Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

An update on the management of urinary tract

infections in the era of antimicrobial resistance

Mazen S Bader, Mark Loeb & Annie A Brooks

To cite this article: Mazen S Bader, Mark Loeb & Annie A Brooks (2016): An update on the
management of urinary tract infections in the era of antimicrobial resistance, Postgraduate
Medicine, DOI: 10.1080/00325481.2017.1246055

To link to this article: http://dx.doi.org/10.1080/00325481.2017.1246055

Accepted author version posted online: 07

Oct 2016.
Published online: 21 Oct 2016.

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POSTGRADUATE MEDICINE, 2017
http://dx.doi.org/10.1080/00325481.2017.1246055

CLINICAL FEATURE
REVIEW

An update on the management of urinary tract infections in the era of antimicrobial

resistance
Mazen S Badera, Mark Loebb and Annie A Brooksc
a
Department of Medicine, Juravinski Hospital and Cancer Centre, Hamilton, Ontario, Canada; bDepartments of Pathology & Molecular Medicine and
Clinical Epidemiology & Biostatistics, McMaster University Michael G DeGroote School of Medicine, Hamilton, Ontario, Canada; cDepartment of
Pharmacy, Hamilton Health Sciences, Juravinski hospital and Cancer Centre, Hamilton, Ontario, Canada

ABSTRACT ARTICLE HISTORY

Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growing Received 10 July 2016
concern due to limited therapeutic options. Gram-negative bacteria, specifically Enterobacteriaceae, Accepted 5 October 2016
are common causes of both community-acquired and hospital acquired UTIs. These organisms can Published online
21 October 2016
acquire genes that encode for multiple antibiotic resistance mechanisms, including extended-spectrum-
lactamases (ESBLs), AmpC- β -lactamase, and carbapenemases. The assessment of suspected UTI KEYWORDS
includes identification of characteristic symptoms or signs, urinalysis, dipstick or microscopic tests, Antibiotic resistance; cystitis;
and urine culture if indicated. UTIs are categorized according to location (upper versus lower urinary Enterobacteriaceae;
tract) and severity (uncomplicated versus complicated). Increasing rates of antibiotic resistance neces- Gram-negative bacteria;
sitate judicious use of antibiotics through the application of antimicrobial stewardship principles. pyelonephritis; urinary tract
Knowledge of the common causative pathogens of UTIs including local susceptibility patterns are infections
essential in determining appropriate empiric therapy. The recommended first-line empiric therapies
for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-day
course of nitrofurantion or a 3-g single dose of fosfomycin tromethamine. Second-line options include
fluoroquinolones and β-lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs due
to AmpC- β -lactamase-producing organisms include fosfomycin, nitrofurantion, fluoroquinolones,
cefepime, piperacillin–tazobactam and carbapenems. In addition, treatment options for UTIs due to
ESBLs–producing Enterobacteriaceae include nitrofurantion, fosfomycin, fluoroquinolones, cefoxitin,
piperacillin-tazobactam, carbapenems, ceftazidime-avibactam, ceftolozane-tazobactam, and aminogly-
cosides. Based on identification and susceptibility results, alternatives to carbapenems may be used to
treat mild-moderate UTIs caused by ESBL-producing Enterobacteriaceae. Ceftazidime-avibactam, colistin,
polymixin B, fosfomycin, aztreonam, aminoglycosides, and tigecycline are treatment options for UTIs
caused by carbapenem-resistant Enterobacteriaceae (CRE). Treatment options for UTIs caused by multi-
drug resistant (MDR)-Pseudomonas spp. include fluoroquinolones, ceftazidime, cefepime, piperacillin-
tazobactam, carbapenems, aminoglycosides, colistin, ceftazidime-avibactam, and ceftolozane-tazobac-
tam. The use of fluoroquinolones for empiric treatment of UTIs should be restricted due to increased
rates of resistance. Aminoglycosides, colistin, and tigecycline are considered alternatives in the setting
of MDR Gram-negative infections in patients with limited therapeutic options.

Introduction associated UTI (HAUTI), which include community-onset

health care-associated infections. Health care-acquired UTIs
Urinary tract infections (UTIs) are among the most common
represent 40% of all hospital-acquired UTIs [1].
bacterial infections managed by clinicians [1]. UTIs exert a
Gram-negative bacteria, specifically Enterobacteriaceae, are
considerable impact on economic and public health resources
common causes of both CAUTI and HAUTI [1]. Antibiotic resis-
and substantially affect the quality of life of those afflicted
tance among causative Gram-negative bacilli is increasing and
with recurrent infections [2]. It is estimated that 0.7% of
considered to be a challenge for clinicians since there are
ambulatory visits are attributed to UTIs, and each year 7
limited treatment options. Common examples of these organ-
million ambulatory care visits by females are due to UTIs
isms include AmpC β-lactamase- and extended-spectrum β-
[3,4]. UTIs are the fourth most common health care-associated
lactamases (ESBLs)-producing Enterobacteriaceae, carbape-
infection with a prevalence of 12.9%, and two-thirds are cathe-
nem-resistant Enterobacteriaceae (CRE), and multidrug-resis-
ter associated [5].
tant (MDR) Pseudomonas aeruginosa [7,8].
The clinical spectrums of UTIs include urethritis, cystitis,
Management of UTIs in the era of antimicrobial resistance
prostatitis, and pyelonephritis [6]. UTIs can also be stratified
requires a systematic approach to diagnose the type of infec-
as either community-associated UTI (CAUTI) or health care-
tion and to select the optimal dose, route, and duration of the

CONTACT Mazen S Bader msbader1@gmail.com Juravinski Hospital and Cancer Centre, Department of Medicine, 711 Concession Street, Hamilton, Ontario
L8V1C3, Canada
© 2016 Informa UK Limited, trading as Taylor & Francis Group
2 M. S. BADER ET AL.
antibiotic regimen. Unfortunately, standardized evidence-based
clinical management is often lacking in general practice [9].
When approaching a patient with a suspected UTI, consid-
eration should be given to the following essential elements.
Does the patient have a UTI?
Patients suspected of having UTIs should be initially evaluated
through history taking and physical examination to assess
signs or symptoms consistent with symptomatic UTI and to
guide the selection of adjunct diagnostic and therapeutic
strategies. Classic symptoms and signs of UTIs include fever,
acute dysuria, urinary urgency or frequency, hematuria, back
pain, suprapubic tenderness, or costovertebral angle pain or
tenderness. Laboratory tests confirming the diagnosis include
bacteriuria (≥100,000 CFU [colony forming unit]/ml) and
pyuria (≥10 WBC/hpf [white blood cells per high power
field]) [6,10,11]. Patients with uncomplicated cystitis usually
require dipstick urinalysis (UA) to support the diagnosis of
UTIs. Conversely, the combination of dysuria and frequency
or urgency without vaginal discharge or irritation increases the
likelihood of acute uncomplicated cystitis to >90% in females.
Therefore, these patients should be treated empirically with-
out further testing [12].
Urinary dipstick, used to detect the presence of leukocyte
esterase and nitrite, exhibits variable test characteristics
depending on the population studied and clinical presenta-
tion. This test has a high negative predictive value (90–100%)
in various patient populations including the elderly. Therefore,
a negative urinary dipstick for leukocyte esterase and nitrite
suggests that further evaluation for UTI is unnecessary, parti-
cularly if the pretest probability of UTIs is low [13]. However,
despite the excellent negative predictive value, a positive
urinary dipstick or UA result is nonspecific with subsequent
low positive predictive values [13]. Asymptomatic pyuria and
asymptomatic bacteriuria are highly prevalent (25–50%) in
elderly patients, particularly in female residents of long-term
care facilities (LTCFs) and patients with indwelling urinary
catheters [10,13,14]. Asymptomatic pyuria or bacteriuria in
the setting of nonspecific symptoms (e.g. fatigue, malaise,
worsening urinary frequency or urgency, incontinence, dizzi-
ness, and confusion) is a trigger for the inappropriate use of
diagnostic tests such as urine culture and inappropriate anti-
biotic use among elderly, commonly in residents of LTCFs
[15,16].
Vaginitis, sexually transmitted diseases (STDs), and pelvic
inflammatory disease can mimic symptoms of UTIs. In fact, a
recent study showed that approximately one-third of cases of
STDs was misdiagnosed as UTIs [17].
What type of UTI does the patient have?
UTIs can be classified according to the specific site of infection
and are often differentiated into upper and lower UTIs. These
include urethritis, cystitis, prostatitis (lower UTIs), and pyelone-
phritis (upper UTIs) [6,18]. Clinical presentation helps differ-
entiate between upper and lower UTIs. Fever in UTIs usually
represents the presence of tissue invasion and inflammation
such as pyelonephritis or prostatitis although it may occur
Table 1. Factors associated with complicated urinary tract infections.
Pregnancy
Diabetes mellitus
Renal failure
Immunocompromised conditions
Kidney transplantation
Infection with antibiotic-resistant pathogens
Hospital-acquired infection
Symptoms persisting ≥7 days prior to seeking medical care
Urinary tract obstruction (benign prostatic hypertrophy, stenosis, stone,
tumor, and hematoma)
Indwelling urethral catheter, stent, nephrostomy tube, or urinary diversion
Functional or anatomic abnormality of the urinary tract (e.g. neurogenic
bladder)
Recent urinary tract instrumentation
with lower UTIs [6]. Urine culture is not indicated in patients
with uncomplicated cystitis since it is not associated with
improved outcomes such symptom scores [19]. However,
urine cultures are indicated in patients with complicated UTIs
(cUTIs), recurrent UTIs, acute pyelonephritis, or in those at risk
of infection with antibiotic-resistant organisms [6,10,11]. Blood
cultures do not contribute to the improved management of
acute pyelonephritis without obtaining an appropriate urine
sample [20].
Does the patient have complicated or uncomplicated
UTI?
UTIs are usually classified as either complicated or uncompli-
cated infections, irrespective of the location and severity of
the infection [18]. An uncomplicated lower UTI is usually
defined as acute cystitis occurring in a healthy, premenopau-
sal, nonpregnant female with no known structural urological
abnormalities [6]. cUTIs are associated with an underlying
condition that increases the risk of recurrent infections or
treatment failure due to functional or anatomic abnormalities
of the urinary tract (Table 1). cUTIs have a greater risk of
morbidity and mortality when compared with uncomplicated
UTIs [18].
It is imperative to determine the severity of infection since
uncomplicated UTIs usually require fewer diagnostic tests and
can be treated with narrow-spectrum antimicrobial agents for
shorter durations. On the other hand, all patients with cUTIs
require urine culture in order to identify the causative patho-
gen due to the wide diversity of potential pathogens and risk
of antimicrobial resistance. Escherichia coli, Klebsiella pneumo-
niae, Enterococcus faecalis, Enterobacter spp., Proteus mirabilis,
Serratia marcescens, and P. aeruginosa are common causative
pathogens in the setting of cUTIs with an increase in relative
frequency of non-E. coli pathogens. Recurrent infection, instru-
mentation, and repeat courses of antimicrobial therapy
increase the risk of antibiotic-resistant organisms causing
cUTIs. [6,20].
Due to a low yield, routine blood cultures are not recom-
mended for all patients with cUTIs but in pyelonephritis [20].
What is the severity of UTI in this patient?
The clinical spectrum of UTIs can range from uncomplicated
cystitis to septic shock due to severe pyelonephritis. It is

