Prevention of Recurrent Urinary Tract Infection in Women: An Update

Abstract

Recurrent urinary tract infection (rUTI) is a significant public health problem in women. General measures to prevent recurrence include behavioral changes and increased fluid intake, cranberry ingest, use of methenamine hippurate, antibiotic prophylaxis, D-mannose, probiotics, or vaccines. We conducted a literature review of the latest updates on preventing rUTI in December 2024. The search concluded with 27 articles that fulfilled our inclusion criteria. Our review demonstrated that behavioral changes such as correct genital hygiene, avoiding postponing micturition or defecation, urinating after sexual intercourse, and ingesting 1.5–2 L of water could prevent rUTI. The ingestion of cranberries reduces the risk of symptomatic, culture-verified urinary tract infections in women with rUTIs. Methenamine hippurate is an alternative to antibiotics to avoid rUTI. Estrogen reduces rUTI in women with hypoestrogenism. Limited evidence supports using D-mannose, probiotics, and vaccines to prevent rUTI. In conclusion, after successful treatment of the acute episode, preventative measures are needed to reduce rUTI frequency and morbidity according to each patient’s characteristics and preferences.

1. Introduction

Urinary tract infection (UTI) is the inflammatory response of the urothelium to bacterial invasion. It has an annual prevalence of 11% in women over 16, increasing with age [1,2]. Some of the risk factors are frequent sexual intercourse, use of vaginal tampons, recent use of antimicrobials, a new sexual partner in the last year, use of spermicides, history of UTI at a young age, and maternal history of UTI [2,3]. The most frequent etiological agent is Escherichia coli (E. coli), followed by Proteus spp., Klebsiella spp., other Enterobacteriaceae, and Staphylococcus saprophyticus [4]. Most bacteria that cause recurrent UTI (rUTI) are part of the intestinal microbiota that can adhere to and colonize the introitus and urethra and migrate to the urinary tract [2,3,4,5].

According to the European Association of Urology (EAU), an uncomplicated UTI is an acute, sporadic, or recurrent lower (cystitis) and/or upper (pyelonephritis) UTI limited to non-pregnant women with no anatomical and functional abnormalities within the urinary tract or comorbidities. An rUTI is a recurrence of uncomplicated and/or complicated UTIs, with a frequency of at least three UTIs/year or two in the last six months [6]. The American Urological Association (AUA) recommends a dipstick and culture with each acute episode. In contrast, the EAU only recommends urine cultures if there are atypical symptoms or antibiotic treatment failure [7].

Different measures have been proposed to prevent rUTI in the past years. General measures to prevent recurrence include avoiding risk factors, increasing fluid intake, and practicing early postcoital urination. Continuous antibiotic prophylaxis at low or postcoital doses, estrogen replacement therapy in postmenopausal women, use of vaccines, vaginal application of Lactobacillus, and ingestion of red berries have also been proposed [8,9,10].

This review aims to propose clinical recommendations for preventing rUTI based on a recent literature review.

2. Materials and Methods

A literature review was conducted in December 2024 using the MEDLINE and Scopus databases without period restrictions. Different searches were performed using the following Medical Subject Heading (MeSH) terms and keywords: “prevention”, “recurrent urinary tract infection”, and “women”. Boolean operators (AND, OR) were used to refine the search. The references for each included study were also reviewed, and no language restrictions were applied. Editorials and letters, unpublished studies, posters, comments, and studies including men were excluded. This literature review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Due to the heterogeneity of study outcomes and the lack of standardized quality appraisal, a narrative data synthesis was performed.

3. Results

The MEDLINE and Scopus searches returned 122 results. After duplicate removal and review of results, 72 were selected, and 7 were excluded, leaving 65 articles for complete analysis. A total of 27 articles that fulfilled our inclusion criteria were selected. The summary of the selection process is represented in Figure 1.

To better understand the present report’s primary purpose, the results were divided into different sections: behavioral modifications and increased fluid intake, cranberry, methenamine hippurate, estrogen, antibiotic prophylaxis, D-mannose, probiotics, and vaccines.

3.1. Behavioral Modifications and Increased Fluid Intake

The recommended behavioral changes and patient education relate to fluid intake, mode of contraception, and genital hygiene.

Most guidelines (AUA, Canadian Urological Association—CUA, and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction—SUFU) made a weak recommendation for behavioral modifications for UTI prevention. They recommended increasing oral fluid intake and changing the method of contraception (i.e., hormonal contraception) [7].

A randomized controlled trial (RCT) conducted by Hooton et al. investigated the effect of increased daily water intake on recurrent cystitis in premenopausal women. They showed that increasing daily water intake by 1.5 L reduces the risk of recurrent cystitis by about 50% in women who are low-volume fluid drinkers [11].

According to a meta-analysis, increasing the daily fluid intake (by 200 to 2000 mL, depending on the trial) significantly lowers the infection rate (OR 0.13 [0.07; 0.25], p < 0.001) over the short term (<6 months), but the effect is no longer seen at 12 months (with the continuation of the increased fluid intake). However, the reason for this outcome is not explained. The authors conclude that clinicians should recommend increased water intake to women with recurrent cystitis, especially those drinking less than 1.5 L of fluids daily [12].

The degree to which altered behavior lowers the frequency of infection is unclear, as no relevant randomized trials have been conducted. Based on case–control studies, infection rates are lower when patients follow recommendations to wipe from front to back after using the toilet and to avoid postponing micturition or defecation. The same holds for recommendations to urinate after sexual intercourse and not to clean the genitals after micturition, as doing so makes infections more common, presumably by damaging the protective vaginal flora. There is only low-level evidence for the benefit of these behavioral changes, but they can be recommended nonetheless, as there is little risk of harm and self-care is reinforced [11,13].

3.2. Cranberry

Cranberry products show promising results in reducing rUTI. The primary active ingredients responsible for this effect are fructose and proanthocyanidins (PACs).

Williams et al. published a Cochrane Review in 2023. It examined the effectiveness of cranberry products in preventing UTIs in susceptible populations. The authors analyzed 50 studies involving 8857 participants. The results showed that cranberry reduces the risk of symptomatic, culture-verified UTIs (E. coli, Pseudomonas, and Klebsiella) in women with rUTIs, children, and people susceptible to UTIs following interventions. The evidence did not support its use in the elderly, patients with bladder emptying problems, or pregnant women. Also, the authors concluded that there is no evidence-based preference for cranberry products, as the studies included in their review exhibited significant differences in formulation (such as juice versus tablets), PAC dosage, and duration of the interventions [14].

On the other side, a prospective randomized clinical trial (PRT) assessing the impact of a cranberry dose per day demonstrated that the intake of 2 × 18.5 mg PACs daily was associated with a non-statistically significant reduction in the risk of symptomatic UTI compared to a daily dose of 2 × 1 mg PACs during a 24-week follow-up period. On the contrary, for women with a history of less than 5 UTIs per year, the daily consumption of 2 × 18.5 mg PACs resulted in a significant reduction in the rate of symptomatic UTI during the trial period compared to 2 × 1 mg PAC [15].

3.3. Methenamine Hippurate

Historically, methenamine has been used to prevent and treat UTIs, particularly before the era of antibiotics [2].

First RCTs showed that methenamine’s efficacy in preventing bacteriuria (like the primary outcome) was slightly lower than continuous antibiotics but higher than placebo. Later studies (non-placebo-controlled) demonstrated that patients using methenamine experienced fewer symptomatic UTI episodes compared to before starting prophylaxis, although not as few as those on continuous antibiotics [2].

In addition, a recent trial, a single-center RCT, affirmed the role of methenamine as an evidence-based intervention to reduce rUTI. In this study, subjects on methenamine had a similar reduction in UTI compared to trimethoprim (TMP) [16].

A meta-analysis from 2021, which includes six RCTs, highlights the potential of methenamine hippurate as an alternative to antibiotics for UTI prevention but emphasizes the need for more robust evidence before clinical recommendations can be made because there is insufficient evidence to make firm recommendations due to the small number of included studies and considerable clinical and statistical heterogeneity [17].

In an RCT not included in the mentioned meta-analysis, the ALTAR trial aimed to determine if methenamine hippurate was non-inferior to antibiotics in reducing UTI incidence over 12 months of treatment. Results showed that methenamine hippurate was non-inferior to antibiotics in preventing UTIs, and both treatments substantially reduced UTI incidence compared to baseline [18].

The last systematic review, published in 2024 by Davison et al., included seven studies (three prospective and four retrospective). Two of the three prospective studies demonstrated no or non-inferior differences in clinical efficacy to prevent rUTI between methenamine and antibiotic prophylaxis, and the third showed decreased rates of UTI with methenamine use in patients with short-term indwelling catheters compared with cranberry alone. The retrospective studies consistently supported the efficacy and safety of methenamine for UTI prophylaxis in various populations and clinical settings [19].

Methenamine is currently not advised for use with antibiotics, with a theoretical risk of crystalluria when used with sulfonamides. Caution is recommended in patients with chronic kidney disease (CKD), particularly those with an estimated glomerular filtration rate (eGFR) ≤ 60. Use should be avoided in patients with eGFR ≤ 30 due to limited modern data [2].

3.4. Estrogen

Multiple RCTs have demonstrated the efficacy of vaginal estrogen preparations in preventing rUTIs in postmenopausal women.

More recently, Ferrante et al. conducted a randomized, placebo-controlled trial comparing two forms of vaginal estrogen (estradiol ring and conjugated estrogen cream) to placebo in postmenopausal women with rUTIs. In the intention-to-treat analysis, significantly fewer women treated with vaginal estrogen experienced a UTI within 6 months compared to placebo (50% vs. 94%, p = 0.041). The estradiol ring appeared particularly effective, with only 38% of women in this group experiencing a UTI compared to 91% in the placebo group (p = 0.041) [20].

In a 2021 meta-analysis, eight RCTs of estrogen therapies versus placebo were included regarding the outcomes of preventing rUTIs. Five studies, including 1936 patients, evaluated the use of vaginal estrogen, which resulted in a significant reduction in rUTIs (relative risk, 0.42; 95% CI, 0.30–0.59). Three studies evaluated the outcomes of oral estrogen in the prevention of UTIs and showed no significant difference in the number of rUTIs compared to treatment with placebo (RR, 1.11; 95% CI, 0.92–1.35). Adverse events associated with vaginal estrogen were reported, including vaginal discomfort, irritation, burning, and itching, and there was no significant increase in the vaginal estrogen group (relative risk, 3.06; 95% CI, 0.79–11.90) [21].

Tan-Kim et al. examined the effectiveness of vaginal estrogen in preventing rUTI in women with hypoestrogenism. The retrospective review included 5638 women prescribed vaginal estrogen from 2009 to 2019. Results showed a significant 51.9% reduction in UTI frequency in the year following prescription, with 55.3% of patients experiencing ≤1 UTI and 31.4% experiencing none. The study concludes that vaginal estrogen effectively reduces UTI frequency in women with hypoestrogenism [22].

The most recent study from 2024 evaluated the efficacy of an ultra-low-dose 0.005% estriol vaginal gel in preventing UTIs in postmenopausal women with genitourinary syndrome of menopause (GSM). The randomized, double-blind, placebo-controlled trial involved 108 women across 28 Spanish sites. Participants received either 1 g of vaginal gel with 50 micrograms of estriol or a placebo gel. The estriol group showed a 26% lower incidence rate of UTIs than the placebo group (32.34 vs. 43.76 per 100 women, p < 0.001). The conclusions of the study showed that the ultra-low-dose estriol vaginal gel is safe and effective in preventing rUTI in postmenopausal women, potentially by improving vaginal pH [23].

3.5. Antibiotic Prophylaxis

Antibiotic therapy has three main approaches: continuous prophylaxis, postcoital prophylaxis, and patient-administered self-treatment.

In March 2022, Kwok et al. reviewed nine rUTI guidelines (EAU, National Institute for Health and Care Excellence (NICE), Society of Obstetricians and Gynaecologists of Canada, American Academy of Family Physicians, Mexican College of Gynaecology and Obstetrics Specialists, Swiss Society of Gynaecology and Obstetrics (SSGO), Spanish Society of Infectious Diseases and Clinical Microbiology, German Association of Scientific Medical Societies (AWMF), and the combined AUA/CUA/SUFU). All guidelines agreed that antibiotic treatment for acute episodes should be less than seven days. They also support continuous and postcoital prophylaxis, though the SSGO and the AWMF stressed that prophylactic antibiotics should be a last resort after other preventive measures are tried [7].

In a meta-analysis conducted by Price et al. in 2016, it was found that there were no significant differences in clinical or microbiological cure rates when comparing prophylactic antibiotic treatment with nitrofurantoin to other antibiotics, such as norfloxacin and trimethoprim/sulfamethoxazole (TMP-SMX), in non-pregnant adult women. The duration of prophylaxis also did not significantly impact the outcomes. However, there were notable differences concerning general adverse effects. Specifically, nitrofurantoin was associated with a higher risk of gastrointestinal adverse effects [24].

A Cochrane review, which analyzed 19 trials involving 1120 patients, demonstrated that antibiotics are more effective than placebo in reducing clinical and microbiological recurrences in premenopausal and postmenopausal women with rUTI. The antibiotics examined in this review included fluoroquinolones, cephalosporins, TMP, SMX, and nitrofurantoin. No single antibiotic was superior to the others [25].

3.5.1. Postcoital Prophylaxis

There is no solid data on choosing one antibiotic over another. Fluoroquinolones and cephalexin are effective but have a greater risk of toxicity; for this reason, regimens with nitrofurantoin or TMP are preferred as the first line.

Furthermore, only TMP-SMX has been directly compared with placebo, but uncontrolled studies have shown reduced urinary tract infections with nitrofurantoin and cephalexin [1].

According to the review by Epp et al., one study showed that sexually active women who took postcoital ciprofloxacin had similar results to women who took ciprofloxacin daily. In another study, they observed that an essential advantage of postcoital prophylaxis was that it produced fewer side effects because women took only one-third the amount of antibiotic used in daily prophylaxis. For postcoital prophylaxis (single dose), the authors recommend, indifferently, 40/200 to 80/400 mg of TMP-SMX, 50 to 100 mg of nitrofurantoin, 125–250 mg of cephalexin, 250 mg of cinoxacin, 125 mg of ciprofloxacin, 200 mg of norfloxacin, or 100 mg of ofloxacin [26].

3.5.2. Continuous Prophylaxis

Regarding the administration regimen, Epp et al. concluded that no optimal recommendation for continuous prophylaxis exists. Some authors suggest doing it every other night or three nights a week. Other studies show that weekly prophylaxis results are better than monthly, but they did not find any studies comparing daily and weekly prophylaxis [26].

A 2016 meta-analysis by Ahmed et al. found that long-term antibiotic treatment reduced rUTIs by 24% in women over 65, compared to alternatives like vaginal estrogens and D-mannose, without increasing adverse effects [27].

In 2015, Schneeberger et al. conducted a review focused on the population of pregnant women. They concluded that there is no evidence that a daily dose of nitrofurantoin and close monitoring prevents rUTI compared to close monitoring alone [28].

For continuous prophylaxis, antibiotics such as TMP-SMX are used as a single dose (40/200 per day) or weekly (40/200 mg 3/week), 100 mg daily of TMP, or 50 to 100 mg of nitrofurantoin per day. Cephalosporins such as cephalexin or cefaclor can be used at 250 mg daily in low doses. Fluoroquinolones (ciprofloxacin, norfloxacin, or cinoxacin) are also recommended in doses of 125 mg, 200 mg, or 250–500 mg per day in the mentioned order [26].

3.6. D-Mannose

Although the anti-adhesive effects of D-mannose have been well-established, currently, there are a small number of pilot studies and clinical trials conducted with limited evidence supporting its routine use in women with rUTI [29].

Hayward et al. assessed the effectiveness of D-mannose in a randomized, double-blind, placebo-controlled study, where they compared the clinical efficacy of D-mannose and placebo powder to prevent UTI in women with rUTI in the United Kingdom. This study provided strong evidence that D-mannose did not reduce the proportion of women with a history of rUTI experiencing a further UTI for which they contacted ambulatory care, with 95% CIs excluding the minimum treatment effect considered necessary by the patient advisory panel [30].

A Cochrane systematic review included seven RCTs (719 participants) in the adult population who had either acute cystitis or a history of recurrent (defined as at least two episodes in six months or three episodes in 12 months) UTIs (symptomatic or asymptomatic). No two studies were comparable (by dose or treatments), and they could not undertake meta-analyses. The systematic review concluded that there is currently little to no evidence to support or refute D-mannose use to prevent or treat UTIs in all populations [29].

Lenger et al. performed a systematic review and meta-analysis to determine whether D-mannose reduces UTI recurrence in adult women with rUTI compared to other prevention agents. Secondary outcomes included side effects and compliance with D-mannose use. They concluded that D-mannose appears to be a protective agent against rUTI (versus placebo) with possibly similar effectiveness as antibiotics. It is well tolerated with minimal side effects, with a small percentage of patients experiencing diarrhea [8].

Kranjcec et al. conducted a randomized clinical trial to determine the effect of taking D-mannose in reducing the rate of rUTI. The trial consisted of a daily intake of 2 g of D-mannose powder for 6 months compared to standard 50 mg of nitrofurantoin daily prophylaxis and no intervention. The study included a total of 308 women with acute cystitis and a positive history of recurrent cystitis episodes. D-mannose powder was shown to be effective in preventing UTI during 6-month prophylaxis with a rate of r UTI of 15% versus 20% in the nitrofurantoin group and 60% in the no-intervention group. The recurrence rate did not differ between patients who took standard nitrofurantoin prophylaxis and those who took D-mannose powder. The D-mannose group had fewer side effects and equal adherence [31].

Synthetic mannosides have also been studied as a blockage to the E. coli type 1 pili binding. There is a phase 1 trial of a vaccine against the FimH adhesin, a mannose-specific adhesin located on the tip of type 1 fimbriae of E. coli that is capable of mediating shear-enhanced bacterial adhesion, that has recently demonstrated safety and immunogenicity [8,32].

The EAU guidelines support D-mannose use as a weak–moderate recommendation [7].

3.7. Probiotics

Depletion of vaginal lactobacilli is associated with rUTI, which suggests that repletion may be beneficial [33].

Stapleton et al. conducted a double-blind, placebo-controlled trial of a Lactobacillus crispatus intravaginal suppository probiotic to prevent rUTI in premenopausal women. One hundred young women with a history of rUTI received antimicrobials for acute UTI. Then, they were randomized to receive either the probiotic or placebo daily for 5 days, then once weekly for 10 weeks. rUTI occurred in 15% of women receiving the suppository probiotic compared with 27% of women receiving placebo. They concluded that the Lactobacillus crispatus intravaginal suppository probiotic treatment for cystitis is associated with reduced rUTI [33].

Czaja et al. performed a phase I trial to assess the safety and tolerance of a Lactobacillus vaginal suppository for the prevention of rUTI. Thirty premenopausal women with a history of rUTI were randomized to use the probiotic or placebo vaginal suppositories daily for five days. The women using probiotics had minimal side effects, and some had mild urinary tract inflammation [34].

A recent Cochrane review on probiotics for preventing rUTI found no significant reduction in incidence, but it relied on small studies of poor quality with inconsistent dosages [35].

3.8. Vaccines

OM-89 (Uro-Vaxom) is an oral vaccine available in Europe made from a lysate of 18 selected E. coli strains. It may enhance immunity by increasing lymphocyte and macrophage activity.

Meta-analyses of RCTs indicate that Uro-Vaxom is safe and effective in reducing UTI recurrence for 6 to 12 months compared to placebo. Extended protection may occur with three monthly 10-day booster courses. While the EAU recommends it, it is unavailable in the United States. Booster vaccines significantly reduced E. coli UTIs in sexually active women less than 52 years old, but primary vaccination alone showed no benefit. Vaginal vaccines for UTIs are not commercially available, and more extensive trials are needed [35].

The AUA/CUA/SUFU guidelines state that there is insufficient evidence to recommend vaccines as a proven treatment for rUTIs [7].

4. Discussion

UTIs are the second most common reason for antibiotic prescription after respiratory infections [1], and it is one of the main reasons for medical consultation, involving a high monetary cost (an estimated cost of 10 billion dollars per year) at the expense of the high prices of antimicrobials and diagnostic procedures [2].

According to the literature, preventive measures such as behavioral changes and increased fluid intake can be recommended to the general population as they are not harmful or expensive. Other preventive measures must be assessed with the patient regarding their clinical situation (e.g., cranberry ingestion, methenamine hippurate, antibiotic prophylaxis, D-mannose, probiotics, or vaccines) (

Table 1. Key points of preventive measures against recurrent urinary tract infections.

Preventive Measure	Key Points (Literature References)
Behavioral changes and increased fluid intake	Change the method of contraception [7]. Ingestion of 1.5–2 L of water [11,12]. Correct genital hygiene, avoid postponing micturition or defecation, and urinate after sexual intercourse [11,13].
Cranberry	It reduces the risk of symptomatic, culture-verified UTIs in women with rUTIs, in children, and in people susceptible to UTIs following interventions [14]. There are no significant differences in formulation, PACs dosage, and the duration of the intervention [14].
Methenamine Hippurate	Alternative to antibiotics for UTI prevention [16,18,19]. Concomitant use of antibiotics is not recommended [2]. Use with caution in the CKD population [2].
Estrogen	Reduces UTI frequency in women with hypoestrogenism [20,22]. Vaginal administration of 0.5 mg estriol 2–3 times per week is recommended [20,21,22].
Antibiotic prophylaxis	Antibiotics are more effective than placebo in reducing rUTI [25,27]. It has not been possible to demonstrate that there is an antibiotic or a treatment regimen superior to the rest [1,24,25,26]. It is indicated if failure of other preventive measures that do not require antibiotic therapy [10].
D-mannose	Limited evidence supports its routine use in women with rUTI [29,30]. It is well tolerated with minimal side effects [31].
Probiotics	More data and placebo-controlled studies are needed in patients with rUTI to recommend probiotics [35]. It is well tolerated with minimal side effects [34].
Vaccines	There is insufficient evidence to recommend vaccines as a proven treatment for rUTIs [7,35].

Abbreviations: rUTI: recurrent urinary tract infection, PACs: proanthocyanidins, UTI: urinary tract infection, CKD: chronic kidney disease.

).

Most guidelines recommend behavioral modifications and increased fluid intake (1500 mL and 2000 mL of water). Although there is only a low level of evidence of the benefit of this preventive measure, it provides a safe and inexpensive alternative to antimicrobial prophylaxis that may help reduce antimicrobial resistance [10,11,12,13]. The distribution of etiological agents and antimicrobial resistance varies according to the geographical location and type of health establishment. In general, we can say that resistance to quinolones exceeds 20%, followed by resistance to cephalosporins (close to 20%) and, to a lesser extent, to aminoglycosides [4,5].

One controversial point is the use of cranberry for rUTI prevention. Its compounds work, in theory, by inhibiting bacteria from attaching to the bladder’s inner lining. This anti-adhesion mechanism helps prevent the establishment and spread of bacterial infections in the urinary system [2,14]. The 2023 Cochrane Review concluded that cranberry products might reduce the risk of symptomatic, culture-verified UTIs in women with rUTI [14]. Furthermore, women with a moderate burden of rUTI may benefit from preventive treatment with a split dose of 37 mg/day of PACs from cranberry extract, with few associated side effects (dyspepsia) [15]. Additional research is needed to investigate the dose-dependent effects of cranberry PACs in preventing rUTIs and their impact on microbiota.

Methenamine hippurate is considered an effective agent for preventing UTI by reducing bacteriuria. It converts to formaldehyde from hexamine in the urine, acting as a bacteriostatic agent without inducing resistance [2]. The use of antiseptics like methenamine hippurate declined and was replaced by antibiotics for treating UTIs. However, because of antibiotic resistance, there is a renewed interest in its use as a preventive measure against rUTIs. Robust evidence from a meta-analysis describes its potential as an alternative to antibiotics for UTI prevention but emphasizes the need for more significant and statistically homogeneous studies. Among the limitations of this meta-analysis, it included only six studies, five of which were published over 30 years ago, and the most recent study was a clinical trial record rather than a peer-reviewed publication. The studies exhibited considerable clinical and statistical heterogeneity, poor reporting of bacterial resistance, and a generally unclear risk of bias [17].

