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Updated: Jun 30, 2025
Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses
Published on: August 30, 2018
Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation
Andrew J Fratoni1, Abigail K Kois1, Jason A Gluck2
1Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
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.
Insights
This study found that imipenem/cilastatin/relebactam, when dosed according to standard guidelines, achieves adequate drug concentrations in critically ill patients on extracorporeal membrane oxygenation (ECMO). This suggests effective treatment for Gram-negative infections in this patient population.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Critical Care Medicine
- Infectious Diseases
Background:
- Extracorporeal membrane oxygenation (ECMO) can alter drug pharmacokinetics, impacting antimicrobial efficacy.
- Imipenem/cilastatin/relebactam is crucial for treating multi-drug resistant Gram-negative infections.
Purpose of the Study:
- To determine the population pharmacokinetics of imipenem and relebactam in critically ill patients receiving ECMO.
- To assess the probability of target attainment (PTA) for imipenem/cilastatin/relebactam in this population.
Main Methods:
- Population pharmacokinetic modeling was used to analyze drug concentrations from seven ECMO patients.
- Creatinine clearance was identified as a covariate influencing drug clearance.
- Monte Carlo simulations evaluated the PTA for imipenem and relebactam at various minimum inhibitory concentrations (MICs).
Main Results:
- A two-compartment model best described the pharmacokinetics of both imipenem and relebactam.
- Key pharmacokinetic parameters (CL0, Vc, K12, K21) were estimated for both drugs.
- Simulations predicted a PTA of ≥90% for susceptible isolates (MIC ≤ 2 mg/L) with standard dosing.
Conclusions:
- Standard dosing of imipenem/cilastatin/relebactam is predicted to provide sufficient drug exposure in ECMO patients.
- This regimen is likely effective against susceptible Gram-negative bacteria, including Pseudomonas aeruginosa.
