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Recurrent simple cystitis in women

Recurrent simple cystitis in women
Author:
Kalpana Gupta, MD, MPH
Section Editor:
Stephen B Calderwood, MD
Deputy Editor:
Allyson Bloom, MD
Literature review current through: Dec 2022. | This topic last updated: Apr 28, 2022.

INTRODUCTION — Recurrent urinary tract infection (UTI) refers to ≥2 infections in six months or ≥3 infections in one year. UTI recurrences are typically acute simple cystitis rather than complicated UTI, as defined in the table (table 1). Most recurrences are thought to represent reinfection rather than relapse (even recurrences caused by the same uropathogenic strain), although occasionally a persistent focus can produce relapsing infection.

The epidemiology, pathogenesis, and prevention of recurrent simple cystitis in nonpregnant women will be reviewed here. These infections are generally caused by the same organisms and share clinical features, diagnostic testing, and treatment regimens with sporadic acute simple cystitis. (See "Acute simple cystitis in females".)

Complicated UTI in adults, including pyelonephritis, is discussed in detail elsewhere. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults".)

The management of asymptomatic bacteriuria, including during pregnancy, is discussed separately. (See "Asymptomatic bacteriuria in adults" and "Urinary tract infections and asymptomatic bacteriuria in pregnancy".)

EPIDEMIOLOGY

Incidence — Recurrent simple cystitis is common among women, even among young, healthy women who have anatomically and physiologically normal urinary tracts. In a study of college women with their first episode of cystitis, 27 percent experienced at least one culture-confirmed recurrence within the six months following the initial infection, and 2.7 percent had a second recurrence during this same time period [1]. When the first infection is caused by Escherichia coli, women appear to be more likely to develop a second cystitis episode within six months than those with a first infection due to another organism [2]. In a Finnish study of women ages 17 to 82 who had E. coli cystitis, 44 percent had a recurrence within one year [3]. The self-reported incidence of cystitis remains high even in older women [4].

Risk factors — Several host behavioral, anatomic, biologic, and genetic factors appear to predispose women to simple cystitis as well as recurrence.

Behavioral risk factors – Sexual intercourse and diaphragm-spermicide use are strong and independent risk factors for acute simple cystitis [5]. Even spermicide-coated condom use is associated with increased risk [6,7]. In one large case-control study of women with and without a history of recurrent cystitis, the frequency of sexual intercourse was the strongest risk factor in a multivariate analysis [8]. Other risk factors identified were:

Spermicide use during the past year

Having a new sex partner during the past year

Having a first urinary tract infection (UTI) at or before 15 years of age

Having a mother with a history of UTIs

The latter two associations are further evidence that inherited factors may be important in some women with recurrent cystitis, as below. No associations were identified with pre- and postcoital voiding patterns, frequency of urination, delayed voiding habits, wiping patterns, douching, use of hot tubs, frequent use of pantyhose or tights, or body mass index [8].

Urologic factors – Among postmenopausal women, urologic factors are associated with recurrence. In a case-control study of 149 healthy postmenopausal women with a history of recurrent cystitis and 53 controls without a history of cystitis, the three mechanical and/or physiologic factors listed below were found to be strongly associated with recurrence [9]. A causal relationship is uncertain. Of note, this study did not assess the association of sexual intercourse with recurrence in postmenopausal women.

Urinary incontinence (41 versus 9 percent for cases and controls, respectively)

Presence of a cystocele (19 versus 0 percent)

Post-voiding residual urine (28 versus 2 percent)

In contrast, in a study of 213 premenopausal women (100 with a history of recurrent cystitis and 113 controls without), there were no differences between cases and controls in urethral length, post-void urine residual, or urine voiding characteristics [10].

Biologic or genetic factors – Studies suggest that women with recurrent cystitis have increased susceptibility to vaginal colonization with uropathogens, even during asymptomatic periods, compared with women without a history of recurrence [11-15]. This susceptibility appears to partially result from a greater propensity for uropathogenic coliforms to adhere to the uroepithelial cells of such women [16-20].

Genetic determinants appear to account for this underlying predisposition in some women. The nonsecretor phenotype is overrepresented among girls and women with recurrent cystitis [21-23]. Uroepithelial cells from women who are nonsecretors of ABH blood group antigens show enhanced adherence of uropathogenic E. coli compared with cells from secretors [24]. The uroepithelial cells of nonsecretors selectively express unique globoseries glycolipid receptors that bind uropathogenic E. coli, which may provide a biochemical explanation for the propensity of nonsecretors to develop recurrent UTI [25]. The association between nonsecretor phenotype and recurrent cystitis may be less important in women who have other strong risk factors for recurrent cystitis, such as spermicide use or frequent sexual intercourse [26].(See "Bacterial adherence and other virulence factors for urinary tract infection".)

Certain virulence determinants of uropathogens have been demonstrated to provide a selective advantage for the ability to colonize and cause infection [27,28]. However, it is not clear whether bacterial virulence determinants of strains causing recurrent cystitis differ from those causing sporadic cystitis. It is also not known whether women with recurrent cystitis have a propensity for colonization with urovirulent strains compared with women who do not have recurrent cystitis.

PATHOGENESIS — The pathogenesis of recurrent cystitis is assumed to be the same as with sporadic infection. In the normal host, most uropathogens originate in the rectal flora, colonize the periurethral area and urethra, and ascend to the bladder. Increasing evidence suggests that alteration of the normal vaginal flora, especially loss of H2O2-producing lactobacilli, may predispose women to introital colonization with E. coli and to cystitis [26]. Studies using newer technologies are beginning to elucidate the relationships between UTI and gut, vaginal, and urinary microbiomes [29].

Some recurrences of cystitis in women due to the same strain may be due to reinfection from a reservoir of pathogens in the epithelium of the bladder, which persist following a previous episode of cystitis. Intracellular populations of bacteria have been identified in exfoliated cells in urine of women with cystitis [30]. Further studies are needed to determine whether this pathway causes same-strain recurrent cystitis and, if so, how it might influence treatment and prophylactic strategies.

EVALUATION

Confirming the diagnosis — Recurrent cystitis refers to ≥2 infections in six months or ≥3 infections in one year. Many women with recurrent cystitis report a history of recurrent episodes of acute onset of typical symptoms, which include dysuria, urinary frequency, urinary urgency, and suprapubic pain. In such cases, the diagnosis of recurrent cystitis is evident, and further urine testing to establish the diagnosis is unnecessary. However, some women attribute nonspecific or chronic urinary symptoms to cystitis, even though noninfectious causes of such symptoms may be more likely; in such cases, urine testing during a symptomatic episode is useful to support or refute the diagnosis of cystitis. The diagnostic approach to simple cystitis is discussed elsewhere. (See "Acute simple cystitis in females", section on 'Diagnostic approach'.)

However, we do not advise prophylactic antibiotics for recurrent cystitis unless the diagnosis has been clearly established based on symptoms, in combination with pyuria and bacteriuria. (See 'Initial approach to prevention' below and 'Antimicrobial prophylaxis in select cases' below.)

Although not necessary in all cases, urine culture is performed during an acute episode of cystitis in the setting of risk factors for antimicrobial resistance (table 2) or severe infection. In women with recurrent cystitis, recent antibiotic use is potentially a primary risk factor for antimicrobial resistance. (See "Acute simple cystitis in females", section on 'Determining the microbial etiology'.)

