.
2595. Rassjo EB and Darj E, “Safe sex advice
is good – but so difficult to follow”.
Views and experiences of the youth in a
health centre in Kampala. From Kiswa
Youth Clinic, Kampala, Uganda. Afr
Health Sci, 2002. 2(3): 107–13.
2596. Ravi G and Motalib MA, Surgical cor-
rection of bilharzial ureteric stricture by
Boari flap technique. Br J Urol, 1993.
71(5): 535–8.
2597. Ray D, Goswami R, Banerjee U,
Dadhwal V, Goswami D, Mandal
P, Sreenivas V, and Kochupillai N,
Prevalence of Candida glabrata and
its response to boric acid vaginal sup-
positories in comparison with oral
fluconazole in patients with diabetes
and vulvovaginal candidiasis. Diabetes
Care, 2007. 30(2): 312–7.
2598. Raz P, Urinary tract infection in elderly
women. Int J Antimicrob Agents, 1998.
10(3): 177–9.
2599. Raz R and Rozenfeld S, 3-day course of
ofloxacin versus cefalexin in the treat-
ment of urinary tract infections in post-
menopausal women. Antimicrob Agents
Chemother, 1996. 40(9): 2200–1.
2600. Raz R and Stamm WE, A controlled
trial of intravaginal estriol in postmen-
opausal women with recurrent urinary
tract infections. N Engl J Med, 1993.
329(11): 753–6.
2601. Raz R, Chazan B, Kennes Y, Colodner
R, Rottensterich E, Dan M, Lavi
I, and Stamm W, Empiric use of

trimethoprim-sulfamethoxazole (TMP-
SMX) in the treatment of women with
uncomplicated urinary tract infec-
tions, in a geographical area with a
high prevalence of TMP-SMX-resistant
uropathogens. Clin Infect Dis, 2002.
34(9): 1165–9.
2602. Raz R, Colodner R, and Kunin CM,
Who are you – Staphylococcus sapro-
phyticus? Clin Infect Dis, 2005. 40(6):
896–8.
2603. Raz R, Colodner R, Rohana Y, Battino
S, Rottensterich E, Wasser I, and
Stamm W, Effectiveness of estriol-
containing vaginal pessaries and nitro-
furantoin macrocrystal therapy in the
prevention of recurrent urinary tract
infection in postmenopausal women.
Clin Infect Dis, 2003. 36(11): 1362–8.
2604. Raz R, Gennesin Y, Wasser J, Stoler
Z, Rosenfeld S, Rottensterich E, and
Stamm WE, Recurrent urinary tract
infections in postmenopausal women.
Clin Infect Dis, 2000. 30(1): 152–6.
2605. Raz R, Hormone replacement therapy or
prophylaxis in postmenopausal women
with recurrent urinary tract infection. J
Infect Dis, 2001. 183 Suppl 1: S74–6.
2606. Raz R, Intravaginal estriol and
the bladder., in The Millennium
Review 2000. The Management of the
Menopause., JAMA, Editor. 1999. p.
1–3.
2607. Raz R, Schiller D, and Nicolle LE,
Chronic indwelling catheter replace-
ment before antimicrobial therapy for
symptomatic urinary tract infection. J
Urol, 2000. 164(4): 1254–8.
2608. Rebbapragada A, Wachihi C, Pettengell
C, Sunderji S, Huibner S, Jaoko W,
Ball B, Fowke K, Mazzulli T, Plummer
FA, and Kaul R, Negative mucosal syn-
ergy between Herpes simplex type 2 and
HIV in the female genital tract. AIDS,
2007. 21(5): 589–98.
2609. Recent trends in antimicrobial resist-
ance among Streptococcus pneumoniae
and Staphylococcus aureus isolates: the
French experience. Euro Surveill, 2008.
13(46).
2610. Reed BD, Zazove P, Pierson CL,
Gorenflo DW, and Horrocks J,
Candida transmission and sexual
References
behaviors as risks for a repeat episode
of Candida vulvovaginitis. J Womens
Health (Larchmt), 2003. 12(10):
979–89.
2611. Reed SD, Landers DV, and Sweet RL,
Antibiotic treatment of tuboovarian
abscess: comparison of broad-spectrum
beta-lactam agents versus clindamycin-
containing regimens. Am J Obstet
Gynecol, 1991. 164(6 Pt 1): 1556–61;
discussion 1561–2.
2612. Rees E, The treatment of pelvic inflam-
matory disease. Am J Obstet Gynecol,
1980. 138(7 Pt 2): 1042–7.
2613. Reeves DS, Treatment of bacteriuria in
pregnancy with single dose fosfomycin
trometamol: a review. Infection, 1992.
20 Suppl 4: S313–6.
2614. Reid G and Bruce AW, Probiotics to pre-
vent urinary tract infections: the ration-
ale and evidence. World J Urol, 2006.
24(1): 28–32.
2615. Reid G and Burton J, Use of
Lactobacillus to prevent infection by
pathogenic bacteria. Microbes Infect,
2002. 4(3): 319–24.
2616. Reid G and Habash MB, Urogenital
microflora and urinary tract infections,
in Medical importance of the normal
microflora, Tannock GW, Editor. 1999,
Chapman & Hall: London. p. 423–440.
2617. Reid G, Biofilms in infectious dis-
ease and on medical devices. Int J
Antimicrob Agents, 1999. 11(3–4):
223–6; discussion 237–9.
2618. Reid G, Biofilms in infectious dis-
eases and on medical devices. Int.
J. of Antimicrob.l Agents, 1999(11):
223–226.
2619. Reid G, Bruce AW, and Taylor M,
Influence of three-day antimicrobial
therapy and lactobacillus vaginal sup-
positories on recurrence of urinary tract
infections. Clin Ther, 1992. 14(1): 11–6.
2620. Reid G, Bruce AW, and Taylor M,
Instillation of Lactobacillus and
stimulation of indigenous organisms to
prevent recurrence of urinary tract infec-
tions. Microecol. Ther., 1995(23): 32–45.
2621. Reid G, Bruce AW, Cook RL, and Llano
M, Effect on urogenital flora of antibi-
otic therapy for urinary tract infection.
Scand J Infect Dis, 1990. 22(1): 43–7.
1129
References
2622. Reid G, Chan RC, Bruce AW, and
Costerton JW, Prevention of urinary
tract infection in rats with an indig-
enous Lactobacillus casei strain. Infect
Immun, 1985. 49(2): 320–4.
2623. Reid G, Charbonneau D, Erb J,
Kochanowski B, Beuerman D,
Poehner R, and Bruce AW, Oral use of
Lactobacillus rhamnosus GR-1 and L.
fermentum RC-14 significantly alters
vaginal flora: randomized, placebo-
controlled trial in 64 healthy women.
FEMS Immunol Med Microbiol, 2003.
35(2): 131–4.
2624. Reid G, Denstedt JD, Kang YS, Lam D,
and Naus C, Microbial adhesion and
biofilm formation on ureteral stents in
vitro and in vivo. J Urol, 1992. 148:
1592–1594.
2625. Reid G, Habash M, Vachon D, Denstedt
J, Riddell J, and Beheshti M, Oral
fluoroquinolone therapy results in
drug adsorption on ureteral stents and
prevention of biofilm formation. Int J
Antimicrob Agents, 2001. 17(4): 317–9;
discussion 319–20.
2626. Reid G, Millsap K, and Bruce AW,
Implantation of Lactobacillus casei var
rhamnosus into vagina. Lancet, 1994.
344(8931): 1229.
2627. Reid G, Potter P, Delaney G, Hsieh J,
Nicosia S, and Hayes K, Ofloxacin for
the treatment of urinary tract infections
and biofilms in spinal cord injury. Int J
Antimicrob Agents, 2000. 13(4): 305–7.
2628. Reid G, Sharma S, Advikolanu K,
Tieszer C, Martin RA, and Bruce AW,
Effects of ciprofloxacin, norfloxacin,
and ofloxacin on in vitro adhesion and
survival of Pseudomonas aeruginosa
AK1 on urinary catheters. Antimicrob
Agents Chemother, 1994. 38(7):
1490–5.
2629. Reid G, The potential role of probiot-
ics in pediatric urology. J Urol, 2002.
168(4 Pt 1): 1512–7.
2630. Reidl S, Lehmann A, Schiller R,
Salam Khan A, and Dobrindt U,
Impact of O-glycosylation on the
molecular and cellular adhesion
properties of the Escherichia coli
autotransporter protein Ag43. Int J
Med Microbiol, 2009.
1130
2631. Reinhart K, Diagnosis of sepsis. Novel
and conventional parameters. Minerva
Anestesiol, 2001. 67(10): 675–82.
2632. Reinhart K, Kuhn HJ, Hartog C,
and Bredle DL, Continuous central
venous and pulmonary artery oxygen
saturation monitoring in the critically
ill. Intensive Care Med, 2004. 30(8):
1572–8.
2633. Reinhart K, Wiegand-Lohnert C,
Grimminger F, Kaul M, Withington
S, Treacher D, Eckart J, Willatts S,
Bouza C, Krausch D, Stockenhuber F,
Eiselstein J, Daum L, and Kempeni J,
Assessment of the safety and efficacy of
the monoclonal anti-tumor necrosis fac-
tor antibody-fragment, MAK 195F, in
patients with sepsis and septic shock: a
multicenter, randomized, placebo-con-
trolled, dose-ranging study. Crit Care
Med, 1996. 24(5): 733–42.
2634. Reljic M and But I, Monitoring parame-
ters in the management of patients with
tubo-ovarian complexes. Int J Gynaecol
Obstet, 1999. 64(3): 273–9.
2635. Reljic M and Gorisek B, C-reactive pro-
tein and the treatment of pelvic inflam-
matory disease. Int J Gynaecol Obstet,
1998. 60(2): 143–50.
2636. Report of the Expert Committee on
the Diagnosis and Classification of
Diabetes Mellitus. Diabetes Care, 1997.
20(7): 1183–97.
2637. Resnick MI, Ultrasonic evaluation
of the prostate and bladder. Semin
Ultrasound, 1980(1): 69.
2638. Reynolds SJ, Shepherd ME, Risbud
AR, Gangakhedkar RR, Brookmeyer
RS, Divekar AD, Mehendale SM, and
Bollinger RC, Male circumcision and
risk of HIV-1 and other sexually trans-
mitted infections in India. Lancet,
2004. 363(9414): 1039–40.
2639. Riccabona M, Mache CJ, and
Lindbichler F, Echo-enhanced
color Doppler cystosonography of
vesicoureteral reflux in children.
Improvement by stimulated acoustic
emission. Acta Radiol, 2003. 44(1):
18–23.
2640. Riccabona M, Urinary tract infections
in children. Curr Opin Urol, 2003.
13(1): 59–62.

2641. Rice JC, Peng T, Kuo YF, Pendyala S,
Simmons L, Boughton J, Ishihara K,
Nowicki S, and Nowicki BJ, Renal allo-
graft injury is associated with urinary
tract infection caused by Escherichia
coli bearing adherence factors. Am J
Transplant, 2006. 6(10): 2375–83.
2642. Rice LB, Yao JD, Klimm K, Eliopoulos
GM, and Moellering RC, Jr., Efficacy
of different beta-lactams against an
extended-spectrum beta-lactamase-pro-
ducing Klebsiella pneumoniae strain in
the rat intra-abdominal abscess model.
Antimicrob Agents Chemother, 1991.
35(6): 1243–4.
2643. Rice TW, Wheeler AP, Morris PE,
Paz HL, Russell JA, Edens TR, and
Bernard GR, Safety and efficacy of
affinity-purified, anti-tumor necrosis
factor-alpha, ovine fab for injection
(CytoFab) in severe sepsis. Crit Care
Med, 2006. 34(9): 2271–81.
2644. Richard G dC, Ruoff G, Corrado M,
Fowler C. Short-course levofloxacin
(250 mg qid) vs ofloxacin (200 mg bid)
in uncomplicated UTI: a double-blind,
randomized trial. Abstract. in 6th Int
Symp New Quinolones. Nov 15–17,
1998. Denver, Colorado, USA.
2645. Richard GA, DeAbate, C.A., Ruoff,
G.E.,Corrado, M., Fowler, C.L.,
Morgan, N., A double-blind, ran-
domised trial of the efficacy and
safety of short-course, once-daily levo-
floxacin versus ofloxacin twice daily in
uncomplicated urinary tract infection.
Infectious Diseases in Clinical Practice,
1998. 9: 323–329.
2646. Richard GA, Klimberg IN, Fowler
CL, Callery-D’Amico S, and Kim SS,
Levofloxacin versus ciprofloxacin versus
lomefloxacin in acute pyelonephritis.
Urology, 1998. 52(1): 51–5.
2647. Richard GA, Mathew CP, Kirstein
JM, Orchard D, and Yang JY, Single-
dose fluoroquinolone therapy of acute
uncomplicated urinary tract infection
in women: results from a randomized,
double-blind, multicenter trial compar-
ing single-dose to 3-day fluoroquinolone
regimens. Urology, 2002. 59(3): 334–9.
2648. Richards MJ, Edwards JR, Culver DH,
and Gaynes RP, Nosocomial infections
References
in medical intensive care units in the
United States. National Nosocomial
Infections Surveillance System. Crit
Care Med, 1999. 27(5): 887–92.
2649. Richards MJ, Edwards JR, Culver DH,
and Gaynes RP, Nosocomial infections
in combined medical-surgical intensive
care units in the United States. Infect
Control Hosp Epidemiol, 2000. 21(8):
510–5.
2650. Richmond D, Zaharievski I, and Bond
A, Management of pregnancy in moth-
ers with spina bifida. Eur J Obstet
Gynecol Reprod Biol, 1987. 25(4):
341–5.
2651. Richter S, Kotliroff O, and Nissenkorn
I, Single preoperative bladder instilla-
tion of povidone-iodine for the preven-
tion of postprostatectomy bacteriuria
and wound infection. Infect Control
Hosp Epidemiol, 1991. 12(10): 579–82.
2652. Richter SS, Galask RP, Messer SA,
Hollis RJ, Diekema DJ, and Pfaller
MA, Antifungal susceptibilities of
Candida species causing vulvovaginitis
and epidemiology of recurrent cases. J
Clin Microbiol, 2005. 43(5): 2155–62.
2653. Rickwood AMK, Hodgson J, and Lonton
AP, Medical and surgical complications
in adolescent and young adult patients
with spina bifida. Health Trends,
1984(16): 91–5.
2654. Riedasch G, Heck P, Rauterberg E, and
Ritz E, Does low urinary sIgA predis-
pose to urinary tract infection? Kidney
Int, 1983. 23(5): 759–63.
2655. Riedasch G, Influence of OM-8930
on secretory IgA in urine of children
with frequent urinary tract infec-
tions. Experimental Report & Rapport
Biometrix. 1985.
2656. Riedner G, Hoffmann O, Rusizoka M,
Mmbando D, Maboko L, Grosskurth
H, Todd J, Hayes R, and Hoelscher M,
Decline in sexually transmitted infec-
tion prevalence and HIV incidence in
female barworkers attending preven-
tion and care services in Mbeya Region,
Tanzania. AIDS, 2006. 20(4): 609–15.
2657. Riehmann M, Goetzman B, Langer E,
Drinka PJ, Rhodes PR, and Bruskewitz
RC, Risk factors for bacteriuria in men.
Urology, 1994. 43(5): 617–20.
1131
References
2658. Rifkin MD and Resnick ML,
Ultrasonography of the prostate, in
Ultrasonography of the urinary tract,
Resnick MI and Rifkin MD, Editors.
1991, Williams & Wilkins: Baltimore,
Md. p. xviii, 502 p.
2659. Rigg D, Miller MM, and Metzger WJ,
Recurrent allergic vulvovaginitis: treat-
ment with Candida albicans allergen
immunotherapy. Am J Obstet Gynecol,
1990. 162(2): 332–6.
2660. Riley DE RS, Limaye AP, Krieger JN.
Inconsistent localization of Gram-
positive bacteria to prostate-specific
specimens from patients with chronic
prostatitis. in American Urological
Association Annual Meeting. 2005. San
Antonio: J Urol.
2661. Riley DK, Classen DC, Stevens LE, and
Burke JP, A large randomized clinical
trial of a silver-impregnated urinary
catheter: lack of efficacy and staphylo-
coccal superinfection. Am J Med, 1995.
98(4): 349–56.
2662. Ringoir S and Vanholder R, Phagocytic
function in the uremic patient. Contrib
Nephrol, 1992. 100: 15–24.
2663. Rippere-Lampe KE, Lang M, Ceri H,
Olson M, Lockman HA, and O’Brien AD,
Cytotoxic necrotizing factor type 1-posi-
tive Escherichia coli causes increased
inflammation and tissue damage to the
prostate in a rat prostatitis model. Infect
Immun, 2001. 69(10): 6515–9.
2664. Rippere-Lampe KE, O’Brien AD,
Conran R, and Lockman HA, Mutation
of the gene encoding cytotoxic necrotiz-
ing factor type 1 (cnf1) attenuates the
virulence of uropathogenic Escherichia
coli. Infect Immun, 2001. 69(6):
3954–64.
2665. Risdon RA, Godley ML, Gordon I, and
Ransley PG, Renal pathology and the
99mTc-DMSA image before and after
treatment of the evolving pyelonephritic
scar: an experimental study. J Urol,
1994. 152(4): 1260–6.
2666. Risdon RA, The small scarred kidney of
childhood. A congenital or an acquired
lesion? Pediatr Nephrol, 1987. 1(4):
632–7.
2667. Ritter W, Pharmacokinetics of azole
compounds, in Sterol biosynthesis
1132
inhibitors, Berg D and Plempel
M Editors. 1988, Ellis Horwood:
Chichester. p. 397–429.
2668. Rittirsch D, Flierl MA, and Ward PA,
Harmful molecular mechanisms in
sepsis. Nat Rev Immunol, 2008. 8(10):
776–87.
2669. Rivers E, Nguyen B, Havstad S,
Ressler J, Muzzin A, Knoblich B,
Peterson E, and Tomlanovich M, Early
goal-directed therapy in the treatment
of severe sepsis and septic shock. N
Engl J Med, 2001. 345(19): 1368–77.
2670. Rives RK, Harty JI, and Amin M,
Renal abscess: emerging concepts of
diagnosis and treatment. J Urol, 1980.
124(4): 446–7.
2671. Rivett AG, Perry JA, and Cohen J,
Urinary candidiasis: a prospective
study in hospital patients. Urol Res,
1986. 14(4): 183–6.
2672. Robert Koch-Institut Available from:
www.rki.de.
2673. Robert-Koch-Institute, Report of
Epidemiology of Tuberculosis in
Germany 2006 2006, Berlin: Robert-
Koch-Institute
2674. Roberts JA and Lipman J,
Antibacterial dosing in intensive care:
pharmacokinetics, degree of disease
and pharmacodynamics of sepsis. Clin
Pharmacokinet, 2006. 45(8): 755–73.
2675. Roberts JA, Kruger P, Paterson DL,
and Lipman J, Antibiotic resistance—
what’s dosing got to do with it? Crit
Care Med, 2008. 36(8): 2433–40.
2676. Roberts JA, Management of pyelone-
phritis and upper urinary tract infec-
tions. Urol Clin North Am, 1999. 26(4):
753–63.
2677. Roberts RO, Lieber MM, Bostwick DG,
and Jacobsen SJ, A review of clinical
and pathological prostatitis syndromes.
Urology, 1997. 49(6): 809–21.
2678. Robinson MR, Arudpragasam ST,
Sahgal SM, Cross RJ, Akdas A, Fittal
B, and Sibbald R, Bacteraemia result-
ing from prostatic surgery: the source of
bacteria. Br J Urol, 1982. 54(5): 542–6.
2679. Rocha PN, Rehem AP, Santana JF,
Castro N, Muniz AL, Salgado K, Rocha
H, and Carvalho EM, The cause of
urinary symptoms among Human T

Lymphotropic Virus Type I (HLTV-I)
infected patients: a cross sectional
study. BMC Infect Dis, 2007. 7: 15.
2680. Rocha SP, Pelayo JS, and Elias WP,
Fimbriae of uropathogenic Proteus
mirabilis. FEMS Immunol Med
Microbiol, 2007. 51(1): 1–7.
2681. Rodhe N, Lofgren S, Matussek A,
Andre M, Englund L, Kuhn I, and
Molstad S, Asymptomatic bacteriuria
in the elderly: high prevalence and high
turnover of strains. Scand J Infect Dis,
2008. 40(10): 804–10.
2682. Rodhe N, Molstad S, Englund L, and
Svardsudd K, Asymptomatic bacteriu-
ria in a population of elderly residents
living in a community setting: preva-
lence, characteristics and associated
factors. Fam Pract, 2006. 23(3): 303–7.
2683. Rodrigues G and Seetharam P,
Management of hydatid disease
(echinococcosis) in pregnancy. Obstet
Gynecol Surv, 2008. 63(2): 116–23.
2684. Rodriguez-Bano J, Alcala JC, Cisneros
JM, Grill F, Oliver A, Horcajada
JP, Tortola T, Mirelis B, Navarro
G, Cuenca M, Esteve M, Pena C,
Llanos AC, Canton R, and Pascual
A, Community infections caused by
extended-spectrum beta-lactamase-
producing Escherichia coli. Arch Intern
Med, 2008. 168(17): 1897–902.
2685. Roehrborn CG and McConnell JD,
Benign prostatic hyperplasia: etiology,
pathophysiology and natural history, in
Campbell-Walsh urology, Campbell MF,
Wein AJ, and Kavoussi LR, Editors.
2007, Saunders Elsevier: Philadelphia,
PA. p. 2727–2765.
2686. Roesch PL, Redford P, Batchelet
S, Moritz RL, Pellett S, Haugen
BJ, Blattner FR, and Welch RA,
Uropathogenic Escherichia coli use
D-serine deaminase to modulate infec-
tion of the murine urinary tract. Mol
Microbiol, 2003. 49(1): 55–67.
2687. Roghmann MC, Wallin MT, Gorman
PH, and Johnson JA, Prevalence and
natural history of colonization with
fluoroquinolone-resistant gram-negative
bacilli in community-dwelling people
with spinal cord dysfunction. Arch Phys
Med Rehabil, 2006. 87(10): 1305–9.
References
2688. Rohde H, Burdelski C, Bartscht
K, Hussain M, Buck F, Horstkotte
MA, Knobloch JK, Heilmann C,
Herrmann M, and Mack D, Induction
of Staphylococcus epidermidis biofilm
formation via proteolytic processing of
the accumulation-associated protein by
staphylococcal and host proteases. Mol
Microbiol, 2005. 55(6): 1883–95.
2689. Romanczuk W and Korczawski R,
Chronic constipation: a cause of recur-
rent urinary tract infections. Turk J
Pediatr, 1993. 35(3): 181–8.
2690. Romanzi LJ, Groutz A, and Blaivas
JG, Urethral diverticulum in women:
diverse presentations resulting in diag-
nostic delay and mismanagement. J
Urol, 2000. 164(2): 428–33.
2691. Romas NA, Renal tuberculosis, in
Current therapy in genitourinary
surgery. 1992, Mosby-Yearbook. p.
369–372.
2692. Romero Perez P and Mira Llinares A,
[Male urethral stenosis: review of com-
plications]. Arch Esp Urol, 2004. 57(5):
485–511.
2693. Romero Perez P and Mira Llinares
A, [Renal and ureteral complications
of urethral stenosis]. Actas Urol Esp,
1995. 19(6): 432–40.
2694. Romero R, Gomez R, Ghezzi F, Yoon
BH, Mazor M, Edwin SS, and Berry
SM, A fetal systemic inflammatory
response is followed by the spontane-
ous onset of preterm parturition. Am J
Obstet Gynecol, 1998. 179(1): 186–93.
2695. Römling U, Characterization of the
rdar morphotype, a multicellular
behaviour in Enterobacteriaceae. Cell
Mol Life Sci, 2005. 62(11): 1234–46.
2696. Ronald A, The etiology of urinary
tract infection: traditional and emerg-
ing pathogens. Dis Mon, 2003. 49(2):
71–82.
2697. Ronald AR and Conway B, An
approach to urinary tract infections
in ambulatory women. Curr Clin Top
Infect Dis, 1988. 9: 76–125.
2698. Roos V and Klemm P, Global gene
expression profiling of the asymptomatic
bacteriuria Escherichia coli strain
83972 in the human urinary tract.
Infect Immun, 2006. 74(6): 3565–75.
1133
References
2699. Root RK, Waldvogel F, Corey L, and
Stamm W, Clinical Infectious Disease:
A Practical Approach. 1992: Oxford
University Press.
2700. Rosales Leal JL, Tallada Bunuel M,
Espejo Maldonado E, Cozar Olmo JM,
Vicente Prados FJ, Martinez Morcillo A,
Buitrago Sivianes S, Rodriguez Herrera
F, and Ortiz Gorraiz M, [Acute prosta-
titis as the 1st symptom of brucellosis].
Arch Esp Urol, 2003. 56(5): 527–9.
2701. Rosedale N and Browne K,
Hyposensitisation in the management
of recurring vaginal candidiasis. Ann
Allergy, 1979. 43(4): 250–3.
2702. Rosen DA, Hooton TM, Stamm WE,
Humphrey PA, and Hultgren SJ,
Detection of intracellular bacterial com-
munities in human urinary tract infec-
tion. PLoS Med, 2007. 4(12): e329.
2703. Rosen DA, Pinkner JS, Jones JM,
Walker JN, Clegg S, and Hultgren SJ,
Utilization of an intracellular bacte-
rial community pathway in Klebsiella
pneumoniae urinary tract infection
and the effects of FimK on type 1 pilus
expression. Infect Immun, 2008. 76(7):
3337–45.
2704. Rosen DA, Pinkner JS, Walker JN,
Elam JS, Jones JM, and Hultgren
SJ, Molecular variations in Klebsiella
pneumoniae and Escherichia coli FimH
affect function and pathogenesis in
the urinary tract. Infect Immun, 2008.
76(7): 3346–56.
2705. Rosenberg AR, Rossleigh MA, Brydon
MP, Bass SJ, Leighton DM, and
Farnsworth RH, Evaluation of acute
urinary tract infection in children by
dimercaptosuccinic acid scintigraphy:
a prospective study. J Urol, 1992. 148(5
Pt 2): 1746–9.
2706. Rosenthal EJ, [Epidemiology of sep-
ticaemia pathogens]. Dtsch Med
Wochenschr, 2002. 127(46): 2435–40.
2707. Rosenthal M, Effect of a bacterial
extract on cellular and humoral
immune responses in humans. J
Immunopharmacol, 1986. 8(3): 315–25.
2708. Rosser CJ, Bare RL, and Meredith JW,
Urinary tract infections in the critically
ill patient with a urinary catheter. Am J
Surg, 1999. 177(4): 287–90.
1134
2709. Roth AC, Milsom I, Forssman L, and
Wahlen P, Intermittent prophylactic
treatment of recurrent vaginal candi-
diasis by postmenstrual application of
a 500 mg clotrimazole vaginal tablet.
Genitourin Med, 1990. 66(5): 357–60.
2710. Roth CC, Hubanks JM, Bright BC,
Heinlen JE, Donovan BO, Kropp BP,
and Frimberger D, Occurrence of uri-
nary tract infection in children with
significant upper urinary tract obstruc-
tion. Urology, 2009. 73(1): 74–8.
2711. Rotterdam H, Chronic endometritis. A
clinicopathologic study. Pathol Annu,
1978. 13 Pt 2: 209–31.
2712. Rottingen JA, Cameron DW, and
Garnett GP, A systematic review of the
epidemiologic interactions between clas-
sic sexually transmitted diseases and
HIV: how much really is known? Sex
Transm Dis, 2001. 28(10): 579–97.
2713. Rousaud F, Algaba F, Donate T, Roda
M, Barcelo P, and Del Rio G, Hydatid
renal cyst disease: 22 Cases reviewed.
Nefrologia, 1994. 14: 663–70.
2714. Roussey-Kesler G, Gadjos V, Idres
N, Horen B, Ichay L, Leclair MD,
Raymond F, Grellier A, Hazart I, de
Parscau L, Salomon R, Champion G,
Leroy V, Guigonis V, Siret D, Palcoux
JB, Taque S, Lemoigne A, Nguyen JM,
and Guyot C, Antibiotic prophylaxis
for the prevention of recurrent urinary
tract infection in children with low
grade vesicoureteral reflux: results from
a prospective randomized study. J Urol,
2008. 179(2): 674–9; discussion 679.
2715. Rowe PJ, WHO manual for the stand-
ardized investigation and diagnosis of
the infertile couple. 1993: Cambridge
University Press on behalf of the World
Health Organization.
2716. Royce RA, Sena A, Cates W, Jr., and
Cohen MS, Sexual transmission of HIV.
N Engl J Med, 1997. 336(15): 1072–8.
2717. Ruben B, Band JD, Wong P, and
Colville J, Person-to-person transmis-
sion of Brucella melitensis. Lancet,
1991. 337(8732): 14–5.
2718. Ruben FL, Dearwater SR, Norden
CW, Kuller LH, Gartner K, Shalley A,
Warshafsky G, Kelsey SF, O’Donnell C,
Means E, and et al., Clinical infections