essential to determine the severity of the infection in order to
guide the choice and route of empiric antibiotic therapy and
determine whether hospital admission is warranted. Severe
infections usually require treatment with broad-spectrum
intravenous empiric antibiotic therapy. Risk factors for severe
UTIs include urinary tract obstruction, hydronephrosis, muco-
sal trauma from indwelling catheters or urologic surgery in the
presence of bacteriuria, prolonged urologic surgery, infection
with certain antibiotic-resistant organism, hospital-acquired
infection, and liver cirrhosis [21–24].
Does the patient have risk factors for UTI with
antibiotic-resistant organisms?
Gram-negative bacteria, specifically Enterobacteriaceae, can
acquire genes to encode for multiple antibiotic resistance
mechanisms, such as AmpC β-lactamase, ESBLs, and carbape-
nemases [25]. Increasing resistance in causative Gram-negative
bacilli complicates selection of empirical antimicrobial agent.
Antimicrobial resistance is associated with inappropriate
empiric antibiotic therapy that can lead to poor clinical out-
comes including treatment failure, development of bactere-
mia, requirement for intravenous therapy, hospitalization, and
extended length of hospital stay [26–28].
Risk factors of UTIs due to antibiotic-resistant Gram-nega-
tive organisms include age older than 60 years, prior UTI
history, cUTIs, presence of a urinary catheter, chronic medical
conditions, recent hospitalizations or antibiotic treatment, and
recent travel [1,2,7,20].
E. coli is the most common organism isolated for CAUTI and
among the most common causes of HAUTI [1,20,29,30]. There
was a substantial increase in E. coli resistance to commonly
used antibiotics for the treatment of UTIs such as ciprofloxacin
(3.6–11.8%) and trimethoprim–sulfamethoxazole (TMP/SMX)
(17.2–22.2%) among outpatient females with UTIs in the per-
iod of 2003–2012 [29]. Furthermore, the resistance rate of E.
coli to ampicillin and cefazolin is high, approximately 40% in
this population [29,31].
AmpC β-lactamase is encoded by genes that are commonly
chromosomally mediated in bacteria (such as Enterobacter
cloacae) but can be mobilized by plasmids to other bacteria.
AmpC β-lactamase-producing Enterobacteriaceae typically
confer clinically relevant resistance to all penicillins, cephalos-
porins, and cephamycins and are not effectively inhibited by
clavulanate or tazobactam [32]. The exact prevalence of UTIs
due to AmpC β-lactamase-producing Enterobacteriaceae is
uncertain. Among the 323 non-ESBL-producing
Enterobacteriaceae identified in community-onset UTIs in
Taiwan, 50 isolates were phenotypically positive for AmpC. E.
coli was the most commonly isolated AmpC-producing organ-
ism (60%), followed by K. pneumoniae (8%), E. cloacae (6%),
and P. mirabilis (6%) [33]. Canadian studies demonstrated that
1.8–2.5% of urine isolates of E. coli were AmpC producers
[34,35], and risk factors include prior use of fluoroquinolones
and cephamycin [33].
Treatment options for UTIs due to AmpC β-lactamase-pro-
ducing Enterobacteriaceae include nitrofurantoin or fosfomycin
for cystitis and cefepime, piperacillin–tazobactam, fluoroqui-
nolones, and carbapenems for pyelonephritis [34,35].
POSTGRADUATE MEDICINE 3
ESBLs in Gram-negative bacteria have emerged as a major
global public health concern, and the rate is rapidly increasing.
They are commonly encountered in nosocomial-acquired
infections or in outbreak settings but are also prevalent in
the community, particularly in LTCFs [36–40]. ESBLs are
reported in other Gram-negative species (e. g. Klebsiella oxy-
toca and Proteus species) in addition to K. pneumonia and E.
coli. Genes that encode for ESBLs are usually found on large
plasmids accompanied by genetic determinants of resistance
against multiple classes of antibiotics, such as aminoglyco-
sides, sulfonamides, and fluoroquinolones [41].
Enterobacteriaceae producing CTX-M-type ESBLs (CTX-M-14
and CTX-M-15 enzymes) are linked to the dissemination of
‘high-risk clone’ sequence type (ST) 131. The H30 and H30Rx
subclones account for most ST131 isolates and for the associa-
tion of ST131 with fluoroquinolones resistance and ESBLs
production [36,42,43]. The prevalence of ESBLs among patho-
gens causing UTIs varies according to region, the patient
population, and risk factors. ESBL production was detected in
8.5% and 8.8% of E. coli and K. pneumoniae in North America
and in 17.6% and 38.9% in Europe, respectively [36]. Risk
factors for UTI caused by ESBL-producing organisms include
hospital-acquired infection, LTCF residence, diabetes, recur-
rent UTIs, and comorbidities [44]. Patients with infection due
to ESBL-producing organisms are more likely to receive inap-
propriate antibiotics to experience longer hospital stays and to
present with severe sepsis and septic shock [24,27].
Fosfomycin trometamol, nitrofurantoin, and pivmecillinam
are active against more than 90% of urinary isolates of ESBL-
producing organisms and are considered choices for the oral
treatment of lower UTIs (Table 2) [45–49]. Treatment options
for pyelonephritis caused by ESBL-producing organisms
include carbapenems, ceftazidime–avibactam, fosfomycin
(intravenous), cefoxitin, cefepime, temocillin, piperacillin–tazo-
bactam, ceftolozane–tazobactam, and aminoglycosides
[45,50–52].
Carbapenemases, such as K. pneumoniae carbapenemase
(KPC), Verona integron-encoded metallo-β-lactamase (VIM),
New Delhi metallo-β-lactamase (NDM), and oxacillin-hydrolyz-
ing (OXA)-48 types, are enzymes that neutralize carbapenems
in addition to penicillins and cephalosporins. KPC, most com-
mon in the USA, and NDM-1 are the most clinically relevant
enzymes in this class [53]. These enzymes are encountered in
Enterobacteriaceae species, particularly K. pneumonia and E.
coli, and less frequently in other Gram-negative organisms
such as P. aeruginosa, Acinetobacter baumannii, and S. marces-
cens [54]. CRE are often resistant to all β-lactam agents and
frequently exhibit various resistance mechanisms such as
AmpCs and ESBLs including genes conferring resistance to
multiple antimicrobial classes, further limiting treatment
options [54]. Although CRE infections are relatively infrequent
worldwide, they are more common in the United States since
emerging [53]. In a recent study, the incidence of CRE was 2.93
per 100,000 population in the US where most CRE cases were
isolated from a urinary source [55]. Rate varies from region to
region, and it is estimated to be 1.8–2.4% based on the US,
European, and Latin American data as reported in the SENTRY
study [56]. Risk factors for infection with CRE include prior
 4