Distinguishing reinfection versus relapse — For women who have rapid or very frequent recurrences of cystitis following treatment, it is useful to try to distinguish clinically whether the episodes reflect reinfection (ie, new infection following eradication of the prior one) or relapse (ie, re-emergence of the prior infection, which was incompletely eradicated). Relapsing infection warrants more extensive urologic evaluation. (See 'Select imaging/urologic evaluation' below.)

Recurrent cystitis is arbitrarily defined as a relapse if the recurrence occurs within two weeks of completion of treatment for the original infection and the infecting uropathogen strain is the same. By contrast, recurrent cystitis that occurs more than two weeks after treatment is considered a reinfection, even if the infecting uropathogen is the same as the original. When urine culture without significant bacterial growth is documented between the two cystitis episodes in a patient off antibiotics or when the recurrent episodes is caused by a different uropathogen strain from the original, the recurrence is also classified as a reinfection.

The vast majority of recurrences of simple cystitis appear to be reinfections. Even repeated infection with the same uropathogenic isolate is consistent with reinfection; the initially infecting strain can persist in the fecal flora after elimination from the urinary tract, subsequently recolonize the introitus and bladder, and ultimately cause recurrent cystitis [31]. In fact, long-term prospective studies have demonstrated that E. coli strains are capable of causing recurrent cystitis one to three years later, despite appropriate treatment and disappearance of the organism in repeated urine cultures prior to the development of the next infection. Nevertheless, most recurrences occur within the first three months after the initial infection [32,33].

Select imaging/urologic evaluation — Most women with recurrent cystitis do not warrant imaging or urologic evaluation. We reserve this for women who have other features suggesting structural or functional abnormalities of the genitourinary tract that may warrant additional intervention.

We typically start with computed tomography (CT) or renal ultrasound to rule out nephrolithiasis or obstructive uropathy in patients with such features, which include:

Relapsing infection (see 'Distinguishing reinfection versus relapse' above)

Repeated isolation of Proteus spp, which is often associated with nephrolithiasis (see "Kidney stones in adults: Struvite (infection) stones")

History of passing stones (see "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Clinical manifestations')

Hematuria that persists following eradication of infection (additional urologic evaluation may also be warranted) (see "Etiology and evaluation of hematuria in adults", section on 'Imaging')

Women who have voiding issues (eg, symptoms suggestive of incomplete voiding, incontinence, prolapse) should be referred for urologic or urogynecologic evaluation.

INITIAL APPROACH TO PREVENTION — We counsel patients on the risk factors for recurrent simple cystitis and behavioral changes (such as increased fluid intake) that might reduce the risk. For postmenopausal women, we suggest vaginal estrogen. Although we do not actively recommend strategies such as cranberry products, probiotics, antiseptics, or D-mannose because of the paucity of clear data supporting their use, we do not discourage women from taking them if they are interested or find them helpful. These issues are discussed in the sections that follow.

Despite its efficacy, we reserve antibiotic prophylaxis as a last resort strategy in women who have bothersome recurrences despite non-antibiotic preventive measures. (See 'Antimicrobial prophylaxis in select cases' below.)

It is important that discussions of preventive strategies be done without judgment to avoid blaming the woman for the urinary tract infection (UTI); there are not many truly modifiable factors that have demonstrated efficacy.

Changes in behavior — Although many behavioral approaches have not been adequately tested in studies, patients and providers often hold very strong biases about their effectiveness. It is reasonable to consider such approaches for the prevention of cystitis as a way of minimizing antibiotic exposure [34].

Liberal fluid intake — We suggest that all otherwise healthy women with recurrent cystitis increase their fluid intake, which can reduce the risk of recurrence. Although the optimal amount of fluid is unknown, we suggest a general daily target of 2 to 3 liters of fluid daily.

In a randomized trial of 140 premenopausal women who had at least three documented episodes of cystitis in the prior year and had low-volume fluid intake at baseline (<1.5 L daily with a 24-hour urine volume <1.2 L), increased fluid intake decreased the incidence of cystitis by about 50 percent [35]. Those randomly assigned to drink an additional 1.5 L of water over their usual daily intake had fewer episodes of cystitis (mean 1.7 versus 3.2 episodes, difference 1.5, 95% CI 1.2-1.8) and required fewer antimicrobial courses for cystitis (mean 1.9 versus 3.6 courses) over 12 months compared with those who maintained their usual fluid intake. There were no serious adverse effects. In a subsequent meta-analysis of seven randomized trials, including this one, that evaluated fluids for cystitis prevention, increased fluid intake reduced the risk of cystitis recurrence at 6 months (OR 0.13, 95% CI 0.07-0.25), although the reduction was not statistically significant at 12 months (OR 0.39, 95% CI 0.15-1.03) [36]. However, there was substantial heterogeneity in type and quantity of liquid consumed and study design across trials.

These findings support the long-held but previously unproven belief that increased fluid intake is beneficial for patients with recurrent cystitis, theoretically because it helps to dilute and clear bacteriuria.

Contraception modification — Women with recurrent cystitis who are sexually active or who use spermicides (particularly in conjunction with diaphragms), should be counseled about the possible association between their infections and sexual intercourse and use of spermicides. Abstinence or changing to an alternate method of contraception that does not include a spermicide-containing product (after a discussion with her contraception provider) would be expected to reduce the risk of cystitis.

Postcoital voiding — It is reasonable to suggest to women that early postcoital voiding might be helpful. This has not been shown in controlled studies to result in a reduced risk of recurrent cystitis, but is unlikely to be harmful.

Hygiene — Although not shown in controlled studies to be beneficial, wiping from front to back to avoid perineal contamination with fecal flora is routinely recommended as a prevention measure.

Topical estrogen for postmenopausal women — We suggest vaginal estrogen for postmenopausal women with recurrent cystitis (eg, three or more episodes per year) to reduce the incidence of cystitis. Adverse effects are generally mild, although some women may find them undesirable, and caution is warranted in women with or at increased risk for estrogen-dependent tumors. There are several formulations of vaginal estrogen (table 3); we typically refer patients to their gynecologists to assess cancer risk-related safety and optimal dosing. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Preparations: Cream, tablet, capsule, ring'.)

Vaginal estrogen has effectively reduced the incidence of cystitis in small trials of postmenopausal women [37-40]. In a randomized trial of 93 postmenopausal women with a history of recurrent cystitis, vaginal estrogen (0.5 mg estriol cream nightly for two weeks then twice weekly for the eight month course of the trial) reduced the incidence of cystitis compared with placebo (0.5 versus 5.9 episodes per patient year; relative risk [RR], 0.25, 95% CI 0.13-0.50) [38]. In another trial of 108 such women, those randomly assigned to receive a vaginal estrogen ring (2 mg estradiol, changed every 12 weeks over 36 weeks) were less likely to have recurrent cystitis after 36 weeks than those assigned to placebo (51 versus 80 percent) [40].

Nevertheless, vaginal estrogen does not seem to be as effective as antibiotic prophylaxis. In a randomized trial of 171 postmenopausal women with a mean of three episodes of cystitis in the prior year, the incidence of recurrent cystitis was higher with vaginal estrogen (0.5 mg estriol vaginal pessary twice weekly) compared with daily nitrofurantoin (2 versus 0.8 episodes per patient-year) [41]. It is unclear if the formulation of estrogen was related to the less favorable outcome in this trial.

