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Review Article SMJ
Patkawat Ramart, M.D.*, Anne Lenore Ackerman, M.D.**
*Division of Urology, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Division of Female Pelvic
Medicine and Reconstructive Surgery, Department of Urology
David Geen School of Medicine, University of California, Los Angeles, United States of America.
Recurrent Urinary Tract Infection in Women from
a Urologist’s Perspective
ABSTRACT
Urinary tract infection (UTI) referred to microbial invasion of the urinary tract system, typically due to bacteria.
UTI is more common in women than men, which is thought to be due to dierences in lower urinary tract anatomy.
Making a diagnosis of UTI begins with the presence of clinical symptoms consistent with either pyelonephritis
and cystitis. When pyelonephritis symptoms are present, it is usually associated with bacterial infection, while the
symptoms of clinical cystitis may or may not be caused by infection. As both urologic and non-urologic conditions
can produce the clinical symptoms of cystitis, diagnosis of UTI requires both pyuria and bacteriuria on urine
examination. Complicated UTI is when the infection is associated with either host or bacterial factors that increase
the chance of reinfection and decrease treatment ecacy, such as altered organism virulence, immunocompromise,
or urinary tract abnormalities. e urologist’s primary role in UTI management is to evaluate for such urinary tract
abnormalities and, if needed, resolve those conditions to prevent recurrent infection. is review will describe the
urologists’ evaluation and management of complicated and recurrent UTI and inform physician about the urinary
tract abnormalities that can predispose to recurrent UTI.
Keywords: Cystitis; urinary tract infection; urologic condition; investigation (Siriraj Med J 2023; 75: 55-61)
Corresponding author: Patkawat Ramart
E-mail: patkawat.ram@mahidol.ac.th
Received 11 November 2022 Revised 15 December 2022 Accepted 15 December 2022
ORCID ID:http://orcid.org/0000-0002-3394-9349
https://doi.org/10.33192/smj.v75i1.260531
All material is licensed under terms of
the Creative Commons Attribution 4.0
International (CC-BY-NC-ND 4.0)
license unless otherwise stated.
INTRODUCTION
Urinary tract infection (UTI) is microbial invasion,
typically bacterial, of the urinary tract. e global number
of individuals with UTIs in 2019 is more than 404.6
million, with an incidence that is higher in women
than in men.1 In the United States, 10.8% of women
self-reported that they had at least one presumed UTI
during the past 12 months.2 Several non-infectious
genitourinary tract conditions can present with the
same symptoms as UTI, so the diagnosis of UTI relies
upon the combination of clinical symptoms consistent
with pyelonephritis or cystitis accompanied by pyuria
on urine analysis (UA) and signicant bacteriuria on
urine culture (UC). Importantly, in a small number
of cases, recurrent episodes may suggest the presence
of factors that increase the chance of reinfection or
decrease treatment ecacy, factors which distinguish
uncomplicated from complicated UTI. ree main factors,
including organism virulence, host immune system,
and urinary tract abnormality, must be considered. To
prevent reinfection, these factors need to be identied
and properly treated. Collaboration among health care
providers, especially infectious disease specialists and
urologists are needed to cure patients with complicated
UTI. From the urologist’s prespective, a wide range of
genitourinary tract conditions can present with the
clinical syndromes of UTI; as these symptoms may or
may not be associated with true bacterial infection, lack
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56
of complete evaluation can frequently result in delayed
or missed diagnoses of underlying conditions. erefore,
this review would like to guide urologists in how to
evaluate and diagnose complicated UTI, particularly
in the context of genitourinary tract abnormalities, as
well as inform physicians about preventive strategy for
patients with uncorrectable conditions.
How to diagnose UTI?
