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 adult and adolescent females".)
Complicated UTI in adults, including pyelonephritis, is discussed in detail elsewhere. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents".)
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".)
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 . 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 . In a Finnish study of women ages 17 to 82 who had E. coli cystitis, 44 percent had a recurrence within one year . The self-reported incidence of cystitis remains high even in older women .
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 . 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 . 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 .
●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 . 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 .
●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 . 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 . 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 .(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 . Studies using newer technologies are beginning to elucidate the relationships between UTI and gut, vaginal, and urinary microbiomes .
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 . 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.
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 clinical diagnosis of recurrent cystitis is evident. 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 adult and adolescent 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 adult and adolescent females", section on 'Urine culture'.)
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 . 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 also suggest vaginal estrogen.
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 . It is important that discussions of preventive behavioral strategies be done without judgment to avoid blaming the woman for the urinary tract infection (UTI); there are not many truly modifiable behaviors that have demonstrated efficacy.
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 . 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) . 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; the dose depends on the formulation, as outlined in the table (table 3). (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) . 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) .
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) . It is unclear if the formulation of estrogen was related to the less favorable outcome in this trial.
Adverse effects of vaginal estrogen are uncommon and can include vaginal bleeding, nonphysiologic discharge, and local discomfort. 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 .
Oral estrogen has not been shown to be effective [37,39].
ADDITIONAL INTERVENTIONS FOR FREQUENT RECURRENCE
Selecting a strategy
●Choosing between antibiotic and antibiotic-sparing strategies – Many women with frequently recurrent cystitis are interested in other preventive strategies. In general, for such individuals, we suggest starting with additional antibiotic-sparing strategies (specifically, methenamine or cranberry products) rather than antibiotic prophylaxis. Evidence suggests that both methenamine and cranberry products can effectively reduce the incidence of cystitis in females, and they are usually well tolerated; the choice between them generally depends on patient and provider preference. (See 'Methenamine' below and 'Cranberry products' below.)
Although data supporting the efficacy of antibiotic prophylaxis are more extensive and more consistent, the potential adverse effects (including direct toxicities, selection for resistance that complicates treatment of future infections, alteration of microbiome, and secondary Clostridioides [formerly Clostridium] difficile infection) likely outweigh the modest reduction in UTI rate compared with antibiotic-sparing strategies. As an example, in one trial, antibiotics prevented approximately less than one additional UTI per year than methenamine . Furthermore, simple cystitis rarely results in poor outcomes; the downsides of prolonged antibiotic use should be weighed against the impact on patient well-being and function. We especially try to avoid antibiotic prophylaxis in patients with cystitis episodes caused by a uropathogen with reduced susceptibility to orally available agents because of the risk of selecting for resistance to that drug class and thus losing the last oral option for therapy.
Nevertheless, for many females with frequent documented recurrences (eg, two or more within six months) who have severe or very bothersome symptoms and understand the potential drawbacks, antibiotic prophylaxis is a reasonable initial approach. We do not use antibiotic prophylaxis in patients who have recurrent signs or symptoms that are not specific to UTI (eg, mental status changes without genitourinary symptoms), even if they are associated with bacteriuria (with or without pyuria), because of the likelihood that this reflects asymptomatic bacteriuria coincident with clinical features related to a separate process. (See 'Antimicrobial prophylaxis in select cases' below.)
Other commonly used antibiotic-sparing strategies include D-mannose and probiotics. Although we do not routinely suggest these agents given lack of supportive data, they are reasonable adjunctive options if patients want to take them. (See 'Optional adjunctive strategies of uncertain role' below.)
●Uncertain value of combining interventions – We do not routinely combine antibiotic-sparing strategies with antibiotic prophylaxis. There is no evidence evaluating whether combining these interventions has any additive benefit, and a primary reason to use methenamine or cranberry is to reduce the need for antibiotics. Nevertheless, if individuals who have chosen to use antibiotic prophylaxis also want to use cranberry products, D-mannose, or probiotics, we do not discourage them as long as they are tolerating those products. We advise against using both methenamine and antibiotic prophylaxis at the same time.
Many individuals also combine antibiotic-sparing strategies (eg, use both methenamine and cranberry products). Similarly, the efficacy of this is unknown, but the potential drawbacks are likely minimal.
