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

• Published in: Journal of antimicrobial chemotherapy 2024-05, Vol.79 (5), p.1118-1125
• Main Authors: Fratoni, Andrew J, Kois, Abigail K, Gluck, Jason A, Nicolau, David P, Kuti, Joseph L
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Azabicyclo Compounds - administration & dosage; Azabicyclo Compounds - pharmacokinetics; Azabicyclo Compounds - therapeutic use; Cilastatin, Imipenem Drug Combination - pharmacokinetics; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Imipenem - administration & dosage; Imipenem - pharmacokinetics; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Tandem Mass Spectrometry
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkae079

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. 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. 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. 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.