Drugs 2010: 70 (13): 1643-1656

THERAPY IN PRACTICE 0012-6667/)0/(Xll3-1643/S65.55/0

2010 Adis Data Information BV All rights reserved

Pyelonephritis in Pregnancy
An Update on Treatment Options for Optimal Outcomes
Jennifer A. Jolley and Deborah A. Wing
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of California,
Irvine, Orange, California, USA

Contents
Abstract 1643
1. Acute Pyelonephritis in Pregnancy 1643
2. Complications of Acute Pyelonephritis in Pregnancy 1645
3. Conventional Therapy 1646
4. Antimicrobial Resistance; A Growing Public Health Concern 1648
4.1 Antimicrobial-Resistant Uropathogens in Antepartum Pyeionephritis 1650
5. Rationaie tor Hospitalization ot Pregnant Patients with Pyelonephritis 1650
6. Ambuiatory Treatment ot Acute Pyelonephritis 1650
6.1 Nonpregnant Patients 1650
6.2 Pregnant Patients 1651
6.3 Recommendations tor Ambuiatory Treatment of Pyelonephritis in Pregnancy 1652
7. Conclusions 1653

Abstract Acute pyelonephritis is one of the most common indications for ante-
partum hospitalization. When acute pyelonephritis is diagnosed, conven-
tional treatment includes intravenous fluid and parenteral antibacterial
I administration. There are litnited data by which to assess the superiority of
; one antibacterial regimen over the other in terms of efficacy, patient accep-
tance and safety for the developing fetus; however, it is important to consider
antimicrobial resistance patterns in the local community when choosing an
agent. Moreover, there are growing public health concerns regarding anti-
microbial resistance to commonly prescribed medications for urinary tract
infections in pregnancy. There is a small body of evidence to support the
ambulatory treatment of pregnant women with pyelonephritis in the first and
early second trimesters, but the majority of women will be managed as in-
patients. This article provides a suggested algorithm for the treatment of
pyelonephritis during pregnancy.

