ALTAR: Methenamine Hippurate versus Daily Antibiotic Prophylaxis for Recurrent UTI
ALTAR was a pragmatic, multicenter, open-label noninferiority randomized trial in 240 women with recurrent urinary tract infection (UTI) at eight UK secondary-care centers that compared methenamine hippurate 1 g twice daily with daily low-dose antibiotic prophylaxis for 12 months. Symptomatic, antibiotic-treated UTIs occurred at 1.38 versus 0.89 episodes per person-year (absolute difference 0.49, 90% CI 0.15 to 0.84), inside the prespecified margin of 1 episode per person-year.[1]
- Design and population
- Pragmatic, multicenter, open-label noninferiority randomized trial. 240 women with recurrent urinary tract infection (at least three episodes in 12 months or two in six months) who needed prophylaxis, recruited at eight UK secondary-care centers.
- Arms
- Methenamine hippurate 1 g twice daily versus daily low-dose antibiotic prophylaxis (nitrofurantoin, trimethoprim or cefalexin)
- Report and follow-up
- 2022 · 12 months of treatment plus 6 months of post-treatment follow-up; final visit January 2020
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| Incidence during the 12-month treatment period, modified intention-to-treat (at least 6 months observed); episodes per person-year; absolute difference, methenamine minus antibiotics | 1.38 per person-year (141 episodes; n=103) vs 0.89 per person-year (90 episodes; n=102) | difference 0.49; 90% CI 0.15–0.84 | Met |
Harms: Participants reporting an adverse reaction: 35/127 (28%) vs 34/142 (24%); Severe adverse event (worst grade per participant): 6/127 (5%) vs 8/142 (6%); Serious adverse reactions: 0 vs 2
ISRCTN70219762; EudraCT 2015-003487-36 · Report DOI
Design
Women aged 18 or older were eligible with at least three symptomatic UTIs in the previous 12 months or two in the previous six, after they and their clinician had decided that prophylaxis was appropriate. Women with a correctable urinary tract abnormality contributing to recurrence (for example, calculi) or with neurogenic lower urinary tract dysfunction were excluded. Women already on prophylaxis needed a three-month washout before randomization. Randomization was 1:1 in permuted blocks, stratified by menopausal status and by UTI frequency in the preceding year (fewer than four versus four or more). Participants, clinicians and local research staff were not masked, and crossover between strategies was allowed.[1]
The primary outcome was the incidence of self-reported, symptomatic UTI that was treated with a discrete antibiotic course, over the 12-month treatment period. A symptom from a Public Health England list plus an antibiotic course for UTI defined an episode, so the prescribing clinician, not a culture result, confirmed the outcome. Antibiotic treatment of breakthrough infections was left to clinicians outside the study. A patient group set the noninferiority margin at one UTI episode per person-year. The sample size of 240 allowed for 25% attrition from 87 participants per group. The primary analysis population was modified intention-to-treat, meaning all participants observed for at least six months, and noninferiority required the upper limit of the 90% confidence interval of the difference to fall below 1. The antimicrobial resistance and asymptomatic bacteriuria comparisons were designated exploratory, and secondary outcomes were not adjusted for multiple testing.[1]
Results
Between June 2016 and June 2018, 120 women were assigned to antibiotics and 120 to methenamine; the modified intention-to-treat population comprised 205 women (102 and 103, 85% and 86%). Participants had a median of 6 self-reported UTIs (interquartile range 4 to 8) in the year before entry, and 59% and 58% of the antibiotic and methenamine groups were peri- or postmenopausal.[1]
