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Antimicrobial Agents and Chemotherapy, June 2009, p. 2569-2578, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01119-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation
Cornelia B. Landersdorfer,1,
Martina Kinzig,1
Jürgen B. Bulitta,1,
Friedrich F. Hennig,2
Ulrike Holzgrabe,3
Fritz Sörgel,1,4* and
Johannes Gusinde2
IBMP—Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany,1 Department of Surgery, University of Erlangen, Erlangen, Germany,2 Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany,3 Department of Pharmacology, University of Duisburg-Essen, Essen, Germany4
Received 20 August 2008/ Returned for modification 17 December 2008/ Accepted 16 March 2009
Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for 
50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (90%) probabilities of target attainment (PTAs) for MICs of 
12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.
* Corresponding author. Mailing address: IBMP—Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, Nürnberg-Heroldsberg D-90562, Germany. Phone: 49-911-518290. Fax: 49-911-5182920. E-mail: ibmp{at}osn.de
Published ahead of print on 23 March 2009.
Present address: Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260.
Antimicrobial Agents and Chemotherapy, June 2009, p. 2569-2578, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01119-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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