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

Abstract

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 (2000 mg infused over 60 min) 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 4 h from start of infusion). Five additional subjects were assigned to a collection timepoint at 6 h, which was added based on concentration data between 1 and 4 h predicting measurable BALF cefiderocol concentrations at 6 h. 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 1.38 mg/L at 1, 2, 4 and 6 h after single intravenous dosing, respectively. Over 6 h, 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.

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

“…The AUC ratios in ELF to total plasma were 0.101 and 0.239 to free plasma, suggesting * 24% penetration into the ELF. AUC ratios in AMs to total plasma and free plasma were 0.0177 and 0.0419, respectively, suggesting much lower penetration into AMs [31]. Future work is needed to assess intrapulmonary penetration in infected patients, particularly those who are critically ill. Drug-drug interaction potentials of cefiderocol were assessed in an open-label, randomized, crossover study of 3 study cohorts.…”

Cefiderocol: A Siderophore Cephalosporin

“…The AUC ratios of ELF to total plasma and free plasma are 0.101 and 0.239, respectively, which is similar to that for other β-lactams used in respiratory tract infections. 62 Cefiderocol is primarily excreted unchanged in the urine (>90% of the administered dose); hepatic metabolism plays a minor role in the excretion of cefiderocol and accounts for less than 7% of the total dose, whereas fecal excretion accounts for 2.79% of the dose. 63 The PK of cefiderocol were assessed following a 1000mg IV 1-hour infusion in patients with renal impairment.…”

Evaluating Cefiderocol in the Treatment of Multidrug-Resistant Gram-Negative Bacilli: A Review of the Emerging Data

“…The intrapulmonary pharmacokinetics of cefiderocol was assessed in healthy adult subjects after administration of a single 2000 mg dose infused over 1 h. 34 The mean epithelial lining fluid (ELF)-to-plasma ratio was of 0.101 and 0.239 based on total drug in plasma and on free drug in plasma, respectively, similar to other cephalosporins. 34 …”