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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 f AUC0–24/MIC ≥ 8 for relebactam, and ≥40% f T > 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. [ABSTRACT FROM AUTHOR]

• Cefepime PK in 6 critically ill patients supported by ECMO is described • In normal or augmented renal function, 2g q8h (3h infusion) achieves ≥70% f T>MIC up to 16 µg/mL • None of the patients experienced cefepime associated neurotoxicity at this dosage • TDM may be useful to balance therapeutic exposure while preventing toxicity This study determined the pharmacokinetics of cefepime in patients requiring extracorporeal membrane oxygenation (ECMO) support to guide dosage selection. Cefepime population pharmacokinetics where characterized in Pmetrics for R for six critically ill patients receiving ECMO. Simulation was employed to determine the f T>MIC and total trough concentration of varying regimens in each patient to evaluate ability to achieve optimal pharmacodynamic exposure and thresholds for cefepime-associated neurotoxicity. Of the six participants, two required continuous veno-venous hemodiafiltration (CVVHDF) while four had a CrCL between 92-199 ml/min. All patients received 2 g q8h as a 3h infusion. A two-compartment model fitted the data best with median (range) parameter estimates as follows: clearance, 5.99 (4.10-10.29) L/h; volume of central compartment, 10.08 (2.45-15.14) L; and intercompartment transfer constants (k 12), 3.58 (2.01-4.99) h-1 and k 21 , 1.70 (1.00-2.88) h-1. The 2g q8h (3h infusion) regimen resulted in >70% f T>MIC in all patients up to an MIC of 16 µg/mL, whereas 2g q12h (0.5h) resulted in 5/6 patients achieving 70% ƒT>MIC at 8 µg/mL but only 1/6 at 16 µg/mL. Aggressive dosing regimens resulted in trough concentrations exceeding conservative neurotoxicity thresholds. No patient demonstrated signs or symptoms of neurotoxicity during treatment. For ECMO patients with normal to augmented renal clearance similar to those presented here, or those receiving CVVHDF, these data support dosing regimens of 2g q8h (3h infusions) to empirically target MICs up to 16 µg/mL. Larger studies are needed to determine how ECMO affects cefepime pharmacokinetics. [ABSTRACT FROM AUTHOR]