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
Urinary tract infection (UTI) is one of the most common bacterial infections worldwide. Defined as the presence of 2 UTIs within a 6-month period or 3 UTIs within 12 months, recurrent UTI can significantly affect women’s quality of life and is a frequent reason for healthcare utilization.
The use of continuous antimicrobial prophylaxis is recommended by international guidelines to prevent recurrent UTI, but increasing rates of antimicrobial resistance has led to a search for non-antimicrobial alternatives.
Methenamine hippurate is a non-antimicrobial treatment that is hydrolysed to formaldehyde in the acidic environment of the urinary tract. This prevents bacterial cell division by denaturing bacterial proteins. However, the evidence for its efficacy in women with recurrent UTI has not been studied previously in randomised trials.
The study by Harding et al. addresses this evidence gap. In total, 240 adult women with uncomplicated recurrent UTI were randomised to receive either methenamine hippurate 1g twice a day or antimicrobial prophylaxis for 12 months. The primary outcome was the incidence of symptomatic, antimicrobial-treated UTI over the 12-month treatment period. The trial was powered to assess non-inferiority of methenamine hippurate compared to continuous antimicrobial prophylaxis.
The average age of the participants in the study was 50 years old. On average, the participants suffered from 6 UTIs in the 12 months prior to trial entry in both arms. Overall, the incidence of UTI over 12 months in the antimicrobial group was 0.89 episodes per person year, compared to 1.38 in the methenamine hippurate group, with the difference falling below the pre-defined non-inferiority limit of 1. The authors concluded that methenamine hippurate is comparable to continuous antimicrobial prophylaxis in preventing recurrent UTI in adult women and should be considered as a non-antibiotic treatment for this condition. The rate of adverse events was low and comparable between groups, with the only 2 serious adverse events occurred in the antimicrobial arm, whilst 4 participants (3%) allocated to the methenamine hippurate arm required hospital admission because of UTI.
The study is a non-blinded, pragmatic trial and as such has limitations. Several antimicrobials were used in the antimicrobial arm limiting assessment of how methenamine hippurate compares to individual antimicrobial drugs. Participants in each group were not required to stop other UTI-preventative strategies (e.g. topical oestrogens). Although this may have affected the overall results reported, it strengthens the “real life” applicability of this study. Future research should assess the efficacy of methenamine hippurate in different patient populations (e.g. neuropathic lower urinary tract dysfunction, male patients).
Overall, this is a practice-changing study. It adds to the evidence base to use methenamine hippurate as a suitable alternative to antimicrobial prophylaxis in women with recurrent UTI.