What is the role of Fosfomycin in treating uncomplicated urinary tract infections?

Fosfomycin for Uncomplicated Urinary Tract Infections

Fosfomycin is an effective first-line treatment option for uncomplicated cystitis in women, administered as a single 3-gram oral dose, though it may have slightly lower early bacteriologic cure rates compared to nitrofurantoin. 1, 2, 3

FDA-Approved Indication

• Fosfomycin is FDA-approved only for uncomplicated urinary tract infections (acute cystitis) in women caused by susceptible E. coli and Enterococcus faecalis. 4
• It is not indicated for pyelonephritis or perinephric abscess, and alternative agents should be selected if bacteriuria persists or reappears after treatment. 4

Guideline Recommendations

First-Line Status

• The Infectious Diseases Society of America (IDSA) and European Society for Microbiology and Infectious Diseases (ESCMID) recommend fosfomycin as a first-line option for uncomplicated cystitis in women, alongside nitrofurantoin and trimethoprim-sulfamethoxazole. 1
• The American College of Physicians (ACP) recommends fosfomycin as a single-dose alternative to nitrofurantoin (5 days) or TMP-SMX (3 days) for uncomplicated bacterial cystitis in women. 1
• The American Urological Association (AUA) lists fosfomycin as one of three first-line therapies with strong recommendation (Grade B evidence). 3

Important Caveat from WHO Expert Committee

• The WHO Expert Committee notably rejected fosfomycin for routine use in lower UTIs based on randomized controlled trial data showing significantly greater clinical and microbiologic resolution at 28 days with 5-day nitrofurantoin compared to single-dose fosfomycin among women with uncomplicated UTIs. 1
• Cost considerations also factored into this decision, as fosfomycin is more expensive than nitrofurantoin. 1

Dosing and Administration

• Standard dose: Single 3-gram oral dose of fosfomycin tromethamine. 3, 4
• The medication achieves mean urinary concentrations of 706 mcg/mL within 2-4 hours under fasting conditions, maintaining concentrations ≥100 mcg/mL for 26 hours. 4
• Fosfomycin can be taken without regard to food, though high-fat meals delay peak urinary concentrations to 6-8 hours without affecting total drug excretion. 4

Clinical Efficacy Data

Comparative Effectiveness

• A 2024 network meta-analysis of 13 RCTs (3,856 patients) ranked fosfomycin highest for both clinical cure (P-score = 0.99) and microbiological cure (P-score = 0.99) among fosfomycin, nitrofurantoin, TMP-SMX, and ciprofloxacin. 5
• However, a 1999 head-to-head trial showed lower early bacteriologic cure rates with fosfomycin (78%) versus nitrofurantoin (86%) at 5-11 days post-treatment (P = 0.02), though rates equalized by one week post-treatment (87% vs 81%, P = 0.17). 6
• Clinical success rates (cure plus improvement) were equivalent at 80% for both agents. 6

Resistance Profile

• Fosfomycin demonstrates minimal cross-resistance with other antibiotic classes due to its unique mechanism of action (inactivation of enolpyruvyl transferase). 4, 7
• It maintains activity against multidrug-resistant pathogens including ESBL-producing organisms, vancomycin-resistant Enterococcus (VRE), and MRSA. 3, 8
• A retrospective study of complicated/MDR UTIs showed 96.4% clinical success and 75% microbiological cure with fosfomycin. 8

Key Advantages

• Single-dose regimen improves adherence compared to 3-7 day courses of other agents. 3, 7
• Minimal collateral damage to intestinal flora, reducing disruption to the gut microbiome. 3, 5
• Safe in pregnancy: European guidelines recommend fosfomycin for asymptomatic bacteriuria in pregnant women. 3
• Low adverse event profile: Most common side effects are mild gastrointestinal symptoms (diarrhea 2.4%, nausea 0.8%, vaginitis 1.8%). 5, 6

Critical Limitations and Contraindications

• Do not use for pyelonephritis or complicated UTIs due to insufficient tissue penetration and limited efficacy data. 3, 4
• Not recommended for routine use in men due to limited clinical efficacy data in this population. 3
• Avoid in infants under 4 months due to risk of hemolytic anemia. 2
• Renal impairment significantly affects excretion: Half-life increases from 11 to 50 hours as creatinine clearance decreases from 54 to 7 mL/min, with urinary recovery dropping from 32% to 11%. 4

Clinical Decision-Making Algorithm

For uncomplicated cystitis in non-pregnant women:

• First-line options: Nitrofurantoin 100 mg BID × 5 days, TMP-SMX 160/800 mg BID × 3 days (if local resistance <20%), or fosfomycin 3 g single dose. 1, 2
• Choose fosfomycin when: Patient adherence is a concern, single-dose therapy is preferred, or the patient has MDR organism with fosfomycin susceptibility. 3, 5
• Choose nitrofurantoin over fosfomycin when: Maximizing early bacteriologic cure is critical or cost is a limiting factor. 1, 6

For pregnant women with asymptomatic bacteriuria:

• Fosfomycin single dose is an appropriate option. 3

Do not use fosfomycin for:

• Pyelonephritis (use fluoroquinolones or ceftriaxone instead). 1, 3, 4
• Complicated UTIs requiring tissue penetration. 3, 4
• Men with UTIs (insufficient data). 3

Follow-Up Considerations

• Routine post-treatment urine cultures are not indicated for asymptomatic patients. 3
• Obtain urine culture and susceptibility testing if symptoms persist or recur within 2 weeks of treatment. 3
• If bacteriuria persists after fosfomycin treatment, select alternative therapeutic agents. 4