Cefepime Has NO Clinically Useful Activity Against Enterococcus faecalis
Cefepime should never be used to treat Enterococcus faecalis infections, as it lacks intrinsic activity against enterococci and is explicitly listed as inactive against this organism. 1
Direct Evidence of Inactivity
The FDA drug label for cefepime explicitly states: "Most isolates of enterococci, e.g., Enterococcus faecalis...are resistant to cefepime." 1 This is consistent with the fundamental microbiological principle that cephalosporins, including all generations, have minimal or no in vitro activity against enterococci. 2
Additional confirmatory evidence:
- A 1994 comprehensive review states unequivocally: "Cefepime is not active in vitro against Enterococcus faecalis." 3
- Clinical case series documented E. faecalis resistance to cefepime in real-world sepsis patients 4
Critical Clinical Implications
When anti-enterococcal coverage is needed, cefepime-based regimens must be supplemented with appropriate agents such as ampicillin, piperacillin-tazobactam, or vancomycin. 5
Guidelines specifically recommend anti-enterococcal therapy should be directed against E. faecalis using:
- Ampicillin (drug of choice) 5, 2
- Piperacillin-tazobactam 5
- Vancomycin (for ampicillin-resistant strains) 5
When Cefepime Regimens Require Enterococcal Coverage
For healthcare-associated intra-abdominal infections where cefepime is used for gram-negative coverage, ampicillin must be added when any of these risk factors are present: 5
- Postoperative infection
- Prior cephalosporin exposure (which selects for enterococci)
- Immunocompromised status
- Valvular heart disease or prosthetic intravascular materials
- Biliary-enteric anastomosis
The Ampicillin-Cefepime Synergy Exception
Cefepime can only contribute to anti-enterococcal activity when combined with ampicillin, not as monotherapy. 6, 7 A 2016 pharmacodynamic study demonstrated that ampicillin-cefepime combinations showed synergistic activity against E. faecalis comparable to the standard ampicillin-ceftriaxone regimen. 6 In vitro studies confirmed synergy at 12-24 hours against all tested E. faecalis strains, with bactericidal activity in 75% (9/12 strains). 7
However, this synergy requires ampicillin as the primary agent—cefepime alone remains completely ineffective. 6, 7
Common Pitfall to Avoid
Never rely on cefepime monotherapy for empiric coverage when enterococci are possible pathogens. 2 The American Heart Association and American College of Cardiology explicitly recommend against using any cephalosporin for enterococcal infections due to lack of intrinsic activity. 2 Using cefepime alone when E. faecalis is present represents treatment failure from the outset. 2