Methenamine hippurate could be an alternative treatment for recurrent UTIs

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

Over 12 months, the incidence of antibiotic-treated UTIs 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 the Freeman Hospital in Newcastle upon Tyne, England.

The agent achieved the study’s non-inferiority margin which was defined as a difference of one UTI episode per year, Harding said in a presentation at the annual congress of the European Urological Association (UAE). . The results were previously reported in The BMJ.

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

Overall, the use of both prophylactic antibiotics and methenamine hippurate significantly reduced the number of UTIs among the 240 trial participants. In the 12 months before entering the trial, 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 intent-to-treat (ITT) population included 205 patients who were able to provide 6-month follow-up data. Harding reported that the non-inferiority margin was not exceeded in other analyses, which included a full ITT analysis of the entire study cohort, as well as a per-protocol analysis of patients. who complied with at least 90% of their treatment protocols.

During the 6-month post-treatment follow-up period, the incidence rate of UTIs 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 perineal swabs and urine specimens collected throughout the trial – a higher proportion of patients assigned to receive antibiotics daily prophylactics showed resistance to at least one antibiotic in Escherichia coli perineal swab isolates, compared to patients assigned to methenamine hippurate.

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

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

Study details

ALTAR was a multicenter, randomized, open-label, non-inferiority trial. It recruited women from secondary care urology and urogynecology centers in the UK 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 last follow-up visit took place in January 2020.

Eligible patients included women (mean age approximately 50 years; majority in perimenopause/postmenopause) who, in consultation with their physicians, determined that UTI prophylaxis was appropriate. For study purposes, recurrent UTIs were defined as at least three episodes of symptomatic UTIs in the previous 12 months or at least two episodes in the last 6 months.

For participants assigned to antibiotic prophylaxis, treatment choices were nitrofurantoin, trimethoprim, or cefalexin given orally once daily, based on previous urine culture results and history of allergy or allergy. intolerance of individuals. Methenamine hippurate was prescribed in an oral dose twice a day. Participants were allowed to switch from one antibiotic to another or from one treatment strategy to another.

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

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

“Correct main result”

Harding explained that ALTAR differed from previous UTI trials in two ways. First, it was based on a primary outcome that did not depend on microbiological culture, but rather on symptomatic UTIs treated with antibiotics self-reported by trial participants and verified from medical records over the period preventive treatment for 12 months.

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

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

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

  • Mike Bassett is a writer who focuses on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by the National Institute of Health Research’s Health Technology Assessment Program and the Urology Foundation.

Harding disclosed relationships with Allergan, Medtronic, Astellas, Teleflex Medical, GSK and Viatris.

Wagenlehner disclosed no relationship with the industry.

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