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Lower urinary tract infection

Introduction
Urinary tract infections (UTIs) are one of the most common bacterial infections, affecting 150 million people each year worldwide. Annually, UTIs result in 10.5
million office visits (constituting 0.9% of all ambulatory visits) and 2 to 3 million emergency department visits in the United States alone. Within the United
States, societal costs, including health care costs and time missed from work, are approximately $3.5 billion per year. It is estimated that up to one out of every
three women has had at least one episode of UTI requiring antimicrobial therapy by 24 years of age, with the lifetime risk being greater than 50%. The
prevalence of UTIs among women is thought to increase even further with age, with 10% of women over 65 years and 30% of women older than 85 years
reporting UTI within the prior 12 months. Clinicians managing urogynecologic patients need to be well-versed not only in management of acute UTIs, but also of
recurrent UTIs (rUTIs) and asymptomatic bacteriuria (ASB) because of high incidence in this population (i.e., postmenopausal women and patients undergoing
procedures that require instrumentation of the genitourinary tract).

By definition, UTIs include cystitis (infection of the bladder/lower urinary tract) and pyelonephritis (infection of the kidney/upper urinary tract) ( Table 36.1 ). UTI
is diagnosed based on the presence of a pathogen in the urinary tract and associated symptoms. Uncomplicated UTIs typically affect individuals who are
otherwise healthy and have no structural or neurological urinary tract abnormalities; these infections are differentiated into lower tract UTIs (cystitis) and upper
tract UTIs (pyelonephritis). In contrast, a complicated UTI refers to cystitis or pyelonephritis in a patient with a variety of factors including urologic abnormalities
(such as nephrolithiasis, strictures, stents, or urinary diversions), immunocompromising conditions (such as neutropenia or advanced human immunodeficiency
virus infection), or poorly controlled diabetes mellitus. Certain populations, such as pregnant women and renal transplant recipients, also have unique
management considerations. There are multiple definitions for rUTI, but the most common is at least two episodes of culture-positive, symptomatic UTIs within 6
months, or at least three in 1 year. Finally, ASB is the presence of one or more species of bacteria growing in the urine at specified quantitative counts (≥10 5
colony-forming units [CFU]/mL), irrespective of the presence of pyuria, in the absence of signs or symptoms attributable to UTI.

TABLE 36.1
Urinary Tract Infection Terminology
Diagnosis Definition
Acute uncomplicated Infection of the lower and/or upper genitourinary tract that is diagnosed based on the presence of a urinary tract pathogen and its
urinary tract infection associated symptoms in an otherwise healthy individual without structural or neurological urinary tract abnormalities
Cystitis Infection of the bladder/lower urinary tract
Pyelonephritis Infection of the kidney/upper urinary tract
Complicated urinary
Cystitis or pyelonephritis in a patient with urologic abnormalities, immunocompromising conditions, or poorly controlled diabetes mellitus
tract infection
Recurrent urinary tract
At least two episodes of culture-positive, symptomatic UTI in 6 months, or three or more in 1 year
infection
Asymptomatic The presence of bacterial growth on urine culture at ≥10 5 colony-forming units/mL in the absence of signs or symptoms attributable to
bacteriuria UTI
Urosepsis Systemic response to uropathogen leading to organ dysfunction
 
UTI, Urinary tract infection.

Acute, symptomatic, uncomplicated lower urinary tract infection

Definitions
Uncomplicated UTIs are differentiated into lower UTIs (cystitis) and upper UTIs (pyelonephritis) ( Table 36.1 ). In this chapter we will discuss the diagnosis and
management of lower UTIs (i.e., cystitis). Management guidelines for acute, symptomatic, uncomplicated UTI have been developed for nonpregnant
premenopausal women without underlying structural urologic abnormalities, but they likely can be extrapolated to postmenopausal women without urological
sequelae and/or recurrent infections.

Pathophysiology
UTIs can be caused by both gram-negative and gram-positive bacteria, but the most common causative agent for uncomplicated UTIs is uropathogenic
Escherichia coli . UTI typically starts with periurethral contamination by a uropathogen residing in the gut, followed by colonization of the urethra and migration

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of the pathogen to the bladder. This process requires microbial virulence factors including flagellae, pili, and other adhesins that facilitate mucosal adherence
and stimulation of the host immune response.

There are multiple factors that typically aid in UTI deterrence. These include: the acidic vaginal environment, the glycosaminoglycan (GAG) layer of the bladder,
and immunoglobulins in the urine. The acidic pH of the vagina in premenopausal women inhibits the growth of enterobacteria such as E. coli and promotes the
growth of Lactobacilli , a genus of microbes associated with health. The GAGs in the bladder lining and immunoglobulins in the urine restrict bacterial
adherence. Tamm–Horsfall proteins secreted by the loop of Henle may also inhibit bacterial adherence to the urothelial cells, and antimicrobial peptides may
serve to modulate the immune response during bacterial presence.

