Implications for methenamine hippurate use in recurrent urinary tract infection management: Formaldehyde resistance and altered urinary composition

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.