in the noninstitutionalized geriatric age
group: methods utilized and incidence
of infections. The Pittsburgh Good
Health Study. Am J Epidemiol, 1995.
141(2): 145–57.
2719. Rubenstein JN and Schaeffer AJ,
Managing complicated urinary tract
infections: the urologic view. Infect Dis
Clin North Am, 2003. 17(2): 333–51.
2720. Rubin G and Dale A, Chronic constipa-
tion in children. BMJ, 2006. 333(7577):
1051–5.
2721. Rubin GL, Ory HW, and Layde PM,
Oral contraceptives and pelvic inflam-
matory disease. Am J Obstet Gynecol,
1982. 144(6): 630–5.
2722. Rubin RH, Beam TR, Jr., and Stamm
WE, An approach to evaluating anti-
bacterial agents in the treatment of
urinary tract infection. Clin Infect Dis,
1992. 14 Suppl 2: S246–51; discussion
S253–4.
2723. Rubin RH, Shapiro ED, Andriole VT,
Davies RJ, Stamm WE, and with
modifications by a European Working
Party (Norrby SR), General guidelines
for the evaluation of new anti-infective
drugs for the treatment of UTI. 1993,
Taufkirchen, Germany: The European
Society of Clinical Microbiology and
Infectious Diseases.
2724. Rubin RH, Shapiro ED, Andriole VT,
Davis RJ, and Stamm WE, Evaluation
of new anti-infective drugs for the
treatment of urinary tract infec-
tion. Infectious Diseases Society of
America and the Food and Drug
Administration. Clin Infect Dis, 1992.
15 Suppl 1: S216–27.
2725. Rubin UH SE, Andriole VT, Davis
RJ, Stamm WE, with a modifica-
tion by a European Working Party
(Norrby SR), General Guidelines for
the evaluation of new anti-infective
drugs for the treatment of urinary tract
infection. The European Society of
Clinical Microbiology and Infectious
diseases, Taukirchen, Germany, 1993:
240–310.
2726. Rubin USE, Andriole VT, Davis RJ,
Stamm WE, Evaluation of new anti-
infective drugs for the treatment of UTI.
Clin Infect Dis, 1992. 15: 216.
References
2727. Ruchel R, Tegeler R, and Trost M, A
comparison of secretory proteinases
from different strains of Candida
albicans. Sabouraudia, 1982. 20(3):
233–44.
2728. Ruden H, Gastmeier P, Daschner FD,
and Schumacher M, Nosocomial and
community-acquired infections in
Germany. Summary of the results of
the First National Prevalence Study
(NIDEP). Infection, 1997. 25(4):
199–202.
2729. Rudenko N and Dorofeyev A,
Prevention of recurrent lower urinary
tract infections by long-term admin-
istration of fosfomycin trometamol.
Double blind, randomized, paral-
lel group, placebo controlled study.
Arzneimittelforschung, 2005. 55(7):
420–7.
2730. Rudnick JR, Beck-Sague CM, Anderson
RL, Schable B, Miller JM, and Jarvis
WR, Gram-negative bacteremia in open-
heart-surgery patients traced to probable
tap-water contamination of pressure-
monitoring equipment. Infect Control
Hosp Epidemiol, 1996. 17(5): 281–5.
2731. Rufener SL, Adusumilli S, Weadock
WJ, and Caoili E, Sonography of uter-
ine abnormalities in postpartum and
postabortion patients: a potential pitfall
of interpretation. J Ultrasound Med,
2008. 27(3): 343–8.
2732. Runde V, Ross S, Trenschel R,
Lagemann E, Basu O, Renzing-Kohler
K, Schaefer UW, Roggendorf M, and
Holler E, Adenoviral infection after
allogeneic stem cell transplantation
(SCT): report on 130 patients from a
single SCT unit involved in a prospec-
tive multi center surveillance study.
Bone Marrow Transplant, 2001. 28(1):
51–7.
2733. Rupp ME, Soper DE, and Archer GL,
Colonization of the female genital tract
with Staphylococcus saprophyticus. J
Clin Microbiol, 1992. 30(11): 2975–9.
2734. Rusch K and Schwiertz A, Candida
autovaccination in the treatment of
vulvovaginal Candida infections. Int J
Gynaecol Obstet, 2007. 96(2): 130.
2735. Rushton HG and Majd M,
Pyelonephritis in male infants: how
1135
References
important is the foreskin? J Urol, 1992.
148(2 Pt 2): 733–6; discussion 737–8.
2736. Rushton HG, Majd M, Chandra R, and
Yim D, Evaluation of 99mtechnetium-
dimercapto-succinic acid renal scans
in experimental acute pyelonephritis
in piglets. J Urol, 1988. 140(5 Pt 2):
1169–74.
2737. Rushton HG, Majd M, Jantausch B,
Wiedermann BL, and Belman AB,
Renal scarring following reflux and
nonreflux pyelonephritis in children:
evaluation with 99mtechnetium-dimer-
captosuccinic acid scintigraphy. J Urol,
1992. 147(5): 1327–32.
2738. Rushton HG, Urinary tract infections
in children. Epidemiology, evaluation,
and management. Pediatr Clin North
Am, 1997. 44(5): 1133–69.
2739. Russell MW and Mestecky J, Humoral
immune responses to microbial infec-
tions in the genital tract. Microbes
Infect, 2002. 4(6): 667–77.
2740. Rutala WA, Gergen MF, and Weber DJ,
Disinfection of a probe used in ultra-
sound-guided prostate biopsy. Infect
Control Hosp Epidemiol, 2007. 28(8):
916–9.
2741. Rutala WA, Kennedy VA, Loflin HB,
and Sarubbi FA, Jr., Serratia marc-
escens nosocomial infections of the
urinary tract associated with urine
measuring containers and urinometers.
Am J Med, 1981. 70(3): 659–63.
2742. Rybak MJ, Abate BJ, Kang SL, Ruffing
M, J., Lerner SA, and Drusano GL,
Prospective evaluation of the effect of an
aminoglycoside dosing regimen on rates
of observed nephrotoxicity and ototox-
icity. Antimicrob Agents Chemother,
1999. 43: 1549–1555.
2743. Rybak MJ, The pharmacokinetic and
pharmacodynamic properties of vanco-
mycin. Clin Infect Dis, 2006. 42 Suppl
1: S35–9.
2744. Ryffel B and Quesniaux V, Draft Report
Study AP001. Comparison of AP-89
versus OM-89 TLR dependence in
macrophage activation. Immunology,
IEM6218, CNRS F-45071 2008:
Orleans.
2745. Ryffel B, Toll-like receptors (TLR)
activation by natural and synthetic
1136
TLR ligands. Final report – project
TR-2002/02. 2003.
2746. Ryu JK, Lee SM, Seong DW, Suh JK,
Kim S, Choe W, Moon Y, and Pai SH,
Tc-99m ciprofloxacin imaging in diag-
nosis of chronic bacterial prostatitis.
Asian J Androl, 2003. 5(3): 179–83.
2747. Saathoff E, Olsen A, Magnussen P,
Kvalsvig JD, Becker W, and Appleton
CC, Patterns of Schistosoma haemato-
bium infection, impact of praziquantel
treatment and re-infection after treat-
ment in a cohort of schoolchildren from
rural KwaZulu-Natal/South Africa.
BMC Infect Dis, 2004. 4: 40.
2748. Saban MR, Hellmich HL, Simpson
C, Davis CA, Lang ML, Ihnat MA,
O’Donnell MA, Wu XR, and Saban
R, Repeated BCG treatment of mouse
bladder selectively stimulates small
GTPases and HLA antigens and inhib-
its single-spanning uroplakins. BMC
Cancer, 2007. 7: 204.
2749. Sabbagh R, McCormack M, Peloquin
F, Faucher R, Perreault JP, Perrotte
P, Karakiewicz PI, and Saad F, A
prospective randomized trial of 1-day
versus 3-day antibiotic prophylaxis for
transrectal ultrasound guided prostate
biopsy. Can J Urol, 2004. 11(2): 2216–9.
2750. Sabri M, Houle S, and Dozois CM,
Roles of the extraintestinal pathogenic
Escherichia coli ZnuACB and ZupT
zinc transporters during urinary tract
infection. Infect Immun, 2009. 77(3):
1155–64.
2751. Sachot JL, Ratajczak A, Ridoux G, and
Lobel B, La tuberculose urogénitale.
A propos de cinquante cas. Ann Urol,
1982. 16(4): 227–29.
2752. Saemann MD, Weichhart T, Horl WH,
and Zlabinger GJ, Tamm-Horsfall pro-
tein: a multilayered defence molecule
against urinary tract infection. Eur J
Clin Invest, 2005. 35(4): 227–35.
2753. Säemann MD, Weichhart T, Horl WH,
and Zlabinger GJ, Tamm-Horsfall pro-
tein: a multilayered defence molecule
against urinary tract infection. Eur J
Clin Invest, 2005. 35(4): 227–35.
2754. Safdar N and Maki DG, The com-
monality of risk factors for nosoco-
mial colonization and infection with

antimicrobial-resistant Staphylococcus
aureus, enterococcus, gram-negative
bacilli, Clostridium difficile, and
Candida. Ann Intern Med, 2002.
136(11): 834–44.
2755. Safdar N, Slattery WR, Knasinski V,
Gangnon RE, Li Z, Pirsch JD, and
Andes D, Predictors and outcomes of
candiduria in renal transplant recipi-
ents. Clin Infect Dis, 2005. 40(10):
1413–21.
2756. Safir MH, Gousse AE, and Raz S,
Bladder diverticula causing urinary
retention in a woman without bladder
outlet obstruction. J Urol, 1998. 160(6
Pt 1): 2146–7.
2757. Saginur R and Nicolle LE, Single-
dose compared with 3-day norfloxacin
treatment of uncomplicated urinary
tract infection in women. Canadian
Infectious Diseases Society Clinical
Trials Study Group. Arch Intern Med,
1992. 152(6): 1233–7.
2758. Sah SP, Bhadani PP, Regmi R, Tewari
A, and Raj GA, Fine needle aspiration
cytology of tubercular epididymitis and
epididymo-orchitis. Acta Cytol, 2006.
50(3): 243–9.
2759. Sahasrabuddhe VV and Vermund SH,
The future of HIV prevention: control of
sexually transmitted infections and cir-
cumcision interventions. Infect Dis Clin
North Am, 2007. 21(1): 241–57, xi.
2760. Sahm DF, Thornsberry C, Mayfield
DC, Jones ME, and Karlowsky JA,
Multidrug-resistant urinary tract iso-
lates of Escherichia coli: prevalence and
patient demographics in the United
States in 2000. Antimicrob Agents
Chemother, 2001. 45(5): 1402–6.
2761. Saint S and Chenoweth CE, Biofilm
and catheter-associated urinary tract
infections. Infect Dis Clin North Am,
2003. 17: 411–432.
2762. Saint S, Kaufman SR, Rogers MA,
Baker PD, Boyko EJ, and Lipsky BA,
Risk factors for nosocomial urinary
tract-related bacteremia: a case-control
study. Am J Infect Control, 2006. 34(7):
401–7.
2763. Saint S, Kaufman SR, Thompson
M, Rogers MA, and Chenoweth
CE, A reminder reduces urinary
References
catheterization in hospitalized patients.
Jt Comm J Qual Patient Saf, 2005.
31(8): 455–62.
2764. Saitoh H, Nakamura K, Hida M, and
Satoh T, Urinary tract infection in olig-
uric patients with chronic renal failure.
J Urol, 1985. 133(6): 990–3.
2765. Sakakibara K, Sato K, Yoshino K,
Oshiro N, Hirahara S, Mahbub
Hasan AK, Iwasaki T, Ueda Y, Iwao Y,
Yonezawa K, and Fukami Y, Molecular
identification and characterization of
Xenopus egg uroplakin III, an egg raft-
associated transmembrane protein that
is tyrosine-phosphorylated upon ferti-
lization. J Biol Chem, 2005. 280(15):
15029–37.
2766. Sakinc T, Kleine B, and Gatermann
SG, Biochemical characterization
of the surface-associated lipase of
Staphylococcus saprophyticus. FEMS
Microbiol Lett, 2007. 274(2): 335–41.
2767. Sakinc T, Kleine B, and Gatermann
SG, SdrI, a serine-aspartate repeat
protein identified in Staphylococcus
saprophyticus strain 7108, is a colla-
gen-binding protein. Infect Immun,
2006. 74(8): 4615–23.
2768. Sakr Y, Payen D, Reinhart K, Sipmann
FS, Zavala E, Bewley J, Marx G, and
Vincent JL, Effects of hydroxyethyl
starch administration on renal function
in critically ill patients. Br J Anaesth,
2007. 98(2): 216–24.
2769. Sakr Y, Vincent JL, Reinhart K, Payen
D, Wiedermann CJ, Zandstra DF,
and Sprung CL, Use of the pulmonary
artery catheter is not associated with
worse outcome in the ICU. Chest, 2005.
128(4): 2722–31.
2770. Sakura M, Kawakami S, Yoshida S,
Masuda H, Kobayashi T, and Kihara
K, Prospective comparative study of
single dose versus 3-day administra-
tion of antimicrobial prophylaxis in
minimum incision endoscopic radical
prostatectomy. Int J Urol, 2008. 15(4):
328–31.
2771. Salahuddin S, Hsu YS, Buchholz NP,
Dieleman JP, Gyssens IC, and Kok DJ,
Is indinavir crystalluria an indicator
for indinavir stone formation? AIDS,
2001. 15(8): 1079–80.
1137
References
2772. Salari MH and Karimi A, Prevalence
of Ureaplasma urealyticum and
Mycoplasma genitalium in men
with non-gonococcal urethritis. East
Mediterr Health J, 2003. 9(3): 291–5.
2773. Salehipour M, Jalaeian H, Salahi H,
Bahador A, Davari HR, Nikeghbalian
S, Sagheb MM, Raiss-Jalali GA,
Roozbeh J, Behzadi S, Janghorban P,
Sepas HN, and Malek-Hosseini SA,
Are large nonfunctional kidneys risk
factors for posttransplantation urinary
tract infection in patients with end-
stage renal disease due to autosomal
dominant polycystic kidney disease?
Transplant Proc, 2007. 39(4): 887–8.
2774. Saling E, Fuhr N, Placht A, and
Schumacher E, [[Initial results of “pre-
ventive self-care by pregnant patients”
for prevention of premature labor].
Arch Gynecol Obstet, 1995. 257(1–4):
178–85.
2775. Salomon J, Denys P, Merle C, Chartier-
Kastler E, Perronne C, Gaillard JL, and
Bernard L, Prevention of urinary tract
infection in spinal cord-injured patients:
safety and efficacy of a weekly oral cyclic
antibiotic (WOCA) programme with a 2
year follow-up—an observational pro-
spective study. J Antimicrob Chemother,
2006. 57(4): 784–8.
2776. Saltzman DH, Evans MI, Robichaux
AG, 3rd, Grossman JH, 3rd, and
Friedman AJ, Nongonococcal pelvic
abscess caused by Salmonella enteri-
tidis. Obstet Gynecol, 1984. 64(4):
585–6.
2777. Sampol BJ, [Obstructive fungus ball
in kidney allografts]. Actas Urol Esp,
2008. 32(2): 267.
2778. Samra Z, Ofir O, Lishtzinsky Y, Madar-
Shapiro L, and Bishara J, Outbreak
of carbapenem-resistant Klebsiella
pneumoniae producing KPC-3 in a
tertiary medical centre in Israel. Int J
Antimicrob Agents, 2007. 30(6): 525–9.
2779. Samuelsson P, Hang L, Wullt B, Irjala
H, and Svanborg C, Toll-like receptor
4 expression and cytokine responses in
the human urinary tract mucosa. Infect
Immun, 2004. 72(6): 3179–86.
2780. Sanabria A, Dominguez LC, Valdivieso
E, and Gomez G, Prophylactic
1138
antibiotics for mesh inguinal hernio-
plasty: a meta-analysis. Ann Surg,
2007. 245(3): 392–6.
2781. Sanchez M, Collvinent B, Miro O,
Horcajada JP, Moreno A, Marco F,
Mensa J, and Milla J, Short-term effec-
tiveness of ceftriaxone single dose in
the initial treatment of acute uncompli-
cated pyelonephritis in women. A ran-
domised controlled trial. Emerg Med J,
2002. 19(1): 19–22.
2782. Sanchez Navarro MD, Coloma Milano
C, Zarzuelo Castaneda A, Sayalero
Marinero ML, and Sanchez-Navarro
A, Pharmacokinetics of ciprofloxacin
as a tool to optimise dosage sched-
ules in community patients. Clin
Pharmacokinet, 2002. 41(14): 1213–20.
2783. Sanchez-Carbayo M, Recent advances
in bladder cancer diagnostics. Clin
Biochem, 2004. 37(7): 562–71.
2784. Sanchez-Carbayo M, Use of high-
throughput DNA microarrays to iden-
tify biomarkers for bladder cancer. Clin
Chem, 2003. 49(1): 23–31.
2785. Sanford JP, Favour CB, Mao FH, and
Harrison JH, Evaluation of the positive
urine culture; an approach to the dif-
ferentiation of significant bacteria from
contaminants. Am J Med, 1956. 20(1):
88–93.
2786. Sangani P, Rutherford G, and
Wilkinson D, Population-based inter-
ventions for reducing sexually transmit-
ted infections, including HIV infection.
Cochrane Database Syst Rev, 2004(2):
CD001220.
2787. Sano M, Hirose T, Nishimura M,
Takahashi S, Matsukawa M, and
Tsukamoto T, Inhibitory action of clari-
thromycin on glycocalyx produced by
MRSA. J Infect Chemother, 1999. 5(1):
10–15.
2788. Santillo VM and Lowe FC, The man-
agement of chronic prostatitis in men
with HIV. Curr Urol Rep, 2006. 7(4):
313–9.
2789. Santucci RA, Joyce GF, and Wise M,
Male urethral stricture disease. J Urol,
2007. 177(5): 1667–74.
2790. Santucci RA, Payne CK, Anger JT, and
Saigal CS, Office dilation of the female
urethra: a quality of care problem

in the field of urology. J Urol, 2008.
180(5): 2068–75.
2791. Sarramon JP, Lhez JM, Courty P,
and Escourrou G, Tuberculose génito-
urinaire. Aspects anatomo-cliniques
et valeur diagnostique des lésions
histologiques. Ann Urol, 1982. 16(4):
241–42.
2792. Sathapornwajana P, Dissaneewate P,
McNeil E, and Vachvanichsanong P,
Timing of voiding cystourethrogram
after urinary tract infection. Arch Dis
Child, 2008. 93(3): 229–31.
2793. Sauerwein D, Urinary tract infection
in patients with neurogenic bladder
dysfunction. Int J Antimicrob Agents,
2002. 19(6): 592–7.
2794. Savage DC, Howie G, Adler K, and
Wilson MI, Controlled trial of therapy
in covert bacteriuria of childhood.
Lancet, 1975. 1(7903): 358–61.
2795. Savage DC, Natural history of covert
bacteriuria in schoolgirls. Kidney Int
Suppl, 1975. 4: S90–5.
2796. Savage WE, Hajj SN, and Kass EH,
Demographic and prognostic characteris-
tics of bacteriuria in pregnancy. Medicine
(Baltimore), 1967. 46(5): 385–407.
2797. Savaris RF, Teixeira LM, Torres
TG, Edelweiss MI, Moncada J, and
Schachter J, Comparing ceftriaxone
plus azithromycin or doxycycline
for pelvic inflammatory disease: a
randomized controlled trial. Obstet
Gynecol, 2007. 110(1): 53–60.
2798. Sawires SR, Dworkin SL, Fiamma A,
Peacock D, Szekeres G, and Coates
TJ, Male circumcision and HIV/AIDS:
challenges and opportunities. Lancet,
2007. 369(9562): 708–13.
2799. Sayegh ES and Dimmette RM, The
fibrotic contracted urinary bladder
associated with schistosomiasis and
chronic ulceration: a clinicopathologi-
cal study including treatment. J Urol,
1956. 75(4): 671–9.
2800. Scaglione F and Paraboni L, Influence
of pharmacokinetics/pharmacodynam-
ics of antibacterials in their dosing regi-
men selection. Expert Rev Anti Infect
Ther, 2006. 4(3): 479–90.
2801. Scavone P, Miyoshi A, Rial A,
Chabalgoity A, Langella P, Azevedo V,
References
and Zunino P, Intranasal immunisation
with recombinant Lactococcus lactis
displaying either anchored or secreted
forms of Proteus mirabilis MrpA fim-
brial protein confers specific immune
response and induces a significant
reduction of kidney bacterial colonisa-
tion in mice. Microbes Infect, 2007.
9(7): 821–8.
2802. Scelzi S, Travaglini F, Nerozzi S,
Dominici A, Ponchietti R, Novelli A,
and Rizzo M, The role of lomefloxacin
in the treatment of chronic prostatitis. J
Chemother, 2001. 13(1): 82–7.
2803. Schaberg DR, Weinstein RA, and
Stamm WE, Epidemics of nosocomial
urinary tract infection caused by mul-
tiply resistant gram-negative bacilli:
epidemiology and control. J Infect Dis,
1976. 133(3): 363–6.
2804. Schaeffer A and Schaeffer E, Infections
of the urinary tract, in Campbell-
Walsh urology, Wein AJ, Kavoussi L,
Novick A, and Partin C, Editors. 2007,
Elsevier Saunders: Philadelphia, Pa.;
Edinburgh. p. xxviii, 528 p.
2805. Schaeffer AJ and Schaeffer EM,
Infections of the urinary tract, in
Campbell-Walsh urology, Campbell MF,
Wein AJ, and Kavoussi LR, Editors.
2007, Saunders Elsevier: Philadelphia,
PA. p. 221–303.
2806. Schaeffer AJ and Stuppy BA, Efficacy
and safety of self-start therapy in
women with recurrent urinary tract
infections. J Urol, 1999. 161(1): 207–11.
2807. Schaeffer AJ, Anderson RU, Krieger
JN, Lobel B, Naber K, Nakagawa M,
Nickel JC, Nyberg L, and Weidner
W, The assessment and manage-
ment of male pelvic pain syndrome
including prostatitis, in Male Lower
Urinary Tract Dysfunction. Evaluation
and Management. 6th International
Consultation in Prostate Cancer and
Prostate Diseases, McConnel J, Abrams
P, Denis L, Khoury S, and Roehrborn
C, Editors. 2006, Health Publications:
Paris. p. 343–385.
2808. Schaeffer AJ, Clinical practice. Chronic
prostatitis and the chronic pelvic
pain syndrome. N Engl J Med, 2006.
355(16): 1690–8.
1139
References
2809. Schaeffer AJ, Diagnosis and treatment
of prostatic infections. Urology, 1990.
36(5 Suppl): 13–7.
2810. Schaeffer AJ, Montorsi F, Scattoni V,
Perroncel R, Song J, Haverstock DC,
and Pertel PE, Comparison of a 3-day
with a 1-day regimen of an extended-
release formulation of ciprofloxacin as
antimicrobial prophylaxis for patients
undergoing transrectal needle biopsy
of the prostate. BJU Int, 2007. 100(1):
51–7.
2811. Schaeffer AJ, Prostatitis: US perspec-
tive. Int J Antimicrob Agents, 1999.
11(3–4): 205–11; discussion 213–6.
2812. Schaeffer AJ, Review of norfloxacin in
complicated and recurrent urinary tract
infections. Eur Urol, 1990. 17 Suppl 1:
19–23.
2813. Schaeffer AJ, Urinary tract infec-
tions, in Adult and pediatric urol-
ogy, Gillenwater JY, Grayhack JT,
Howards SS, and Mitchell ME, Editors.
2002, Lippincott Williams & Wilkins:
Philadelphia, Pa.; London. p. 211–272.
2814. Schaeffer AJ, Wendel EF, Dunn JK,
and Grayhack JT, Prevalence and sig-
nificance of prostatic inflammation. J
Urol, 1981. 125(2): 215–9.
2815. Schaeffer AJ, Wu SC, Tennenberg AM,
and Kahn JB, Treatment of chronic bac-
terial prostatitis with levofloxacin and
ciprofloxacin lowers serum prostate spe-
cific antigen. J Urol, 2005. 174(1): 161–4.
2816. Schalamon J, Ainoedhofer H, Schleef J,
Singer G, Haxhija EQ, and Hollwarth
ME, Management of acute scrotum in
children—the impact of Doppler ultra-
sound. J Pediatr Surg, 2006. 41(8):
1377–80.
2817. Schappert SM, National ambula-
tory medical survey: 1990 summary.
Advance data from vital and health
statistics: no. 213. 1992, Hyattsville,
Maryland, USA: National Center for
Health Statistics.
2818. Schatteman PH, Hoekx L, Wyndaele
JJ, Jeuris W, and Van Marck E,
Inflammation in prostate biopsies of
men without prostatic malignancy or
clinical prostatitis: correlation with
total serum PSA and PSA density. Eur
Urol, 2000. 37(4): 404–12.
1140
2819. Scheen AJ, Medications in the kidney.
Acta Clin Belg, 2008. 63(2): 76–80.
2820. Scheklakow ND, Deletorski WW,
and Goldoa OA, Veränderungen der
Ultrastruktur von Candida albi-
cans unter Einwirkung von Polyen-
Antibiotika. Mykosen, 1980. 24:
140–52.
2821. Schembri MA and Klemm P,
Coordinate gene regulation by fimbriae-
induced signal transduction. Embo J,
2001. 20(12): 3074–81.
2822. Schenker I and Gross E, [Male circum-
cision and HIV/AIDS: convincing evi-
dence and their implication for the state
of Israel]. Harefuah, 2007. 146(12):
957–63, 997.
2823. Scherberich JE and Hartinger A,
Impact of Toll-like receptor signal-
ling on urinary tract infection. Int J
Antimicrob Agents, 2008. 31 Suppl 1:
S9–14.
2824. Schiefer HG, Microbiology of male ure-
throadnexitis: diagnostic procedures
and criteria for aetiologic classification.
Andrologia, 1998. 30 Suppl 1: 7–13.
2825. Schierholz JM, Konig DP, Beuth J, and
Pulverer G, The myth of encrustation
inhibiting materials. J Hosp Infect,
1999. 42(2): 162–3.
2826. Schiff M, Jr., Glickman M, Weiss RM,
Ahern MJ, Touloukian RJ, Lytton B,
and Andriole VT, Antibiotic treatment
of renal carbuncle. Ann Intern Med,
1977. 87(3): 305–8.
2827. Schilling JD, Lorenz RG, and
Hultgren SJ, Effect of trimethoprim-
sulfamethoxazole on recurrent bac-
teriuria and bacterial persistence
in mice infected with uropathogenic
Escherichia coli. Infect Immun, 2002.
70(12): 7042–9.
2828. Schilling JD, Mulvey MA, Vincent CD,
Lorenz RG, and Hultgren SJ, Bacterial
invasion augments epithelial cytokine
responses to Escherichia coli through
a lipopolysaccharide-dependent
mechanism. J Immunol, 2001. 166(2):
1148–55.
2829. Schiotz HA and Guttu K, Value of uri-
nary prophylaxis with methenamine
in gynecologic surgery. Acta Obstet
Gynecol Scand, 2002. 81(8): 743–6.

2830. Schiotz HA, Antiseptic catheter gel and
urinary tract infection after short-term
postoperative catheterization in women.
Arch Gynecol Obstet, 1996. 258(2):
97–100.
2831. Schito GC, Naber KG, Botto H, Palou
J, Mazzei T, Gualco L, and Marchese
A, The ARESC study: an international
survey on the antimicrobial resist-
ance of pathogens involved in uncom-
plicated urinary tract infections. Int
J Antimicrob Agents, 2009. 34(5):
407–13.
2832. Schito GC, Why fosfomycin trometamol
as first line therapy for uncomplicated
UTI? Int J Antimicrob Agents, 2003. 22
Suppl 2: 79–83.
2833. Schjorring S, Struve C, and Krogfelt
KA, Transfer of antimicrobial resist-
ance plasmids from Klebsiella pneumo-
niae to Escherichia coli in the mouse
intestine. J Antimicrob Chemother,
2008. 62(5): 1086–93.
2834. Schlager TA, Anderson S, Trudell J,
and Hendley JO, Effect of cranberry
juice on bacteriuria in children with
neurogenic bladder receiving intermit-
tent catheterization. J Pediatr, 1999.
135(6): 698–702.
2835. Schlager TA, Clark M, and Anderson S,
Effect of a single-use sterile catheter for
each void on the frequency of bacteriuria
in children with neurogenic bladder on
intermittent catheterization for bladder
emptying. Pediatrics, 2001. 108(4): E71.
2836. Schlager TA, Dilks S, Trudell J,
Whittam TS, and Hendley JO,
Bacteriuria in children with neurogenic
bladder treated with intermittent cath-
eterization: natural history. J Pediatr,
1995. 126(3): 490–6.
2837. Schlager TA, Johnson JR, Ouellette
LM, and Whittam TS, Escherichia coli
colonizing the neurogenic bladder are
similar to widespread clones causing
disease in patients with normal blad-
der function. Spinal Cord, 2008. 46(9):
633–8.
2838. Schlicht MJ, Lovrich SD, Sartin JS,
Karpinsky P, Callister SM, and Agger
WA, High prevalence of genital myco-
plasmas among sexually active young
adults with urethritis or cervicitis
References
symptoms in La Crosse, Wisconsin. J
Clin Microbiol, 2004. 42(10): 4636–40.
2839. Schmidhammer S, Ramoner R, Holtl
L, Bartsch G, Thurnher M, and Zelle-
Rieser C, An Escherichia coli-based
oral vaccine against urinary tract infec-
tions potently activates human den-
dritic cells. Urology, 2002. 60(3): 521–6.
2840. Schmitt CP, Keimspektrum und
Resitenzlage bei Harnwegsinfektionen
im Kindesalter. Monatsschr
Kinderheilkd, 2007. 155(3): 228 – 233.
2841. Schmoll T, Hoschutzky H,
Morschhauser J, Lottspeich F, Jann K,
and Hacker J, Analysis of genes coding
for the sialic acid-binding adhesin and
two other minor fimbrial subunits of
the S-fimbrial adhesin determinant of
Escherichia coli. Mol Microbiol, 1989.
3(12): 1735–44.
2842. Schmutzhard J, Merete Riedel H,
Zweygberg Wirgart B, and Grillner
L, Detection of herpes simplex virus
type 1, herpes simplex virus type 2 and
varicella-zoster virus in skin lesions.
Comparison of real-time PCR, nested
PCR and virus isolation. J Clin Virol,
2004. 29(2): 120–6.
2843. Schneeberger C, Stolk RP, Devries JH,
Schneeberger PM, Herings RM, and
Geerlings SE, Differences in the pat-
tern of antibiotic prescription profile
and recurrence rate for possible urinary
tract infections in women with and
without diabetes. Diabetes Care, 2008.
31(7): 1380–5.
2844. Schneede P, Tenke P, and Hofstetter
AG, Sexually transmitted diseases
(STDs)—a synoptic overview for urolo-
gists. Eur Urol, 2003. 44(1): 1–7.
2845. Schneider SM, Veyres P, Pivot X,
Soummer AM, Jambou P, Filippi J,
van Obberghen E, and Hebuterne X,
Malnutrition is an independent factor
associated with nosocomial infections.
Br J Nutr, 2004. 92(1): 105–11.
2846. Schnell JD, Epidemiology and the
prevention of peripartal mycoses.
Chemotherapy, 1982. 28 Suppl 1:
66–72.
2847. Schoen EJ, Should newborns be cir-
cumcised? Yes. Can Fam Physician,
2007. 53(12): 2096–8, 2100–2.
1141
References
2848. Scholes D, Hawn TR, Li SS, and et
al., Family UTI history and increased
risk of recurrent UTI and pyelone-
phritis, in 48th Annual Interscience
Conference on Antimicrobial Agents
and Chemotherapy (ICAAC) and the
Infectious Diseases Society of America
(IDSA) 46th Annual Meeting. October
25–28, 2008: Washington, DC,. p. a.
L-604, p. 583.
2849. Scholes D, Hooton TM, Roberts PL,
Gupta K, Stapleton AE, and Stamm
WE, Risk factors associated with acute
pyelonephritis in healthy women. Ann
Intern Med, 2005. 142(1): 20–7.
2850. Scholes D, Hooton TM, Roberts PL,
Stapleton AE, Gupta K, and Stamm
WE, Risk factors for recurrent urinary
tract infection in young women. J Infect
Dis, 2000. 182(4): 1177–82.
2851. Scholtmeijer RJ and Nijman RJ,
Vesicoureteric reflux and videourody-
namic studies: results of a prospective
study after three years of follow-up.
Urology, 1994. 43(5): 714–8.
2852. Scholz H NKaaEGotP-E-SfCP,
Classification of the oral cepha-
losporins. Arzneimitteltherapie, 2000.
18: 17–19.
2853. Scholz M, Graf N, Steffens J,
Schonkofer H, Jeanelle JP, Schofer
O, and Sitzmann FC, Mumpsorchitis
im Jugend und Erwachsenenalter. Dt.
Arztbl, 1996. 93: 2087–2090.
2854. Schortgen F, Lacherade JC, Bruneel F,
Cattaneo I, Hemery F, Lemaire F, and
Brochard L, Effects of hydroxyethyl-
starch and gelatin on renal function in
severe sepsis: a multicentre randomised
study. Lancet, 2001. 357(9260): 911–6.
2855. Schroder J, Staubach KH, Zabel P,
Stuber F, and Kremer B, Procalcitonin
as a marker of severity in septic shock.
Langenbecks Arch Surg, 1999. 384(1):
33–8.
2856. Schroeder-Printzen I, Zumbe J,
Bispink L, Palm S, Schneider U,
Engelmann U, and Weidner W,
Microsurgical epididymal sperm aspi-
ration: aspirate analysis and straws
available after cryopreservation in
patients with non-reconstructable
obstructive azoospermia. MESA/TESE
1142
Group Giessen. Hum Reprod, 2000.
15(12): 2531–5.
2857. Schrooten W, Colebunders R, Youle
M, Molenberghs G, Dedes N, Koitz G,
Finazzi R, de Mey I, Florence E, and
Dreezen C, Sexual dysfunction associ-
ated with protease inhibitor containing
highly active antiretroviral treatment.
AIDS, 2001. 15(8): 1019–23.
2858. Schubert GE, Haltaufderheide T, and
Golz R, Frequency of urogenital tuber-
culosis in an unselected autopsy series
from 1928 to 1949 and 1976 to 1989.
Eur Urol, 1992. 21(3): 216–23.
2859. Schulman CC, Corbusier A, Michiels H,
and Taenzer HJ, Oral immunotherapy
of recurrent urinary tract infections: a
double-blind placebo-controlled mul-
ticenter study. J Urol, 1993. 150(3):
917–21.
2860. Schultz EH, Jr. and Klorfein EH,
Emphysematous pyelonephritis. J Urol,
1962. 87: 762–6.
2861. Schumm K and Lam TB, Types of
urethral catheters for management of
short-term voiding problems in hospi-
talised adults. Cochrane Database Syst
Rev, 2008(2): CD004013.
2862. Schurch B, de Seze M, Denys P,
Chartier-Kastler E, Haab F, Everaert
K, Plante P, Perrouin-Verbe B, Kumar
C, Fraczek S, and Brin MF, Botulinum
toxin type a is a safe and effective
treatment for neurogenic urinary
incontinence: results of a single treat-
ment, randomized, placebo controlled
6-month study. J Urol, 2005. 174(1):
196–200.
2863. Schwab S, Hinthorn D, Diederich
D, Cuppage F, and Grantham J,
PH-dependent accumulation of clin-
damycin in a polycystic kidney. Am J
Kidney Dis, 1983. 3(1): 63–6.
2864. Schwab SJ, Bander SJ, and Klahr S,
Renal infection in autosomal dominant
polycystic kidney disease. Am J Med,
1987. 82(4): 714–8.
2865. Schwaber MJ and Carmeli Y,
Mortality and delay in effective
therapy associated with extended-
spectrum beta-lactamase production
in Enterobacteriaceae bacteraemia: a
systematic review and meta-analysis.

