In VivoPharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models

Abstract

ABSTRACTThe pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with thein vivoefficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused byPseudomonas aeruginosashowed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT>MIC) rather than the free peak level divided by the MIC (fCmax/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT>MICdetermined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected thein vivoefficacy of cefiderocol than the %fT>MICdetermined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MICof cefiderocol required for a 1-log10reduction against 10 strains ofEnterobacteriaceaeand 3 strains ofPseudomonas aeruginosain the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MICforEnterobacteriaceae,P. aeruginosa,Acinetobacter baumannii, andStenotrophomonas maltophiliain the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that thein vivoefficacy correlated with thein vitroMIC under iron-deficient conditions.