title: Bone penetration of amoxicillin and clavulanic acid evaluated by population pharmacokinetics and Monte Carlo simulation.
abstract: 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 > or = 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 (> or = 90%) probabilities of target attainment (PTAs) for MICs of < or = 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.
authors.affiliation: Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, Nürnberg-Heroldsberg D-90562, Germany.
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: Martina
authors.initials: M
authors.lastname: Kinzig
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.forename: Friedrich F
authors.initials: FF
authors.lastname: Hennig
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
authors.forename: Johannes
authors.initials: J
authors.lastname: Gusinde
mesh_terms: D000328:Adult; D000368:Aged; D000658:Amoxicillin / Q000493:pharmacokinetics* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001842:Bone and Bones / Q000378:metabolism*; D019818:Clavulanic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D010019:Osteomyelitis / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D019818:Clavulanic Acid; D000658:Amoxicillin