Diagnosis
There is currently no “gold standard” definition for an acute UTI, which poses a challenge not only for clinical care but also for epidemiologic research.
Historically, establishing a diagnosis of symptomatic UTI requires a patient to have symptoms and signs of UTI with laboratory tests confirming the diagnosis
(bacteriuria ≥10 5 CFU/mL). Some experts advocate for relaxing these diagnostic criteria to include symptomatic patients with urine culture of 100 CFU/mL or
more. Lower colony counts on culture may represent a partially treated infection, an earlier stage of infection, the effects of diluting the bacterial concentration
with urination, or the mode of specimen collection (i.e., voided vs. catheterized sampling).

Cystitis in women usually causes dysuria, although it may also cause frequency, urgency, and suprapubic discomfort. Occasionally, mild incontinence and
hematuria may occur. Gross hematuria is rare. Upper tract infections commonly present with fever, chills, malaise, flank pain, costovertebral angle tenderness,
and occasionally nausea and vomiting. In young women, patients with dysuria and frequency without vaginal discharge or irritation have a 90% probability of a
UTI. Dysuria remains the most discriminating symptom in older women seen in urogynecologic offices. However, in older women symptoms of frequency and
urgency are less specific because of the high prevalence of other bladder symptom conditions like overactive bladder in aging populations.

Diagnostic testing
Urine dipstick.
For many women with dysuria, lack of vaginal discharge, and classic acute simple cystitis (not in the setting of rUTI), no additional testing is warranted to make
the diagnosis. For those with suggestive, but not clearly diagnostic, features, a urinary dipstick can be helpful to rule out an infection but may have less of a role
in confirming an infection. In these settings, the absence of nitrites and leukocyte esterase lowers the probability of UTI. Nitrites are seen in the setting of gram-
negative bacteria because these types of bacteria convert nitrates to nitrites. Leukocyte esterase on urinary dipstick corresponds to pyuria, or white blood cells
in the urine. False-negative nitrite results could occur in the setting of gram-positive bacteria, but cystitis is uncommon in patients without pyuria. More
commonly, false-positive urine dipstick results are seen, especially when voided specimens are used. In women, poor collection techniques and vaginal
contamination with voided samples contribute to false-positive findings ( ). Therefore, although urine dipsticks can provide clinical information, ultimately the
provider should incorporate clinical judgment and/or additional diagnostic testing when making final decisions regarding treatment.

Microscopic urinalysis.
Microscopic examination of urine can detect the presence of bacteria, leukocytes, and red blood cells. Pyuria is defined as 10 or more leukocytes/mL or 3 or
more leukocytes/high-powered field of unspun urine. As earlier, in the absence of pyuria, the diagnosis of UTI should be questioned. Pyuria has been proposed
as a way to differentiate between acute UTI and ASB, but recent guidelines recommend that the diagnosis of ASB can be made even in the setting of pyuria.
Patients could exhibit pyuria with negative urine culture (i.e., sterile pyuria) if urinalysis is performed after initiating antimicrobial therapy. Neither microscopic
hematuria nor bacteriuria on urinalysis is a particularly sensitive finding for UTI. However, microscopic urinalysis is the gold standard for evaluation of hematuria
outside of infection (see Chapter 40 ). Beyond this standard indication for testing, it is likely an unnecessary cost.

Urine culture.
Urine culture may not be necessary for acute cystitis, but the primary disadvantage of symptom-based diagnosis is that it may result in overtreatment and
inappropriate antibiotic use. This is especially possible in older women, where symptoms of UTI overlap with other noninfectious bladder symptom conditions.
Urine culture is considered the reference standard for diagnosis of UTI. Cultures should be submitted for scenarios such as negative urine dipstick test in a
symptomatic patient, poor response to initial therapy, and recurrent symptoms less than 1 month after treatment for a previous UTI. As mentioned previously,
although a culture result of 10 5 CFU/mL or more in a voided urine sample has historically been considered diagnostic for UTI, some feel that 100 CFU/mL or
more should suffice in a patient who has symptoms consistent with UTI, as well as pyuria. If there is a suspicion for pyelonephritis (i.e., fever, costovertebral
tenderness/flank pain), then a urine culture and antibiotic susceptibilities should always be obtained.

Clinical management
Antibiotics for simple cystitis.
The Infectious Diseases Society of America (IDSA) published an updated clinical practice guideline on the treatment of women with acute uncomplicated cystitis
and pyelonephritis in 2010. They note that the focus of these guidelines is treatment of nonpregnant, premenopausal women with no known urological
abnormalities. Postmenopausal women, those without rUTI, and/or those with well-controlled diabetes without urological sequelae can usually be treated with
the same recommendations.

The three first-line antibiotics for UTI treatment are nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), and fosfomycin ( Table 36.2 ). Fluoroquinolones
should only be used if there is any suspicion for early pyelonephritis.