Adverse effects of vaginal estrogen include vaginal bleeding, nonphysiologic discharge, and local discomfort. These are generally mild, but the withdrawal rate for such effects was 28 percent in one trial [38]. Vaginal estrogen has not been demonstrated to increase the risk of recurrence of cancer, but clinicians should consult the oncologist or gynecologist before suggesting vaginal estrogen in patients with a history of or at high risk for estrogen-dependent cancer (eg, breast cancer). (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Patients with breast cancer' and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Serum absorption'.)

The effect of topical estrogen on cystitis risk is thought to be related to normalization of the vaginal flora. Women who received estriol cream in the trial described above had an increase in the prevalence of lactobacilli and decrease in E. coli vaginal colonization [37].

Oral estrogen has not been shown to be effective [37,39].

Optional strategies of uncertain benefit

Methenamine — We do not routinely suggest methenamine for prevention of cystitis. Some data suggest that the risk of recurrent cystitis with methenamine may be clinically similar to that with antibiotic prophylaxis, but the overall effectiveness and safety of long-term use are uncertain [42,43]. Furthermore, in our experience, patient adherence with methenamine is suboptimal. Nevertheless, it is a reasonable antibiotic-sparing strategy for interested patients, particularly in those who have antibiotic intolerances or resistance. If given, the typical dose of methenamine hippurate is 1 g orally twice daily. The addition of vitamin C to methenamine to try to achieve and maintain an acidified urine is a common practice, but there are no clinical data to support this approach. Methenamine should not be coadministered with sulfonamide antibiotics (including trimethoprim-sulfamethoxazole) because of concern for sulfonamide crystallization in the urine.

Methenamine salts are converted to formaldehyde in acidified urine and thus have general antibacterial activity. In an open-label trial, 240 adult females who had recurrent cystitis (median of six self-reported episodes in the prior year) and no correctable urinary tract abnormalities that would contribute to recurrent UTI (eg, nephrolithiasis or neurogenic bladder) were randomly assigned to receive methenamine 1 g twice daily or a once-daily antibiotic (nitrofurantoin, trimethoprim, or cephalexin, depending on prior urine culture results) for 12 months [42]. The subsequent rate of cystitis was higher in the methenamine group compared with the antibiotic group (1.38 versus 0.89 episodes per person per year, absolute difference 0.49 episodes, 90% CI 0.15-0.84); this difference met the study’s prespecified noninferiority criteria.

Methenamine was not clearly associated with a reduced risk for subsequent antimicrobial resistance in this study. Rates of resistance among urine isolates from episodes of symptomatic cystitis were largely similar between the two groups. More data are needed to further inform the risk of resistance with methenamine use. The rate of adverse events was similar between the two groups. However, in the methenamine group, four subjects were hospitalized for UTI and six reported fever (≥38°C) during a UTI episode, whereas no such events occurred in the antibiotic group.

Limitations of the study include the substantial crossover between groups, with 18 percent of participants in the methenamine group and 6 percent in the antibiotic group switching to the other intervention, which reduces confidence in the observed outcome. Additionally, the diagnosis of cystitis relied on symptoms and a physician’s decision to treat with an antibiotic without requiring microbiologic confirmation, which further contributes to potential bias in this non-blinded study. An assessment of urine pH or the value of urine acidification was not performed in this study.

Further study of methenamine as an antimicrobial-sparing approach for the prevention of recurrent cystitis is warranted. Notwithstanding the findings from the trial detailed above, more information is needed on efficacy, effect of urine pH, risk of more serious complications, and long-term safety data.

Cranberry products — We do not routinely suggest cranberry products (juice, tablets, or capsules) to reduce the incidence of recurrent cystitis. Although there are plausible biological mechanisms for such an effect, clinical studies to date have not definitively demonstrated efficacy in prevention of recurrent simple cystitis. However, for women with recurrent cystitis who are already using cranberry or who are interested in trying cranberry products and can tolerate it, there is likely little harmful effect (other than an increase in calorie and glucose intake with juice). There may also be an increased likelihood of gastrointestinal side effects such as heartburn with cranberry juice, as suggested by some studies [44]. For those who want to take cranberry products, studies to date have not supported a specific dose or intake frequency.

Clinical studies on the efficacy of cranberry juice have been limited by suboptimal study design (underpowered, not blinded, or limited by other design flaws) and mixed results [44-54]. In a meta-analysis of nine randomized trials, there was a decreased risk of UTI among 639 patients who used cranberry products compared with 536 control patients (RR 0.62, 95% CI 0.49-0.80) [52]. This reduction was even more marked in patients with recurrent UTI (RR, 0.53; 95% CI, 0.33-0.83). However, the meta-analysis was limited by substantial statistical and clinical heterogeneity, including lack of appropriate controls in several studies, extensive variability in dosing and administration of cranberry products, and variable definitions of UTI across studies. Furthermore, the meta-analysis excluded a randomized trial of 319 women presenting with an acute UTI, among whom drinking 8 ounces of 27 percent cranberry juice twice per day did not decrease the six-month incidence of recurrent UTI compared with drinking a placebo juice [45]. Of note, this study also had methodological issues including a very low event rate and lack of power [55]. An updated Cochrane meta-analysis included data from this latter study and concluded that cranberry products did not significantly reduce the occurrence of symptomatic UTI in women with recurrent UTIs (RR 0.74, 95% CI 0.42-1.31) [53]. It also concluded that cranberry juice may be unacceptable to consume over a long period. Similarly, in a subsequent trial of 185 female nursing home residents randomly assigned to cranberry capsules (72 mg of the active ingredient) or placebo for a year, cranberry capsules did not reduce adjusted rates of bacteriuria plus pyuria (29 percent for both groups) or symptomatic UTI (10 versus 12 episodes) [56]. However, a large drop-out rate and consistent trends toward fewer hospitalizations, fewer antibiotics administered for suspected UTIs, and lower total antimicrobial utilization among those assigned to cranberry tablets reduce confidence in the primary finding of no benefit. A subsequent meta-analysis did suggest a reduction in UTI incidence with cranberry use, but the analysis was not restricted to randomized trials and thus reflects lower quality evidence [57].

These clinical studies have not clearly supported the in vitro evidence that suggested that cranberry products would have a beneficial effect. Laboratory studies have demonstrated that cranberry juice inhibits adherence of uropathogens to uroepithelial cells [58,59]. The mediators of this anti-adherence effect may be fructose, which could interfere with adhesion of type 1 fimbriated E. coli to uroepithelium [60], and proanthocyanidins, which can inhibit adherence of P-fimbriated E. coli [61]. The reduction in urinary P-fimbriated E. coli strains in the cranberry group of one study of 176 women, while not statistically significant, supported the biological plausibility of cranberry activity [44].

D-mannose — We do not routinely suggest D-mannose, a natural sugar available in health food stores and online, for prevention of cystitis given the lack of convincing clinical efficacy. However, the drawbacks are likely limited, and we do not discourage its use in females who are interested in trying it as an antimicrobial-sparing strategy. We discuss with patients, as appropriate, the biological rationale for its use and the uncertainty around the clinical effect. The optimal dose is also uncertain.

D-mannose is an example of a compound that mimics the host uroepithelial receptors used by uropathogens. Such compounds are hypothesized to competitively bind to bacterial surface ligands, decrease the number of bacteria attaching to the mucosa, and alter the delicate balance of host-bacterial interaction in favor of the host [43,62].

However, the published clinical evidence on the effectiveness of D-mannose for preventing cystitis is spare and of low quality [63,64]. Furthermore, it is not known what urinary levels of D-mannose might be protective and whether oral administration of D-mannose can achieve such levels with the doses recommended by the manufacturers.