During the 12-month treatment period there were 90 episodes over 101 person-years with antibiotics and 141 over 102 person-years with methenamine, an incidence of 0.89 versus 1.38 per person-year; the absolute difference of 0.49 (90% CI 0.15 to 0.84) met the noninferiority criterion. The 95% CI of the difference was 0.08 to 0.90, and the adjusted incidence rate ratio was 1.52 (95% CI 1.16 to 1.98), in favor of antibiotics. Strict intention-to-treat (0.53, 90% CI 0.20 to 0.86) and per-protocol analyses (0.42, 90% CI 0.05 to 0.79) agreed. In a post hoc strict per-protocol analysis restricted to women adherent to their originally allocated treatment, the difference was 0.30 (90% CI −0.08 to 0.67).[1] The authors judged the difference of 0.49 to have limited clinical consequence and reported that about half of participants were UTI-free during treatment (43% with methenamine and 54% with antibiotics).[1]
In the six months after treatment, incidence was 1.72 per person-year with methenamine and 1.19 with antibiotics (difference 0.53, 95% CI −0.03 to 1.09). Of the 231 treatment-period episodes in the primary analysis population, 183 (79%) had a urine sample and 96 of those (52%) were culture-positive; microbiologically confirmed UTI occurred at 0.53 versus 0.41 per person-year on methenamine and antibiotics (difference 0.11, 95% CI −0.12 to 0.35)[2]. In the six months after treatment, microbiologically confirmed incidence was 0.86 versus 0.48 (difference 0.38, 95% CI 0.04 to 0.72)[2]. More participants in the methenamine arm received therapeutic antibiotics for UTI during treatment (67, 56%, versus 51, 43%), and in the six months after treatment the median total days on therapeutic antibiotics among the 52 methenamine and 48 antibiotic recipients was 13.5 versus 7.5.[1][2]
Perineal-swab E. coli showed resistance to at least one antibiotic at the 6- or 12-month visit in 46 of 64 participants (72%) on antibiotics and 39 of 70 (56%) on methenamine (P = 0.05); at month 18, multidrug resistance was more frequent after methenamine, in 9 of 45 (20%) versus 2 of 39 (5%; P = 0.06). Resistance in E. coli from symptomatic urine samples did not differ overall between groups, although resistance to co-trimoxazole during treatment (6 of 13 versus 3 of 14) and to trimethoprim after treatment (6 of 8 versus 5 of 13) was higher in the antibiotic arm.[1] Post hoc, asymptomatic bacteriuria was found in 44 of 326 urine samples (14%) on methenamine and 22 of 323 (7%) on antibiotics.[1]
The NIHR monograph, which adds a lifetime Markov cost-effectiveness model, reports that methenamine was on average less costly and more effective in quality-adjusted life-years but that this was not consistent over the longer term, and that progressive data loss limited the economic evaluation.[2]
A laboratory analysis of stored ALTAR urines and 191 sequenced E. coli isolates found that 11 (5.8%), from five participants, grew in more than 1 mM formaldehyde: 10 isolates from four methenamine participants and one month-0 swab isolate from an antibiotic participant. Eight carried FrmR repressor substitutions and three carried plasmid-encoded frmA homologues; in two participants the authors infer evolution during methenamine exposure over roughly 180 to 270 days. In HPLC analysis of stored urines, 15 of 49 identified components had higher peak areas with methenamine and 3 of 49 with antibiotics, including formaldehyde, formate and glucose. The authors note that the analysis was retrospective.[3]
Surgery and treatment delivery
The antibiotic arm received once-daily nitrofurantoin 50 or 100 mg (66 of 120, 55%), trimethoprim 100 mg (30, 25%) or cefalexin 250 mg (24, 20%), chosen from previous cultures and allergy history. The methenamine arm received 1 g twice daily. Switching occurred in 22 of 120 methenamine-assigned women (18%), who moved to antibiotic prophylaxis, and 7 of 120 antibiotic-assigned women (6%), who moved to methenamine; the primary analysis kept women in their allocated arm.[1]
Participants were seen every three months to month 18, with central-laboratory urine culture at baseline, at each visit and at each UTI, renal and liver blood tests, and optional perineal swabs. Adherence of at least 90% with any trial treatment was reached by 86 of 103 methenamine and 84 of 102 antibiotic women in the primary population. Blood tests showed little difference in renal or liver measurements between arms.[1]
Adverse events
