Fosfomycin Coverage Against Klebsiella
Fosfomycin does provide coverage against Klebsiella pneumoniae, but susceptibility is highly variable (39-99%) and must be confirmed by antimicrobial susceptibility testing before use—it should be used as part of combination therapy rather than monotherapy for serious infections. 1, 2
Spectrum of Activity and Susceptibility Patterns
Fosfomycin demonstrates in vitro activity against K. pneumoniae, including carbapenem-resistant strains (CRKP), with the FDA label specifically listing Klebsiella pneumoniae and Klebsiella oxytoca as susceptible organisms. 3
Susceptibility rates are highly variable and depend on local epidemiology, ranging from 39% to 99% in carbapenem-resistant K. pneumoniae, with resistance mediated primarily by FosA-like genes (particularly FosA3). 1, 2, 4
Research demonstrates that only 31.8% of carbapenemase-producing K. pneumoniae isolates showed susceptibility to fosfomycin in one study, with high-level resistance (MIC >256 mg/L) occurring when FosA3 overexpression combines with transporter mutations (glpT or uhpT). 4
Among carbapenemase-producing strains, resistance rates are higher (45% resistant) compared to carbapenemase-negative strains (25% resistant). 5
Critical Implementation Requirements
Mandatory susceptibility testing must be performed before initiating fosfomycin therapy, as susceptibility testing is not routinely performed in many clinical laboratories and cannot be assumed based on other resistance patterns. 1, 2, 6
The E-test method shows 100% categorical agreement with the reference agar dilution method and is recommended over automated systems like Phoenix, which showed only 86% agreement and larger MIC discrepancies. 5
Antimicrobial synergy testing should be performed when possible to confirm synergistic effects of fosfomycin-containing combinations against the specific isolate. 1
Recommended Clinical Use
For serious K. pneumoniae infections (including CRKP), fosfomycin should be used as part of combination therapy, not monotherapy, as monotherapy is associated with high treatment failure rates and rapid emergence of resistance. 1, 2, 7
Appropriate combination partners include:
Fosfomycin-containing combination therapy demonstrated 114 fewer deaths per 1000 patients (RR=0.55,95% CI 0.28-1.10) compared to other antimicrobial combinations in observational studies of CRKP infections, though evidence quality is very low. 1
In a retrospective cohort of 104 CRKP sepsis cases, fosfomycin combination therapy was associated with improved survival (OR: 4.71,95% CI: 1.03-21.65, P=0.034) and shorter duration of mechanical ventilation. 9
Route-Specific Considerations
Intravenous fosfomycin is recommended for serious infections including sepsis, bacteremia, and complicated urinary tract infections caused by K. pneumoniae. 1, 2
Oral fosfomycin may be appropriate only for uncomplicated urinary tract infections when susceptibility is confirmed. 3
Contraindications and Monitoring
Fosfomycin is contraindicated in patients with hypernatremia, cardiac insufficiency, or renal insufficiency due to the high sodium content of the IV formulation. 1, 2, 10
Monitor serum potassium levels closely, as reversible severe hypokalemia occurs in approximately 6% of ICU patients receiving IV fosfomycin. 2, 10
In renal impairment, the half-life increases from 11 hours to 50 hours, and urinary recovery decreases from 32% to 11%. 3
Mechanism and Resistance Considerations
Fosfomycin irreversibly blocks enolpyruvyl transferase, an early step in bacterial cell wall synthesis, resulting in generally no cross-resistance with β-lactams or aminoglycosides. 6, 3
Time-kill assays demonstrate that fosfomycin enhances the bactericidal activity of imipenem, ertapenem, tigecycline, colistin, and amikacin against KPC-producing K. pneumoniae. 8
Monotherapy rapidly selects for resistant subpopulations within 48 hours, but combination therapy prevents propagation of both fosfomycin and partner drug resistance. 7