Bone penetration of amoxicillin and clavulanic acid evaluated by population pharmacokinetics and monte carlo simulation

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 Y50 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 (a?Y90 ) 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.