Sometime during their lives, between 50-80 per cent of women experience acute urinary tract infections (UTI). About a quarter of these experience frequent recurrences.

Guidelines worldwide emphasise the importance of prophylaxis, such as low-dose antibiotics taken daily, to prevent recurrent UTIs. Obviously, this approach encourages antibiotic resistance as well as increasing the risk of Clostridium difficile infection and other complications. So, researchers are exploring alternatives to antibiotics.

In acidic conditions, such as those in the distal renal tubules, methenamine hippurate is hydrolysed to formaldehyde, which denatures bacterial proteins and nucleic acids and is, therefore, bactericidal. A Cochrane review concluded that methenamine hippurate may prevent UTIs, but called for further randomised controlled trials. Now the ALTAR study reports that methenamine hippurate offers an alternative to antibiotics for women with recurrent UTIs.

Eight UK centres participated in the open-label, non-inferiority trial, funded by the National Institute for Health Research Health Technology Assessment programme.

Researchers randomly assigned 240 adult women who needed prophylactic treatment for recurrent UTIs to receive antibiotics or methenamine hippurate. The women experienced at least three symptomatic UTIs during the 12 months before the study or at least two episodes in the previous six months. The women were treated for 12 months and followed for a further six months after treatment ended.

Of the women taking once-daily antibiotic prophylaxis, 55 per cent received nitrofurantoin (50 or 100mg), 25 per cent trimethoprim (100mg) and 20 per cent cefalexin (250mg). Eighteen per cent of women allocated to methenamine hippurate switched to antibiotics. Six per cent allocated to antibiotics switched to methenamine hippurate.

During the 12-month study, 43 per cent and 56 per cent of patients in the antibiotic prophylaxis and methenamine hippurate groups respectively received antibiotics for acute UTIs.

Focus groups revealed that patients considered a reduction of one UTI a year to be “clinically meaningful”, which the authors used as the non-inferiority limit.

Results

Methenamine hippurate (1g twice daily oral) was non-inferior to antibiotics during the 12-month study: the incidence of acute UTIs needing antibiotics was 1.38 and 0.89 episodes per person year respectively. “[T]he absolute difference was just 0.49 UTI episodes per year, which has limited clinical consequence[s],” the authors comment.

Further statistical analysis confirmed that methenamine hippurate was non-inferior to antibiotics as UTI prophylaxis. During the six months after treatment, the UTI incidence was 1.19 and 1.72 episodes per person year in the antibiotic and methenamine hippurate groups. Again, the absolute difference (0.53 episodes a year) was below the non-inferiority limit.

After six or 12 months, Escherichia coli isolates from perineal swabs that were resistant to at least one antibiotic were significantly more common in the antibiotic than methenamine hippurate group: 72 per cent and 56 per cent respectively. Other microbiological analyses confirmed that resistance was more common with antibiotic prophylaxis than methenamine hippurate.

At 18 months, however, multidrug resistant E. coli from perineal swabs were more common with methenamine hippurate than with antibiotics (20 per cent and 5 per cent respectively), although this was not statistically significant. “This difference could be due to a sustained effect of daily antibiotics on the faecal microbiome or the greater incidence of antibiotic treated acute UTIs in the methenamine hippurate group during follow-up,” the authors suggest.

Similar proportions of patients in the methenamine hippurate (28 per cent) and antibiotic groups (24 per cent) reported adverse events, most of which were mild. The two serious adverse events (abdominal pain that needed hospital admission and severely abnormal liver function tests) that were possibly or probably related to treatment occurred in the antibiotic arm.

Ten patients were admitted to hospital for UTI or febrile UTI, all of whom received methenamine hippurate. “This information … can also be used by patients and clinicians in the decision making process when choosing UTI preventive treatments,” the authors suggest.

Further research should focus on using methenamine hippurate to prevent recurrent UTI in more narrowly defined groups, explore any added value of urinary acidification (some clinicians combine methenamine hippurate with vitamin C to acidify urine) and confirm long-term safety.

Overall, about half of the women did not develop UTI during prophylaxis: 43% for methenamine hippurate group and 54% for antibiotics. The authors concluded that: “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.”