Methenamine hippurate as prophylaxis for recurrent urinary tract infections in older women - a triple-blind, randomised, placebo-controlled, phase IV trial (ImpresU)

Objectives: This study aims to investigate the preventive effect of the antiseptic methenamine hippurate on recurrent urinary tract infections (rUTIs) in older women. Methods: Triple-blind, randomised, placebo-controlled phase IV trial with a 6-month treatment period and a 6-month follow-up. Women ≥70 years with rUTIs were recruited from general practice in Norway, Sweden, Poland, and The Netherlands. Recruitment started in December 2019, with follow-up completed at the end of June 2023. Participants were randomly assigned to methenamine hippurate 1g × 2 or placebo 1 tablet × 2 for 6 months. The primary outcome was the number of antibiotic treatments for urinary tract infections (UTIs) during the treatment period. Secondary outcomes included the number of antibiotic treatments for UTIs during the follow-up period, UTI symptom severity and episode duration. Differences in complications were measured as safety outcomes. Results: Of 289 recruited women, 281 (97%) were included in the main analysis (140 in the methenamine hippurate group, 141 in the placebo group). During the treatment period, the methenamine hippurate group had a lower incidence of antibiotic treatments for UTIs than the placebo group, with an incidence rate ratio of 0.75 (95% CI: 0.57–1.0, p 0.049). In the follow-up period, the ratio was reversed: the methenamine hippurate group had a higher incidence of antibiotic treatments for UTIs than the placebo group, with an incidence rate ratio of 1.7 (95% CI:1.3–2.3, p<0.001). There were no important differences in UTI symptom severity/duration or complications between the groups. Discussion: Methenamine hippurate reduces the frequency of rUTIs in older women with a point estimate of a 25% reduction, suggesting advantages over low-dose antibiotic prophylaxis because of its low potential for selection for antimicrobial resistance and mild side effects. However, discontinuation after 6-month treatment duration seems to increase the risk of UTI relapses, and physicians should be aware of this risk when initiating or discontinuing treatment. Trial registration number: ClinicalTrials.gov Registry (NCT04077580); EudraCT: 2018-002235.