Methenamine Hippurate vs Antibiotics for Recurrent UTI

In December 2024, the UK’s National Institute for Health and Care Excellence added methenamine hippurate to its guidance as a first-line non-antibiotic option for women with recurrent urinary tract infections [1]. That was a quiet but significant shift. Methenamine is a 1960s drug most GPs trained in the last two decades had barely heard of. Now it sits next to low-dose antibiotic prophylaxis on the prescribing ladder.

The evidence behind that shift came from a trial called ALTAR, published in the BMJ in March 2022 [2]. Two hundred and forty women with recurrent UTI, randomised to either a year of daily antibiotics or a year of methenamine hippurate at 1 g twice daily. The question was simple: does an old urinary antiseptic work as well as the antibiotics we’ve been handing out since the 1980s?

The answer, within the margins the researchers pre-agreed with patients, was yes.

Key Takeaways

• ALTAR (2022) was the first adequately powered non-inferiority trial comparing methenamine hippurate to antibiotic prophylaxis in women with recurrent UTI
• Methenamine hippurate 1g twice daily produced 1.38 UTI episodes per year versus 0.89 on low-dose antibiotics — non-inferior at the pre-specified margin
• A 2025 meta-analysis of five RCTs (421 participants) replicated the finding across different settings
• Resistance to methenamine does not develop, because the active agent (formaldehyde) works non-specifically on bacteria
• NICE endorsed methenamine as an antibiotic-sparing alternative in December 2024; Hiprex is available in Australia on prescription
• It does not treat active UTIs — this is prophylaxis only

How a 100-Year-Old Drug Works

Methenamine was patented in 1899. For most of the 20th century it sat quietly on formularies as a second-line urinary antiseptic, overshadowed first by sulphonamides and then by the trimethoprim-nitrofurantoin wave of the 1970s. Its mechanism is unusual enough that it’s worth understanding why it survived.

Methenamine is a prodrug. The tablet itself does nothing antibacterial in the bloodstream. It’s excreted unchanged into the urine, where — in acid conditions — it breaks down into formaldehyde and ammonia. Formaldehyde is broadly toxic to bacteria. It cross-links proteins and DNA, a mechanism bacteria cannot easily evolve around.

This is why methenamine resistance is essentially non-existent in the literature. You don’t develop resistance to formaldehyde the way you develop resistance to trimethoprim or nitrofurantoin. The trade-off is that the drug only works where formaldehyde can form — in sufficiently acidic urine, concentrated in the bladder. Urine pH needs to be under about 5.5 for reliable activity. This is why methenamine is often co-prescribed or taken with acidifying agents (ascorbic acid, cranberry) in older protocols, though the ALTAR protocol didn’t require this and still showed non-inferiority.

The drug doesn’t circulate as an antibiotic. It doesn’t wipe out gut flora. It doesn’t contribute measurably to community antimicrobial resistance. Those three properties are the entire argument for reviving it.

What the ALTAR Trial Actually Tested

Harding and colleagues at Newcastle University ran a multicentre, open-label, randomised non-inferiority trial across eight UK hospitals between June 2016 and June 2018 [2]. The follow-up extended through 2020.

Eligibility. Adult women with at least three UTI episodes in the previous year or two in the previous six months, who had made an informed decision with their clinician that daily prophylaxis was appropriate.

Intervention. 120 women randomised to daily low-dose antibiotic prophylaxis (nitrofurantoin, trimethoprim, or cefalexin — chosen by their clinician based on prior sensitivities); 120 to methenamine hippurate 1 g twice daily. Both arms ran for 12 months.

Primary outcome. Antibiotic-treated UTI episodes per person-year during the treatment phase.

Non-inferiority margin. Pre-specified by a patient and public involvement group at 1.0 episode per person-year. This is looser than many non-inferiority trials use, and it was deliberate — patients set the margin they considered clinically acceptable, not statisticians.

Results. The modified intention-to-treat analysis included 205 women. Antibiotic group: 0.89 UTI episodes per person-year (95% CI 0.65 to 1.12). Methenamine group: 1.38 (95% CI 1.05 to 1.72). Absolute difference: 0.49 episodes per person-year (90% CI 0.15 to 0.84). Because the upper bound of that confidence interval (0.84) stayed below the pre-specified margin of 1.0, non-inferiority was established.

Adverse events. 24% of the antibiotic group and 28% of the methenamine group reported adverse reactions. Most were mild — nausea, dyspepsia, rash, bladder discomfort. No signal of serious harm from either drug.

Antibiotic use. Women on methenamine took 38% fewer antibiotic prescriptions over the 12-month period than they would have on daily prophylaxis. That’s the antibiotic stewardship argument in a single number.

The trial is often summarised as “methenamine works as well as antibiotics.” That’s not quite what it shows. What it shows is that methenamine is not meaningfully worse than antibiotics within a margin patients considered acceptable — one extra UTI per year, at the outer bound of the confidence interval.

