What is the mechanism of action of methenamine hippurate in treating urinary tract infections (UTIs)?

From the Guidelines

Methenamine hippurate is a valuable alternative to prophylactic antibiotics in preventing urinary tract infections (UTIs), particularly in patients with intact bladder anatomy, as it works locally in the urinary tract and reduces the risk of developing antibiotic resistance. The mechanism of action of methenamine hippurate involves the release of formaldehyde in acidic urine, resulting in bacteriostasis 1. This unique pH-dependent mechanism makes it essential for patients to maintain acidic urine (pH below 5.5) by avoiding alkalinizing agents and possibly consuming vitamin C or cranberry products. Methenamine hippurate is typically dosed at 1 gram twice daily for adults.

Some key points to consider when using methenamine hippurate include:

• It is most effective against lower urinary tract infections and requires adequate urine flow and kidney function to work properly.
• The hippuric acid component helps maintain urine acidity, which is essential for the conversion of methenamine to formaldehyde.
• Methenamine hippurate does not act systemically, reducing the risk of disrupting the normal gut microbiome.
• It is a useful option for prophylaxis in patients with recurrent UTIs, as it minimizes the risk of developing antibiotic resistance.

According to the most recent and highest quality study, methenamine hippurate was found to be noninferior to antibiotics in preventing recurrent UTIs in women aged 18 years and older 1. This study, published in 2024, provides strong evidence for the use of methenamine hippurate as an alternative to prophylactic antibiotics in patients with intact bladder anatomy.

From the FDA Drug Label

Methenamine hippurate tablets has antibacterial activity because the methenamine component is hydrolyzed to formaldehyde in acid urine. Hippuric acid, the other component, has some antibacterial activity and also acts to keep the urine acid. The drug is generally active against E. coli, enterococci and staphylococci.

The mechanism of action of methenamine hippurate in treating urinary tract infections (UTIs) is through its antibacterial activity. The drug works by:

• Hydrolyzing to formaldehyde in acid urine, which has antibacterial properties
• Hippuric acid contributing to antibacterial activity and maintaining an acid urine pH The drug is effective against certain bacteria, including E. coli, enterococci, and staphylococci 2.

From the Research

Mechanism of Action of Methenamine Hippurate

• Methenamine hippurate is a urinary antiseptic used as a non-antibiotic prophylactic measure in patients with recurrent urinary tract infections (UTIs) 3, 4, 5, 6, 7.
• The mechanism of action of methenamine hippurate involves the release of formaldehyde in the urine, which has antibacterial properties 3.
• Methenamine hippurate has been shown to be effective in preventing UTIs in patients without renal tract abnormalities, particularly when used for short-term prophylaxis 3.

Efficacy of Methenamine Hippurate

• Studies have demonstrated that methenamine hippurate may be effective in preventing UTIs in patients without renal tract abnormalities, with a significant reduction in symptomatic UTI in those without renal tract abnormalities 3, 6.
• Methenamine hippurate has been compared to antibiotic prophylaxis in several studies, with results suggesting that it is not inferior to antibiotics in preventing recurrent UTIs in women 6.
• A systematic review and meta-analysis found that methenamine hippurate showed a non-statistically significant trend of benefit versus antibiotics over 12 months, and a non-statistically significant trend versus any antibiotic for abacteruria 4.

Safety and Tolerability

• Methenamine hippurate has been shown to be well-tolerated, with a low rate of adverse events 3, 6.
• The rate of adverse events was low, but poorly described in some studies 3.
• Methenamine hippurate may be an effective and well-tolerated antibiotic-sparing option for UTI prophylaxis, with a low risk of antimicrobial resistance 7.

Limitations and Future Research

• There is a need for further large, well-conducted randomized controlled trials to clarify the efficacy and safety of methenamine hippurate in preventing UTIs, particularly for longer-term use and in vulnerable patient populations 3, 4, 5.
• Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics 6.