TABLE 36.2
Antibiotic Regimen for Acute Cystitis
Estimated Clinical
Dose Side Effects and Contraindications
Efficacy
First-Line Antibiotics

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Estimated Clinical
Dose Side Effects and Contraindications
Efficacy
•
GI distress

•
Minimal resistance propensity

Nitrofurantoin
100 mg BID × 5 days • 79%–92%
monohydrate/macrocrystals
Avoid if CrCl <30 mL/min

•
Rare pulmonary toxicity

•
GI distress

•
Allergic response to sulfa component
Trimethoprim/sulfamethoxazole 160/800 mg BID × 3 days 79%–100%

•
Avoid if regional resistance >20%

•
Minimal resistance propensity

•
Fosfomycin trometamol 3 g single dose 63%–91%
May have lower clinical efficacy than other
medications

Second-Line Antibiotics
•
GI distress

•
Dose varies; typically 3- to 5- Allergic response
β-lactams
d regimen
•
Decreased efficacy compared with other options

•
High resistance prevalence

Fluoroquinolones Dose varies; typically for 3–5 days •

Possible risk of musculoskeletal adverse events

 
BID , twice a day; GI , gastrointestinal; CrCl , creatinine clearance.

Nitrofurantoin is bacteriostatic and therapeutically active only in the lower urinary tract. It is effective against E. coli and many gram-negative species with low
levels of resistance. However, it can be ineffective against other uropathogens. TMP-SMX is a broad-spectrum antibiotic that covers gram-positive bacteria,
including methicillin-resistant Staphylococcus aureus, and most gram-negative bacteria. In regions where there is greater than 20% local E. coli resistance to
TMP-SMX, an alternative treatment should be given. Reported duration of TMP-SMX treatment has ranged from 3 to 14 days, with the 3-day course having
similar efficacy to 5- to 10-day regimens. Finally, fosfomycin tromethamine, the stable salt form of fosfomycin, is taken in a single dose that becomes highly
concentrated in the urine, resulting in urine levels that persist for 30 to 40 hours. Fosfomycin has activity against both gram-positive and gram-negative bacteria,
including S. aureus , Enterococcus , Pseudomonas aeruginosa , and Klebsiella pneumoniae . There are relatively low levels of resistance to fosfomycin, making
it a drug of choice in infections with multidrug-resistant organisms, but there is some suggestion that single-dose regimen may have less efficacy than other
therapies. When first-line medications are not available or cannot be prescribed because of patient allergies, intolerances, or bacterial resistance, second-line
antimicrobials, β-lactams, and fluoroquinolones can be used. Although 3-day fluoroquinolone regimens (i.e., ciprofloxacin and levofloxacin) are efficacious, they
are not first-line agents because of increasing resistance, higher expense, and serious adverse events, as described in a 2016 Food and Drug Administration
warning.

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Antimicrobial-sparing strategies.
Given that acute simple cystitis has a low risk of progression in patients without risk factors for serious infection ( ), antimicrobial-sparing strategies are attractive
to consider. Delaying antimicrobial therapy while awaiting urine culture results appears to be a reasonable approach in women without comorbidities, especially
if empiric therapy is complicated by resistance or drug intolerance. In a randomized trial of nonpregnant women younger than 75 years of age with acute simple
cystitis, symptom duration and severity were similar with immediate antimicrobial therapy compared with four other strategies, including delayed antimicrobial
therapy and antimicrobial therapy based on a symptom score, urinalysis findings, or urine culture results ( ). One large, retrospective database analysis of
patients 65 years of age or older with lower UTI suggested an association between delaying antimicrobial therapy and subsequent bloodstream infection within
60 days, but this study had significant limitations, including potential misdiagnosis of cystitis ( ).

Substituting antiinflammatory agents for antimicrobial therapy has also been evaluated, but currently is not recommended as the initial approach to
management of symptomatic acute simple cystitis. Two trials comparing nonsteroidal antiinflammatory drugs (ibuprofen and diclofenac) to antibiotics
(fosfomycin and norfloxacin) showed that between 50% and 75% of women achieved symptom improvement, but there were higher incidences of pyelonephritis
or additional therapy in the nonsteroidal antiinflammatory arms ( ; ).

Complicated urinary tract infections

Definition
UTIs are considered to be “complicated” when there are host factors (e.g., poorly controlled diabetes or immunosuppression), anatomical abnormalities (e.g.,
outlet obstruction), or functional abnormalities (e.g., incomplete voiding because of detrusor muscle dysfunction) that lead to an infection that could be more
difficult to eradicate than uncomplicated infections ( ).

Pathophysiology and clinical management

Because the underlying comorbidities that may predispose to complicated UTI are heterogenous, there is not one unifying pathophysiologic mechanism.
Important guiding principles include the continued necessity of assessing relevant clinical symptoms (e.g., dysuria, urgency, frequency, flank pain,
costovertebral angle tenderness, suprapubic pain, and fever) to diagnose UTI. In some clinical situations, the symptoms may be atypical (i.e., neurogenic
bladder disturbances, catheter-associated UTI), but it is important to maintain discretion regarding antibiotic usage and to remember that many lower urinary
tract symptoms and systemic symptoms are not always attributed to UTI. Pretreatment urine cultures are an important component of management for patients
with suspected complicated UTI, as bacteria are more likely to be resistant to antibiotics in this population.