Studies are underway to identify related compounds that are well absorbed and have high affinity for the bacterial surface ligand.

Probiotics — We do not routinely suggest probiotics to reduce the risk of recurrent cystitis given lack of demonstrated clinical efficacy, but if patients are interested in them, we do not discourage them given the low risk of drawbacks other than cost.

Clinical trials of oral probiotics have not been encouraging. In a review of four randomized controlled trials of Lactobacillus probiotics for bacterial genitourinary infections in women, only one demonstrated a reduction in rates of cystitis recurrence [65]. However, most of these studies did not determine whether the probiotic led to vaginal colonization with the probiotic strain. A subsequent trial, in which postmenopausal women with a history of recurrent cystitis were randomly assigned to take trimethoprim-sulfamethoxazole (n = 127) or Lactobacillus tablets (n = 125) for 12 months, reported that women in the Lactobacillus group had more frequent clinical recurrences over the year (mean 3.3 versus 2.9 events) and shorter time to recurrence (three versus six months) than women in the antibiotic group [66]. Notably, a higher proportion of patients in the Lactobacillus group discontinued therapy because of adverse effects (12.2 versus 5.2 percent), and the probiotic strain of Lactobacillus tested for could not be identified by polymerase chain reaction in the vaginal flora of any women.

Delivery of Lactobacillus through other methods may be more promising. In a placebo-controlled trial of premenopausal women with recurrent cystitis, a vaginal capsule containing a strain of Lactobacillus crispatus (which constitutes nearly 90 percent of the vaginal microbial flora) resulted in high levels of vaginal colonization, administered as a vaginal capsule, among premenopausal women with recurrent cystitis. Vaginal Lactobacillus treatment (n = 50) was well tolerated, achieved high levels of vaginal colonization, and was associated with decreased rates of recurrent UTI (15 versus 27 percent of women in the placebo group) [67].

Probiotics are thought to have the potential to protect against vaginal colonization by uropathogens through a variety of mechanisms, including:

Steric hindrance or blocking potential sites of attachment

Production of hydrogen peroxide, which is microbicidal to E. coli and other uropathogens

Maintenance of a low pH

Induction of anti-inflammatory cytokine responses in epithelial cells

While the probiotic approach has a credible scientific basis, additional adequately designed clinical trials need to be performed before its routine use can be recommended.

ANTIMICROBIAL PROPHYLAXIS IN SELECT CASES

Indications — We prefer that women attempt antibiotic-sparing preventive modalities prior to using antibiotic prophylaxis (see 'Initial approach to prevention' above). We reserve antibiotic prophylaxis for women with recurrent simple cystitis who have frequent recurrences (eg, two or more within six months) and who are bothered enough by their symptoms to choose to use antibiotic prophylaxis after being counseled about the potential adverse consequences of this approach. As above, we ensure the diagnosis of recurrent cystitis prior to embarking on antibiotic prophylaxis (see 'Confirming the diagnosis' above). We do not use antibiotic prophylaxis in patients who have recurrent symptoms that are not specific to urinary tract infection (eg, mental status changes without genitourinary symptoms or fever), even if they are associated with bacteriuria (with or without pyuria), because of the likelihood that this reflects asymptomatic bacteriuria coincident with symptoms related to a separate process.

Other clinical factors that inform the use of antibiotic prophylaxis include the antibiotic susceptibilities of previously isolated uropathogens. As an example, if a patient's cystitis episodes have been caused by a uropathogen susceptible to only one drug class with an oral option, we have a higher threshold to use antibiotic prophylaxis given the possibility of selecting for resistance to that drug class and thus losing the last oral agent for therapy.

An alternative strategy for women who have clearly documented recurrent infections, are motivated and adherent to medical instructions, and have a good relationship with a medical provider is self-diagnosis and self-treatment. This is discussed elsewhere. (See 'Treatment of recurrent episodes' below.)

Antibiotic prophylaxis has been demonstrated to be highly effective in reducing the risk of recurrent cystitis in women, as discussed below. However, we are selective about using antibiotic prophylaxis because the potential adverse effects (including direct toxicities, selection of resistance, alteration of microbiome, and secondary Clostridioides [formerly Clostridium] difficile infection) often outweigh the benefit of reducing the risk of an infection that rarely results in poor outcomes (see 'Adverse effects' below). If women are concerned, we counsel them that there is no evidence that recurrent cystitis leads to chronic health problems, such as hypertension or renal disease, in the absence of anatomic or functional abnormalities of the urinary tract.

Options — If antibiotic prophylaxis is used, postcoital prophylaxis can be used for women with cystitis episodes associated with sex, and continuous prophylaxis can be used otherwise.

Continuous prophylaxis — For women in whom the decision to use antibiotic prophylaxis has been made, continuous (ie, regular long-term) prophylaxis is appropriate if recurrent cystitis episodes have no temporal relation to sexual activity. Several antibiotic regimens are options for continuous prophylaxis in nonpregnant women (table 4). The choice of antibiotic should be based upon the susceptibility patterns of the strains causing the patient's previous cystitis, history of drug allergies, and potential for interactions with other medications. We mainly choose between nitrofurantoin and trimethoprim-sulfamethoxazole, although trimethoprim and beta-lactams are also options if susceptibility of prior uropathogens permits. Data on use of fosfomycin for prophylaxis are limited, although we use fosfomycin on infrequent occasions, when other options are not appropriate and the patient strongly favors antibiotic suppression. We generally avoid using fluoroquinolones for prophylaxis against recurrent cystitis unless there are no other options because of resistance or intolerance and the patient has highly frequent episodes of cystitis; in most cases, the potential for adverse effects likely outweighs the benefits. (See "Fluoroquinolones", section on 'Benefits and risks of use'.)

Antibiotic selection for prophylaxis of recurrent cystitis in pregnant women is discussed elsewhere. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on 'Management of recurrent cystitis'.)

Before any prophylaxis regimen is initiated, we check a urine culture one to two weeks after treatment of an acute episode of cystitis to ensure that there is no high-grade bacteriuria (eg, >100,000 colony-forming units/mL). Another reasonable strategy is to start prophylaxis immediately after a treatment course for acute cystitis (assuming symptoms resolve) to reduce the likelihood that the urine becomes recolonized with bacteria prior to prophylaxis.

The doses of antibiotics studied (and given) for prophylaxis are generally lower than those used for treatment (table 4). As examples, nitrofurantoin is given as 50 to 100 mg once daily, trimethoprim-sulfamethoxazole as half of a single-strength tablet (40 mg/200 mg) once daily to three times weekly, and cephalexin 125 to 250 mg once daily. The dosing interval of fosfomycin that optimizes the reduction in cystitis recurrence while minimizing the harms of developing resistance and other adverse effects is uncertain; effective doses in trials were 3 g every 7 or 10 days [68,69], but some experts have used shorter time intervals (eg, one dose every three to four days).

Numerous studies have demonstrated that continuous prophylaxis decreases recurrences substantially compared with placebo or with patients' prior experience. A 2004 Cochrane meta-analysis included 10 trials that evaluated antibiotic prophylaxis versus placebo for 6 to 12 months among 430 healthy nonpregnant women (both pre- and postmenopausal) with recurrent cystitis; all but one trial evaluated continuous prophylaxis [70]. During the course of active prophylaxis, antibiotics reduced both microbiologic and clinical recurrence compared with placebo:

Microbiologic recurrence – 0 to 0.9 episodes per patient-year in the antibiotic group versus 0.8 to 3.6 in the placebo group; RR 0.21, 95% CI 0.13-0.33.

