Journal of Antimicrobial Chemotherapy (2001) 48, 259-267
© 2001 The British Society for Antimicrobial Chemotherapy
Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillin–tazobactam
a Department of Pharmacy Research, b Division of Infectious Diseases and c Office of Research, Hartford Hospital, Hartford, CT 06102, USA
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-
) 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-) 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 
32 mg/L, while a similar value for the 6.0/0.75 g regimen was 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.
* Correspondence address. Division of Infectious Diseases, 80 Seymour Street, Hartford, CT 06102, USA. Tel: +1-860-545-3941; Fax: +1-860-545-3992; E-mail: dnicola{at}harthosp.org
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