J Antimicrob Chemother, 2007. 60(5):
913–20.
2866. Schwaber MJ, Graham CS, Sands BE,
Gold HS, and Carmeli Y, Treatment
with a broad-spectrum cephalosporin
versus piperacillin-tazobactam and the
risk for isolation of broad-spectrum
cephalosporin-resistant Enterobacter
species. Antimicrob Agents Chemother,
2003. 47(6): 1882–6.
2867. Schwaber MJ, Navon-Venezia S,
Kaye KS, Ben-Ami R, Schwartz D,
and Carmeli Y, Clinical and economic
impact of bacteremia with extended-
spectrum-beta-lactamase-producing
Enterobacteriaceae. Antimicrob
Agents Chemother, 2006. 50(4):
1257–62.
2868. Schwan WR, Flagella allow uropatho-
genic Escherichia coli ascension into
murine kidneys. Int J Med Microbiol,
2008. 298(5–6): 441–7.
2869. Schwartz BF and Stoller ML,
Nonsurgical management of infection-
related renal calculi. Urol Clin North
Am, 1999. 26(4): 765–78, viii.
2870. Schwartz BF, Swanzy S, and Thrasher
JB, A randomized prospective compari-
son of antibiotic tissue levels in the cor-
pora cavernosa of patients undergoing
penile prosthesis implantation using
gentamicin plus cefazolin versus an
oral fluoroquinolone for prophylaxis. J
Urol, 1996. 156(3): 991–4.
2871. Schwartz EJ, Szczech LA, Ross
MJ, Klotman ME, Winston JA, and
Klotman PE, Highly active antiret-
roviral therapy and the epidemic of
HIV+ end-stage renal disease. J Am Soc
Nephrol, 2005. 16(8): 2412–20.
2872. Schwartz GJ and Gauthier B, A simple
estimate of glomerular filtration rate in
adolescent boys. J Pediatr, 1985. 106(3):
522–6.
2873. Schwartz GJ, Feld LG, and Langford
DJ, A simple estimate of glomerular
filtration rate in full-term infants dur-
ing the first year of life. J Pediatr, 1984.
104(6): 849–54.
2874. Schwartz GJ, Haycock GB, Edelmann
CM, Jr., and Spitzer A, A simple esti-
mate of glomerular filtration rate in
children derived from body length and
References
plasma creatinine. Pediatrics, 1976.
58(2): 259–63.
2875. Sciarra A, Di Silverio F, Salciccia S,
Autran Gomez AM, Gentilucci A, and
Gentile V, Inflammation and chronic
prostatic diseases: evidence for a link?
Eur Urol, 2007. 52(4): 964–72.
2876. Sciarra A, Mariotti G, Salciccia S,
Gomez AA, Monti S, Toscano V, and Di
Silverio F, Prostate growth and inflam-
mation. J Steroid Biochem Mol Biol,
2008. 108(3–5): 254–60.
2877. Scott FB, Prosthetic infections. J Urol,
1987. 138(1): 113.
2878. Scottish Intercollegiate Guidelines
Network, Management of suspected
bacterial urinary tract infection in
adults. A national clinical guideline..
July 2006.
2879. Scottish_Intercollegiate_Guidelines_
Network S, Antibiotic prophylaxis in
surgery. A national clinical guideline,
Scotland NQI, Editor. 2008: Edinburgh.
2880. Sebat F, Johnson D, Musthafa AA,
Watnik M, Moore S, Henry K, and
Saari M, A multidisciplinary commu-
nity hospital program for early and
rapid resuscitation of shock in non-
trauma patients. Chest, 2005. 127(5):
1729–43.
2881. Secura H, Vesicourteral reflux and void-
ing dysfunction: a prospective study. J
Urol, 1989. 142: 494 – 501.
2882. Sedberry-Ross S and Pohl HG, Urinary
tract infections in children. Curr Urol
Rep, 2008. 9(2): 165–71.
2883. Sedelmeier EA and Bessler WG,
Biological activity of bacterial cell-
wall components: immunogenic-
ity of the bacterial extract OM-89.
Immunopharmacology, 1995. 29(1):
29–36.
2884. Sedor J and Mulholland SG, Hospital-
acquired urinary tract infections
associated with the indwelling cath-
eter. Urol Clin North Am, 1999. 26(4):
821–8.
2885. Segura JW and Kelalis PP, Localized
renal parenchymal infections in chil-
dren. J Urol, 1973. 109(6): 1029–32.
2886. Sehouli J, Stupin JH, Schlieper U,
Kuemmel S, Henrich W, Denkert
C, Dietel M, and Lichtenegger W,
1143
References
Actinomycotic inflammatory disease
and misdiagnosis of ovarian cancer.
A case report. Anticancer Res, 2006.
26(2C): 1727–31.
2887. Seiffert L, Die Darm-Siphonblase. Arch
Klin Chir, 1935(183): 569–73.
2888. Selvaraj SK and Prasadarao NV,
Escherichia coli K1 inhibits proinflam-
matory cytokine induction in monocytes
by preventing NF-kappaB activation. J
Leukoc Biol, 2005. 78(2): 544–54.
2889. Semetkowska-Jurkiewicz E, Horoszek-
Maziarz S, Galinski J, Manitius A, and
Krupa-Wojciechowska B, The clinical
course of untreated asymptomatic bac-
teriuria in diabetic patients—14-year
follow-up. Mater Med Pol, 1995. 27(3):
91–5.
2890. Sener A, House AA, Jevnikar
AM, Boudville N, McAlister VC,
Muirhead N, Rehman F, and Luke
PP, Intravenous immunoglobulin as a
treatment for BK virus associated neph-
ropathy: one-year follow-up of renal
allograft recipients. Transplantation,
2006. 81(1): 117–20.
2891. Senger SS, Arslan H, Azap OK,
Timurkaynak F, Cagir U, and Haberal
M, Urinary tract infections in renal
transplant recipients. Transplant Proc,
2007. 39(4): 1016–7.
2892. Serniak PS, Denisov VK, Guba GB,
Zakharov VV, Chernobrivtsev PA,
Berko EM, Luneva AG, Oleshenko ND,
and Aziukovskaia IS, [The diagnosis of
urosepsis]. Urol Nefrol (Mosk), 1990(4):
9–13.
2893. Servin AL, Pathogenesis of Afa/Dr dif-
fusely adhering Escherichia coli. Clin
Microbiol Rev, 2005. 18(2): 264–92.
2894. Sessler DI, McGuire J, Hynson
J, Moayeri A, and Heier T,
Thermoregulatory vasoconstriction
during isoflurane anesthesia mini-
mally decreases cutaneous heat loss.
Anesthesiology, 1992. 76(5): 670–5.
2895. Sha SH and Schacht J, Stimulation of
free radical formation by aminoglyco-
side antibiotics. Hear Res, 1999. 128(1–
2): 112–8.
2896. Shaffer DN, Bautista CT, Sateren
WB, Sawe FK, Kiplangat SC, Miruka
1144
AO, Renzullo PO, Scott PT, Robb ML,
Michael NL, and Birx DL, The pro-
tective effect of circumcision on HIV
incidence in rural low-risk men cir-
cumcised predominantly by traditional
circumcisers in Kenya: two-year follow-
up of the Kericho HIV Cohort Study.
J Acquir Immune Defic Syndr, 2007.
45(4): 371–9.
2897. Shah BR and Hux JE, Quantifying the
risk of infectious diseases for people
with diabetes. Diabetes Care, 2003.
26(2): 510–3.
2898. Shah DT, Glover DD, and Larsen B, In
situ mycotoxin production by Candida
albicans in women with vaginitis.
Gynecol Obstet Invest, 1995. 39(1):
67–9.
2899. Shah PM and Isaacs RD, Ertapenem,
the first of a new group of carbapenems.
J Antimicrob Chemother, 2003. 52(4):
538–42.
2900. Shahin R, Engberg I, Hagberg L, and
Svanborg-Edén C, Neutrophil recruit-
ment and bacterial clearance correlated
with LPS responsiveness in local gram-
negative infection. J Immunol, 1987.
10(10): 3475–3480.
2901. Shahinian V, Rajaraman S, Borucki
M, Grady J, Hollander WM, and Ahuja
TS, Prevalence of HIV-associated neph-
ropathy in autopsies of HIV-infected
patients. Am J Kidney Dis, 2000. 35(5):
884–8.
2902. Shaikh N, Abedin S, and Docimo SG,
Can ultrasonography or uroflowmetry
predict which children with voiding
dysfunction will have recurrent urinary
tract infections? J Urol, 2005. 174(4 Pt
2): 1620–2; discussion 1622.
2903. Shandera KC, Thibault GP, and
Deshon GE, Jr., Efficacy of one dose
fluoroquinolone before prostate biopsy.
Urology, 1998. 52(4): 641–3.
2904. Shankar N, Coburn P, Pillar C, Haas
W, and Gilmore M, Enterococcal
cytolysin: activities and association
with other virulence traits in a patho-
genicity island. Int J Med Microbiol,
2004. 293(7–8): 609–18.
2905. Shapiro RL, Drawing lines in the sand:
the boundaries of the HIV pandemic in

perspective. Soc Sci Med, 2002. 55(12):
2189–91.
2906. Sharami SH, Afrakhteh M, and
Shakiba M, Urinary tract infections in
pregnant women with bacterial vagi-
nosis. J Obstet Gynaecol, 2007. 27(3):
252–4.
2907. Sharfi AR and Elarabi YE, The ‘water-
ing-can’ perineum: presentation and
management. Br J Urol, 1997. 80(6):
933–6.
2908. Sharfi AR and Rayis AB, The con-
tinuing challenge of bilharzial ureteric
stricture. Scand J Urol Nephrol, 1989.
23(2): 123–6.
2909. Sharfi AR, Complicated male urethral
strictures: presentation and manage-
ment. Int Urol Nephrol, 1989. 21(5):
491–7.
2910. Sharifi Aghdas F, Akhavizadegan
H, Aryanpoor A, Inanloo H, and
Karbakhsh M, Fever after percutane-
ous nephrolithotomy: contributing fac-
tors. Surg Infect (Larchmt), 2006. 7(4):
367–71.
2911. Sharma VK and Dellinger RP, The
International Sepsis Forum’s contro-
versies in sepsis: my initial vasopressor
agent in septic shock is norepinephrine
rather than dopamine. Crit Care, 2003.
7(1): 3–5.
2912. Sharp M, 14th annual retrovirus con-
ference (CROI). HIV prevention update.
Some bad news, some good news. Posit
Aware, 2007. 18(3): 26–7.
2913. Shay AC and Miller LG, An estimate of
the incidence of Candiduria among hos-
pitalized patients in the United States.
Infect Control Hosp Epidemiol, 2004.
25(11): 894–5.
2914. Shcherban MN, Kul’chavenia EV,
Brizhatiuk EV, Kaveshnikova E, and
Sveshnikova NN, [Male and female gen-
ital tuberculosis. Reproductive function
in a patient with tuberculosis]. Probl
Tuberk Bolezn Legk, 2008(9): 3–6.
2915. Sheehan RE, Wells AU, Milne DG, and
Hansell DM, Nitrofurantoin-induced
lung disease: two cases demonstrating
resolution of apparently irreversible
CT abnormalities. J Comput Assist
Tomogr, 2000. 24(2): 259–61.
References
2916. Shei Dei Yang S and Wang CC,
Outpatient biofeedback relaxation of
the pelvic floor in treating pediatric
dysfunctional voiding: a short-course
program is effective. Urol Int, 2005.
74(2): 118–22.
2917. Shepard BD and Gilmore MS,
Differential expression of virulence-
related genes in Enterococcus faecalis
in response to biological cues in serum
and urine. Infect Immun, 2002. 70(8):
4344–52.
2918. Sheth PM, Danesh A, Sheung A,
Rebbapragada A, Shahabi K, Kovacs
C, Halpenny R, Tilley D, Mazzulli T,
MacDonald K, Kelvin D, and Kaul
R, Disproportionately high semen
shedding of HIV is associated with
compartmentalized cytomegalovirus
reactivation. J Infect Dis, 2006. 193(1):
45–8.
2919. Shigemura K, Okada H, Shirakawa
T, Tanaka K, Arakawa S, Kinoshita
S, Gotoh A, and Kamidono S,
Susceptibilities of Neisseria gonor-
rhoeae to fluoroquinolones and other
antimicrobial agents in Hyogo and
Osaka, Japan. Sex Transm Infect,
2004. 80(2): 105–7.
2920. Shigemura K, Tanaka K, Okada
H, Nakano Y, Kinoshita S, Gotoh
A, Arakawa S, and Fujisawa M,
Pathogen occurrence and antimicro-
bial susceptibility of urinary tract
infection cases during a 20-year period
(1983–2002) at a single institution in
Japan. Jpn J Infect Dis, 2005. 58(5):
303–8.
2921. Shigeta M, Komatsuzawa H, Sugai M,
Suginaka H, and Usui T, Effect of the
growth rate of Pseudomonas aeruginosa
biofilms on the susceptibility to antimi-
crobial agents. Chemotherapy, 1997.
43(2): 137–41.
2922. Shih MC, Leung DA, Roth JA, and
Hagspiel KD, Percutaneous extrac-
tion of bilateral renal mycetomas in
premature infant using mechanical
thrombectomy device. Urology, 2005.
65(6): 1226.
2923. Shilling AM and Raphael J, Diabetes,
hyperglycemia, and infections. Best
1145
References
Pract Res Clin Anaesthesiol, 2008.
22(3): 519–35.
2924. Shim YH, Lee JW, and Lee SJ, The risk
factors of recurrent urinary tract infec-
tion in infants with normal urinary
systems. Pediatr Nephrol, 2009. 24(2):
309–12.
2925. Shimada K, Matsui T, Ogino T, and
Ikoma F, New development and pro-
gression of renal scarring in children
with primary VUR. Int Urol Nephrol,
1989. 21(2): 153–8.
2926. Shimizu M, Katayama K, Kato E,
Miyayama S, Sugata T, and Ohta
K, Evolution of acute focal bacterial
nephritis into a renal abscess. Pediatr
Nephrol, 2005. 20(1): 93–5.
2927. Shin KY, Park HJ, Lee JJ, Park HY,
Woo YN, and Lee TY, Role of early
endourologic management of tubercu-
lous ureteral strictures. J Endourol,
2002. 16(10): 755–8.
2928. Shinabarger D, Mechanism of action of
the oxazolidinone antibacterial agents.
Expert Opin Investig Drugs, 1999. 8(8):
1195–202.
2929. Shoff W. Pyelonephritis, Acute. 2008;
Available from: http://www.emedicine.
com/Med/topic2843.htm.
2930. Shokeir AA, El-Azab M, Mohsen T, and
El-Diasty T, Emphysematous pyelone-
phritis: a 15-year experience with 20
cases. Urology, 1997. 49(3): 343–6.
2931. Shokeir AA, Gaballah MA, Ashamallah
AA, and Ghoneim MA, Optimization
of replacement of the ureter by ileum. J
Urol, 1991. 146(2): 306–10.
2932. Shokeir AA, Ibrahim AM, Hamid MY,
Shalaby MA, Hussein HE, and Badr M,
Urinary bilharziasis in upper Egypt.
I. A clinicopathological study. East Afr
Med J, 1972. 49(4): 298–311.
2933. Shokeir AA, Squamous cell carcinoma
of the bladder: pathology, diagnosis
and treatment. BJU Int, 2004. 93(2):
216–20.
2934. Short RV, New ways of preventing
HIV infection: thinking simply, simply
thinking. Philos Trans R Soc Lond B
Biol Sci, 2006. 361(1469): 811–20.
2935. Short RV, The HIV/AIDS pandemic:
new ways of preventing infection in men.
Reprod Fertil Dev, 2004. 16(5): 555–9.
1146
2936. Short VL, Totten PA, Ness RB, Astete
SG, Kelsey SF, and Haggerty CL,
Clinical presentation of Mycoplasma
genitalium Infection versus Neisseria
gonorrhoeae infection among women
with pelvic inflammatory disease. Clin
Infect Dis, 2009. 48(1): 41–7.
2937. Shortliffe LM and Spigelman SS,
Infection stones. Evaluation and man-
agement. Urol Clin North Am, 1986.
13(4): 717–26.
2938. Shortliffe LM, The management of uri-
nary tract infections in children with-
out urinary tract abnormalities. Urol
Clin North Am, 1995. 22(1): 67–73.
2939. Shortliffe LMD, Infection and inflam-
mation of the pediatric genitourinary
tract in Campbell-Walsh urology,
Campbell MF, Wein AJ, and Kavoussi
LR, Editors. 2007, Saunders Elsevier:
Philadelphia, Pa.; [Edinburgh]. p.
3232–3268.
2940. Shortliffe LMD, Shinghal R, and Seto
EH, Pediatric urinary tract infections,
in Pediatric urology, Gearhart JP, Rink
RC, and Mouriquand PDE, Editors.
2001, W.B. Saunders Co: Philadelphia.
p. 237–258.
2941. Shoskes DA, Nickel JC, Dolinga R,
and Prots D, Clinical phenotyping
of patients with chronic prostatitis/
chronic pelvic pain syndrome and
correlation with symptom severity.
Urology, 2009. 73(3): 538–42; discus-
sion 542–3.
2942. Shoskes DA, Use of antibiotics in
chronic prostatitis syndromes. Can J
Urol, 2001. 8 Suppl 1: 24–8.
2943. Shrim A, Garcia-Bournissen F, and
Koren G, Pharmaceutical agents and
pregnancy in urology practice. Urol
Clin North Am, 2007. 34(1): 27–33.
2944. Shu T, Green JM, and Orihuela E,
Renal and perirenal abscesses in
patients with otherwise anatomically
normal urinary tracts. J Urol, 2004.
172(1): 148–50.
2945. Shulman A, Maymon R, Shapiro A, and
Bahary C, Percutaneous catheter drain-
age of tubo-ovarian abscesses. Obstet
Gynecol, 1992. 80(3 Pt 2): 555–7.
2946. Sicard D, Deaths from Clostridium
sordellii after medical abortion. N Engl

J Med, 2006. 354(15): 1645–7; author
reply 1645–7.
2947. Siegel JF, Smith A, and Moldwin R,
Minimally invasive treatment of renal
abscess. J Urol, 1996. 155(1): 52–5.
2948. Siegfried N, Does male circumcision
prevent HIV infection? PLoS Med,
2005. 2(11): e393.
2949. Siegfried N, Muller M, Volmink J,
Deeks J, Egger M, Low N, Weiss H,
Walker S, and Williamson P, Male cir-
cumcision for prevention of heterosexual
acquisition of HIV in men. Cochrane
Database Syst Rev, 2003(3): CD003362.
2950. Siegmund-Schultze E, Hoyme
UB, Wenzlaff P, Schneider A, and
Bitzer EM, Inanspruchnahme der
pH-Selbstmessung zur Reduktion
der Frühgeburtlichkeit. Geburtsh
Frauenheilk, 2008(68): S1-S194.
2951. Sillen U, Vesicoureteral reflux in
infants. Pediatr Nephrol, 1999. 13(4):
355–61.
2952. Silva JM, Diniz JS, Silva AC, Azevedo
MV, Pimenta MR, and Oliveira EA,
Predictive factors of chronic kid-
ney disease in severe vesicoureteral
reflux. Pediatr Nephrol, 2006. 21(9):
1285–92.
2953. Silva JM, Santos Diniz JS, Marino VS,
Lima EM, Cardoso LS, Vasconcelos
MA, and Oliveira EA, Clinical course
of 735 children and adolescents with
primary vesicoureteral reflux. Pediatr
Nephrol, 2006. 21(7): 981–8.
2954. Silva V, Hermosilla G, and Abarca
C, Nosocomial candiduria in women
undergoing urinary catheterization.
Clonal relationship between strains iso-
lated from vaginal tract and urine. Med
Mycol, 2007. 45(7): 645–51.
2955. Silverberg MJ and Abrams DI, AIDS-
defining and non-AIDS-defining
malignancies: cancer occurrence in the
antiretroviral therapy era. Curr Opin
Oncol, 2007. 19(5): 446–51.
2956. Silverstein A and Donatucci CF,
Bacterial biofilms and implantable
prosthetic devices. Int J Impot Res,
2003. 15 Suppl 5: S150–4.
2957. Simmanowski UA and Seitz H K,
Diagnosis of Schistsomiasis, in
Schistsomiasis, Ikimger U, Koraitim
References
M, and Seitz H K, Editors. 1994,
Ullspein Mosby: Berlin.
2958. Simms I, Eastick K, Mallinson H,
Thomas K, Gokhale R, Hay P, Herring
A, and Rogers PA, Associations between
Mycoplasma genitalium, Chlamydia tra-
chomatis and pelvic inflammatory dis-
ease. J Clin Pathol, 2003. 56(8): 616–8.
2959. Simms I, Warburton F, and Westrom
L, Diagnosis of pelvic inflammatory
disease: time for a rethink. Sex Transm
Infect, 2003. 79(6): 491–4.
2960. Simoes e Silva AC, Silva JM, Diniz JS,
Pinheiro SV, Lima EM, Vasconcelos
MA, Pimenta MR, and Oliveira EA,
Risk of hypertension in primary vesi-
coureteral reflux. Pediatr Nephrol,
2007. 22(3): 459–62.
2961. Simon DM and Levin S, Infectious com-
plications of solid organ transplanta-
tions. Infect Dis Clin North Am, 2001.
15(2): 521–49.
2962. Simpson C, Blitz S, and Shafran SD,
The effect of current management on
morbidity and mortality in hospitalised
adults with funguria. J Infect, 2004.
49(3): 248–52.
2963. Sindhwani P and Wilson CM,
Prostatitis and serum prostate-specific
antigen. Curr Urol Rep, 2005. 6(4):
307–12.
2964. Singer A, The uterine cervix from ado-
lescence to the menopause. Br J Obstet
Gynaecol, 1975. 82(2): 81–99.
2965. Singh HK, Bubendorf L, Mihatsch
MJ, Drachenberg CB, and Nickeleit V,
Urine cytology findings of polyomavirus
infections. Adv Exp Med Biol, 2006.
577: 201–12.
2966. Singh N and Yu VL, Rational empiric
antibiotic prescription in the ICU.
Chest, 2000. 117(5): 1496–9.
2967. Singh S, Sobel JD, Bhargava P, Boikov
D, and Vazquez JA, Vaginitis due to
Candida krusei: epidemiology, clinical
aspects, and therapy. Clin Infect Dis,
2002. 35(9): 1066–70.
2968. Singh-Grewal D, Macdessi J, and Craig
J, Circumcision for the prevention of
urinary tract infection in boys: a sys-
tematic review of randomised trials and
observational studies. Arch Dis Child,
2005. 90(8): 853–8.
1147
References
2969. Siroky MB, Pathogenesis of bacteriuria
and infection in the spinal cord injured
patient. Am J Med, 2002. 113 Suppl
1A: 67S-79S.
2970. Sjovall J, Huitfeldt B, Magni L, and
Nord CE, Effect of beta-lactam prodrugs
on human intestinal microflora. Scand
J Infect Dis Suppl, 1986. 49: 73–84.
2971. Skerk V, Krhen I, Kalenic S, Francetic I,
Barsic B, Kuzmic AC, Derezic D, Jeren
T, Kes P, Kraus O, Kuvacic I, Andrasevic
AT, Tesovic G, and Vrcic H, [Guidelines
for antimicrobial treatment and prophy-
laxis of urinary tract infections]. Lijec
Vjesn, 2004. 126(7–8): 169–81.
2972. Skjeldestad FE, Nordbo SA, and Hadgu
A, Sentinel surveillance of Chlamydia
trachomatis infection in women ter-
minating pregnancy. Genitourin Med,
1997. 73(1): 29–32.
2973. Sklar AH, Caruana RJ, Lammers JE,
and Strauser GD, Renal infections in
autosomal dominant polycystic kidney
disease. Am J Kidney Dis, 1987. 10(2):
81–8.
2974. Skolarikos A, Alivizatos G, and de la
Rosette J, Extracorporeal shock wave
lithotripsy 25 years later: complications
and their prevention. Eur Urol, 2006.
50(5): 981–90; discussion 990.
2975. Skutil V, Varsa J, and Obsitnik M, Six-
month chemotherapy for urogenital
tuberculosis. Eur Urol, 1985. 11(3):
170–6.
2976. Slavin MA, The epidemiology of can-
didaemia and mould infections in
Australia. J Antimicrob Chemother,
2002. 49 Suppl 1: 3–6.
2977. Slotki IN and Asscher AW, Prevention
of scarring in experimental pyelone-
phritis in the rat by early antibiotic
therapy. Nephron, 1982. 30(3): 262–8.
2978. Smaill F and Hofmeyr GJ, Antibiotic
prophylaxis for cesarean section.
Cochrane Database Syst Rev, 2002(3):
CD000933.
2979. Smaill F and Vazquez JC, Antibiotics
for asymptomatic bacteriuria in preg-
nancy. Cochrane Database Syst Rev,
2007(2): CD000490.
2980. Smaill F, Antibiotics for asymptomatic
bacteriuria in pregnancy. Cochrane
Database Syst Rev, 2001(2): CD000490.
1148
2981. Smego RA, Jr., Bhatti S, Khaliq AA,
and Beg MA, Percutaneous aspiration-
injection-reaspiration drainage plus
albendazole or mebendazole for hepatic
cystic echinococcosis: a meta-analysis.
Clin Infect Dis, 2003. 37(8): 1073–83.
2982. Smellie J, Edwards D, Hunter N,
Normand IC, and Prescod N, Vesico-
ureteric reflux and renal scarring.
Kidney Int Suppl, 1975. 4: S65–72.
2983. Smellie JM and Normand IC, Reflux
Nephropathy in Childhood, in Reflux
Nephropathy, Hodson J and Kincaid-
Smith P, Editors. 1979, Masson
Publishing USA: New York. p. 14–20.
2984. Smellie JM and Rigden SP, Pitfalls
in the investigation of children with
urinary tract infection. Arch Dis Child,
1995. 72(3): 251–5; discussion 255–8.
2985. Smellie JM, Barratt TM, Chantler C,
Gordon I, Prescod NP, Ransley PG, and
Woolf AS, Medical versus surgical treat-
ment in children with severe bilateral
vesicoureteric reflux and bilateral neph-
ropathy: a randomised trial. Lancet,
2001. 357(9265): 1329–33.
2986. Smellie JM, Edwards D, and Hunter N,
VUR and renal scarring. Kidney Int,
1975. 8: 65 – 72.
2987. Smellie JM, Gruneberg RN, Bantock
HM, and Prescod N, Prophylactic co-
trimoxazole and trimethoprim in the
management of urinary tract infection
in children. Pediatr Nephrol, 1988.
2(1): 12–7.
2988. Smellie JM, Gruneberg RN, Normand
IC, and Bantock HM, Trimethoprim-
sulfamethoxazole and trimethoprim
alone in the prophylaxis of childhood
urinary tract infection. Rev Infect Dis,
1982. 4(2): 461–6.
2989. Smellie JM, Katz G, and Gruneberg
RN, Controlled trial of prophylactic
treatment in childhood urinary-tract
infection. Lancet, 1978. 2(8082):
175–8.
2990. Smellie JM, Ransley PG, Normand
IC, Prescod N, and Edwards D,
Development of new renal scars: a col-
laborative study. Br Med J (Clin Res
Ed), 1985. 290(6486): 1957–60.
2991. Smellie JM, Rigden SP, and Prescod
NP, Urinary tract infection: a

