Intrapulmonary Pharmacokinetic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients With Pneumonia and Healthy Subjects.

Cefiderocol is a siderophore cephalosporin for the treatment of infections caused by gram-negative bacteria including carbapenem-resistant strains. The aim of this study was to develop an intrapulmonary pharmacokinetic (PK) model of cefiderocol and assess the PK profile in lungs. An intrapulmonary PK model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 patients with pneumonia requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 patients with nosocomial pneumonia. Monte Carlo simulations were performed to calculate the probability of target attainment for the percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over the dosing interval (%fT>MIC,ELF ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for patients with pneumonia compared to healthy subjects. Lung penetration ratio of cefiderocol in patients with pneumonia was calculated to be 34%, which was 1.4-fold that in healthy subjects. The estimated %fT>MIC,ELF was 100% in most of patients with nosocomial pneumonia, and no PK/pharmacodynamic relationship with %fT>MIC,ELF was found for microbiological or clinical outcome. The probability of target attainment for 100% fT>MIC,ELF was ≥ 99.5% against MICs ≤2 µg/mL and ≥87.0% against MICs ≤4 µg/mL regardless of renal function. The median of simulated ELF trough concentrations at steady state was >4 µg/mL regardless of renal function. These results reveal the adequacy of cefiderocol exposure in plasma and ELF at the recommended dosing regimens adjusted on the basis of renal function in critically ill patients with pneumonia.