Table 2. Treatment options for uncomplicated cystitis and pyelonephritis.

Dosing for
uncomplicated Dosing for uncomplicated
Anti-infective cystitis pyelonephritis Advantages Disadvantages Adverse effects Comments
Nitrofurantoin monohydrate 100 mg twice daily N/A Active against many common urinary No activity against S. marcescens, Nausea Not recommended for empiric
macrocrystals with food for pathogens such as Staphylococcus Morganella spp., P. mirabilis, P. Headache treatment for hospital-acquired
M. S. BADER ET AL.

5 days saprophyticus, Enterococci, E. coli, K. aeruginosa, and CRE Cough UTIs

pneumoniae, and AmpC β-lactamase Not recommended for CrCl of Dyspnea
and ESBL-producing Gram-negative <40 ml/min Rare side effects such as
organisms High failure rate for short-course acute allergic
High urine concentration therapy (3 days) pneumonitis, bone
Low rates of resistance Contraindicated for marrow suppression,
Low risk of Clostridium difficile pyelonephritis and hepatotoxicity
infection Hemolysis in patients with
Pregnancy category B glucose-6-phosphate
dehydrogenase
deficiency and
neuropathy in patients
with chronic kidney
disease
Trimethoprim– 160 mg/800 mg 160 mg/800 mg twice Active against S. saprophyticus, E. coli, No activity against Enterococci, P. Nausea Not recommended for empiric
sulfamethoxazole twice daily for daily for 7–14 days K. pneumoniae, and P. mirabilis aeruginosa, and CRE. Vomiting treatment of pyelonephritis
3 days (females) (definitive treatment) Definitive therapy for susceptible Increasing resistance to common Hypersensitivity reactions Avoid empiric use for cystitis if
OR for 7 days AmpC β-lactamase and ESBL- uropathogens such as E. coli such as fever, rash, resistance rate in the community
(males) producing Gram-negative organisms and AmpC β-lactamase and urticarial, and Stevens– is >20%
Short-course therapy ESBL-producing Gram- Johnson syndrome Avoid coadministration with
Indicated for both negative organisms Bone marrow suppression spironolactone, angiotensin-
uncomplicated cystitis and Not recommended in pregnancy Acute kidney injury converting enzyme inhibitors, or
uncomplicated pyelonephritis (avoid in first trimester and Hyperkalemia and angiotensin-receptor blockers due
High urine concentration last 6 weeks) hyponatremia to increased potential risk of
Low risk of C. difficile infection Potential drug–drug interactions: Hemolysis in patients with hyperkalemia and sudden death
warfarin, phenytoin, and glucose-6-phosphate
sulfonylureas dehydrogenase
Requires dose adjustment in deficiency
renal impairment
Trimethoprim 100 mg twice daily N/A Active against S. saprophyticus, E. coli, No activity against Enterococci, P. Nausea and vomiting Not recommended for empiric
or 200 mg once K. pneumoniae, and P. mirabilis aeruginosa, and CRE. Rash treatment of cystitis if resistance
daily for 3 days High urine concentration Increasing resistance to common Hyperkalemia and rate in the community is >20%
Low risk of C. difficile infection uropathogens such as E. coli, hyponatremia
AmpC β-lactamase, and ESBL- Bone marrow suppression
producing Gram-negative Megaloblastic anemia
organisms Methemoglobinemia
Not indicated for pyelonephritis Acute kidney injury
Drug–drug interaction: dapsone,
methotrexate, and phenytoin
Not recommended in first
trimester of pregnancy
Requires dose adjustment in
renal impairment
(Continued )
Table 2. (Continued).
Dosing for
uncomplicated Dosing for uncomplicated
Anti-infective cystitis pyelonephritis Advantages Disadvantages Adverse effects Comments
Fosfomycin tromethamine 3 g sachet as a N/A Active against many common urinary No activity against Morganella Diarrhea For cUTIs, administer 3 g once daily
single dose pathogens such as S. saprophyticus, spp., Acinetobacter spp., and P. Nausea for 3–5 days or every 48–72 h for
Enterococci, E. coli, K. pneumoniae, Aeruginosa Dyspepsia 3–5 doses (off-label use)
AmpC β-lactamase, and ESBL- Increasing resistance of ESBLs-K. Headache Not recommended for empiric
producing Gram-negative organisms pneumoniae and ESBLs 025b/ Vaginitis treatment of hospital-acquired
and CRE B2 E. coli strains Esophageal discomfort UTIs
Low rates of resistance Oral formulation contraindicated Transient elevation of liver
No cross-resistance with other for pyelonephritis due to low enzymes
antimicrobial classes plasma concentrations
High urine concentration Limited worldwide availability of
Good safety profile IV formulation
Improved compliance (single-dose Drug–drug interaction: antacids
therapy)
Oral formulation
Pregnancy category B
Low risk of C. difficile infection
Fluoroquinolones Ciprofloxacin: Ciprofloxacin 500 mg Active against S. saprophyticus, No activity against Enterococci Nausea For patients who cannot tolerate
250 mg twice twice daily for 7 days Enterobacteriaceae, and P. and CRE Vomiting oral therapy, give first dose IV
daily for 3 days (definitive treatment) aeruginosa Increasing resistance to common Diarrhea If local resistance for
(females) OR for OR 1 g extended- Definitive therapy for susceptible uropathogens such as E. coli, Headache fluoroquinolones exceeds 10%,
7 days (males) release daily for 7 days AmpC β-lactamase and ESBL- AmpC β-lactamase, ESBL- Drowsiness use other options for treatment of
OR (definitive treatment) producing Gram-negative organisms producing Gram-negative Insomnia pyelonephritis such as ceftriaxone
levofloxacin: OR Short-course therapy – lower cost, organisms, P. aeruginosa, and Dizziness or ampicillin–gentamycin
250 mg daily for levofloxacin 500 mg daily improved compliance, and less Acinetobacter spp. Photosensitivity/ combination
3 days (female) for 7 days (definitive adverse effects High risk of C. difficile infection phototoxicity Not recommended for empiric
OR for 7 days treatment) Short course for uncomplicated Pregnancy category C Vaginitis treatment of hospital-acquired
(male) OR pyelonephritis for definitive (contraindicated in pregnancy QTc prolongation UTIs
OR levofloxacin 750 mg daily treatment and breast-feeding) Seizures
norfloxacin for 5 days (definitive Indicated for both uncomplicated Drug–drug interactions: cations Tendinitis and tendon
400 mg twice treatment) cystitis and uncomplicated (antacids and vitamins), rupture
daily for 3 days pyelonephritis warfarin, and theophylline
(female) OR for High urine concentration (monitor)
7 days (male) Require dose adjustment in renal
impairment
Amoxicillin–clavulanate CrCl >30 ml/min CrCl >30 ml/min 875/ Active against S. saprophyticus, No activity against P. aeruginosa, Diarrhea Variation in the clavulanate
875/125 mg 125 mg twice daily Enterococci, E. coli, K. pneumoniae, Morganella morganii, Nausea concentration used by EUCAST
twice daily for 10–14 days and P. mirabilis Providencia stuartii, AmpC β- Vomiting and CLSI results in variable
5–7 days CrCl <30 ml/min 500 mg Definitive treatment for susceptible lactamase, and ESBL- Allergic reactions: rash, susceptibility testing results,
CrCl <30 ml/min twice daily for ESBL-producing Gram-negative producing Gram-negative urticarial, or particularly among ESBL-
500 mg twice 10–14 days organisms organisms and CRE anaphylactic reaction producing E. coli isolates
daily for Pregnancy category B Longer treatment courses Vaginitis Not recommended for empiric
5–7 days required Headaches treatment of acute pyelonephritis
High rates of relapse and failure and hospital-acquired UTIs
even when organism
susceptible
Low urine concentration
High risk of C. difficile infection
POSTGRADUATE MEDICINE

Requires dose adjustment in

renal impairment
(Continued )
5
 6
M. S. BADER ET AL.

