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Antimicrobial Agents and Chemotherapy, July 2007, p. 2497-2507, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01477-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers{triangledown}

J. B. Bulitta,1,{dagger} S. B. Duffull,2 M. Kinzig-Schippers,1 U. Holzgrabe,3 U. Stephan,1,4 G. L. Drusano,5 and F. Sörgel1,4*

Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany,1 School of Pharmacy, University of Otago, Dunedin, New Zealand,2 Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany,3 Department of Pharmacology, University of Duisburg-Essen, Essen, Germany,4 Ordway Research Institute, Albany, New York5

Received 23 November 2006/ Returned for modification 11 February 2007/ Accepted 27 April 2007

Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ± 7.8 kg) and 26 healthy volunteers (WT, 71.1 ± 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (≥90%) probability-of-target attainment (PTA) for MICs of ≤12 mg/liter in CF patients and ≤16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of ≤16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.

* Corresponding author. Mailing address: Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, D-90562 Nürnberg-Heroldsberg, Germany. Phone: 49-911-518290. Fax: 49-911-5182920. E-mail: ibmp{at}osn.de

{triangledown} Published ahead of print on 7 May 2007.

{dagger} Present address: Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260.

Antimicrobial Agents and Chemotherapy, July 2007, p. 2497-2507, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01477-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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