●Reevaluation of selected approach – Regardless of which strategy the patient selected, we reevaluate at approximately three to six months to assess tolerance and effectiveness of the approach. Patients who have had multiple breakthrough episodes of cystitis or have not tolerated the intervention can switch to another strategy or have an intervention-free period. In particular, for individuals with breakthrough cystitis despite antibiotic prophylaxis, an antibiotic-free period may be helpful. Changes to the perineal and vaginal flora with long-term antibiotic use may paradoxically increase the risk for cystitis, and a period off antibiotics could allow repopulation of protective flora .
Methenamine — For females with recurrent cystitis, we suggest methenamine as an antibiotic-sparing strategy to reduce the risk of recurrence. The typical dose of methenamine hippurate is 1 g orally twice daily. Adding vitamin C to methenamine to try to achieve and maintain an acidified urine is a common practice, but we do not routinely do this; studies that demonstrated efficacy of methenamine did not include additional acidifiers. Methenamine should not be coadministered with sulfonamide antibiotics (including trimethoprim-sulfamethoxazole) because of concern for sulfonamide crystallization in the urine. Methenamine salts are not considered antibiotics as they do not have a specific target of action, but they are converted to formaldehyde in acidified urine, which is toxic to bacteria, and thus have general antimicrobial activity.
Data suggest that the risk of recurrent cystitis with methenamine may be clinically similar to that with antibiotic prophylaxis [42,44]. 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 . The subsequent rates of cystitis were clinically similar although were statistically higher in the methenamine group compared with the antibiotic group (1.38 versus 0.89 episodes per person per year, adjusted rate ratio 1.52, 95% CI 1.16-1.98 and absolute difference 0.49 episodes, 90% CI 0.15-0.84). The overall reduction in both groups from a median of six UTIs was considered a benefit and the small difference in UTI rate (less than one additional UTI per year with methenamine compared with antibiotic) met the prespecified noninferiority criteria.
During the intervention period, rates of resistance among E. coli isolates from perineal swabs were lower with methenamine than antibiotics. However, the long-term impact on resistance remains uncertain. The rate of adverse events was similar between the two groups. In the methenamine group, four subjects were hospitalized for UTI, whereas no such events occurred in the antibiotic group; details on whether these occurred on therapy or during the post-intervention monitoring period are not available.
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. An assessment of urine pH or the value of urine acidification was not performed in this study.
Cranberry products — For females with recurrent cystitis, we suggest cranberry products as an antibiotic-sparing strategy to reduce the risk of recurrence. The optimal formulation and dose are unknown, and there is no standardization across formulations in the amount of the potentially active ingredients. Acknowledging these limitations, we typically suggest an 8-ounce (approximately 240 mL) glass of cranberry juice once or twice daily or cranberry concentrate tablets 500 mg to 1000 mg total daily dose.
The overall clinical evidence suggests that cranberry products may reduce the frequency of simple cystitis, particularly in females without major underlying urologic abnormalities [45-48], and there are plausible biological mechanisms for such an effect, although individual clinical studies are limited by suboptimal study design and mixed results [45,49-58]. In a 2023 Cochrane meta-analysis of 26 trials that included 6211 individuals, cranberry products reduced the risk of symptomatic, culture confirmed UTI overall (relative risk [RR] 0.70, 95% CI 0.58-0.84) . A similar effect was observed among females with a history of prior UTI, specifically, although the estimated effect was less precise (eight trials, 1555 participants, RR 0.74, 95% CI 0.55-0.99). There was substantial statistical and clinical heterogeneity across studies, including extensive variability in type, dosing, and administration of cranberry products (including use of combination products with non-cranberry components), different comparators, and variable definitions of UTI (including variable microbiologic thresholds). The analysis also did not detect a beneficial effect among the subgroup of elderly individuals in long-term care facilities (RR 0.93, 95% CI 0.67-1.30 among 1489 participants) or among adults with underlying bladder abnormalities (eg, neurogenic bladder; RR 0.97, 95% CI 0.78-1.19 among 464 participants).
In vitro evidence has also suggested that cranberry products could have a beneficial effect. Laboratory studies have demonstrated that cranberry juice inhibits adherence of uropathogens to uroepithelial cells [59,60]. The mediators of this anti-adherence effect may be fructose, which could interfere with adhesion of type 1 fimbriated E. coli to uroepithelium , and proanthocyanidins, which can inhibit adherence of P-fimbriated E. coli . 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 .