Table 2. (Continued).
Dosing for
uncomplicated Dosing for uncomplicated
Anti-infective cystitis pyelonephritis Advantages Disadvantages Adverse effects Comments
Ampicillin (IV) Only if unable to Ampicillin IV 1 to 2 g Active against S. saprophyticus, E. No activity against K. Diarrhea Not recommended for empiric
Amoxicillin tolerate oral every 6 h with faecalis, E. coli, and P. mirabilis pneumoniae, P. aeruginosa, M. Nausea treatment of either cystitis or
formulation gentamicin 5 mg/kg Pregnancy category B morganii (%), P. stuartii, AmpC Vomiting pyelonephritis
500 mg every 8 h every 24 h for β-lactamase, and ESBL- Allergic reactions: rash,
for 5–7 days 10–14 days producing Gram-negative urticarial, or
organisms and CRE anaphylactic reaction
Generally inferior to Vaginitis
fluoroquinolones Headaches
High rate of resistance among S.
saprophyticus
Low urine concentration
High risk of C. difficile infection
Requires dose adjustment in
renal impairment
Ceftriaxone N/A 1 to 2 g IV every 24 h for Active against E. coli, K. pneumoniae, P. No activity against Enterococci, P. Diarrhea
7–14 days mirabilis, Enterobacter, Serratia, aeruginosa, AmpC β- Thrombocytopenia,
Citrobacter, Morganella spp., and P. lactamase, and ESBL- thrombocytosis, and
stuartii producing Gram-negative leukopenia
For empiric use of pyelonephritis organisms and CRE Biliary pseudolithiasis
No dose adjustment required in renal Low urine concentration Risk of cross-reactivity in
dysfunction High risk of C. difficile infection patients with beta-
Administered once daily lactam allergy
Pregnancy category B
N/A: not applicable; ESBLs: extended-spectrum β-lactamases; CRE: carbapenem-resistant Enterobacteriaceae; CrCl: creatinine clearance; UTIs: urinary tract infections; cUTIs: complicated UTIs; IV: intravenous; EUCAST: the
European Committee on Antimicrobial Susceptibility Testing; CLSI: clinical and laboratory standards institute.