Basically, there are two clinical syndromes of UTI:
pyelonephritis when the infection occurs in the upper
urinary tract and cystitis for infection of the lower urinary
tract. e symptoms of pyelonephritis are fever, ank
pain, and/or chills, while the symptoms of cystitis are
dysuria, frequency, urgency, urgency urinary incontinence,
hematuria, and/or suprapubic pain. A meta-analysis
examining the accuracy and precision of factors derived
from the history and physical examination for UTI
diagnosis in women showed that four symptoms: dysuria,
frequency, hematuria, and back pain with costovertebral
angle tenderness on exam signicantly increased the
probability of UTI. When dysuria and frequency were
combined without vaginal discharge or irritation, the
probability of UTI was greater than 90%.3 However,
while these clinical syndromes are most commonly
linked to infections, non-infectious conditions, such
as malignancy, may sometimes present with similar
symptoms. To diagnose UTI correctly, urine examination
including urine analysis (UA) and urine culture (UC) are
essential. To be consistent with a diagnosis of UTI, UA
should demonstrate pyuria, dened as the presence of ≥ 3
white blood cells per high power eld of unspun urine or
≥ 10 white blood cell per cubic millimeter4 and signicant
bacteriuria. Pyuria without bacteriuria, termed sterile
pyuria, may indicate urologic malignancy, urolithiasis,
or genitourinary tract tuberculosis. It is also important
to note that the presence of bacteriuria on UA is not
always indicative of an infection. Both colonization and
contamination can present with signicant bacteriuria, so
symptoms are an important component of the diagnosis
of UTI.
Urine culture (UC) is still considered the gold
standard investigation for diagnosis of bacterial UTI;
but there is substantial debate about the appropriate
threshold of colony forming units (CFU) count. Previously,
a cut-o value of 105 CFU/ml was widely accepted as
signicant bacteriuria consistent with infection. However,
in patients with convince ing signs and symptoms of
infection, a lower threshold of 102 CFU/ml is reasonable.5
In addition, standard clinical urine culture does not
detect all bacteria equally, preferentially detecting aerobic
bacteria. If anaerobic bacterial or mycobacterial infections
are suspected, special staining, culture techniques, or
molecular diagnostic approaches, such as polymerase
chain reaction (PCR), may be required.
In summary, a diagnosis of UTI requires the
combination of the constellation of symptoms seen
in UTI clinical syndromes and abnormal urine testing
demonstrating pyuria and signicant bacteriuria.
What is complicated UTI?
To determine appropriate management, UTI should
be divided into uncomplicated and complicated subtypes.
Complicated UTI is dened as infections associated
with factors that increase the chance of reinfection and/
or decrease treatment ecacy, such as atypical, highly
virulent or drug-resistant organisms, host immune
dysregulation, and urinary tract abnormalities.5 e
management of complicated UTI requires thorough
evaluation and management of any correctable factors
to break the cycle of recurrence.
Recurrent UTI is dened as ≥ 2 episodes within 6 months
or ≥ 3 episodes of within 12 months of microbiologically
diagnosed UTI. With these infections, symptoms should
resolve between episodes prior to diagnosis of another
UTI.5,6 Risk factors for recurrent UTIs dier between
age groups. In women age less than 40 years of age, risk
factors typically relate to sexual behavior and spermicide
use.7-9 In postmenopausal women, a history of previous
UTIs, prior urogenital surgery, symptomatic urinary
incontinence, presence of cystocele on vaginal examination,
maximal urine ow ≤ 15 ml/sec dened by uroowmetry,
and elevated post-void residuals were associated with
a higher risk of recurrent UTI.10 erefore, there is a
higher likelihood of functional and anatomic urinary tract
abnormalities in this older population, which necessitates
thorough investigation.
Conditions associated with clinical cystitis
Most episodes of clinical pyelonephritis are bacterial
infections, which typically requires hospital admission for
evaluation and treatment. In contrast, the clinical syndrome
of cystitis is typically managed in the outpatient setting,
and thus is not always thoroughly evaluated. Multiple
urologic and non-urologic conditions with or without
simultaneous bacterial infection can cause recurrent
clinical cystitis symptoms. In addition to uncomplicated
cystitis, other urologic conditions, such as malignancy,
urolithiasis, neurogenic lower urinary tract dysfunction,
tuberculosis of urinary tract, ketamine-induced cystitis,
radiation-induced cystitis, interstitial cystitis, bladder
diverticulum, urethral diverticulum, urethral stricture,
Ramart et al.
