{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T18:59:23Z","timestamp":1774637963175,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014081","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["13\/88\/21"],"award-info":[{"award-number":["13\/88\/21"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["NU-015900"],"award-info":[{"award-number":["NU-015900"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/Y004302\/1"],"award-info":[{"award-number":["BB\/Y004302\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Urology Foundation","award":["NU-015458"],"award-info":[{"award-number":["NU-015458"]}]},{"DOI":"10.13039\/501100007901","name":"Microbiology Society","doi-asserted-by":"publisher","award":["GA004815"],"award-info":[{"award-number":["GA004815"]}],"id":[{"id":"10.13039\/501100007901","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    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\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    is encoded by the\n                    <jats:italic>frmRAB<\/jats:italic>\n                    operon. The genes\n                    <jats:italic>frmAB<\/jats:italic>\n                    encode the enzymes responsible for detoxification, while\n                    <jats:italic>frmR<\/jats:italic>\n                    encodes a repressor of the system. ALTAR derived\n                    <jats:italic>E. coli<\/jats:italic>\n                    isolates were screened for growth in the presence of formaldehyde with 5.8% able to grow in &gt; 1 mM formaldehyde. Bioinformatics identified 4\n                    <jats:italic>frmR<\/jats:italic>\n                    alleles encoding non-functional FrmR variants and two plasmid-encoded\n                    <jats:italic>frmA<\/jats:italic>\n                    homologues. Growth in artificial urine confirmed that\n                    <jats:italic>E. coli<\/jats:italic>\n                    was susceptible to methenamine-formaldehyde conversion at pH6.0 and 5.6. All strains encoding\n                    <jats:italic>frmR<\/jats:italic>\n                    alleles grew in the presence of &gt; 1 mg\/ml methenamine at pH 5.6. The identification of FDH\n                    <jats:sup>R<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014081","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:40:06Z","timestamp":1774374006000},"page":"e1014081","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Implications for methenamine hippurate use in recurrent urinary tract infection management: Formaldehyde resistance and altered urinary composition"],"prefix":"10.1371","volume":"22","author":[{"given":"Niamh C.","family":"Hodgkinson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tabarak","family":"Al-Rubaye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas C. P.","family":"Reed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Mowbray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Sarkissian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"Cowley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Sargent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Hall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyanka","family":"Krishnaswamy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Harding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6488-7593","authenticated-orcid":true,"given":"Phillip D.","family":"Aldridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"issue":"8","key":"ppat.1014081.ref001","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1093\/jac\/dkz163","article-title":"Antibiotic prescribing for common infections in UK general practice: variability and drivers","volume":"74","author":"V Palin","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"ppat.1014081.ref002","first-page":"1","article-title":"Recurrent Urinary Tract Infection: A Mystery in Search of Better Model Systems","author":"BO Murray","year":"2021"},{"issue":"2","key":"ppat.1014081.ref003","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.eururo.2015.05.010","article-title":"Adherence to European Association of Urology Guidelines on prophylactic antibiotics: an important step in antimicrobial stewardship","volume":"69","author":"T Cai","year":"2016","journal-title":"Eur Urol"},{"issue":"10325","key":"ppat.1014081.ref004","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis","volume":"399","author":"Antimicrobial Resistance Collaborators","year":"2022","journal-title":"Lancet"},{"key":"ppat.1014081.ref005","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1093\/jac\/dkt363","article-title":"Antimicrobial stewardship: English Surveillance Programme for Antimicrobial Utilization and Resistance (ESPAUR)","volume":"68","author":"English Surveillance Programme for Antimicrobial Utilization and Resistance Oversight Group","year":"2013","journal-title":"J Antimicrob Chemother"},{"key":"ppat.1014081.ref006","article-title":"A baker\u2019s dozen of top antimicrobial stewardship intervention publications in 2022","author":"RK Barfield","year":"2022","journal-title":"J Antimicrob Chemother"},{"issue":"6","key":"ppat.1014081.ref007","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11934-022-01094-w","article-title":"Non-antibiotic approaches to preventing pediatric UTIs: a role for D-Mannose, Cranberry, and Probiotics?","volume":"23","author":"CB Ching","year":"2022","journal-title":"Curr Urol Rep"},{"key":"ppat.1014081.ref008","doi-asserted-by":"crossref","unstructured":"Iftimie S, Ladero-Palacio P, L\u00f3pez-Azcona AF, Pujol-Galarza L, Pont-Salvad\u00f3 A, Gabald\u00f3-Barrios X. 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Osman","year":"2016","journal-title":"J Biol Chem"},{"key":"ppat.1014081.ref031","article-title":"Antibiotic persistence does not cause phenotypic heterogeneity in tolerance of Escherichia coli to formaldehyde stress but can preserve it through time","author":"ID Jordan","year":"2022","journal-title":"BioRvix"},{"issue":"382","key":"ppat.1014081.ref032","article-title":"Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections","volume":"9","author":"HL 4th Schreiber","year":"2017","journal-title":"Sci Transl Med"},{"issue":"6","key":"ppat.1014081.ref033","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1128\/jcm.10.6.766-771.1979","article-title":"Role of bacterial growth rates in the epidemiology and pathogenesis of urinary infections in women","volume":"10","author":"JD Anderson","year":"1979","journal-title":"J Clin Microbiol"},{"key":"ppat.1014081.ref034","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1099\/mic.0.27924-0","article-title":"Continuous culture--making a comeback?","volume":"151","author":"PA Hoskisson","year":"2005","journal-title":"Microbiol"},{"issue":"23","key":"ppat.1014081.ref035","doi-asserted-by":"crossref","first-page":"6645","DOI":"10.1128\/JB.182.23.6645-6650.2000","article-title":"Novel formaldehyde-activating enzyme in Methylobacterium extorquens AM1 required for growth on methanol","volume":"182","author":"JA Vorholt","year":"2000","journal-title":"J Bacteriol"},{"key":"ppat.1014081.ref036","article-title":"Longitudinal impact of methenamine hippurate on the urobiome of postmenopausal women with recurrent UTIs","author":"MH Khan","year":"2025","journal-title":"Int Urogynecol J"},{"key":"ppat.1014081.ref037","doi-asserted-by":"crossref","first-page":"1093922","DOI":"10.3389\/fmicb.2023.1093922","article-title":"Evasion of toll-like receptor recognition by 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