Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model

Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to describe the pharmacokinetics, pharmacodynamics and 24-h efficacy of cefiderocol using dose-ranging methods in a neutropenic murine thigh infection model. Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg at 4 days and 1 day prior to inoculation, respectively) with eight Pseudomonas aeruginosa isolates [minimum inhibitory concentration (MIC) range 0.063-0.5 mu g/mL] that displayed variable in vivo activity against previously tested beta-lactams with siderophore moieties. Renal excretion was controlled by administration of 5 mg/kg uranyl nitrate 3 days prior to inoculation. Cefiderocol was administered subcutaneously in eight escalating doses [4.2-166.7 mg/kg every 8 h (q8h)]. In pharmacokinetic studies, cefiderocol manifested similar pharmacokinetics across tested doses (4, 100 and 250 mg/kg) with a mean half-life of 0.86 h. In pharmacodynamic studies, the change in CFU after 24 h from the initial inoculum ranged from +3.4 to -3.1 log(10) with doses of 4.2-166.7 mg/kg q8h. Dose-response curves for the eight isolates assumed the characteristic sigmoidal shape, with greater CFU reductions as the dose increased. Focusing on the previously defined efficacy parameter of fT (> MIC) (time that the free drug concentration exceeds the MIC) for this compound, targets for stasis and 1 log(10) and 2 log(10) reductions ranged from 44.4-94.7, 50.2-97.5 and 62.1-100, respectively. Cefiderocol displayed sustained antibacterial effects against these MDR P. aeruginosa isolates. These data support the cefiderocol dose selected for clinical trials. (c) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.