Best practices include hospitalization for patients with suspected complicated UTI and associated systemic symptoms. The initial antimicrobial regimen should
be chosen based on local resistance data and previous urine culture results from the patient, if available. Efforts should be made to improve contributing host
factors and/or to mitigate or remove any structural or anatomic factors whenever possible. The antibiotic regimen should then be tailored on the basis of
susceptibility results. Finally, longer courses of antibiotics (i.e., 7–14 days) are recommended for most cases.

Recurrent symptomatic urinary tract infection

Definition
There are multiple definitions for rUTI. We support the culture-based definition of at least two culture-proven episodes in 6 months, or at least three in 1 year (
Table 36.1 ). It is assumed that these episodes are separate events; however, there is no consensus recommendation to document resolution of any episode
with posttreatment culture. Generally, a recurrence is thought to be return of symptoms at least 2 weeks after prior treatment, or documentation of clearance. In
the absence of documentation of clearance, a patient may also have a persistent infection that was not adequately cleared with initial therapy.

Diagnosis
When first seeing a patient with possible rUTI it is imperative to obtain clarification surrounding the details of UTI events, including UTI testing and culture
results when available, as well as current prevention practices. The symptoms that the patient attributes to the UTI should be documented, including duration
and response to therapy, because these may vary between patients. Symptoms are typically acute in onset and include dysuria, urinary frequency and urgency,
suprapubic or flank pain, hematuria, and/or documented fever. Patients often attribute many nonspecific symptoms (i.e., foul-smelling urine, cloudy urine,
general malaise, confusion) to UTI, although these are signs more consistent with ASB (see later).

Pathophysiology
Classically, major risk factors for UTI include sexual activity and a history of UTI, but the factors predisposing postmenopausal women to rUTI have been
significantly less investigated than those for premenopausal women. Some women have a genetic predisposition to UTI owing to differences in mucosal
bacterial binding properties, which could be related to certain red blood cell antigens.

Premenopausal.
For premenopausal women, the pathogenesis of recurrent cystitis is assumed to be the similar to that of sporadic infection. Most uropathogens originate in the
rectal flora, colonize the periurethral area and urethra, and ascend to the bladder. In studies of young women, frequency of sexual intercourse, spermicide
exposure (with or without diaphragm use), a new sexual partner within the past year, a history of first UTI before the age of 15 years, and a maternal history of
UTI have been demonstrated to increase risk of rUTI. Increasing evidence suggests that alteration of the normal vaginal flora, especially loss of hydrogen
peroxide–producing lactobacilli, may predispose women to introital colonization with E. coli and ensuing cystitis ( ).

Postmenopausal.
The urogenital microbiome undergoes changes as women age, often reducing a woman’s natural defense mechanisms against UTI. The healthy
premenopausal vagina is known to be largely colonized by Lactobacilli . After menopause, decreased systemic and local estrogen levels result in an elevated
vaginal pH, which in turn results in fewer Lactobacilli in the vagina. Together, these factors increase the chance of microbes with uropathogenic capability
establishing residence in the vagina and distal urethra. Recently, the discovery of the female urobiome has raised the possibility of alternatives to antibiotic
treatment that modulate or boost the innate healthy commensal urinary microbiome. Despite sharing many bacterial species, the urinary microbiome is a unique

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niche that is related to, but not the same as, the vaginal microbiome. Ongoing studies will help clarify how components of the female urinary microbiome relate
to the pathophysiology of UTIs in postmenopausal women.

In rUTI, similar to acute UTI, E. coli is the most common uropathogen. Preclinical data show that E. coli has the capacity to form intracellular bacterial
communities (IBCs) that allow bacteria to survive in the urinary bladder after antibiotic treatment. These IBCs also shield bacteria from the host immune
response. The detection of exfoliated urothelial cells with IBCs in the urine of women with UTI supports the hypothesis that intracellular bacterial niches persist,
which may have important implications for UTI recurrence and treatment. Although E. coli remains the most common uropathogen, among postmenopausal
women there is a higher proportion of non– E. coli bacteria, with up to 35% of rUTIs occurring in the setting of other microbes. K. pneumoniae and Enterococcus
faecalis are other common uropathogens in postmenopausal UTIs, which raises questions as to whether rUTIs occur because of changes in the host immune
response. Overall, risk factors for non– E. coli UTI include history of rUTI, recent pelvic surgery, and older age. Prolapse and urinary incontinence do not seem
to be related to presence of non– E. coli uropathogens.

Evaluation
Initial physical examination should include abdominal and focused neurologic examinations, as well as pelvic examination, to detect manageable conditions,
including genitourinary atrophy in postmenopausal women or urethral diverticulum. An assessment of bladder emptying should be considered by urethral
catheterization or bladder scan (ultrasonography), especially in patients with neurologic disease, diabetes, or significant prolapse.