1. Acute Pyelonephritis in Pregnancy complicating 1-2% of all pregnancies. Women with

asymptomatic bacteriuria (ASB), traditionally
Acute pyelonephritis is one of the most com- defined as a urine culture from mid-stream col-
mon indications for antepartum hospitalization. lection with a single isolate of more than 100000
 1644
colony-forming units (cfu) of a uropathogen,'']
have a 20- to 30-fold increased risk of deve-
loping pyelonephritis in pregnancy compared
with women without bacteriuria.'-] In addition,
treatment of ASB in pregnancy decreases the risk
of subsequent pyelonephritis from approximately
20-35% to 1-4%.'-''] Pyelonephritis in pregnancy
occurs mostly prior to delivery, with 10-20%
of cases diagnosed in the first trimester'''-^] and
the majority of cases occurring in the second and
third trimesters. Pyelonephritis can also occur
postpartum.'*]
Numerous physiological changes predispose
the pregnant woman to urinary tract infection
(UTI). Ureteral and renal calyceal dilatation are
evident as early as 12 weeks' gestation, thought
to be due to progesterone-induced relaxation.
Ureteral peristalsis slows and the enlarging uterus
compresses the ureters, particularly on the right
side. Mechanical compression of the bladder and
decreased detrusor tone lead to increased capa-
city and incomplete emptying of the bladder. All
of these factors contribute to ureteral dilatation
and urinary stasis. Increases in glomerular filtra-
tion with resultant elevations in urinary glucose
levels and alkalization of urine also facilitate
bacterial growth.
Women with urinary tract anomalies such
as incompetent vesicourethral valves and renal
calculi, medical conditions including diabetes
mellitus, sickle cell disease or trait, and neuro-
logical problems such as paralysis from spinal
cord injury, are at increased risk for acquiring
pyelonephritis in pregnancy. Pyelonephritis is
also more likely to occur in women of low socio-
economic status.'^'**] In a retrospective review
of 242 nonpregnant women aged 18^9 years
with pyelonephritis, other risk factors for the dis-
ease included frequency of sexual intercourse in
the previous 30 days, recent spermicide use, re-
cent UTI and recent incontinence.'^] The over-
lap of these risk factors with those described
for women with cystitis supports the view that
pyelonephritis usually involves ascent of infect-
ing microbes from the bladder.'^' Another study
noted that low expression of an interleukin re-
ceptor may confer a familial susceptibility to
pyelonephritis.''"]
2010 Adis Data Information BV. AN rights reserved.
Jolle]/ & Wing
Clinical signs and symptoms of acute pyelo-
nephritis include fever, shaking chills, flank pain,
nausea and vomiting, costovertebral angle ten-
derness (CVAT) and, less commonly, symptoms
of cystitis such as dysuria and increased fre-
quency.'*' Urinary dipstick testing for the pre-
sence of leukocyte esterase and nitrites may be
positive.'"'^] The diagnosis is confirmed by urine
culture, obtained usually by midstream clean-
catch, but occasionally by suprapubic aspiration
or urethral catheterization. To obtain a proper
clean-catch specimen, the patient should be in-
structed to wipe her introitus from front to back
prior to micturition in order to avoid contamina-
tion with periurethral bacteria. According to the
Infectious Diseases Society of America (IDSA)
consensus definition of pyelonephritis, colony
counts of >100 000 cfu/mL from clean-catch voided
specimens are acceptable for use in antimicrobial
treatment studies, and provide a sensitivity of
90-95%.1'-^] One or two bacteria per high-power
field on an unspun catheterized urine specimen.
or more than 20 bacteria per high-power field
on spun urine, closely correlates with > 100 000 cfu/
mL bacteria on urine culture.''''] Pyuria or the
presence of leukocyte casts are also consistent
with the diagnosis.
Uropathogens responsible for pyelonephritis
are taxonomically the same as those that cause
ASB and cystitis. The most common uropatho-
gen is Escherichia coli, which is cultured from
70-85% of patients.'''''] Other Gram-negative uro-
pathogens include Klebsiella, Enterohacter and
Proteus spp. A contemporary cohort study'''!
noted far fewer infections caused by Klebsiellu
or Enterobacter species (3%) than the 23% of cases
reported historically.'^] Gram-positive organisms
that are frequently identified include Enlerococcus
faecalis and group B streptococci. Gram-positive
microbes are found more commonly as pregnancy
progresses.''']
The pathogenesis of ASB and risk factors
for progression to symptomatic UTI, including
pyelonephritis, are incompletely understood. A
complex interplay between virulence factors of
uropathogenic bacterial species, such as E. coli
and Proteus mirabilis, and host defence mech-
anisms likely dictates the severity of UTIs in
Drugs 2010; 70(13)
Treatment of Pyelonephritis in Pregnancy
women. For example, E. coli from a small group
of 0-serotypes have characteristics epidemiolo-
gically associated with acute pyelonephritis, chro-
nic or recurrent infection, parenchymal scarring
and renal failure in the normal urinary tract.''^'
The main reservoir for E. coli causing UTI is the
intestinal tract, but only a small proportion of
E. coli bacteria that inhabit the intestines actually
cause UTI. Factors that enhance the adherence of
E. coli to uroepithelial cells and thereby protect
the bacteria from urinary lavage and increase
their ability to multiply and invade renal tissue
have been identified. These include adhesins such
as P-fimbria and S-fimbria,'"'"'''' and haemolysin
production.'-"' Adhesins can bind erythrocyte
membranes and inhibit serum bactericidal activ-
ity by expression of genes associated with ampi-
cillin resistance.'-^'' The class of Dr adhesins has
been associated with pyelonephritis in pregnancy
and a high rate of preterm delivery in mice.'-'"'''
Individual genetic factors may also be associated
with human bladder immune responses prior to
the development of symptomatic UTIs.'^'*' Contrib-
utors to the uropathogenic potential of F. mirabilis
include fimbriae and urease production.'-'''
In addition to urinalysis and urine culture,
laboratory evaluation often includes a complete
blood cell count and serum chemistry evaluation.
Evidence of haemolysis with elevated lactate de-
hydrogenase levels may be encountered and is
attributed to endotoxin-mediated haemolysis.''^'''
Electrolyte abnormalities are also common. Tran-
sient renal insufficiency as demonstrated by a
decrease in creatinine clearance by 50% or more
occurs in some women. Previous estimates
were that a quarter of women with acute pyelo-
nephritis in pregnancy developed renal insuffi-
ciency,'^-''' but modern studies suggest that the
rate may be lower (2%), possibly due to earlier
presentation for treatment and intravenous fluid
hydration.''*'^*'' Spontaneous resolution of the ab-
normal renal function should be expected as the
acute infection clears.