comparison of four methods of inves-
tigation. Arch Dis Child, 1995. 72(3):
247–50.
2992. Smellie JM, Tamminen-Mobius T,
Olbing H, Claesson I, Wikstad I, Jodal
U, and Seppanen U, Five-year study of
medical or surgical treatment in chil-
dren with severe reflux: radiological
renal findings. The International Reflux
Study in Children. Pediatr Nephrol,
1992. 6(3): 223–30.
2993. Smilack JD, Trimethoprim-
sulfamethoxazole. Mayo Clin Proc,
1999. 74(7): 730–4.
2994. Smith HS, Hughes JP, Hooton TM,
Roberts P, Scholes D, Stergachis
A, Stapleton A, and Stamm WE,
Antecedent antimicrobial use increases
the risk of uncomplicated cystitis in
young women. Clin Infect Dis, 1997.
25(1): 63–8.
2995. Smith HS, Hughes JP, Hooton TM,
Roberts P, Scholes D, Stergaehis
A, Stapleton A, and Stamm WE,
Antecedent antimicrobial use increases
the risk of uncomplicated cystitis in
young women. Clin Infect Dis, 1997. 25:
63–68.
2996. Smith JM and O’Flynn JD, Vesical
stone: The clinical features of 652 cases.
Ir Med J, 1975. 68(4): 85–9.
2997. Smith JW, Prognosis in pyelonephritis:
promise or progress? Am J Med Sci,
1989. 297(1): 53–62.
2998. Smith Moland E, Hanson ND, Herrera
VL, Black JA, Lockhart TJ, Hossain A,
Johnson JA, Goering RV, and Thomson
KS, Plasmid-mediated, carbapenem-
hydrolysing beta-lactamase, KPC-2,
in Klebsiella pneumoniae isolates. J
Antimicrob Chemother, 2003. 51(3):
711–4.
2999. Smith SL, Immunologic Aspects of
Organ Transplantation, in Organ
Transplantation: Concepts, Issues,
Practice And Outcomes, Smith SL,
Editor. 2002, published electronically
on Medscape (www.medscape.com/
viewpublication/704_about).
3000. Snodgrass W, Relationship of voiding
dysfunction to urinary tract infection
and vesicoureteral reflux in children.
Urology, 1991. 38(4): 341–4.
References
3001. Snodgrass WT, Elmore J, and Adams
R, Bladder neck sling and appendi-
covesicostomy without augmentation for
neurogenic incontinence in children. J
Urol, 2007. 177(4): 1510–4; discussion
1515.
3002. Snyder JA, Haugen BJ, Buckles EL,
Lockatell CV, Johnson DE, Donnenberg
MS, Welch RA, and Mobley HL,
Transcriptome of uropathogenic
Escherichia coli during urinary tract
infection. Infect Immun, 2004. 72(11):
6373–81.
3003. Snydman DR, Jacobus NV, McDermott
LA, Lonks JR, and Boyce JM,
Comparative In vitro activities of
daptomycin and vancomycin against
resistant gram-positive pathogens.
Antimicrob Agents Chemother, 2000.
44(12): 3447–50.
3004. Sobel J and Kaye D, Urinary tract
infections, in Mandell, Douglas, and
Bennett’s principles and practice
of infectious diseases, Mandell GL,
Douglas RG, Bennett JE, and Dolin R,
Editors. 1995, Churchill Livingstone:
New York. p. 662–90.
3005. Sobel JD and Lundstrom T,
Management of candiduria. Curr Urol
Rep, 2001. 2(4): 321–5.
3006. Sobel JD, Bradshaw SK, Lipka CJ,
and Kartsonis NA, Caspofungin in the
treatment of symptomatic candiduria.
Clin Infect Dis, 2007. 44(5): e46–9.
3007. Sobel JD, Kauffman CA, McKinsey
D, Zervos M, Vazquez JA, Karchmer
AW, Lee J, Thomas C, Panzer H, and
Dismukes WE, Candiduria: a rand-
omized, double-blind study of treat-
ment with fluconazole and placebo.
The National Institute of Allergy and
Infectious Diseases (NIAID) Mycoses
Study Group. Clin Infect Dis, 2000.
30(1): 19–24.
3008. Sobel JD, Management of recurrent
vulvovaginal candidiasis with intermit-
tent ketoconazole prophylaxis. Obstet
Gynecol, 1985. 65(3): 435–40.
3009. Sobel JD, Myers PG, Kaye D, and
Levison ME, Adherence of Candida
albicans to human vaginal and buc-
cal epithelial cells. J Infect Dis, 1981.
143(1): 76–82.
1149
References
3010. Sobel JD, Pathogenesis of urinary
tract infection. Role of host defenses.
Infect Dis Clin North Am, 1997. 11(3):
531–49.
3011. Sobel JD, Vazquez J, Lynch M,
Meriwether C, and Zervos MJ,
Vaginitis due to Saccharomyces cerevi-
siae: epidemiology, clinical aspects, and
therapy. Clin Infect Dis, 1993. 16(1):
93–9.
3012. Sobel JD, Vulvovaginal candidosis.
Lancet, 2007. 369(9577): 1961–71.
3013. Sobel JD, Vulvovaginitis due to
Candida glabrata. An emerging prob-
lem. Mycoses, 1998. 41 Suppl 2: 18–22.
3014. Sobel JD, Wiesenfeld HC, Martens
M, Danna P, Hooton TM, Rompalo A,
Sperling M, Livengood C, 3rd, Horowitz
B, Von Thron J, Edwards L, Panzer H,
and Chu TC, Maintenance fluconazole
therapy for recurrent vulvovaginal can-
didiasis. N Engl J Med, 2004. 351(9):
876–83.
3015. Sobel JD, Zervos M, Reed BD, Hooton
T, Soper D, Nyirjesy P, Heine MW,
Willems J, and Panzer H, Fluconazole
susceptibility of vaginal isolates
obtained from women with complicated
Candida vaginitis: clinical implica-
tions. Antimicrob Agents Chemother,
2003. 47(1): 34–8.
3016. Société de Pathologie Infectieuse de
Langue Française (SPILF), Deuxième
conférence de consensus en thérapeu-
tique anti-infectieuses: antibiothérapie
des infections urinaires. Médecine et
Maladies infectieuses, 1991: 51–4.
3017. Sode J, Obel N, Hallas J, and Lassen
A, Use of fluroquinolone and risk of
Achilles tendon rupture: a popula-
tion-based cohort study. Eur J Clin
Pharmacol, 2007. 63(5): 499–503.
3018. Sofer M and Denstedt JD, Encrustation
of biomaterials in the urinary tract.
Curr Opin Urol, 2000. 10(6): 563–9.
3019. Soilleux EJ and Coleman N, Expression
of DC-SIGN in human foreskin may
facilitate sexual transmission of HIV. J
Clin Pathol, 2004. 57(1): 77–8.
3020. Sokol WN, Nine episodes of anaphy-
laxis following cystoscopy caused by
Cidex OPA (ortho-phthalaldehyde)
high-level disinfectant in 4 patients
1150
after cytoscopy. J Allergy Clin Immunol,
2004. 114(2): 392–7.
3021. Sokolova IE, [Antibiotic sensitivity of
the microflora isolated from the uterine
cavity of patients with postabortion
endometritis]. Antibiot Med Biotekhnol,
1986. 31(9): 687–90.
3022. Soler R, Pombo F, Gayol A, and
Rodriguez J, Focal xanthogranuloma-
tous pyelonephritis in a teenager: MR
and CT findings. Eur J Radiol, 1997.
24(1): 77–9.
3023. Soler Soler JL, Hidalgo Dominguez
MR, Zuluaga Gomez A, Martinez
Torres JL, Lardelli Claret P, Liebana
Urena J, and Saharour G, [Bacterial
content of the enucleated prostate
gland]. Arch Esp Urol, 1999. 52(8):
823–34.
3024. Sollima S, Osio M, Muscia F, Gambaro
P, Alciati A, Zucconi M, Maga T, Adorni
F, Bini T, and d’Arminio Monforte A,
Protease inhibitors and erectile dys-
function. AIDS, 2001. 15(17): 2331–3.
3025. Somani J, Bhullar VB, Workowski KA,
Farshy CE, and Black CM, Multiple
drug-resistant Chlamydia trachomatis
associated with clinical treatment fail-
ure. J Infect Dis, 2000. 181(4): 1421–7.
3026. Song F and Glenny AM, Antimicrobial
prophylaxis in colorectal surgery: a sys-
tematic review of randomized controlled
trials. Br J Surg, 1998. 85(9): 1232–41.
3027. Song J, Bishop BL, Li G, Duncan MJ,
and Abraham SN, TLR4-initiated and
cAMP-mediated abrogation of bacte-
rial invasion of the bladder. Cell Host
Microbe, 2007. 1(4): 287–98.
3028. Song J, Duncan MJ, Li G, Chan C,
Grady R, Stapleton A, and Abraham
SN, A novel TLR4-mediated signaling
pathway leading to IL-6 responses in
human bladder epithelial cells. PLoS
Pathog, 2007. 3(4): e60.
3029. Song SH, Lee SB, Park YS, and Kim
KS, Is antibiotic prophylaxis necessary
in infants with obstructive hydroneph-
rosis? J Urol, 2007. 177(3): 1098–101;
discussion 1101.
3030. Soo Park B, Lee SJ, Wha Kim Y,
Sik Huh J, Il Kim J, and Chang SG,
Outcome of nephrectomy and kidney-
preserving procedures for the treatment

of emphysematous pyelonephritis.
Scand J Urol Nephrol, 2006. 40(4):
332–8.
3031. Sorensen JL, Thranov I, Hoff G, and
Dirach J, Early- and late-onset of pelvic
inflammatory disease among women
with cervical Chlamydia trachomatis
infection at the time of induced abor-
tion: A follow-up study. Infection,
1994(22): 242–246.
3032. Sorgel F and Kinzig M,
Pharmacokinetics of gyrase inhibitors,
Part 2: Renal and hepatic elimination
pathways and drug interactions. Am J
Med, 1993. 94(3A): 56S-69S.
3033. Soriano F and Tauch A,
Microbiological and clinical features
of Corynebacterium urealyticum: uri-
nary tract stones and genomics as the
Rosetta Stone. Clin Microbiol Infect,
2008. 14(7): 632–43.
3034. Sorour M, The pathology and morbid
histology of the bilharzial lesions in
various parts of the body. Congr Int
Trop Hyg, Cairo, 1928. 4: 322.
3035. Soto GE and Hultgren SJ, Bacterial
adhesins: common themes and varia-
tions in architecture and assembly. J
Bacteriol, 1999. 181(4): 1059–71.
3036. Soto SM, Smithson A, Martinez JA,
Horcajada JP, Mensa J, and Vila J,
Biofilm formation in uropathogenic
Escherichia coli strains: relationship
with prostatitis, urovirulence factors
and antimicrobial resistance. J Urol,
2007. 177(1): 365–8.
3037. Soulen MC, Fishman EK, Goldman
SM, and Gatewood OM, Bacterial renal
infection: role of CT. Radiology, 1989.
171(3): 703–7.
3038. Souli M, Galani I, and Giamarellou H,
Emergence of extensively drug-resistant
and pandrug-resistant Gram-negative
bacilli in Europe. Euro Surveill, 2008.
13(47).
3039. Southwell-Keely JP, Russo RR, March
L, Cumming R, Cameron I, and
Brnabic AJ, Antibiotic prophylaxis in
hip fracture surgery: a metaanalysis.
Clin Orthop Relat Res, 2004(419):
179–84.
3040. Soylu A, Demir BK, Turkmen M,
Bekem O, Saygi M, Cakmakci H, and
References
Kavukcu S, Predictors of renal scar in
children with urinary infection and
vesicoureteral reflux. Pediatr Nephrol,
2008. 23(12): 2227–2232.
3041. Sozen EE, Aksoy F, Aydin K, Koksal I,
Yilmaz G, and Aksoy HZ, [Isolation of
Brucella melitensis from ejaculate cul-
ture of a brucellosis patient with epidi-
dymoorchitis]. Mikrobiyol Bul, 2007.
41(3): 465–8.
3042. Spacek J, Jilek P, Buchta V, Forstl
M, Hronek M, and Holeckova M, The
serum levels of calcium, magnesium,
iron and zinc in patients with recurrent
vulvovaginal candidosis during attack,
remission and in healthy controls.
Mycoses, 2005. 48(6): 391–5.
3043. Spach DH, Bauwens JE, Myerson
D, Mustafa MM, and Bowden RA,
Cytomegalovirus-induced hemorrhagic
cystitis following bone marrow trans-
plantation. Clin Infect Dis, 1993. 16(1):
142–4.
3044. Spach DH, Stapleton AE, and Stamm
WE, Lack of circumcision increases the
risk of urinary tract infection in young
men. JAMA, 1992. 267(5): 679–81.
3045. Spaulding EH, Chemical disinfec-
tion of medical and surgical materi-
als, in Disinfection, sterilization, and
preservation, Lawrence CA and Block
SS, Editors. 1968, Lea & Febiger:
Philadelphia,. p. viii, 808 p.
3046. Spencer RC, Moseley DJ, and
Greensmith MJ, Nitrofurantoin modi-
fied release versus trimethoprim or
co-trimoxazole in the treatment of
uncomplicated urinary tract infec-
tion in general practice. J Antimicrob
Chemother, 1994. 33 Suppl A: 121–9.
3047. Spinillo A, Capuzzo E, Egbe TO,
Baltaro F, Nicola S, and Piazzi G,
Torulopsis glabrata vaginitis. Obstet
Gynecol, 1995. 85(6): 993–8.
3048. Sporer A and Oppenheimer G,
Tuberculosis of prostate and seminal
vesicles. J Urol, 1957. 78(3): 278–86.
3049. Spratt BG, The mechanism of action of
mecillinam. J Antimicrob Chemother,
1977. 3 Suppl B: 13–9.
3050. Sprung CL, Annane D, Keh D,
Moreno R, Singer M, Freivogel K,
Weiss YG, Benbenishty J, Kalenka
1151
References
A, Forst H, Laterre PF, Reinhart K,
Cuthbertson BH, Payen D, and Briegel
J, Hydrocortisone therapy for patients
with septic shock. N Engl J Med, 2008.
358(2): 111–24.
3051. Sreenarasimhaiah S and Hellerstein
S, Urinary tract infections per se do not
cause end-stage kidney disease. Pediatr
Nephrol, 1998. 12(3): 210–3.
3052. St John A, Boyd JC, Lowes AJ, and
Price CP, The use of urinary dipstick
tests to exclude urinary tract infec-
tion: a systematic review of the litera-
ture. Am J Clin Pathol, 2006. 126(3):
428–36.
3053. Stamey T, Pathogenesis and Treatment
of Urinary Tract Infections. 1980,
Baltimore: Williams and Wilkins.
3054. Stamey TA, Bushby SR, and Bragonje
J, The concentration of trimethoprim
in prostatic fluid: nonionic diffusion
or active transport? J Infect Dis, 1973.
128: Suppl:686–92 p.
3055. Stamey TA, Meares EM, Jr., and
Winningham DG, Chronic bacterial
prostatitis and the diffusion of drugs
into prostatic fluid. J Urol, 1970.
103(2): 187–94.
3056. Stamey TA, Pathogenesis and treat-
ment of urinary tract infections.
1980, Baltimore; London: Williams &
Wilkins. ix,612p.
3057. Stamm W, Urinary tract infections in
young men., in Urinary tract infections,
Bergan T, Editor. 1997, Karger: Basel.
p. 46–47.
3058. Stamm WE and Hooton TM,
Management of urinary tract infections
in adults. N Engl J Med, 1993. 329(18):
1328–34.
3059. Stamm WE and Raz R, Factors contrib-
uting to susceptibility of postmenopau-
sal women to recurrent urinary tract
infections. Clin Infect Dis, 1999. 28(4):
723–5.
3060. Stamm WE, Batteiger BE, McCormack
WM, Totten PA, Sternlicht A, and Kivel
NM, A Randomized, Double-Blind
Study Comparing Single-Dose Rifalazil
With Single-Dose Azithromycin for the
Empirical Treatment of Nongonococcal
Urethritis in Men. Sex Transm Dis,
2007.
1152
3061. Stamm WE, Counts GW, Running
KR, Fihn S, Turck M, and Holmes
KK, Diagnosis of coliform infection in
acutely dysuric women. N Engl J Med,
1982. 307(8): 463–8.
3062. Stamm WE, Estrogens and urinary-
tract infection. J Infect Dis, 2007.
195(5): 623–4.
3063. Stamm WE, Handsfield HH, Rompalo
AM, Ashley RL, Roberts PL, and Corey
L, The association between genital ulcer
disease and acquisition of HIV infec-
tion in homosexual men. JAMA, 1988.
260(10): 1429–33.
3064. Stamm WE, Hooton TM, Johnson JR,
Johnson C, Stapleton A, Roberts PL,
Moseley SL, and Fihn SD, Urinary
tract infections: from pathogenesis to
treatment. J Infect Dis, 1989. 159(3):
400–6.
3065. Stamm WE, Martin SM, and Bennett
JV, Epidemiology of nosocomial infec-
tion due to Gram-negative bacilli:
aspects relevant to development and
use of vaccines. J Infect Dis, 1977. 136
Suppl: S151–60.
3066. Stamm WE, McKevitt M, and Counts
GW, Acute renal infection in women:
treatment with trimethoprim-sulfam-
ethoxazole or ampicillin for two or six
weeks. A randomized trial. Ann Intern
Med, 1987. 106(3): 341–5.
3067. Stamm WE, McKevitt M, Roberts PL,
and White NJ, Natural history of recur-
rent urinary tract infections in women.
Rev Infect Dis, 1991. 13(1): 77–84.
3068. Stamm WE, Measurement of pyuria
and its relation to bacteriuria. Am J
Med, 1983. 75(1B): 53–8.
3069. Stamm WE, Protocol for diagnosis of
urinary tract infection: reconsidering
the criterion for significant bacteriuria.
Urology, 1988. 32(2 Suppl): 6–12.
3070. Stamm WE, Urinary tract infections in
young men, in Urinary tract infections,
Bergan T, Editor. 1997, Karger: Basel;
London. p. vii,142p.
3071. Stansfeld JM, Duration of treatment for
urinary tract infections in children. Br
Med J, 1975. 3(5975): 65–6.
3072. Stapleton A and Stamm WE, Prevention
of urinary tract infection. Infect Dis
Clin North Am, 1997. 11(3): 719–33.

3073. Stapleton A, Latham RH, Johnson C,
and Stamm WE, Postcoital antimicro-
bial prophylaxis for recurrent urinary
tract infection. A randomized, double-
blind, placebo-controlled trial. JAMA,
1990. 264(6): 703–6.
3074. Stapleton A, Urinary tract infections
in patients with diabetes. Am J Med,
2002. 113 Suppl 1A: 80S-84S.
3075. Stark RP and Maki DG, Bacteriuria in
the catheterized patient. What quantita-
tive level of bacteriuria is relevant? N
Engl J Med, 1984. 311(9): 560–4.
3076. Stathi M, Flemetakis A, Miriagou V,
Avgerinou H, Kyriakis KP, Maniatis
AN, and Tzelepi E, Antimicrobial sus-
ceptibility of Neisseria gonorrhoeae in
Greece: data for the years 1994–2004.
J Antimicrob Chemother, 2006. 57(4):
775–9.
3077. Stauffer CM, van der Weg B, Donadini
R, Ramelli GP, Marchand S, and
Bianchetti MG, Family history and
behavioral abnormalities in girls with
recurrent urinary tract infections: a
controlled study. J Urol, 2004. 171(4):
1663–5.
3078. Stearns DB, Seminal Vesiculitis: A
Diagnostic Problem. J Int Coll Surg,
1963. 40: 354–63.
3079. Steele BW and Carson CC, Recognizing
the urologic manifestations of HIV and
AIDS. Contemp Urol, 1997. 9: 39–53.
3080. Stein G and Funfstuck R,
[Asymptomatic bacteriuria]. Med Klin
(Munich), 2000. 95(4): 195–200.
3081. Stein G, Eichhorn T, and Fünfstück
R, Urinary tract infections in patients
with renal insufficiency. Nieren- and
Hochdruckkrankh, 2007. 36: 288–291.
3082. Stein GE, Comparison of single-dose
fosfomycin and a 7-day course of
nitrofurantoin in female patients with
uncomplicated urinary tract infection.
Clin Ther, 1999. 21(11): 1864–72.
3083. Stein GE, Single-dose treatment of acute
cystitis with fosfomycin tromethamine.
Ann Pharmacother, 1998. 32(2): 215–9.
3084. Steinberg JP, Braun BI, Hellinger
WC, Kusek L, Bozikis MR, Bush AJ,
Dellinger EP, Burke JP, Simmons B,
and Kritchevsky SB, Timing of anti-
microbial prophylaxis and the risk of
References
surgical site infections: results from
the Trial to Reduce Antimicrobial
Prophylaxis Errors. Ann Surg, 2009.
250(1): 10–6.
3085. Steiner GE, Newman ME, Paikl D,
Stix U, Memaran-Dagda N, Lee C, and
Marberger MJ, Expression and func-
tion of pro-inflammatory interleukin
IL-17 and IL-17 receptor in normal,
benign hyperplastic, and malignant
prostate. Prostate, 2003. 56(3): 171–82.
3086. Steiner GE, Stix U, Handisurya A,
Willheim M, Haitel A, Reithmayr F,
Paikl D, Ecker RC, Hrachowitz K,
Kramer G, Lee C, and Marberger M,
Cytokine expression pattern in benign
prostatic hyperplasia infiltrating T
cells and impact of lymphocytic infiltra-
tion on cytokine mRNA profile in pro-
static tissue. Lab Invest, 2003. 83(8):
1131–46.
3087. Steiner T, Traue C, and Schubert J,
[Perioperative antibiotic prophylaxis
in transperitoneal tumor nephrectomy:
does it lower the rate of clinically signif-
icant postoperative infections?]. Urologe
A, 2003. 42(1): 34–7.
3088. Steinke DT, Seaton RA, Phillips G,
MacDonald TM, and Davey PG, Prior
trimethoprim use and trimethoprim-
resistant urinary tract infection: a
nested case-control study with multi-
variate analysis for other risk factors.
J Antimicrob Chemother, 2001. 47(6):
781–7.
3089. Stengel B, Billon S, Van Dijk PC, Jager
KJ, Dekker FW, Simpson K, and Briggs
JD, Trends in the incidence of renal
replacement therapy for end-stage renal
disease in Europe, 1990–1999. Nephrol
Dial Transplant, 2003. 18(9): 1824–33.
3090. Stenqvist K, Dahlen-Nilsson I, Lidin-
Janson G, Lincoln K, Oden A, Rignell
S, and Svanborg-Eden C, Bacteriuria
in pregnancy. Frequency and risk of
acquisition. Am J Epidemiol, 1989.
129(2): 372–9.
3091. Stenqvist K, Sandberg T, Lidin-
Janson G, Orskov F, Orskov I, and
Svanborg-Eden C, Virulence factors
of Escherichia coli in urinary isolates
from pregnant women. J Infect Dis,
1987. 156(6): 870–7.
1153
References
3092. Stensballe J, Tvede M, Looms D,
Lippert FK, Dahl B, Tonnesen E, and
Rasmussen LS, Infection risk with
nitrofurazone-impregnated urinary
catheters in trauma patients: a rand-
omized trial. Ann Intern Med, 2007.
147(5): 285–93.
3093. Stenutz R, Weintraub A, and Widmalm
G, The structures of Escherichia coli
O-polysaccharide antigens. FEMS
Microbiol Rev, 2006. 30(3): 382–403.
3094. Stepanshina VN, Panfertsev EA,
Korobova OV, Shemyakin IG,
Stepanshin YG, Medvedeva IM, and
Dorozhkova IR, Drug-resistant strains
of Mycobacterium tuberculosis isolated
in Russia. Int J Tuberc Lung Dis, 1999.
3(2): 149–52.
3095. Stevenson KB, Moore J, Colwell H,
and Sleeper B, Standardized infection
surveillance in long-term care: inter-
facility comparisons from a regional
cohort of facilities. Infect Control Hosp
Epidemiol, 2005. 26(3): 231–8.
3096. Stevenson MM and Radcliffe KW,
Preventing pelvic infection after abor-
tion. Int J STD AIDS, 1995. 6(5):
305–12.
3097. Stevermer JJ and Easley SK,
Treatment of prostatitis. Am Fam
Physician, 2000. 61(10): 3015–22,
3025–6.
3098. Steward DK, Wood GL, Cohen RL,
Smith JW, and Mackowiak PA, Failure
of the urinalysis and quantitative urine
culture in diagnosing symptomatic
urinary tract infections in patients
with long-term urinary catheters. Am J
Infect Control, 1985. 13(4): 154–60.
3099. Stewart WF, Van Rooyen JB, Cundiff
GW, Abrams P, Herzog AR, Corey R,
Hunt TL, and Wein AJ, Prevalence
and burden of overactive bladder in
the United States. World J Urol, 2003.
20(6): 327–36.
3100. Stickler DJ, Evans A, Morris N, and
Hughes G, Strategies for the control of
catheter encrustation. Int J Antimicrob
Agents, 2002. 19(6): 499–506.
3101. Stickler DJ, Williams T, Jarman C,
Howe N, and Winters C, The encrusta-
tion of urethral catheters, in The life
and death of biofilm, Wimpenny J,
1154
Handley P, Gilbert P, and Lappin-Scott
H, Editors. 1995, Bioline: Cardiff. p.
119–125.
3102. Stimson JB and Fihn SD, Benign pro-
static hyperplasia and its treatment. J
Gen Intern Med, 1990. 5(2): 153–65.
3103. Stokes T, Screening for Chlamydia in
general practice: a literature review
and summary of the evidence. J Public
Health Med, 1997. 19(2): 222–32.
3104. Stone KM, Avoiding sexually transmit-
ted diseases. Obstet Gynecol Clin North
Am, 1990. 17(4): 789–99.
3105. Stothers L, A randomised trial to eval-
uate effectiveness and cost effectiveness
of naturopathic cranberry products as
prophylaxis against urinary tract infec-
tion in women. Can J Urol, 2002. 9(3):
1558–62.
3106. Stranne J, Aus G, Hansson C, Lodding
P, Pileblad E, and Hugosson J, Single-
dose orally administered quinolone
appears to be sufficient antibiotic
prophylaxis for radical retropubic pros-
tatectomy. Scand J Urol Nephrol, 2004.
38(2): 143–7.
3107. Stratchounski LS and Rafalski VV,
Antimicrobial susceptibility of patho-
gens isolated from adult patients with
uncomplicated community-acquired
urinary tract infections in the Russian
Federation: two multicentre stud-
ies, UTIAP-1 and UTIAP-2. Int J
Antimicrob Agents, 2006. 28 Suppl 1:
S4–9.
3108. Streem SB, Yost A, and Dolmatch B,
Combination “sandwich” therapy for
extensive renal calculi in 100 consecu-
tive patients: immediate, long-term and
stratified results from a 10-year experi-
ence. J Urol, 1997. 158(2): 342–5.
3109. Strohmaier WL and Bichler KH,
Comparison of symptoms, morphologi-
cal, microbiological and urodynamic
findings in patients with chronic
prostatitis/pelvic pain syndrome. Is it
possible to differentiate separate catego-
ries? Urol Int, 2000. 65(2): 112–6.
3110. Strömberg N, Marklund BI, Lund
B, Ilver D, Hamers A, Gaastra W,
Karlsson KA, and Normark S, Host-
specificity of uropathogenic Escherichia
coli depends on differences in

