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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 model of cefiderocol and assess pharmacokinetic profile in lungs. An intrapulmonary pharmacokinetic model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 pneumonia patients requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 nosocomial pneumonia patients. Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC,ELF ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for pneumonia patients compared to healthy subjects. Lung penetration ratio of cefiderocol in pneumonia patients was calculated to be 34%, which was 1.4 fold of that in healthy subjects. The estimated %fT>MIC,ELF was 100% in most of nosocomial pneumonia patients, and no pharmacokinetic/pharmacodynamic relationship with %fT>MIC,ELF was found for microbiological or clinical outcome. The PTA 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 higher than 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 based on renal function in critically ill pneumonia patients. This article is protected by copyright. All rights reserved.

Aim Coronavirus disease (COVID‐19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID‐19 patients. The aim of this study is to identify pathological microthrombi in COVID‐19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. Methods Forty‐three post‐mortem liver biopsy samples from COVID‐19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. Results We found liver sinusoidal microthrombosis in 23 COVID‐19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10‐fold, p = 0.04; AST: 11‐fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p