Blood cultures are often obtained when pyelo-
nephritis is suspected, although the utility of
this practice has been questioned since the iso-
lates of blood cultures rarely differ from those of
urine cultures.l-'*'^''' In a retrospective study of
f 2010 Adis Data Information BV. Aii rigiits reserved.
1645
391 patients with pyelonephritis in pregnancy,
only 6% of patients required changes in antibac-
terial therapy, most commonly for persistent
fever and not correlated with urine or blood cul-
ture results.'^^' A change in management because
of bacteraemia alone occurred in only 1% of
cases.'''^' The limited utility of routine cultures in
the clinical management of patients suggested
that patient care would not be compromised in
their absence. Some authors recommend obtain-
ing blood cultures only if the patient has a high
temperature, e.g. >39C, appears to have sepsis or
has a major co-morbidity such as adult respira-
tory distress syndrome (ARDS).'''--''^^^'
When acute pyelonephritis during pregnancy
is diagnosed and treated in a timely fashion, the
outcome for both mother and fetus is generally
good. However, there are serious complications
that can arise. The aim of this article is to provide
an overview of the diagnosis, possible compli-
cations, and management options for women
with pyelonephritis during pregnancy. This guide
serves as an update of a 2001 article detailing
treatment options for optimal outcomes.'''^' Al-
though the management of the disease has not
changed appreciably over the last 10 years, the
disturbing trend of antibacterial resistance has
created new challenges in the treatment of women
with this disease.
2. Complications of Acute Pyeioneptiritis
in Pregnancy
There are both maternal and fetal complica-
tions of acute pyelonephritis in pregnancy. Anaemia
is the most common complication encountered
in association with the disease, occurring in ap-
proximately 25% of patients.'"*' Approximately
15-20% of women with pyelonephritis will have
bacteraemia.'^l Gram-negative bacteria possess
endotoxins that, when released into the maternal
circulation, can lead to a cascade response of
cytokines, histamine and bradykinins.'""*' The re-
sulting capillary endothelial damage, diminished
vascular resistance and alterations in cardiac
output may lead to serious complications such
as septic shock, disseminated intravascular co-
agulation, respiratory insufficiency or ARDS.
Drugs 2010, 70(13)
 1646
The incidence of ARDS with pyelonephritis ranges
from 1% to 8%.[^'l It manifests with symptoms of
dyspnoea, tachypnoea and hypoxaemia. Chest
radiographs reveal pulmonary oedema. This con-
dition is usually adequately treated with supple-
mental oxygen therapy and diuresis. However, it
can progress to ventilator dependence. In one ret-
rospective investigation, ARDS was diagnosed
more frequently in women who had been treated
with -sympathomimetic tocolytic therapy and
had received excessive intravenous hydration.'"*"!
Septic shock occurs as a result of endotoxae-
mia. Patients with septic shock require intensive
care, often with pulmonary artery catheterization.
Antimicrobial therapy and fluid resuscitation
should be instituted at once. Dopamine may be
required to maintain systolic blood pressure and
adequate urine output.
Recurrent pyelonephritis occurs in approxi-
mately 20% of women before delivery.'*' Issues
relating to costs of care and the possibility of per-
manent renal damage must be considered when
discussing recurrent infection. The frequency of
recurrences may be reduced with careful post-
treatment surveillance for recurrent infection and
the use of suppressive therapy.
The risk of preterm labour and delivery attrib-
utable to pyelonephritis in pregnancy is difficult
to estimate, particularly because delivery may not
occur during the admission for the acute disease,
and the risk factors for both pyelonephritis and
preterm delivery overlap.'^^1 Of 368 women de-
livered at Parkland Hospital (Dallas, TX, USA)
with a history of pyelonephritis during the preg-
nancy, 19 (5%) delivered at less than 37 weeks and
only 4 (1%) delivered preterm during their ad-
mission for acute pyelonephritis.^ Although
most will not deliver, the majority of women with
pyelonephritis in the second and third trimesters
will experience uterine contractions;''"''^! thus,
the threat of preterm delivery is taken seriously.
Despite the presence of uterine contractions,
there is often little or no cervical change. It has
been suggested that the use of tocolytic therapy
be reserved for those patients who do exhibit
cervical change, as tocolysis may aggravate the
response to endotoxaemia and predispose preg-
nant women to pulmonary oedema.'""I
2010 Adis Data Information BV. Ail rights reserved.
Jolle}/ & Wing
3. Conventional Therapy
The historical approach to pyelonephritis in
both nonpregnant and pregnant women has been
hospitalization and treatment with parenteral
antibacterials. The safety profile for the mother
and fetus is of utmost importance when choosing
an antimicrobial agent for treatment of UTI in
pregnancy. Unfortunately, the human data on
drug toxicity to mother and fetus are unusually
limited, and animal studies of fetal toxicity arc-
often difficult to extrapolate to humans.
As a general rule, amino- and carboxy-
penicillin derivatives (either alone or in combi-
nation with clavulanic acid), ureidopenicillins
and cephalosporins are considered to have good
safety when used during pregnancy. Penicilliti
derivatives and cephalosporins achieve good renal
parenchymal and urine concentrations shortly
after administration, and have effective spectrums
of coverage for common uropathogens. Ampi-
cillin had been the mainstay of treatment for
pyelonephritis in pregnancy given the low cost,
minimal risk to mother and fetus, and its histor-
ical efficacy, but it has a high frequency of re-
sistance in multiple organisms. Approximately
45-60% of E. coli strains are resistant to ampi-
cillin.[2'.32,43] ^5 3 result, first-generation cepha-
losporins have replaced ampicillin as first-hne
monotherapy for pyelonephritis during preg-
nancy. Cefazolin possesses the same spectrum
of activity as broader-spectrum cephalosporins
against the common causative microbes and is
less expensive.[-^^!
Tetracyclines are generally contraindicated
during pregnancy. These antimicrobials can che-
late calcium in fetal structures, and in utero
exposure may result in tooth discoloration and
inhibition of bone growth.I'*'*! Although fiuoro-
quinolones attain high renal concentration and
are a preferred treatment for UTI in nonpregnant
patients, the risk of fetal arthropathy proscribes
their use during pregnancy.
Aminoglycosides concentrate in renal tissue as
they are reabsorbed and bound in the proximal
tubular epithelium;'"*^! thus, they may have a
distinctive place in the treatment of pyelone-
phritis.''"'! The use of aminoglycosides should be
Drugs 2010: 70(13)
Treatment of Pyelonephritis in Pregnancy 1647