binding specificity to Gal alpha 1–4Gal-
containing isoreceptors. Embo J, 1990.
9(6): 2001–10.
3111. Strömberg N, Nyholm PG, Pascher I,
and Normark S, Saccharide orienta-
tion at the cell surface affects glycolipid
receptor function. Proc Natl Acad Sci U
S A, 1991. 88(20): 9340–4.
3112. Strowig T, Brilot F, Arrey F, Bougras
G, Thomas D, Muller WA, and Munz C,
Tonsilar NK cells restrict B cell trans-
formation by the Epstein-Barr virus via
IFN-gamma. PLoS Pathog, 2008. 4(2):
e27.
3113. Stryjewski ME and Chambers HF, Skin
and soft-tissue infections caused by
community-acquired methicillin-resist-
ant Staphylococcus aureus. Clin Infect
Dis, 2008. 46 Suppl 5: S368–77.
3114. Studer UE, Danuser H, Merz VW,
Springer JP, and Zingg EJ, Experience
in 100 patients with an ileal low pres-
sure bladder substitute combined with
an afferent tubular isoperistaltic seg-
ment. J Urol, 1995. 154(1): 49–56.
3115. Stunell H, Buckley O, Feeney J,
Geoghegan T, Browne RF, and
Torreggiani WC, Imaging of acute
pyelonephritis in the adult. Eur Radiol,
2007. 17(7): 1820–8.
3116. Sturm PD, Moodley P, Khan N,
Ebrahim S, Govender K, Connolly C,
and Sturm AW, Aetiology of male ure-
thritis in patients recruited from a pop-
ulation with a high HIV prevalence. Int
J Antimicrob Agents, 2004. 24 Suppl
1: S8–14.
3117. Stutley JE and Gordon I, Vesico-
ureteric reflux in the damaged non-
scarred kidney. Pediatr Nephrol, 1992.
6(1): 25–9.
3118. Su X, Jiang F, Qimuge, Dai X, Sun H,
and Ye S, Surveillance of antimicrobial
susceptibilities in Neisseria gonor-
rhoeae in Nanjing, China, 1999–2006.
Sex Transm Dis, 2007. 34(12): 995–9.
3119. Suby HI and Albright F, Dissolution of
phosphatic urinary calculi by the retro-
grade introduction of a citrate solution
containing magnesium. New Eng J
Med, 1943. 228: 81–91.
3120. Sue DE, Chicola C, Brant-Zawadzki
MN, Scidmore GF, Hart JB, and Hanna
References
JE, MR imaging in seminal vesiculitis.
J Comput Assist Tomogr, 1989. 13(4):
662–4.
3121. Sullivan A, Edlund C, and Nord CE,
Effect of antimicrobial agents on the
ecological balance of human microflora.
Lancet Infect Dis, 2001. 1(2): 101–14.
3122. Sullivan A, Edlund C, Svenungsson B,
Emtestam L, and Nord CE, Effect of
perorally administered pivmecillinam
on the normal oropharyngeal, intesti-
nal and skin microflora. J Chemother,
2001. 13(3): 299–308.
3123. Suman E, Gopalkrishna Bhat K, and
Hegde BM, Bacterial adherence and
immune response in recurrent urinary
tract infection. Int J Gynaecol Obstet,
2001. 75(3): 263–8.
3124. Sumner TE, Crowe JE, and Resnick MI,
Diagnosis of ectopic ureterocele using
ultrasound. Urology, 1980. 15(1): 82–5.
3125. Sunden F, Hakansson L, Ljunggren
E, and Wullt B, Bacterial interfer-
ence—is deliberate colonization with
Escherichia coli 83972 an alternative
treatment for patients with recur-
rent urinary tract infection? Int J
Antimicrob Agents, 2006. 28 Suppl 1:
S26–9.
3126. Sundén F, Håkansson L, Ljunggren E,
and Wullt B, E. coli 83972 bacteriuria
protects against symptomatic urinary
tract infections in patients with dys-
functional voiding. manuscript, 2009.
3127. Sundqvist M and Kahlmeter G, Effect
of excluding duplicate isolates of
Escherichia coli and Staphylococcus
aureus in a 14 year consecutive data-
base. J Antimicrob Chemother, 2007.
59(5): 913–8.
3128. Suriano F, Gallucci M, Flammia GP,
Musco S, Alcini A, Imbalzano G, and
Dicuonzo G, Bacteriuria in patients
with an orthotopic ileal neobladder:
urinary tract infection or asymptomatic
bacteriuria? BJU Int, 2008. 101(12):
1576–9.
3129. Surveillance of antibiotic resistance
in Neisseria gonorrhoeae in the WHO
Western Pacific Region, 2005. Commun
Dis Intell, 2006. 30(4): 430–3.
3130. Svanborg C and Godaly G, Bacterial
virulence in urinary tract infection.
1155
References
Infect Dis Clin North Am, 1997. 11(3):
513–29.
3131. Svanborg C, Bergsten G, Fischer H,
Godaly G, Gustafsson M, Karpman
D, Lundstedt AC, Ragnarsdottir
B, Svensson M, and Wullt B,
Uropathogenic Escherichia coli as a
model of host-parasite interaction. Curr
Opin Microbiol, 2006. 9(1): 33–9.
3132. Svanborg-Edén C, Hanson LA, Jodal
U, Lindberg U, and Sohl-Åkerlund A,
Variable adherence to normal urinary
tract epithelial cells of Escherichia coli
strains associated with various forms of
urinary tract infections. Lancet, 1976.
II: 490–492.
3133. Svare JA, Schmidt H, Hansen BB, and
Lose G, Bacterial vaginosis in a cohort
of Danish pregnant women: prevalence
and relationship with preterm delivery,
low birthweight and perinatal infec-
tions. BJOG, 2006. 113(12): 1419–25.
3134. Svensson L, Mardh PA, Ahlgren M, and
Nordenskjold F, Ectopic pregnancy and
antibodies to Chlamydia trachomatis.
Fertil Steril, 1985. 44(3): 313–7.
3135. Swan SK and Bennett WM, Drug dos-
ing guidelines in patients with renal
failure. West J Med, 1992. 156(6):
633–8.
3136. Swartz MA, Morgan TM, and Krieger
JN, Complications of scrotal surgery for
benign conditions. Urology, 2007. 69(4):
616–9.
3137. Sweet R and Keane WF, Perinephric
abscess in patients with polycystic kid-
ney disease undergoing chronic hemodi-
alysis. Nephron, 1979. 23(5): 237–40.
3138. Sweet RL, Bacteriuria and pyelonephri-
tis during pregnancy. Semin Perinatol,
1977. 1(1): 25–40.
3139. Sweet RL, Bartlett JG, Hemsell DL,
Solomkin JS, and Tally F, Evaluation
of new anti-infective drugs for the
treatment of acute pelvic inflammatory
disease. Infectious Diseases Society
of America and the Food and Drug
Administration. Clin Infect Dis, 1992.
15 Suppl 1: S53–61.
3140. Sylvan S and Christenson B, Increase
in Chlamydia trachomatis infection in
Sweden: time for new strategies. Arch
Sex Behav, 2008. 37(3): 362–4.
1156
3141. Szabados F, Kleine B, Anders A,
Kaase M, Sakinc T, Schmitz I, and
Gatermann S, Staphylococcus sapro-
phyticus ATCC 15305 is internalized
into human urinary bladder carcinoma
cell line 5637. FEMS Microbiol Lett,
2008. 285(2): 163–9.
3142. Szabo R and Short RV, How does male
circumcision protect against HIV infec-
tion? Bmj, 2000. 320(7249): 1592–4.
3143. Szczech LA, Edwards LJ, Sanders LL,
van der Horst C, Bartlett JA, Heald
AE, and Svetkey LP, Protease inhibi-
tors are associated with a slowed pro-
gression of HIV-related renal diseases.
Clin Nephrol, 2002. 57(5): 336–41.
3144. Szczepanska M, Szprynger K, and
Adamczyk P, [Effect of urinary tract
infections in children with chronic
renal failure on peritoneal dialysis]. Pol
Merkur Lekarski, 2004. 16(93): 223–7.
3145. Sziller I, Fedorcsak P, Csapo Z, Szirmai
K, Linhares IM, Papp Z, and Witkin
SS, Circulating antibodies to a con-
served epitope of the Chlamydia tra-
chomatis 60-kDa heat shock protein is
associated with decreased spontaneous
fertility rate in ectopic pregnant women
treated by salpingectomy. Am J Reprod
Immunol, 2008. 59(2): 99–104.
3146. Sziller I, Witkin SS, Ziegert M, Csapo
Z, Ujhazy A, and Papp Z, Serological
responses of patients with ectopic preg-
nancy to epitopes of the Chlamydia
trachomatis 60 kDa heat shock protein.
Hum Reprod, 1998. 13(4): 1088–93.
3147. Szucs K, O’Neil KM, and Faden H,
Urinary findings in asymptomatic
subjects with spina bifida treated with
intermittent catheterization. Pediatr
Infect Dis J, 2001. 20(6): 638–9.
3148. Tack J, Talley NJ, Camilleri M,
Holtmann G, Hu P, Malagelada JR, and
Stanghellini V, Functional gastroduo-
denal disorders. Gastroenterology,
2006. 130(5): 1466–79.
3149. Tagliamonte M, Vidal N, Tornesello
ML, Peeters M, Buonaguro FM, and
Buonaguro L, Genetic and phylogenetic
characterization of structural genes
from non-B HIV-1 subtypes in Italy.
AIDS Res Hum Retroviruses, 2006.
22(10): 1045–51.

3150. Taha TE, Hoover DR, Dallabetta
GA, Kumwenda NI, Mtimavalye LA,
Yang LP, Liomba GN, Broadhead
RL, Chiphangwi JD, and Miotti PG,
Bacterial vaginosis and disturbances
of vaginal flora: association with
increased acquisition of HIV. AIDS,
1998. 12(13): 1699–706.
3151. Tahir H, Thomas G, Sheerin N,
Bettington H, Pattison JM, and
Goldsmith DJ, Successful medical
treatment of acute bilateral emphyse-
matous pyelonephritis. Am J Kidney
Dis, 2000. 36(6): 1267–70.
3152. Tai HC, Emphysematous prostatic
abscess: a case report and review of lit-
erature. J Infect, 2007. 54(1): e51–4.
3153. Taira AV, Neukermans CP, and Sanders
GD, Evaluating human papillomavirus
vaccination programs. Emerg Infect
Dis, 2004. 10(11): 1915–23.
3154. Takahashi S, Hashimoto K, Miyamoto
S, Takeyama K, Takagi Y, and
Tsukamoto T, Clinical relevance of
nucleic acid amplification test for
patients with urinary tuberculosis dur-
ing antituberculosis treatment. J Infect
Chemother, 2005. 11(6): 300–2.
3155. Takai K, Tollemar J, Wilczek HE, and
Groth CG, Urinary tract infections
following renal transplantation. Clin
Transplant, 1998. 12(1): 19–23.
3156. Takala J, Jousimies H, and Sievers K,
Screening for and treatment of bacte-
riuria in a middle-aged female popula-
tion. I. The prevalence of bacteriuria,
urinary tract infections under treat-
ment and symptoms of urinary tract
infections in the Sakyla-Koylio project.
Acta Med Scand, 1977. 202(1–2):
69–73.
3157. Takasaki E, Suzuki T, Honda M, Imai
T, Maeda S, and Hosoya Y, Chemical
compositions of 300 lower urinary tract
calculi and associated disorders in the
urinary tract. Urol Int, 1995. 54(2):
89–94.
3158. Takeuchi H, Hida S, Yoshida O, and
Ueda T, [Clinical study on efficacy of a
Foley catheter coated with silver-protein
in prevention of urinary tract infec-
tions]. Hinyokika Kiyo, 1993. 39(3):
293–8.
References
3159. Takeyama K, Matsukawa M,
Kunishima Y, Takahashi S, Hotta
H, Nishiyama N, and Tsukamoto T,
Incidence of and risk factors for sur-
gical site infection in patients with
radical cystectomy with urinary diver-
sion. J Infect Chemother, 2005. 11(4):
177–81.
3160. Takeyama K, Takahashi S, Maeda T,
Mutoh M, Kunishima Y, Matsukawa
M, and Takagi Y, Comparison of 1-day,
2-day, and 3-day administration of
antimicrobial prophylaxis in radical
prostatectomy. J Infect Chemother,
2007. 13(5): 320–3.
3161. Talan DA, Klimberg IW, Nicolle LE,
Song J, Kowalsky SF, and Church DA,
Once daily, extended release cipro-
floxacin for complicated urinary tract
infections and acute uncomplicated
pyelonephritis. J Urol, 2004. 171(2 Pt
1): 734–9.
3162. Talan DA, Moran GJ, Mower WR,
Newdow M, Ong S, Slutsker L,
Jarvis WR, Conn LA, and Pinner RW,
EMERGEncy ID NET: an emergency
department-based emerging infections
sentinel network. The EMERGEncy ID
NET Study Group. Ann Emerg Med,
1998. 32(6): 703–11.
3163. Talan DA, Naber KG, Palou J, and
Elkharrat D, Extended-release cipro-
floxacin (Cipro XR) for treatment of uri-
nary tract infections. Int J Antimicrob
Agents, 2004. 23 Suppl 1: S54–66.
3164. Talan DA, Stamm WE, Hooton
TM, Moran GJ, Burke T, Iravani A,
Reuning-Scherer J, and Church DA,
Comparison of ciprofloxacin (7 days)
and trimethoprim-sulfamethoxazole (14
days) for acute uncomplicated pyelone-
phritis pyelonephritis in women: a
randomized trial. Jama, 2000. 283(12):
1583–90.
3165. Talja M, Korpela A, and Jarvi K,
Comparison of urethral reaction to full
silicone, hydrogen-coated and silicon-
ised latex catheters. Br J Urol, 1990.
66(6): 652–7.
3166. Talukdar A, Khandokar MR,
Bandopadhyay SK, and Detels R, Risk
of HIV infection but not other sexually
transmitted diseases is lower among
1157
References
homeless Muslim men in Kolkata. Aids,
2007. 21(16): 2231–5.
3167. Tambi_ A, Tambi_, T., Ku_i_ec-Tepe_,
N., Prevalence and antibiotic sensitivity
pattern variations of bacterial isolates
in different settings and different peri-
ods of time. Acta med Croatica, 1996.
50: 5–10.
3168. Tambyah PA and Maki DG, Catheter-
associated urinary tract infection is
rarely symptomatic: a prospective study
of 1,497 catheterized patients. Arch
Intern Med, 2000. 160(5): 678–82.
3169. Tambyah PA and Maki DG, The rela-
tionship between pyuria and infection
in patients with indwelling urinary
catheters: a prospective study of 761
patients. Arch Intern Med, 2000.
160(5): 673–7.
3170. Tambyah PA, Halvorson KT, and Maki
DG, A prospective study of pathogenesis
of catheter-associated urinary tract
infections. Mayo Clin Proc, 1999. 74(2):
131–6.
3171. Tambyah PA, Knasinski V, and Maki
DG, The direct costs of nosocomial
catheter-associated urinary tract infec-
tion in the era of managed care. Infect
Control Hosp Epidemiol, 2002. 23(1):
27–31.
3172. Tammen H, Immunobiotherapy with
Uro-Vaxom in recurrent urinary tract
infection. The German Urinary Tract
Infection Study Group. Br J Urol, 1990.
65(1): 6–9.
3173. Tan JS and File TM, Jr., Treatment of
bacteriuria in pregnancy. Drugs, 1992.
44(6): 972–80.
3174. Tan PK, Tan AS, Tan HK, Vathsala
A, and Tay SK, Pregnancy after
renal transplantation: experience in
Singapore General Hospital. Ann Acad
Med Singapore, 2002. 31(3): 285–9.
3175. Taneja N, Meharwal SK, Sharma SK,
and Sharma M, Significance and char-
acterisation of pseudomonads from uri-
nary tract specimens. J Commun Dis,
2004. 36(1): 27–34.
3176. Tang HJ, Li CM, Yen MY, Chen YS,
Wann SR, Lin HH, Lee SS, and Liu
YC, Clinical characteristics of emphy-
sematous pyelonephritis. J Microbiol
Immunol Infect, 2001. 34(2): 125–30.
1158
3177. Tapisiz OL, Reyhan H, Cavkaytar S,
and Aydogdu T, Pelvic tuberculosis
mimicking ovarian carcinoma. Int J
Gynaecol Obstet, 2005. 90(1): 76–7.
3178. Tapsall J, Surveillance of antibiotic
resistance in Neisseria gonorrhoeae in
the WHO Western Pacific region 2006.
Commun Dis Intell, 2008. 32(1): 48–51.
3179. Tapsall JW, Neisseria gonorrhoeae and
emerging resistance to extended spec-
trum cephalosporins. Curr Opin Infect
Dis, 2009. 22(1): 87–91.
3180. Tarkkanen AM, Allen BL, Westerlund
B, Holthöfer H, Kuusela P, Risteli L,
Clegg S, and Korhonen TK, Type V col-
lagen as the target for type-3 fimbriae,
enterobacterial adherence organelles.
Mol Microbiol, 1990. 4(8): 1353–61.
3181. Tarry W, Fisher M, Shen S, and
Mawhinney M, Candida albicans: the
estrogen target for vaginal colonization.
J Surg Res, 2005. 129(2): 278–82.
3182. Taylor CM and Roberts IS, Capsular
polysaccharides and their role in
virulence. Contrib Microbiol, 2005. 12:
55–66.
3183. Taylor CM, Corkery JJ, and White RH,
Micturition symptoms and unstable
bladder activity in girls with primary
vesicoureteric reflux. Br J Urol, 1982.
54(5): 494–8.
3184. Taylor WN, Alton D, Toguri A,
Churchill BM, and Schillinger JF,
Bladder diverticula causing posterior
urethral obstruction in children. J Urol,
1979. 122(3): 415.
3185. Taylor-Robinson D, Gilroy CB, and Hay
PE, Occurrence of Mycoplasma geni-
talium in different populations and its
clinical significance. Clin Infect Dis,
1993. 17 Suppl 1: S66–8.
3186. Taylor-Robinson D, Gilroy CB, Thomas
BJ, and Hay PE, Mycoplasma genital-
ium in chronic non-gonococcal urethri-
tis. Int J STD AIDS, 2004. 15(1): 21–5.
3187. te Slaa E, De Wildt MJ, Debruyne
FM, De Graaf R, and De La Rosette
JJ, Urinary tract infections following
laser prostatectomy: is there a need for
antibiotic prophylaxis? Br J Urol, 1996.
77(2): 228–32.
3188. Teare EL, Cookson B, French GL,
Jenner EA, Scott G, Pallett A, Gould

D, Schweiger M, Wilson J, and Stone
S, UK handwashing initiative. J Hosp
Infect, 1999. 43(1): 1–3.
3189. Techakehakij W and Feldman RD,
Cost-effectiveness of HPV vaccination
compared with Pap smear screening
on a national scale: a literature review.
Vaccine, 2008. 26(49): 6258–65.
3190. Teisala K and Heinonen PK, C-reactive
protein in assessing antimicrobial treat-
ment of acute pelvic inflammatory dis-
ease. J Reprod Med, 1990. 35(10): 955–8.
3191. Tejirian T, DiFronzo LA, and Haigh PI,
Antibiotic prophylaxis for preventing
wound infection after breast surgery: a
systematic review and metaanalysis. J
Am Coll Surg, 2006. 203(5): 729–34.
3192. Teklu B and Ostrow JH, Urinary tuber-
culosis: a review of 44 cases treated
since 1963. J Urol, 1976. 115(5): 507–9.
3193. Telenti A, Torres VE, Gross JB, Jr.,
Van Scoy RE, Brown ML, and Hattery
RR, Hepatic cyst infection in autosomal
dominant polycystic kidney disease.
Mayo Clin Proc, 1990. 65(7): 933–42.
3194. Tencer J, Asymptomatic bacteriuria—a
long-term study. Scand J Urol Nephrol,
1988. 22(1): 31–4.
3195. Tenke P, Kovacs B, Benko R, Ashaber
D, and Nagy E, Continuous versus
intermittent levofloxacin treatment in
complicated urinary tract infections
caused by urinary obstruction tempo-
rarily relieved by foreign body inser-
tion. Int J Antimicrob Agents, 2006. 28
Suppl 1: S82–5.
3196. Tenke P, Kovacs B, Bjerklund Johansen
TE, Matsumoto T, Tambyah PA, and
Naber KG, European and Asian guide-
lines on management and prevention of
catheter-associated urinary tract infec-
tions. Int J Antimicrob Agents, 2008.
31 Suppl 1: S68–78.
3197. Tenke P, Kovacs B, Jackel M, and Nagy
E, The role of biofilm infection in urol-
ogy. World J Urol, 2006. 24(1): 13–20.
3198. Tenney JH and Warren JW, Bacteriuria
in women with long-term catheters:
paired comparison of indwelling and
replacement catheters. J Infect Dis,
1988. 157(1): 199–202.
3199. Tenney JH and Warren JW, Long-term
catheter-associated bacteriuria: species
References
at low concentration. Urology, 1987.
30(5): 444–6.
3200. Terai A, Ichioka K, Kohei N, Ueda N,
Utsunomiya N, and Inoue K, Antibiotic
prophylaxis in radical prostatectomy:
1-day versus 4-day treatments. Int J
Urol, 2006. 13(12): 1488–93.
3201. Tessarz AS and Cerwenka A, The
TREM-1/DAP12 pathway. Immunol
Lett, 2008. 116(2): 111–6.
3202. The Gonococcal Resistance to
Antimicrobials Surveillance
Programmem G. GRASP annual report
2006. 2007; Available from: http://
www.hpa.org.uk/web/HPAwebFile/
HPAweb_C/1194947393147.
3203. The Medical Letter Handbook of
adverse Drug Interaction. 2000.
3204. The prevention and management of uri-
nary tract infections among people with
spinal cord injuries. National Institute
on Disability and Rehabilitation
Research Consensus Statement.
January 27–29, 1992. J Am Paraplegia
Soc, 1992. 15(3): 194–204.
3205. The use of systemic fluoroquinolones.
Pediatrics, 2006. 118(3): 1287–92.
3206. Theoharides TC, Whitmore K, Stanford
E, Moldwin R, and O’Leary MP,
Interstitial cystitis: bladder pain and
beyond. Expert Opin Pharmacother,
2008. 9(17): 2979–94.
3207. Thibon P, Le Coutour X, Leroyer R, and
Fabry J, Randomized multi-centre trial
of the effects of a catheter coated with
hydrogel and silver salts on the inci-
dence of hospital-acquired urinary tract
infections. J Hosp Infect, 2000. 45(2):
117–24.
3208. Thiruchelvam N, Yeoh SL, and
Keoghane SR, MRSA in urology: a UK
hospital experience. Eur Urol, 2006.
49(5): 896–9.
3209. Thoeny HC, Sonnenschein MJ,
Madersbacher S, Vock P, and Studer
UE, Is ileal orthotopic bladder substitu-
tion with an afferent tubular segment
detrimental to the upper urinary tract
in the long term? J Urol, 2002. 168(5):
2030–4; discussion 2034.
3210. Thomas J, Fishel SB, Hall JA,
Green S, Newton TA, and Thornton
SJ, Increased polymorphonuclear
1159
References
granulocytes in seminal plasma in
relation to sperm morphology. Hum
Reprod, 1997. 12(11): 2418–21.
3211. Thomas TM, Plymat KR, Blannin
J, and Meade TW, Prevalence of uri-
nary incontinence. Br Med J, 1980.
281(6250): 1243–5.
3212. Thompson C, Verani R, Evanoff G, and
Weinman E, Suppurative bacterial
pyelonephritis as a cause of acute renal
failure. Am J Kidney Dis, 1986. 8(4):
271–3.
3213. Thompson M, Simon SD, Sharma V,
and Alon US, Timing of follow-up void-
ing cystourethrogram in children with
primary vesicoureteral reflux: devel-
opment and application of a clinical
algorithm. Pediatrics, 2005. 115(2):
426–34.
3214. Thompson RH, Chen JJ, Pugach J,
Naseer S, and Steinhardt GF, Cessation
of prophylactic antibiotics for manag-
ing persistent vesicoureteral reflux. J
Urol, 2001. 166(4): 1465–9.
3215. Thompson RL, Haley CE, Searcy MA,
Guenthner SM, Kaiser DL, Groschel
DH, Gillenwater JY, and Wenzel RP,
Catheter-associated bacteriuria. Failure
to reduce attack rates using periodic
instillations of a disinfectant into uri-
nary drainage systems. JAMA, 1984.
251(6): 747–51.
3216. Thomson KS and Moland ES, Cefepime,
piperacillin-tazobactam, and the
inoculum effect in tests with extended-
spectrum beta-lactamase-producing
Enterobacteriaceae. Antimicrob Agents
Chemother, 2001. 45(12): 3548–54.
3217. Thorley JD, Jones SR, and Sanford
JP, Perinephric abscess. Medicine
(Baltimore), 1974. 53(6): 441–51.
3218. Thumbikat P, Berry RE, Schaeffer
AJ, and Klumpp DJ, Differentiation-
induced uroplakin III expression pro-
motes urothelial cell death in response
to uropathogenic E. coli. Microbes
Infect, 2008.
3219. Thumbikat P, Berry RE, Zhou G,
Billips BK, Yaggie RE, Zaichuk T, Sun
TT, Schaeffer AJ, and Klumpp DJ,
Bacteria-induced uroplakin signaling
mediates bladder response to infection.
PLoS Pathog, 2009. 5(5): e1000415.
1160
3220. Thurman AR, Livengood CH, and
Soper DE, Chronic endometritis in
DMPA users and Chlamydia trachoma-
tis endometritis. Contraception, 2007.
76(1): 49–52.
3221. Thurman AR, Steed LL, Hulsey T, and
Soper DE, Bacteriuria in pregnant
women with sickle cell trait. Am J
Obstet Gynecol, 2006. 194(5): 1366–70.
3222. Tidd MJ, Gow JG, Pennington JH,
Shelton J, and Scott MR, Comparison
of hydrophilic polymer-coated latex,
uncoated latex and PVC indwelling bal-
loon catheters in the prevention of uri-
nary infection. Br J Urol, 1976. 48(4):
285–91.
3223. Tietz HJ, Gezieltes vorgehen gegen
problemkeine. Gyn Geburtsh, 2009.
7–8: 41–44.
3224. Timmons JW, Jr., Malek RS, Hattery
RR, and Deweerd JH, Caliceal diver-
ticulum. J Urol, 1975. 114(1): 6–9.
3225. Tipping PG, Toll-like receptors: the
interface between innate and adaptive
immunity. J Am Soc Nephrol, 2006.
17(7): 1769–71.
3226. Tokunaga S, Ohkawa M, Oshinoya Y,
Nakashima T, Hisazumi H, Nishikawa
T, Shimamura M, and Miyagi T,
Bacteremia from transurethral pros-
tatic resection under prophylactic use
of antibiotics. Kansenshogaku Zasshi,
1991. 65(6): 698–702.
3227. Tomas MS, Claudia Otero M, Ocana V,
and Elena Nader-Macias M, Production
of antimicrobial substances by lactic
acid bacteria I: determination of hydro-
gen peroxide. Methods Mol Biol, 2004.
268: 337–46.
3228. Tomlinson MJ, Barratt CL, and Cooke
ID, Prospective study of leukocytes and
leukocyte subpopulations in semen
suggests they are not a cause of male
infertility. Fertil Steril, 1993. 60(6):
1069–75.
3229. Tooley PJ, Patient and doctor prefer-
ences in the treatment of vaginal can-
didosis. Practitioner, 1985. 229(1405):
655–60.
3230. Topal J, Conklin S, Camp K, Morris V,
Balcezak T, and Herbert P, Prevention
of nosocomial catheter-associated
urinary tract infections through

computerized feedback to physicians
and a nurse-directed protocol. Am J
Med Qual, 2005. 20(3): 121–6.
3231. Toprak U, Erdogan A, Gulbay M,
Karademir MA, Pasaoglu E, and Akar
OE, Preoperative evaluation of renal
anatomy and renal masses with heli-
cal CT, 3D-CT and 3D-CT angiogra-
phy. Diagn Interv Radiol, 2005. 11(1):
35–40.
3232. Tostain J and Gilloz A, Cancer dével-
oppé sur rein mastic tuberculeux. Une
nouvelle observation. Ann Urol, 1982.
16(4): 245–46.
3233. Touiti D, Deligne E, Badet L,
Colombel M, Martin X, and Gelet A,
[Emphysematous pyelonephritis: report
of 3 cases]. Prog Urol, 2001. 11(4):
703–6.
3234. Toya SP, Schraufnagel DE, and
Tzelepis GE, Candiduria in intensive
care units: association with heavy
colonization and candidaemia. J Hosp
Infect, 2007. 66(3): 201–6.
3235. TranVan Nhieu G, Clair C, Grompone
G, and Sansonetti P, Calcium signal-
ling during cell interactions with bacte-
rial pathogens. Biol Cell, 2004. 96(1):
93–101.
3236. Trautner BW, Hull RA, Thornby JI, and
Darouiche RO, Coating urinary catheters
with an avirulent strain of Escherichia
coli as a means to establish asympto-
matic colonization. Infect Control Hosp
Epidemiol, 2007. 28(1): 92–4.
3237. Trauzzi SJ, Kay CJ, Kaufman DG, and
Lowe FC, Management of prostatic
abscess in patients with human immu-
nodeficiency syndrome. Urology, 1994.
43(5): 629–33.
3238. Trei JS, Canas LC, and Gould PL,
Reproductive tract complications asso-
ciated with Chlamydia trachomatis
infection in US Air Force males within
4 years of testing. Sex Transm Dis,
2008. 35(9): 827–33.
3239. Trinchieri A, Braceschi L, Tiranti D,
Dell’Acqua S, Mandressi A, and Pisani
E, Secretory immunoglobulin A and
inhibitory activity of bacterial adher-
ence to epithelial cells in urine from
patients with urinary tract infections.
Urol Res, 1990. 18(5): 305–8.
References
3240. Trobos M, Lester CH, Olsen JE,
Frimodt-Moller N, and Hammerum
AM, Natural transfer of sulphonamide
and ampicillin resistance between
Escherichia coli residing in the human
intestine. J Antimicrob Chemother,
2009. 63(1): 80–6.
3241. Troeger H, Richter JF, Beutin L,
Gunzel D, Dobrindt U, Epple HJ,
Gitter AH, Zeitz M, Fromm M,
and Schulzke JD, Escherichia coli
alpha-haemolysin induces focal
leaks in colonic epithelium: a novel
mechanism of bacterial transloca-
tion. Cell Microbiol, 2007. 9(10):
2530–40.
3242. Trumbore DJ and Sobel JD, Recurrent
vulvovaginal candidiasis: vaginal epi-
thelial cell susceptibility to Candida
albicans adherence. Obstet Gynecol,
1986. 67(6): 810–2.
3243. Tryfonas GJ, Avtzoglou PP, Chaidos C,
Zioutis J, Gavopoulos S, and Limas C,
Renal hydatid disease: diagnosis and
treatment. J Pediatr Surg, 1993. 28(2):
228–31.
3244. Trzeciak S, Dellinger RP, Abate NL,
Cowan RM, Stauss M, Kilgannon JH,
Zanotti S, and Parrillo JE, Translating
research to clinical practice: a 1-year
experience with implementing early
goal-directed therapy for septic shock in
the emergency department. Chest, 2006.
129(2): 225–32.
3245. Tsai JD, Huang FY, and Tsai TC,
Asymptomatic vesicoureteral reflux
detected by neonatal ultrasonographic
screening. Pediatr Nephrol, 1998. 12(3):
206–9.
3246. Tsanadis G, Kalantaridou SN, Kaponis
A, Paraskevaidis E, Zikopoulos K,
Gesouli E, Dalkalitsis N, Korkontzelos
I, Mouzakioti E, and Lolis DE,
Bacteriological cultures of removed
intrauterine devices and pelvic inflam-
matory disease. Contraception, 2002.
65(5): 339–42.
3247. Tsang V, Lui S, Hilson A, Moorhead J,
Fernando O, and Sweny P, Gallium-67
scintigraphy in the detection of infected
polycystic kidneys in renal transplant
recipients. Nucl Med Commun, 1989.
10(3): 167–70.
1161
References
3248. Tsang VC and Wilkins PP,
Immunodiagnosis of schistosomiasis.
Screen with FAST-ELISA and confirm
with immunoblot. Clin Lab Med, 1991.
11(4): 1029–39.
3249. Tse NK, Yuen SL, Chiu MC, Lai WM,
and Tong PC, Imaging studies for first
urinary tract infection in infants less
than 6 months old: can they be more
selective? Pediatr Nephrol, 2009. 24(9):
1699–703.
3250. Tseng CC, Huang JJ, Ko WC, Yan JJ,
and Wu JJ, Decreased predominance of
papG class II allele in Escherichia coli
strains isolated from adults with acute
pyelonephritis and urinary tract abnor-
malities. J Urol, 2001. 166(5): 1643–6.
3251. Tseng CC, Wu JJ, Wang MC, Hor LI,
Ko YH, and Huang JJ, Host and bacte-
rial virulence factors predisposing to
emphysematous pyelonephritis. Am J
Kidney Dis, 2005. 46(3): 432–9.
3252. Tsiodras S, Gold HS, Sakoulas G,
Eliopoulos GM, Wennersten C,
Venkataraman L, Moellering RC, and
Ferraro MJ, Linezolid resistance in
a clinical isolate of Staphylococcus
aureus. Lancet, 2001. 358(9277):
207–8.
3253. Tsugawa M, Monden K, Nasu Y,
Kumon H, and Ohmori H, Prospective
randomized comparative study of anti-
biotic prophylaxis in urethrocystoscopy
and urethrocystography. Int J Urol,
1998. 5(5): 441–3.
3254. Tsujimoto H, Ono S, Efron PA, Scumpia
PO, Moldawer LL, and Mochizuki H,
Role of Toll-like receptors in the devel-
opment of sepsis. Shock, 2008. 29(3):
315–21.
3255. Tsukamoto T, Matsukawa M, Sano M,
Takahashi S, Hotta H, Itoh N, Hirose
T, and Kumamoto Y, Biofilm in com-
plicated urinary tract infection. Int
J Antimicrob Agents, 1999. 11(3–4):
233–6; discussion 237–9.
3256. Tubbs RS, Wellons JC, 3rd, Blount
JP, and Oakes WJ, Transient ven-
triculoperitoneal shunt dysfunction in
children with myelodysplasia and uri-
nary bladder infection. Report of three
cases. J Neurosurg, 2005. 102(2 Suppl):
221–3.
1162
3257. Turck M, Goffe BS, and Petersdorf RG,
Bacteriuria of pregnancy. Relation to
socioeconomic factors. N Engl J Med,
1962. 266: 857–60.
3258. Turk TM, Koleski FC, and Albala DM,
Incidence of urolithiasis in cystectomy
patients after intestinal conduit or con-
tinent urinary diversion. World J Urol,
1999. 17(5): 305–7.
3259. Turkvatan A, Kelahmet E, Yazgan C,
and Olcer T, Sonographic findings in
tuberculous epididymo-orchitis. J Clin
Ultrasound, 2004. 32(6): 302–5.
3260. Turney JH, Renal conservation for
gas-forming infections. Lancet, 2000.
355(9206): 770–1.
3261. Twickler DM, Setiawan AT, Evans RS,
Erdman WA, Stettler RW, Brown CE,
and Cunningham FG, Imaging of puer-
peral septic thrombophlebitis: prospec-
tive comparison of MR imaging, CT,
and sonography. AJR Am J Roentgenol,
1997. 169(4): 1039–43.
3262. Tодоров B, Пенкова C, and Монов A,
Към проблема за хроничния пиелонефрит
при бъбречная поликистоза. Вътрешни
болести, 1989. 28(3): 77–81.
3263. Überempfindlichkeitsreaktionen auf
“Impfstoff” STROVAC (Hypersensitivity
reactions to “vaccine” STROVAC).
Arznei-Telegram, 2007. 38(2): 31.
3264. Ubhi SS and Cooke TJ, Infective
arthritis secondary to bladder outflow
obstruction. Postgrad Med J, 1990.
66(782): 1076–7.
3265. Ueda H, Togashi K, Kataoka ML,
Koyama T, Fujiwara T, Fujii S, and
Konishi J, Adnexal masses caused
by pelvic inflammatory disease: MR
appearance. Magn Reson Med Sci,
2002. 1(4): 207–15.
3266. Uehara S, Monden K, Nomoto K, Seno
Y, Kariyama R, and Kumon H, A pilot
study evaluating the safety and effec-
tiveness of Lactobacillus vaginal sup-
positories in patients with recurrent
urinary tract infection. Int J Antimicrob
Agents, 2006. 28 Suppl 1: S30–4.
3267. Uehling DT, Hopkins WJ, Balish
E, Xing Y, and Heisey DM, Vaginal
mucosal immunization for recurrent
urinary tract infection: phase II clinical
trial. J Urol, 1997. 157(6): 2049–52.

