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Antimicrobial Agents and Chemotherapy, December 2004, p. 4718-4724, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4718-4724.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

Thomas P. Lodise Jr.,1 Ben Lomaestro,2 Keith A. Rodvold,3 Larry H. Danziger,3 and George L. Drusano4*

Albany College of Pharmacy,1 Albany Medical Center,2 Ordway Research Institute, New York State Department of Health, Albany, New York,4 Colleges of Pharmacy and Medicine, University of Illinois at Chicago, Chicago, Illinois3

Received 17 June 2004/ Returned for modification 8 August 2004/ Accepted 8 September 2004

The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 µg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.

* Corresponding author. Mailing address: Ordway Research Institute, New York State Department of Health, 150 New Scotland Ave., Albany, NY 12208. Phone: (518) 262-6330. Fax: (518) 641-6304. E-mail: GDrusano{at}ordwayresearch.org.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4718-4724, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4718-4724.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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