hospitalizations, indwelling devices, prolonged intensive care
unit (ICU) stay, surgery or invasive procedures, and prior car-
bapenems exposure [55,57–59]. Infections with CRE are asso-
ciated with higher mortality rates than those for infections
caused by carbapenem-susceptible organisms but not specifi-
cally in patients with UTIs [60,61].
Limited treatment options for UTIs due to CRE include
ceftazidime–avibactam, carbapenems, colistin, polymyxin B,
aztreonam, aminoglycosides, fosfomycin, and tigecycline
[62,63]. Despite in vitro resistance, high-dose meropenem
may be an option against infections caused by CRE, particu-
larly OXA-48 carbapenemases and in settings where the mini-
mum inhibitory concentration (MIC) for the CRE pathogen is
≤8 mg/l [64]. Synergy with combination treatment for CRE has
been an area with emerging data although clear guidance is
limited.
Combination therapy may be considered for severely ill
patients [65]. Combination of ertapenem-containing double-
carbapenem therapy was associated with 67% success in
treating UTIs due to carbapenem-resistant K. pneumo-
niae [66].
P. aeruginosa also represents a major cause of UTIs and
often exhibit decreased susceptibility to various antimicrobial
agents. MDR Pseudomonas spp.is defined as an isolate that is
nonsusceptible to at least one agent in three antimicrobial
classes that have activity against Pseudomonas spp. [25]. It is
usually associated with health-care infections where it is the
second most common isolated pathogens in catheter-asso-
ciated UTIs (CAUTIs). MDR Pseudomonas spp. account for 14%
of cUTIs, and the resistance rates for fluoroquinolones, carba-
penem, piperacillin–tazobactam, and aminoglycoside were
34%, 21%, 17%, and 11%, respectively [67]. Among a total of
7272 unique patient clinical urinary isolates collected from
patients with UTIs in 71 US medical centers in a period of
2012–2014 as part of the International Network for Optimal
Resistance Monitoring program, 6% were due to Pseudomonas
spp. The resistance rate of Pseudomonas spp. to ceftazidime,
levofloxacin, piperacillin–tazobactam, meropenem, and cefta-
zidime–avibactam was 8.1%, 26.9%, 6.3%, 13.6%, and 2.3%,
respectively. The rates increase significantly once the isolate
develops resistance to one of these antibiotics except for
ceftazidime–avibactam [63]. The Study for Monitoring
Antimicrobial Resistance Trends study which has monitored
the susceptibilities of Gram-negative bacilli from inpatient UTIs
since late 2009 in 24 sites in the USA showed that P. aerugi-
nosa accounted for 9.6% of the isolates. The susceptibility rate
of P. aeruginosa to cefepime, imipenem, ciprofloxacin, and
piperacillin–tazobactam was 67.6%, 68%, 52.5%, and 74%,
respectively [68].
Treatment options of UTIs due to MDR-Pseudomonas spp.
include aminoglycosides (amikacin, gentamycin, and tobra-
mycin), fluoroquinolones (ciprofloxacin and levofloxacin),
antipseudomonal cephalosporins (ceftazidime and cefe-
pime), antipseudomonal penicillins (piperacillin–tazobactam),
carbapenems (meropenem, imipenem, and doripenem),
colistin, aztreonam, ceftazidime–avibactam, and ceftolo-
zane–tazobactam [63,67,68]. Ceftolozane–tazobactam and
ceftazidime–avibactam are therapeutic options for UTIs due
POSTGRADUATE MEDICINE 7
to meropenem-, piperacillin–tazobactam-, and ceftazidime-
resistant Pseudomonas spp. [63,69].
Where should the patient be treated?
The majority of uncomplicated UTIs including pyelonephritis
can be treated in the outpatient setting. However, patients
with pyelonephritis or cUTIs who are moderately–severely ill
are not responding to outpatient therapy and have concomi-
tant unstable comorbid conditions and should be managed in
the hospital setting [6,10].
What are the indications for imaging?
Imaging is useful in diagnosing the underlying structural
causes of cUTIs including calculi, tumor, abscesses, and
infected cysts. Imaging at initial evaluation of UTIs is typically
not necessary unless one suspects a concomitant emergent
condition requiring prompt intervention, such as an obstruc-
tive uropathy by a renal stone or tumor. Other indications for
imaging include persistent fever for 72 h after appropriate
antibiotic therapy, rapid recurrence after antibiotic treatment,
and in diabetics who have a higher incidence of complications
(e.g. emphysematous pyelonephritis which may require
immediate nephrectomy and obstruction from necrotic renal
papillae that are sloughed into the collecting system and
obstruct the ureter). Imaging with kidney and bladder ultra-
sound or a non-contrast computed tomography scan of the
abdomen and pelvis may be useful for these indications [70].
Treatment
The management of uncomplicated cystitis includes confirm-
ing the diagnosis with urinary dipstick or UA if required,
initiating narrow-spectrum antibiotics, and then assessing
response to empiric therapy (Table 2). The management of
cUTIs and acute pyelonephritis in general includes obtaining
urine culture, initiating broad-spectrum antibiotic, and de-
escalating the empiric antibiotic selection once susceptibility-
testing results are available (Table 2) [6,10].
Key considerations in the selection of empiric antibiotic
therapy for UTIs include the bacterial spectrum, local resis-
tance patterns, comorbid conditions (e.g. renal impairment
and liver impairment), history of drug allergy, prior antibiotic
exposure, antibiotic safety profile, and urinary concentrations
of antibiotics [6,10]. The most frequently isolated pathogens
from outpatients with UTIs include E. coli (64.9%), K. pneumo-
niae (10.1%), P. mirabilis (5.0%), E. faecalis (4.1%), and P. aeru-
ginosa (2.7%) [29,71]. The most frequently isolated pathogens
from inpatients with UTIs or cUTIs are E. coli (48.9%),
Enterococcus spp. (18%), K. pneumoniae (14.5%), P. aeruginosa
(9.6%), P. mirabilis (6.4%), E. cloacae (4.6%), K. oxytoca (2.5%),
and others such as Citrobacter freundii, Citrobacter koseri,
Enterobacter aerogenes, M. morganii, and S. marcescens
[20,68,71].
Assessment of a patient’s previous urinary pathogen and
susceptibility profile is essential in selecting appropriate
empiric antibiotic therapy. Prior microbiologic data improved
8 M. S. BADER ET AL.
the rate of accuracy of the empiric treatment against the
pathogen for UTIs from 32% to 76% [72].
Understanding the local susceptibility patterns for common
Gram-negative pathogens is important to guide empiric anti-
biotic therapy for UTIs [6,10,73].
Clinicians should strive to streamline empiric antibiotic
therapy once culture and susceptibility profiles are available.
Selective pressure exerted by broad-spectrum antibiotics plays
a crucial role in the emergence of antibiotic-resistant bac-
teria [74].
Without treatment, 25–42% of uncomplicated acute cystitis
cases in females will resolve spontaneously. In fact, in the
absence of effective treatment, only approximately 2% of
uncomplicated acute cystitis will progress to pyelonephritis.
Thus, delaying antibiotic treatment while evaluating sympto-
matic lower UTIs generally does not lead to adverse outcomes
[75–77].
Nitrofurantoin
Nitrofurantoin remains a reliable first-line agent for the empiri-
cal treatment of acute uncomplicated cystitis [6,31,78]. E. coli
resistance to nitrofurantoin among outpatient adult females
with UTIs is low (0.9%) and have remained unchanged in the
period of 2003–2012 in the US [29]. There is a growing con-
cern of increasing resistance of ESBL-producing organisms
against nitrofurantoin, particularly in hospital-acquired infec-
tions. In Canada, the rate of susceptibility of urinary isolates of
ESBLs-E. coli to nitrofurantoin has decreased from 91% to 83%
in the period of 2007–2013 [35]. There is a high resistance rate
to nitrofurantoin (20–30%) among E. cloacae, E. aerogenes, K.
pneumoniae, and Serratia spp. [29,71]. Risk factors of resistance
to nitrofurantoin include male gender, hospital-acquired infec-
tion, resistant to other oral antibiotics including ciprofloxacin,
and ESBL-producing organisms [29,35,79]. Other relevant
information is summarized in Table 2 [6,80–82].
Fosfomycin
It is available in oral (fosfomycin tromethamine) and intrave-
nous (disodium fosfomycin) formulations, which are not
widely available except in a few countries [83]. Fosfomycin is
recommended as first-line definitive treatment for acute
uncomplicated cystitis in females as a single oral dose of
fosfomycin trometamol 3 g (Table 2) [6]. The susceptibility of
uropathogens to fosfomycin has remained relatively stable
over time [84]. About 99.4% of 868 urinary isolates of E. coli
obtained by clinical laboratories across Canada from 2010 to
2013 were fosfomycin susceptible [35]. It is a valuable oral
option for treatment of UTIs due to MDR pathogens such as
ESBL-producing Enterobacteriaceae in both community and
health-care settings [85]. It is the most active agent in hospi-
talized patients or in patients presenting to the emergency
department with UTIs due to MDR pathogens where 94.5% of
organisms including ESBLs are susceptible [8]. In addition, 95%
and 97% of ESBLs- and AmpC-producing E. coli isolates,
respectively, obtained by clinical laboratories across Canada
from 2007 to 2013 were susceptible [35]. Fosfomycin tro-
methamine is as effective as and less costly than carbapenems
for the treatment of cUTIs caused by ESBL-producing
Enterobacteriaceae, particularly ESBLs-E. coli [86,87].
Although there is still a low rate of resistance of uropatho-
gens to fosfomycin worldwide, there is a growing concern
with resistance, particularly to ESBLs-K. pneumonia, hospital-
acquired strains, and certain strains of ESBLs-E. coli. The resis-
tance rate to fosfomycin was 19.9% among 204 MDR Gram-
negative uropathogens collected from January 2010 to June
2013 in the Boston area where 32% of ESBL-Klebsiella spp.
uropathogens were resistant to fosfomycin [88]. Fosfomycin
resistance varies according to ESBL type where CTX-M-15 and
O25b/phylogroup B2 isolates are associated with fosfomycin-
resistant ESBL-E. coli [89].
Trimethoprim–sulfamethoxazole
Unfortunately, TMP/SMX is no longer recommended as first-
line empiric therapy for outpatients with uncomplicated cysti-
tis, cUTIs, and acute pyelonephritis due to the high rate of
resistance in several communities [6,20]. E. coli resistance to
TMP/SMX increased significantly from 17.2% to 22.2% among
outpatient adult females in the period of 2003–2012 in the US
[29]. In regions where TMP–SMX resistance is lower than 20%,
TMP–SMX is not a reliable empiric treatment option for UTIs in
patients with recent exposure to either TMP–SMX or ciproflox-
acin, in patients with prior UTIs with ESBL-producing E. coli or
in those who have traveled recently to an area with high rates
of TMP–SMX resistance [20,31,35]. TMP-SMX is not recom-
mended as empiric treatment option of UTIs caused by
ESBL-E. coli or K. pneumonia and AmpC β-lactamase-producing
E. coli due to high levels of resistance, >66% and 35–40%,
respectively [20,35,89].
However, TMP–SMX can be used as definitive therapy if the
isolated organism is susceptible [6]. Other information is sum-
marized in Table 2 [90,91].
Fluoroquinolones
Fluoroquinolones (norfloxacin, ciprofloxacin, and levofloxacin)
are second-line options for uncomplicated cystitis and one of
the treatment options for cUTIs and pyelonephritis when the
overall resistance rate is less than 10% (Table 2) [6,10].
Fluoroquinolone resistance among urinary pathogens is on
the rise in both community and hospital settings. Resistance
of E. coli to ciprofloxacin among outpatient adult females from
the US increased from 3.6% to 11.8% in the period of
2003–2012 [29]. There is a high resistance rate of E. coli
(34.5%) and P. aeruginosa (34%) to fluoroquinolones among
hospitalized patients with UTIs [92,93]. Furthermore, these
agents are not recommended for empiric treatment of UTIs
due to ESBL-producing Enterobacteriaceae. Only 7% and 18%
of ESBL-E. coli and ESBL-K. pneumonia, respectively, are sus-
ceptible to ciprofloxacin among hospitalized patients with
UTIs in North America [36,68]. Infection with ESBL-producing
organism particularly CTX-M-15 strain, urinary catheterization,
recent hospitalization, hospital-acquired infection, residents of
LTCFs, elderly patients, male gender, previous UTI, previous
exposure to TMP–SMX, metronidazole, cephalosporins, and

