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Antimicrobial Agents and Chemotherapy, September 2007, p. 3290-3297, Vol. 51, No. 9
0066-4804/07/$08.00+0 doi:10.1128/AAC.01410-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Population Pharmacokinetics at Two Dose Levels and Pharmacodynamic Profiling of Flucloxacillin
Cornelia B. Landersdorfer,1,
Carl M. J. Kirkpatrick,2
Martina Kinzig-Schippers,1
Jürgen B. Bulitta,1,
Ulrike Holzgrabe,3
George L. Drusano,4 and
Fritz Sörgel1,5*
Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany,1 University of Queensland, Brisbane, Australia,2 Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany,3 Ordway Research Institute, Inc., Albany, New York 12208,4 Department of Pharmacology, University of Duisburg-Essen, Essen, Germany5
Received 11 November 2006/ Returned for modification 12 April 2007/ Accepted 8 June 2007
Flucloxacillin is often used for the treatment of serious infections due to sensitive staphylococci. The pharmacokinetic (PK)-pharmacodynamic (PD) breakpoint of flucloxacillin has not been determined by the use of population PK. Targets based on the duration of non-protein-bound concentrations above the MIC (fT>MIC) best correlate with clinical cure rates for beta-lactams. We compared the breakpoints for flucloxacillin between several dosage regimens. In a randomized, two-way crossover study, 10 healthy volunteers received 500 mg and 1,000 mg flucloxacillin as 5-min intravenous infusions. Drug concentrations were determined by high-pressure liquid chromatography. We used the programs WinNonlin for noncompartmental analysis and statistics and NONMEM for population PK and Monte Carlo simulation. We compared the probability of target attainment (PTA) for intermittent- and continuous-dosage regimens based on the targets of fT>MICs of 
50% and 30% of the dosing interval. The clearance and the volume of distribution were very similar after the administration of 500 mg and 1,000 mg flucloxacillin. We estimated renal and nonrenal clearances of 5.37 liters/h (coefficient of variation, 19%) and 2.73 liters/h (33%). For near maximal killing (target, fT>MIC of 50%) flucloxacillin showed a robust (90%) PTA up to MICs of 0.75 to 1 mg/liter (PTA of 86% at 1 mg/liter) for a continuous or a prolonged infusion of 6 g/day. Short-term infusions of 6 g/day had a lower breakpoint of 0.25 to 0.375 mg/liter. The flucloxacillin PK was linear for doses of 500 mg and 1,000 mg. Prolonged and continuous infusion at a 66% lower daily dose achieved the same PK-PD breakpoints as short-term infusions. Prolonged infusion and continuous infusion are appealing options for the treatment of serious infections caused by sensitive staphylococci.
* 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
Published ahead of print on 18 June 2007.
Present address: Department of Pharmaceutics, State University of New York at Buffalo, NY 14260.
Antimicrobial Agents and Chemotherapy, September 2007, p. 3290-3297, Vol. 51, No. 9
0066-4804/07/$08.00+0 doi:10.1128/AAC.01410-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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