Fosfomycin Coverage of ESBL-Producing Proteus mirabilis
Fosfomycin demonstrates excellent in vitro activity against ESBL-producing Proteus mirabilis and is an appropriate treatment option, but ONLY for uncomplicated lower urinary tract infections (cystitis) in women—it should NOT be used for complicated UTIs, pyelonephritis, or any systemic infections. 1, 2
In Vitro Activity and Microbiological Evidence
- Fosfomycin shows robust activity against Proteus mirabilis, including ESBL-producing strains, with the FDA label specifically listing P. mirabilis as a susceptible organism 3
- A 2017 in vitro study demonstrated that fosfomycin inhibited 100% of ESBL-positive P. mirabilis strains isolated from urine using standardized susceptibility testing methods 4
- The bactericidal mechanism involves irreversible inhibition of enolpyruvyl transferase, blocking bacterial cell wall synthesis, with no cross-resistance to beta-lactams or aminoglycosides 3
Critical Clinical Limitations
The European Association of Urology restricts fosfomycin to uncomplicated cystitis ONLY, explicitly excluding complicated UTIs and pyelonephritis regardless of the pathogen 1, 5. This is a crucial distinction that must guide clinical decision-making.
When Fosfomycin IS Appropriate:
- Uncomplicated cystitis in women caused by ESBL-producing P. mirabilis: single 3-gram oral dose 1, 2
- Achieves therapeutic urinary concentrations of 706 mcg/mL within 2-4 hours, maintaining levels >100 mcg/mL for 26 hours 3
- Can be taken without regard to food 3
When Fosfomycin is NOT Appropriate:
- Complicated UTIs or pyelonephritis: carbapenems (ertapenem) are preferred 1
- Systemic ESBL infections: carbapenems remain first-line, with alternatives including ceftazidime/avibactam or ceftolozane/tazobactam 1
- Bacteremic patients: fosfomycin has poor plasma concentrations and should be avoided 6
Important Caveats
Tigecycline lacks in vitro activity against Proteus species (along with other Enterobacteriaceae like Serratia and Morganella), making fosfomycin a superior choice for uncomplicated P. mirabilis cystitis when other agents are contraindicated 6, 2
Resistance is emerging: While historical data showed excellent susceptibility, fosfomycin resistance among ESBL-producing Enterobacteriaceae is increasing over time, though specific P. mirabilis resistance rates remain favorable 7
Treatment Algorithm for ESBL-Producing P. mirabilis
- Uncomplicated cystitis in women: Fosfomycin 3g oral single dose 1, 2
- Complicated UTI or pyelonephritis: Ertapenem or other carbapenem 1
- Systemic/severe infection: Carbapenem first-line; consider ceftazidime/avibactam or ceftolozane/tazobactam if carbapenem-sparing needed 1
- Intra-abdominal infection with ESBL P. mirabilis: Ceftolozane/tazobactam with metronidazole or carbapenem 6
The key pitfall to avoid: Do not extrapolate fosfomycin's excellent in vitro activity against P. mirabilis to clinical scenarios beyond uncomplicated cystitis—the evidence and guidelines uniformly restrict its use to this narrow indication despite microbiological susceptibility 1, 5.