Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation

Abstract

Background: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. Methods: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC≥8 for relebactam, and ≥40% fT>MIC for imipenem for each approved dosing regimen. Results: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean±standard deviation parameters were: CL0, 15.21±6.52 L/h; Vc, 10.13±2.26 L; K12, 2.45±1.16 h-1 and K21, 1.76±0.49 h-1 for imipenem, and 6.95±1.34 L/h, 9.81±2.69 L, 2.43±1.13 h-1 and 1.52±0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. Conclusions: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.