<i>In Vivo</i> Pharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models

Abstract

The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the <i>in vivo</i> efficacy 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 by <i>Pseudomonas aeruginosa</i> showed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%<i>fT</i>_>MIC) rather than the free peak level divided by the MIC (<i>fC</i>_max/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (<i>f</i>AUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %<i>fT</i>_>MIC determined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected the <i>in vivo</i> efficacy of cefiderocol than the %<i>fT</i>_>MIC determined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %<i>fT</i>_>MIC of cefiderocol required for a 1-log₁₀ reduction against 10 strains of <i>Enterobacteriaceae</i> and 3 strains of <i>Pseudomonas aeruginosa</i> in the thigh infection models were 73.3% and 77.2%, respectively. The mean %<i>fT</i>_>MIC for <i>Enterobacteriaceae</i>, <i>P. aeruginosa</i>, <i>Acinetobacter baumannii</i>, and <i>Stenotrophomonas maltophilia</i> in 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 the <i>in vivo</i> efficacy correlated with the <i>in vitro</i> MIC under iron-deficient conditions.