Is fosfomycin (phosphonic acid antibiotic) effective against Enterococcus species and Escherichia coli (E. coli) producing Extended-Spectrum Beta-Lactamases (ESBL)?

Fosfomycin Coverage for Enterococcus Species and ESBL-Producing E. coli

Fosfomycin provides excellent coverage for ESBL-producing E. coli (96-100% susceptibility) and good coverage for Enterococcus faecalis (94-97% susceptibility), but it should only be used for uncomplicated cystitis in women—not for complicated UTIs, pyelonephritis, or systemic infections where carbapenems are required. 1, 2

Coverage Spectrum and Susceptibility Data

ESBL-Producing E. coli

• Fosfomycin demonstrates exceptional in vitro activity against ESBL-producing E. coli, with 96.8-100% susceptibility rates across multiple studies 3, 4, 5, 6
• The FDA label confirms fosfomycin has activity against E. coli as one of its primary indications for uncomplicated UTI 7
• Clinical data support 93.8% clinical effectiveness when oral fosfomycin-trometamol was used for lower UTIs caused by ESBL-producing E. coli 4

Enterococcus Species

• Enterococcus faecalis shows 94-97% susceptibility to fosfomycin, making it a reliable option for uncomplicated cystitis 3, 5, 8
• The FDA label specifically lists Enterococcus faecalis as an approved indication 7
• Vancomycin-resistant E. faecium demonstrates 81-93% susceptibility, though this is lower than E. faecalis 5, 8
• The same single 3-gram dose recommended for standard UTIs is appropriate for VRE-caused uncomplicated UTIs 2

Critical Clinical Limitations

When Fosfomycin Should NOT Be Used

• The European Association of Urology explicitly restricts fosfomycin to uncomplicated cystitis in women only—it must not be used for complicated UTIs, pyelonephritis, or systemic infections 1, 2
• For complicated UTIs or pyelonephritis caused by ESBL organisms, carbapenems (particularly ertapenem) are the preferred first-line treatment 1
• Fosfomycin is not recommended for routine use in men with UTIs due to limited efficacy data 2
• Oral fosfomycin achieves inadequate tissue concentrations outside the urinary tract, limiting its use to lower UTI only 1, 2

Systemic ESBL Infections

• For systemic ESBL infections, carbapenems remain first-line therapy, with alternatives including tigecycline, ceftazidime/avibactam, or ceftolozane/tazobactam 1
• The WSES guidelines note that fosfomycin can be considered for carbapenem-resistant Enterobacter infections as part of combination therapy, but this applies to IV formulations in critically ill patients, not oral therapy for simple UTI 9

Practical Dosing and Administration

Standard Regimen for Uncomplicated Cystitis

• Single 3-gram oral dose of fosfomycin tromethamine provides therapeutic urinary concentrations for 24-48 hours 2, 7
• Can be taken without regard to food, though high-fat meals delay peak concentration from 2-4 hours to 6-8 hours without affecting total urinary excretion 7
• Approximately 38% of the dose is recovered unchanged in urine, achieving mean concentrations of 706 mcg/mL within 2-4 hours 7

Special Populations

• Use with caution in patients with hypernatremia, cardiac insufficiency, or renal insufficiency, as elimination half-life increases from 5.7 hours to 40-50 hours in anuric patients 2, 7
• Safe in pregnancy and recommended by European Urology guidelines for asymptomatic bacteriuria in pregnant women 2
• No dosage adjustment needed in elderly patients 7

Treatment Algorithm

For Uncomplicated Cystitis in Women

1. If ESBL-producing E. coli or Enterococcus faecalis is suspected or documented: Fosfomycin 3 grams orally as single dose 1, 2
2. If symptoms persist beyond 2-3 days or recur within 2 weeks: Obtain urine culture and consider alternative agents (nitrofurantoin 5 days, TMP-SMX 3 days, or fluoroquinolones 3 days) 2

For Complicated UTI or Pyelonephritis

1. Do not use oral fosfomycin 1, 2
2. First-line: Ertapenem or other carbapenems for ESBL-producing organisms 1
3. Alternatives: Ceftazidime/avibactam, ceftolozane/tazobactam, or tigecycline if carbapenem-sparing is needed 1

Key Advantages and Caveats

Advantages

• Minimal collateral damage to intestinal flora compared to fluoroquinolones and cephalosporins, reducing C. difficile risk 2, 8
• Single-dose convenience improves adherence compared to 3-7 day regimens 2
• Low resistance rates (only 2.6% in initial E. coli infections) 2
• No cross-resistance with beta-lactams or aminoglycosides 7

Common Pitfalls to Avoid

• Do not use fosfomycin for upper tract infections or complicated UTIs despite good in vitro susceptibility data—clinical efficacy is unproven in these settings 1, 2
• Do not assume Enterococcus faecium has the same susceptibility as E. faecalis—E. faecium shows lower susceptibility (81-93% vs 94-97%) 5, 8
• Do not use in men without strong justification, as clinical data are limited in this population 2
• Klebsiella pneumoniae (including ESBL-producing strains) shows more variable susceptibility (81-84%) compared to E. coli, making it a less reliable choice 4, 8