Treatment of Methicillin-resistant Staphylococcus aureus experimental Osteomyelitis with bonetargeted Vancomycin

Introduction: Methicillin-resistant S. aureus (MRSA) is a common cause of bone and joint infection. BT2- peg2-vancomycin is an investigational bone-targeted formulation of vancomycin which we hypothesized would have increased antimicrobial activity compared to conventional vancomycin in a chronic experimental MRSA osteomyelitis model. Methods: We tested bone affinity using an hydroxyapatite (HA) binding assay, assessed the in vitro antimicrobial susceptibility of 30 MRSA isolates, and compared vancomycin and BT2-peg2- vancomycin in a rat experimental osteomyelitis model. Results: Vancomycin did not bind to hydroxyapatite (HA binding index = 0), whereas BT2-peg2- vancomycin showed appreciable binding (HA binding index = 57). The MIC₅₀ was 1 μg/ml and the MIC₉₀ was 2 μg/ml for both vancomycin and BT2-peg2-vancomycin. The MBC₉₀ was 16 and 4 μg/ml for vancomycin and BT2-peg2-vancomycin, respectively. Treatment with 50 mg/kg of vancomycin every 12 hours (median, 4.73 log₁₀ cfu/g), 63.85 mg/kg (equivalent to 50 mg/kg vancomycin) of BT2-peg2-vancomycin every 12 hours (median, 3.93 log₁₀ cfu/g) or 63.85 mg/kg of BT2-peg2-vancomycin once per week (median, 5.00 log₁₀ cfu/g) was more active than no treatment (median, 5.22 log₁₀ cfu/g) (P =0.0481). Treatment with 63.85 mg/kg of BT2-peg2-vancomycin every 12 hours was more active than all other treatment regimens evaluated (P≤0.0150), but was associated with high plasma BT2-peg2- vancomycin levels, decreased animal weight, increased kidney size, creatinine and BUN, and leukocytosis with tubulointerstitial nephritis. Conclusion: With optimization of pharmacokinetic parameters to prevent toxicity, BT2-peg2-vancomycin may be useful in the treatment of MRSA osteomyelitis.