Adverse reactions were reported by 35 of 127 participants on methenamine (28%) and 34 of 142 on antibiotics (24%), analyzed by treatment received, and were mostly mild; severe worst-grade events occurred in 6 (5%) and 8 (6%). The two serious adverse reactions, severe abdominal pain requiring admission and severe derangement of liver function tests, both occurred with antibiotics. Over the 18-month trial period, four participants allocated to methenamine were admitted to hospital for UTI and six had a febrile UTI (temperature of at least 38 degrees C); the report states that all of these participants were in the methenamine arm. Nausea was reported by 5 of 127 (4%) on methenamine and 12 of 142 (8%) on antibiotics.[1]
Limitations
The trial was open-label, and the primary outcome was patient-reported and defined by an antibiotic prescription from clinicians outside the study, although a blinded clinician agreed with the allocation of the primary outcome in a random sample. The antibiotics were heterogeneous and eligibility was broad, which prevented subgroup analysis by agent or patient type. Women with neurogenic bladder dysfunction or a correctable urinary tract abnormality were excluded. Fifteen percent of randomized women (35 of 240) had under six months of observation and were outside the primary analysis, and 18% of methenamine-assigned women switched to antibiotics. Urinary acidification (for example, vitamin C) was not tested, treatment lasted 12 months, and the authors note that long-term safety data for methenamine are scarce. The resistance and bacteriuria comparisons were exploratory and used optional swabs (64 and 70 participants at the 6- or 12-month visit).[1]
In conversation
Same setting MERIT (2024)
Guidelines and approvals
- AUA/CUA/SUFU (Recurrent Uncomplicated UTI in Women, 2019; confirmed 2022; amended 2025), statement 15. Clinicians may offer methenamine hippurate for prophylaxis for women with recurrent UTI . The rationale describes ALTAR as adding to a body of supporting evidence and as sufficient for the panel to regard methenamine as an effective alternative to antibiotics, and it advises against concomitant vitamin C with methenamine.[4]
- EAU (Urological Infections, limited update March 2026), section 3.5.4. Use methenamine hippurate to reduce recurrent cystitis episodes in women without abnormalities of the urinary tract . The evidence summary cites the 240-woman randomized trial as showing noninferiority of twice-daily methenamine hippurate to daily antibiotic prophylaxis (level of evidence 1b).[5]
- NICE (NG112, last updated December 2024), recommendation 1.2.8. Consider methenamine hippurate as an alternative to daily antibiotic prophylaxis in women, and in trans men and non-binary people with a female urinary system, who are not pregnant, whose current UTI has been adequately treated and whose recurrent UTI has not been adequately improved by behavioral and personal hygiene measures, vaginal estrogen or single-dose antibiotic prophylaxis, where any of these were appropriate and applicable. NICE advises specialist advice for pregnancy, recurrent upper or complicated lower UTI, men and children, and review within 6 months and then every 12 months.[6]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2022-03-09 | 12-month randomized report (BMJ) · primary | — | Incidence during the 12-month treatment period, modified intention-to-treat (at least 6 months observed); episodes per person-year; absolute difference, methenamine minus antibiotics: 1.38 per person-year (141 episodes; n=103) vs 0.89 per person-year (90 episodes; n=102); difference 0.49; 90% CI 0.15–0.84 Met Prespecified sensitivity analysis, strict intention-to-treat (all randomized); episodes per person-year; absolute difference, methenamine minus antibiotics: 1.40 per person-year (n=120) vs 0.88 per person-year (n=120); difference 0.53; 90% CI 0.2–0.86 Prespecified sensitivity analysis, per protocol (at least 90% adherence with any trial preventive treatment); episodes per person-year; absolute difference, methenamine minus antibiotics: 1.29 per person-year (n=86) vs 0.87 per person-year (n=84); difference 0.42; 90% CI 0.05–0.79 Post hoc strict per-protocol analysis (at least 90% adherence with the originally allocated treatment only); episodes per person-year; absolute difference, methenamine minus antibiotics: 1.13 per person-year (n=71) vs 0.83 per person-year (n=82); difference 0.3; 90% CI -0.08–0.67 