A Possible Alternative to Prophylactic Antibiotics for Recurrent Urinary Tract Infections

InpharmD™ Clinical Literature Summaries — S3E13

4 min readApr 21, 2022


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On behalf of all of us here at InpharmD, whether you’re listening to this from your home or on the front lines, we hope you’re well and we thank you for the important work you’re doing.

With this podcast, we recap innovative, practice changing studies in ten minutes or less. And remember, nothing here is medical advice; we just present the evidence and our (sometimes hot) takes.

A Possible Alternative to Prophylactic Antibiotics for Recurrent Urinary Tract Infections

A common clinical problem is women who have recurrent urinary tract infections or UTI’s for short. About 25% of women who develop a UTI may go on to experience frequent recurrences. This results in a significant burden to our healthcare system, with over a million emergency department visits annually due to UTI’s.

Recurrent UTI is defined as 2 or more episodes in the past 6 months or 3 or more episodes in the past year. The American Urological Association does list prophylactic antibiotics as a moderate recommendation with grade B evidence for recurrent UTI. They do not endorse the common non-antibiotic strategy of cranberry juice very strongly. But given the growing concern for antibiotic resistance, researchers have been trying to find alternatives to prophylactic antibiotics.

So today we’ve got an article hot off the press examining a compound called methenamine hippurate for recurrent UTI’s. This agent does have FDA approval for UTI prophylaxis, but isn’t commonly used due to lack of evidence. Long story short, in the urine methenamine is broken down into ammonia and formaldehyde. The formaldehyde has antibacterial properties that are thought to help reduce UTI’s.

The researchers randomized over 200 female patients with recurrent UTI’s to receive open label standard antibiotic prophylaxis or methenamine hippurate for one year. Antibiotic prophylaxis was with daily cephalexin, Bactrim, or nitrofurantoin depending on patient allergies and urine culture results. Crossover between arms was allowed. The goal of the trial was to see if methenamine hippurate was non-inferior to standard antibiotic prophylaxis.

The pre-defined non-inferiority margin was determined in conjunction with a patient and public involvement group. From a patient perspective, it was felt that if methenamine hippurate could lower the number of UTI’s per person per year to within one occurrence of prophylactic antibiotics, then this would be considered non-inferior, thus the non-inferiority margin was set at 1.

Over 80% of patients originally randomized were observed for over 6 months and included in the final analysis. The authors found that there was an absolute difference of about 0.5 UTI’s per person per year, with fewer episodes seen in the standard antibiotic prophylaxis group. Interestingly though, the 95% confidence interval did not cross the pre-defined non-inferiority margin of a 1 episode per person per year difference. Thus despite the numbers favoring the antibiotic prophylaxis group, methenamine hippurate was shown to be non-inferior.

Adverse reactions were generally infrequent and comparable between the treatment groups, however one of the secondary outcomes was hospitalization for UTI, which occurred in 4 patients, all in the methenamine hippurate group. Additionally, febrile UTI occurred in 6 patients, again all in the methenamine hippurate group.

So what can we make of this study? While the most recent American Urological Association guidelines only mention methenamine hippurate to say that there is not yet enough evidence for its use, this study was published after the guidelines!

So despite standard antibiotics appearing to be a bit better, we did see non-inferiority proven with this trial. That being said, there were some limitations to keep in mind. First and foremost, crossover from methenamine hippurate to antibiotic prophylaxis occurred in 18% of patients, whereas only 6% crossed over to methenamine. Given the fact that antibiotic prophylaxis trended to a better outcome than methenamine, this crossover may have made the results between the two groups more similar and thus favored a finding of non-inferiority.

Participants were also not blinded to what they were receiving which could have allowed for bias to enter the picture. Lastly, the trial was not powered to be able to examine specific subgroups to determine if methenamine may be better for certain people or compared to specific antibiotics. So while the study did prove non-inferiority, it wasn’t perfect and we have to take the results with a grain of salt.

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Other papers/resources used:

1. Chwa A, Kavanagh K, Linnebur SA, Fixen DR. Evaluation of methenamine for urinary tract infection prevention in older adults: a review of the evidence. Ther Adv Drug Saf. 2019;10:2042098619876749. Published 2019 Sep 23. doi:10.1177/2042098619876749


3. Anger et al. Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline, Journal of Urology, 1 Aug 2019, https://doi.org/10.1097/JU.0000000000000296




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