Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

Abstract Background: Piperacillin/tazobactam is commonly used for empirical or directed treatment of infections during extracorporeal membrane oxygenation therapy (ECMO). Critical illness and extracorporeal circulation, such as ECMO and continuous renal replacement therapy may alter the pharmacokinetic parameters. We aimed to develop a population pharmacokinetic model of piperacillin/tazobactam in ECMO patients and investigate the optimal dosage regimen to achieve a pharmacodynamics target.Methods: This was a prospective observational study of 26 ECMO patients who received piperacillin/tazobactam. A population PK model was developed using non-linear mixed-effects models and simulations were performed to evaluate patient variables, MIC levels, and dosage regimens in relation to the probability of target attainment (PTA). The acceptable piperacillin PTA was set at ≥90% for 50%ƒT >16 mg/L.Results: A total of 244 samples were collected (163 during ECMO and 81 weaned from ECMO). Thirteen patients (50%) underwent continuous venovenous hemodiafiltration (CVVHDF). In a 2-compartment model, clearance increased by 10.1% when patients weaned from ECMO. Because patients on CVVHDF had a significant residual renal function, CVVHDF was found non-relevant to clearance. Instead, volume overload which was main cause of CVVHDF and membrane adsorption might contribute to the increased volume of distribution. Creatinine clearance (CrCL) calculated by Cockcroft-Gault equation had a significant impact on clearance. Simulation demonstrated that extended infusion should be considered in ECMO patients with CrCL >60 mL/min. Our proposed regimen was extended infusion of 2/0.25 g q8h, 2/0.25 g 6h, 3/0.375 g q 6h, and 4/0.5g q6h for CrCL ≤40, 40–60, 60–130, and >130 mL/min, respectively. Furthermore, even a higher dose would be required when patients did not receive CVVHDF after weaning from ECMO, which was 4/0.5g q6h for CrCL >110 mL/minConclusions: Piperacillin/tazobactam PK changes observed in ECMO patients were associated with critical illness rather than ECMO itself. A recent guideline dose may result in underexposure against P.aeruginosa when ECMO patients have CrCL > 110 mL/min; therefore, close monitoring of renal clearance is crucial in ECMO patients who received piperacillin/tazobactam regardless of CVVHDF use to provide effective treatment of infections and promote recovery. Overall, this study provides preliminary insights into the incremental effects of critical illness, ECMO and CVVHDF on piperacillin/tazobactam PK.Trial Registration: Clinicaltrials.gov NCT02581280, December 1st, 2014.