The adverse effects of cranberry products are minimal. Drinking juice results in additional caloric and glucose intake. Cranberry products are also associated with gastrointestinal side effects, such as heartburn .
Some clinicians recommend a product that is advertised as a formulation of soluble proanthocyanidins extracted from concentrated cranberry juice. However, this product is often more expensive than other cranberry products, and there are no data indicating that it results in improved clinical outcomes [63,64]. We do not specifically recommend this product over other cranberry formulations.
Optional adjunctive strategies of uncertain role
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 [44,65].
However, the published clinical evidence on the effectiveness of D-mannose for preventing cystitis is spare and of low quality [66,67]. 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 . 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 . 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) .
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
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 [71,72], 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 . 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 [50,69,71,74,75]. 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 . 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 .
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 [73,76]. 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 [33,77]. 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) . Uncontrolled studies suggest a comparable reduction in infection rates with postcoital trimethoprim-sulfamethoxazole, nitrofurantoin, cephalexin, or a fluoroquinolone [79-83]. In another randomized trial, postcoital ciprofloxacin was as effective as daily ciprofloxacin in sexually active young women .
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 .
Some authorities advocate prophylaxis for two or more years in women who continue to have symptomatic infections . Use of trimethoprim-sulfamethoxazole or other agents for as long as five years has been reported to be effective and well tolerated [33,86]. Nitrofurantoin has also been shown to be safe and well tolerated in long-term (12 months) prophylaxis regimens . Of note, there are concerns about toxicity with long term nitrofurantoin use, as discussed elsewhere. (See 'Adverse effects' below.)
Although many 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 one meta-analysis)  some data suggest that prophylaxis is associated with a lower rate of UTI even after cessation, at least in the short term . For individuals who have multiple breakthrough episodes on antibiotic prophylaxis, a trial of an antibiotic-free period is also reasonable.
●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) , 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 . 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 . (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 [69,75,84,86,90]. 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 [69,86]. 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) . 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 .
TREATMENT OF RECURRENT EPISODES
●General approach to treatment – 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 adult and adolescent females", section on 'Patients with MDR risk factors'.)
●Have a high threshold for treating cystitis – 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 , and it may be able to reduce the overall burden of antibiotic use for recurrent cystitis.
●Option for 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 [93-95].
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 [96-98], 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 . Another promising approach under development is a vaccine based upon the E. coli type 1 fimbrial adhesion protein, FimH . 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) . 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 . 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.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●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 adult and adolescent 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'.)
●Additional interventions for frequent recurrences – For women with frequently recurrent cystitis who are interested in additional preventive interventions, we suggest the antibiotic-sparing strategies of methenamine or cranberry products rather than antibiotic prophylaxis (Grade 2C). Although the data supporting the efficacy of antibiotic prophylaxis are more extensive and more consistent than those for methenamine or cranberry, the potential adverse effects with antibiotics likely outweigh the benefit of a small reduction in UTI rate compared with antibiotic-sparing strategies, given that infection that rarely results in poor outcomes. Nevertheless, antibiotic prophylaxis is a reasonable option for women with frequent recurrences (eg, two or more within six months) who have severe or bothersome symptoms and prefer antibiotics after counseling on this risk/benefit balance. (See 'Selecting a strategy' above.)
•Antibiotic-sparing strategies – The dose of methenamine hippurate is 1 g orally twice daily. The optimal dose and formulation of cranberry products are uncertain; common doses are an 8-ounce (approximately 240 mL) glass of cranberry juice once or twice daily and cranberry concentrate tablets 500 mg to 1000 mg total daily dose. (See 'Methenamine' above and 'Cranberry products' above.)
•Antibiotic prophylaxis – Postcoital prophylaxis can be used for women whose cystitis is temporally associated with sex, and continuous prophylaxis is 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. Doses and other options are listed in the table (table 4). (See 'Antimicrobial prophylaxis in select cases' above.)
•Reevaluation – We reevaluate preventive strategies after three to six months. (See 'Selecting a strategy' 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 adult and adolescent females", section on 'Management'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas M Hooton, MD, who contributed to earlier versions of this topic review.
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