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Implications for methenamine hippurate use in recurrent urinary tract infection management: Formaldehyde resistance
Niamh C Hodgkinson1,2, Tabarak Al-Rubaye1,2, Thomas C P Reed1
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Abstract:
Methenamine is a urinary antiseptic used to prevent urinary tract infections (UTI) via conversion to formaldehyde in the urinary tract. Methenamine hippurate (MH) is non-inferior compared to antibiotic (ABX) prophylaxis to manage recurrent UTI (rUTI) as demonstrated in the clinical trial ALTAR. Treatments such as MH, can improve antibiotic stewardship, as the primary treatment option for UTI is antibiotics. However, MH exhibits an elevated incidence risk with respect to breakthrough UTI as defined during ALTAR. Formaldehyde is highly toxic, while also a common byproduct of cellular metabolism. Powerful detoxification pathways exist to overcome formaldehyde toxicity. One example is the thiol-dependent metabolism of formaldehyde to formate in bacteria. The urinalysis of ALTAR urines detected formaldehyde in 85% of participant urines who were taking MH. HPLC analysis of a subset of urines from MH and ABX ALTAR participants, determined a significant change in urine composition. This included elevated levels of formate in urines from MH users. The thiol-dependant formaldehyde detoxification system of Escherichia coli is encoded by the frmRAB operon. The genes frmAB encode the enzymes responsible for detoxification, while frmR encodes a repressor of the system. ALTAR derived E. coli isolates were screened for growth in the presence of formaldehyde with 5.8% able to grow in > 1 mM formaldehyde. Bioinformatics identified 4 frmR alleles encoding non-functional FrmR variants and two plasmid-encoded frmA homologues. Growth in artificial urine confirmed that E. coli was susceptible to methenamine-formaldehyde conversion at pH6.0 and 5.6. All strains encoding frmR alleles grew in the presence of > 1 mg/ml methenamine at pH 5.6. The identification of FDHR in a clinical context and the changes in urine composition can improve the managed use of MH. However, a mindset change is needed to accept that MH, like antibiotics, has its own associated risks, including bacterial resistance.
Insights
Methenamine hippurate (MH) prevents urinary tract infections but can lead to breakthrough infections. Studies show MH users excrete formaldehyde and formate, indicating bacterial adaptation to this antiseptic.
Area of Science:
- Microbiology
- Pharmacology
- Clinical Medicine
Background:
- Methenamine hippurate (MH) is a urinary antiseptic used for recurrent urinary tract infections (rUTI).
- While effective, MH use is associated with breakthrough UTIs, necessitating further understanding of its mechanisms and risks.
- Antibiotic stewardship is a concern, making alternatives like MH valuable, but their safety profiles require thorough investigation.
Purpose of the Study:
- To investigate the in vivo conversion of methenamine to formaldehyde and its subsequent metabolism in patients.
- To explore the bacterial response to formaldehyde exposure in the urinary tract.
- To assess the potential for bacterial resistance to methenamine-based prophylaxis.
Main Methods:
- Analysis of urine samples from the ALTAR clinical trial for formaldehyde and formate levels using HPLC.
- Screening of Escherichia coli isolates from ALTAR participants for formaldehyde resistance.
- Bioinformatic analysis of formaldehyde detoxification genes (frmRAB operon) in resistant E. coli strains.
- Growth assays of E. coli in artificial urine with varying pH and methenamine concentrations.
Main Results:
- Formaldehyde was detected in 85% of urines from MH users.
- Elevated formate levels were observed in MH users' urine, suggesting formaldehyde detoxification.
- 5.8% of E. coli isolates exhibited formaldehyde resistance, linked to non-functional FrmR variants or plasmid-encoded frmA.
- E. coli demonstrated susceptibility to methenamine-formaldehyde conversion, but resistant strains could tolerate higher methenamine levels.
Conclusions:
- Methenamine is converted to formaldehyde in the urinary tract, which is then metabolized by bacteria.
- Bacterial resistance mechanisms to formaldehyde exist and can be selected for during MH treatment.
- Understanding these mechanisms is crucial for optimizing MH use and managing potential risks, including resistance development.
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