{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:06:33Z","timestamp":1792181193095,"version":"4.4.0"},"reference-count":58,"publisher":"National Institute for Health and Care Research","issue":"23","license":[{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/non-commercial-government-licence\/non-commercial-government-licence.htm"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["13\/88\/21"],"award-info":[{"award-number":["13\/88\/21"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"<jats:sec id=\"abs1-1\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-2\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex\n                      <jats:sup>\u00ae<\/jats:sup>\n                      ; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-3\">\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months\u2019 treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-4\">\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>Eight UK NHS secondary care sites.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-5\">\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-6\">\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>A central randomisation system allocated participants 1\u2009:\u20091 to the experimental (methenamine hippurate: 1\u2009g twice daily) or control (once-daily low-dose antibiotics: 50\/100\u2009mg of nitrofurantoin, 100\u2009mg of trimethoprim or 250\u2009mg of cefalexin) arm. Crossover between treatment arms was permitted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-7\">\n                    <jats:title>Main outcome measures<\/jats:title>\n                    <jats:p>The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient\u2019s expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-8\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102\/120 (85%) participants in the antibiotics arm and 103\/120 (86%) participants in the methenamine hippurate arm] with at least 6 months\u2019 data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46\/64; 72%) demonstrated antibiotic resistance in\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      cultured from perineal swabs than participants in the methenamine hippurate arm (39\/70; 56%) (\n                      <jats:italic>p<\/jats:italic>\n                      -value\u2009=\u20090.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew\n                      <jats:italic>E. coli<\/jats:italic>\n                      resistant to trimethoprim\/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9\/45; 20%) demonstrated multidrug resistance in\n                      <jats:italic>E. coli<\/jats:italic>\n                      isolated from perineal swabs than participants in the antibiotic arm (2\/39; 5%) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.06). All other secondary outcomes and adverse events were similar in both arms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-9\">\n                    <jats:title>Limitations<\/jats:title>\n                    <jats:p>This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-10\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-11\">\n                    <jats:title>Recommendations for research<\/jats:title>\n                    <jats:p>Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-12\">\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-13\">\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>\n                      This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in\n                      <jats:italic>Health Technology Assessment<\/jats:italic>\n                      ; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3310\/qoiz6538","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T06:08:42Z","timestamp":1652162922000},"page":"1-172","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT"],"prefix":"10.3310","volume":"26","clinical-trial-number":[{"clinical-trial-number":"isrctn70219762","registry":"10.18810\/isrctn","type":"results"},{"clinical-trial-number":"2015-003487-36","registry":"10.18810\/euctr","type":"results"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9407-382X","authenticated-orcid":true,"given":"Chris","family":"Harding","sequence":"first","affiliation":[{"name":"Department of Urology, 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