Methenamine hippurate in the prevention of urinary tract infections (UTIs)

Methenamine hippurate in the prevention of urinary tract infections

• is approved by the US Food and Drug Administration (FDA) for prophylaxis of recurrent UTI in patients age 6 years and older, and studies have demonstrated its efficacy as an antimicrobial-sparing alternative in this patient population (1)
• works as an antiseptic
• does not pose a risk of organisms developing resistance
• in an acidic environment, methenamine is hydrolyzed to ammonia and formaldehyde
• mechanism of action
  • driven by the formation of bactericidal formaldehyde, which possesses nonspecific antimicrobial activity by denaturing proteins and nucleic acid of bacteria
  • has little antimicrobial activity in an alkaline environment, as formation of formaldehyde does not occur until the pH of the environment falls below 6
    • to ensure this reaction occurs, some treatment regimens include the use of ascorbic acid to further acidify the urinary environment

A pragmatic, multicentre, randomised, open label, non-inferiority trial compared clinical effectiveness of low dose antibiotic prophylaxis, the current standard treatment for recurrent UTI prevention, with the urinary antiseptic methenamine hippurate (2)

• showed that methenamine hippurate is not inferior to the current standard care of daily low-dose antibiotics in preventing recurrent urinary tract infections in women during 12 months of prophylactic treatment
  • methenamine hippurate was prescribed as a twice daily oral dose (1g)
  • efficacy of both treatments in the primary and sensitivity analyses was found to be comparable, suggesting that methenamine hippurate might be appropriate for women with a history of recurrent urinary tract infection
  • demonstrated high levels of efficacy from methenamine hippurate in terms of UTI prevention, and have shown that this efficacy is comparable to the current guideline recommended prophylaxis (that is, long course, low dose antibiotic treatment)
• increased rates of antimicrobial resistance development associated with the antibiotic arm as shown in the primary uropathogen E coli might encourage patients and clinicians to consider methenamine hippurate as a first line treatment for UTI prevention in women
• the study 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

NICE state (3):

Consider methenamine hippurate as an alternative to daily antibiotic prophylaxis for recurrent UTI in women, and trans men and non-binary people with a female urinary system, if:

• they are not pregnant and
• any current UTI has been adequately treated and
• they have recurrent UTI that has not been adequately improved by behavioural and personal hygiene measures, vaginal oestrogen or single-dose antibiotic prophylaxis (if any of these have been appropriate and are applicable)

Seek specialist advice if considering methenamine hippurate as an alternative to daily antibiotic prophylaxis for recurrent UTI:

• during pregnancy
• in people with recurrent upper UTI or complicated lower UTI
• in men, and trans women and non-binary people with a male genitourinary system
• in children and young people

If discussing methenamine hippurate as a preventative treatment, explain that:

• over-the-counter sachets that make urine more alkaline (such as sachets used to relieve UTI symptoms that contain potassium citrate or sodium citrate) should not be used while taking methenamine hippurate because these can make the medicine less effective
• medical help should be sought for acute UTI symptoms

Review treatment with methenamine hippurate within 6 months, and then every 12 months, or earlier if agreed with the person (3).

Reference:

1. Chwa A, Kavanagh K, Linnebur SA, Fixen DR. Evaluation of methenamine for urinary tract infection prevention in older adults: a review of the evidence. Ther Adv Drug Saf. 2019;10:2042098619876749. Published 2019 Sep 23. doi:10.1177/2042098619876749
2. Harding C, Mossop H, Homer T, Chadwick T, King W, Carnell S et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial BMJ 2022; 376 :e068229 doi:10.1136/bmj-2021-0068229
3. NICE (December 2024). Urinary tract infection (recurrent): antimicrobial prescribing