Irrespective of in-vitro susceptibility results, cefepime should be avoided in the treatment of serious ESBL infections associated with bacteremia, pneumonia, intraabdominal infection, endocarditis, bone/joint infection or whenever a high bacterial inoculum is suspected. Cefepime should be considered only in non-severe infections (eg, uncomplicated urinary tract infection) when the minimum inhibitory concentration (MIC) is 2 mg/L or less (1).

To date, clinical studies comparing cefepime vs carbapenem have been small and/or retrospective, often with conflicting results (1). A 2016 propensity score-matched study of patients with ESBL bacteremia receiving cefepime therapy followed by carbapenem therapy vs carbapenem for the entire treatment duration found higher 14 day mortality in the cefepime group (41% vs 20% in the carbapenem group) (2).  Of note, 2 of the patients receiving cefepime who died were infected with an ESBL organism with MIC of 1 mcg/mL. 

Another study found cefepime to be inferior to carbapenem therapy in ESBL bacteremic patients with better outcome when cefepime MIC was 1 ug/m or less (3).

Two studies involving patients with ESBL UTIs found no significant difference between cefepime and carbapenem in clinical and microbiological response or in-hospital mortality, while another UTI study with a high rate of septic shock (33%) found that cefepime was inferior to carbapenem in clinical and microbiological response (2).

The diminished efficacy of cefepime for the treatment of ESBL infections may be related to its “inoculum effect” ie, marked increase in MIC with increased inoculum size compared to that used in standard laboratory susceptibility testing (1,4).   

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References

1. Karaiskos I, Giamarellou H. Carbapenem-sparing strategies for ESBL producers: when and how. Antibiotics 2020;9,61. https://pubmed.ncbi.nlm.nih.gov/32033322/
2. Wang R, Cosgrove S, Tschudin-Sutter S, et al. Cefepime therapy for cefepime-susceptible extended-spectrum beta-lactamase-producing Enerobacteriaceae bacteremia. Open Forum Infect Dis 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942761/
3. Lee NY, Lee CC, Huang WH, et al. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis 203;56:488-95. https://academic.oup.com/cid/article/56/4/488/351224
4. Smith KP, Kirby JE. The inoculum effect in the era of multidrug resistance:minor differences in inoculum have dramatic effect on MIC determination. Antimicrob Agents Chemother 2018;62:e00433-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105823/

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