Cefepime Does NOT Treat E. faecalis
Cefepime is inactive against Enterococcus faecalis and should never be used as monotherapy for E. faecalis infections. 1
FDA-Labeled Spectrum Excludes Enterococci
The FDA drug label explicitly states that "most isolates of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime." 1 This is a critical limitation that clinicians must recognize when selecting empiric or targeted therapy.
Mechanism of Resistance
- Cefepime lacks adequate binding affinity to the penicillin-binding proteins (PBPs) of E. faecalis, which explains its inherent lack of activity against this organism 1
- Unlike ceftobiprole or ceftaroline, which demonstrate high-affinity binding to enterococcal PBPs, cefepime does not achieve the molecular target engagement necessary for bactericidal activity 2
Alternative Beta-Lactam Combinations That DO Work
While cefepime fails against E. faecalis, ampicillin combined with specific cephalosporins demonstrates excellent activity:
Standard of Care
- Ampicillin plus ceftriaxone remains the established standard for serious E. faecalis infections, including endocarditis, with clinical cure rates of 67-100% in patients completing therapy 3
Validated Alternatives Using Cefepime
- Ampicillin plus cefepime demonstrates synergistic and bactericidal activity equivalent to ampicillin-ceftriaxone in vitro 4, 5
- This combination was synergistic at 12-24 hours against all tested E. faecalis strains and bactericidal against 75% (9/12) of endocarditis-associated isolates 5
- The key distinction: cefepime requires ampicillin co-administration—it contributes to dual beta-lactam synergy through PBP saturation but cannot work alone 4
Other Effective Dual Beta-Lactam Regimens
- Meropenem plus ceftaroline demonstrated activity equivalent to ampicillin-ceftriaxone with no regrowth or MIC increases at 48 hours 6
- Ampicillin plus ceftobiprole with prolonged infusion achieved aggressive PK/PD targets and demonstrated bactericidal activity in severe invasive E. faecalis infections 2
Clinical Bottom Line
For E. faecalis infections:
- Never use cefepime monotherapy 1
- If using cefepime at all, it must be combined with ampicillin in a dual beta-lactam regimen 4, 5
- First-line therapy remains ampicillin plus ceftriaxone or ampicillin plus gentamicin (if aminoglycoside-susceptible) 3
- Consider ampicillin-cefepime as an alternative when ceftriaxone is contraindicated or when avoiding VRE promotion is a priority 4