Incidence in the 6 months after treatment; episodes per person-year; absolute difference, methenamine minus antibiotics: 1.72 per person-year vs 1.19 per person-year; difference 0.53; 95% CI -0.03–1.09 Incidence during the 12-month treatment period; episodes per person-year; absolute difference, methenamine minus antibiotics: 0.53 per person-year vs 0.41 per person-year; difference 0.11; CI -0.12–0.35 Incidence in the 6 months after treatment; episodes per person-year; absolute difference, methenamine minus antibiotics: 0.86 per person-year vs 0.48 per person-year; difference 0.38; CI 0.04–0.72 Participants with at least one therapeutic antibiotic course for UTI during the 12-month treatment period: 67 (56%) vs 51 (43%); — Participants with no UTI episode during the 12-month treatment period: 43% vs 54%; — Participants with E. coli (optional perineal swabs) resistant to at least one antibiotic at the 6- or 12-month visit: 39/70 (56%) vs 46/64 (72%); P 0.05 Participants with multidrug-resistant E. coli (optional perineal swabs) at month 18, six months after treatment: 9/45 (20%) vs 2/39 (5%); P 0.06 Urine samples with a positive culture during the 12-month treatment period (post hoc analysis): 44/326 (14%) vs 22/323 (7%); P 0.0048 Mean treatment satisfaction questionnaire for medication convenience score (SD): 82.2 (18.4) vs 91.4 (12.7); P 0.001 | Harding C, Mossop H, Homer T, et al. "Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial." *BMJ.* 2022;376:e068229. doi:10.1136/bmj-2021-0068229 DOI |
| 2022 | NIHR HTA monograph with economic evaluation · secondary | — | Incremental cost per quality-adjusted life-year gained, Markov cohort model over the expected lifetime: The abstract states that methenamine was on average less costly and more effective in quality-adjusted life-years than antibiotics, but that this finding was not consistent over the longer term, and that progressive data loss hampered the economic evaluation. Cost and QALY values are not given in the abstract.; — | Harding C, Chadwick T, Homer T, et al. "Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT." *Health Technol Assess.* 2022;26(23):1-172. doi:10.3310/QOIZ6538 DOI |
| 2026-03-24 | Formaldehyde resistance and urine composition (PLOS Pathogens) · biomarker | — | Sequenced ALTAR E. coli isolates growing in more than 1 mM formaldehyde (11 of 191, 5.8%, from 5 participants); isolates by arm: 10 isolates from 4 participants vs 1 isolate from 1 participant (month-0 swab, before treatment); — Descriptive HPLC components of 49 identified with higher peak area, methenamine (120 samples, 20 participants with detectable formaldehyde) versus antibiotic (55 samples, 10 participants): 15 of 49 components higher vs 3 of 49 components higher; P <0.0001 Descriptive | Hodgkinson NC, Al-Rubaye T, Reed TCP, et al. "Implications for methenamine hippurate use in recurrent urinary tract infection management: formaldehyde resistance and altered urinary composition." *PLoS Pathog.* 2026;22(3):e1014081. doi:10.1371/journal.ppat.1014081 DOI |
References
1. Harding C, Mossop H, Homer T, et al. "Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial." BMJ. 2022;376:e068229. doi:10.1136/bmj-2021-0068229
2. Harding C, Chadwick T, Homer T, et al. "Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT." Health Technol Assess. 2022;26(23):1–172. doi:10.3310/QOIZ6538
3. Hodgkinson NC, Al-Rubaye T, Reed TCP, et al. "Implications for methenamine hippurate use in recurrent urinary tract infection management: formaldehyde resistance and altered urinary composition." PLoS Pathog. 2026;22(3):e1014081. doi:10.1371/journal.ppat.1014081
4. American Urological Association, Canadian Urological Association and Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction. Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline. 2019; confirmed 2022; amended 2025. Statement 15.
5. Bonkat G, Kranz J, Cai T, et al. EAU Guidelines on Urological Infections. Arnhem: EAU Guidelines Office; limited update March 2026. Section 3.5.4.
6. National Institute for Health and Care Excellence. Urinary tract infection (recurrent): antimicrobial prescribing (NG112). Published October 31, 2018; last updated December 12, 2024. Recommendations 1.2.8 to 1.2.11.