Is fosfomycin effective against Klebsiella pneumoniae?

Fosfomycin Coverage Against Klebsiella pneumoniae

Yes, fosfomycin demonstrates excellent in vitro activity against Klebsiella pneumoniae, including carbapenem-resistant strains, with 81.3% of ESBL-producing K. pneumoniae and 82% of KPC-producing K. pneumoniae susceptible to fosfomycin. 1, 2

Spectrum of Activity

Fosfomycin maintains robust activity against K. pneumoniae across resistance phenotypes:

• ESBL-producing K. pneumoniae: 608 of 748 isolates (81.3%) demonstrated susceptibility using a breakpoint of ≤64 mg/L 1
• KPC-producing K. pneumoniae: 82% of carbapenem-resistant isolates showed susceptibility in vitro 2
• Carbapenem-resistant K. pneumoniae (CRKP): Susceptibility rates range from 39% to 99% depending on local epidemiology 3

The FDA recognizes K. pneumoniae as a pathogen against which fosfomycin demonstrates in vitro activity, though clinical significance requires adequate controlled trials 4

Clinical Efficacy Evidence

For severe infections caused by KPC-producing K. pneumoniae in critically ill patients, fosfomycin-containing combination regimens significantly outperform non-fosfomycin regimens. 5

The most compelling clinical data comes from a 2024 study showing:

• Higher clinical cure: 89.2% vs 65.9% (P=0.017) 5
• Improved microbiological eradication: 87.5% vs 62.2% (P=0.027) 5
• Reduced 30-day mortality: 13.5% vs 34.2% (P=0.039), with fosfomycin independently associated with survival (HR=0.29,95% CI 0.09-0.93) 5
• This mortality benefit was particularly pronounced for KPC-producing K. pneumoniae infections 5

Critical Implementation Requirements

Mandatory susceptibility testing must be performed before initiating fosfomycin therapy, as susceptibility is not routinely tested in many laboratories and resistance patterns vary significantly by institution. 3

Combination Therapy is Essential

Fosfomycin should never be used as monotherapy for serious K. pneumoniae infections:

• Monotherapy leads to rapid emergence of resistance within 48 hours despite initial bacterial killing 6
• The IDSA recommends fosfomycin-containing combination therapy when the isolate demonstrates susceptibility or synergistic effects 3
• Combination with polymyxin B, aminoglycosides (particularly amikacin), tigecycline, or carbapenems demonstrates additive/synergistic effects 6, 7

Optimal Combination Partners

Based on in vitro synergy studies against KPC-producing K. pneumoniae:

• Fosfomycin + amikacin: Shows persistent bactericidal effect and is the most effective therapeutic candidate 7
• Fosfomycin + polymyxin B: Achieves >6 log₁₀ CFU/mL reduction while preventing resistance amplification when fosfomycin MIC ≤8 mg/L 6
• Fosfomycin + tigecycline, colistin, or carbapenems: All demonstrate significant additive effects 7

Route-Specific Considerations

Oral Fosfomycin (Fosfomycin Tromethamine)

• Limited to uncomplicated lower urinary tract infections caused by susceptible K. pneumoniae 4, 1
• Achieves mean urinary concentrations of 706 mcg/mL within 2-4 hours, maintaining >100 mcg/mL for 26 hours 4
• Can be taken without regard to food 4

Intravenous Fosfomycin

• Required for complicated UTIs, bloodstream infections, and intra-abdominal infections caused by carbapenem-resistant K. pneumoniae 8, 3
• Recommended by ESCMID guidelines for complicated UTI without septic shock based on the ZEUS trial 8

Contraindications and Monitoring

Fosfomycin is contraindicated in patients with:

• Hypernatremia (due to high sodium content of IV formulation) 3, 9
• Cardiac insufficiency 3, 9
• Renal insufficiency 3, 9

Monitor serum potassium levels closely, as hypokalemia occurs in approximately 6% of ICU patients receiving IV fosfomycin 9

Common Pitfalls to Avoid

• Do not assume susceptibility: Resistance genes (particularly FosA-like) are increasingly prevalent in carbapenem-resistant strains; always confirm susceptibility 3
• Do not use monotherapy: Even with susceptible isolates, monotherapy rapidly selects resistant subpopulations 6
• Do not use oral formulation for serious infections: Oral fosfomycin achieves therapeutic levels only in urine and is inadequate for systemic infections 4, 1
• Do not overlook electrolyte disturbances: The high sodium content and risk of hypokalemia require vigilant monitoring 3, 9