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Review Article SMJ
periurethral fibrosis, and functional bladder outlet
obstruction, can cause cystitis-like symptoms. Non-
urologic conditions can be of a gynecologic (e.g., pelvic
organ prolapse, endometriosis, and uterine/cervical/vaginal
tumor) or colorectal (colovesical stula, diverticulitis, and
rectal tumor) origin. (Fig 1 & 2) Other rare conditions
Fig 1. (A) Ultrasonography demonstrates a bladder diverticulum, an outpouching lesion arising from the posterior bladder wall. (B)
Computed tomography demonstrates a rectovesical stula, occurring aer low anterior resection for rectal cancer. (Yellow arrows) (C)
Magnetic resonance imaging shows a urethral diverticulum, an outpouching lesion arising from and wrapping around the urethra. (Yellow
circle) (D) Cystoscopy demonstrated endometriosis, involved posterior bladder wall, seen as tortuous dark-blue lesions. (White arrows)
(E) Vaginal examination demonstrated mesh extrusion (white circle) aer pelvic organ prolapse repair, causing of vaginal infection and
clinical cystitis-like symptoms. (F) Intraoperative ndings from abdominal cystotomy demonstrated a severely contracted and inamed
bladder wall (white circle) from ketamine abuse.
causing clinical symptoms of cystitis are pelvic congestion
syndrome and non-relaxing pelvic oor dysfunction.
All conditions can initially be evaluated with careful
history and physical examination. If needed, additional
investigations can be considered to conrm the suspected
diagnosis.
Fig 2. Voiding cystourethrography with concomitant intravesical pressure measurement on videourodynamics demonstrated urethral
distortion (Red circle) and high detrusor contraction with low urine ow (Graph) consistent with bladder outlet obstruction aer anterior
vaginal wall repair.
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58
Investigation for recurrent UTIs
Generally, anatomical evaluation for urinary tract
abnormalities can include ultrasonography (US), intravenous
urography (IVU), computed tomography (CT), and
magnetic resonance imaging (MRI). Multiple studies,
however, have shown little benet for routine anatomical
investigation in women with recurrent UTI.11,12 IVU is
rarely helpful; more than 80% of IVU in women with
recurrent UTIs are completely normal.13-15 As an initial
investigation in women in whom there is suspicion
of anatomic abnormalities, US is recommended as an
initial investigation to replace IVU; US is inexpensive,
non-invasive, confers no radiation exposure, and can
provide guidance for further investigations.16 CT and
MRI are not routinely performed and only recommended
in cases in which specic conditions, such as colovesical
stula, are suspected or abnormalities were previously
detected on physical examination or US. Cystoscopy rarely
provides any information that would alter management;
the most common nding is mucosal inammation.12,14,17
If no abnormal ndings are seen on US or CT, 94%
of subsequent cystoscopies are normal.17 Therefore,
cystoscopy is only considered in specic conditions,
such as hematuria, suspected malignancy, or suspicion
for other specic clinical condition.
If anatomic investigation fails to demonstrate an
abnormality, it is reasonable to consider functional
investigation of the lower urinary tract.12,18 Investigation
can include non-invasive uroowmetry (UFM), assessment
of post-void residual urine (PVR), and urodynamic
(UDS) assessment with or without video assessment
(VUDS). In principle, functional abnormalities should
be focused on incomplete bladder emptying and voiding
dysfunction. VUDS showed evidence of lower urinary
tract dysfunction in 67 – 90% in women with recurrent
UTIs.18,19 e most common nding was bladder outlet
dysfunctions in 63% of women, with a hypocontractile
detrusor seen in 16%.19 Together, this evidence suggests
an algorithmic investigation of women with recurrent
UTI. (Fig 3)
(*) Cystourethroscopy when US, CT or MRI demonstrates lower urinary tract abnormality or history of lower urinary tract surgery.
