The β-lactamase inhibitor concentration-dependent minimum inhibitory concentration (MICcBLI) as methodology to assess the pharmacokinetic/pharmacodynamic relationship of piperacillin/tazobactam for dosing optimization

Abstract Background and objectives The MIC, determined in vitro using a fixed tazobactam concentration, is used as basis for the pharmacokinetic/pharmacodynamic (PK/PD) index of piperacillin/tazobactam. The β-lactamase inhibitor (BLI) concentration-dependent MIC (MICcBLI) represents a promising alternative PD metric accounting for varying tazobactam concentrations observed in vivo. The aim was to investigate how the effect of varying in vivo tazobactam concentrations can be incorporated through the in vitro MICcBLI as a PD metric to assess the probability of three piperacillin/tazobactam dosing regimens to achieve predefined target values. Methods The MICcBLI for six isolates was evaluated as function of tazobactam concentrations. Two nonlinear mixed-effects PK models for piperacillin and tazobactam were developed based on data from 44 critically ill patients. Probability of target attainment (PTA) analysis was performed, and PTA values for the PK/PD targets 100% fT > MIC and 100% fT > MICcBLI were assessed. Results The susceptibility against piperacillin was dependent on the tazobactam concentration for all isolates. A two-compartment PK model with inter-occasion variability on clearance (CL) and inter-individual variability on CL and both volumes, with creatinine clearance as a covariate on CL, described the PK of piperacillin and tazobactam best. The PTA analysis revealed differences between the isolates, three infusion types and the two metrics. Conclusions By adopting this framework, dosing optimization can be approached to provide support for the rational design of piperacillin/tazobactam dosing regimens and other β-lactam/β-lactamase combinations. The shift from the conventional MIC to a β-lactamase inhibitor concentration-dependent metric clearly improved the knowledge of the susceptibility of a pathogen against piperacillin/tazobactam.