In Vivo 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 in vivo 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 Pseudomonas aeruginosa showed 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>MIC determined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected the in vivo efficacy of cefiderocol than the %fT>MIC determined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MIC of cefiderocol required for a 1-log10 reduction against 10 strains of Enterobacteriaceae and 3 strains of Pseudomonas aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MIC for Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia 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 in vivo efficacy correlated with the in vitro MIC under iron-deficient conditions.

Activities of Cefiderocol with Simulated Human Plasma Concentrations against Carbapenem-Resistant Gram-Negative Bacilli in an In Vitro Chemostat Model

“…The results of the in vitro chemostat model using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) were consistent with the observation from several in vivo animal studies, which have been used to evaluate the potential use of cefiderocol to treat the infections caused by carbapenem-resistant Gram-negative bacteria with a MIC of ≤4 μg/ml. The PK/PD studies using mouse thigh infection models caused by a variety of Gram-negative bacteria showed that a 1-log 10 reduction in bacteria burden at 24 h was associated with 75% of the percentage of time that free cefiderocol concentrations are above the MIC (% fT MIC ) on average ( 16 ). The Monte-Carlo simulation showed that a dose of 2 g every 8 h as a 3-h infusion provided >90% probability of target attainment with a pharmacodynamic target of 75 or 100% % fT MIC for a MIC of ≤4 μg/ml in nosocomial pneumonia patients ( 17 ).…”

Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-Resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety

“…Compared to cefepime, which showed %fT > MIC of 61.7% and 87.7% to reach a bacterial stasis and a 1 log10 CFU reduction, cefiderocol demonstrated lower values of %fT > MIC of 47.5% and 57.6%, respectively [26]. To achieve a 1-log10 reduction, %fT > MIC for Enterobacteriaceae and P. aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively [26]. Against Enterobacteriaceae, P. aeruginosa, A. baumannii, and S. maltophilia in the lung infection model, %fT > MIC were 64.4%, 70.3%, 88.1%, and 53.9%, respectively [26].…”

“…To achieve a 1-log10 reduction, %fT > MIC for Enterobacteriaceae and P. aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively [26]. Against Enterobacteriaceae, P. aeruginosa, A. baumannii, and S. maltophilia in the lung infection model, %fT > MIC were 64.4%, 70.3%, 88.1%, and 53.9%, respectively [26]. A. baumannii required higher %fT > MIC values than those for Enterobacteriaceae and P. aeruginosa, which demonstrated similar efficacy in both thigh and lung infection models [26].…”

“…Furthermore, cefiderocol exhibited potent activity against all P. aeruginosa isolates, which were resistant to cefepime and levofloxacin [27]. The third study investigated the in vivo efficacy of cefiderocol against Enterobacteriaceae and P. aeruginosa in neutropenic thigh models and Enterobacteriaceae, P. aeruginosa, A. baumannii, and S. maltophilia in lung infection models [26]. Compared to cefepime, which showed %fT > MIC of 61.7% and 87.7% to reach a bacterial stasis and a 1 log10 CFU reduction, cefiderocol demonstrated lower values of %fT > MIC of 47.5% and 57.6%, respectively [26].…”

“…The third study investigated the in vivo efficacy of cefiderocol against Enterobacteriaceae and P. aeruginosa in neutropenic thigh models and Enterobacteriaceae, P. aeruginosa, A. baumannii, and S. maltophilia in lung infection models [26]. Compared to cefepime, which showed %fT > MIC of 61.7% and 87.7% to reach a bacterial stasis and a 1 log10 CFU reduction, cefiderocol demonstrated lower values of %fT > MIC of 47.5% and 57.6%, respectively [26]. To achieve a 1-log10 reduction, %fT > MIC for Enterobacteriaceae and P. aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively [26].…”