3268. Uehling DT, Hopkins WJ, Beierle LM,
Kryger JV, and Heisey DM, Vaginal
mucosal immunization for recurrent
urinary tract infection: extended phase
II clinical trial. J Infect Dis, 2001. 183
Suppl 1: S81–3.
3269. Uehling DT, Hopkins WJ, Elkahwaji
JE, Schmidt DM, and Leverson GE,
Phase 2 clinical trial of a vaginal
mucosal vaccine for urinary tract infec-
tions. J Urol, 2003. 170(3): 867–9.
3270. Uhlén P, Laestadius A, Jahnukainen
T, Söderblom T, Bäckhed F, Celsi G,
Brismar H, Normark S, Aperia A, and
Richter-Dahlfors A, Alpha-haemolysin
of uropathogenic E. coli induces Ca2+
oscillations in renal epithelial cells.
Nature, 2000. 405(6787): 694–7.
3271. Ulett GC, Valle J, Beloin C, Sherlock
O, Ghigo JM, and Schembri MA,
Functional analysis of antigen 43 in
uropathogenic Escherichia coli reveals
a role in long-term persistence in the
urinary tract. Infect Immun, 2007.
75(7): 3233–44.
3272. Ulleryd P, Zackrisson B, Aus G,
Bergdahl S, Hugosson J, and Sandberg
T, Prostatic involvement in men with
febrile urinary tract infection as meas-
ured by serum prostate-specific antigen
and transrectal ultrasonography. BJU
Int, 1999. 84(4): 470–4.
3273. Ulleryd P, Zackrisson B, Aus G,
Bergdahl S, Hugosson J, and Sandberg
T, Selective urological evaluation in
men with febrile urinary tract infection.
BJU Int, 2001. 88(1): 15–20.
3274. Unal S and Garcia-Rodriguez JA,
Activity of meropenem and compara-
tors against Pseudomonas aeruginosa
and Acinetobacter spp. isolated in the
MYSTIC Program, 2002–2004. Diagn
Microbiol Infect Dis, 2005. 53(4):
265–71.
3275. Ungheri D, Albini E, and Belluco G,
In-vitro susceptibility of quinolone-
resistant clinical isolates of Escherichia
coli to fosfomycin trometamol. J
Chemother, 2002. 14(3): 237–40.
3276. Upadhyay J, Bolduc S, Bagli DJ,
McLorie GA, Khoury AE, and Farhat
W, Use of the dysfunctional voiding
symptom score to predict resolution of
References
vesicoureteral reflux in children with
voiding dysfunction. J Urol, 2003.
169(5): 1842–6; discussion 1846; author
reply 1846.
3277. Update to CDC’s sexually transmitted
diseases treatment guidelines, 2006:
fluoroquinolones no longer recom-
mended for treatment of gonococcal
infections. MMWR Morb Mortal Wkly
Rep, 2007. 56(14): 332–6.
3278. Upmalis DH, Cone FL, Lamia CA,
Reisman H, Rodriguez-Gomez G,
Gilderman L, and Bradley L, Single-
dose miconazole nitrate vaginal ovule
in the treatment of vulvovaginal can-
didiasis: two single-blind, controlled
studies versus miconazole nitrate 100
mg cream for 7 days. J Womens Health
Gend Based Med, 2000. 9(4): 421–9.
3279. Upton JD and Das S, Prophylactic
antibiotics in transurethral resection
of bladder tumors: are they necessary?
Urology, 1986. 27(5): 421–3.
3280. Urakawa M and Ueda Y, [A case of
urinary retention secondary to aseptic
meningitis]. No To Shinkei, 2001. 53(8):
742–6.
3281. US Department of Health and Human
Services Public Health Service,
National Center for Health Statistics.
National Hospital Discharge Survey
Public Use Data Tape Documentation
1994. 1996, Hyattsville, MD: Centers
for Disease Control and Prevention.
3282. US Department of Health and Human
Services, Public Health Service, Agency
for Health Care Policy and Research,
1992: 115–27.
3283. Ushioda N, Matsuo K, Nagamatsu M,
Kimura T, and Shimoya K, Maternal
urinoma during pregnancy. J Obstet
Gynaecol Res, 2008. 34(1): 88–91.
3284. Uvin SC and Caliendo AM,
Cervicovaginal human immunodefi-
ciency virus secretion and plasma viral
load in human immunodeficiency virus-
seropositive women. Obstet Gynecol,
1997. 90(5): 739–43.
3285. Vahlensieck W, Infizierte
Harnstauungsniere und Pyonephrose, in
Facharztwissen Urologie, Schmelz HU,
Sparwasser, C., Weidner, W., Editor.
2006, Springer: Heidelberg. p. 24.
1163
References
3286. Vaillancourt S, McGillivray D, Zhang
X, and Kramer MS, To clean or not to
clean: effect on contamination rates in
midstream urine collections in toilet-
trained children. Pediatrics, 2007.
119(6): e1288–93.
3287. Valayatham V, Salmonella: the pelvic
masquerader. Int J Infect Dis, 2009.
13(2): e53–5.
3288. Valera B, Gentil MA, Cabello V,
Fijo J, Cordero E, and Cisneros JM,
Epidemiology of urinary infections in
renal transplant recipients. Transplant
Proc, 2006. 38(8): 2414–5.
3289. Valle J, Mabbett AN, Ulett GC,
Toledo-Arana A, Wecker K, Totsika M,
Schembri MA, Ghigo JM, and Beloin
C, UpaG, a new member of the trimeric
autotransporter family of adhesins
in uropathogenic Escherichia coli. J
Bacteriol, 2008. 190(12): 4147–61.
3290. Van Bambeke F, Michot JM, Van
Eldere J, and Tulkens PM, Quinolones
in 2005: an update. Clin Microbiol
Infect, 2005. 11(4): 256–80.
3291. Van den Berghe G, Wilmer A,
Hermans G, Meersseman W, Wouters
PJ, Milants I, Van Wijngaerden E,
Bobbaers H, and Bouillon R, Intensive
insulin therapy in the medical ICU. N
Engl J Med, 2006. 354(5): 449–61.
3292. van den Berghe G, Wouters P, Weekers
F, Verwaest C, Bruyninckx F, Schetz
M, Vlasselaers D, Ferdinande P,
Lauwers P, and Bouillon R, Intensive
insulin therapy in the critically ill
patients. N Engl J Med, 2001. 345(19):
1359–67.
3293. van der Linden PD, Sturkenboom
MC, Herings RM, Leufkens HG, and
Stricker BH, Fluoroquinolones and
risk of Achilles tendon disorders: case-
control study. BMJ, 2002. 324(7349):
1306–7.
3294. van der Meer JW and Gyssens IC,
Quality of antimicrobial drug prescrip-
tion in hospital. Clin Microbiol Infect,
2001. 7 Suppl 6: 12–5.
3295. van der Snoek EM, Chin ALRA, de
Ridder MA, Willems PW, Verkooyen RP,
and van der Meijden WI, [Prevalence
of sexually transmitted diseases (STD)
and HIV-infection among attendees
1164
of STD Outpatient Clinic, Dijkzigt
University Hospital in Rotterdam;
comparative analysis of years 1993 and
1998]. Ned Tijdschr Geneeskd, 2000.
144(28): 1351–5.
3296. van Dijk Azn R, Wetzels JF, ten Dam
MA, Aarts NJ, Schimmelpenninck-
Scheiffers ML, Freericks MP, Said
SA, Geenen RW, Stuurman A, and
van Everdingen JJ, [Guideline
‘Precautionary measures for contrast
media containing iodine’]. Ned Tijdschr
Geneeskd, 2008. 152(13): 742–6.
3297. Van Dissel JT, Numan SC, and Van’t
Wout JW, Chills in ‘early sepsis’: good
for you? J Intern Med, 2005. 257(5):
469–72.
3298. van Etten EW, van den Heuvel-de
Groot C, and Bakker-Woudenberg
IA, Efficacies of amphotericin
B-desoxycholate (Fungizone), lipo-
somal amphotericin B (AmBisome)
and fluconazole in the treatment of
systemic candidosis in immunocompe-
tent and leucopenic mice. J Antimicrob
Chemother, 1993. 32(5): 723–39.
3299. van Gool JD, Kuitjen RH,
Donckerwolcke RA, Messer AP, and
Vijverberg M, Bladder-sphincter dys-
function, urinary infection and vesico-
ureteral reflux with special reference
to cognitive bladder training. Contrib
Nephrol, 1984. 39: 190–210.
3300. van Harmelen J, Wood R, Lambrick
M, Rybicki EP, Williamson AL, and
Williamson C, An association between
HIV-1 subtypes and mode of transmis-
sion in Cape Town, South Africa. AIDS,
1997. 11(1): 81–7.
3301. Van Howe RS, Circumcision and HIV
infection: review of the literature and
meta-analysis. Int J STD AIDS, 1999.
10(1): 8–16.
3302. Van Howe RS, Svoboda JS, and Hodges
FM, HIV infection and circumcision:
cutting through the hyperbole. J R Soc
Health, 2005. 125(6): 259–65.
3303. van Kasteren ME, Mannien J, Kullberg
BJ, de Boer AS, Nagelkerke NJ,
Ridderhof M, Wille JC, and Gyssens
IC, Quality improvement of surgi-
cal prophylaxis in Dutch hospitals:
evaluation of a multi-site intervention

by time series analysis. J Antimicrob
Chemother, 2005. 56(6): 1094–102.
3304. van Kasteren ME, Mannien J, Ott A,
Kullberg BJ, de Boer AS, and Gyssens
IC, Antibiotic prophylaxis and the risk
of surgical site infections following total
hip arthroplasty: timely administration
is the most important factor. Clin Infect
Dis, 2007. 44(7): 921–7.
3305. van Loosdrecht MC, Lyklema J, Norde
W, Schraa G, and Zehnder AJ, The role
of bacterial cell wall hydrophobicity
in adhesion. Appl Environ Microbiol,
1987. 53(8): 1893–7.
3306. van Loosdrecht MC, Lyklema J,
Norde W, Schraa G, and Zehnder AJ,
Electrophoretic mobility and hydro-
phobicity as a measured to predict
the initial steps of bacterial adhesion.
Appl Environ Microbiol, 1987. 53(8):
1898–901.
3307. van Merode T, Nys S, Raets I, and
Stobberingh E, Acute uncomplicated
lower urinary tract infections in general
practice: clinical and microbiological
cure rates after three- versus five-day
treatment with trimethoprim. Eur J
Gen Pract, 2005. 11(2): 55–8.
3308. Van Pienbroek E, Hermans J, Kaptein
AA, and Mulder JD, Fosfomycin
trometamol in a single dose versus
seven days nitrofurantoin in the treat-
ment of acute uncomplicated urinary
tract infections in women. Pharm World
Sci, 1993. 15(6): 257–62.
3309. van Vollenhoven P, Heyns CF, de Beer
PM, Whitaker P, van Helden PD, and
Victor T, Polymerase chain reaction in
the diagnosis of urinary tract tuberculo-
sis. Urol Res, 1996. 24(2): 107–11.
3310. van Zoelen MA, Laterre PF, van Veen
SQ, van Till JW, Wittebole X, Bresser
P, Tanck MW, Dugernier T, Ishizaka A,
Boermeester MA, and van der Poll T,
Systemic and local high mobility group
box 1 concentrations during severe
infection. Crit Care Med, 2007. 35(12):
2799–804.
3311. Vanholder R, Ringoir S, Dhondt A, and
Hakim R, Phagocytosis in uremic and
hemodialysis patients: a prospective
and cross sectional study. Kidney Int,
1991. 39(2): 320–7.
References
3312. Vapalahti O, Mustonen J, Lundkvist A,
Henttonen H, Plyusnin A, and Vaheri
A, Hantavirus infections in Europe.
Lancet Infect Dis, 2003. 3(10): 653–61.
3313. Vardi A, Guy L, and Boiteux JP,
[Circumcision and HIV.]. Prog Urol,
2008. 18(6): 331–336.
3314. Varela JA, Otero L, Garcia MJ, Palacio
V, Carreno F, Cuesta M, Sanchez C,
and Vazquez F, Trends in the preva-
lence of pathogens causing urethritis
in Asturias, Spain, 1989–2000. Sex
Transm Dis, 2003. 30(4): 280–3.
3315. Varkarakis J, Sebe P, Pinggera GM,
Bartsch G, and Strasser H, Three-
dimensional ultrasound guidance for
percutaneous drainage of prostatic
abscesses. Urology, 2004. 63(6): 1017–
20; discussion 1020.
3316. Vatopoulos A, High rates of metallo-
beta-lactamase-producing Klebsiella
pneumoniae in Greece—a review of the
current evidence. Euro Surveill, 2008.
13(4).
3317. Vaziri ND, Cesarior T, Mootoo K, Zeien
L, Gordon S, and Byrne C, Bacterial
infections in patients with chronic renal
failure: occurrence with spinal cord
injury. Arch Intern Med, 1982. 142(7):
1273–6.
3318. Vazquez JA, Martin E, Galarza P,
Gimenez MJ, Aguilar L, and Coronel
P, In vitro susceptibility of Spanish
isolates of Neisseria gonorrhoeae to
cefditoren and five other antimicrobial
agents. Int J Antimicrob Agents, 2007.
29(4): 473–4.
3319. Vazquez JC and Villar J, Treatments
for symptomatic urinary tract infections
during pregnancy. Cochrane Database
Syst Rev, 2000(3): CD002256.
3320. Velasco M, Horcajada JP, Mensa J,
Moreno-Martinez A, Vila J, Martinez
JA, Ruiz J, Barranco M, Roig G, and
Soriano E, Decreased invasive capacity
of quinolone-resistant Escherichia coli
in patients with urinary tract infec-
tions. Clin Infect Dis, 2001. 33(10):
1682–6.
3321. Velasco M, Mateos JJ, Martinez JA,
Moreno-Martinez A, Horcajada JP,
Barranco M, Lomena F, and Mensa J,
Accurate topographical diagnosis of
1165
References
urinary tract infection in male patients
with (111)indium-labelled leukocyte
scintigraphy. Eur J Intern Med, 2004.
15(3): 157–161.
3322. Velicko I, Kuhlmann-Berenzon S, and
Blaxhult A, Reasons for the sharp
increase of genital chlamydia infections
reported in the first months of 2007 in
Sweden. Euro Surveill, 2007. 12(10):
E5–6.
3323. Velraeds MM, van der Mei HC, Reid G,
and Busscher HJ, Inhibition of initial
adhesion of uropathogenic Enterococcus
faecalis by biosurfactants from
Lactobacillus isolates. Appl Environ
Microbiol, 1996. 62(6): 1958–63.
3324. Veneziano S, Pavlica P, and Mannini D,
Color Doppler ultrasonographic scan-
ning in prostatitis: clinical correlation.
Eur Urol, 1995. 28(1): 6–9.
3325. Venier AG, Talon D, Patry I, Mercier-
Girard D, and Bertrand X, Patient
and bacterial determinants involved
in symptomatic urinary tract infection
caused by Escherichia coli with and
without bacteraemia. Clin Microbiol
Infect, 2007. 13(2): 205–8.
3326. Venmans LM, Bont J, Gorter KJ,
Verheij TJ, Rutten GE, and Hak E,
Prediction of complicated lower respira-
tory tract infections in older patients
with diabetes. Br J Gen Pract, 2008.
58(553): 564–8.
3327. Venmans LM, Gorter KJ, Rutten GE,
Schellevis FG, Hoepelman AI, and
Hak E, A clinical prediction rule for
urinary tract infections in patients
with type 2 diabetes mellitus in pri-
mary care. Epidemiol Infect, 2009.
137(2): 166–72.
3328. Venmans LM, Sloof M, Hak E, Gorter
KJ, and Rutten GE, Prediction of
complicated urinary tract infections in
patients with type 2 diabetes: a ques-
tionnaire study in primary care. Eur J
Epidemiol, 2007. 22(1): 49–54.
3329. Ventilation with lower tidal volumes
as compared with traditional tidal
volumes for acute lung injury and
the acute respiratory distress syn-
drome. The Acute Respiratory Distress
Syndrome Network. N Engl J Med,
2000. 342(18): 1301–8.
1166
3330. Vera-Sempere FJ, Rubio L, Moreno-
Baylach MJ, Garcia A, Prieto M,
Camanas A, Mayordomo F, Sanchez-
Plumed J, Beneyto I, Ramos D, Zamora
I, and Simon J, Polymerase chain
reaction detection of BK virus and
monitoring of BK nephropathy in renal
transplant recipients at the University
Hospital La Fe. Transplant Proc, 2005.
37(9): 3770–3.
3331. Verber IG and Meller ST, Serial 99mTc
dimercaptosuccinic acid (DMSA)
scans after urinary infections present-
ing before the age of 5 years. Arch Dis
Child, 1989. 64(11): 1533–7.
3332. Vercaigne LM and Zhanel GG,
Recommended treatment for urinary
tract infection in pregnancy. Ann
Pharmacother, 1994. 28(2): 248–51.
3333. Verleyen P, De Ridder D, Van Poppel
H, and Baert L, Clinical application of
the Bardex IC Foley catheter. Eur Urol,
1999. 36(3): 240–6.
3334. Vernazza PL, Gilliam BL, Dyer J,
Fiscus SA, Eron JJ, Frank AC, and
Cohen MS, Quantification of HIV in
semen: correlation with antiviral treat-
ment and immune status. AIDS, 1997.
11(8): 987–93.
3335. Vernon SJ, Coulthard MG, Lambert
HJ, Keir MJ, and Matthews JN, New
renal scarring in children who at age
3 and 4 years had had normal scans
with dimercaptosuccinic acid: follow up
study. BMJ, 1997. 315(7113): 905–8.
3336. Verpooten GA, Giuliano RA, Verbist L,
Eestermans G, and De Broe ME, Once-
daily dosing decreases renal accumula-
tion of gentamicin and netilmicin. Clin
Pharmacol Ther, 1989. 45(1): 22–7.
3337. Vesic S, Vukicevic J, Dakovic Z,
Tomovic M, Dobrosavljevic D, Medenica
L, and Pavlovic MD, Male urethritis
with and without discharge: rela-
tion to microbiological findings and
polymorphonuclear counts. Acta
Dermatovenerol Alp Panonica Adriat,
2007. 16(2): 53–7.
3338. Vester U, Kardorff R, Traore M, Traore
HA, Fongoro S, Juchem C, Franke D,
Korte R, Gryseels B, Ehrich JH, and
Doehring E, Urinary tract morbid-
ity due to Schistosoma haematobium

infection in Mali. Kidney Int, 1997.
52(2): 478–81.
3339. Vianna LE, Lo Y, and Klein RS, Serum
prostate-specific antigen levels in older
men with or at risk of HIV infection.
HIV Med, 2006. 7(7): 471–6.
3340. Vicari E and Mongioi A, Effectiveness
of long-acting gonadotrophin-releasing
hormone agonist treatment in combi-
nation with conventional therapy on
testicular outcome in human orchitis/
epididymo-orchitis. Hum Reprod, 1995.
10(8): 2072–8.
3341. Vidal L, Gafter-Gvili A, Borok S,
Fraser A, Leibovici L, and Paul M,
Efficacy and safety of aminoglycoside
monotherapy: systematic review and
meta-analysis of randomized controlled
trials. J Antimicrob Chemother, 2007.
60(2): 247–57.
3342. Viehweg B, Junghans U, Stepan H,
Voigt T, and Faber R, Der Nutzen vagi-
naler pH-Messungen für die Erkennung
potentieller Frühgeburten. Zentralbl
Gynäkol, 1997(119): 33–37.
3343. Vieler E, Jantos C, Schmidts HL,
Weidner W, and Schiefer HG,
Comparative efficacies of ofloxacin,
cefotaxime, and doxycycline for treat-
ment of experimental epididymitis due
to Escherichia coli in rats. Antimicrob
Agents Chemother, 1993. 37(4):
846–50.
3344. Vilana R, Corachan M, Gascon J, Valls
E, and Bru C, Schistosomiasis of the
male genital tract: transrectal sono-
graphic findings. J Urol, 1997. 158(4):
1491–3.
3345. Villar J, Lydon-Rochelle MT,
Gulmezoglu AM, and Roganti A,
Duration of treatment for asympto-
matic bacteriuria during pregnancy.
Cochrane Database Syst Rev, 2000(2):
CD000491.
3346. Villegas MV, Lolans K, Correa A,
Kattan JN, Lopez JA, and Quinn JP,
First identification of Pseudomonas
aeruginosa isolates producing a
KPC-type carbapenem-hydrolyzing
beta-lactamase. Antimicrob Agents
Chemother, 2007. 51(4): 1553–5.
3347. Villegas MV, Lolans K, Correa A,
Suarez CJ, Lopez JA, Vallejo M, and
References
Quinn JP, First detection of the plas-
mid-mediated class A carbapenemase
KPC-2 in clinical isolates of Klebsiella
pneumoniae from South America.
Antimicrob Agents Chemother, 2006.
50(8): 2880–2.
3348. Vincent JL and de Backer D, The
International Sepsis Forum’s contro-
versies in sepsis: my initial vasopres-
sor agent in septic shock is dopamine
rather than norepinephrine. Crit Care,
2003. 7(1): 6–8.
3349. Vincent JL, Bernard GR, Beale R, Doig
C, Putensen C, Dhainaut JF, Artigas
A, Fumagalli R, Macias W, Wright T,
Wong K, Sundin DP, Turlo MA, and
Janes J, Drotrecogin alfa (activated)
treatment in severe sepsis from the glo-
bal open-label trial ENHANCE: further
evidence for survival and safety and
implications for early treatment. Crit
Care Med, 2005. 33(10): 2266–77.
3350. Vincent JL, Bihari DJ, Suter PM,
Bruining HA, White J, Nicolas-
Chanoin MH, Wolff M, Spencer RC,
and Hemmer M, The prevalence of
nosocomial infection in intensive
care units in Europe. Results of the
European Prevalence of Infection in
Intensive Care (EPIC) Study. EPIC
International Advisory Committee.
JAMA, 1995. 274(8): 639–44.
3351. Vincent JL, Procalcitonin: THE marker
of sepsis? Crit Care Med, 2000. 28(4):
1226–8.
3352. Vink P, Residual formaldehyde in
steam-formaldehyde sterilized materi-
als. Biomaterials, 1986. 7(3): 221–4.
3353. Vinsonneau C, Camus C, Combes A,
Costa de Beauregard MA, Klouche
K, Boulain T, Pallot JL, Chiche JD,
Taupin P, Landais P, and Dhainaut JF,
Continuous venovenous haemodiafiltra-
tion versus intermittent haemodialysis
for acute renal failure in patients with
multiple-organ dysfunction syndrome:
a multicentre randomised trial. Lancet,
2006. 368(9533): 379–85.
3354. Viray M, Linkin D, Maslow JN, Stieritz
DD, Carson LS, Bilker WB, and
Lautenbach E, Longitudinal trends in
antimicrobial susceptibilities across
long-term-care facilities: emergence
1167
References
of fluoroquinolone resistance. Infect
Control Hosp Epidemiol, 2005. 26(1):
56–62.
3355. Viscoli C, Girmenia C, Marinus A,
Collette L, Martino P, Vandercam
B, Doyen C, Lebeau B, Spence D,
Krcmery V, De Pauw B, and Meunier F,
Candidemia in cancer patients: a pro-
spective, multicenter surveillance study
by the Invasive Fungal Infection Group
(IFIG) of the European Organization
for Research and Treatment of Cancer
(EORTC). Clin Infect Dis, 1999. 28(5):
1071–9.
3356. Vishnevskiy BI and Steklova LN,
Frequency and structure of drug resist-
ance Mycobacteria tuberculosis in
different localizations. Probl Tuberk,
2008. 12: 5–8.
3357. Viswaroop B, Johnson P, Kurian
S, Chacko N, Kekre N, and
Gopalakrishnan G, Fine-needle aspi-
ration cytology versus open biopsy
for evaluation of chronic epididymal
lesions: a prospective study. Scand J
Urol Nephrol, 2005. 39(3): 219–21.
3358. Vogel T, Verreault R, Gourdeau M,
Morin M, Grenier-Gosselin L, and
Rochette L, Optimal duration of antibi-
otic therapy for uncomplicated urinary
tract infection in older women: a dou-
ble-blind randomized controlled trial.
Cmaj, 2004. 170(4): 469–73.
3359. Vorobieva V, Firsova N, Ababkova T,
Leniv I, Haldorsen BC, Unemo M, and
Skogen V, Antibiotic susceptibility of
Neisseria gonorrhoeae in Arkhangelsk,
Russia. Sex Transm Infect, 2007. 83(2):
133–5.
3360. Wadie GM, Tirabassi MV, Courtney
RA, and Moriarty KP, The deflux pro-
cedure reduces the incidence of urinary
tract infections in patients with vesi-
coureteral reflux. J Laparoendosc Adv
Surg Tech A, 2007. 17(3): 353–9.
3361. Wagenlehner E, Niemetz A, and Naber
G, [Spectrum of pathogens and resist-
ance to antibiotics in urinary tract
infections and the consequences for
antibiotic treatment: study of urology
inpatients with urinary tract infections
(1994–2001)]. Urologe A, 2003. 42(1):
13–25.
1168
3362. Wagenlehner FM and Naber KG,
[Therapy of prostatitis syndrome].
Urologe A, 2001. 40(1): 24–8.
3363. Wagenlehner FM and Naber KG,
Antimicrobial treatment of prostatitis.
Expert Rev Anti Infect Ther, 2003. 1(2):
275–82.
3364. Wagenlehner FM and Naber KG,
Current challenges in the treatment of
complicated urinary tract infections
and prostatitis. Clin Microbiol Infect,
2006. 12 Suppl 3: 67–80.
3365. Wagenlehner FM and Naber KG,
Fluoroquinolone antimicrobial agents
in the treatment of prostatitis and
recurrent urinary tract infections
in men. Curr Urol Rep, 2004. 5(4):
309–16.
3366. Wagenlehner FM and Naber KG,
Fluoroquinolone Antimicrobial Agents
in the Treatment of Prostatitis and
Recurrent Urinary Tract Infections in
Men. Curr Infect Dis Rep, 2005. 7(1):
9–16.
3367. Wagenlehner FM and Naber KG, New
drugs for Gram-positive uropathogens.
Int J Antimicrob Agents, 2004. 24
Suppl 1: S39–43.
3368. Wagenlehner FM and Naber KG,
Prostatitis: the role of antibiotic treat-
ment. World J Urol, 2003. 21(2): 105–8.
3369. Wagenlehner FM and Naber KG,
Treatment of bacterial urinary tract
infections: presence and future. Eur
Urol, 2006. 49(2): 235–44.
3370. Wagenlehner FM, Diemer T, Naber
KG, and Weidner W, Chronic bacterial
prostatitis (NIH type II): diagnosis,
therapy and influence on the fertility
status. Andrologia, 2008. 40(2): 100–4.
3371. Wagenlehner FM, Kees F, Weidner
W, Wagenlehner C, and Naber KG,
Concentrations of moxifloxacin in
plasma and urine, and penetration into
prostatic fluid and ejaculate, following
single oral administration of 400 mg
to healthy volunteers. Int J Antimicrob
Agents, 2008. 31(1): 21–6.
3372. Wagenlehner FM, Krcmery S, Held
C, Klare I, Witte W, Bauernfeind
A, Schneider I, and Naber KG,
Epidemiological analysis of the spread
of pathogens from a urological ward

