Fosfomycin Coverage of Gram-Negative Rods
Yes, fosfomycin demonstrates broad-spectrum activity against gram-negative rods, including multidrug-resistant strains, though susceptibility varies by species and resistance patterns. 1, 2
Spectrum of Activity Against Gram-Negative Rods
FDA-Approved Coverage
The FDA label confirms fosfomycin has in vitro activity against a broad range of gram-negative aerobic microorganisms, with established clinical efficacy for: 1
- Escherichia coli - Primary indication with demonstrated clinical efficacy 1
- Proteus mirabilis - Clinical efficacy established 1
Additional Gram-Negative Coverage (In Vitro Data)
Fosfomycin achieves MICs ≤64 mcg/mL against ≥90% of strains for: 1
- Citrobacter diversus and C. freundii
- Enterobacter aerogenes
- Klebsiella oxytoca and K. pneumoniae
- Proteus vulgaris
- Serratia marcescens
Multidrug-Resistant Organisms
For carbapenem-resistant Enterobacteriaceae (CRE), fosfomycin-containing combination therapy is conditionally recommended when the isolate is susceptible or demonstrates synergistic effects. 3
- Fosfomycin susceptibility rates in carbapenem-resistant K. pneumoniae (CRKP) range from 39% to 99%, though FosA-like resistance genes may be prevalent 3
- In observational studies, fosfomycin combination therapy showed 114 fewer deaths per 1000 patients (RR=0.55,95% CI 0.28-1.10) compared to other combinations, though evidence quality is very low 3
- Real-world data from Greece showed 77.7% of K. pneumoniae isolates (including carbapenem-resistant strains) remained susceptible to fosfomycin 4
For Pseudomonas aeruginosa, fosfomycin should be used as part of combination therapy rather than monotherapy due to high resistance development risk. 5
- Susceptibility rates for P. aeruginosa are more variable (64.5% in one Greek study) and depend heavily on local antibiograms 4
- Fosfomycin-containing combinations with polymyxins, aminoglycosides, or carbapenems may be considered for carbapenem-resistant P. aeruginosa 5
Critical Implementation Considerations
Mandatory Susceptibility Testing
Before initiating fosfomycin therapy for gram-negative infections, confirm susceptibility through antimicrobial susceptibility testing or demonstrate synergistic effects through combination testing. 3
This is particularly crucial because:
- Susceptibility testing is not routinely performed in many clinical laboratories 5
- Resistance patterns vary significantly by geographic region and institution 4
Contraindications and Precautions
Avoid fosfomycin in patients with: 3
- Hypernatremia
- Cardiac insufficiency
- Renal insufficiency (due to high sodium content of IV formulation)
Formulation-Specific Limitations
Oral fosfomycin tromethamine is FDA-approved only for uncomplicated urinary tract infections, not for systemic gram-negative infections. 6, 1
- Single 3-gram oral dose achieves therapeutic urinary concentrations for 24-48 hours 6
- Oral bioavailability is <50%, limiting systemic use 7
- Approximately 38% of oral dose is recovered in urine 1
Intravenous fosfomycin is required for systemic gram-negative infections but is not available in the United States. 2, 7
Clinical Context and Resistance Patterns
Mechanism of Action Advantage
Fosfomycin irreversibly blocks an early step in bacterial cell wall synthesis (enolpyruvyl transferase inhibition), distinct from β-lactams, resulting in: 1, 2
- Generally no cross-resistance with β-lactams or aminoglycosides 1
- Synergistic effects when combined with agents having different mechanisms 2, 7
Resistance Development Risk
Fosfomycin monotherapy should be avoided for systemic infections due to rapid resistance development. 7
- Combination therapy is essential for serious infections 5, 7
- Resistance genes (particularly FosA-like) are increasingly prevalent in carbapenem-resistant strains 3
Clinical Efficacy Evidence Quality
The evidence supporting fosfomycin for multidrug-resistant gram-negative infections is predominantly observational with very low certainty: 3, 8