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

Melissa J. Karau, Suzannah M. Schmidt-Malan, Kerryl E. Greenwood-Quaintance, Jayawant Mandrekar, Jian Cai, William M. Pierce, Kevyn Merten, Robin Patel

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalSpringerPlus
Volume2
Issue number1
DOIs
StatePublished - 2013

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Osteomyelitis
Vancomycin
Methicillin-Resistant Staphylococcus aureus
Durapatite
Bone and Bones
Interstitial Nephritis
Blood Urea Nitrogen
Leukocytosis

Keywords

  • BT2-peg2-vancomycin
  • Experimental osteomyelitis
  • MRSA
  • Vancomycin

ASJC Scopus subject areas

  • General

Cite this

Treatment of Methicillin-resistant Staphylococcus aureus experimental Osteomyelitis with bonetargeted Vancomycin. / Karau, Melissa J.; Schmidt-Malan, Suzannah M.; Greenwood-Quaintance, Kerryl E.; Mandrekar, Jayawant; Cai, Jian; Pierce, William M.; Merten, Kevyn; Patel, Robin.

In: SpringerPlus, Vol. 2, No. 1, 2013.

Research output: Contribution to journalArticle

Karau, Melissa J. ; Schmidt-Malan, Suzannah M. ; Greenwood-Quaintance, Kerryl E. ; Mandrekar, Jayawant ; Cai, Jian ; Pierce, William M. ; Merten, Kevyn ; Patel, Robin. / Treatment of Methicillin-resistant Staphylococcus aureus experimental Osteomyelitis with bonetargeted Vancomycin. In: SpringerPlus. 2013 ; Vol. 2, No. 1.
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AU - Mandrekar, Jayawant

AU - Cai, Jian

AU - Pierce, William M.

AU - Merten, Kevyn

AU - Patel, Robin

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N2 - 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.

AB - 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.

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