considered carefully as there is the potential for
ototoxicity with their use. To date, gentamicin
has been widely used in pregnancy as first-line
therapy for Gram-negative coverage with no re-
ports of congenital complications. However, it is
a Food and Drug Administration (FDA) cate-
gory C drug in the US, meaning that studies have
shown that the drug exerts teratogenic or em-
bryocidal effects in animals, but there are no
controlled trials in women. In addition, ototoxi-
city has been demonstrated following fetal ex-
posure to related aminoglycoside compounds
such as kanamycin and streptomycin.'"''"'''' Acute
renal dysfunction associated with pyelonephritis
appears to be less common'"*' than the 20% rate
noted previously;'^' thus, empirical treatment
with gentamicin while awaiting serum creatinine
measurement may be appropriate. However, if
gentamicin is chosen, monitoring of serum con-
centrations should be performed and adjustments
made in the dose administration as needed. This
is partly because of concerns regarding any toxic
effects such as exacerbation of renal insufficiency,
but also because maternal serum concentrations
near term are more likely to be subtherapeutic
because of enhanced drug clearance.'^"'''
The optimal antibacterial regimen for the
treatment of acute pyelonephritis in pregnancy
would be characterized by the following: (i) prov-
en effectiveness in properly conducted, prospec-
tive, randomized, double-blind trials; (ii) activity
against the uropathogens likely to be responsi-
ble for the symptomatic upper UTI; (iii) ability to
maintain adequate tissue and serum concentra-
tions throughout the treatment period; (iv) lack
of association with the development of resistance
to antibacterials; (v) inexpensive; (vi) well tolerat-
ed; and (vii) safety for the developing fetus. There
are insufficient data to recommend a specific
treatment regimen for pyelonephritis in pregnancy
as few studies exist comparing the efficacy of
different antibacterial agents.'^^"^^' A Cochrane
Database review found that all antibacterials stud-
ied were effective in clearing infections and de-
creasing the incidence of complications such as
prolonged pyrexia and preterm delivery.'^'' Many
regimens are acceptable and appear to be effec-
tive (table I).
Intravenous antimicrobial therapy is usually
continued until the patient is afebrile for 48 hours
and symptoms have improved; afterward, the
patient is treated with oral antibacterials. The
course of oral therapy lasts for 10-14 days. After
completion of therapy, a urine culture should
be obtained to verify resolution of the bacteri-
uria. The appropriate duration of therapy for
eradication of pyelonephritis has not been sub-
jected to scientific scrutiny.