fluoroquinolones are risk factors associated with increased
fluoroquinolones resistance [8,31,71,94–97].
Cephalosporins
Ceftriaxone is a reasonable empiric treatment option for cUTIs
and acute pyelonephritis since the majority of urinary patho-
gens are susceptible (Table 2) [6,10]. For example, 89%, 92%,
and 96% of E. coli, K. pneumoniae, and P. mirabilis isolated
from hospitalized patients with UTIs in North America were
susceptible to ceftriaxone [36]. However, a high rate of resis-
tance to ceftriaxone has been reported among AmpC β-lacta-
mase- and ESBL-producing organisms and in patients from
LTCFs [68,92]. Therefore, ceftriaxone should be used with cau-
tion as empiric treatment of HAUTIs and should be avoided in
patients with pyelonephritis who are critically ill or at risk of
ESBLs, Pseudomonas spp., or other resistant organisms.
Ceftazidime has similar antibacterial activity to ceftriaxone
in addition to activity against Pseudomonas spp. (Table 3) and
is considered a reasonable empiric treatment option for cUTIs
and acute pyelonephritis [36,63,68,71].
Cefepime has similar antibacterial activity to ceftazidime
(Table 3). Cefepime is relatively stable to AmpC hydrolysis,
and 96.6% AmpC β-lactamase-producing E. coli are susceptible
to cefepime; therefore, it is an option for treating cUTIs and
pyelonephritis caused by these organisms [33,34,98,99]. A high
dose of cefepime (2 g every 12 h or 1 to 2 g every 8 h) is
recommended for organisms with MIC 4–8 μg/ml in order to
maximize the pharmacodynamics profile [100]. Up to 53% of
ESBL-E. coli and 58% ESBLs-K. pneumonia are susceptible to
cefepime; however, this agent should not be used for the
treatment of ESBL infections, particularly in critically ill patients
or when MICs >2 μg/ml [34]. Cefepime is rapidly hydrolyzed
by ESBLs such as CTX-M-10 and TEM-10 [101,102].
The Food and Drug Administration (FDA) has approved the
ceftazidime–avibactam combination for treatment of cUTIs,
including pyelonephritis, in patients with limited or no alter-
native treatment options (Table 3). Avibactam is a novel
bridged diazabicyclooctane, a semisynthetic, non-β-lactam, β-
lactamase inhibitor that is active against Ambler class A (e.g.
SHV, TEM, CTX-M, and KPC), class C (e.g. AmpC, FOX, CMY-2,
and AAC-1), and some class D (e.g. OXA-48) serine β-lacta-
mases. Therefore, avibactam improves the antimicrobial activ-
ity of ceftazidime against AmpC β-lactamases, ESBL-producing
Enterobacteriaceae, ceftazidime-resistant E. cloacae, KPC-pro-
ducing K. pneumonia, and MDR-P. aeruginosa [39,63,103–105].
A Phase II, prospective, randomized, double-blind trial that
included 135 patients with cUTIs (63% had pyelonephritis)
caused by a Gram-negative pathogen (mainly E. coli, 93%)
demonstrated a favorable microbiological response in 70.4%
(19/27) of patients treated with ceftazidime–avibactam in
comparison with 71.4% (25/35) treated with imipenem (differ-
ence of −1.1%, 95% confidence interval [CI]: −27.2% to 25%)
[106]. In a subgroup analysis, the efficacy of ceftazidime–avi-
bactam (72.7%, 93.8%) and imipenem (61.5%, 90.9%) was less
for ESBL-producing Enterobacteriaceae than non-ESBL-produ-
cing Enterobacteriaceae. The clinical response for both ceftazi-
dime–avibactam and imipenem was lower in cUTIs due to
POSTGRADUATE MEDICINE 9
ST131-like E. coli isolate (75%, 66.7%) than non-ST131-like
isolate (93.8% versus 86.7%, respectively) [107].
REPRISE (Ceftazidime-Avibactam for the Treatment of
Infections Due to Ceftazidime Resistant Pathogens) is an inter-
national, randomized, open-label, Phase III trial that recruited
patients with cUTIs and complicated intra-abdominal infection
due to ceftazidime-resistant Enterobacteriaceae and P. aerugi-
nosa from hospitals across 16 countries worldwide. It showed
that the clinical cure at the test-of-cure visit, 7–10 days after
last infusion of study therapy, was similar between ceftazi-
dime–avibactam and the best available therapy, carbapenem,
in patients with cUTIs [108].
Ceftolozane–tazobactam is a novel cephalosporin com-
bined with a β-lactamase inhibitor, and it has potent in vitro
activity against MDR-P. aeruginosa and other common Gram-
negative pathogens, including most ESBL-producing
Enterobacteriaceae spp. (Table 3) [69,109]. In Phase III, rando-
mized, multicenter, double-blind studies, 1083 adult hospita-
lized patients with either pyelonephritis, 82% of study
patients, or cUTIs were randomly to receive either ceftolo-
zane–tazobactam 1.5 g every 8 h (n = 543) or levofloxacin
750 mg daily (n = 540) for 7 days. Ceftolozane–tazobactam
demonstrated improved overall cure rate compared to high-
dose levofloxacin (76.9% of 398 vs. 68.4% of 402, respectively;
95% CI: 2.3–14.6) [110]. In a post hoc analysis, ceftolozane/
tazobactam demonstrated significantly higher composite cure
rates than levofloxacin in UTIs due to levofloxacin-resistant
organisms (60.0% vs. 39.3%) and ESBL-producing uropatho-
gens (58.3% of patients vs. 34.9%). In patients with levoflox-
acin-resistant P. aeruginosa, eradication was achieved in 100%
who received ceftolozane/tazobactam and 37.5% who
received levofloxacin (95% CI for the treatment difference,
22.1–86.3%) [111].
β-Lactam and β-lactamase inhibitor
Amoxicillin and ampicillin should be avoided as empiric treat-
ment for UTIs; however, these agents are effective as definitive
therapy if the pathogen proves susceptible (Table 2) [6]. The
resistance rate of E. coli against ampicillin was 41% in out-
patient adult females with uncomplicated cystitis [29]. The
percentage of resistance of E. coli, K. pneumonia, and P. mir-
abilis to amoxicillin–clavulanate was 3.9%, 3.1%, and 0.8%,
respectively [29]. Although amoxicillin–clavulanate is consid-
ered a second-line agent for UTIs, the increasing prevalence of
E. coli resistance to TMP–SMX and fluoroquinolones may be
driving increased reliance on this agent for the management
of cystitis (Table 2). In 2014, the European Committee on
Antimicrobial Susceptibility Testing introduced a urinary
amoxicillin–clavulanate susceptible breakpoint of ≤32 µg/ml
for uncomplicated UTI, which may explain high failure rates of
amoxicillin–clavulanate compared to ciprofloxacin for the
treatment of acute uncomplicated cystitis [112,113].
Piperacillin–tazobactam is a broad-spectrum antibiotic that
has activity against Enterobacteriaceae and Pseudomonas spp.
[34,36,63,68,69,71] and is one of the empiric treatment options
for moderate–severe cUTIs and HAUTIs (Table 3) [6,10].
The role of β-lactam/β-lactamase inhibitors (BLBLIs) (amox-
icillin–clavulanic acid, piperacillin–tazobactam, ampicillin–
 10

Table 3. Drugs for treatment of urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative organisms.
Anti-infective Dosing Advantages Disadvantages Adverse effects Comments
Ceftazidime 1 to 2 g IV every 8 h Active against E. coli, K. pneumoniae, P. mirabilis, Proteus Lacks activity against Enterococci and CRE Seizures Avoid in patients with history of
vulgaris, Enterobacter, Serratia, Citrobacter, Morganella spp., High resistance rate of AmpC β- Encephalopathy cephalosporin-associated
P. stuartii, and P. aeruginosa including some MDR lactamase and ESBL-producing Gram- Prolonged prothrombin hemolytic anemia
Pseudomonas strains negative organisms and A. baumannii time
High urine concentration Increasing resistance of P. aeruginosa Local infusion-related
Pregnancy category B Not indicated UTI due to S. saprophyticus effects
Risk of cross-reactivity with penicillins Nausea
M. S. BADER ET AL.

