The antiseptic methenamine hippurate (MH) is known to sterilize urine and its use has been suggested to prevent urinary tract infections (UTIs), but strong evidence is lacking so far. Now, researchers led by clinicians and scientists in Newcastle-upon-Tyne have provided her with the ALTAR trial (an alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women).
Daily low-dose antibiotics, as recommended by current guidelines for the prophylactic treatment of recurrent UTIs, have been associated with antibiotic resistance. Using MH as an alternative could play an important role in solving the global problem of rising antibiotic resistance, the team said.
They recruited 240 women aged 18 or over with recurrent UTIs requiring prophylactic treatment at eight secondary care urology and urogynaecology centers in the UK between June 2016 and June 2018. The women were randomized to receive MH or daily low-dose antibiotics for 12 months, with follow-up for another 6 months beyond that.
Before entering the trial, the women had experienced an average of more than six episodes of UI per year. During the 12-month treatment period, in the modified intention-to-treat population, 90 episodes of symptomatic UI treated with antibiotics were reported out of 101 person-years of follow-up in the antibiotic group, and 141 episodes out of 102 people -years. years in the MH group.
This gave a UTI rate of 0.89 episodes per person-year in the antibiotic group versus 1.38 in the HD group, an absolute difference of 0.49 episodes per person-year. During the 6-month post-treatment follow-up period, the incidence rate of UTIs was 1.19 episodes per person-year in the prophylactic antibiotic group and 1.72 in the HD group, a difference absolute of 0.53.
Prior to the trial, a patient and public involvement group had predefined the non-inferiority margin as one UI episode per person-year. The small difference between the two groups was less than this, confirming the non-inferiority of HD to antibiotic prophylaxis in this setting. This result was consistent across modified intention-to-treat, strict intention-to-treat, per-protocol, and modified-protocol (post hoc) analyses.
Thus, ALTAR results showed that HD was no worse than antibiotics at preventing UTIs, and HD was also associated with reduced antibiotic use.
The vast majority of participants were more than 90% compliant with the assigned treatment. Patient satisfaction was generally high and rates of adverse events and adverse reactions generally low, and both were comparable between treatment groups. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the HD group, and most reactions were mild. In the antibiotic group, there were 2 serious adverse events (severe abdominal pain and increased alanine transaminase), while 6 participants in the HD group reported an episode of febrile UTI and 4 were hospitalized due to an UTI.
Substantial global health issue
At least 50% and up to 80% of all women have at least one acute UTI in their lifetime, most commonly acute uncomplicated cystitis. About a quarter of them continue to suffer from recurrent infections, defined as three or more repeated infections in the past year, or two infections in the previous 6 months. Frequent recurrences therefore represent “a substantial global health problem”, according to the authors.
Guidelines from the UK, Europe and the USA recognize the need for preventative strategies and strongly recommend the daily use of low dose antibiotics as standard prophylactic treatment. However, the UK’s antimicrobial resistance strategy recommends a “strong focus on infection prevention” and aims to reduce antimicrobial use in humans by 15% by 2024.
“To achieve this, exploring non-antibiotic preventative treatments for common conditions such as UTIs is essential,” the team said.
HD is one such non-antibiotic treatment. It is bactericidal and works by denaturing bacterial proteins and nucleic acids. Although previous Cochrane systematic reviews concluded that it may be effective in preventing UTIs, further large trials were needed.
“This trial adds to the evidence base for the use of HD for prophylactic treatment in adult women with recurrent UTIs. Although the HD group had a rate of 55 episodes of UTIs % higher than the antibiotic group, the absolute difference was only 0.49 UTI episodes per year, which has limited clinical consequences,” the team concluded.
Findings could ‘support a change in practice’
In older patients in particular, the risks of long-term antibiotic prophylaxis may outweigh the benefits, and the authors said their findings “could support a change in practice in terms of preventive treatments for recurrent UTIs.” and provide patients and clinicians with a credible alternative to daily antibiotics, giving them the confidence to pursue strategies that avoid long-term antibiotic use”.
They acknowledged the limitations of the study, including that treatment allocation was not masked, that crossing over between arms was allowed, and that differences in antibiotics prescribed may have affected the results. In addition, data regarding the long-term safety of MH are scarce.
However, they said the trial accurately represented the wide range of women with recurrent UTIs and that its results “may encourage patients and clinicians to consider HD as a first-line treatment for Prevention of urinary tract infections in women“.
In a linked editorial, scientists from the Institute for Evidence-Based Healthcare at Bond University in Queensland, Australia, commented: “Although the results require careful interpretation, they are in line with others, and This new research increases the confidence that MH can be offered as an option for women in need of prophylaxis against recurrent urinary tract infections.”