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The Obstetrician & Gynaecologist 10.1576/toag.10.1.017.27372 www.rcog.org.uk/togonline 2008;10:1721 Review

Review Recurrent urinary tract

infection in gynaecological
practice
Authors Neil Harris / Roderick Teo / Christopher Mayne / Douglas Tincello

Key content:
Urinary tract infection (UTI) is the result of interaction between host defences
and bacterial pathogenic mechanisms.
Recurrent UTI can be associated with urinary tract abnormalities.
Urinary tract imaging is useful in a minority of women to identify pathological,
structural or functional abnormalities.
Adequate fluid intake, topical estrogens and prophylactic antibiotics can be
useful in the management of recurrent infections.
Symptoms often reappear despite adequate treatment.

Learning objectives:
To understand the pathogenesis of recurrent UTI in women.
To appreciate the value and limitations of urinary tract imaging.
To develop an appropriate management strategy.

Ethical issues:
Women with dipstick haematuria, but without bacteriological confirmation of a
UTI, should be referred for urological evaluation.
There is no evidence that the risk of altering antibiotic resistance patterns
through the use of prophylactic antibiotics outweighs the advantage of reducing
UTI in susceptible individuals.
Keywords midstream specimen of urine (MSSU) / prophylactic antibiotics /
recurrent urinary tract infection / topical estrogens
Please cite this article as: Harris N, Teo R, Mayne C, Tincello D. Recurrent urinary tract infection in gynaecological practice. The Obstetrician & Gynaecologist 2008;10:1721.

Author details
Neil Harris MD FRCS(Urol)
Clinical Fellow in Female Urology
Department of Urogynaecology,
Leicester General Hospital, Gwendolen Road,
Leicester LE5 4PW, UK
Roderick Teo MRCOG Christopher Mayne FRCOG Douglas Tincello MD FRCOG
Subspecialty Trainee in Urogynaecology Consultant Urogynaecologist Senior Lecturer and Honorary Consultant
Department of Urogynaecology, Department of Urogynaecology, Urogynaecologist
Leicester General Hospital. Leicester General Hospital. Reproductive Science Section, Cancer Studies
and Molecular Medicine, Leicester Royal
Infirmary, Leicester LE2 7LX, UK
Email: dgt4@le.ac.uk
(corresponding author)