High risk of C. difficile infection Vomiting

Requires dose adjustment in renal Diarrhea
impairment
Sodium content: 54 mg/g
Cefepime 1 to 2 g IV every 8 h or 2 g IV Active against many common urinary pathogens including S. It has no activity against Enterococci and Hypersensitivity For UTIs due to organisms with an
every 12 h saprophyticus, E. coli, K. pneumoniae, AmpC β-lactamase- CRE (except OXA-lactamases such as Encephalopathy MIC range of 4–8 μg/ml, a higher
producing Gram-negative organisms, and P. aeruginosa OXA-48, OXA-181) associated with doses may be required (2 g every
High urine concentration High resistance rate of ESBL-producing higher doses in 12 h or 1 to 2 g every 8 h)
Pregnancy category B Gram-negative organisms and A. setting of renal Avoid in patients with history of
baumannii dysfunction cephalosporin-associated
Increasing resistance of P. aeruginosa Rash hemolytic anemia
Risk of cross-reactivity with penicillins Diarrhea
High risk of C. difficile infection Nausea
Requires dose adjustment in renal Vomiting
impairment
Ceftazidime– 2.5 g IV every 8 h Activity similar to ceftazidime in addition to activity against Lacks activity against Enterococci, class B
Seizures Avoid in patients with history of
avibactam AmpC β-lactamase and ESBL-producing Gram-negative metallo-β-lactamases (e.g. NDM, VIM,
Myoclonia cephalosporin-associated
organisms, CRE, and MDR-P. aeruginosa IMP, VEB, and PER) and A. baumanniiNausea hemolytic anemia
Approved for cUTIs and pyelonephritis Risk of cross-reactivity with penicillins
Constipation
High urine concentration Requires dose adjustment in renal Vomiting
Pregnancy category B impairment Elevated liver enzymes
Risk of C. difficile infection Dizziness
Limited data for the use in the elderly
Headache
population Hypertension
Sodium content: 146 mg per 2.5 g Insomnia
Cough
Ceftolozane– 1.5 g IV every 8 h Active against common urinary pathogens such as E. coli, K. Lacks activity against Enterococci and CRE Nausea Avoid in patients with history of
tazobactam pneumoniae, AmpC β-lactamase and ESBL-producing Gram- Reduced efficacy in patients with Diarrhea cephalosporin-associated
negative organisms, and MDR-P. aeruginosa moderate renal impairment Headaches hemolytic anemia
Approved for treatment of cUTIs and pyelonephritis Risk of cross-reactivity with penicillins Pyrexia
High urine concentration Requires dose adjustment in renal
Pregnancy category B impairment
Risk of C. difficile infection
Piperacillin– 3.375 g IV every 6 h or 4.5 g Active against common urinary pathogens such as S. Lacks activity against most ESBL- Rash Not indicated for empiric treatment
tazobactam every 8 h saprophyticus, Enterococci, E. coli, K. pneumoniae, AmpC β- producing Gram-negative organisms Nausea of UTIs in patients at risk of ESBL-
lactamase producing Gram-negative organisms, ESBLs-E. and CRE Diarrhea producing Gram-negative
coli, and MDR-P. aeruginosa Increasing resistance rates for P. Neutropenia organisms
Indicated for both cUTIs and pyelonephritis aeruginosa Hypokalemia Continuous infusion may increase
High urine concentration Requires dose adjustment in renal Prolonged prothrombin activity through optimizing
Pregnancy category B impairment time (specifically in pharmacodynamics
Moderate risk of C. difficile infection renal failure)
Drug–drug interaction: reduces
elimination of methotrexate
Sodium 64 mg/g of piperacillin
(Continued )
Table 3. (Continued).
Anti-infective Dosing Advantages Disadvantages Adverse effects Comments
Carbapenems Ertapenem 1 g IV daily Active against common urinary pathogens such as S. Lacks activity against CRE and E. faecium Seizures Carbapenems are considered first-
Meropenem 500 mg every saprophyticus, Enterococci, E. coli, K. pneumoniae, AmpC β- Ertapenem has no activity against Diarrhea line options for serious systemic
6 h up to 1 g IV every 8 h lactamase, ESBL-producing Gram-negative organisms, P. Enterococci, P. aeruginosa, and A. Nausea infections caused by ESBL-
Doripenem 500 mg IV every aeruginosa, and A. baumannii baumannii Rash producing Gram-negative
8h Indicated for cUTIs and pyelonephritis Increasing resistance rates of ESBL- Headache organisms
Imipenem/cilastatin 500 mg High urinary concentration producing Gram-negative organisms Hypokalemia Combination therapy (dual
IV every 6 h Once-daily dosing for ertapenem (particularly K. pneumonia and P. Elevated liver enzymes carbapenem regimen) may exert
Low risk of C. difficile infection mirabilis), P. aeruginosa, effect against CRE
Pregnancy category B (meropenem, ertapenem, and and A. baumannii Continuous infusion may increase
doripenem) Require dose adjustment in renal activity through optimizing
impairment pharmacodynamics
Risk of cross-reactivity with penicillins
Pregnancy category C for imipenem
Aminoglycosides Gentamicin 5 mg/kg IV once Active against common urinary pathogens such as E. coli, K. Lacks activity against S. saprophyticus, Nephrotoxicity Dosing based on ideal body weight
daily pneumoniae, AmpC β-lactamase, ESBL-producing Gram- Enterococci Vestibulocochlear Monitor trough levels
Tobramycin 5 mg/kg IV once negative organisms, MDR-P. aeruginosa, CRE, and A. Increasing resistance rates of ESBL- toxicity Amikacin is preferred over
daily baumannii producing Gram-negative organisms, Neurotoxicity gentamicin when used for empiric
Amikacin 15 mg/kg IV once Indicated for cUTIs and pyelonephritis P. aeruginosa, Edema treatment due to antibiotic-
daily High urine concentration and A. baumannii resistant Gram-negative
Once-daily dosing Require dose adjustment in renal organisms such ESBL-producing
Low risk of C. difficile infection impairment Enterobacteriaceae or MDR-P.
Increased risk of nephrotoxicity with aeruginosa
concomitant nephrotoxins Combination therapy is
Pregnancy category D recommended (e.g. with
ampicillin) when used as empiric
treatment
Monotherapy is acceptable if used as
definitive therapy
Polymixins Polymixin B 15,000–25,000 Active against common urinary pathogens such as E. coli, K. Lacks activity against S. saprophyticus, Nephrotoxicity Dosing is based on ideal body
Units/kg/day IV every pneumoniae, AmpC β-lactamase, ESBL-producing Gram- Enterococci, Proteus spp., Providencia Neurotoxicity weight
q12 h (maximum daily negative organisms, MDR-P. aeruginosa, CRE, and A. spp., S. marcescens, and M. morganii Neuromuscular Colistin (polymixin E) is preferred
dose 2 million units) baumannii Colistin resistance is emerging in A. blockade over polymixin B because of its
Polymixin E (colistin) 2.5– Bladder irrigation may be an option for those who cannot baumannii and K. pneumonia, MDR-P. Respiratory arrest higher urine concentration
5 mg CBA/kg/day in two to tolerate intravenous aeruginosa, and E. coli
four divided doses Low resistance rates Increased failure rate with monotherapy,
High urine concentration for polymixin E particularly in patients with
Low risk of C. difficile infection bacteremia
Low urine concentration for polymixin B
These agents exhibit a narrow
therapeutic window.
Require dose adjustment in renal
impairment
Safety in pregnancy has not been
established for polymixin B
Polymixin E is pregnancy category C
MDR: multidrug resistant; ESBLs: extended-spectrum β-lactamases; CRE: carbapenem-resistant Enterobacteriaceae; IV: intravenous; CBA: colistin base activity; cUTIs: complicated UTIs; NDM: New Delhi metallo-β-lactamase; q 12
POSTGRADUATE MEDICINE

hours: every 12 hours; MIC: minimal inhibitory concentration.

