Is fosfomycin (phosphonic acid antibiotic) effective against Klebsiella pneumoniae that produces Extended-Spectrum Beta-Lactamases (ESBL)?

Fosfomycin Coverage for ESBL-Producing Klebsiella

Fosfomycin has limited and unreliable activity against ESBL-producing Klebsiella pneumoniae and should not be used as monotherapy; susceptibility testing is mandatory before considering it as part of combination therapy. 1, 2

Susceptibility Profile: Species-Specific Differences

The critical distinction is between E. coli and Klebsiella pneumoniae:

• ESBL-producing E. coli: Fosfomycin demonstrates excellent activity with 95.5-96.8% susceptibility rates, making it a viable treatment option for urinary tract infections 1, 2
• ESBL-producing K. pneumoniae: Fosfomycin shows significantly lower susceptibility at only 57.6-81.3%, with marked variability between isolates 1, 2

This substantial difference in activity means fosfomycin cannot be reliably used empirically for Klebsiella ESBL infections. 1

When Fosfomycin May Be Considered for ESBL Klebsiella

Fosfomycin should only be used for ESBL-producing Klebsiella when susceptibility testing confirms the isolate is susceptible, and only as part of combination therapy—never as monotherapy. 3, 4

For carbapenem-resistant K. pneumoniae (which often co-produces ESBLs):

• Intravenous fosfomycin-containing combination therapy may be used when susceptibility is confirmed 5
• Combination partners include tigecycline, polymyxin, or carbapenems based on synergy testing 5
• Fosfomycin susceptibility in carbapenem-resistant K. pneumoniae ranges from 39-99%, making testing essential 5

Resistance Mechanisms in Klebsiella

The poor activity against Klebsiella is explained by multiple resistance mechanisms:

• 70% of fosfomycin-non-susceptible K. pneumoniae harbor MurA amino acid substitutions that increase MICs 8- to 16-fold 6
• 97% have functionless transporters (GlpT and UhpT) preventing drug uptake 6
• FosA-like genes are prevalent in carbapenem-resistant K. pneumoniae 5

Testing Method Considerations

For K. pneumoniae, agar dilution is the only reliable reference method for determining fosfomycin resistance; automated systems show poor agreement. 7, 8

• Categorical agreement for K. pneumoniae was >90% for most methods except VITEK 2 (84%) 7
• Marked discrepancies exist between testing methods for K. pneumoniae, unlike E. coli where agreement is excellent 8
• Disk diffusion may underestimate susceptibility compared to agar dilution 1

Critical Contraindications

Before using fosfomycin for any indication, exclude:

• Hypernatremia 5, 3
• Cardiac insufficiency 5, 3
• Renal insufficiency 5, 3

These contraindications exist because intravenous fosfomycin contains high sodium content. 5

Preferred Alternatives for ESBL Klebsiella

For ESBL-producing Klebsiella infections, carbapenems remain first-line therapy; for carbapenem-resistant strains, novel β-lactam/β-lactamase inhibitor combinations are preferred over fosfomycin. 5

For urinary tract infections specifically:

• Simple cystitis: Single-dose aminoglycoside 3
• Complicated UTI/pyelonephritis: Ceftazidime-avibactam (first-line), meropenem-vaborbactam, or imipenem-relebactam 3
• Alternative for complicated UTI: Plazomicin 3

Common Pitfalls to Avoid

• Never use oral fosfomycin for ESBL Klebsiella: The single 3-gram oral dose achieves adequate urinary concentrations only for highly susceptible organisms like E. coli 4, 9
• Never use fosfomycin monotherapy: High risk of resistance development during treatment 4
• Do not assume E. coli susceptibility data applies to Klebsiella: The 20-40% difference in susceptibility rates is clinically significant 1, 2
• Verify susceptibility before use: Fosfomycin susceptibility testing is not routinely performed in many laboratories 4