Cefepime pharmacodynamic targets against Enterobacterales employing neutropenic murine lung infection and in vitro pharmacokinetic models

Abstract

Background: Very limited studies, so far, have been conducted to identify the pharmacodynamic targets of cefepime, a well-established fourth-generation cephalosporin. As a result, conventional targets representing the cephalosporin class are used for cefepime target attainment analysis. Objectives: We employed both a neutropenic murine lung infection model and an in vitro pharmacokinetic model (IVPM) to determine cefepime's pharmacodynamic target [percentage of the dosing interval during which unbound drug concentrations remain higher than the MIC (%fT>MIC)] for bacteriostatic and 1 log10 kill effects. Methods: Ten strains with cefepime MICs ranging from 0.03 to 16 mg/L were studied in the lung infection. In the IVPM, five cefepime-resistant strains with cefepime/tazobactam (fixed 8 mg/L) MICs ranging from 0.25 to 8 mg/L were included. Through 24 h dose fractionation, both in lung infection and IVPM (in the latter case, tazobactam 8 mg/L continuous infusion was used to protect cefepime), varying cefepime exposures and corresponding pharmacodynamic effect scenarios were generated to identify the pharmacodynamic targets. Results: Using a non-linear sigmoidal maximum-effect (Emax) model, the cefepime's plasma fT>MIC for 1 log10 kill in lung infection ranged from 17% to 53.7% and a combined exposure-response plot yielded 30%. In the case of IVPM, T>MIC ranged from 6.9% to 75.4% with a mean value of 34.2% for 1 log10 kill. Conclusions: Both in vivo and in vitro studies showed that cefepime's pharmacodynamic requirements are lower than generally reported for cephalosporins (50%-70% fT>MIC). The lower requirement for cefepime could be linked with factors such as cefepime's better permeation properties and multiple PBP affinity-driven enhanced bactericidal action.