Clinical recurrence – RR 0.15, 95% CI 0.08-0.28.

However, pooled analysis of two of the included trials did not identify a difference in microbiologic recurrence rates following discontinuation of prophylaxis (RR 0.82, 95% CI 0.44-1.53). Overall, the studies suffered from risk of bias (unclear allocation concealment and high loss to follow-up rates), which reduces confidence in the findings. None of these studies assessed clinical recurrence after stopping prophylaxis.

Nevertheless, subsequent trials have also demonstrated the efficacy of antibiotic prophylaxis (against either placebo or non-antibiotic strategies), even in patients who may have underlying urologic abnormalities [46,66,68,71,72]. As an example, in a randomized trial of approximately 400 adults who practiced intermittent self-catheterization, continuous antibiotic prophylaxis (nitrofurantoin, trimethoprim, or cephalexin, as selected by the clinician) reduced the rate of clinical cystitis (1.3 versus 2.6 episodes per patient-year, RR 0.52, 95% CI 0.44-0.61) and microbiologically confirmed cystitis (0.74 versus 1.5 episodes per patient-year, RR 0.49, 95% CI 0.39-0.6) compared with no prophylaxis [72]. However, antibiotic prophylaxis is generally avoided in individuals with urinary catheters because of the risk of resistance. (See "Placement and management of urinary bladder catheters in adults", section on 'Prophylactic antibiotics'.)

Observational studies also support the efficacy of antibiotic prophylaxis [71].

Several trials have compared various antibiotic regimens, and there is no evidence that one regimen is superior to any others, although the available evidence is of low quality [70,73]. The prophylactic efficacy of any antimicrobial agent depends upon the continued susceptibility to the drug of potential uropathogens colonizing the patient's fecal, periurethral, and vaginal flora [33,74]. The increasing baseline prevalence of resistance among uropathogenic E. coli strains to trimethoprim or trimethoprim-sulfamethoxazole may complicate prophylaxis with these agents.

Postcoital prophylaxis — Postcoital prophylaxis (a single postcoital dose of an antibiotic) may be a more efficient method of prevention than continuous prophylaxis in women whose cystitis episodes are temporally related to sexual intercourse. Depending upon the frequency of intercourse, postcoital prophylaxis usually results in receipt of smaller amounts of antimicrobials than continuous prophylaxis.

The antibiotic options for postcoital prophylaxis in nonpregnant women are largely similar to those for continuous prophylaxis, but are given as a single dose (table 4). The choice of antibiotic should be based upon the susceptibility patterns of the strains causing the patient's previous cystitis, history of drug allergies, and potential for interactions with other medications. We mainly choose between nitrofurantoin and trimethoprim-sulfamethoxazole, although trimethoprim and beta-lactams are also options if susceptibility of prior uropathogens permits.

Antibiotic selection for prophylaxis of recurrent cystitis in pregnant women is discussed elsewhere. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on 'Management of recurrent cystitis'.)

Before any prophylaxis regimen is initiated, we check a urine culture one to two weeks after treatment of an acute episode of cystitis to ensure that there is no high-grade bacteriuria (eg, >100,000 colony-forming units/mL).

In the only placebo-controlled trial of postcoital prophylaxis, the infection rate was lower in patients receiving postcoital trimethoprim-sulfamethoxazole (40 mg/200 mg) compared with placebo (0.3 versus 3.6 episodes per patient-year) [75]. Uncontrolled studies suggest a comparable reduction in infection rates with postcoital trimethoprim-sulfamethoxazole, nitrofurantoin, cephalexin, or a fluoroquinolone [76-80]. In another randomized trial, postcoital ciprofloxacin was as effective as daily ciprofloxacin in sexually active young women [81].

Duration — When antibiotic prophylaxis is administered, we usually give it as an initial trial for three months to assess for response (depending on the frequency of infections prior to prophylaxis) and tolerability. After that trial, if prophylaxis has been tolerated and there have been no recurrences, we discuss the option of continuing prophylaxis, with the understanding that prophylaxis does not appear to have any lasting effect after being stopped [73]. It appears that most women revert back to the previous pattern of recurrent infections once prophylaxis is stopped (RR for at least one microbiologic recurrence 0.82, 95% CI 0.44 -1.53 in the above meta-analysis) [70]. Modification of other risk factors, such as sexual activity or diaphragm-spermicide use, would probably be beneficial in this regard. (See 'Changes in behavior' above.)

Some authorities advocate prophylaxis for two or more years in women who continue to have symptomatic infections [82]. Use of trimethoprim-sulfamethoxazole or other agents for as long as five years has been reported to be effective and well tolerated [33,83]. Nitrofurantoin has also been shown to be safe and well tolerated in long-term (12 months) prophylaxis regimens [84]. Of note, there are concerns about toxicity with long term nitrofurantoin use, as discussed elsewhere. (See 'Adverse effects' below.)

Adverse effects

Direct toxicities – Although agents most commonly used for prophylaxis of simple cystitis are well tolerated, patients should be warned about potential toxicities. The most common side effects reported in trials include vaginal and oral candidiasis and gastrointestinal symptoms (nausea, diarrhea) [70], but toxicities can uncommonly be more severe. In particular, long-term exposure to nitrofurantoin has been rarely associated with pulmonary reactions, chronic hepatitis, and neuropathy. Nitrofurantoin use should generally be avoided in patients with creatinine clearance <30 mL/minute in whom efficacy may be decreased and the risk for toxicity may be greater [85]. Toxicities of trimethoprim-sulfamethoxazole and beta-lactams are discussed in detail elsewhere. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Adverse effects and precautions' and "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Adverse effects'.)

We do not routinely use fluoroquinolones for continuous prophylaxis of simple cystitis. Fluoroquinolones have a number of potential adverse effects and should be reserved for more serious infections than acute simple cystitis [86]. (See "Fluoroquinolones", section on 'Benefits and risks of use'.)

Selection for resistant bacteria – With continuous prophylaxis, emergence of uropathogens resistant to the prophylactic agent has been increasingly reported [66,72,81,83,87]. Resistance in uropathogens complicates future UTI treatment for the individual and contributes to the population burden of resistant pathogenic bacteria in the community.

Development of resistance is a particular issue with trimethoprim-sulfamethoxazole [66,83]. As an example, in a randomized trial comparing daily oral trimethoprim-sulfamethoxazole to the probiotic Lactobacillus for prophylaxis of recurrent cystitis, microbiologically confirmed symptomatic recurrences were documented in 49 percent of women taking trimethoprim-sulfamethoxazole (76 percent of these were caused by E. coli) [66]. Over 90 percent of these E. coli isolates were resistant to trimethoprim-sulfamethoxazole compared with less than 30 percent of the asymptomatic bacteriuria E. coli strains isolated at baseline. In contrast, fewer than 30 percent of the E. coli strains causing symptomatic recurrences during Lactobacillus prophylaxis were resistant to trimethoprim-sulfamethoxazole, which was lower than the baseline prevalence among asymptomatic bacteriuria E. coli strains.