using genotypic, phenotypic and clinical
parameters. Int J Antimicrob Agents,
2002. 19(6): 583–91.
3373. Wagenlehner FM, Lehn N, Witte W, and
Naber KG, In vitro activity of dapto-
mycin versus linezolid and vancomycin
against gram-positive uropathogens and
ampicillin against enterococci, causing
complicated urinary tract infections.
Chemotherapy, 2005. 51(2–3): 64–9.
3374. Wagenlehner FM, Lunz JC, Kees F,
Wieland W, and Naber KG, Serum
and prostatic tissue concentrations of
moxifloxacin in patients undergoing
transurethral resection of the prostate.
J Chemother, 2006. 18(5): 485–9.
3375. Wagenlehner FM, Niemetz A, Dalhoff
A, and Naber KG, Spectrum and anti-
biotic resistance of uropathogens from
hospitalized patients with urinary tract
infections: 1994–2000. Int J Antimicrob
Agents, 2002. 19(6): 557–64.
3376. Wagenlehner FM, Niemetz AH,
Weidner W, and Naber KG, Spectrum
and antibiotic resistance of uropatho-
gens from hospitalised patients with
urinary tract infections: 1994–2005. Int
J Antimicrob Agents, 2008. 31 Suppl
1: S25–34.
3377. Wagenlehner FM, Pilatz A, Naber KG,
and Weidner W, Therapeutic challenges
of urosepsis. Eur J Clin Invest, 2008.
38 Suppl 2: 45–9.
3378. Wagenlehner FM, Wagenlehner C,
Schinzel S, and Naber KG, Prospective,
randomized, multicentric, open, com-
parative study on the efficacy of a
prophylactic single dose of 500 mg levo-
floxacin versus 1920 mg trimethoprim/
sulfamethoxazole versus a control group
in patients undergoing TUR of the pros-
tate. Eur Urol, 2005. 47(4): 549–56.
3379. Wagenlehner FM, Weidner W, and
Naber KG, Chlamydial infections in
urology. World J Urol, 2006. 24(1):
4–12.
3380. Wagenlehner FM, Weidner W, and
Naber KG, Pharmacokinetic char-
acteristics of antimicrobials and
optimal treatment of urosepsis. Clin
Pharmacokinet, 2007. 46(4): 291–305.
3381. Wagenlehner FM, Weidner W, and
Naber KG, Therapy for prostatitis,
References
with emphasis on bacterial prostati-
tis. Expert Opin Pharmacother, 2007.
8(11): 1667–74.
3382. Wagenlehner FM, Weidner W, Sorgel F,
and Naber KG, The role of antibiotics
in chronic bacterial prostatitis. Int J
Antimicrob Agents, 2005. 26(1): 1–7.
3383. Wagenlehner FME, Naber KG,
Bschleipfer T, Brähler E, and Weidner
W, Diagnostik und Therapie der
Prostatitis und des männlichen
Beckenschmerzsyndroms. Dtsch
Ärzteblatt, in press.
3384. Waites K, Canupp K, Armstrong S, and
DeVivo M, Effect of cranberry extract on
bacteriuria and pyuria in persons with
neurogenic bladder secondary to spinal
cord injury. J Spinal Cord Med, 2004.
27(1): 35–40.
3385. Waites KB, Canupp KC, and DeVivo
MJ, Epidemiology and risk factors for
urinary tract infection following spinal
cord injury. Arch Phys Med Rehabil,
1993. 74(7): 691–5.
3386. Waites KB, Canupp KC, and DeVivo
MJ, Eradication of urinary tract infec-
tion following spinal cord injury.
Paraplegia, 1993. 31(10): 645–52.
3387. Waites KB, Canupp KC, and DeVivo
MJ, Phagocytosis of urinary pathogens
in persons with spinal cord injury. Arch
Phys Med Rehabil, 1994. 75(1): 63–6.
3388. Wajnberg M and Wajnberg A, [A com-
parative double blind trial with vagi-
nal creams of cyclopyroxolamine and
miconazole in vulvovaginal candidosis
(author’s transl)]. Mykosen, 1981.
24(12): 721–30.
3389. Wald HL, Ma A, Bratzler DW, and
Kramer AM, Indwelling urinary cath-
eter use in the postoperative period:
analysis of the national surgical infec-
tion prevention project data. Arch Surg,
2008. 143(6): 551–7.
3390. Walker CK and Wiesenfeld HC,
Antibiotic therapy for acute pelvic
inflammatory disease: the 2006 Centers
for Disease Control and Prevention
sexually transmitted diseases treatment
guidelines. Clin Infect Dis, 2007. 44
Suppl 3: S111–22.
3391. Walker E, Barney D, Michelsen J,
Walton R, and Mickelsen R, Cranberry
1169
References
concentrate: UTI prophylaxis (letter). J
Fam Pract, 1997. 45(2): 167–8.
3392. Walker KE, Moghaddame-Jafari S,
Lockatell CV, Johnson D, and Belas R,
ZapA, the IgA-degrading metallopro-
tease of Proteus mirabilis, is a virulence
factor expressed specifically in swarmer
cells. Mol Microbiol, 1999. 32(4): 825–36.
3393. Walker PP, Reynolds MT, Ashbee HR,
Brown C, and Evans EG, Vaginal
yeasts in the era of “over the counter”
antifungals. Sex Transm Infect, 2000.
76(6): 437–8.
3394. Walker RC, The fluoroquinolones. Mayo
Clin Proc, 1999. 74(10): 1030–7.
3395. Walsh IK, Williams SG, Mahendra V,
Nambirajan T, and Stone AR, Artificial
urinary sphincter implantation in the
irradiated patient: safety, efficacy and
satisfaction. BJU Int, 2002. 89(4):
364–8.
3396. Walsh TR, Clinically significant car-
bapenemases: an update. Curr Opin
Infect Dis, 2008. 21(4): 367–71.
3397. Wan YL, Lee TY, Bullard MJ, and
Tsai CC, Acute gas-producing bacte-
rial renal infection: correlation between
imaging findings and clinical outcome.
Radiology, 1996. 198(2): 433–8.
3398. Wan YL, Lo SK, Bullard MJ, Chang
PL, and Lee TY, Predictors of outcome
in emphysematous pyelonephritis. J
Urol, 1998. 159(2): 369–73.
3399. Wang B, Xu JS, Wang CX, Mi ZH,
Pu YP, Hui M, Ling TK, and Chan
CY, Antimicrobial susceptibility of
Neisseria gonorrhoeae isolated in
Jiangsu Province, China, with a focus
on fluoroquinolone resistance. J Med
Microbiol, 2006. 55(Pt 9): 1251–5.
3400. Wang CY, Brodland DG, and Su WP,
Skin cancers associated with acquired
immunodeficiency syndrome. Mayo Clin
Proc, 1995. 70(8): 766–72.
3401. Wang H and Ma S, The cytokine storm
and factors determining the sequence
and severity of organ dysfunction in
multiple organ dysfunction syndrome.
Am J Emerg Med, 2008. 26(6): 711–5.
3402. Wang H, Chen ZH, Zhu YY, Wang T,
and Wu XJ, [Penetrability and thera-
peutic effect of vancomycin to the pros-
tates of rats with bacterial prostatitis
1170
(BP) or BPH-BP]. Zhonghua Nan Ke
Xue, 2006. 12(6): 490–5.
3403. Wang H, Li ZC, Luo ZH, and Chen ZH,
[Penetrability of amikacin into prostate
tissues in rat models of chronic bacte-
rial prostatitis]. Zhonghua Nan Ke
Xue, 2008. 14(7): 583–9.
3404. Wang J, Hou C, Zhang W, Zheng X, Xu
Z, Wang W, and Lin H, [Micturition
alert device dedicated to neurogenic
bladders]. Zhongguo Xiu Fu Chong
Jian Wai Ke Za Zhi, 2008. 22(5):
597–601.
3405. Wang JH, Sheu MH, and Lee RC,
Tuberculosis of the prostate: MR
appearance. J Comput Assist Tomogr,
1997. 21(4): 639–40.
3406. Wang LJ, Wong YC, Chen CJ, and Lim
KE, CT features of genitourinary tuber-
culosis. J Comput Assist Tomogr, 1997.
21(2): 254–8.
3407. Wang LP, Wong HY, and Griffith DP,
Treatment options in struvite stones.
Urol Clin North Am, 1997. 24(1):
149–62.
3408. Wang X, Preston JF, 3rd, and Romeo
T, The pgaABCD locus of Escherichia
coli promotes the synthesis of a polysac-
charide adhesin required for biofilm
formation. J Bacteriol, 2004. 186(9):
2724–34.
3409. Wang Y, Liang CL, Wu JQ, Xu C, Qin
SX, and Gao ES, Do Ureaplasma urea-
lyticum infections in the genital tract
affect semen quality? Asian J Androl,
2006. 8(5): 562–8.
3410. Wang YH, Grenabo L, Hedelin H, and
Pettersson S, The effects of sodium
citrate and oral potassium citrate on
urease-induced crystallization. Br J
Urol, 1994. 74(4): 409–15.
3411. Wang YH, Grenabo L, Hedelin H,
McLean RJ, Nickel JC, and Pettersson
S, Citrate and urease-induced crystal-
lization in synthetic and human urine.
Urol Res, 1993. 21(2): 109–15.
3412. Wang YH, Tsai HC, Lee SS, Mai MH,
Wann SR, Chen YS, and Liu YC,
Clinical manifestations of actinomy-
cosis in Southern Taiwan. J Microbiol
Immunol Infect, 2007. 40(6): 487–92.
3413. Ward V and Great Britain. Public
Health Laboratory Service., Preventing

hospital-acquired infection: clinical
guidelines. 1997, [London]: Public
Health Laboratory Service. 42 p.
3414. Warren J, Bakke A, and
Desgranchamps F, Catheter-associated
bacteriuria and the role of biomate-
rial in prevention, in Nosocomial
and health care associated infections
in urology, Naber KG, Pechere JC,
Kumazawa J, Khoury S, Gerberding
IL, and Schaeffer AJ, Editors. 2001,
Health Publication Ltd: Plymouth. p.
207 p.
3415. Warren J, Bakke A, Desgranchamps
F, Johnson JR, Kumon H, Shah J,
and Tambyah P Catheter-Associated
Bacteriuria and the Role of Biomaterial
in Prevention. Nosocomial and Health
Care Associated Infections In Urology.
2000.
3416. Warren JW, Abrutyn E, Hebel JR,
Johnson JR, Schaeffer AJ, and Stamm
WE, Guidelines for antimicrobial treat-
ment of uncomplicated acute bacterial
cystitis and acute pyelonephritis in
women. Infectious Diseases Society of
America (IDSA). Clin Infect Dis, 1999.
29(4): 745–58.
3417. Warren JW, Anthony WC, Hoopes
JM, and Muncie HL, Jr., Cephalexin
for susceptible bacteriuria in afebrile,
long-term catheterized patients. JAMA,
1982. 248(4): 454–8.
3418. Warren JW, Catheter-associated uri-
nary tract infections. Infect Dis Clin
North Am, 1997. 11(3): 609–22.
3419. Warren JW, Catheter-associated uri-
nary tract infections. Int J Antimicrob
Agents, 2001. 17(4): 299–303.
3420. Warren JW, Damron D, Tenney JH,
Hoopes JM, Deforge B, and Muncie
HL, Jr., Fever, bacteremia, and death as
complications of bacteriuria in women
with long-term urethral catheters. J
Infect Dis, 1987. 155(6): 1151–8.
3421. Warren JW, Platt R, Thomas RJ,
Rosner B, and Kass EH, Antibiotic irri-
gation and catheter-associated urinary-
tract infections. N Engl J Med, 1978.
299(11): 570–3.
3422. Warren JW, Providencia stuartii: a
common cause of antibiotic-resistant
bacteriuria in patients with long-term
References
indwelling catheters. Rev Infect Dis,
1986. 8(1): 61–7.
3423. Warren JW, Tenney JH, Hoopes JM,
Muncie HL, and Anthony WC, A pro-
spective microbiologic study of bacteriu-
ria in patients with chronic indwelling
urethral catheters. J Infect Dis, 1982.
146(6): 719–23.
3424. Watson C and Calabretto H,
Comprehensive review of conventional
and non-conventional methods of man-
agement of recurrent vulvovaginal can-
didiasis. Aust N Z J Obstet Gynaecol,
2007. 47(4): 262–72.
3425. Watson MC, Grimshaw JM, Bond
CM, Mollison J, and Ludbrook A, Oral
versus intra-vaginal imidazole and
triazole anti-fungal agents for the treat-
ment of uncomplicated vulvovaginal
candidiasis (thrush): a systematic
review. BJOG, 2002. 109(1): 85–95.
3426. Watterson SA and Drobniewski FA,
Modern laboratory diagnosis of myco-
bacterial infections. J Clin Pathol,
2000. 53(10): 727–32.
3427. Wawer MJ, Sewankambo NK,
Serwadda D, Quinn TC, Paxton LA,
Kiwanuka N, Wabwire-Mangen F, Li
C, Lutalo T, Nalugoda F, Gaydos CA,
Moulton LH, Meehan MO, Ahmed
S, and Gray RH, Control of sexually
transmitted diseases for AIDS preven-
tion in Uganda: a randomised commu-
nity trial. Rakai Project Study Group.
Lancet, 1999. 353(9152): 525–35.
3428. Weaver E and Craswell P, Pregnancy
outcome in women with reflux neph-
ropathy—a review of experience at the
Royal Women’s Hospital Brisbane,
1977–1986. Aust N Z J Obstet
Gynaecol, 1987. 27(2): 106–11.
3429. Webster GD and Sherman ND,
Management of male incontinence fol-
lowing artificial urinary sphincter
failure. Curr Opin Urol, 2005. 15(6):
386–90.
3430. Webster RI, Smith G, Farnsworth RH,
Rossleigh MA, Rosenberg AR, and
Kainer G, Low incidence of new renal
scars after ureteral reimplantation
for vesicoureteral reflux in children: a
prospective study. J Urol, 2000. 163(6):
1915–8.
1171
References
3431. Wei ZQ, Du XX, Yu YS, Shen P, Chen
YG, and Li LJ, Plasmid-mediated
KPC-2 in a Klebsiella pneumoniae
isolate from China. Antimicrob Agents
Chemother, 2007. 51(2): 763–5.
3432. Weidner W and Anderson RU,
Evaluation of acute and chronic bacte-
rial prostatitis and diagnostic manage-
ment of chronic prostatitis/chronic
pelvic pain syndrome with special refer-
ence to infection/inflammation. Int J
Antimicrob Agents, 2008. 31 Suppl 1:
S91–5.
3433. Weidner W and Krause W, Orchitis, in
Encyclopedia of Reproduction. 1999. p.
524–527.
3434. Weidner W, Diemer T, Huwe P,
Rainer H, and Ludwig M, The role of
Chlamydia trachomatis in prostatitis.
Int J Antimicrob Agents, 2002. 19(6):
466–70.
3435. Weidner W, Editorial comment. Eur
Urol, 2006. 49: 152–3.
3436. Weidner W, Epididymitis, in
Diagnostik und Therapie sexuell über-
tragbarer Erkrankungen. Leitlinien
2001 der Deutschen STD Gesellschaft,
Petzold D and Gross G, Editors. 2001,
Springer: Berlin. p. 13–18.
3437. Weidner W, Garbe C, Weissbach L,
Harbrecht J, Kleinschmidt K, Schiefer
HG, and Friedrich HJ, [Initial therapy
of acute unilateral epididymitis using
ofloxacin. II. Andrological findings].
Urologe A, 1990. 29(5): 277–80.
3438. Weidner W, Garbe C, Weissbach L,
Harbrecht J, Kleinschmidt K, Schiefer
HG, and Friedrich HJ, [Initial therapy
of acute unilateral epididymitis using
ofloxacin. I. Clinical and microbiological
findings]. Urologe A, 1990. 29(5): 272–6.
3439. Weidner W, Jantos C, Schiefer HG,
Haidl G, and Friedrich HJ, Semen
parameters in men with and without
proven chronic prostatitis. Arch Androl,
1991. 26(3): 173–83.
3440. Weidner W, Krause W, and Ludwig
M, Relevance of male accessory gland
infection for subsequent fertility with
special focus on prostatitis. Hum
Reprod Update, 1999. 5(5): 421–32.
3441. Weidner W, Ludwig M, Brahler E, and
Schiefer HG, Outcome of antibiotic
1172
therapy with ciprofloxacin in chronic
bacterial prostatitis. Drugs, 1999. 58
Suppl 2: 103–6.
3442. Weidner W, Schiefer HG, and Garbe
C, Acute nongonococcal epididymitis.
Aetiological and therapeutic aspects.
Drugs, 1987. 34 Suppl 1: 111–7.
3443. Weidner W, Schiefer HG, Krauss
H, Jantos C, Friedrich HJ, and
Altmannsberger M, Chronic prostati-
tis: a thorough search for etiologically
involved microorganisms in 1,461
patients. Infection, 1991. 19 Suppl 3:
S119–25.
3444. Weidner W, Wagenlehner FM, Marconi
M, Pilatz A, Pantke KH, and Diemer
T, Acute bacterial prostatitis and
chronic prostatitis/chronic pelvic pain
syndrome: andrological implications.
Andrologia, 2008. 40(2): 105–12.
3445. Weigelt J, Itani K, Stevens D, Lau W,
Dryden M, and Knirsch C, Linezolid
versus vancomycin in treatment of com-
plicated skin and soft tissue infections.
Antimicrob Agents Chemother, 2005.
49(6): 2260–6.
3446. Weighart H and Holzmann B, Role of
Toll-like receptor response for sepsis
pathogenesis. Immunobiology, 2008.
212: 715–722.
3447. Weightman NC and Banfield KR,
Protective over-shoes are unnecessary in
a day surgery unit. J Hosp Infect, 1994.
28(1): 1–3.
3448. Weil DA, Ruckle HC, Lui PD, and
Saukel W, Kaposi’s sarcoma of the testi-
cle. AIDS Read, 1999. 9(7): 455–6, 461.
3449. Weinberger M, Cytron S, Servadio C,
Block C, Rosenfeld JB, and Pitlik SD,
Prostatic abscess in the antibiotic era.
Rev Infect Dis, 1988. 10(2): 239–49.
3450. Weinstein RA, Nosocomial infection
update. Emerg Infect Dis, 1998. 4(3):
416–20.
3451. Weiss HA, Halpernr D, Bailey RC,
Hayes RJ, Schmid G, and Hankins C,
Male circumcision for HIV prevention:
from evidence to action? Aids, 2008.
22(5): 567–574.
3452. Weiss HA, Male circumcision as a pre-
ventive measure against HIV and other
sexually transmitted diseases. Curr
Opin Infect Dis, 2007. 20(1): 66–72.

3453. Weiss HA, Quigley MA, and Hayes
RJ, Male circumcision and risk of HIV
infection in sub-Saharan Africa: a sys-
tematic review and meta-analysis. Aids,
2000. 14(15): 2361–70.
3454. Weiss R, Duckett J, and Spitzer A,
Results of a randomized clinical trial
of medical versus surgical management
of infants and children with grades III
and IV primary vesicoureteral reflux
(United States). The International
Reflux Study in Children. J Urol, 1992.
148(5 Pt 2): 1667–73.
3455. Weissman Z and Kornitzer D, A fam-
ily of Candida cell surface haem-
binding proteins involved in haemin
and haemoglobin-iron utilization. Mol
Microbiol, 2004. 53(4): 1209–20.
3456. Welch RA, Burland V, Plunkett G, 3rd,
Redford P, Roesch P, Rasko D, Buckles
EL, Liou SR, Boutin A, Hackett J,
Stroud D, Mayhew GF, Rose DJ, Zhou
S, Schwartz DC, Perna NT, Mobley
HL, Donnenberg MS, and Blattner FR,
Extensive mosaic structure revealed
by the complete genome sequence of
uropathogenic Escherichia coli. Proc
Natl Acad Sci U S A, 2002. 99(26):
17020–4.
3457. Wells WG, Woods GL, Jiang Q, and
Gesser RM, Treatment of complicated
urinary tract infection in adults: com-
bined analysis of two randomized, dou-
ble-blind, multicentre trials comparing
ertapenem and ceftriaxone followed by
appropriate oral therapy. J Antimicrob
Chemother, 2004. 53 Suppl 2: ii67–74.
3458. Welz-Barth A, [Incontinence in old
age: a social and economic problem].
Urologe A, 2007. 46(4): 363–4, 366–7.
3459. Wemeau L, Mazeman E, Biserte J,
Schauvliège T, and Bailleul JP, Aspects
actuels de la tuberculose urinaire. Ann
Urol, 1982. 16(4): 235–38.
3460. Wennergren HM, Oberg BE, and
Sandstedt P, The importance of leg sup-
port for relaxation of the pelvic floor
muscles. A surface electromyograph
study in healthy girls. Scand J Urol
Nephrol, 1991. 25(3): 205–13.
3461. Wennerstrom M, Hansson S, Jodal U,
Sixt R, and Stokland E, Renal function
16 to 26 years after the first urinary
References
tract infection in childhood. Arch
Pediatr Adolesc Med, 2000. 154(4):
339–45.
3462. Werman HA and Brown CG, Utility of
urine cultures in the emergency depart-
ment. Ann Emerg Med, 1986. 15(3):
302–7.
3463. Werner G, Coque TM, Hammerum
AM, Hope R, Hryniewicz W, Johnson
A, Klare I, Kristinsson KG, Leclercq R,
Lester CH, Lillie M, Novais C, Olsson-
Liljequist B, Peixe LV, Sadowy E,
Simonsen GS, Top J, Vuopio-Varkila J,
Willems RJ, Witte W, and Woodford N,
Emergence and spread of vancomycin
resistance among enterococci in Europe.
Euro Surveill, 2008. 13(47).
3464. Wesolowski LG, MacKellar DA,
Facente SN, Dowling T, Ethridge
SF, Zhu JH, and Sullivan PS, Post-
marketing surveillance of OraQuick
whole blood and oral fluid rapid HIV
testing. AIDS, 2006. 20(12): 1661–6.
3465. West DA, Cummings JM, Longo WE,
Virgo KS, Johnson FE, and Parra
RO, Role of chronic catheterization
in the development of bladder cancer
in patients with spinal cord injury.
Urology, 1999. 53(2): 292–7.
3466. Westenfelder M, Vahlensieck W, and
Reinhartz U, Patient compliance and
efficacy of low-dose, long-term prophy-
laxis in patients with recurrent urinary
tract infection. Chemioterapia, 1987.
6(2 Suppl): 530–2.
3467. Westhoff C, IUDs and coloniza-
tion or infection with Actinomyces.
Contraception, 2007. 75(6 Suppl):
S48–50.
3468. Westrom L and Wolner-Hanssen P,
Pathogenesis of pelvic inflammatory dis-
ease. Genitourin Med, 1993. 69(1): 9–17.
3469. Westrom L, Incidence, prevalence, and
trends of acute pelvic inflammatory dis-
ease and its consequences in industrial-
ized countries. Am J Obstet Gynecol,
1980. 138(7 Pt 2): 880–92.
3470. Westwood ME, Whiting PF, Cooper
J, Watt IS, and Kleijnen J, Further
investigation of confirmed urinary
tract infection (UTI) in children under
five years: a systematic review. BMC
Pediatr, 2005. 5(1): 2.
1173
References
3471. Wettergren B, Fasth A, and Jacobsson
B, UTI during the first year of life in a
Göteborg area 1977–79. Pediatr Res,
1980. 14: 981.
3472. Wettergren B, Hellstrom M, Stokland
E, and Jodal U, Six year follow up of
infants with bacteriuria on screening.
BMJ, 1990. 301(6756): 845–8.
3473. Whalley P, Bacteriuria of pregnancy.
Am J Obstet Gynecol, 1967. 97(5):
723–38.
3474. Whalley PJ, Adams RH, and Combes
B, Tetracycline Toxicity in Pregnancy.
Liver and Pancreatic Dysfunction.
JAMA, 1964. 189: 357–62.
3475. Wheeler D, Vimalachandra D, Hodson
EM, Roy LP, Smith G, and Craig
JC, Antibiotics and surgery for vesi-
coureteric reflux: a meta-analysis of
randomised controlled trials. Arch Dis
Child, 2003. 88(8): 688–94.
3476. Whiley DM, Limnios EA, Ray S, Sloots
TP, and Tapsall JW, Diversity of penA
alterations and subtypes in Neisseria
gonorrhoeae strains from Sydney,
Australia, that are less susceptible
to ceftriaxone. Antimicrob Agents
Chemother, 2007. 51(9): 3111–6.
3477. Whiting P, Westwood M, Watt I, Cooper
J, and Kleijnen J, Rapid tests and
urine sampling techniques for the diag-
nosis of urinary tract infection (UTI) in
children under five years: a systematic
review. BMC Pediatr, 2005. 5(1): 4.
3478. Whitmore WF, Jr., Natural history and
staging of prostate cancer. Urol Clin
North Am, 1984. 11(2): 205–20.
3479. WHO Task Force on The Diagnosis and
Treatment of Infertility, Towards more
objectivity in diagnosis and manage-
ment of male infertility. Int J Androl,
1987(Suppl 7): 1–53.
3480. Whyte W, Hambraeus A, Laurell G,
and Hoborn J, The relative importance
of routes and sources of wound contam-
ination during general surgery. I. Non-
airborne. J Hosp Infect, 1991. 18(2):
93–107.
3481. Wiebe E, Guilbert E, Jacot F, Shannon
C, and Winikoff B, A fatal case of
Clostridium sordellii septic shock
syndrome associated with medical
1174
abortion. Obstet Gynecol, 2004. 104(5
Pt 2): 1142–4.
3482. Wiesenfeld HC, Hillier SL, Krohn MA,
Amortegui AJ, Heine RP, Landers DV,
and Sweet RL, Lower genital tract
infection and endometritis: insight into
subclinical pelvic inflammatory disease.
Obstet Gynecol, 2002. 100(3): 456–63.
3483. Wikstrom A and Jensen JS,
Mycoplasma genitalium: a common
cause of persistent urethritis among
men treated with doxycycline. Sex
Transm Infect, 2006. 82(4): 276–9.
3484. Wild S, Roglic G, Green A, Sicree R,
and King H, Global prevalence of dia-
betes: estimates for the year 2000 and
projections for 2030. Diabetes Care,
2004. 27(5): 1047–53.
3485. Wildbolz H, Ueber urogenical tuberku-
lose. Schweiz Med Wochenschr, 1937.
67: 1125.
3486. Wiles TJ, Dhakal BK, Eto DS, and
Mulvey MA, Inactivation of host Akt/
protein kinase B signaling by bacte-
rial pore-forming toxins. Mol Biol Cell,
2008. 19(4): 1427–38.
3487. Willemsen J and Nijman RJ,
Vesicoureteral reflux and videourody-
namic studies: results of a prospective
study. Urology, 2000. 55(6): 939–43.
3488. William S, Botros S, Ismail M,
Farghally A, Day TA, and Bennett
JL, Praziquantel-induced tegumental
damage in vitro is diminished in schis-
tosomes derived from praziquantel-
resistant infections. Parasitology, 2001.
122 Pt 1: 63–6.
3489. Williams BG, Lloyd-Smith JO, Gouws
E, Hankins C, Getz WM, Hargrove J,
de Zoysa I, Dye C, and Auvert B, The
potential impact of male circumcision
on HIV in Sub-Saharan Africa. PLoS
Med, 2006. 3(7): e262.
3490. Williams DH and Schaeffer AJ, Current
concepts in urinary tract infections.
Minerva Urol Nefrol, 2004. 56(1):
15–31.
3491. Williams G, Lee A, and Craig J,
Antibiotics for the prevention of urinary
tract infection in children: A systematic
review of randomized controlled trials.
J Pediatr, 2001. 138(6): 868–74.