Radiographic imaging studies of the upper and lower urinary tract should only be considered in occasional scenarios, such as in patients with poor response to
appropriate antimicrobial therapy, infections caused by unusual organisms such as Proteus, a history of calculi, potential ureteral obstruction, recurrent
pyelonephritis, suspected urethral diverticula, or a history of many UTIs during childhood. The indications for cystourethroscopy in women with UTI are
controversial, because findings often do not often alter management. However, it is reasonable to consider cystoscopy in patients with inadequate response to
appropriate antimicrobial therapy, gross hematuria, suspected urethral diverticulum, and suspected mesh or nonabsorbable suture material in the bladder or
urethra. It should also be considered in older patients for whom bladder cancer may be of concern for other reasons.

Acute infections
Compared with uncomplicated UTI, the most important difference in management for those with rUTIs is that clinicians should obtain urine culture and
sensitivity with each symptomatic acute cystitis episode before initiating treatment. This is because of the lower prevalence of E. coli and the higher chance of
antibiotic resistance in this patient population, as well as the need for confirmation of UTI diagnoses in more complex clinical scenarios. Similar to patients
without a history of rUTI, clinicians should offer hydration and urinary analgesics for patient comfort while awaiting urine culture results. Patients who have
classic symptoms (i.e., dysuria, new-onset urinary urgency and/or frequency) and prefer prompt antibiotic therapy can provide urine samples for testing and
initiate empirical therapy based on microbial history, allergy profile, and medical status. Two heterogeneous trials have evaluated this management strategy with
different approaches. studied single-dose versus short-course antibiotics after UTI-predisposing conditions, and compared intermittent TMP-SMX versus daily
prophylactic TMP-SMX. Both trials were very small, and, with recent concerns for antimicrobial resistance, existing guidelines suggest that empiric or self-start
therapy should at least be preceded by a urine culture collection to guide antibiotic management. Treatment refinements can follow final urine culture results.
Management of symptomatic UTIs should be informed by microbial identification and susceptibility, as well as the local antibiogram, which provides clinicians
with information regarding microbial resistance patterns in the local community. Most patients with rUTI can be prescribed 3 to 5 days of an appropriate
antibiotic for each cystitis episode, but for those with refractory infections, short interval between infection, or multiple recent recurrent episodes, a longer course
of antibiotics can be initiated. It is usually unnecessary to use antibiotics for longer than a 7-day period.

Prevention strategies
The goal of rUTI prevention is to avoid or suppress subsequent infections. Although the most robust evidence is found with vaginal estrogen and antibiotics,
alternative nonantibiotic options exist as well. In an era of antimicrobial stewardship, we generally consider starting with estrogen prophylaxis for appropriate
candidates and adding antibiotics if needed for persistent rUTIs.

Vaginal estrogen prophylaxis.

The pathogenesis of rUTIs in peri- and postmenopausal women may, in part, be related to the vaginal microbial changes associated with menopause. Lower
systemic and local estrogen levels raise the vaginal pH and decrease the lactobacillus-dominant vaginal flora typical for premenopausal women. Together, these
factors increase the chance that microbes with uropathogenic capability establish residence in the vagina.

In peri- or postmenopausal women, there is high-quality evidence that vaginal estrogen therapy can reduce the risk of rUTI, but there is little evidence
recommending one formulation over another. Vaginal estrogen cream (17β-estradiol or conjugate equine estrogen), vaginal ring (17β-estradiol), or vaginal tablet
(estradiol hemihydrate) could likely be used to prevent UTI recurrence, although one study suggests lower efficacy of the ring. The vaginal tablet has not
technically been evaluated specifically for UTI prevention. In contrast to vaginal estrogen, oral estrogen has not been shown to decrease rUTI and has a much
different risk and benefit profile.

Antibiotic prophylaxis.
There is a large body of evidence-based literature supporting antibiotic prophylaxis for treatment of rUTIs. The most recent systematic review identified 28 trials
with sample sizes ranging from 26 to 308 ( n = 2758) ( ). Of the trials that compared prophylactic antibiotics to placebo, antibiotics were associated with a
decreased likelihood of experiencing at least one UTI recurrence (relative risk [RR] 0.26, 95% confidence interval [CI] 0.18–0.37), and there was no difference
when comparing nitrofurantoin to other antibiotics (RR 0.81, 95% CI 0.63–1.03). Unfortunately, the majority of trials were completed before 1995, and therefore
do not necessarily consider growing antibiotic resistance.

The most common adverse events associated with antibiotic prophylaxis include gastrointestinal side effects, vaginal and/or oral candidiasis, and skin rash.
Nitrofurantoin specifically has rare but potentially serious pulmonary and hepatic toxicity in the range of 0.001% to 0.7% of cases of long-term nitrofurantoin use.
Current recommendations are to avoid nitrofurantoin use when creatinine clearance is below 30 mL/min, and the potential serious risks of long-term use should
be discussed with patients.

