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

Abstract

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), K₁₂, and K₂₁ 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·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.