Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial

Abstract

Objective: To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections with the current standard prophylaxis of daily low dose antibiotics.

Design: Multicentre, open label, randomised, non-inferiority trial.

Setting: Eight centres in the UK, recruiting from June 2016 to June 2018.

Participants: Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment.

Interventions: Random assignment (1:1, using permuted blocks of variable length via a web based system) to receive antibiotic prophylaxis or methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed.

Main outcome measure: Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment. A patient and public involvement group predefined the non-inferiority margin as one episode of urinary tract infection per person year. Analyses performed in a modified intention-to-treat population comprised all participants observed for at least six months.

Results: Participants were randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The modified intention-to-treat analysis comprised 205 (85%) participants (antibiotics, n=102 (85%); methenamine hippurate, n=103 (86%)). Incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.89 episodes per person year (95% confidence interval 0.65 to 1.12) in the antibiotics group and 1.38 (1.05 to 1.72) in the methenamine hippurate group, with an absolute difference of 0.49 (90% confidence interval 0.15 to 0.84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the methenamine group and most reactions were mild.

Conclusion: Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial.

Trial registration: ISRCTN70219762.

Fig 1

Trial profile (CONSORT flowchart)

Fig 2

Antibiotic resistance rates in Escherichia coli isolated from perineal swabs, and urine samples taken during an episode of symptomatic urinary tract infection. Top left panel: proportion of participants (with E coli isolated) showing resistance to at least one antibiotic in E coli isolated from perineal swabs at baseline, six or 12 month follow-up, and 18 month follow-up (P values from χ² test). Top right panel: proportion of participants (with E coli isolated) showing multidrug resistance in E coli isolated from perineal swabs at baseline, six or 12 month follow-up, and 18 month follow-up (P values from Fisher’s exact test). Remaining rows: proportion of participants showing resistance in E coli isolated from any symptomatic urine sample submitted during the 12 month preventive treatment period or six month observational period after treatment (out of those participants with E coli isolated from a symptomatic urine sample)