3492. Williams GJ, Wei L, Lee A, and Craig
JC, Long-term antibiotics for prevent-
ing recurrent urinary tract infection in
children. Cochrane Database Syst Rev,
2006. 3: CD001534.
3493. Williams M and Hole DJ, Bacteriuria
in patients undergoing prostatectomy. J
Clin Pathol, 1982. 35(11): 1185–9.
3494. Wilson C, Recurrent vulvovaginitis can-
didiasis; an overview of traditional and
alternative therapies. Adv Nurse Pract,
2005. 13(5): 24–9; quiz 30.
3495. Wilson C, Sandhu SS, and Kaisary AV,
A prospective randomized study com-
paring a catheter-valve with a stand-
ard drainage system. Br J Urol, 1997.
80(6): 915–7.
3496. Wilson CH, Bhatti AA, Rix DA, and
Manas DM, Routine intraoperative
ureteric stenting for kidney transplant
recipients. Cochrane Database Syst
Rev, 2005(4): CD004925.
3497. Wilson L, Ryan J, Thelning C, Masters
J, and Tuckey J, Is antibiotic prophy-
laxis required for flexible cystoscopy?
A truncated randomized double-blind
controlled trial. J Endourol, 2005.
19(8): 1006–8.
3498. Wilson SK and Delk JR, 2nd, Inflatable
penile implant infection: predisposing
factors and treatment suggestions. J
Urol, 1995. 153(3 Pt 1): 659–61.
3499. Wilson SK, Carson CC, Cleves MA,
and Delk JR, 2nd, Quantifying risk of
penile prosthesis infection with elevated
glycosylated hemoglobin. J Urol, 1998.
159(5): 1537–9; discussion 1539–40.
3500. Wilson SK, Zumbe J, Henry GD, Salem
EA, Delk JR, and Cleves MA, Infection
reduction using antibiotic-coated inflat-
able penile prosthesis. Urology, 2007.
70(2): 337–40.
3501. Wilson W, Taubert K, Gewitz M,
Lockhart P, Baddour L, and Levison
M, Prevention of infective endocarditis.
Guidelines from the AHA. A Guideline
From the AHA Rheumatic Fever,
Endocarditis, and Kawasaki Disease
Committee Council on Cardiovascular
Surgery and Anesthesia, and the
Quality of Care and Outcomes Research
Interdisciplinary Working Group.
References
3502. Wilson WT, Frenkel E, Vuitch F, and
Sagalowsky AI, Testicular tumors in
men with human immunodeficiency
virus. J Urol, 1992. 147(4): 1038–40.
3503. Wimmerstedt A and Kahlmeter G,
Associated antimicrobial resistance
in Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus,
Streptococcus pneumoniae and
Streptococcus pyogenes. Clin Microbiol
Infect, 2008. 14(4): 315–21.
3504. Winberg J, Andersen HJ, Bergstrom
T, Jacobsson B, Larson H, and Lincoln
K, Epidemiology of symptomatic uri-
nary tract infection in childhood. Acta
Paediatr Scand Suppl, 1974(252): 1–20.
3505. Winberg J, Bergstrom T, and Jacobsson
B, Morbidity, age and sex distribu-
tion, recurrences and renal scarring in
symptomatic urinary tract infection in
childhood. Kidney Int Suppl, 1975. 4:
S101–6.
3506. Winberg J, Bollgren I, Kallenius G,
Mollby R, and Svenson SB, Clinical
pyelonephritis and focal renal scar-
ring. A selected review of pathogenesis,
prevention, and prognosis. Pediatr Clin
North Am, 1982. 29(4): 801–14.
3507. Winberg J, Management of primary
vesico-ureteric reflux in children—oper-
ation ineffective in preventing progres-
sive renal damage. Infection, 1994. 22
Suppl 1: S4–7.
3508. Winberg J, What antibiotics should be
used for prophylaxis against recurrent
urinary tract infections in childhood?
Pediatr Nephrol, 1990. 4: 244.
3509. Winer RL, Hughes JP, Feng Q, O’Reilly
S, Kiviat NB, Holmes KK, and Koutsky
LA, Condom use and the risk of geni-
tal human papillomavirus infection
in young women. N Engl J Med, 2006.
354(25): 2645–54.
3510. Wing DA, Hendershott CM, Debuque
L, and Millar LK, A randomized trial of
three antibiotic regimens for the treat-
ment of pyelonephritis in pregnancy.
Obstet Gynecol, 1998. 92(2): 249–53.
3511. Winokur PL, Canton R, Casellas JM,
and Legakis N, Variations in the preva-
lence of strains expressing an extended-
spectrum beta-lactamase phenotype
1175
References
and characterization of isolates from
Europe, the Americas, and the Western
Pacific region. Clin Infect Dis, 2001. 32
Suppl 2: S94–103.
3512. Winston JA, Bruggeman LA, Ross
MD, Jacobson J, Ross L, D’Agati
VD, Klotman PE, and Klotman ME,
Nephropathy and establishment of a
renal reservoir of HIV type 1 during
primary infection. N Engl J Med, 2001.
344(26): 1979–84.
3513. Wise GJ and Marella VK,
Genitourinary manifestations of tuber-
culosis. Urol Clin North Am, 2003.
30(1): 111–21.
3514. Wise GJ and Shteynshlyuger A, How
to diagnose and treat fungal infections
in chronic prostatitis. Curr Urol Rep,
2006. 7(4): 320–8.
3515. Wise GJ, Kozinn PJ, and Goldberg P,
Amphotericin B as a urologic irrigant
in the management of noninvasive can-
diduria. J Urol, 1982. 128(1): 82–4.
3516. Wisell KT, Kahlmeter G, and Giske
CG, Trimethoprim and enterococci in
urinary tract infections: new perspec-
tives on an old issue. J Antimicrob
Chemother, 2008. 62(1): 35–40.
3517. Wiswell TE and Hachey WE, Urinary
tract infections and the uncircumcised
state: an update. Clin Pediatr (Phila),
1993. 32(3): 130–4.
3518. Wiswell TE, Miller GM, Gelston HM,
Jr., Jones SK, and Clemmings AF, Effect
of circumcision status on periurethral
bacterial flora during the first year of
life. J Pediatr, 1988. 113(3): 442–6.
3519. Witkin SS and Linhares IM,
Chlamydia trachomatis in subfertile
women undergoing uterine instrumen-
tation: an alternative to direct micro-
bial testing or prophylactic antibiotic
treatment. Hum Reprod, 2002. 17(8):
1938–41.
3520. Witkin SS, Giraldo P, and Linhares D,
New insights into the immune patho-
genesis of recurrent vulvovaginal candi-
diasis. Int J Gynaecol Obstet, 2000. 3:
114–8.
3521. Witkin SS, Immunological aspects
of genital chlamydia infections. Best
Pract Res Clin Obstet Gynaecol, 2002.
16(6): 865–74.
1176
3522. Witkin SS, Jeremias J, and Ledger WJ,
A localized vaginal allergic response
in women with recurrent vaginitis. J
Allergy Clin Immunol, 1988. 81(2):
412–6.
3523. Witkin SS, Neuer A, Giraldo P,
Jeremias J, Tolbert V, Korneeva IL,
Kneissl D, and Bongiovanni AM,
Chlamydia trachomatis Infection,
Immunity, and Pregnancy Outcome.
Infect Dis Obstet Gynecol, 1997. 5(2):
128–32.
3524. Wizemann TM, Adamou JE, and
Langermann S, Adhesins as targets for
vaccine development. Emerg Infect Dis,
1999. 5(3): 395–403.
3525. Wolf JS, Jr., Bennett CJ, Dmochowski
RR, Hollenbeck BK, Pearle MS, and
Schaeffer AJ, Best practice policy state-
ment on urologic surgery antimicro-
bial prophylaxis. J Urol, 2008. 179(4):
1379–90.
3526. Wolf LE, Tuberculous abscess of the
prostate in AIDS. Ann Intern Med,
1996. 125(2): 156.
3527. Wolter CE and Hellstrom WJ, The
hydrophilic-coated inflatable penile
prosthesis: 1-year experience. J Sex
Med, 2004. 1(2): 221–4.
3528. Wong ES and Stamm WE, Urethral
infections in men and women. Annu
Rev Med, 1983. 34: 337–58.
3529. Wong ES, Guideline for prevention of
catheter-associated urinary tract infec-
tions. Am J Infect Control, 1983. 11(1):
28–36.
3530. Wong ES, McKevitt M, Running K,
Counts GW, Turck M, and Stamm WE,
Management of recurrent urinary tract
infections with patient-administered
single-dose therapy. Ann Intern Med,
1985. 102(3): 302–7.
3531. Wong SH and Lau WY, The surgical
management of non-functioning tuber-
culous kidneys. J Urol, 1980. 124(2):
187–91.
3532. Wong SH, Lau WY, Poon GP, Fan ST,
Ho KK, Yiu TF, and Chan SL, The
treatment of urinary tuberculosis. J
Urol, 1984. 131(2): 297–301.
3533. Wood DP, Jr., Bianco FJ, Jr., Pontes JE,
Heath MA, and DaJusta D, Incidence
and significance of positive urine

cultures in patients with an ortho-
topic neobladder. J Urol, 2003. 169(6):
2196–9.
3534. Wood MJ, The comparative efficacy and
safety of teicoplanin and vancomycin.
J Antimicrob Chemother, 1996. 37(2):
209–22.
3535. Woodfield JC, Beshay NM, Pettigrew
RA, Plank LD, and van Rij AM,
American Society of Anesthesiologists
classification of physical status as a
predictor of wound infection. ANZ J
Surg, 2007. 77(9): 738–41.
3536. Woodford N, Tierno PM, Jr., Young K,
Tysall L, Palepou MF, Ward E, Painter
RE, Suber DF, Shungu D, Silver LL,
Inglima K, Kornblum J, and Livermore
DM, Outbreak of Klebsiella pneumo-
niae producing a new carbapenem-
hydrolyzing class A beta-lactamase,
KPC-3, in a New York Medical Center.
Antimicrob Agents Chemother, 2004.
48(12): 4793–9.
3537. Woodford N, Zhang J, Kaufmann
ME, Yarde S, Tomas Mdel M, Faris
C, Vardhan MS, Dawson S, Cotterill
SL, and Livermore DM, Detection
of Pseudomonas aeruginosa isolates
producing VEB-type extended-spec-
trum beta-lactamases in the United
Kingdom. J Antimicrob Chemother,
2008. 62(6): 1265–8.
3538. Woodhams SD, Greenwell TJ, Smalley
T, and Mundy AR, Factors causing var-
iation in urinary N-nitrosamine levels
in enterocystoplasties. BJU Int, 2001.
88(3): 187–91.
3539. Woodhouse CR and Lennon GN,
Management and aetiology of stones in
intestinal urinary reservoirs in adoles-
cents. Eur Urol, 2001. 39(3): 253–9.
3540. Woodhouse CR, Progress in the man-
agement of children born with spina
bifida. Eur Urol, 2006. 49(5): 777–8.
3541. Woodside JR, Reed WP, and Borden
TA, Immunoglobulin in urine from
ileal conduit and nephrostomy
patients. Invest Urol, 1979. 16(6):
473–5.
3542. Workowski KA and Berman SM,
Sexually transmitted diseases treat-
ment guidelines, 2006. MMWR
Recomm Rep, 2006. 55(RR-11): 1–94.
References
3543. World Health Organization,
Antituberculosis drug resistance
in the world. Report No.4 (2008).
2008, Geneva: WHO. WHO/HTM/
TB/2008.394.
3544. World Health Organization,
Global Tuberculosis Control 2008:
Surveillance, Planning, Financing.
2008, Geneva: WHO. WHO/HTM/TB
2008.39.
3545. World Health Organization, Global
Tuberculosis Control: Surveillance,
Planning, Financing. 2006, Geneva:
World Health Organization. 362.
3546. World Health Organization, Treatment
of tuberculosis: guidelines for national
programmes. Revision approved
by STAG, June 2004. 3rd ed. 2004,
Geneva: World Health Organization.
vii, 43 p.
3547. World Health Organization, Treatment
of Tuberculosis: Guidelines for National
Programs. Third Edition ed. 2003,
Geneva: WHO.
3548. World Health Organization, WHO Fact
Sheet N 104, August, 2002. 2002.
3549. World Health Organization, WHO Stop
TB Programme. Global Tuberculosis
Control, WHO Report 2005. 2005,
Geneva: World Health Organization.
3550. World Health Organization. Global
Tuberculosis Control, Surveillance,
Planning, Financing. 2008; Available
from: http://www.who.int/tb/publica-
tions/global_report/2008/pdf/report_
without_annexes.pdf.
3551. World Health Organization.
Schistosomiasis: Burden and Trends.
2008; Available from: http://www.who.
int/bulletin/volumes/86/10/08–058669/
en/.
3552. Worthen NJ and Gunning JE,
Percutaneous drainage of pelvic
abscesses: management of the tubo-
ovarian abscess. J Ultrasound Med,
1986. 5(10): 551–6.
3553. Wozniak KL, Palmer G, Kutner R,
and Fidel PL, Jr., Immunotherapeutic
approaches to enhance protective immu-
nity against Candida vaginitis. Med
Mycol, 2005. 43(7): 589–601.
3554. Wright KJ and Hultgren SJ, Sticky
fibers and uropathogenesis: bacterial
1177
References
adhesins in the urinary tract. Future
Microbiol, 2006. 1: 75–87.
3555. Wright KJ, Seed PC, and Hultgren
SJ, Development of intracellular bac-
terial communities of uropathogenic
Escherichia coli depends on type 1 pili.
Cell Microbiol, 2007. 9(9): 2230–41.
3556. Wright SW, Wrenn KD, and Haynes ML,
Trimethoprim-sulfamethoxazole resist-
ance among urinary coliform isolates. J
Gen Intern Med, 1999. 14(10): 606–9.
3557. Wright SW, Wrenn KD, Haynes M, and
Haas DW, Prevalence and risk factors
for multidrug resistant uropathogens in
ED patients. Am J Emerg Med, 2000.
18(2): 143–6.
3558. Wu XR, Lin JH, Walz T, Haner M, Yu
J, Aebi U, and Sun TT, Mammalian
uroplakins. A group of highly conserved
urothelial differentiation-related mem-
brane proteins. J Biol Chem, 1994.
269(18): 13716–24.
3559. Wu X-R, Sun T-T, and Medina J, In
vitro binding of type 1 fimbriated
Esherichia coli to uroplakins Ia and
Ib: relation to urinary tract infec-
tions. Proc. Natl. Acad. Sci., 1996. 93:
9630–9635.
3560. Wu YJ, Veale JL, and Gritsch HA,
Urological complications of renal
transplant in patients with prolonged
anuria. Transplantation, 2008. 86(9):
1196–8.
3561. Wullt B, Agace W, and Mansson W,
Bladder, bowel and bugs—bacteriuria
in patients with intestinal urinary
diversion. World J Urol, 2004. 22(3):
186–95.
3562. Wullt B, Bergsten G, Carstensen J,
Gustafsson E, Gebratsedik N, Holst
E, and Mansson W, Mucosal host
responses to bacteriuria in colonic and
ileal neobladders. Eur Urol, 2006.
50(5): 1065–71; discussion 1071–2.
3563. Wullt B, Bergsten G, Connell H,
Rollano P, Gebratsedik N, Hang L, and
Svanborg C, P-fimbriae trigger mucosal
responses to Escherichia coli in the
human urinary tract. Cell Microbiol,
2001. 3(4): 255–64.
3564. Wullt B, Bergsten G, Connell H,
Rollano P, Gebretsadik N, Hull R,
and Svanborg C, P fimbriae enhance
1178
the early establishment of escherichia
coli in the human urinary tract. Mol
Microbiol, 2000. 38(3): 456–64.
3565. Wullt B, Connell H, Rollano P,
Mansson W, Colleen S, and Svanborg
C, Urodynamic factors influence the
duration of Escherichia coli bacteriuria
in deliberately colonized cases. J Urol,
1998. 159(6): 2057–62.
3566. Wullt B, Holst E, Steven K, Carstensen
J, Pedersen J, Gustafsson E, Colleen S,
and Mansson W, Microbial flora in ileal
and colonic neobladders. Eur Urol,
2004. 45(2): 233–9.
3567. Wybran J, Libin M, and Schandene
L, Enhancement of cytokine produc-
tion and natural killer activity by an
Escherichia coli extract. Onkologie,
1989. 12 Suppl 3: 22–5.
3568. Wynd MA and Paladino JA, Cefepime:
a fourth-generation parenteral cepha-
losporin. Ann Pharmacother, 1996.
30(12): 1414–24.
3569. Wyndaele JJ and Maes D, Clean inter-
mittent self-catheterization: a 12-year
followup. J Urol, 1990. 143(5): 906–8.
3570. Xiao CG, Reinnervation for neurogenic
bladder: historic review and introduc-
tion of a somatic-autonomic reflex path-
way procedure for patients with spinal
cord injury or spina bifida. Eur Urol,
2006. 49(1): 22–8; discussion 28–9.
3571. Xu F, Sternberg MR, Kottiri BJ,
McQuillan GM, Lee FK, Nahmias
AJ, Berman SM, and Markowitz LE,
Trends in herpes simplex virus type 1
and type 2 seroprevalence in the United
States. JAMA, 2006. 296(8): 964–73.
3572. Xu J, Schwartz K, Bartoces M, Monsur
J, Severson RK, and Sobel JD, Effect of
antibiotics on vulvovaginal candidiasis:
a MetroNet study. J Am Board Fam
Med, 2008. 21(4): 261–8.
3573. Yahr TL, A critical new pathway for
toxin secretion? N Engl J Med, 2006.
355(11): 1171–2.
3574. Yamamoto S, Ishitoya S, Segawa T,
Kamoto T, Okumura K, and Ogawa O,
Antibiotic prophylaxis for transrectal
prostate biopsy: a prospective rand-
omized study of tosufloxacin versus
levofloxacin. Int J Urol, 2008. 15(7):
604–6.

3575. Yamamoto S, Kanamaru S, Kunishima
Y, Ichiyama S, and Ogawa O,
Perioperative antimicrobial prophylaxis
in urology: a multi-center prospec-
tive study. J Chemother, 2005. 17(2):
189–97.
3576. Yaman O, Gogus C, Tulunay O, Tokatli
Z, and Ozden E, Increased prostate-spe-
cific antigen in subclinical prostatitis:
the role of aggressiveness and extension
of inflammation. Urol Int, 2003. 71(2):
160–4.
3577. Yang SS and Chang SJ, The effects of
bladder over distention on voiding func-
tion in kindergarteners. J Urol, 2008.
180(5): 2177–82; discussion 2182.
3578. Yang SS, Tsai YC, Wu CC, Liu SP, and
Wang CC, Highly potent and moder-
ately potent topical steroids are effec-
tive in treating phimosis: a prospective
randomized study. J Urol, 2005. 173(4):
1361–3.
3579. Yang SS, Wang CC, and Chen YT,
Effectiveness of alpha1-adrenergic
blockers in boys with low urinary
flow rate and urinary incontinence.
J Formos Med Assoc, 2003. 102(8):
551–5.
3580. Yang WJ, Cho IR, Seong do H, Song
YS, Lee DH, Song KH, Cho KS, Sung
Hong W, and Kim HS, Clinical impli-
cation of serum C-reactive protein in
patients with uncomplicated acute
pyelonephritis as marker of pro-
longed hospitalization and recurrence.
Urology, 2009. 73(1): 19–22.
3581. Yang Y, Liao M, Gu WM, Bell K, Wu
L, Eng NF, Zhang CG, Chen Y, Jolly
AM, and Dillon JA, Antimicrobial sus-
ceptibility and molecular determinants
of quinolone resistance in Neisseria
gonorrhoeae isolates from Shanghai.
J Antimicrob Chemother, 2006. 58(4):
868–72.
3582. Yasuda M, Maeda S, and Deguchi
T, In vitro activity of fluoroquinolo-
nes against Mycoplasma genitalium
and their bacteriological efficacy for
treatment of M. genitalium-positive
nongonococcal urethritis in men. Clin
Infect Dis, 2005. 41(9): 1357–9.
3583. Yen YT, Kostakioti M, Henderson IR,
and Stathopoulos C, Common themes
References
and variations in serine protease
autotransporters. Trends Microbiol,
2008. 16(8): 370–9.
3584. Yeni P, Update on HAART in HIV. J
Hepatol, 2006. 44(1 Suppl): S100–3.
3585. Yeniyol CO, Sorguc S, Minareci S, and
Ayder AR, Role of interferon-alpha-2B
in prevention of testicular atrophy with
unilateral mumps orchitis. Urology,
2000. 55(6): 931–3.
3586. Yetkin MA, Erdinc FS, Bulut C, and
Tulek N, Epididymoorchitis due to
brucellosis in central Anatolia, Turkey.
Urol Int, 2005. 75(3): 235–8.
3587. Yeung CK, Godley ML, Dhillon HK,
Gordon I, Duffy PG, and Ransley PG,
The characteristics of primary vesico-
ureteric reflux in male and female
infants with pre-natal hydronephrosis.
Br J Urol, 1997. 80(2): 319–27.
3588. Yeung CK, Sreedhar B, Sihoe JD,
and Sit FK, Renal and bladder func-
tional status at diagnosis as predic-
tive factors for the outcome of primary
vesicoureteral reflux in children. J
Urol, 2006. 176(3): 1152–6; discussion
1156–7.
3589. Yi FX, Wei Q, Li H, Li X, Shi M, Dong
Q, and Yang YR, Risk factors for pros-
tatic inflammation extent and infection
in benign prostatic hyperplasia. Asian J
Androl, 2006. 8(5): 621–7.
3590. Yigit H, Queenan AM, Anderson GJ,
Domenech-Sanchez A, Biddle JW,
Steward CD, Alberti S, Bush K, and
Tenover FC, Novel Carbapenem-
Hydrolizing _-Lactamase, KPC-1,
from a Carbapenem-Resistant Strain
of Klebsiella Pneumoniae. Antimicrob
Agents Chemother, 2008. 52: 809.
3591. Yigit H, Queenan AM, Anderson
GJ, Domenech-Sanchez A, Biddle
JW, Steward CD, Alberti S, Bush K,
and Tenover FC, Novel carbapenem-
hydrolyzing beta-lactamase, KPC-1,
from a carbapenem-resistant strain
of Klebsiella pneumoniae. Antimicrob
Agents Chemother, 2001. 45(4):
1151–61.
3592. Yigit H, Queenan AM, Rasheed
JK, Biddle JW, Domenech-Sanchez
A, Alberti S, Bush K, and Tenover
FC, Carbapenem-resistant strain of
1179
References
Klebsiella oxytoca harboring carbapen-
em-hydrolyzing beta-lactamase KPC-2.
Antimicrob Agents Chemother, 2003.
47(12): 3881–9.
3593. Yildirim G, Gungorduk K, Guven HZ,
Aslan H, Celikkol O, Sudolmus S, and
Ceylan Y, When should we perform pro-
phylactic antibiotics in elective cesar-
ean cases? Arch Gynecol Obstet, 2009.
280(1): 13–8.
3594. Yip PP, Chan WH, Yip KT, Que TL,
Kwong NS, and Ho CK, The use of
polymerase chain reaction assay ver-
sus conventional methods in detecting
neonatal chlamydial conjunctivitis. J
Pediatr Ophthalmol Strabismus, 2008.
45(4): 234–9.
3595. Yokoi S, Deguchi T, Ozawa T, Yasuda
M, Ito S, Kubota Y, Tamaki M, and
Maeda S, Threat to cefixime treatment
for gonorrhea. Emerg Infect Dis, 2007.
13(8): 1275–7.
3596. Yokoi S, Maeda S, Kubota Y, Tamaki
M, Mizutani K, Yasuda M, Ito S,
Nakano M, Ehara H, and Deguchi T,
The role of Mycoplasma genitalium and
Ureaplasma urealyticum biovar 2 in
postgonococcal urethritis. Clin Infect
Dis, 2007. 45(7): 866–71.
3597. Yong SM, Dublin N, Pickard R, Cody
DJ, Neal DE, and N’Dow J, Urinary
diversion and bladder reconstruction/
replacement using intestinal segments
for intractable incontinence or following
cystectomy. Cochrane Database Syst
Rev, 2003(1): CD003306.
3598. Yoo J, Yoo C, Cho Y, Park H, Oh HB,
and Seong WK, Antimicrobial resist-
ance patterns (1999–2002) and char-
acterization of ciprofloxacin-resistant
Neisseria gonorrhoeae in Korea. Sex
Transm Dis, 2004. 31(5): 305–10.
3599. Yosry A, Schistosomiasis and neoplasia.
Contrib Microbiol, 2006. 13: 81–100.
3600. Youd ME, Ferguson AR, and Corley
RB, Synergistic roles of IgM and com-
plement in antigen trapping and follic-
ular localization. Eur J Immunol, 2002.
32(8): 2328–37.
3601. Young GL and Jewell D, Topical treat-
ment for vaginal candidiasis (thrush)
in pregnancy. Cochrane Database Syst
Rev, 2001(4): CD000225.
1180
3602. Young GPH, Wahle GR, and Raz S,
Female urethral diverticulum, in
Female urology, Raz S, Editor. 1996,
Saunders: Philadelphia. p. 477–489.
3603. Yu JT, Tang WY, Lau KH, Chong LY,
and Lo KK, Asymptomatic urethral
infection in male sexually transmit-
ted disease clinic attendees. Int J STD
AIDS, 2008. 19(3): 155–8.
3604. Yucel S, Akkaya E, Guntekin E,
Kukul E, Akman S, Melikoglu M, and
Baykara M, Can alpha-blocker therapy
be an alternative to biofeedback for dys-
functional voiding and urinary reten-
tion? A prospective study. J Urol, 2005.
174(4 Pt 2): 1612–5; discussion 1615.
3605. Yudin MH, Hillier SL, Wiesenfeld HC,
Krohn MA, Amortegui AA, and Sweet
RL, Vaginal polymorphonuclear leuko-
cytes and bacterial vaginosis as mark-
ers for histologic endometritis among
women without symptoms of pelvic
inflammatory disease. Am J Obstet
Gynecol, 2003. 188(2): 318–23.
3606. Yumuk Z, Afacan G, Nicolas-Chanoine
MH, Sotto A, and Lavigne JP, Turkey:
a further country concerned by com-
munity-acquired Escherichia coli clone
O25-ST131 producing CTX-M-15. J
Antimicrob Chemother, 2008. 62(2):
284–8.
3607. Yuyun MF, Angwafo IF, Koulla-Shiro S,
and Zoung-Kanyi J, Urinary tract infec-
tions and genitourinary abnormalities
in Cameroonian men. Trop Med Int
Health, 2004. 9(4): 520–5.
3608. Zackrisson B, Ulleryd P, Aus G, Lilja H,
Sandberg T, and Hugosson J, Evolution
of free, complexed, and total serum
prostate-specific antigen and their
ratios during 1 year of follow-up of men
with febrile urinary tract infection.
Urology, 2003. 62(2): 278–81.
3609. Zafriri D, Ofek I, Adar R, Pocino M,
and Sharon N, Inhibitory activity of
Cranberry juice on adherence of type 1
and type P fimbriated Escherichia coli
to eucaryotic cells. Antimicrob Agents
Chemother, 1989. 33(1): 92–8.
3610. Zalata A, Hafez T, Van Hoecke MJ,
and Comhaire F, Evaluation of beta-
endorphin and interleukin-6 in semi-
nal plasma of patients with certain

andrological diseases. Hum Reprod,
1995. 10(12): 3161–5.
3611. Zaleskis R, Global epidemiology of
MDR-TB and the role of WHO in fight-
ing MDR-TB //Pres. on Interagency
Coordinating Committee – 4th meet-
ing focusing on TB. Prioritized Areas
of TB Control in Modern Social and
Epidemiological Enironment. 28 Nov
– 1 Dec 2006, Yekaterinburg, Russia
2006.
3612. Zamir G, Sakran W, Horowitz Y, Koren
A, and Miron D, Urinary tract infec-
tion: is there a need for routine renal
ultrasonography? Arch Dis Child, 2004.
89(5): 466–8.
3613. Zanetti G, Montanari E, and Trinchieri
A, SWL and urinary infection in
pretreatment non-infected patients.
Urology, ed. Giuliani L and Puppo P
1992, Bologna: Monduzzi Editore.
3614. Zanetti G, Seveso M, Montanari E,
Guarneri A, Del Nero A, Nespoli R, and
Trinchieri A, Renal stone fragments fol-
lowing shock wave lithotripsy. J Urol,
1997. 158(2): 352–5.
3615. Zarate G, Santos V, and Nader-Macias
ME, Protective Effect of Vaginal
Lactobacillus paracasei CRL 1289
against Urogenital Infection Produced
by Staphylococcus aureus in a Mouse
Animal Model. Infect Dis Obstet
Gynecol, 2007. 2007: 48358.
3616. Zarember KA and Godowski PJ, Tissue
expression of human Toll-like recep-
tors and differential regulation of
Toll-like receptor mRNAs in leukocytes
in response to microbes, their prod-
ucts, and cytokines. J Immunol, 2002.
168(2): 554–61.
3617. Zdziarski J, Svanborg C, Wullt B,
Hacker J, and Dobrindt U, Molecular
basis of commensalism in the urinary
tract: low virulence or virulence attenu-
ation? Infect Immun, 2008. 76(2):
695–703.
3618. Zelenitsky S, Ariano R, Harding G, and
Forrest A, Evaluating ciprofloxacin
dosing for Pseudomonas aeruginosa
infection by using clinical outcome-
based Monte Carlo simulations.
Antimicrob Agents Chemother, 2005.
49(10): 4009–14.
References
3619. Zhanel GG, Hisanaga TL, Laing NM,
DeCorby MR, Nichol KA, Palatnik LP,
Johnson J, Noreddin A, Harding GK,
Nicolle LE, and Hoban DJ, Antibiotic
resistance in outpatient urinary iso-
lates: final results from the North
American Urinary Tract Infection
Collaborative Alliance (NAUTICA).
Int J Antimicrob Agents, 2005. 26(5):
380–8.
3620. Zhanel GG, Hisanaga TL, Laing
NM, DeCorby MR, Nichol KA,
Weshnoweski B, Johnson J, Noreddin
A, Low DE, Karlowsky JA, and
Hoban DJ, Antibiotic resistance in
Escherichia coli outpatient urinary
isolates: final results from the North
American Urinary Tract Infection
Collaborative Alliance (NAUTICA).
Int J Antimicrob Agents, 2006. 27(6):
468–75.
3621. Zhang D, Zhang G, Hayden MS,
Greenblatt MB, Bussey C, Flavell RA,
and Ghosh S, A toll-like receptor that
prevents infection by uropathogenic
bacteria. Science, 2004. 303(5663):
1522–6.
3622. Zhang R, Zhou HW, Cai JC, and Chen
GX, Plasmid-mediated carbapenem-
hydrolysing beta-lactamase KPC-2 in
carbapenem-resistant Serratia marc-
escens isolates from Hangzhou, China.
J Antimicrob Chemother, 2007. 59(3):
574–6.
3623. Zhang W and McManus DP, Recent
advances in the immunology and
diagnosis of echinococcosis. FEMS
Immunol Med Microbiol, 2006. 47(1):
24–41.
3624. Zhang W, Li J, and McManus DP,
Concepts in immunology and diagnosis
of hydatid disease. Clin Microbiol Rev,
2003. 16(1): 18–36.
3625. Zhao X and Drlica K, A unified anti-
mutant dosing strategy. J Antimicrob
Chemother, 2008. 62(3): 434–6.
3626. Zhong S, Randhawa PS, Ikegaya
H, Chen Q, Zheng HY, Suzuki M,
Takeuchi T, Shibuya A, Kitamura T,
and Yogo Y, Distribution patterns of
BK polyomavirus (BKV) subtypes and
subgroups in American, European and
Asian populations suggest co-migration
1181
References
of BKV and the human race. J Gen
Virol, 2009. 90(Pt 1): 144–52.
3627. Zhou G, Mo WJ, Sebbel P, Min G,
Neubert TA, Glockshuber R, Wu XR,
Sun TT, and Kong XP, Uroplakin Ia is
the urothelial receptor for uropatho-
genic Escherichia coli: evidence from in
vitro FimH binding. J Cell Sci, 2001.
114(Pt 22): 4095–103.
3628. Zimakoff JD, Pontoppidan B, Larsen
SO, Poulsen KB, and Stickler DJ,
The management of urinary catheters:
compliance of practice in Danish hos-
pitals, nursing homes and home care
to national guidelines. Scand J Urol
Nephrol, 1995. 29(3): 299–309.
1182
3629. Zmerli S, Ayed M, Horchani A, Chami
I, El Ouakdi M, and Ben Slama MR,
Hydatid cyst of the kidney: diagnosis
and treatment. World J Surg, 2001.
25(1): 68–74.
3630. Zorc JJ, Kiddoo DA, and Shaw KN,
Diagnosis and management of pediatric
urinary tract infections. Clin Microbiol
Rev, 2005. 18(2): 417–22.
3631. zur Hausen H and de Villiers EM,
Human papillomaviruses. Annu Rev
Microbiol, 1994. 48: 427–47.
3632. Zvara P, Folsom JB, and Plante MK,
Minimally invasive therapies for
prostatitis. Curr Urol Rep, 2004. 5(4):
320–6.