The urinary antiseptic methenamine hippurate (Hiprex) was non-inferior to antibiotic prophylaxis in women with a history of recurrent urinary tract infections (UTI), according to results from the ALTAR trial.

Over the course of 12 months, the incidence of antibiotic-treated UTI was 0.89 and 1.38 episodes per year in patients treated with prophylactic antibiotics or methenamine hippurate, respectively (absolute difference 0.49 episodes, 90% CI 0.15-0.84), reported Christopher Harding, MD, of Freeman Hospital in Newcastle upon Tyne, England.

The agent met the study’s non-inferiority margin that was defined as a difference of one UTI episode per year, Harding said in a presentation at the European Association of Urology (EAU) annual congress. Results were previously reported in The BMJ.

“Let’s remember that daily antibiotics are the current guideline-recommended standard,” he noted. “I think that this trial provides good evidence that methenamine hippurate could be considered as a new standard first-line option for the prevention of UTI in women.”

On the whole, the use of both prophylactic antibiotics and methenamine hippurate substantially reduced the number of UTI among the 240 trial participants. In the 12 months preceding trial entry, women in the antibiotic cohort had an average of 6.8 self-reported UTIs, while those in the methenamine hippurate group had an average of 7.0.

ALTAR’s modified intention-to-treat (ITT) population included 205 patients who were able to provide 6 months follow-up data. Harding reported that the non-inferiority margin was not breached in other analyses, which included a full ITT analysis of the entire study cohort, as well as a per-protocol analysis of patients who had at least 90% compliance with their treatment protocols.

In the 6-month post-treatment follow-up period, the UTI incidence rate was 1.19 (95% CI 0.86-1.52) and 1.72 (95% CI 1.27-2.18) episodes per year in the antibiotic prophylaxis and methenamine hippurate groups, respectively.

As for the secondary outcome of antibiotic resistance — explored in cultures from both perineal swabs and urine samples collected throughout the trial — a higher proportion of patients assigned to receive daily prophylactic antibiotics showed resistance to at least one antibiotic in Escherichia coli isolates from perineal swabs, compared with patients assigned to methenamine hippurate.

“It must be said, however, for balance, that we also looked at multidrug resistance at the end of the trial and multidrug resistance was slightly higher in those who had been allocated to methenamine,” Harding noted.

Regarding adverse events, the majority were “mild,” Harding reported. However, there were six cases of febrile UTI, all in the methenamine group, four of which resulted in hospitalization.

Study Details

ALTAR was a multi-center, randomized, open label, non-inferiority trial. It recruited women from secondary care urology and urogynecology centers in the U.K. from June 2016 and included a 12-month treatment period followed by a 6-month follow-up period. Recruitment was completed in June 2018 and the final follow-up visit took place in January 2020.

Eligible patients included women (mean age about 50; majority perimenopausal/postmenopausal) who, in consultation with their physicians, determined that prophylaxis for UTI was appropriate. For purposes of the study, recurrent UTI was defined as at least three episodes of symptomatic UTI in the previous 12 months or at least two episodes in the past 6 months.

For participants assigned to antibiotic prophylaxis, treatment choices were nitrofurantoin, trimethoprim, or cefalexin given orally once daily, depending on previous urine culture results and individuals’ history of allergy or intolerance. Methenamine hippurate was prescribed as a twice daily oral dose. Participants were allowed to switch between antibiotic drugs or between treatment strategies.

Of those patients assigned to antibiotic prophylaxis, 55% received nitrofurantoin, 25% trimethoprim, and 20% cefalexin. A total of 22 (18%) participants allocated to methenamine hippurate switched to receive antibiotic prophylaxis, while seven (6%) switched from antibiotic prophylaxis to methenamine hippurate.

ALTAR limitations included lack of blinding, and a lack of data on long-term safety of methenamine hippurate, but that “question was outside of the scope of the current trial. Increased adoption of this treatment as prophylaxis against recurrent UTI will allow for the generation of long-term safety data now that efficacy has been demonstrated in our study,” according to Harding and colleagues.

‘Correct Primary Outcome’

Harding explained that ALTAR differed from previous UTI trials in two ways. First, it relied on a primary outcome that did not depend on microbiological culture, but instead on symptomatic antibiotic-treated UTI self-reported by the trial participants and verified from medical records during the 12-month period of preventative treatment.

“This is, indeed, the correct primary outcome we want to have,” said EAU discussant Florian Wagenlehner, MD, of Justus Liebig University in Giessen, Germany. “There is a clear recommendation not to treat asymptomatic bacteriuria and save antibiotics, and therefore we are interested in the symptomatic episodes and not in the microbiology.”

“The second thing that makes this trial slightly different is the non-inferiority margin was completely decided by the patients,” Harding added. “And they told us that if we were looking at two treatments and one of them had just one more UTI per year, they would think that would be inferior. So our non-inferiority margin was set at one UTI episode per year.”

Wagenlehner agreed that methenamine hippurate could be an appropriate alternative for women with recurrent UTIs “informed by patient preferences and antibiotic stewardship,” but noted that there are a number of different strategies that can be offered to these women and that it remains to be seen which women are most likely to benefit from methenamine. In the U.S., the antiseptic agent is approved as a “prophylactic or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is considered necessary. This drug should only be used after eradication of the infection by other appropriate antimicrobial agents.”

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