title: Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillin-tazobactam.
abstract: 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.
authors.affiliation: Department of Pharmacy Research, Division of Infectious Diseases and Office of Research, Hartford Hospital, Hartford, CT 06102, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Kim
authors.forename: D
authors.initials: D
authors.lastname: Xuan
authors.forename: R
authors.initials: R
authors.lastname: Quintiliani
authors.forename: C H
authors.initials: CH
authors.lastname: Nightingale
authors.forename: D P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D010878:Piperacillin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077725:Piperacillin, Tazobactam Drug Combination
chemical_list: D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin