Urinary tract infections (UTIs) are the most common bacterial infection and are especially common in postmenopausal women, who often experience recurrent UTIs. Women with recurrent UTIs are commonly treated with antibiotics, but side effects, collateral damage to commensal bacteria, and antimicrobial resistance result from frequent antibiotic use. The Centers for Disease Control and Prevention estimate that drug resistance contributes to 23,000 deaths, 2,049,442 illnesses, and $20 billion dollars in excess direct healthcare costs in the United States annually. Thus, it is paramount that researchers develop non-antibiotic treatment strategies for UTIs.

Several non-antibiotic strategies may be successful in preventing recurrent UTIs in postmenopausal women. One is low-dose vaginal estrogen, which may decrease the rate of recurrent UTIs by decreasing inflammation, promoting bladder repair, and promoting retention of lactobacilli. Another is d-mannose, a natural sugar that may decrease bacterial adherence to the urothelium. Methenamine hippurate has regained interest recently. First, it causes few side effects. Second, it functions by producing formaldehyde in the urine, which kills bacteria by denaturing bacterial proteins, RNA, and DNA. Thus far, no methenamine-resistant bacteria have been reported to develop in vivo. Lastly, several studies have demonstrated that 2 grams daily of methenamine reduces the incidence of UTI and is likely comparable to the antibiotic nitrofurantoin for UTI prophylaxis. However, in the investigators' clinical experience, women often require multiple therapies in order to prevent recurrence. There are currently few guidelines to help clinicians identify optimal treatment regimens for prevention of UTI. The clinical challenge is to optimize individual treatment regimens by maximizing efficacy and minimizing the number of medications, cost, side effects, and nonadherence for each individual.

The purpose of this pilot study is to 1) examine the feasibility of developing a sequential, multiple assignment, randomization trial (SMART) and 2) examine the treatment effect of methenamine hippurate in combination with vaginal estrogen and D-mannose on prevention of UTI. This adaptive study design allows the investigators to examine the efficacy of non-antibiotic prophylaxis and initiation of subsequent preventative therapies based on individual responses. It is a pragmatic, longitudinal approach that mimics patients' clinical experiences and physicians' decision points during management of UTI prophylaxis. Given the efficacy and relative safety of methenamine hippurate, the investigators are particularly interested in its efficacy among those who have had suboptimal response to vaginal estrogen and D-mannose. The timing of this study is ideal, as the investigators are also currently conducting a trial of vaginal estrogen plus D-mannose in postmenopausal women. Through this randomized, controlled pilot study, this proposal would allow the investigators to examine the feasibility of conducting a larger-scale, adaptive study trial on the use of methenamine hippurate in combination with vaginal estrogen plus D-mannose, and estimate the treatment effect of a non-antibiotic regimen augmented with methenamine hippurate in women who continue to develop recurrence.

This study is a planned extension of a previously proposed clinical trial on d-mannose and vaginal estrogen (IRB#:201711120); however, any postmenopausal women with a history of recurrent UTI, who then develop UTI while on a combined prophylaxis regimen of d-mannose and vaginal estrogen will be eligible for the randomized controlled trial on methenamine augmentation. The investigators plan to examine the efficacy of the addition of methenamine hippurate to low dose vaginal estrogen and d-mannose in the UTI prevention through randomization to methenamine + vaginal estrogen + D-mannose vs continuing vaginal estrogen + D-mannose alone. Patients will be randomized to either the addition of methenamine hippurate or continuing with vaginal estrogen + D-mannose alone. The primary outcome will be the proportion of patients who have symptomatic, culture-proven UTI during a 3 month treatment period. The investigators hypothesize that women on low dose vaginal estrogen, d-mannose, and methenamine hippurate will be less likely to have recurrent UTI than those with low dose vaginal estrogen and d-mannose alone. As part of the study, baseline information and vaginal, urine, and fecal samples may be taken. Additionally, as part of examining feasibility of a larger study, recruitment, retention, refusal, non-compliance, and adherence rates will be collected. Patients who decline or drop out of the study will be contacted to answer questions on reasons for refusal or withdrawal. Subjects who undergo randomization will either add methenamine to their ongoing vaginal estrogen + D-mannose, or continue on vaginal estrogen + D-mannose alone. They will receive weekly calls or text reminders to record study diaries and to take their medications. Patients will follow up at the end of 3 months, at their usual follow up appointment, for routine examination, questionnaires, and urine and possible vaginal and fecal samples. Follow up may be extended up to 1 month prior or 6 months afterward their baseline visit (2-6 months after the baseline visit) for those who do not make their 3 months appointment. The investigators also plan to describe the uropathogen profile and antibiotic resistance of UTIs that occur during prophylaxis with vaginal estrogen + d-mannose, with or without methenamine hippurate. Lastly, the investigators hope to examine the impact of a non-antibiotic prophylaxis regimen that includes methenamine hippurate on the bladder microenvironment as well as the urinary, vaginal, and intestinal microbiomes.