Table I. Examples of dosage administration regimens of antibacterial agents for the treatment of pyelonephritis in pregnancy with US FDA
classification for use in pregnancy
Agent Dosage (intravenous administration) Frequency FDA pregnancy class
Ampicillin (combined with gentamicin as below) 1-2 g q6h B
Gentamicin (may be given alone) 2 mg/kg to load then 1.7 mg/kg in three divided doses q8h C
Ampicillin/sulbactam 3g q6h B
Cefazolin 1-2 g q6-8h B
Ceftriaxone 1-2 g q24h B
Cefuroxime 0.75-1.5 g qSh B
Cefofaxime 1-2g q8-12h B
Cefepime lg q12h B
Cefofetan 2g q12h B
Mezlocillin 3g q6h B
Piperacillin 4g q8h B
Aztreonam" ig q8-12h B
a May be used in the setting of |i-lactam allergy.
q x h = every x hours.

a 2010 Adis Data Informafion BV. All righfs reserved. Drugs 2010: 70 (13)
 1648
Recurrent pyelonephritis occurs in 6-8% of
women.!*"'*'') The incidence of recurrent pyelo-
nephritis is decreased in patients treated with
antimicrobial suppression for the duration of preg-
nancy.!*^-*^) Thus, after treatment for pyelonephri-
tis, patients should receive prophylaxis with
nitrofurantoin lOOmg or cephalexin 250-500 mg
orally every night during the pregnancy and for
4-6 weeks postpartum. Some practitioners choose
to prescribe cotrimoxazole (sulfamethoxazole/
trimethoprim), but its use is generally restricted
to the second trimester due to its inhibitory effect
on folate metabolism in the first trimester and the
theoretical risk of inducing neonatal hyperbili-
rubinaemia when given close to the time of delivery.
The sulfonamide moiety of cotrimoxazole com-
petes with bilirubin for binding to plasma albu-
min after birth, although no cases of kernicterus
after in utero exposure to sulfonamides have been
reported.!**' It must be noted that prolonged use
of antimicrobials such as cephalexin can predis-
pose women to chronic vaginal candidiasis;!*^'
thus, symptoms should be monitored periodi-
cally. In addition to continuous antimicrobial
suppression, monthly urine cultures should be
obtained to screen for recurrent bacteriuria.
Because most patients with pyelonephritis are
dehydrated, intravenous hydration is usually given.
Urinary output is monitored carefully. Patients
who are treated for pyelonephritis with the appro-
priate antimicrobial agent usually respond within
48 hours. If the patient fails to respond clinically by
72 hours, further evaluation should ensue for
bacterial resistance to the antibacterial used, uro-
lithiasis, perinephric abscess formation or urin-
ary tract abnormalities, and the antibacterial agent
should be changed to include an aminoglycoside.
Patients with recurrent pyelonephritis or those
who fail to respond quickly to aminoglycoside
therapy should undergo imaging evaluation for
the presence of an anatomic malformation or
nephrolithiasis. This may be accomplished safely
in pregnancy with ultrasonography or with intra-
venous pyelography (IVP). To minimize the ra-
diation exposure to the fetus, only one exposure
at 20-30 minutes should be obtained for the IVP.
Magnetic resonance imaging also may be used if
urinary tract obstruction is suspected.
2010 Adis Data Information BV. All rights reserved.
Jolky &
An algorithm for the treatment of pyelone-
phritis during pregnancy is presented in figure 1.
4. Antimicrobiai Resistance: A Growing
Public Health Concern
Treatment of UTI in nonpregnant patients has
been altered dramatically by changing patterns of
antimicrobial resistance. Extensive use of amox-
icillin after its introduction in the 1970s led to the
development of widespread resistance of com-
mon uropathogens to this antibacterial. In 1999,
the IDSA suggested that uncomplicated UTIs be
treated with cotrimoxazole unless local resistance
rates o E. coli to the drug exceeded 10-20%, in
which case a uoroquinolone should be used.I*'''
With the subsequent broad use of cotrimoxazole
since that time, increasing levels of resistance
to this antimicrobial have been reported.'*'''''**1
Fluoroquinolones have also been impacted, with
concomitantly rising resistance rates in a number ,
of uropathogens.f'^l Interestingly, E. coli resis-
tance to nitrofurantoin is reported to be low at
1.1-2.3%,'*^*''1 leading some authors to suggest
that it be considered the first-line treatment for
uncomplicated UTI.'*'*)
In 2005, the North American Urinary Tract
Infection Collaborative Alliance (NUTICA)
reported on the susceptibility of outpatient uro-
pathogen isolates to antibacterials commonly
used to treat UTI.1*^1 1990 urinary isolates were
obtained from 41 centres in the US and Canada.
E. c'o//represented 57.5% of all outpatient urinary
isolates, with Klebsiella pneumoniae (12.4%),
Enterococcus spp. (6.6%) and P. mirabilis (5.4%)
making up the remaining majority. Among all ol'
the isolates, 45.9% were resistant to ampicillin,
20.4% to cotrimoxazole, 14.3% to nitrofurantoin.
9.1% io ciprofloxacin and 8.1 % to levoOoxacin.'*^'
Although all of the characteristics of the patients
from whom the samples were derived were not
known to the authors, they noted that the obser-
vations from the study did not necessarily apply
to young ambulatory women with uncomplicated
UTIs, but rather might be more relevant to older
patients with complicated infections. Of note,
resistance rates were higher in the US than in
Canada and varied by geographical region. A sep-
Drugs 2010; 70 (13)
Treatment of Pyelonephritis in Pregnancy 1649

arate study corroborated that in the US, the
highest prevalence of multidrug-resistant pheno-
types is found on the Pacific Coast.']
Recent prior antibacterial treatment is one of
the most important determinants for infection with
a resistant microbe.''"' Although there are several
important differences between recommendations
for treatment of gestational pyelonephritis and
antimicrobials commonly used in uncomplicated
UTI, the significance of antimicrobial steward-
ship when selecting a treatment regimen remains
vital.'^-] The IDSA published guidelines for de-
veloping an institutional programme to enhance
antimicrobial stewardship,'"'^] designed to opti-
mize clinical outcomes and minimize unintended
consequences of antimicrobial use including the
development of resistant organisms. Utilization
of these guidelines as well as a comprehensive
infection control programme may limit the
emergence and transmission of antimicrobial-
resistant bacteria.'^-'] Because resistance patterns
vary with location and antibacterial therapy