In a systematic review by Davidson et al., the retrospective studies consistently supported the efficacy and safety of methenamine for UTI prophylaxis in various populations and clinical settings [19]. Methenamine is currently not advised for use with antibiotics because of side effects, and it should be used with precaution in the CKD population. Further investigation of the use of methenamine hippurate in the CKD population could be useful to understand its practical utility.

The risk of UTI increases in women after menopause. Its pathophysiology is multifactorial. Estrogen deficiency leads to thinning of the urethral and vaginal epithelia, decreased glycogen content in vaginal cells, loss of lactobacilli, and increased vaginal pH. These changes create a more hospitable environment for uropathogenic bacteria. Additionally, estrogen deficiency causes bladder and pelvic floor changes that may impair urinary function [1,2]. Different studies showed a significant reduction in rUTI, especially in postmenopausal women, by improving vaginal pH [21,22,23].

According to the evidence, the use of oral estrogen in the prevention of UTIs showed no significant difference in the number of rUTIs compared to placebo. It would be necessary to study its different pharmacokinetics than vaginal administration [21].

When prescribing vaginal estrogen, clinicians should consider factors that may impact adherence and efficacy. Despite the evidence supporting its efficacy, vaginal estrogen remains underutilized for UTI prevention. Barriers include the lack of the Food and Drug Administration of the United States (FDA) approval for this specific indication, inadequate screening and diagnosis of GSM, and misperceptions about the safety of vaginal estrogen. Therefore, estrogen education for medical providers and patients is needed to promote the correct use of this preventive measure because a substantial body of evidence supports the use of vaginal estrogen as an effective and safe preventive measure for rUTIs in postmenopausal women. In medical practice, the vaginal administration of 0.5 mg estriol 2–3 times per week is recommended.

In recent years, numerous studies have examined the effectiveness of long-term antibiotic treatment for the prophylaxis of rUTI. The benefit seems straightforward, but prolonged antibiotic treatment can cause side effects like diarrhea, nausea, headaches, and vaginal burning. Also, serious risks are described, including pulmonary toxicity from nitrofurantoin and severe skin reactions from TMP-SMX. The use of long-term antibiotics promotes antibiotic resistance [1]. For all the above, and to help reduce the antimicrobial resistance, the guidelines agree that the prophylactic antibiotics for rUTI, continuous and postcoital, should be the last option only after preventive measures are tried [7].

Premenopausal women with a clear relationship between sexual relations and UTI could benefit from postcoital prophylaxis. In this type of patient, it is also recommended to perform examinations to detect alternative causes of the symptoms since, in this group, a higher incidence of sexually transmitted infections has been seen, especially Chlamydia trachomatis and Trichomonas vaginalis [2]. To avoid specific medical toxicities, regimens with nitrofurantoin or TMP are preferred as the first line. Still, there is no clear recommendation for which antibiotic should be used as the first line [1,24,25,26]. Prophylactic treatment should be reviewed regularly. Discontinuation may be reasonable if intercourse frequency decreases or if the patient has fewer sexual partners, as these factors are associated with UTIs.

Continuous antibiotic prophylaxis reduces clinical recurrences by 80%. Still, it needs to be considered that most studies that compare antibiotics in a constant regimen with placebo have been carried out in premenopausal patients, so it would not be appropriate to extrapolate this to postmenopausal patients [2]. Specific populations, such as elderly patients and pregnant women, have unique healthcare needs. In older people, the risk of antibiotic resistance is heightened, so antibiotic prophylaxis must be justified by evidence showing that its benefits outweigh the harms. It is also crucial to distinguish between bladder dysfunction and localized vaginal symptoms, as treating these with antibiotics can lead to resistance without benefit. The optimal duration for continuous antibiotic prophylaxis is unclear. While there have been reports of extended use, the studies are generally small. Recent data indicate potential harm from long-term use, so it is advisable to reassess the need for prophylaxis every six months. This is especially important if a patient has a concerning number of breakthrough infections rather than switching antibiotics immediately [2]. There is no optimal recommendation for continuous prophylaxis (daily or weekly doses), and the optimal duration is unclear [26].

