Wade C, Lacy ME, Harris L et al: Methenamine prophylaxis for recurrent urinary tract infections in a tertiary referral center. Urol Pract 2021; 8: 699.

Methenamine hippurate (MH) was introduced as a urinary antiseptic in 1899.¹ In the acidic environment of urine, the drug is hydrolyzed to formaldehyde, which has bacteriostatic action.^1–3 Although it is indicated for prophylaxis of recurrent urinary tract infection (UTI),³ its use varies among urologists, and a recent guideline noted insufficient evidence to draw reliable conclusions about its efficacy.⁴ However, after the guideline review concluded, 2 new studies (both retrospective) showed that MH decreased UTI frequency for kidney transplant recipients¹ and for older adults in a primary care practice.⁵ The goal of our study was to evaluate MH efficacy in a tertiary urological population, with the primary focus on women with recurrent uncomplicated UTIs.⁶

We reviewed patients who were prescribed MH from the urology clinic between January 2013 (when our ambulatory electronic health record launched) to January 2019. We collected pre-MH baseline data, then for return visits we noted treatment adherence and number of patient-reported UTIs since last visit. We used patient-reported UTIs because uncomplicated UTIs are usually self-evident and also because many patients live far from our center and do not come here for individual UTI episodes. We used a binary outcome of success or failure. Based on the standard definition of recurrent UTIs, >1 UTI in 6 months or >2 UTIs in 1 year,⁴ we defined success as 0 to 1 UTI in 6 months or 0 to 2 UTIs in 1 year. Patients with <6 months of followup on MH were excluded unless the patient had 2 UTIs in <6 months, in which case they were included and counted as failures.

From our initial query, we identified 162 eligible women with recurrent uncomplicated UTIs (see figure). Success rates on MH were 78% for the group overall, 83% for premenopausal women (41) and 77% for postmenopausal women (121). We anticipated that MH would be more likely to fail in patients with UTI risk factors, ie diabetes, immunosuppression, high-tone pelvic floor dysfunction or (if postmenopausal) not using vaginal estrogen. It turned out, however, that MH still had high success rates (68%–87%) in these patient groups. Consistent with our findings, MH also was successful in a recent study with renal transplant recipients.¹ Thus, risk factors for developing UTIs do not necessarily portend failure of MH. We suggest considering a trial of MH even if these risk factors are present.

Figure. Flow diagram for inclusion and exclusion of patients in primary study population.

Our initial query found 30 patients who stopped MH due to side effects, most commonly gastrointestinal (GI) upset (14 patients) and bladder/urethral/vaginal irritation (8 patients). These side effects are consistent with those listed in the package insert (GI upset, dysuria and rash)³ and reported for older adults in a primary practice (GI side effects and dysuria).⁵

Moving beyond the uncomplicated UTI population, we decided to explore our outcomes for patients using catheters. We went back to the original query and identified patients who were using catheters (most commonly for spinal cord injury, spina bifida and nonneurogenic urinary retention) but otherwise met inclusion criteria. We defined the same outcome of success/failure, and defined UTI as a patient-reported symptom episode attributed to UTI, either systemic (eg fever, flank pain) or local (eg increased incontinence, needing to catheterize more often). We did not expect MH to be effective for patients with indwelling catheters because its mechanism of action requires a dwell time in the bladder. As expected, we found no benefit of MH in this group (12 patients). In contrast, patients using intermittent catheterization did appear to benefit. Among our 30 patients using intermittent catheterization, MH success rates were 67% overall, 57% (8 of 14) for patients with high-pressure neurogenic bladders and 75% (12 of 16) for patients with low-pressure urinary retention (neurogenic or nonneurogenic). Of course, we cannot draw valid conclusions from this small and heterogeneous group, but we hope to inspire future research with MH for patients doing intermittent catheterization.

Our findings, combined with the other recent publications, increase the evidence base to support the efficacy of MH as an antibiotic-sparing prophylaxis for women with recurrent uncomplicated UTIs. Of course, these are all retrospective reviews. It will be interesting to see the results of a randomized noninferiority trial currently in progress, comparing MH vs antibiotic prophylaxis for recurrent uncomplicated UTIs in women.⁷

Our study was limited by the retrospective design. Our tertiary center serves a large geographic area, and travel difficulties impair patients’ ability to return for followup. In addition, our retrospective study depended on electronic notes to provide numerical estimates of UTI frequency. We also depended on patient recollection of UTI frequency. We are confident that women with uncomplicated UTIs can recognize individual episodes accurately. In fact, self-reported UTIs will be the primary outcome in the ongoing trial of MH vs antibiotics.⁷ However, patients returning for interval followup may not recall the precise number of interim UTIs. We also recognize the limitation of our small sample size; our findings may not be generalizable to other patient populations. Finally, with regard to patients using catheters, our exploration indicated no benefit of MH for patients with indwelling catheters, as expected based on its mechanism of action. In contrast, patients doing intermittent catheterization will have a bladder dwell time and may benefit from MH, so future research should be considered.