11
12 M. S. BADER ET AL.
sulbactam, cefoperazone–sulbactam, and ticarcillin–clavulanic
acid) in the treatment of infections caused by ESBL producers
is controversial [114–117]. In vitro activity of amoxicillin–clavu-
lanate against ESBL-E. coli isolates obtained by clinical labora-
tories across Canada from 2007 to 2013 was 33% susceptible
and 55% intermediate [35]. In North America, >80% of ESBL-E.
coli, almost 100% of ESBL-P. mirabilis, and 20–30% of ESBL-
Klebsiella spp. were susceptible to piperacillin–tazobactam
[36,37,63,68,71].
The systematic review by Vardakas et al. and the post hoc
analysis by Rodriguez-Bano showed that BLBLIs were non-inferior
to carbapenems as empiric or definitive treatment of bacteremia
due to ESBL-producing Enterobacteriaceae, particularly E. coli
[114,115]. A recent study showed the superiority of carbapenems
over piperacillin–tazobactam for the treatment of bacteremia due
to ESBL-producing Enterobacteriaceae (only 20% of the bacteremia
were of urinary source) [116]. It should be noted that these organ-
isms could confer resistance to piperacillin–tazobactam and amox-
icillin–clavulanic acid by AmpC β-lactamases, efflux pumps, loss of
porin channels, and alterations in penicillin-binding proteins [116].
In summary [117], amoxicillin–clavulanate may be effective
as definitive treatment of lower UTIs due to susceptible ESBL-E.
coli. Piperacillin–tazobactam may be used in the definitive treat-
ment of mild–moderate cUTIs and acute pyelonephritis due to
ESBL-producing E. coli when the MIC is ≤16 mg/L, but prefer-
ably ≤8 mg/L. A higher dose or prolonged or continuous infu-
sion of piperacillin–tazobactam can be used to maximize
pharmacodynamic properties of the agent in these infections
and is associated with decreased mortality [118]. Posttreatment
urine culture may be indicated if these antibiotics are used to
treat UTIs due to susceptible ESBL-producing uropathogens.
BLBLIs should be avoided in severe UTIs and in areas where
resistance to BLBLIs is common, especially where ESBL-produ-
cing K. pneumoniae is prevalent. They should be avoided in
UTIs, particularly moderate–severe infection, caused by E. coli
ST131 due to the presence of OXA-1/30, which can confer
resistance to both piperacillin and tazobactam, and K. pneumo-
nia with the OXA-1/30 enzyme [119].
Carbapenems
Carbapenems (imipenem, meropenem, doripenem, and erta-
penem) are broad-spectrum antibiotics that retain the greatest
level of activity against ESBL-negative Enterobacteriaceae and
ESBL-positive E. coli overall in both North America and Europe
(Table 3) [36,48,68,71,106]. Carbapenems are active against
most ESBL-producing strains and have been recommended
as first-line empiric therapy. These agents are also options
for targeted therapy in critically ill patients with severe infec-
tions when there is a risk or documentation of ESBL-producing
Gram-negative bacteria [106,114,116,120]. However, there is a
growing concern of reduced susceptibility of Pseudomonas
spp., K. pneumonia, particularly ESBL-producing strain, and P.
mirabilis to carbapenems [36,63]. The Carbapenem
Antimicrobials Pseudomonas Isolate Testing At regional
Locations surveillance program which collected P. aeruginosa
clinical isolates, 11.4% were urinary, from 100 sites throughout
the USA and Puerto Rico showed that doripenem was the
most active of the carbapenem agents, with 11.4% of isolates
being resistant to doripenem, in comparison with 21.9% and
15.4% resistance for imipenem and meropenem, respectively.
The resistance rate of Pseudomonas isolates to carbapenems
was even higher in ICU patients (doripenem 14.8%, merope-
nem 20.1%, and imipenem 29.1%) [121]. A study that collected
bacterial isolates from patients hospitalized with UTIs at 73
medical centers across all nine US census bureau regions
during 2012 showed that only 65% of ESBLs-K. pneumonia
were susceptible to meropenem [122]. Prior use of carbape-
nems is associated with colonization and infection with carba-
penem-resistant bacteria [57,58]. Therefore, carbapenems
should be restricted to the aforementioned indication, and
when possible, carbapenems must be discontinued or de-
escalated [45,48,52]. Non-carbapenem treatment options can
be used in mild–moderate UTIs and as step-down therapy
from carbapenems [123,124].
Aminoglycosides
Aminoglycosides are almost exclusively renally excreted, achieve
high urinary levels, and are approved by the FDA for the treat-
ment of UTIs (Table 3) [125]. The risk of nephrotoxicity and
vestibulocochlear toxicity and increasing antimicrobial resistance
limits the utility of aminoglycosides. Amikacin can be used for
the empiric treatment of cUTIs and acute pyelonephritis due to
antibiotic-resistant Gram-negative organisms including ESBL-
producing organisms, MDR-Pseudomonas spp., and
Acinetobacter spp. Clinical and microbiologic success with ami-
kacin was achieved in 97.2% and 94.1% of patients with cUTIs
due to ESBL-producing bacteria, particularly E. coli [126]. A recent
study reported that 98%, 100%, 94%, and 92% of urinary isolates
of P. aeruginosa, ceftazidime-non-susceptible P. aeruginosa, mer-
openem-non-susceptible P. aeruginosa, and A. baumannii were
susceptible to amikacin, respectively, in hospitalized patients
with UTIs [122]. Amikacin may have a role in treatment of UTIs
due to CRE since ceftazidime–avibactam has activity against
some class D (e.g. OXA-48) serine β-lactamases and no activity
versus class B metallo-β-lactamases [127].
To minimize the risk of nephrotoxicity, a single dose of amikacin
monotherapy or in combination therapy with other antibiotics (e.
g. ampicillin) can be used as an empiric treatment option of cUTI or
acute pyelonephritis in patients at risk of infection with antibiotic-
resistant organisms such as ESBL-producing organisms or MDR-
pseudomonas spp. pending final results of culture and susceptibil-
ity testing [128]. Gentamicin or tobramycin is not a viable empiric
option due to high antibiotic-resistant Gram-negative organisms
such as ESBL-producing organisms and MDR-Pseudomonas spp.
[48,79,122]. Similar to other antimicrobials, resistance to aminogly-
cosides is emerging in Gram-negative organisms and is commonly
encountered among hospital-acquired ESBL-E. coli, ESBL-K. pneu-
moniae, and Acinetobacter spp. [36,68].
Polymixins
Polymixins include polymixin B and polymixin E (colistin) given
in the form of the sodium salt of colistin methanesulfonate,
which is also known as colistimethate (Table 3). The polymix-
ins are used as a last-resort treatment of MDR bacterial

infections caused by CRE, MDR-P. aeruginosa, and A. bauman-
nii [121,122,127,129]. Among hospitalized patients with UTIs,
98%, 100%, 97%, and 100% of urinary isolates of P. aeruginosa,
ceftazidime-non-susceptible P. aeruginosa, meropenem-non-
susceptible P. aeruginosa, and A. baumannii were susceptible
to colistin, respectively [121,122]. Colistin is administered intra-
venously to treat cUTIs and acute pyelonephritis. However,
colistin bladder irrigation (100,000 IU of colistin in 50 ml of
isotonic saline solution given through a single urinary catheter
three times a day for 3–7 days) can be used to treat cystitis
due to MDR-organisms such as Acinetobacter spp. in patients
with kidney dysfunction who cannot be treated with systemic
colistin [130]. The rate of resistance to colistin remains low;
however, with increased use, resistance is emerging in A.
baumannii, K. pneumonia, MDR-Pseudomonas, and E. coli. The
resistance to colistin occurs as a result of alterations in lipid A
as a consequence of chromosomal mutations and by mcr-1
gene that is carried on a plasmid and can transfer colistin
resistance [131,132]. Strategies to potentially decrease failure
rate and resistance include optimizing dose, interval, and
duration of therapy as well as combination therapy (for carba-
penemase-producing K. pneumoniae strains, pathogen with an
MIC greater than 1 mg/l, or patients with creatinine clearance
greater than approximately 80 ml/min) [129].
Tigecycline
Tigecycline is a glycylcycline antibiotic and a derivative of
minocycline [133]. Tigecycline is not usually recommended
for the treatment of UTIs due to low peak serum concentra-
tions, limited excretion into urine, and subsequent develop-
ment of resistance [134]. In the absence of effective and safe
antibiotic options for UTIs, high-dose tigecycline (e.g. loading
dose of 200–400 mg followed by 100–200 mg daily) can be
considered an alternate option to treat infections due to anti-
biotic-resistant organisms and minimize the risk of resistance
[135]. Tigecycline should not be used as monotherapy for the
treatment of moderate-to-severe UTIs, particularly in the pre-
sence of bacteremia and should be combined with other
active antibiotic such as carbapenems, colistin, or aminoglyco-
sides [65]. Tigecycline use was associated with increased all-
cause mortality in patients with severe infections [136].
Conclusion
The assessment of suspected UTI involves identifying charac-
teristic signs or symptoms associated with symptomatic UTI
and appropriate interpretation of three potential tests: bed-
side urinary dipstick, UA, and urine culture [11]. Obtaining a
UA in the absence of consistent initial history and physical
examination may lead to inappropriate use of diagnostic tests
such as urine culture and inappropriate antibiotic therapy for
asymptomatic bacteriuria [15–17].
Consideration of the limited options for oral treatment of
ESBLs-Enterobacteriaceae infections, it may be prudent to
reserve fosfomycin for management of culture-confirmed
MDR infections rather than using it as a first-line agent for
empirical therapy of common UTIs [8,19,78,84,89].
POSTGRADUATE MEDICINE 13
Fluoroquinolones are not recommended for empiric treat-
ment of uncomplicated cystitis, cUTIs with risk of fluoroquino-
lones resistance, and hospital-acquired UTIs [6,10,93].
Management of ESBL UTIs is challenging given the limited
treatment options available outside the hospital setting.
Carbapenem-sparing strategy can be applied to treat mild–
moderate UTIs due to ESBL-producing Enterobacteriaceae, parti-
cularly in case of E. coli, if the isolated organism is susceptible to
alternatives. However, alternatives to carbapenems should not
be used in the definitive treatment of severe infections caused
by these organisms or when the pathogen is not susceptible or
empiric treatment in patients at risk of infection by these organ-
isms [45,114–116]. Consultation with an infectious diseases spe-
cialist and microbiologist for the management and treatment of
these infections including performing and interpretation of the
susceptibility testing is highly recommended.
Future options for antibiotic-resistant Gram-negative
organisms including plazomicin, eravacycline, carbavance
(meropenem/RPX7009), imipenem–cilistatin/relebactam, cef-
taroline–avibactam, and aztreonam–avibactam are currently
in development phase [137–140].
Funding
This article was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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