Pyelonephritis diagnosed
Urine culture sent

Consider
outpatient
treatment

Signs of sepsis,
urinary tract abnormality,
medical co-morbidity

Ves

Empirical parenteral antibacterial treatment

(see table I)
IV fluid hydration
fvtonitor fluid balance
Monitor pulse oximetry
Uterine activity and fetal monitoring
as appropriate

Afebrile x 48 hours, Clinical deterioration or

symptomatically improved continued spiking fevers after
>72 hours of antibacterial ttierapy

Discharge to home to complete

10- to 14-day course of PO antibacterials Renal ultrasound to
evaluate for
nephrolithiasis or abscess

At completion of treatment
send urine culture as test of cure
Ensure appropriate treatment
based on urine culture sensitivities

Continue antibacterial prophylaxis Evaluate for other sources

for remainder of pregnancy of infection

Check monthly urine culture

Fig. 1. Algorithm for treatment of pyelonephritis during pregnancy. IV = intravenous; PO = oral.

2010 Adis Data Information BV, All rights reserved. Drugs 2010; 70(13)
 1650 Jolley & Wing

is initiated empirically, knowledge of resistance sponse to the initial antibacterial therapy.'''^1 The
patterns in the local community may infiuence antibacterial sensitivity of the uropathogen did
the selection of the initial antimicrobial for treat- not predict clinical cure. Susceptibility testing for
ment of pyelonephritis in pregnant patients. antimicrobials established by the National Com-
mittee for Clinical Laboratory Standards is based
4.1 Antimicrobial-Resistant Uropathagens on serum concentrations.'^'^' In vitro resistance may
in Antepartum Pyeionepiiritis not adequately predict therapeutic failure because
the concentration of most antimicrobial agents used
It has been suggested that infections with for UTIs is higher in the urine than in serum.'''^' For
antimicrobial-resistant organisms may increase this reason, we advocate that changes in antibac-
the risk of complications and mortality.''''*' This terial therapy should be directed by clinical response
concept is of growing importance in the manage- rather than culture results alone. Surveillance of
ment of antepartum pyelonephritis as increasing microbial drug resistance at a given institution may,
rates of antimicrobial-resistant uropathogens are however, facilitate selection of the appropriate first-
id'2'"43] line antibacterial therapy.
g
Greer et al.'''"'I investigated the outcomes in
patients with acute antepartum pyelonephritis 5. Rationale for Hospitaiization
caused by ampicillin-resistant bacteria in a sec- of Pregnant Patients with
ondary analysis of a prospective cohort study. Pyeionephritis
After being diagnosed with pyelonephritis, every
patient was presumptively treated with ampiciiiin Over 20 years ago, the American College of
and gentamicin. Fifty-one percent of the or- Obstetricians and Gynecologists stated in a Techni-
ganisms identified with sufficient cfu to receive cal Bulletin that hospitaiization of pregnant women
antibacterial sensitivity testing were resistant to am- with pyelonephritis is necessary.'^''' Theoretically,
piciiiin, 92% of which were E. coli. The patients this approach will circumvent serious complica-
infected with ampicillin-resistant organisms were tions associated with pyelonephritis, including res-
more likely to be older and multiparous, but there piratory insufficiency, septic shock, preterm labour
were no significant differences in complications and delivery, and recurrences with the possibility ol"
between the groups. The rates of anaemia, renal permanent renal damage. However, the recommen-
dysfunction, respiratory insufficiency and pre- dation to hospitalize all women with pyelonephritis
term birth were comparable. There were also no was not based on evidence from clinical trials. The
significant differences in length of hospital stay, high cost of medical care and concerns for cost con-
days of intravenous antibacterials required, ad- tainment have provided motivation to study ambu-
mission to extended care unit or rate of hospital latory methods of therapy for the pregnant patient.
readmission. The results of this study appear to Because pyelonephritis is one of the most common
contradict the notion that antimicrobial-resistant reasons for hospitaiization during pregnancy, at-
tention has been directed toward developing a safe
organisms cause increased morbidity; however,
and effective approach to outpatient treatment of
an important consideration is that all of these
acute pyelonephritis. Based on the evidence pre-
women were concomitantly treated with genta-
sented in this review, this approach in pregnancy
micin, and all but one of the organisms cultured
has only limited utility.
was sensitive to this drug.''*-^'
There is possibly a difference between micro-
biological resistance and clinical resistance to 6. Ambuiatory Treatment of Acute
an antibacterial medication, as noted by Wing Pyeionephritis
et al.'-''-' in their study of the clinical utility of 6.1 Nonpregnant Patients
blood and urine cultures in the treatment of
pyelonephritis in pregnancy. In their analysis, As observational studies'""^^' and random-
94% of patients had an acceptable clinical re- ized controlled trials"*'''^'' have demonstrated the

