Cefiderocol pharmacokinetics in critically-ill patients receiving extra-corporeal membrane oxygenation (ECMO)

Objective: Critical illness and organ support such as extracorporeal membrane oxygenation (ECMO) may influence antimicrobial pharmacokinetics. This study investigated cefiderocol pharmacokinetics in critically-ill patients receiving ECMO to understand if standard dosing achieves optimal exposure. Methods: Cefiderocol was prescribed according to approved package insert recommendations based on creatinine clearance (CL). Blood sampling was performed at steady-state. Protein binding was determined by ultrafiltration. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. The fT > MIC for each patient was assessed at MICs of 4, 8, and 16 mg/L. Total AUC(24h) was calculated to evaluate comparative exposure to non-ECMO patients. Results: Five patients receiving 1.5 g q8h to 2 g q6h dosing regimens were enrolled. Three patients received venous-arterial and two veno-venous ECMO (mean flow rate of 3.9 [range: 2.7-4.9] L/min). A two-compartment model fitted the data best with mean +/- standard deviation estimates for CL, volume of the central compartment (V), K-12, and K-21 of 2.3 +/- 0.5 L/h, 4.8 +/- 2.3 L, 5.1 +/- 2.8 h(-1), and 3.9 +/- 3.3 h(-1), respectively. Mean protein binding was 41% (range: 31%-50%). Prescribed dosing regimens achieved 100% fT > MIC up to 16 mg/L for all patients, with a total steady-state AUC(24h) of 2501 (range: 1631-3276) mg/L<middle dot>h. Conclusions: These are the first data to describe cefiderocol pharmacokinetics in critically-ill patients undergoing ECMO. The currently labelled dosing recommendations based on creatinine CL in these patients were well tolerated and achieved 100% fT > MIC against susceptible bacteria and AUC exposures similar to values in non-ECMO patients.