Population Pharmacokinetics of Meropenem in Plasma and Subcutis from Patients on Extracorporeal Membrane Oxygenation Treatment

The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) treatment and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 h. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed using NONMEM. Time above clinical breakpoint MIC for Pseudomonas aeruginosa (8 mg/liter) was predicted for each patient. The following targets were evaluated: time for which the free (unbound) concentration is maintained above the MIC of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4×MIC. For all dosing regimens simulated in both plasma and SCT, 40% fT>MIC was attained. However, prolonged meropenem infusion would be needed for 100% fT>MIC and 100% fT>4×MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCLCr). Simulations showed that in patients with increased eCLCr, dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40% fT>MIC for standard meropenem dosing of 1 g intravenously every 8 h is likely to provide sufficient meropenem concentration to treat the problematic pathogen P. aeruginosa for patients receiving ECMO treatment. However, for patients with an increased eCLCr, or if more aggressive targets, like 100% fT>MIC or 100% fT>4×MIC, are adopted, incremental dosing or continuous infusion may be needed.