International guidelines generally recommend the use of daily low-dose antibiotics as standard prophylactic treatment for recurrent urinary tract infection (UTI). Due to growing concerns over antimicrobial resistance, prophylactic strategies that do not rely on antibiotics are desirable. A Cochrane review published in 2012 concluded that while methenamine hippurate, a non-antibiotic treatment, might be effective in preventing UTIs, new well-executed and randomized trials were needed to ascertain efficacy. Methenamine hippurate exerts a bactericidal activity after its conversion into formaldehyde in the acidic environment of the distal tubules of the kidney, which in turn denatures the proteins and nucleic acids of the bacteria. The recently published, open label, randomized ALTAR trial conducted in the United Kingdom evaluated whether methenamine hippurate was noninferior to a standard antibiotic prophylaxis for the prevention of recurrent UTIs.
ALTAR enrolled 240 adult women (mean age 50 years) with recurrent UTIs requiring a prophylactic treatment. All the patients had a minimum of three episodes of symptomatic UTI in the previous year or a minimum of two episodes within six months preceding enrollment. The patients were randomized to receive either oral methenamine hippurate at a dose of one gram twice daily or a standard antibiotic prophylaxis for 12 months. The antibiotic prophylactic regimen was based on prior culture results and any history of allergy and/or drug intolerance. Regimens included nitrofurantoin (50 to 100 mg), trimethoprim (100 mg), or cefalexin (250 mg), each taken once daily. The primary outcome of the trial was the incidence of antibiotic treated symptomatic UTIs during the 12-month period. The noninferiority of methenamine hippurate therapy would be demonstrated if the upper limit of the 90% confidence interval (CI) for the treatment difference between the two groups was under one UTI per person-year. After the end of the treatment, the patients were followed for an additional six months.
In the per-protocol analysis that included 170 patients (71%), the incidence of UTIs during treatment was 1.29 per person-year with methenamine hippurate and 0.87 per person-year with the antibiotic prophylaxis. The absolute between-group difference was 0.42 UTIs per person-year, with a 90% CI of 0.05 to 0.79 per person-year. Similar results were obtained in the intention-to-treat analysis that included all 240 patients, with an absolute between-group difference of 0.53 UTIs per person-year and a 90% CI of 0.20 to 0.86. In both analyses, the upper limit of the CI was less than one, therefore meeting the criteria for noninferiority. Both groups exhibited similar incidences of microbiologically confirmed UTI during treatment (0.53 vs. 0.41 per person-year, p > 0.05), similar rates of antibiotic resistance (56% vs. 72%, p = 0.05), and similar rates of adverse events, which were generally mild.
This study indicates that treatment with methenamine hippurate is noninferior to standard prophylactic antibiotic treatment for the prevention of recurrent UTIs. The lack of blinding seen in this trial would usually be a major limitation in a “regular” (superiority) randomized trial. However, in this noninferiority trial, lack of blinding (which likely favors antibiotics, given both patients’ and clinicians’ belief that antibiotics are effective) is not likely to threaten the validity of the results. In conclusion, the ALTAR trial suggests that methenamine hippurate has a comparable efficacy to the current guideline recommended antibiotic prophylaxis and might be considered as a first line treatment for UTI prevention in women.
For more information, see the topic Recurrent Cystitis in Women in DynaMed®.