(#) UDS or VUDS is indicated when uroowmetry shows abnormality or PVR measurement is more than 20% of bladder capacity.
Fig 3. Proposed investigation ow for women with recurrent UTI
Ramart et al.
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Review Article SMJ
Reasons of treatment failure in urinary tract abnormality
UTIs can continue to recur due to antimicrobial
resistance, biolm formation, and immunocompromise
in the host, as well as the anatomical and functional
abnormalities discussed above. When the underlying
cause is clearly diagnosed and appropriately treated
either with surgery or medication, UTI can oen be
cured without recurrences. Unfortunately, majority of
cases are combined between both abnormalities. Even
aer correcting an anatomical abnormality, UTI can
still recur, frequently because of a previously co-existing
or new-onset functional abnormality. Such new-onset
(“de novo”) abnormalities may or may not be associated
with the surgical repair. It is important to consider re-
evauation if UTIs continue to recur aer anatomical
correction, although this should only proceed aer an
appropriate interval for healing to avoid confounding
factors occurring aer surgery. Occasionally, it is not
possible to correct the urinary tract abnormalities and
continuous preventive strategies are necessary.
Prevention for recurrent UTIs
Prevention strategies aim to decrease UTI episodes
in patients waiting for denitive treatment, those with
uncorrectable conditions who have little chance of complete
bacterial eradication, or those who are unable or unt
for surgical correction of their underlying condition.
Strategies include antibiotic and non-antibiotic prophylaxis
regimens.
Antibiotic prophylaxis regimens including continuous
low-dose and post-coital antibiotics. One systematic
review indicated that continuous antibiotic prophylaxis
for 6 – 12 months could signicantly reduce the rates of
UTI in comparison to placebo.20 Post-coital antibiotics
are a reasonable option for prevention in patients whose
cases of UTI are associated with sexual intercourse.20
While continuous antibiotic prophylaxis can prevent
recurrent episodes, however, this regimen potentially
increases urinary and fecal antibiotic resistance. In addition,
infections tend to recur once the antibiotics are stopped.21
Given these limitations, there are many agents to use
for non-antibiotic prophylaxis, including probiotics,
estrogen, urine acidication agents, cranberries, and
D-mannose.
Probiotics
Food and Agriculture Organization of the United
Nations (FAO) and the World Health Organization
(WHO) defines probiotics as live microorganisms
which, when administered in adequate amounts, confer
a health benet to the host.22 e most common probiotic
used for preventing UTI in women is Lactobacillus. A
randomized, double-blinded, non-inferiority trial comparing
antibiotic prophylaxis with 480 mg of trimethoprim-
sulfamethoxazole once daily to oral capsules containing
Lactobacilli twice daily for 12 months demonstrated that
Lactobacilli were not inferior to antibiotic prophylaxis
in the prevention of UTI. Moreover, Lactobacilli did not
increase antibiotic resistance.23 However, given only a
small number of equivocal studies, a lack of consistent
probiotic formulations, and a high risk of bias, a recent
systematic review and meta-analysis study concluded
there was insucient evidence to determine the benet
of probiotics for UTI.24
Estrogen
Lack of estrogen in postmenopausal women may
contribute to a risk of recurrent UTI because the changing
vaginal environment. Loss of the normal ora may allow
pathogens to colonize and infect the lower urinary tract.
A systematic review and meta-analysis showed that while
oral estrogen did not signicantly reduce the number
of women with UTI in comparison to placebo, vaginal
estrogen use signicantly reduced the number of UTI when
compared to both placebo and no treatment.25 Reported
adverse events were rare, but include breast tenderness,
vaginal bleeding or spotting, vaginal discharge, and vaginal
irritation or burning.25 While typical vaginal estrogen
doses are associated with little systemic absorption,
treatment with estrogen must be used with caution
in endometrial cancer, breast cancer, cardiovascular
disease, deep venous thrombosis, pulmonary embolism
and chronic liver disease.
