Pharmacokinetics And Pharmacodynamics Of Iperacillin/tazobactam Administered By Prolonged Infusion Or Optimized Two-step Infusion In Aged Critically Ill Patients

Objective：The objective of this study were（ⅰ） to compare the plasma concentration–timeprofiles and to evaluate the pharmacokinetics and pharmacodynamics of piperacillin/tazobactam（as the PIP4.0g）, administered by prolonged infusion （4g/3h）or optimizedtwo-step infusion （2g/0.5h＋2g/2.5h）in hospitalised aged critically ill patients requiringantimicrobial therapy and（ⅱ）to use population pharmacokinetics to perform Monte Carlodosing simulations in order to calculate%fT>MIC, Cmax/MIC and the probability oftarget attainment (PTA) at different MICs, assess the two infusion methods and the besttherpay method was chosen.Methods：20aged patients who were hospitalised in a24-bed facilities Critical Care Unit wereeligible for the study. All patients required antimicrobial therapy for a suspected ordocumented bacterial infection, they were randomised to receive the same doses ofpiperacillin/tazobactam(as the PIP4.0g/q8h) by prolonged infusion （4g/3h）or optimizedtwo-step infusion（2g/0.5h＋2g/2.5h）.2ml blood samples were collected at the time of0h,0.25h,0.5h,1h,2h,3h,4h,5h,6h,8h, respectively, then centrifugated10minutes with3000rpm and extracted from the supernatant and stored at–80℃refrigerator. Plasmapiperacillin and tazobactam concentrations were measured using ultra performance liquidchromatography tandem mass spectrometry (UPLC-MS). Pharmacokinetic parameters ofpiperacillin, such as plasma clearance (CL), the apparent volume of distribution (Vd), theelimination half-life (t1/2), peak concentration (Cmax), time to peak (Tmax), the area underthe curve (AUC0-8) and other pharmacokinetic parameters, were determined by noncompartmental model of Winnonlin5.2. In addition, using populationpharmacokinetics gained above, Monte Carlo simulations (10000patients) wereperformed to calculate Cmax/MIC,%T>MIC and the the probability of target attainment(PTA) at different MICs, then to compare the effect of two infusion models. Thepharmacodynamic target was piperacillin concentration remaining above the MIC for50%of the dosing interval.Results：The two groups patients were aged aged critically ill patients, the sex ratio, age,weight, and creatinine values and APACHE Ⅱscores between the two groups had nosignificant difference(P＞0.05), the albumin and plasma protein between the two groups hadsignificant difference(P＜0.05). In the prolonged infusion group and the optimizedtwo-step group,the mean serum concentrations（mg/L） of piperacillin patients at the timeof0h,0.25h,0.5h,1h,2h,3h,4h,5h,6h,8h were22.16,37.39,55.65,76.1,105.21,91.37,61.72,41.74,29.14,18.80and25.07,84.36,124.76,95.13,89.15,80.13,53.36,39.23,30.03,16.36, respectively；In prolonged infusion therapy group, mean±standarddeviation maximum serum concentrations, half-life,volume of distribution and clearance ofpiperacillin were105.21±17.77mg/L,2.21±0.60h,2h,25.45±6.62L,8.3±2.04L/h; and inoptimized two-step infusion therapy model, those of piperacillin were124.76±24.17mg/L,2.35±0.49h,0.5h,26.85±9.25L,7.81±1.32L/h, respectively.In Monte Carlo simulation, Cmax/MIC of the prolonged group were4.52±0.93and2.26±0.43,%fT>MICwere91.24%±20.67and56.39%±12.73, PTAs were99.86%and67.19%; In group Cmax/MIC were3.32±1.04and1.66±0.52,%fT>MICwere92.92%±17.54and60.07%±8.95, PTAs were92.92%±17.54and60.07%±8.95, respectively, at MICswere16ug/ml and32μg/ml.Conclusions：It was considered that it was possible to obtain sufficient%fT＞MICand Cmax, andshort Tmaxby OTIT in comparison with PIT in the two dosing models against eachtarget MIC.These results suggested that OTIT with sufficient pharmacokinetic conditions couldbe useful for enhancing the therapeutic efficacy of piperacillin/tazobactam.