What ALTAR Didn’t Answer

The trial was open-label. Women knew which drug they were on. That introduces bias in self-reported symptoms, although the primary outcome (antibiotic-treated UTI episodes) was anchored to clinician decisions, which blunts the effect.

Crossover was permitted. 15% of women switched arms during the trial. The analysis handled this, but a pure intention-to-treat interpretation is complicated by it.

The population was UK women with predominantly simple recurrent UTI. The trial excluded women with structural urinary tract abnormalities, immunosuppression, or a history of resistant organisms. ALTAR doesn’t tell you whether methenamine works in these groups.

Urinary pH wasn’t systematically monitored. Methenamine’s mechanism depends on acid urine. Some women probably had urine too alkaline for optimal formaldehyde formation. The fact that non-inferiority held despite this is either reassuring (the drug still worked in real-world conditions) or troubling (it might have worked better with pH protocols). Nobody has run the head-to-head trial that would tell us.

The 2025 Replication

The 2025 BMC Urology meta-analysis pooled five RCTs comparing methenamine to antibiotic prophylaxis — 421 patients total across different settings and populations [3]. The headline numbers were consistent with ALTAR:

• Symptomatic UTI episodes: RR 1.15 (95% CI 0.88 to 1.50) — no statistically significant difference
• Positive urine cultures: RR 1.20 (0.84 to 1.72) — no significant difference
• Adverse effects: RR 0.98 (0.73 to 1.31) — essentially identical

Trial sequential analysis suggested the evidence base is approaching, but hasn’t yet reached, the futility boundary that would settle the question definitively. In plain English: more trials would help, but the direction of effect is consistent enough that regulators are acting on what exists.

The 2025 ImpresU trial added a specific piece of evidence for older women. It was a triple-blind, placebo-controlled phase IV trial in women aged 70+ recruited from general practice in four European countries [4]. Results support methenamine’s prophylactic effect specifically in the older population, which ALTAR was underpowered to address.

Methenamine vs the Alternatives

Option	Evidence level	Typical regimen	Key benefit	Main limitation
Low-dose antibiotic prophylaxis	Strong (multiple RCTs, decades)	Daily nitrofurantoin, trimethoprim, or cefalexin for 6-12 months	Largest effect size for UTI prevention	Antimicrobial resistance, gut flora disruption
Methenamine hippurate (Hiprex)	Strong (ALTAR 2022 + 2025 meta-analysis)	1 g twice daily for 12 months	No resistance, stewardship benefit, PBS-listed in AU	Slightly higher UTI rate than antibiotics (within patient-agreed margin)
Cranberry products	Mixed (Cochrane: ~27% risk reduction with PAC-standardised products)	36 mg PACs daily	OTC, no prescription	Product quality variable; not all products deliver standardised dose
D-mannose	Moderate (several RCTs)	2 g daily	Works for E. coli UTI specifically	Does not prevent non-E. coli UTIs
Topical vaginal oestrogen	Strong in postmenopausal women (multiple RCTs)	Twice weekly cream or ring	Addresses underlying atrophic changes	Postmenopausal women only
NAC	Early (biofilm lab data, combination trials)	600-1,200 mg daily	Biofilm disruption	No standalone UTI prevention RCT

The practical point: methenamine is the only option in this list with direct head-to-head RCT data against antibiotic prophylaxis showing non-inferiority. Cranberry, D-mannose, and NAC compare against placebo or observation, not against the prescription alternative.

Who Should Consider It

The ALTAR trial population gives a reasonable profile of who is likely to benefit: women with three or more UTIs in 12 months (or two in six), who have made a decision with their clinician that daily prophylaxis is warranted, and who would otherwise be starting daily low-dose antibiotics.

The specific cases where methenamine often makes more sense than antibiotics:

• You’ve already developed resistance or intolerance to multiple antibiotic prophylaxis options. This happens often after 1-2 years on nitrofurantoin or trimethoprim.
• You’re concerned about contributing to AMR in your household or community. The antibiotic stewardship case is real, not theoretical.
• You’ve had Clostridioides difficile or recurrent yeast infections on antibiotic prophylaxis. Methenamine spares the gut and vaginal microbiome.
• You’re managing UTI alongside other conditions. Fewer interactions than trimethoprim (which affects folate, warfarin, and potassium).
• You want to get pregnant in the next 12 months. Methenamine can be used in pregnancy under clinician supervision, whereas some prophylactic antibiotics (trimethoprim, particularly in the first trimester) are avoided.

When Methenamine Isn’t the Right Answer

This is not a universal swap for antibiotics. Methenamine is not appropriate if:

• You currently have a symptomatic urinary tract infection. Get antibiotics. Methenamine is prevention, not treatment.
• You have severe kidney disease (eGFR below 30). The drug isn’t excreted efficiently and can accumulate.
• You have significant liver disease. Ammonia is a breakdown product; the liver clears it.
• You have gout. Methenamine can increase uric acid excretion and trigger flares.
• You have indwelling urinary catheters. Bacteriuria in catheterised patients is a different problem; methenamine has limited evidence there.
• You take sulphonamides concurrently. There’s a theoretical risk of crystalluria with sulphonamide-formaldehyde combinations.
• You have urine that’s persistently alkaline despite acidifying measures. If your urine pH stays above 6, the drug isn’t activating.

