Is fosfomycin (Fosfomycin) effective against Extended-Spectrum Beta-Lactamase (ESBL)-producing organisms?

Fosfomycin Coverage Against ESBL-Producing Organisms

Yes, fosfomycin demonstrates excellent in vitro activity against ESBL-producing Enterobacteriaceae, particularly E. coli, with 96.8% susceptibility, making it a valuable treatment option specifically for uncomplicated urinary tract infections caused by these resistant organisms. 1

Activity Against ESBL Producers

Fosfomycin maintains robust activity against ESBL-producing pathogens, with the following susceptibility rates:

• E. coli (ESBL-producing): 96.8% susceptible (1,604/1,657 isolates) 1
• Klebsiella pneumoniae (ESBL-producing): 81.3% susceptible (608/748 isolates) 1
• Overall ESBL producers: 97.4% susceptible in one large study of 428 isolates 2

The mechanism of action—irreversible inhibition of enolpyruvyl transferase—results in no cross-resistance with beta-lactams or aminoglycosides, which is why fosfomycin retains activity despite ESBL production 3, 2.

Critical Clinical Limitations

Fosfomycin is ONLY appropriate for uncomplicated cystitis in women caused by ESBL-producing organisms—it should NOT be used for complicated UTIs, pyelonephritis, or systemic infections. 4, 5

Specific Restrictions:

• Uncomplicated cystitis only: Single 3-gram oral dose provides therapeutic urinary concentrations for 24-48 hours 5, 3
• NOT for complicated UTIs: European Association of Urology explicitly restricts fosfomycin to uncomplicated cystitis 4
• NOT for pyelonephritis: Insufficient efficacy data for upper tract infections 5
• NOT for systemic infections: Limited clinical experience outside urinary tract 6

Clinical Efficacy Data

In clinical studies, oral fosfomycin achieved 93.8% clinical cure rates (75/80 patients) for lower UTIs caused by ESBL-producing E. coli. 1

Additional efficacy considerations:

• Comparable clinical outcomes to other first-line agents for uncomplicated cystitis, despite somewhat lower bacteriological eradication rates 5
• Single-dose convenience improves adherence compared to 3-7 day regimens 5
• Minimal collateral damage to intestinal flora, reducing risk of secondary resistance 5

Important Caveats and Pitfalls

Species-Specific Resistance Patterns:

Klebsiella species show significantly higher fosfomycin resistance (46%) compared to E. coli (4%) among ESBL producers. 7

• Resistance rates vary by geographic region: 0.3-7.2% for E. coli, up to 46% for Klebsiella 2, 7
• The fosA3 gene (fosfomycin-modifying enzyme) is the primary resistance mechanism, often co-located with ESBL genes on transferable plasmids 8

When NOT to Use Fosfomycin:

1. Complicated UTIs or pyelonephritis: Use carbapenems (ertapenem for ESBL producers) or newer beta-lactam/beta-lactamase inhibitor combinations 6
2. Systemic ESBL infections: Carbapenems remain first-line; tigecycline, ceftazidime/avibactam, or ceftolozane/tazobactam are alternatives 6
3. Carbapenem-resistant Enterobacteriaceae (CRE): Fosfomycin has limited clinical data and should only be considered as part of combination therapy for MBL-producing CRE, not as monotherapy 6
4. Non-fermenting organisms: Fosfomycin lacks efficacy data and should not be used 4

Alternative Options for ESBL Infections

For infections beyond uncomplicated cystitis:

• Carbapenems (Group 1): Ertapenem has activity against ESBL producers but not Pseudomonas or Enterococcus 6
• Newer combinations: Ceftazidime/avibactam and ceftolozane/tazobactam are approved for complicated intra-abdominal infections with ESBL producers 6
• Tigecycline: Viable option for complicated infections with favorable activity against ESBL and carbapenemase-producing Enterobacteriaceae, though caution advised in bacteremia 6

Practical Algorithm

For ESBL-producing organisms:

1. Uncomplicated cystitis in women → Fosfomycin 3g single oral dose 5, 1
2. Complicated UTI or pyelonephritis → Ertapenem or other carbapenem 6
3. Systemic/severe infection → Carbapenem first-line; consider ceftazidime/avibactam or tigecycline if carbapenem-sparing needed 6
4. If Klebsiella species → Consider susceptibility testing before fosfomycin use due to higher resistance rates 7

Always obtain susceptibility testing for ESBL-producing organisms to guide definitive therapy, as resistance patterns vary geographically. 6