In a non‑pregnant adult with a new episode of uncomplicated cystitis (and possible recurrent episodes), should I use a single dose of fosfomycin or methenamine hippurate for treatment/prophylaxis, and how do renal function and dosing influence the choice?

Fosfomycin for Acute Uncomplicated Cystitis, Methenamine Hippurate for Prophylaxis

For a new episode of uncomplicated cystitis in a non-pregnant adult, use fosfomycin 3 g as a single oral dose; for prophylaxis of recurrent episodes, use methenamine hippurate 1 g twice daily with urinary pH maintained below 6.0. 1, 2

Treatment of Acute Uncomplicated Cystitis

First-Line Therapy: Fosfomycin

• Fosfomycin 3 g as a single oral dose is recommended as first-line therapy for acute uncomplicated cystitis, achieving approximately 91% clinical cure rates while maintaining therapeutic urinary concentrations for 24–48 hours. 2
• The single-dose regimen provides comparable clinical efficacy to 3-day courses of trimethoprim-sulfamethoxazole or fluoroquinolones, despite slightly lower bacteriological efficacy, with the advantage of superior adherence and minimal disruption to intestinal flora. 2
• Fosfomycin demonstrates excellent activity against multidrug-resistant pathogens including ESBL-producing E. coli, VRE, and MRSA, with resistance rates remaining low at only 2.6% in initial infections. 2, 3

When to Choose Fosfomycin Over Other First-Line Agents

• Select fosfomycin when local E. coli resistance to trimethoprim-sulfamethoxazole exceeds 20%, or when the patient has received TMP-SMX within the prior 3 months. 2
• Fosfomycin is particularly appropriate when single-dose convenience is desired to improve adherence, or when the patient cannot tolerate nitrofurantoin (the other preferred first-line agent). 2
• The agent is safe in pregnancy and can be used throughout all trimesters for uncomplicated lower UTI. 4

Critical Limitations of Fosfomycin

• Do not use fosfomycin for suspected pyelonephritis or upper urinary tract infections due to insufficient tissue penetration and lack of efficacy data for complicated disease. 2
• If symptoms persist after 2–3 days or recur within 2 weeks, obtain urine culture and switch to a different antibiotic class (nitrofurantoin for 5 days, TMP-SMX for 3 days, or fluoroquinolones for 3 days) for a full 7-day course. 2

Prophylaxis of Recurrent UTIs

First-Line Prophylaxis: Methenamine Hippurate

• Methenamine hippurate 1 g orally twice daily is recommended for prophylaxis in patients aged 12 years and older with recurrent UTIs (≥2 culture-positive episodes in 6 months or ≥3 in 12 months) who have intact bladder anatomy and fully functional bladders. 1
• Methenamine demonstrates a 73% reduction in UTI episodes compared to placebo and is non-inferior to antibiotic prophylaxis in multiple randomized controlled trials. 1, 5
• Unlike conventional antibiotics, acquired resistance does not develop to formaldehyde (the active metabolite), making methenamine an excellent choice for long-term prophylaxis without promoting antimicrobial resistance. 1

Essential Requirement: Urinary Acidification

• Urinary pH must be maintained below 6.0 for methenamine to be effective, as the drug is hydrolyzed to bacteriostatic formaldehyde only in acidic urine. 6, 1
• Ascorbic acid in dosages up to 4 g per day shows no significant effect on urinary pH; dosages as high as 12 g per day or more frequent administration may be required to adequately acidify urine. 6
• The optimal method to achieve low urinary pH is not established by current evidence, but ammonium chloride may be more effective than ascorbic acid. 6

Patient Selection Criteria for Methenamine

• Methenamine is most effective in patients without incontinence and with fully functional bladders; it should not be used in patients with long-term indwelling urethral or suprapubic catheters (A-III recommendation). 6, 1
• The agent is appropriate for postmenopausal women when topical estrogen is contraindicated or declined, and for premenopausal women with infections unrelated to sexual activity. 1
• Do not use methenamine in patients with spinal cord injury or neurogenic bladder managed with intermittent or indwelling catheterization, as a randomized trial showed no benefit (hazard ratio 0.96; 95% CI 0.68–1.35). 6

Duration of Prophylaxis

• Methenamine hippurate should be used for 6–12 months for prevention of recurrent UTIs, with continuation beyond this period if recurrent UTIs persist as a clinical problem. 1
• The agent has a low rate of adverse events with better tolerability than nitrofurantoin, and the most common side effect is nausea, which is rare. 1

Renal Function Considerations

Fosfomycin Dosing in Renal Impairment

• Fosfomycin can be used at standard dosing (3 g single dose) without adjustment for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). 2
• Monitor electrolytes during and after treatment, as fosfomycin can cause hypokalemia, hypocalcemia, hypomagnesemia, and hypernatremia, particularly in patients with pre-existing renal dysfunction. 2
• Use fosfomycin with caution in patients with hypernatremia, cardiac insufficiency, or severe renal insufficiency, as the elimination half-life increases from 5.7 hours to 40–50 hours in anuric patients. 2

Methenamine in Renal Impairment

• Methenamine requires adequate urine concentration and bladder dwell time for effectiveness, which may be compromised in renal dysfunction. 1
• For patients with acute kidney injury or CKD stage 3b (eGFR 30–44 mL/min/1.73 m²), consider increasing daily oral fluid intake by approximately 1.5 L as a non-pharmacologic alternative while renal function stabilizes. 1

Comparative Efficacy: Methenamine vs. Antibiotics

• A 2022 randomized trial comparing methenamine hippurate with trimethoprim for recurrent UTI prophylaxis found identical 65% recurrence rates at 12 months in both groups, with similar adverse effect profiles. 7
• A 2025 meta-analysis of 5 randomized controlled trials (421 patients) demonstrated non-inferiority of methenamine hippurate compared to antibiotic prophylaxis for symptomatic UTI episodes (RR 1.15; 95% CI 0.96–1.38; p=0.41). 5
• However, the control group (antibiotics) showed decreased frequency of asymptomatic bacteriuria compared to methenamine (RR 1.91; 95% CI 1.29–2.81; p=0.0001), though this outcome has unclear clinical significance. 5

Clinical Algorithm

1. For acute uncomplicated cystitis: Prescribe fosfomycin 3 g as a single oral dose. 2
2. If symptoms persist or recur within 2 weeks: Obtain urine culture and switch to nitrofurantoin 100 mg twice daily for 5 days or TMP-SMX 160/800 mg twice daily for 3 days (if local resistance <20%). 2
3. For recurrent UTI prophylaxis: Verify patient has intact bladder anatomy, fully functional bladder, and no long-term catheterization. 1
4. Initiate methenamine hippurate 1 g twice daily and implement urinary acidification strategy to maintain pH <6.0. 1
5. Continue prophylaxis for 6–12 months, monitoring for breakthrough infections and adjusting urinary acidification as needed. 1

Common Pitfalls to Avoid

• Do not use fosfomycin for pyelonephritis or complicated UTIs—it lacks adequate tissue penetration and efficacy data for upper tract infections. 2
• Do not prescribe methenamine without ensuring urinary acidification—the drug is ineffective at pH ≥6.0. 6, 1
• Do not use methenamine in catheterized patients or those with neurogenic bladder—randomized trials show no benefit in these populations. 6
• Do not assume ascorbic acid will adequately acidify urine—standard doses (up to 4 g/day) have no significant effect on urinary pH. 6