Blood in your urine, fever, flank pain, or symptoms that have been building for more than 48 hours mean you need to be assessed — not started on a prevention drug. Recurrent UTIs that follow a clear recognisable pattern are what methenamine prevents. UTIs that behave differently from your baseline pattern need investigation, including for bacterial cystitis with resistant organisms, stones, or bladder abnormalities that a prevention drug will not address.

The Australian Context

In Australia, methenamine is sold as Hiprex by iNova Pharmaceuticals. It has been available for decades but prescribing has increased markedly since ALTAR, and particularly since the 2024 NICE guidance crossed the Tasman through clinical networks. It is PBS-listed for specific indications. Most GPs can prescribe it for recurrent UTI without specialist referral, though some clinicians still refer to a urologist or urogynaecologist for the prescription decision.

The typical starting protocol is 1 g twice daily. Some clinicians trial a 3-month course first and continue if effective. Urine pH can be checked with over-the-counter dipstick strips if symptoms persist despite adherence — if urinary pH is consistently above 6, adding ascorbic acid or cranberry may help activate the drug, though ALTAR didn’t require this.

Common Questions

Can I take methenamine with other prophylactic supplements?

Methenamine is compatible with D-mannose, cranberry products, and probiotics. It shouldn’t be combined with sulphonamide antibiotics due to a theoretical crystalluria risk. If you’re taking NAC for biofilm disruption, there’s no known interaction — the two target different aspects of recurrent UTI biology.

How long before methenamine starts working?

Protective effects depend on reaching therapeutic urinary formaldehyde levels. This takes several days of consistent dosing. ALTAR data showed the effect developing over the first 1-2 months and sustaining for the remainder of the 12-month treatment period. Do not expect the same rapid onset that antibiotics deliver.

Does methenamine affect urine tests?

It can. Methenamine can cause false positives for protein on dipstick and interfere with some urine chemistry assays. Tell the lab you’re on it before giving a sample. Urine cultures are not affected — if you need a culture, the drug doesn’t obscure the result.

Is it safe in pregnancy and breastfeeding?

Methenamine can be used in pregnancy under clinician supervision. It is not associated with teratogenicity in the available data, though it crosses the placenta. Breastfeeding is similarly considered compatible. This is a genuine advantage over trimethoprim (which is typically avoided in the first trimester) and nitrofurantoin (which is avoided near delivery).

What if I get a UTI while taking methenamine?

You still need antibiotics for the active infection. The prevention drug doesn’t treat it. Continue methenamine through the antibiotic course unless your GP advises otherwise — there’s no pharmacological reason to stop. After the antibiotic finishes, methenamine continues for the remainder of your prophylactic period.

How does it compare to cranberry and D-mannose combined?

No head-to-head trial has tested methenamine against cranberry-D-mannose combinations. The evidence bases aren’t directly comparable. Methenamine has the stronger standalone RCT data against an active comparator. Cranberry and D-mannose have placebo-controlled data showing smaller effect sizes. In practice, some women combine low-dose methenamine with D-mannose for additional anti-adhesion effect, though the combined protocol has not been formally studied.

What This Means Now

The ALTAR finding, confirmed by the 2025 meta-analysis and endorsed by NICE, has shifted recurrent UTI prevention. Methenamine hippurate is no longer a second-string option. It’s a reasonable first-line choice for women who want prevention without antibiotics, or who have run out of antibiotic options.

The trial does not say methenamine is better than antibiotics. It says it is not meaningfully worse, within a margin patients themselves agreed was clinically tolerable. For a significant proportion of women with recurrent UTI, that trade — one additional UTI per year in exchange for not contributing to antimicrobial resistance and sparing the gut flora — is a trade they will take.

Talk to your GP about it if you’re on rotating antibiotic prophylaxis, intolerant to your current options, or starting a prevention regimen for the first time. The research now supports a conversation that wasn’t possible before 2022.

References

1. National Institute for Health and Care Excellence. Urinary tract infection (recurrent): antimicrobial prescribing — methenamine hippurate guidance update. December 2024. NICE

2. 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 (ALTAR). BMJ. 2022;376:e068229. PubMed

3. Updated systematic review, meta-analysis and trial sequential analysis of methenamine hippurate RCTs for UTI prevention. BMC Urology. 2025;25:41. PubMed

4. ImpresU Study Group. Methenamine hippurate as prophylaxis for recurrent urinary tract infections in older women: a triple-blind, randomised, placebo-controlled, phase IV trial. Clinical Microbiology and Infection. 2025. ScienceDirect

5. Lo TS, Hammer KD, Zegarra M, Cho WC. Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era. Expert Review of Anti-infective Therapy. 2014;12(5):549-554.

6. Harding C, Mossop H, Homer T, et al. Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT — scientific summary. Health Technology Assessment. 2022. NCBI