Urine acidication agents
Bacterial growth is inhibited by acidied urine,
so agents which can reduce urine pH may be eective
treatments. Commonly used agents are Methenamine
Hippurate and ascorbic acid. While the concept of
urinary acidication has promoted the use of ascorbic
acid, known as vitamin C, for UTI prevention, there is
no strong evidence to support its use in prevention of
recurrent UTI. Methenamine hippurate will also acidify
the urine and has an additional bacteriostatic eect
due to its peripheral metabolism into formaldehyde
in the urinary tract. Dosage ranges between 1 and 4 g
daily. Common adverse events are gastrointestinal
irritation, abdominal cramps, anorexia, rash, stomatitis,
and dysuria. While previous data had suggested a small
benet in patients without urinary tract abnormalities, a
systematic review and meta-analysis demonstrated that
the overall quality of the previous studies was poor, oen
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60
examining heterogenous populations.26 As a result, this
agent had not been recommended in any guidelines. A
recent, randomized clinical trial, however, demonstrated
non-inferiority of methenamine to continuous antibiotic
prophylaxis in the prevention of recurrent UTI, suggesting
this agent may have utility in UTI prophylaxis.27
Cranberries
A-type proanthocyanidins (PACs), found in high
levels in cranberries, can prevent bacterial adhesion.28
As a result, cranberries have been suggested as non-
antibiotic prophylaxis for UTI because many studies
had demonstrated that it can prevent bacterial adhesion
to the urothelium in vitro.29,30 Focusing on the outcome
of women with recurrent UTI in systematic review and
meta-analysis study, a meta-analysis of four studies
comparing between cranberry and placebo or no treatment
showed a small, non-signicant reduction in risk of repeat
symptomatic UTI but the analysis of two studies comparing
cranberry product and antibiotic prophylaxis showed
equally eective.31 Importantly, cranberry tablets may
alter urinary oxalate and uric acid excretion, so patients
with a history of urolithiasis should be counselled about
this risk before choosing cranberry as a preventative
approach.32 Until now, the evidence to support a role of
cranberries for UTI prevention is inconclusive. Recent
evidence, however, suggests that some of the conicting
evidence regarding cranberry ecacy in UTI prevention
may come from dierences in cranberry formulations
and products; varying amounts of bioactive PACs within
each product may underlie diering ecacies in UTI
prevention.33,34 As no serious adverse events have been
reported, cranberries may be used in patients who desire
a non-antibiotic approach.
D-mannose
D-mannose, a type of sugar, prevents bacterial adhesion
to the urothelium both in vitro and in animal studies
by binding to bacterial pili.35,36 For clinical use, a recent
meta-analysis of two randomized controlled trials and
one prospective study showed that D-mannose treatment
had similar eectiveness in preventing subsequent UTIs
as antibiotic prophylaxis with minimal adverse events,
but the studies were again of poor to fair quality due to
allocation concealment and lack of blinding. Dosage was
various from 420 to 6,000 mg daily, varying signicantly
between studies and formulations used. Adverse events,
such as diarrhea and gastrointestinal irritation, were
typically mild.37
CONCLUSION
Urinary tract infection (UTI) is a common problem
in women. Many urologic and non-urologic conditions
may present with the same clinical syndrome as UTI,
including pyelonephritis and cystitis. erefore, urine
examination including urine analysis and culture is
critical to conrm infection. In addition, some of these
non-infectious conditions can confer an increased risk of
recurrent UTI; therefore, in cases in which an anatomic
abnormality is suspected from history and physical
examination or recurrent episodes are refractory to
treatment, further investigation should be considered.
In cases of complicated UTI that are unable to be cured
by denitive treatment, preventive strategies should be
employed to decrease UTI episodes and prevent further
consequences.
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