Other preventive measures, such as D-mannose, probiotics, or vaccines, do not have enough evidence. D-mannose is a food supplement found in some fruits and vegetables. It is a monosaccharide isomer of glucose that may inhibit bacterial adherence to uroepithelial cells by binding to a site on the tip of the fimbria. With this mechanism of action, the D-mannose-based inhibitors can block uropathogenic E. coli adhesion and invasion of the uroepithelial cells [29]. It is absorbed in the upper gastrointestinal tract. It is well tolerated with minimal adverse side effects, such as gastrointestinal symptoms, including diarrhea, which is then excreted in the urine [30]. The data reviewed supports that although it is well-tolerated and has minimal side effects, there is little to no evidence to support or refute D-mannose use to prevent or treat UTIs in all populations [29,30]. However, the high cost of this over-the-counter food supplement (approximately 29 dollars per month in the United States of America) [30] reinforces the need to prove its clinical efficacy. According to the literature, there is still insufficient evidence for its routine use as a preventive measure against rUTI.

Regarding probiotics, the instillation of Lactobacillus into the vagina could stop the ascension of uropathogens into the bladder. Lactobacillus crispatus is one of the most common vaginal Lactobacillus species. It produces hydrogen peroxide (H₂O₂+) that adheres to uroepithelial cells, interferes with the attachment and growth of uropathogens, and persists in the vagina, helping to restore the normal vaginal microbiota in women [33,34].

Available studies suggest that probiotics can be beneficial, and most authors consider this approach promising [2,4,26]. They also have the advantage of minimum side effects. Nonetheless, no substantial evidence supports probiotics’ role in rUTI prevention, and most of the evidence comes from small studies.

More data and placebo-controlled studies are needed in patients with rUTI to recommend D-mannose and probiotics [36].

Finally, immunotherapy (vaccines) requires more extensive trials and evidence to be a proven recommendation against rUTIs [35]. In addition to Uro-Vaxom, there are emerging vaccines under study, such as ExPEC4V, Uromune, and Solco-Urovac. ExEPC4V contains the O antigen of four strains of E. coli. Solco-Urovac, on the other hand, contains multiple heat-inactivated strains of E. coli, Proteus mirabilis, Proteus morganii, Enterococcus faecalis (E. faecalis), and Klebsiella pneumoniae (K. pneumoniae); and Uromune contains E. coli, K. pneumoniae, E. faecalis, and Proteus vulgaris. Studies have demonstrated greater efficacy with booster doses, but the results are not conclusive, making this an area for future research. Therefore, there is limited evidence to suggest that vaccinations are effective at reducing rUTI in adult female patients in the short term [37].

This review may lead to further studies exploring the geographical and demographic variability of preventive measures against rUTI to better understand their applicability. A recent cohort study in the United States addressed the adherence to non-antibiotic preventive measures for rUTI, such as methenamine hippurate, D-mannose, and vaginal estrogen. Of a total of ninety women with a mean age of 64.7, vaginal estrogen (81.1%) was the most prescribed prophylactic regimen, followed by methenamine hippurate (26.7%). Treatment adherence was low, at 37%. No demographic or clinical factors were associated with adherence to non-antibiotic prophylactic regimens [38].

The present study has limitations that must be acknowledged. Some of the study outcomes vary widely, and there is no standardized quality assessment. Furthermore, additional RCTs are needed to validate certain preventive measures and analyze their cost-effectiveness.

5. Conclusions

Preventing rUTI in women is essential in public health, given the worldwide economic burden of UTI. Following successful treatment of the acute episode, preventative measures are needed to reduce rUTI frequency and morbidity. Several therapeutic approaches aim to lower the recurrence rate. Still, they must be considered according to each patient’s characteristics and preferences and the latest published evidence to ensure their effectiveness.