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There are scant data on the long-term impacts of antibiotic prophylaxis on antibiotic resistance. One study evaluating lactobacilli compared with antibiotics for
UTI prevention showed that E. coli resistance in fecal and urine isolates increased to approximately 80% to 95% after only 1 month of trimethoprim-
sulfamethoxazole prophylaxis ( ). The most common prophylactic options are presented in Table 36.3 .

TABLE 36.3
Prophylactic Antibiotic Options
Medication Dose
Trimethoprim 100 mg once daily
Trimethoprim-sulfamethoxazole 40/200 mg once daily
Nitrofurantoin monohydrate/macrocrystals 50 mg daily
100 mg daily
Cephalexin 125 mg daily
250 mg daily
Fosfomycin 3 g every 10 days
 

Given side effects, potential harm related to antibiotic resistance, and possible nonantibiotic alternatives, we recommend an initial 3- to 6-month trial of antibiotic
suppression in appropriately selected patients, with cessation of antibiotics if UTIs cease over this period.

Postcoital prophylaxis.
If women note a temporal relationship of UTIs to sexual activity, a one-time dose of antibiotics, either before or after intercourse, has been shown to significantly
reduce UTIs, with generally less antibiotic burden than once-daily dosing. This is likely to be a more effective option in premenopausal women, but, as it
decreases total antibiotic burden, it is a reasonable option in postmenopausal women who report postcoital UTIs.

Increasing antimicrobial resistance has stimulated interest in nonantibiotic prophylaxis of rUTIs. The most commonly reported options were recently reviewed in
a systematic review ( ).

Lactobacilli supplements.
Although there has been a lot of interest in lactobacilli probiotics for prevention of rUTI, current guidelines are unable to support their use, given the lack of data.
Oral capsules of lactobacilli did not meet noninferiority criteria compared with TMP-SMX for prevention of UTIs, but there was less antibiotic resistance after
Lactobacillus use. Although one trial showed a trend in UTI reduction after vaginal Lactobacillus crispatus suppositories, this trial was conducted in young
women with a median age of 21 years, and the final results were not statistically significant when considering the confidence interval. It is possible that
lactobacilli probiotics hold promise if administered in an optimal way to a targeted population, but, in general, pooled effects do not show significant benefits in
the three available trials (RR 1.01, 95% CI 0.45–2.26).

Cranberry supplements.
Cranberry supplements have been used for decades as a preventative measure for UTI, with a proposed mechanism related to proanthocyanidins (PACs) that
prevent adhesion of bacteria to the urothelium. Previous studies have used a wide variety of dosing protocols and cranberry formulations including tablets, juice,
and more recently concentrated PACs. In a systematic review, cranberry was associated with decreased risk of at least one UTI recurrence as compared with
placebo (five trials, RR 0.67, 95% CI 0.54–0.83), and the data comparing cranberry to antibiotics are limited ( ). More recently, a multicenter randomized
controlled trial (RCT) in sexually active adult women suggested that a daily dose of 36 mg PACs or more provided an optimal antibacterial effect in the urine ( ).
This 36-mg dose is currently available under the trade name Ellura, and ongoing research may be able to determine whether this dosing significantly improves
the rate of UTI recurrence.

Immunoactive prophylaxis.
Various bacterial lysates have been proposed for the indication of rUTI prophylaxis. To be effective, a bacterial extract must be able to stimulate the host’s
immune system to produce antibodies and cytokines. The oral immunostimulant OM-89 (Uro-Vaxom) is an extract of 18 different serotypes of heat-killed
uropathogenic E. coli that stimulates innate immunity. It has been shown that, after repeated administration of OM-89, strain-specific immunoglobulin G and
immunoglobulin A levels are increased in the urogenital tract of immunized mice. A total of four studies ( n = 891) have evaluated the administration of oral OM-
89 versus placebo capsule daily with a pooled RR for the development of at least one UTI of 0.61 and a 95% CI 0.48–0.78 ( ). A similar number of adverse
events were reported in the vaccine and placebo groups. Urovac is a vaginal vaccine that contains 10 heat-killed uropathogenic bacteria (six different serotypes
of uropathogenic E. coli and one strain each of Proteus vulgaris , K. pneumoniae , Morganella morganii, and E. faecalis ). No differences were found in the
proportion of women with at least one UTI after primary immunization compared with placebo, but there is some suggestion that booster doses may decrease
time to first reinfection. Up to 27.8% of women reported vaginal irritation shortly after suppository insertion, which may limit uptake of this method. Recent
studies have begun to explore vaccine candidates with O-antigens of various serotypes of pathogenic E. coli . Although immunostimulants and vaccinations
may play a future role in rUTI prevention, there is currently insufficient evidence to recommend clinical use.

Intravesical instillations.
Nonantibiotic instillations, including hyaluronic acid and chondroitin sulfate along with gentamicin, have been studied, but are either not clinically available in the
United States or do not have enough evidence to support their use in a nonneurogenic population.

