Ceftriaxone bone penetration in patients with septic non-union of the tibia

Abstract

Objectives: A main determinant of clinical response to antibiotic treatment is drug concentration at the infected site. Data on ceftriaxone (CFX) bone penetration are lacking. We measured CFX concentrations in infected bone to verify their relationship with pharmacodynamic microbiological markers.

Methods: Eleven patients undergoing debridement for septic non-union of the tibia and receiving intravenous CFX were studied. Plasma and bone specimens were collected intraoperatively at a variable interval after CFX administration. Drug concentrations were measured by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method.

Results: Bone samples were extracted at a mean of 3.3 h (range 1.5-8.0 h) since the start of CFX infusion. The mean±standard deviation intraoperative CFX plasma concentration was 128.4±30.8 mg/l; the corresponding bone concentrations were 9.6±3.4 mg/l (7.8%) in the cortical compartment and 30.8±8.6 mg/l (24.3%) in the cancellous compartment. The mean 24-h area under the concentration-time curve (AUC(24)) values were 176.8±62.2 h*mg/l in cortical bone and 461.5±106.8 h*mg/l in cancellous bone. The time above the minimum inhibitory concentration (T>MIC) was 24 h in all compartments. The estimated mean free AUC/MIC ratios and T>MIC were 140 and 24.4 h, respectively, in cancellous bone and 42.4 and 21 h, respectively, in cortical bone.

Conclusions: CFX bone penetration was poor (<15%) in the cortical compartment and satisfactory in the more vascularized cancellous bone. The T>MIC and AUC/MIC ratios suggest that CFX achieves a satisfactory pharmacokinetic exposure in cancellous bone as far as pathogens with a MIC of <0.5 are concerned. However, considering free drug concentrations, pharmacokinetic/pharmacodynamic targets may not be fully achieved in cortical bone. As antibiotic exposure can be suboptimal in the infected cortical compartment, and drug penetration may be impaired into necrotic bone and sequesters, a radical surgical removal of purulent and necrotic tissues appears essential to shorten treatment duration and to prevent treatment failures.