Introduction
Fosfomycin is a broad-spectrum bactericidal antibiotic first isolated from Streptomyces species in 1969. It represents a unique class of phosphonic acid antibiotics with a distinct mechanism of action. Fosfomycin is particularly valued for its activity against multidrug-resistant pathogens and is available in both oral (fosfomycin tromethamine) and intravenous (fosfomycin disodium) formulations.
Mechanism of Action
Fosfomycin exerts its bactericidal effect by irreversibly inhibiting the initial step in bacterial cell wall synthesis. It specifically targets and inactivates the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), which catalyzes the transfer of enolpyruvate from phosphoenolpyruvate to UDP-N-acetylglucosamine. This inhibition prevents the formation of N-acetylmuramic acid, an essential component of peptidoglycan precursors, ultimately disrupting bacterial cell wall synthesis.
Indications
FDA-Approved Indications:- Uncomplicated urinary tract infections (UTIs) caused by susceptible strains of Escherichia coli and Enterococcus faecalis (oral formulation)
- Complicated UTIs caused by susceptible strains of E. coli (IV formulation)
- Serious infections including sepsis, hospital-acquired pneumonia, and complicated skin and soft tissue infections when caused by susceptible organisms (IV formulation)
- Prostatitis
- Multidrug-resistant infections including those caused by MRSA, VRE, and carbapenem-resistant Enterobacteriaceae
- Surgical prophylaxis in select urological procedures
Dosage and Administration
Oral (fosfomycin tromethamine):- Uncomplicated UTI: Single 3g sachet dissolved in 4 ounces of water
- Repeat dosing not recommended within 48 hours
- Adults: 12-24g daily in 2-4 divided doses
- Severe infections: Up to 16g every 6-8 hours
- Dosing adjustment required for renal impairment
- Renal impairment: Dose adjustment based on creatinine clearance
- Hepatic impairment: No specific adjustment needed
- Elderly: Consider renal function adjustments
- Pediatrics: Limited data available; consult specialist
Pharmacokinetics
Absorption: Oral bioavailability approximately 30-40% (fasting); decreased with food Distribution: Widely distributed to tissues and body fluids including kidneys, prostate, bones, and cerebrospinal fluid (with inflammation) Protein binding: Minimal (<5%) Metabolism: Not significantly metabolized Elimination: Primarily renal excretion (85-90% unchanged) Half-life: 4-8 hours (prolonged in renal impairment)Contraindications
- Hypersensitivity to fosfomycin or any component of the formulation
- Severe renal impairment (CrCl <10 mL/min) for multiple dosing
- Concomitant use with metoclopramide (reduces fosfomycin concentrations)
Warnings and Precautions
- Clostridioides difficile-associated diarrhea: May occur during or after treatment
- Renal impairment: Requires dose adjustment; monitor renal function
- Electrolyte imbalances: IV formulation contains significant sodium content (14.4 mEq Na per 4g)
- Superinfection: Prolonged use may result in fungal or bacterial superinfection
- Hepatic function: Monitor liver enzymes during prolonged therapy
Drug Interactions
Clinically Significant Interactions:- Metoclopramide: Decreases fosfomycin absorption (avoid concomitant use)
- Cimetidine: May increase fosfomycin concentrations
- Probenecid: May decrease renal excretion of fosfomycin
- Other nephrotoxic drugs: Increased risk of renal toxicity
Adverse Effects
Common (≥1%):- Diarrhea (9%)
- Nausea (5%)
- Headache (4%)
- Vaginitis (3%)
- Dizziness (2%)
- Anaphylaxis
- Severe cutaneous adverse reactions
- Blood dyscrasias
- Hepatotoxicity
- Nephrotoxicity (with high IV doses)
Monitoring Parameters
- Clinical response to therapy
- Renal function (serum creatinine, BUN)
- Liver function tests (with prolonged therapy)
- Complete blood count (with prolonged therapy)
- Electrolytes (with IV therapy)
- Signs of superinfection or C. difficile infection
Patient Education
- Complete the full course of therapy as prescribed
- Oral sachet should be taken on an empty stomach (2-3 hours after meals)
- Dissolve oral powder in 4 ounces of water and consume immediately
- Report any severe diarrhea, abdominal pain, or blood in stool
- Inform healthcare provider of all medications being taken
- Maintain adequate hydration during treatment
- Use additional contraceptive methods if taking oral contraceptives (potential decreased efficacy)
References
1. FDA Prescribing Information: Monurol (fosfomycin tromethamine) 2. FDA Prescribing Information: Foscrox (fosfomycin disodium) 3. Falagas ME, et al. Fosfomycin: Use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2016;62(11):1409-1415. 4. Popovic M, et al. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis. 2010;29(2):127-142. 5. Kirby T, et al. Fosfomycin: A look at its various analytical methods. J Pharm Biomed Anal. 2016;120:317-331. 6. Michalopoulos AS, et al. Intravenous fosfomycin for the treatment of multidrug-resistant pathogens: what is the evidence? Int J Antimicrob Agents. 2011;37(1):1-5. 7. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 32nd ed. CLSI supplement M100. 2022.