Does cefepime have activity against multidrug‑resistant (MDR) Gram‑negative organisms such as ESBL‑producing Enterobacteriaceae and Pseudomonas aeruginosa?

Cefepime Coverage for MDR Organisms

Cefepime has limited and unreliable activity against most MDR organisms, particularly ESBL-producing Enterobacteriaceae, and should not be used as monotherapy for suspected or confirmed MDR infections. 1

Activity Against ESBL-Producing Enterobacteriaceae

• Cefepime is NOT recommended for ESBL-producing organisms despite in vitro susceptibility. The use of cefepime for ESBL infections is controversial and unsafe, particularly in patients previously exposed to third-generation cephalosporins. 1

• Even with the revised CLSI breakpoints (≤8 μg/mL for susceptibility), cefepime fails to identify many ESBL-producing E. coli, K. pneumoniae, and K. oxytoca isolates, with clinical efficacy remaining unclear for isolates with MICs in the susceptible range. 1

• Surveillance data show cefepime susceptibility rates of only 92.5% for ESBL-producing Klebsiella spp. and 93.8% for ESBL-producing E. coli, compared to 99.3-100% for carbapenems. 2

• Carbapenems remain the reliable choice for ESBL-producing Enterobacteriaceae, with ertapenem specifically recommended for these infections when Pseudomonas and Enterococcus are not concerns. 1, 3

Activity Against AmpC-Producing Organisms

• Cefepime demonstrates effectiveness against AmpC-producing organisms (Enterobacter, Citrobacter, Serratia), which represents its primary advantage over third-generation cephalosporins. 1

• This activity is due to cefepime's low affinity for chromosomal AmpC β-lactamases and minimal induction capacity, even at low periplasmic concentrations. 4, 5

• However, third-generation cephalosporins should never be used for Enterobacter species due to high frequency of resistance developing during therapy. 1

Activity Against Pseudomonas aeruginosa

• Cefepime shows activity against P. aeruginosa with susceptibility rates of 84-88%, similar to imipenem (86.9%). 2

• This activity does NOT extend to MDR Pseudomonas strains. Strains producing large amounts of β-lactamase may be resistant to both ceftazidime and cefepime. 5

• For MDR Pseudomonas infections, combination therapy with aminoglycosides or consideration of polymyxins is necessary. 1

Critical Limitations and Pitfalls

• Cefepime lacks activity against:

  • Carbapenem-resistant Enterobacteriaceae (CRE) 3
  • Methicillin-resistant Staphylococcus aureus (MRSA) 4
  • Enterococcus species 3, 4
  • Anaerobic bacteria—must be combined with metronidazole 1, 6

• When ESBL-producing organisms are suspected or isolated, third-generation cephalosporins and cefepime should be avoided as monotherapy, and carbapenems should be used instead. 1

• The emergence of resistance during therapy is a significant concern, particularly for Enterobacter species and P. aeruginosa. 1

Future Role with β-Lactamase Inhibitors

• Four new cefepime/β-lactamase inhibitor combinations are in clinical development (cefepime/zidebactam, cefepime/taniborbactam, cefepime/enmetazobactam, cefepime/tazobactam) that show promise against ESBL-producers, KPC-producers, and some MBL-producing organisms. 7

• These combinations may offer carbapenem-sparing options in the future, but their clinical role remains to be determined through Phase III trials. 7

Practical Algorithm for MDR Coverage

If ESBL-producing Enterobacteriaceae suspected or confirmed:

• Use ertapenem (if no Pseudomonas/Enterococcus concern) or meropenem/imipenem (if broader coverage needed) 1, 3
• Do NOT use cefepime monotherapy 1

If AmpC-producing organisms (Enterobacter, Citrobacter, Serratia) suspected:

• Cefepime is appropriate at 2g every 8 hours 1
• Alternative: carbapenem 1

If MDR Pseudomonas suspected:

• Use antipseudomonal carbapenem (meropenem, imipenem, doripenem) plus aminoglycoside or fluoroquinolone 1
• Cefepime monotherapy is insufficient 1