Population Pharmacokinetics Of Caspofungin And Polymyxin B Among Extracorporeal Membrane Oxygenation Patients

BackgroundExtracorporeal membrane oxygenation(ECMO)is a viable ultimate support therapy for patients with severe heart failure and/or respiratory failure.An increasing number of studies have shown that ECMO is associated with significant pharmacokinetic(PK)alterations,including an increased volume of distribution and reduced clearance.Optimal antibiotic therapy is required to improve ECMO patient outcomes.Suboptimal antibiotic dosing may likely lead to treatment failures and importantly,to the development of bacterial resistance.Antifungal prophylaxis in lung transplant recipients may reduce the incidence of fungal infections and the risk of death.In our center,we use caspofungin for universal antifungal prophylaxis in patients without a high risk of invasive fungal infections.Studies on whether the PK of caspofungin will change in patients receiving ECMO are very limited and controversial.Multi-drug-resistant bacterial infections in the intensive care unit(ICU)are complex and refractory,which will prolong the hospital stay and increase the mortality rate of patients.Polymyxin B has been identified as a a"last resort" for fighting multidrug-resistant(MDR)bacteria.However,there have been no studiesthat have investigated the effect of extracorporeal membrane oxygenation(ECMO)on the PK of polymyxin B,and only a limited amount of data is available with regards to PK studies and the optimization of the dose for administration in critically ill patients.Objects and Methods1.Among the patients after lung transplantation,we recruited ECMO patients,non-ECMO patients as a control group,and patients before and after ECMO weaning as self-controls.Eight serial blood samples were collected from each patient for PK analysis.The aim of this study was to describe population PK of caspofungin in patients with and without ECMO during the postoperative period of lung transplantation(LTx)and to investigate covariates influencing caspofungin PK.2.We recruited ECMO patients who received intravenous polymyxin B in the ICU,and recruited non-ECMO patients as a control group.Eight serial blood samples were collected from each patient in a steady state.The aim of this study was to describe population PK of polymyxin B in critically ill patients with and without ECMO and to investigate covariates influencing polymyxin BPK.Thearea under the concentration-time curve from time zero to 24 h(AUC0-24)/minimum inhibitory concentration(MIC)≥50was defined as the pharmacokinetics/pharmacodynamic target for polymyxin B.Monte Carlo simulations(n=1,000)were also performed to calculate probability of target attainment(PTA)values for different dosing regimens.Results1.Twelve ECMO and 7 non-ECMO lung transplant recipients were enrolled in this study.A total of 271 blood samples were collected for PK analysis.The PK of caspofungin was best described by a two-compartment model.In the final model,we found that there was a significant association between the male gender and increased distribution volume,that a higher sequential organ failure assessment score was related to an increase in intercompartmental clearance,and that a longer operative time was related to an increase in clearance and the volume of distribution.ECMO did not have a significant impact on the PK of caspofungin in patients after LTx.2.We recruited44 patients,including 8 patients undergoing extracorporeal membrane oxygenation;in total 342 plasma assays for polymyxin B were carried out.The PK of polymyxin B was best described by a two-compartment model.Of the covariates studied,only creatinine clearance(CLCR)had a significant impact on the clearance of polymyxin B.Based on Monte Carlo simulations,a higher CLCR and/or MIC value were associated with a lower PTA.The 50mg every 12h may represent the optimal regimen for all patients with a MIC≤0.25mg/L,and for patients had a CLCR≤120ml/L with a MIC=0.5mg/L.Conculsion1.According to the final model,ECMO did not have a significant impact on the PK of caspofungin in patients after LTx.Sex,SOFA score,and operative time are the most significant factors influencing the PK of caspofungin.2.Our modelindicate that ECMO did not have a significant impact on the PK of polymyxin B in critically ill patients.The dosage selection for polymyxin B should be based on CLCR and the lower PTA values were associated with higher CLCR and/or MIC values.