Pharmacodynamics of Cefepime Combined with Tazobactam against Clinically Relevant Enterobacteriaceae in a Neutropenic Mouse Thigh Model

Abstract

ABSTRACT The lack of new antibiotics has prompted investigation of the combination of two existing agents—cefepime, a broad-spectrum cephalosporin, and tazobactam—to broaden their efficacy against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae . We determined the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the combination in a murine neutropenic thigh model in order to establish its exposure-response relationships (ERRs). The PK of cefepime were determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al., Antimicrob Agents Chemother 59:3373–3376, 2015, https://doi.org/10.1128/AAC.04402-14 ). The PK were linear for both compounds. The estimated mean (standard deviation [SD]) half-life of cefepime was 0.33 (0.12) h, and that of tazobactam was 0.176 (0.026) h; the volumes of distribution ( V ) were 0.73 liters/kg and 1.14 liters/kg, respectively. PD studies of cefepime administered every 2 h (q2h) with or without tazobactam, including dose fractionation studies of tazobactam, were performed against six ESBL-producing isolates. A sigmoidal maximum-effect ( E max ) model was fitted to the data. In the dose fractionation study, the q2h regimen was more efficacious than the q4h and q6h regimens, indicating time-dependent activity of tazobactam. The threshold concentration ( C T ) best correlating with tazobactam efficacy was 0.25 mg/liter, as evidenced by the best fit of the percentage of time above the threshold concentration (% fT > C T ) and response. A mean % fT > C T of 24.6% (range, 11.4 to 36.3%) for a C T of 0.25 mg/liter was required to obtain a bacteriostatic effect. We conclude that tazobactam enhanced the effect of cefepime in otherwise resistant isolates of Enterobacteriaceae and that the % fT > C T of 0.25 mg/liter best correlated with efficacy. These studies provide the basis for the development of human dosing regimens for this combination.