Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects

Background Cefiderocol, a novel siderophore cephalosporin, has shown potent activity against Gram-negative bacteria, including MDR pathogens. Cefiderocol is under clinical investigation for the treatment of serious Gram-negative infections including nosocomial pneumonia. Objectives This study assessed intrapulmonary penetration after a single intravenous dose of cefiderocol (2000mg infused over 60min) in healthy adult males. Materials and methods Each subject underwent one bronchoscopy with bronchoalveolar lavage (BAL) to collect BAL fluid (BALF). Fifteen subjects were assigned to one of three collection timepoints (1, 2 or 4h from start of infusion). Five additional subjects were assigned to a collection timepoint at 6h, which was added based on concentration data between 1 and 4h predicting measurable BALF cefiderocol concentrations at 6h. Results Cefiderocol concentrations in plasma, epithelial lining fluid (ELF) and alveolar macrophages (AMs) were calculated for each subject. The ELF concentration of cefiderocol was 13.8, 6.69, 2.78 and 1.38mg/L at 1, 2, 4 and 6h after single intravenous dosing, respectively. Over 6h, geometric mean concentration ratios ranged from 0.0927 to 0.116 for ELF to total plasma and from 0.00496 to 0.104 for AMs to total plasma. AUC ratios of ELF and AMs to plasma were 0.101 and 0.0177 based on total drug in plasma, respectively, and 0.239 and 0.0419 based on free drug in plasma, respectively. There were no major drug-related adverse events. Conclusions Results of this study indicate that cefiderocol penetrates into ELF, and ELF and plasma concentrations appear to be parallel.