Is cefepime effective for infections caused by AmpC β‑lactamase‑producing bacteria?

Cefepime is Effective for AmpC-Producing Bacteria

Cefepime is an effective and recommended treatment option for infections caused by AmpC β-lactamase-producing Enterobacterales, with clinical outcomes comparable to carbapenems and the advantage of carbapenem-sparing therapy. 1, 2, 3

Guideline Recommendations

• The World Society of Emergency Surgery explicitly states that cefepime is a fourth-generation cephalosporin with broader spectrum activity than third-generation cephalosporins and is effective against AmpC-producing organisms. 1

• The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines note that cefepime may be active against AmpC-producing organisms, with variation in results depending on resistance mechanism—specifically finding no difference in outcomes in studies addressing AmpC producers. 1

• The Infectious Diseases Society of America recommends cefepime as first-line monotherapy for serious infections requiring broad-spectrum Gram-negative coverage. 4

Clinical Evidence Supporting Effectiveness

Most Recent High-Quality Evidence

• A 2025 systematic review and meta-analysis of 7 studies encompassing 1,099 patients with AmpC-producing Enterobacterales bloodstream infections found no statistically significant difference in all-cause mortality between cefepime and carbapenem treatment (log OR, 0.15 [95% CI, -0.33 to 0.64]; P = 0.54), with a nonsignificant trend actually favoring cefepime. 3

• A 2024 retrospective cohort study of 270 episodes of AmpC-producing Enterobacterales bloodstream infections found that cefepime was not associated with adverse outcomes compared to carbapenems in both univariable and multivariable analyses, with the exception of shorter length of hospital stay among survivors treated with cefepime. 2

Supporting Evidence from Earlier Studies

• A 2023 study of 315 patients with E. cloacae, K. aerogenes, or C. freundii bacteremia found that high-dose cefepime was not associated with increased risk of 30-day mortality compared with carbapenem therapy (adjusted HR, 1.45; 95% CI, 0.79-2.14). 5

• A 2013 propensity-matched study of 96 patients with confirmed AmpC β-lactamase-producing organisms found no difference in 30-day mortality (OR, 0.63; 95% CI, 0.23-2.11; P = 0.36) or length of hospital stay between cefepime and meropenem groups. 6

Critical MIC Considerations

• Cefepime is most reliable when the MIC is ≤2 µg/mL (CLSI) or ≤1 mg/mL (EUCAST), though higher doses may be considered for MICs in the 4-8 mg/mL range. 7

• The ESCMID guidelines note that in one small subgroup of patients with higher cefepime MIC in the susceptible dose-dependent category, mortality was higher with cefepime (5 of 7 versus 2 of 11, p = 0.045), though this was a very small sample. 1

• High-dose cefepime showed similar outcomes to carbapenems even for isolates with cefepime-susceptible dose-dependent (SDD) MIC of 4-8 µg/mL (adjusted HR, 1.19; 95% CI, 0.52-1.77). 5

Important Caveats and Pitfalls

• Do not confuse AmpC-producing organisms with ESBL-producing organisms—cefepime performs differently against these two resistance mechanisms. The ESCMID guidelines note higher mortality sometimes reported with cefepime for ESBL infections, but no difference in outcomes specifically for AmpC producers. 1

• Cefepime lacks anaerobic activity and must be combined with metronidazole for intra-abdominal infections. 1, 4

• Ensure adequate source control is achieved, as this is critical for successful outcomes with cefepime therapy for AmpC-producing infections. 6

• Prolonged-infusion β-lactam administration was identified as protective (adjusted HR, 0.67; 95% CI, 0.40-0.89) in one study, suggesting consideration of extended infusion strategies. 5

Clinical Algorithm for Use

• For bloodstream infections or complicated urinary tract infections caused by AmpC-producing Enterobacterales with cefepime MIC ≤2 µg/mL: Use high-dose cefepime as definitive therapy. 2, 3, 5

• For isolates with cefepime MIC 4-8 µg/mL (SDD range): High-dose cefepime remains a reasonable option with similar outcomes to carbapenems. 5

• For intra-abdominal infections: Combine cefepime with metronidazole due to lack of anaerobic coverage. 1

• Ensure phenotypic exclusion of ESBL co-production before selecting cefepime, as outcomes differ for ESBL-producing organisms. 1, 2