title: Treatment of Methicillin-resistant Staphylococcus aureus experimental Osteomyelitis with bone-targeted Vancomycin.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  With optimization of pharmacokinetic parameters to prevent toxicity, BT2-peg2-vancomycin may be useful in the treatment of MRSA osteomyelitis.
authors: Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 5905 USA.
authors: Melissa J
authors: MJ
authors: Karau
authors: Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 5905 USA.
authors: Suzannah M
authors: SM
authors: Schmidt-Malan
authors: Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 5905 USA.
authors: Kerryl E
authors: KE
authors: Greenwood-Quaintance
authors: Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN USA.
authors: Jayawant
authors: J
authors: Mandrekar
authors: Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY USA.
authors: Jian
authors: J
authors: Cai
authors: Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY USA ; Pradama Inc, Louisville, KY USA.
authors: William M
authors: WM
authors: Pierce
authors: Pradama Inc, Louisville, KY USA.
authors: Kevyn
authors: K
authors: Merten
authors: Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 5905 USA ; Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN USA.
authors: Robin
authors: R
authors: Patel
keywords: BT2-peg2-vancomycin; Experimental osteomyelitis; MRSA; Vancomycin