2010 Adis Data information BV. Ail rights reserved.

Drugs 2010; 70(13)
Treatment of Pyelonephritis in Pregnancy
safety of outpatient management of acute pyelo-
nephritis in nonpregnant patients, the hospitali-
zation rate for these patients has decreased from
almost 100% to 7-30% in recent decades.''^**-^'*-^!
Most of the evidence for ambulatory treatment
stems from data collected in emergency depart-
ments and investigations have reinforced the
importance of careful patient selection for ambu-
latory therapy. Equally as important is the need
for an initial period of observation for hydration
and subsequent triage.1^'^! A meta-analysis of the
existing literature on oral therapy for pyelone-
phritis'**''! indicates that patients who do not have
diabetes or sepsis and who are not immunocom-
promised, can tolerate oral intake, and do not
have chronic illness can be treated for upper UTI
with oral agents. From these data, a regimen for
the outpatient treatment of pregnant women with
acute pyelonephritis may be extrapolated; how-
ever, the application of ambulatory therapy for
upper UTI in pregnancy appears to be quite
limited.
6.2 Pregnant Patients
There are few trials on the ambulatory man-
agement of pyelonephritis in pregnancy, with
most published in the last 2 decades.''''-''''^^^'*'
Several investigators have attempted to simulate
outpatient management such that all care during
the hospitalization after initial therapy could
have been accomplished at home.'^*'-^^! In one
trial, 90 pregnant women were treated with oral
cephalexin every 6 hours or intravenous cepha-
lothin every 6 hours until there was a decrease in
CVAT and no fever for 48 hours.'-'*'! More than
90% of the patients were treated successfully with
either treatment modality. Similarly, once-daily
intravenous ceftriaxone therapy was compared
with multiple-dose intravenous cefazolin therapy
in a randomized, double-blind clinical trial of
178 hospitalized patients.'''''! Approximately 5%
of patients in both groups failed to respond to
initial therapy, and similar numbers in each
group also demonstrated continued positive
urine cultures at follow-up evaluation.
Brooks and Garite'^^! reported a 12% treat-
ment failure rate of outpatient treatment of
2010 Adis Data Information BV. Ali rights reserved.
1651
21 pregnant women with pyelonephritis in preg-
nancy at 26 weeks or earlier. Initial evaluation
was for 2 hours in an obstetric emergency room
with chnic follow-up for daily intramuscular in-
jections of ceftriaxone until both fever and CVAT
resolved, then a 10-day course of oral antibac-
terials. The authors estimated that 50% of preg-
nant patients reporting to an obstetric emergency
room could be treated as outpatients. A later in-
vestigation with a different approach using home
health nurse visits after initial intramuscular
treatment in the emergency room followed by
10 days of oral cephalexin found 90% effective-
ness in 120 pregnant women at less than 24 weeks'
gestation.'-^**! Ten percent of the outpatients were
eventually hospitalized because of sepsis, abnor-
mal laboratory tests, deviation from study pro-
tocol and recurrent pyelonephritis while on oral
therapy. Overall, the authors estimated that
5% of patients with pyelonephritis at less than
24 weeks" gestation who are considered candi-
dates for outpatient therapy will not be able to be
These results are sharply contrasted by a sim-
ilar trial conducted by the same authors in
women with pregnancies after 24 weeks gesta-
tional age.'**^! Over 60%, or 154 of 246 women
evaluated, were ineligible for outpatient man-
agement for reasons such as preterm labour,
obvious sepsis or respiratory compromise, or pre-
existing maternal medical condition or fetal
malformation. After two doses of intramuscular
ceftriaxone 24 hours apart, all women received
oral cephalexin for 10 days. Inpatients received
oral antibacterials until they were afebrile for
48 hours, and then were discharged from the hos-
pital. Nearly 30% (13/46) of planned outpatients
remained hospitalized after 24 hours because
of clinical sepsis, bacteraemia, excessive leuko-
cytosis (>20 OOO/mm-*), preterm labour and other
medical complications. Six outpatients and one
inpatient failed to respond to initial therapy.
Although there were no differences in clinical
responses or birth outcomes of inpatients or
outpatients after 24 weeks if they completed
their assigned protocols, because of the inability
to discharge 30% of the outpatients, the au-
thors concluded that most women with acute
Drugs 2010: 70 (13)
 1652
pyelonephritis after 24 weeks' gestation were not
candidates for ambulatory therapy'**^' and, there-
fore, this approach is quite limited in the third
trimester.
There are no trials describing outpatient oral
therapy for acute pyelonephritis in pregnancy.
6.3 Recommendations for Ambulatory
Treatment of Pyelonephritis
in Pregnancy
Cumulatively, the results of the existing trials
are only encouraging for the ambulatory treat-
ment of acute pyelonephritis in pregnancy in the
first and early second trimesters of pregnancy.
Outpatient treatment of acute pyelonephritis in
pregnancy beyond 24 weeks appears to have
limited utility, and it would appear most prudent