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Introduction
Urinary tract infection (UTI) is a general term that
can be applied to a spectrum of clinical conditions,
ranging from fulminant pyelonephritis with
urosepsis to the asymptomatic presence of bacteria
in the urine. Recurrent UTI can be defined as three
or more episodes of UTI during a 12-month period.
Almost 50% of women experience at least one UTI
during their lifetime and epidemiological studies
have shown that up to 27% of women experience at
least one culture-confirmed recurrence within the
6 months following initial infection.1 The presence
of haematuria and urgency during the initial
infection appear to be the strongest predictors of
recurrent infection. Recurrent UTI is a source of
considerable morbidity and in the evaluation of
these women it is important to differentiate
between recurrent and incompletely treated
infection, as the management of the two is likely to
differ. Recurrent infection implies re-infection,
which can be caused by a different organism. These
infections are often associated with increased host
susceptibility (see below). Incompletely treated
infection implies bacterial persistence and is more
likely to be associated with an underlying
pathological, anatomical or functional
abnormality; for example, urethral diverticulum,
incompletely emptying bladder, urolithiasis.
Classification
One of the most clinically useful ways of classifying
UTI is based upon whether the infection is
complicated or uncomplicated. Complicated UTI
occurs when an underlying anatomical or
functional abnormality that predisposes to urinary
infection is present. Examples of such
abnormalities are urinary tract stones, duplex
collecting systems and neuropathic bladders.
Urinary tract infection can also be classified
according to the part of the urinary tract affected.
Involvement of the bladder alone, with little or no
systemic upset, is known as cystitis, whereas
pyelonephritis is infection in the renal parenchyma,
often with features of systemic sepsis. These
classifications are important, not only for
epidemiological and data collection purposes, but
also to guide clinicians towards appropriate
treatment.
Pathogenesis of recurrent UTI
The endpoint of any UTI is bacterial colonisation
of the uroepithelium, resulting in inflammation
and, occasionally, bacterial dissemination. This
process involves a complex interaction between
host and micro-organism. A number of factors are
known to be important in the pathogenesis of UTI
and it is convenient to divide these into host and
microbial factors.
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Host factors
The lower urinary tract has several intrinsic
mechanisms designed to inhibit bacterial
colonisation. Some of the general host factors that
help prevent colonisation by uropathogens include:
Unobstructed urine flow, facilitating mechanical
washout of bacteria, along with the rapid
urothelial cell turnover. This helps to prevent
colonisation. Women with congenital or
acquired functional voiding disorders, for
example, spina bifida, urethral stenosis and
following major pelvic surgery, may be more
prone to infection, partly as a result of
incomplete bladder emptying.
Uromucoid (also known as TammHorsfall
protein), mucopolysaccharides, and
immunoglobulin, which augment this barrier
function and inhibit bacterial adherence.
Vaginal colonisation by lactobacilli, promoted by
estrogens, in premenopausal women. This
colonisation results in the production of lactic
acid, maintaining a low pH that inhibits growth
of many pathogenic bacteria. However, in
postmenopausal women, lactobacilli are not
present and the vagina becomes primarily
colonised with enterobacteria, in particular
Escherichia coli (E. coli). This is a major factor
leading to increased susceptibility to clinically
significant UTI.
Certain host behavioural factors are known to
predispose to recurrent UTI. These include voiding
dysfunction, sexual intercourse frequency, use of
spermicidal lubricant and the use of oral
contraceptives.2 Interestingly, although associated
with UTI in general, such behavioural factors have
not been shown specifically to influence the
development of recurrent UTI.1 Pedigree analysis
suggests a genetic predisposition for UTI among
certain young women and a number of putative
candidate genes have been identified. For example,
women who are non-secretors of blood group
antigens have a three- to four-fold increased risk of
developing recurrent UTI.3 Interleukin-8 receptor
(CXCR1) expression, certain human leukocyte
antigen (HLA) loci,
Toll-like receptors, and TammHorsfall protein
expression are also known to influence
susceptibility to UTI.46 Another explanation for the
pathogenesis of recurrent UTI is the observation
that some bacteria can survive within the
uroepithelium in quiescent intracellular reservoirs
(QIRs),7 despite establishment of sterile urine with
antibiotics.
Microbial factors
Bacterial virulence mechanisms facilitate
colonisation and growth of micro-organisms
within uroepithelium. There are three main
categories of virulence mechanism and these often
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reflect an intrinsic characteristic of a particular
bacterial species.
Adherence mechanisms
The most important adherence factors are thought
to be fimbriae (pili), which mediate binding of
bacteria to receptors on urothelial cells. Pathogenic
E. coli possess two main types of fimbriae, known as
type I and type P. Type I pili are present on the
majority of E. coli causing lower urinary tract
infection, whereas type P pili have been found in up
to 80% of E. coli isolates causing pyelonephritis. In
contrast, the afimbrial adherence mechanisms
mainly consist of the glycocalix forming the
bacterial cell wall (e.g. lipopolysaccharide). In
addition, uropathogenic E. coli have a greater
capacity for adherence to uroepithelial cells in
women who are non-secretors of blood group
antigens, than to cells from antigen secretors.
Direct virulence against the host
Bacterial production of endotoxin, exotoxin and
