Treatment of Methicillin-resistant Staphylococcus aureus experimental Osteomyelitis with bone-targeted 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.