Clostridioides difficile infection – Antibiotic use is a well-known risk factor for C. difficile infection, which has been associated with all antibiotics. Symptomatic C. difficile infection can range from mild illness to fulminant and life-threatening disease. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Antibiotic use' and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Alterations in gut microbiome – Systemic antibiotics have a substantial and sometimes lasting effect on the population of commensal bacteria that inhabit the intestinal tract, altering their abundance, diversity, function, and cross-species interactions. Alteration of the gut microbiome is one of the mechanisms by which antibiotics increase the risk of C. difficile infection. Other clinical effects of alterations in the gut microbiome have not been fully elucidated, although disruptions in the gut microbiome appear to be associated with a wide range of chronic diseases, including gastroenterologic, metabolic, and cardiovascular illnesses [88].

TREATMENT OF RECURRENT EPISODES — Management of acute episodes of recurrent cystitis is generally the same as for isolated cases of cystitis. For patients who were treated for cystitis within the prior three months or who are taking antibiotic prophylaxis, we check a urine culture to inform the selection of antibiotic regimen given the risk of resistance. (See "Acute simple cystitis in females", section on 'High risk for resistance'.)

For healthy women who have no risk factors for severe infection (eg, no underlying urologic condition or immunocompromising condition), we also counsel them on being judicious about alerting their provider about an episode of cystitis. Since cystitis symptoms are often transient and can resolve on their own, we sometimes advise such women to increase their fluid intake when they start to have mild cystitis symptoms and to wait to see if their symptoms persist beyond 24 hours before contacting their provider for treatment. This approach is supported by evidence suggesting that briefly deferring antibiotic therapy of cystitis is a safe strategy [89], and it may be able to reduce the overall burden of antibiotic use for recurrent cystitis.

Self-treatment – Women who have clearly documented recurrent infections, are motivated, adherent to medical instructions, and have a good relationship with a medical provider are candidates for self-diagnosis and self-treatment of cystitis. This may be a particularly attractive approach for women who are traveling and may otherwise have limited access to treatment for acute symptoms. We give such women a prescription for a typical course of antibiotics to use for a clear episode of acute cystitis with instructions to contact their provider if the symptoms are not completely resolved by 48 hours. Several studies have shown that cystitis can be accurately self-diagnosed by women >85 to 95 percent of the time, and that self-treatment is effective [90-92].

INVESTIGATIONAL PREVENTIVE STRATEGIES — A number of strategies to prevent recurrent cystitis are being evaluated.

A safe and effective vaccine to reduce the risk of recurrent urinary tract infection (UTI) would be a welcome breakthrough. Whole-cell vaccines, made from combinations of heat-killed uropathogenic strains delivered by injection or by a vaginal suppository, have to date had only partial success [93-95], and the protective effect appears to wane over several weeks. A phase 1 trial of a bioconjugate vaccine containing the O antigens of four E. coli serotypes was well tolerated and elicited functional antibody responses against all vaccine serotypes [96]. Another promising approach under development is a vaccine based upon the E. coli type 1 fimbrial adhesion protein, FimH [97]. Virtually all uropathogenic strains of E. coli assemble type 1 pili that contain the FimH adhesin. (See "Bacterial adherence and other virulence factors for urinary tract infection", section on 'Adhesins'.)

Oral immunostimulants have been investigated. In a systematic review and meta-analysis of four trials that included 891 participants, OM-89, an extract of 18 different serotypes of heat killed uropathogenic E. coli given orally to stimulate innate immunity, decreased the rate of UTI recurrence (relative risk [RR] 0.61, 95% CI 0.48-0.78) [37]. The adverse event rate was similar to that in the placebo groups. Another preparation, MV-140, which is composed of inactivated whole-cell strains of E. coli, Klebsiella pneumoniae, Enterococcus faecalis, and Proteus mirabilis and is administered sublingually, reduced the risk of recurrent cystitis compared with placebo (RR 0.56, 95% CI 0.41-0.76 with 6 months of therapy) without excess adverse effects [98]. These agents are available, either commercially or through special access programs, in some European countries and elsewhere but not in the United States.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urinary tract infections in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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Beyond the Basics topic (see "Patient education: Urinary tract infections in adolescents and adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Recurrent urinary tract infections (UTIs) are typically episodes of acute simple cystitis (table 1). Recurrent simple cystitis is common among women, even young healthy women who have anatomically and physiologically normal urinary tracts. (See 'Introduction' above and 'Epidemiology' above.)

Risk factors – Risk factors for recurrent cystitis include frequent sexual intercourse, use of spermicides, and mechanical and/or physiologic factors that impede bladder emptying. Women with recurrent cystitis also appear to have increased susceptibility to vaginal colonization with uropathogens, even during asymptomatic periods. (See 'Risk factors' above.)

Confirmation of the diagnosis – In women with recurrent cystitis characterized by acute onset of typical symptoms (dysuria, urinary frequency, urinary urgency, and suprapubic pain), further urine testing to confirm the diagnosis is unnecessary. We favor urine testing to support or refute the diagnosis of cystitis in women who have nonspecific or chronic urinary symptoms that have been attributed to cystitis or if antibiotic prophylaxis is being considered. (See 'Confirming the diagnosis' above and "Acute simple cystitis in females", section on 'Diagnostic approach'.)

Limited role for imaging or urologic evaluation – We reserve these for women who have features suggesting structural or functional abnormalities of the genitourinary tract that may warrant additional intervention. These include relapsing infection (recurrence of infection with same uropathogen strain within two weeks of treatment completion), repeated isolation of Proteus spp, history of nephrolithiasis, persistent hematuria, and voiding abnormalities. (See 'Select imaging/urologic evaluation' above.)

Initial preventive strategies – For women with recurrent cystitis, we start with non-antimicrobial preventive strategies:

Increasing fluid intake can reduce the risk of recurrence. We suggest that women with recurrent cystitis generally target 2 to 3 liters of fluid intake daily (Grade 2B). Although other behavioral approaches (eg, avoiding spermicides, postcoital voiding) have not been adequately studied, these are reasonable approaches to try to reduce cystitis risk. (See 'Changes in behavior' above.)

For postmenopausal women with recurrent cystitis, we suggest vaginal estrogen (Grade 2B). There are several formulations (table 3); we typically refer patients to their gynecologists to assess cancer risk-related safety and optimal dosing. (See 'Topical estrogen for postmenopausal women' above and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Preparations: Cream, tablet, capsule, ring'.)

Data do not support a clear role for other non-antimicrobial agents, such as methenamine, cranberry products, probiotics, and D-mannose, in preventing recurrent cystitis. Although we do not actively advise patients to use such agents, we do not discourage interested patients from trying them. (See 'Optional strategies of uncertain benefit' above.)

Antibiotic prophylaxis for select patients – We suggest not routinely using antibiotic prophylaxis as a first-line preventive strategy (Grade 2C). Despite its efficacy, we use it selectively because the potential adverse effects often outweigh the benefit of reducing the risk of an infection that rarely results in poor outcomes. It is reasonable for women with frequent recurrences (eg, two or more within six months) and bothersome symptoms who desire prophylaxis after counseling on this risk/benefit balance. We do not use antibiotic prophylaxis in patients with nonspecific recurrent symptoms (eg, mental status changes without genitourinary symptoms or fever), even in the setting of bacteriuria with or without pyuria. (See 'Indications' above and 'Adverse effects' above.)

If used, postcoital prophylaxis can be used for women whose cystitis is temporally associated with sex, and continuous prophylaxis can be used for other women. The choice of antibiotic should be based upon the susceptibility patterns of the strains causing the patient's previous cystitis, history of drug allergies, and potential for interactions with other medications. We mainly choose between nitrofurantoin and trimethoprim-sulfamethoxazole, if possible. Doses and other options are listed in the table (table 4). We reevaluate prophylaxis after three months. (See 'Continuous prophylaxis' above and 'Postcoital prophylaxis' above and 'Duration' above.)