haemolysin assist in the process of microbial
invasion and may also be responsible for the
generalised toxaemia that can occur with systemic
urosepsis. In particular, the lipid A component of
the lipopolysaccharide cell wall of Gram-negative
bacteria is thought to be at least partly responsible
for triggering the systemic effects of endotoxaemia.
Antibiotic resistance
Bacteria can develop resistance to antibacterial
agents by various methods. These include reduced
drug accumulation as a result of active efflux,
antibiotic inactivation (e.g. enzymatic deactivation
of penicillin by beta-lactamases) and alteration of
target sites (e.g. alteration of penicillin binding
protein [PBP] in MRSA).
Bacterial adherence to the uroepithelium can be
followed by colonisation, tissue damage and, in
some instances, invasion and dissemination.
Expression of capsular K antigen, production of
haemolysin and anti-IgA proteases all affect the
invasive capacity and the virulence of
uropathogenic bacteria.
Pathogens in UTI
The majority of community and hospital
acquired urinary tract pathogens are Gram-
negative bacteria. The recent ECOSENS study8
was designed to investigate the prevalence and
antimicrobial susceptibility of pathogens causing
community-acquired UTI in 16 European
countries. Within the community setting,
7080% of UTIs are caused by E. coli. However,
the Gram-positive organisms (especially
Staphylococcus saprophyticus) may be responsible
for up to 8% of infections and exhibit seasonal
variability.8 Other organisms occasionally
encountered include Klebsiella, Pseudomonas spp,
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Proteus spp. and Enterococcus faecalis. Genitourinary
candidiasis and tuberculosis can cause infection,
particularly in immunocompromised women.
Diagnosis of UTI
The diagnosis of clinically significant UTI requires
both clinical assessment of symptoms and
bacteriological evaluation. Most UTIs result in
urothelial inflammation and women experience a
variety of symptoms, including dysuria, urinary
frequency, urgency and haematuria. A recent meta-
analysis9 of evidence relating to the use of rapid
urinalysis showed that dipstick assessment offers a
useful screening test if both urinary nitrite and
leucocyte esterase are assessed. Nitrites are
produced from the reduction of urea by urea-
splitting bacteria. Leucocyte esterase is produced as
a result of leucocyte degradation in urine and can
be regarded as a surrogate marker of pyuria.
However, these tests have limited sensitivity and/or
specificity when used in isolation and we would
advocate use of the urine dipstick as a screening
tool for UTI. If a positive result for leucocyte
esterase or nitrite is demonstrated, a midstream
specimen of urine (MSSU) should be sent for
formal bacteriological evaluation (see below). If
there is a clinical suspicion of UTI, empirical
treatment with antibiotics and appropriate advice
on fluid intake should be given before the MSSU
results are available. In asymptomatic women, it
may be more appropriate to wait for the results
before commencing antimicrobial treatment.
Pyuria is conventionally defined as the presence of
10 white blood cells (WBCs) per high power field
(HPF) in microscopy of a centrifuged urine
specimen. However, levels of pyuria as low as
25 WBCs/HPF can be important in women with
appropriate symptoms. The presence of sterile
pyuria (i.e. no bacteria are identified) should lead
the clinician to consider a diagnosis of urinary tract
tuberculosis, although there are other causes of
sterile pyuria.
The gold standard bacteriological evaluation of an
uncomplicated UTI comprises microscopy,
quantitative culture and sensitivity testing of a
freshly voided MSSU. In women with indwelling
urinary catheters, a catheter specimen of urine
(CSU) is required and in children, a suprapubic
aspiration may be necessary. Further systemic
assessment is indicated if severe infection is
suspected or if the woman is systemically unwell.
The MSSU should be processed as soon as possible;
each bacterium will form a single colony on the
culture plate. The microbiological criteria for
diagnosing UTI are not arbitrary but based on a
series of elegant experiments by Kass that correlate
UTI syndromes with the quantity of organisms in
urine. The number of colony-forming units (CFUs)
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conventionally taken to indicate infection is
100 000 per ml.10 However, clinically significant
UTI can still be present with lower counts under
certain clinical circumstances, for example
following suprapubic aspirations and when pure
growths of a single organism are identified.
Additional investigations
and imaging
Women with a single, uncomplicated UTI do not
generally need any further investigation. However,
development of a second or subsequent infection is
an indication for further evaluation. At the very
least this should involve ultrasonography of the
renal tract. Additional investigations are
determined by the clinical scenario. For example, if
renal stones are suspected, we would recommend
initial assessment with an X-ray of the kidneys,
ureter and bladder (KUB) and more detailed
evaluation with intravenous urography (IVU) or
computerised tomography (CT), where indicated.
If voiding dysfunction is likely, uroflowometry is
usually the initial investigation.
Where formal urological evaluation is deemed
necessary, it is usually focused initially on the lower
urinary tract to reveal abnormalities of clinical
importance. Following even a single UTI, if there is
pathology requiring surgical intervention, it will
almost always be associated with a history of
voiding difficulty, acute retention or haematuria.11
There is no consensus on the need for endoscopic
evaluation in women with UTI. Most urologists
would not recommend cystoscopy in younger
women (50 years of age), following a single
bacteriologically proven infection. However, recent
data12 has shown that up to 8% of women 50 years
of age with recurrent infection will have significant
abnormalities detected during cystoscopy. It is,
therefore, reasonable to consider undertaking