D-mannose.
D-mannose is a sugar that may inhibit bacterial adherence to uroepithelial cells by competitively binding to the type 1 pili of enteric bacteria. In a recent RCT of
308 women with acute UTIs and history of rUTI who were first treated for their acute UTI and then randomized to 2 g of D-mannose daily for 6 months, 50 mg of

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nitrofurantoin daily, or no prophylaxis, the rate of rUTI was 15%, 20%, and 60%, respectively ( ). The D-mannose group had significantly fewer side effects and
equal adherence.

Methenamine salts.
Hiprex (methenamine hippurate) is thought to have urinary antiseptic properties via conversion to formaldehyde in the urine, and therefore should not induce
antimicrobial resistance. A 2012 Cochrane review demonstrated an acceptable side-effect profile, low reported adverse events, and likely some benefit (pooled
RR for symptomatic UTI: 0.24, 95% CI 0.07–0.89) in patients without renal tract abnormalities ( ).

Asymptomatic bacteriuria
Definition and diagnosis
ASB is the presence of one or more species of bacteria growing in the urine at specified quantitative counts (≥10 5 CFU/mL), irrespective of the presence of
pyuria, in the absence of signs or symptoms attributable to UTI ( Table 36.1 ). For women, two consecutive specimens should be obtained, preferably within 2
weeks, to confirm the persistence of bacteriuria. Between 10% and 60% of women, varying with the population, do not have persistent bacteriuria on repeat
screening after an initial positive specimen. ASB is a common finding in many healthy female populations. The incidence of ASB increases from 3.5% in the
general population to 16% to 18% in women older than 70 years of age, and some longitudinal studies report that it affects up to 50% of older women.

Importantly, pyuria has previously been thought to be helpful in terms of discriminating between ASB and acute UTI. However, multiple studies have shown that
pyuria is not a reliable discriminating factor. Ultimately, the presence or absence of urinary symptoms remains the most discriminating factor guiding therapy.

Pathophysiology
The microbiology of ASB is similar to that of symptomatic UTI, although some strains capable of producing ASB may have subtle adaptations that facilitate
pathogenesis. For example, attachment of bacteria via fimbrial adhesins is thought to be important for the establishment and persistence of symptomatic
infection. Some bacterial strains with reduced capability for fimbriae expression appear to have the capacity for relatively rapid growth, thus allowing them to
cause ASB. Alternatively, strains implicated in ASB may simply be less virulent. The absence of symptoms in patients with ASB could also reflect differences in
the host response, as studies in mice have shown a potential role for toll-like receptor inactivation in ASB carrier states.

Recently, it has been discovered that, in its normal healthy state, the bladder harbors a unique microbial community called the urinary microbiome. The human
microbiome refers to the collective genomes of microorganisms that may augment their environment in a myriad of ways that are essential for human health. An
imbalance of urinary microbiota may predispose women to certain bladder disorders. The study of the impact of the urinary microbiome on ASB and UTI is in its
infancy, and its relevance to these conditions remains to be determined.

Clinical management
In 2019, the IDSA published an updated guideline with recommendations for the management of ASB in adults ( ). Since the previous guideline was published
in 2005, antimicrobial stewardship programs have identified nontreatment of ASB as an important opportunity for decreasing inappropriate antimicrobial use.

For the general population, screening for ASB is not recommended. Historical studies failed to show differences in the frequency of subsequent UTI during 1
year of follow-up after treatment of bacteriuric women with a 1-week course of therapy of nitrofurantoin or placebo. Recent studies also refute the adage of a
higher chance of symptomatic UTI in women with bacteriuria, and there does not seem to be an association between ASB and long-term morbidity such as
chronic kidney disease or mortality.

Treatment of presumed UTI in long-term care facilities, despite absence of minimum signs and symptoms, is common. In general, the IDSA recommends
against antibiotic therapy for older patients with functional and/or cognitive impairment, delirium, and/or falls who have bacteriuria in the absence of localizing
urinary symptoms, although they state that this is based on very low-quality evidence. There is agreement that dysuria is the most discriminating factor of UTI,
but other urinary symptoms such as urgency/frequency, especially in a population with chronic lower urinary tract symptoms, complicate diagnostic acumen.
Specific biomarkers to help discriminate between ASB and acute UTI are needed.

This has been a significant paradigm shift over the last few decades from bacteriuria being considered a harmful clinical finding requiring identification and
treatment to being considered a benign observation requiring no management in nonpregnant women. The optimal management of bacteriuria for most
populations is well-characterized, although antibiotic stewardship programs and patient education are necessary to implement a “do not treat” approach.