to admit women for conventional treatment with
intravenous hydration and antibacterials if their
gestational ages exceed this threshold.
Clearly, careful selection of appropriate can-
didates for outpatient therapy of acute pyelone-
phritis in pregnancy is required. Patients should
be less than 24 weeks pregnant, relatively healthy
and able to comply with outpatient therapy. They
should not have excessive fever (>38C), severe
nausea and vomiting, recurrent upper urinary
tract disease, signs of sepsis including tachypnoea,
tachycardia, rigors or hypotension, immuno-
compromise, significant medical conditions such
as diabetes or previous renal disease, history of
substance abuse, concurrent preterm labour or
uncertain diagnosis. Liberalizing the criteria for
outpatient therapy, in the absence of supporting
data, may lead to serious detriment.
A period of observation is required, during
which the patient should be hydrated and anti-
bacterial therapy with intramuscular ceftriaxone
initiated. Laboratory studies (complete blood cell
count, serum chemistry panel including serum
blood urea nitrogen and creatinine, and urine
culture) should be obtained. Although urine cul-
ture may not aid in the immediate clinical man-
agement, approximately 6-10% of patients will
not be successfully treated in an ambulatory set-
ting and the results of the cultures may guide
subsequent therapy. Surveillance of resistance
2010 Adis Data Informafian BV. Aii righfs reserved.
Jolle}/ &
rates to empirically chosen antibacterial therapies
is mandatory. The period of observation should
be long enough to review laboratory results
and to assess the ability to tolerate oral intake,
and the patient's clinical response to therapy. If
women with gestational ages beyond 24 weeks arc
to be managed on an ambulatory basis, even
longer periods of observation with continuous
fetal heart rate and uterine activity monitoring
are required to ensure both maternal and fetal
stability before discharge from the observation
unit, although more recent data would indicate
that the risk of preterm delivery associated
with acute pyelonephritis is lower than previously
estimated.''*'
Emphasis must be placed on close outpatient
follow-up evaluation until both chnical and
microbiological cure are obtained. Follow-up
evaluation within 24 hours may take place in an
office, clinic or emergency room. Alternatively,
a home health nursing visit may be performed. At
this evaluation, an additional dose of ceftriaxone
should be given and an assessment made of the
chnical condition. After the second dose, the anti-
bacterial may be changed to oral cephalexin
500 mg four times a day (or a similar substitute)
for 10 days, or daily intramuscular administra-
tion could be continued until all symptoms have
resolved. The daily intramuscular administration
regimen does not exceed 5 days. If the change
to oral therapy is made, another outpatient
clinical evaluation should be made within the
24 hours after the change. After completion of the
daily ceftriaxone, oral treatment for 7-10 days
is continued with cephalexin or with another
antibacterial to which the causative organism is
susceptible.
Clinic follow-up evaluation within 2 weeks
after acute therapy should also be required.
A urine culture should also be obtained as a
'test of cure". Throughout the remainder of the
pregnancy, the patient should be followed for
symptoms of recurrent infection and monthly
urine cultures should be performed until delivery.
Antimicrobial prophylaxis should be initiated
in all patients for the remainder of the preg-
nancy and should be continued until 4-6 weeks
postpartum.
Drugs 2010, 70(13)
Treatment of Pyelonephritis in Pregnancy
7. Conclusions
The standard approach to the treatment
of acute pyelonephritis in pregnancy is hospitali-
zation and administration of intravenous hydra-
tion, antipyretics and parenteral antimicrobial
therapy. There is insufficient data to recommend
one antibacterial regimen at the current time,
although consideration should be given to the
antimicrobial resistance patterns at a given hos-
pital. As more microorganisms become resistant
to antimicrobial therapies, clinicians will be faced
with additional treatment challenges. There is
a small body of evidence to support the ambula-
tory treatment of pregnant women at less than
24 weeks gestational age with acute pyeloneph-
ritis provided these women are relatively healthy
and do not manifest signs or symptoms of respira-
tory insufficiency or sepsis. Ambulatory treatment
of acute pyelonephritis in pregnancy beyond
24 weeks appears to be limited in its applicability
and is therefore not recommended.
Aci<nowleclgements
No sources of funding were used to assist in the prepara-
tion of this review. The authors have no conflicts of interest
that are directly relevant to the content of this review.
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Correspondence: Dr Deborah A. Wing, University of
California, Irvine, Department of Obstetrics and Gynecol-
ogy, 101 The City Drive, Building 56, Suite 800, Orange,
CA 92868, USA.
E-mail; mfm@ud.edu
Drugs 2010; 70 (13)
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