Management of acute episodes – For patients who were treated for cystitis within the prior three months or who are taking antibiotic prophylaxis, we check a urine culture to inform the selection of antibiotic regimen given the risk of resistance. Self-diagnosis with self-treatment is an alternative strategy for women who have clearly documented recurrent infections, are motivated and adherent to medical instructions, and have a good relationship with a medical provider. (See 'Treatment of recurrent episodes' above and "Acute simple cystitis in females", section on 'Management'.)

  1. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990; 80:331.
  2. Foxman B, Gillespie B, Koopman J, et al. Risk factors for second urinary tract infection among college women. Am J Epidemiol 2000; 151:1194.
  3. Ikäheimo R, Siitonen A, Heiskanen T, et al. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis 1996; 22:91.
  4. Foxman B, Barlow R, D'Arcy H, et al. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 2000; 10:509.
  5. Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996; 335:468.
  6. Fihn SD, Boyko EJ, Normand EH, et al. Association between use of spermicide-coated condoms and Escherichia coli urinary tract infection in young women. Am J Epidemiol 1996; 144:512.
  7. Fihn SD, Boyko EJ, Chen CL, et al. Use of spermicide-coated condoms and other risk factors for urinary tract infection caused by Staphylococcus saprophyticus. Arch Intern Med 1998; 158:281.
  8. Scholes D, Hooton TM, Roberts PL, et al. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000; 182:1177.
  9. Raz R, Gennesin Y, Wasser J, et al. Recurrent urinary tract infections in postmenopausal women. Clin Infect Dis 2000; 30:152.
  10. Hooton TM, Stapleton AE, Roberts PL, et al. Perineal anatomy and urine-voiding characteristics of young women with and without recurrent urinary tract infections. Clin Infect Dis 1999; 29:1600.
  11. Stamey TA, Timothy M, Millar M, Mihara G. Recurrent urinary infections in adult women. The role of introital enterobacteria. Calif Med 1971; 115:1.
  12. Pfau A, Sacks T. The bacterial flora of the vaginal vestibule, urethra and vagina in premenopausal women with recurrent urinary tract infections. J Urol 1981; 126:630.
  13. Fowler JE Jr, Latta R, Stamey TA. Studies of introital colonization in women with recurrent urinary infections. VIII. The role of bacterial interference. J Urol 1977; 118:296.
  14. Stamey TA, Sexton CC. The role of vaginal colonization with enterobacteriaceae in recurrent urinary infections. J Urol 1975; 113:214.
  15. Schaeffer AJ, Stamey TA. Studies of introital colonization in women with recurrent urinary infections. IX. The role of antimicrobial therapy. J Urol 1977; 118:221.
  16. Schaeffer AJ, Jones JM, Falkowski WS, et al. Variable adherence of uropathogenic Escherichia coli to epithelial cells from women with recurrent urinary tract infection. J Urol 1982; 128:1227.
  17. Svanborg-Edén C, Jodal U. Attachment of Escherichia coli to urinary sediment epithelial cells from urinary tract infection-prone and healthy children. Infect Immun 1979; 26:837.
  18. Fowler JE Jr, Stamey TA. Studies of introital colonization in women with recurrent urinary infections. VII. The role of bacterial adherence. J Urol 1977; 117:472.
  19. Källenius G, Winberg J. Bacterial adherence to periurethral epithelial cells in girls prone to urinary-tract infections. Lancet 1978; 2:540.
  20. Schaeffer AJ, Jones JM, Dunn JK. Association of in vitro Escherichia coli adherence to vaginal and buccal epithelial cells with susceptibility of women to recurrent urinary-tract infections. N Engl J Med 1981; 304:1062.
  21. Hooton TM, Roberts PL, Stamm WE. Effects of recent sexual activity and use of a diaphragm on the vaginal microflora. Clin Infect Dis 1994; 19:274.
  22. Kinane DF, Blackwell CC, Brettle RP, et al. ABO blood group, secretor state, and susceptibility to recurrent urinary tract infection in women. Br Med J (Clin Res Ed) 1982; 285:7.
  23. Sheinfeld J, Schaeffer AJ, Cordon-Cardo C, et al. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N Engl J Med 1989; 320:773.
  24. Lomberg H, Cedergren B, Leffler H, et al. Influence of blood group on the availability of receptors for attachment of uropathogenic Escherichia coli. Infect Immun 1986; 51:919.
  25. Stapleton A, Nudelman E, Clausen H, et al. Binding of uropathogenic Escherichia coli R45 to glycolipids extracted from vaginal epithelial cells is dependent on histo-blood group secretor status. J Clin Invest 1992; 90:965.
  26. Gupta K, Stamm WE. Pathogenesis and management of recurrent urinary tract infections in women. World J Urol 1999; 17:415.
  27. Svanborg C, Godaly G. Bacterial virulence in urinary tract infection. Infect Dis Clin North Am 1997; 11:513.
  28. Johnson JR. Microbial virulence determinants and the pathogenesis of urinary tract infection. Infect Dis Clin North Am 2003; 17:261.
  29. Meštrović T, Matijašić M, Perić M, et al. The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics (Basel) 2020; 11.
  30. Rosen DA, Hooton TM, Stamm WE, et al. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med 2007; 4:e329.
  31. Russo TA, Stapleton A, Wenderoth S, et al. Chromosomal restriction fragment length polymorphism analysis of Escherichia coli strains causing recurrent urinary tract infections in young women. J Infect Dis 1995; 172:440.
  32. Kraft JK, Stamey TA. The natural history of symptomatic recurrent bacteriuria in women. Medicine (Baltimore) 1977; 56:55.
  33. Stamm WE, McKevitt M, Roberts PL, White NJ. Natural history of recurrent urinary tract infections in women. Rev Infect Dis 1991; 13:77.
  34. Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med 2012; 366:1028.
  35. Hooton TM, Vecchio M, Iroz A, et al.. Effect of Increased Daily Water Intake in Premenopausal Women With Recurrent Urinary Tract Infections: A Randomized Clinical Trial. JAMA Intern Med 2018.
  36. Scott AM, Clark J, Mar CD, Glasziou P. Increased fluid intake to prevent urinary tract infections: systematic review and meta-analysis. Br J Gen Pract 2020; 70:e200.
  37. Beerepoot MA, Geerlings SE, van Haarst EP, et al. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J Urol 2013; 190:1981.
  38. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753.
  39. Perrotta C, Aznar M, Mejia R, et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev 2008; :CD005131.
  40. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol 1999; 180:1072.
  41. Raz R, Colodner R, Rohana Y, et al. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin Infect Dis 2003; 36:1362.
  42. Harding C, Mossop H, Homer T, et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial. BMJ 2022; 376:e068229.
  43. Edén CS, Freter R, Hagberg L, et al. Inhibition of experimental ascending urinary tract infection by an epithelial cell-surface receptor analogue. Nature 1982; 298:560.
  44. Stapleton AE, Dziura J, Hooton TM, et al. Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc 2012; 87:143.
  45. Barbosa-Cesnik C, Brown MB, Buxton M, et al. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis 2011; 52:23.
  46. Beerepoot MA, ter Riet G, Nys S, et al. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med 2011; 171:1270.
  47. Avorn J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994; 271:751.