Special circumstances
Pregnancy
In pregnancy, approximately 20% to 35% of women with bacteriuria will progress to symptomatic UTI. The incidence of pyelonephritis is also higher than in the
general population, likely as a result of physiologic changes in the urinary tract during pregnancy. Importantly, untreated bacteriuria has been associated with an
increased risk of preterm birth and low birth weight at the time of delivery. In this population, E. coli remains the predominant uropathogen. Screening with urine
culture should occur between 12 and 16 weeks of gestation, and treatment should be based on results. Nitrofurantoin, amoxicillin, and cephalexin are safe in
pregnancy. Additionally, a single dose of fosfomycin trometamol (Monurol) also appears safe and effective in pregnancy ( ). A urine culture should be completed
approximately 1 week after treatment to document clearance of bacteriuria. Notably, women with group B streptococcus (GBS) bacteriuria early in pregnancy do
not require additional GBS screening closer to delivery. Rather, GBS bacteriuria at any time during pregnancy is thought to be a sign of heavy anorectal
colonization with GBS. Thus, women with GBS bacteriuria should receive intrapartum GBS prophylaxis at the time of delivery. Regardless of the microbe, for
women with recurrent symptomatic cystitis or any instance of pyelonephritis during pregnancy, suppressive antibiotics should be continued for the remainder of
the pregnancy.

Patients undergoing onabotulinum toxin A injection

UTI is very common after onabotulinum toxin A (BTX-A) injection, with reported rates ranging from 3.6% to 54.5% and four randomized trials reporting a rate of
UTI of greater than 40.0% after injection. In terms of post–BTX-A UTI prevention, we adhere to the American Urological Association (AUA) guideline

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recommendations for the use of prophylactic antibiotics for cystoscopy with manipulation for all patients. These guidelines suggest administering antibiotics at
the time of BTX-A injection, but specific recommendations are lacking. Dosages can range from a single dose to use for 3 days before and 3 days after injection
( ). A recent retrospective study of different prophylactic protocols found that starting antibiotics 1 day before BTX-A injection and continuing for 3  days
afterwards decreased the odds of postinjection UTI compared with women who received postprocedure antibiotic prophylaxis only (odds ratio = 0.23; 95% CI
0.07–0.73; P = .01) ( ). Similarly, the largest, most recent RCT used ciprofloxacin 500 mg on the day of the procedure and for 3 days postprocedure ( ). The
aforementioned AUA guidelines recommend fluoroquinolones, trimethoprim-sulfamethoxazole, or even a second-generation cephalosporin, depending on
patient allergies or intolerances.

Additionally, the FDA-provided safety instructions for BTX-A state that it should not be administered in a patient suffering from a UTI owing to concerns over
adverse events. Although this recommendation may be considered, it should be noted that, with high rates of ASB in the elderly, current or recent bacteriuria
may not be absolute contraindications to injection. In a cohort of patients undergoing BTX-A injection for either idiopathic or neurogenic detrusor overactivity,
38.8% of patients had ASB. There was a higher chance of postprocedure symptomatic UTI in the ASB group, but there were no differences in serious adverse
events like urosepsis, and similar efficacy was observed among ASB and non-ASB patients. Furthermore, performing BTX-A injection within 30 days of a recent
UTI does not increase the odds of postprocedure UTI. Our practice is to inquire about clinical symptoms and perform a urine dipstick analysis on the day of
injection. Depending on degree of symptoms and presence of suspicious findings on dipstick analysis, we may proceed with injection or delay injection until a
later date.

Patients undergoing urogynecologic surgery

UTI is also common after surgery for either pelvic organ prolapse or stress urinary incontinence. Approximately 7% to 40% of these surgical patients will
develop a postoperative UTI despite prophylactic antibiotics and other preventive measures.

Recent AUA guidelines for management of ASB recommend screening for ASB in patients undergoing endourological procedures, because of the concern for
sepsis ( ). However, this is mostly based on high risk of infectious morbidity after procedures that breach the mucosal lining (i.e., transurethral surgery of the
prostate or the bladder, ureteroscopy including lithotripsy, percutaneous stone surgery). Diagnostic or other urological procedures that do not breach the
mucosal lining are considered low risk for infectious complications. Given the high incidence of UTI after urogynecologic surgery and the fact that a positive day-
of-surgery urine culture may be associated with a higher chance of postoperative symptomatic UTI, it may be reasonable to screen for ASB before surgery.
However, it is unclear if antibiotics above and beyond standard perioperative prophylactic antibiotics are necessary.

Finally, the frequency of postoperative UTI is compounded by the rate of postoperative urinary retention requiring short-term catheterization, which is up to 50%,
depending on the procedures performed. Two high-quality RCTs have not shown a benefit of postoperative antibiotics for women who require short-term
catheterization after urogynecologic surgery.

Conclusions
UTI and rUTI are common problems in urogynecologic patients. However, in this population diagnostic accuracy is not ideal when using symptoms alone. The
combination of urinalysis and urine culture in symptomatic patients is useful to confirm the diagnosis of acute UTI. For prevention of rUTIs, evidence suggests
that vaginal estrogen and judicious use of prophylactic antibiotics are helpful in reducing ongoing infections. Other supplements like cranberry and D-mannose
have limited data but could be helpful. In urogynecologic patients, ASB is also common. Evidence-based guidelines state that ASB should not be treated.
Therefore, laboratory testing including urine cultures should only be initiated when patients report symptoms of possible UTI. Ongoing studies in the urinary
microbiome may be helpful to increase diagnostic precision and optimize preventative strategies in the future.

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