Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillin-tazobactam

A multiple-dose, open-labelled, randomized, two period crossover human volunteer study was performed (i) to describe the pharmacokinetic profile and safety profile of piperacillin and tazobactam (P/T) administered 6.0/0.75 g and 8.0/1.0 g q12h and (ii) to characterize the pharmacodynamic profile of these regimens against a variety of common targeted pathogens. Blood samples were collected after the third dose and concentrations of P/T were determined by a validated high-performance liquid chromatography assay. Pharmacokinetic profiles of P/T were determined by non-compartment analysis. Percentage time above the MIC (%T > MIC) of piperacillin was calculated for a range of MICs. In this study, no adverse events were attributed after multiple administrations of either 6.0/0.75 g or 8.0/1.0 g dose regimens. The peak concentration, half-life and area under the curve (AUC0-(0-tau)) of piperacillin were significantly different by a paired t-test (P < 0.05) between the two study regimens. The trough concentration, half-life and area under the curve (AUC0-(0-tau)) of tazobactam were substantially different from parameters reported previously for conventional regimens. The 8.0/1.0 g regimen provided 50% T > MIC for MICs < or =32 mg/L, while a similar value for the 6.0/0.75 g regimen was < or = 16 mg/L. High-dose P/T regimens with extended interval were well tolerated and provide adequate dynamic exposure for a variety of susceptible pathogens.