  48. Kontiokari T, Sundqvist K, Nuutinen M, et al. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001; 322:1571.
  49. Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol 2002; 9:1558.
  50. Walker EB, Barney DP, Mickelsen JN, et al. Cranberry concentrate: UTI prophylaxis. J Fam Pract 1997; 45:167.
  51. Raz R, Chazan B, Dan M. Cranberry juice and urinary tract infection. Clin Infect Dis 2004; 38:1413.
  52. Wang CH, Fang CC, Chen NC, et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 2012; 172:988.
  53. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2012; 10:CD001321.
  54. Maki KC, Kaspar KL, Khoo C, et al. Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection. Am J Clin Nutr 2016; 103:1434.
  55. Eells SJ, McKinnell JA, Miller LG. Daily cranberry prophylaxis to prevent recurrent urinary tract infections may be beneficial in some populations of women. Clin Infect Dis 2011; 52:1393.
  56. Juthani-Mehta M, Van Ness PH, Bianco L, et al. Effect of Cranberry Capsules on Bacteriuria Plus Pyuria Among Older Women in Nursing Homes: A Randomized Clinical Trial. JAMA 2016; 316:1879.
  57. Luís Â, Domingues F, Pereira L. Can Cranberries Contribute to Reduce the Incidence of Urinary Tract Infections? A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Clinical Trials. J Urol 2017; 198:614.
  58. Sobota AE. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urol 1984; 131:1013.
  59. Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios 1988; 55:173.
  60. Zafriri D, Ofek I, Adar R, et al. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob Agents Chemother 1989; 33:92.
  61. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med 1998; 339:1085.
  62. Zopf D, Roth S. Oligosaccharide anti-infective agents. Lancet 1996; 347:1017.
  63. Kranjčec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol 2014; 32:79.
  64. Cooper TE, Teng C, Howell M, et al. D-mannose for preventing and treating urinary tract infections. Cochrane Database Syst Rev 2022; 8:CD013608.
  65. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clin Ther 2008; 30:453.
  66. Beerepoot MA, ter Riet G, Nys S, et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med 2012; 172:704.
  67. Stapleton AE, Au-Yeung M, Hooton TM, et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis 2011; 52:1212.
  68. Rudenko N, Dorofeyev A. Prevention of recurrent lower urinary tract infections by long-term administration of fosfomycin trometamol. Double blind, randomized, parallel group, placebo controlled study. Arzneimittelforschung 2005; 55:420.
  69. Costantini E, Zucchi A, Salvini E, et al. Prulifloxacin vs fosfomycin for prophylaxis in female patients with recurrent UTIs: a non-inferiority trial. Int Urogynecol J 2014; 25:1173.
  70. Albert X, Huertas I, Pereiró II, et al. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev 2004; :CD001209.
  71. Ahmed H, Davies F, Francis N, et al. Long-term antibiotics for prevention of recurrent urinary tract infection in older adults: systematic review and meta-analysis of randomised trials. BMJ Open 2017; 7:e015233.
  72. Fisher H, Oluboyede Y, Chadwick T, et al. Continuous low-dose antibiotic prophylaxis for adults with repeated urinary tract infections (AnTIC): a randomised, open-label trial. Lancet Infect Dis 2018; 18:957.
  73. Smith AL, Brown J, Wyman JF, et al. Treatment and Prevention of Recurrent Lower Urinary Tract Infections in Women: A Rapid Review with Practice Recommendations. J Urol 2018; 200:1174.
  74. Nicolle LE. Prophylaxis: recurrent urinary tract infection in women. Infection 1992; 20 Suppl 3:S203.
  75. Stapleton A, Latham RH, Johnson C, Stamm WE. Postcoital antimicrobial prophylaxis for recurrent urinary tract infection. A randomized, double-blind, placebo-controlled trial. JAMA 1990; 264:703.
  76. Chew LD, Fihn SD. Recurrent cystitis in nonpregnant women. West J Med 1999; 170:274.
  77. Pfau A, Sacks T, Engelstein D. Recurrent urinary tract infections in premenopausal women: prophylaxis based on an understanding of the pathogenesis. J Urol 1983; 129:1153.
  78. Pfau A, Sacks TG. Effective prophylaxis of recurrent urinary tract infections in premenopausal women by postcoital administration of cephalexin. J Urol 1989; 142:1276.
  79. Pfau A, Sacks TG. Effective postcoital quinolone prophylaxis of recurrent urinary tract infections in women. J Urol 1994; 152:136.
  80. Nicolle LE, Harding GK, Thompson M, et al. Prospective, randomized, placebo-controlled trial of norfloxacin for the prophylaxis of recurrent urinary tract infection in women. Antimicrob Agents Chemother 1989; 33:1032.
  81. Melekos MD, Asbach HW, Gerharz E, et al. Post-intercourse versus daily ciprofloxacin prophylaxis for recurrent urinary tract infections in premenopausal women. J Urol 1997; 157:935.
  82. Nicolle LE, Ronald AR. Recurrent urinary tract infection in adult women: diagnosis and treatment. Infect Dis Clin North Am 1987; 1:793.
  83. Nicolle LE, Harding GK, Thomson M, et al. Efficacy of five years of continuous, low-dose trimethoprim-sulfamethoxazole prophylaxis for urinary tract infection. J Infect Dis 1988; 157:1239.
  84. Brumfitt W, Hamilton-Miller JM. Efficacy and safety profile of long-term nitrofurantoin in urinary infections: 18 years' experience. J Antimicrob Chemother 1998; 42:363.
  85. Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence. Ann Pharmacother 2013; 47:106.
  86. US Food and Drug Administration. FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm (Accessed on May 26, 2016).
  87. Ronald AR, Conway B. An approach to urinary tract infections in ambulatory women. Curr Clin Top Infect Dis 1988; 9:76.
  88. Lynch SV, Pedersen O. The Human Intestinal Microbiome in Health and Disease. N Engl J Med 2016; 375:2369.
  89. Little P, Moore MV, Turner S, et al. Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial. BMJ 2010; 340:c199.
  90. Wong ES, McKevitt M, Running K, et al. Management of recurrent urinary tract infections with patient-administered single-dose therapy. Ann Intern Med 1985; 102:302.
  91. Schaeffer AJ, Stuppy BA. Efficacy and safety of self-start therapy in women with recurrent urinary tract infections. J Urol 1999; 161:207.
  92. Gupta K, Hooton TM, Roberts PL, Stamm WE. Patient-initiated treatment of uncomplicated recurrent urinary tract infections in young women. Ann Intern Med 2001; 135:9.
  93. Uehling DT, Hopkins WJ, Balish E, et al. Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial. J Urol 1997; 157:2049.
  94. Uehling DT, Hopkins WJ, Elkahwaji JE, et al. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J Urol 2003; 170:867.
  95. Hopkins WJ, Elkahwaji J, Beierle LM, et al. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol 2007; 177:1349.
  96. Eldridge GR, Hughey H, Rosenberger L, et al. Safety and immunogenicity of an adjuvanted Escherichia coli adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study. Hum Vaccin Immunother 2021; 17:1262.
  97. Langermann S, Palaszynski S, Barnhart M, et al. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 1997; 276:607.
  98. Lorenzo-Gómez MF, Foley S, Nickel JC, et al.. Sublingual MV140 for Prevention of Recurrent Urinary Tract Infections. N Eng J Med Evid 2022.
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