Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO).
Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure.
Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks.
Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%).
Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates.
Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).
*These authors contributed equally to this work and are co–first authors.
Supported by the Australian and New Zealand College of Anaesthetists (S12/001 and S13/021), Prince Charles Hospital Foundation, National Health and Medical Research Council (Centre of Research Excellence APP1079421 and Practitioner Fellowship APP1099452 to J.A.R.), Society of Hospital Pharmacists of Australia, Intensive Care Foundation, and an Advancing Queensland Clinical Fellowship (J.A.R.).
Author Contributions: Study conception: K.S., J.F.F., and J.A.R. Study design and methodology: K.S., F.B., H.B., E.G., B.J.L., S.M., R.P., V.P., S.R., S.C.W., S.A.W., J.F.F., and J.A.R. Data collection and management: M.H.A.-A., V.C., H.B., Y.-J.C., A.C., A.D., E.G., S.M.J., H.-S.K., S.Y.L., S.M., R.P., V.P., Y.-A.Q., C.R., S.R., S.A.W., and D.Z. Sample bioanalysis: M.H.A.-A., V.C. and S.C.W. Pharmacokinetic and data analysis: M.H.A.-A. and V.C. Data interpretation: K.S., M.H.A.-A., and J.A.R. Writing and original draft preparation: M.H.A.-A. Writing, review, and editing: all authors critically reviewed and revised the manuscript and approved the final manuscript.
Ethics approval: Ethical approval was provided by the lead site (The Prince Charles Hospital, Brisbane, Australia; HREC/11/QPCH/121) with individual institutional approvals obtained according to local protocols: Auckland City Hospital, Auckland, New Zealand (LRS/12/06/020/AM08); The Alfred Hospital, Melbourne, Australia (541/12); Bern University Hospital, Bern, Switzerland (2017–01315); Seoul National University Bundang Hospital, Seoul, Republic of Korea (B-1804/465–305); and St Vincent’s Hospital, Sydney, Australia (HREC/11/SVH/9).
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202207-1393OC on October 10, 2022