flexible cystoscopy in women with recurrent UTI,
to exclude underlying intravesical pathology.
Treatment of UTI
For simple uncomplicated urinary infection the
traditional treatment is oral nitrofurantoin,
Box 1 Sexually active women should be advised to void after
Prophylactic measures for recurrent
urinary tract infection
sexual intercourse and avoid the use of spermicidally
lubricated contraceptives where possible.
Perineal hygiene is important: women with recurrent UTI
should be encouraged to shower after sexual intercourse to
reduce colonisation by faecal and perineal organisms.
Postmenopausal women can be prescribed oral or topical
estrogens. This will help shift the vaginal flora from potentially
pathogenic enterobacteria to protective lactobacilli.
Drinking an adequate daily fluid intake will encourage
mechanical washout of bacteria from the bladder and
make colonisation less likely.
Cranberry juice has been shown to reduce bacterial
adherence and bacteriuria in vivo. However, data showing a
beneficial effect on reducing clinical UTI is less clear.
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trimethoprim or a suitable cephalosporin. Short
course therapy (3 days) is recommended, as studies
have failed to demonstrate any advantage to longer
treatments.13 Single dose therapy is occasionally
used but treatment failure rates are higher.
Women with complicated UTI require 1014 days
of antimicrobial therapy and may need parenteral
medication with additional supportive treatment.
Increasing quinolone resistance (23%) in
community-acquired E. coli infection is a cause for
concern and use of this class of antibiotic in
uncomplicated UTI should generally be
discouraged. In addition, E. coli resistance to
trimethoprim is now 1520% in most European
countries and this should inform empirical
antibiotic-prescribing guidelines.8 However,
guidance on microbial sensitivities should be
obtained from the local microbiology service on a
regular basis.
Recurrent UTI
Around 2030% of women with simple cystitis
develop recurrent UTIs.1 In most cases these are
uncomplicated, but a small proportion will have an
underlying pathological, functional or anatomical
abnormality and may require further urological
investigation. In general, treatment should aim to
eradicate the infection and this should be
confirmed with a post-treatment MSSU.
Women who suffer recurrent infections should be
encouraged to undertake additional prophylactic
measures (Box 1). Most of these have a sound basis
for recommendation but randomised evidence,
proving efficacy, is lacking.
Prophylactic antibiotics
Recurrent UTI in healthy nonpregnant women is
defined as three or more episodes of UTI during a
12-month period. Under such circumstances,
continuous antibiotic prophylaxis for 612 months
has been shown in meta-analysis to reduce the rate
of UTI,14 compared with placebo (relative risk
0.21), and is widely recommended.15 We would
recommend either of the following regimens:
cefalexin 125250 mg at night
trimethoprim 100 mg at night
nitrofurantoin 50100 mg at night
Development of candidiasis and gastrointestinal
upset are occasionally seen. There is also a
theoretical risk of increasing antibiotic resistance,
although the regimens suggested have minimal
effects on faecal and vaginal flora. Whilst not
based upon any good evidence, one possible
strategy is to rotate these antibiotics on a regular
basis to reduce the theoretical risk of antibiotic
resistance.
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Unfortunately, prophylactic antibiotics may not
alter the natural history of recurrences and up to
60% of women will re-establish their pattern of
recurrence when prophylactic treatment is
stopped.14 Nevertheless, we would suggest that,
where indicated, prophylactic antibiotics should be
used for 6 months in the first instance. If recurrence
remains a problem, longer periods and,
occasionally, indefinite use of prophylactic
antibiotics will be necessary.
Alternative strategies
Antibiotic self-commencement. Women who
are prone to UTI can keep a supply of antibiotics
at home and start treatment as soon as they
develop symptoms. However, they should be
encouraged to produce an MSSU before starting
the antibiotics to allow accurate microbiological
evaluation of any infection.
Postcoital antibiotics. A single dose of
trimethoprim, nitrofurantoin or cephalexin after
intercourse can reduce UTI in some women who
are prone to intercourse-related UTI.
Box 2 shows a simple algorithm for use in the
management of women with recurrent UTI. Not all
steps are appropriate in every case but it provides a
useful strategy for formulating treatment.
Summary
Recurrent UTI is a common problem encountered
in many areas of clinical practice. It is a cause of
significant morbidity: urinary infection is one of
the commonest indications for antibiotic
prescription in community and hospital settings.
The majority of cases are uncomplicated and
respond rapidly to appropriate treatment.
In the management of women with any type of
UTI, it is important to have an appreciation of the
pathogenesis, host and bacterial interaction,
methods of diagnosis, treatment algorithms and
local antibiotic sensitivities.
It should be remembered that 2030% of women
with UTI develop at least one recurrent infection.
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1. Ensure history is appropriate for recurrent UTI. Box 2
2. Confirm bacteriological evidence of infection.
Algorithm for use in management
of recurrent UTI
3. Exclude underlying anatomical or functional abnormality
using appropriate imaging and endoscopic evaluation.
4. Advise on prophylactic lifestyle changes.
5. Consider a prophylactic antibiotic regimen.
6. Consider alternative strategies.
In addition, a few women have underlying
anatomical or functional abnormalities
(complicated UTI) and require further evaluation
and treatment. The majority of women, however,
do have any significant underlying abnormalities.
An algorithm for managing women with recurrent
UTI is presented above.
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