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Antimicrob Agents Chemother. Pharmacodynamics of a simulated single 1200 mg dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant Staphylococcus aureus infection
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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Pharmacodynamics of a simulated single 1200 mg dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant Staphylococcus aureus infection
Adam Belley 1↴, Francis F. Arhin 1, Ingrid Sarmiento 1, Hong Deng 2, Warren Rose 3 and Greg Moeck 1
Author Affiliations: <SUP>1</SUP>The Medicines Company. 7170 Frederick Banting, Second floor, St. Laurent, Quebec, Canada, H4S 2A1; <SUP>2</SUP>Laboratoires de la qualit? et conformit?, 6100 Royalmount, Montr?al, Quebec, Canada, H4P 2R2; <SUP>3</SUP>Pharmacy Practice Division, University of Wisconsin-Madison, School of Pharmacy. 777 Highland Avenue, Madison, WI 53705-2222
ABSTRACT
The safety and efficacy of a single 1200 mg dose of the lipoglycopeptide oritavancin is currently being investigated in two global Phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1200 mg dose of oritavancin to once-daily dosing with 6 mg/kg daptomycin and twice-daily dosing with 1000 mg vancomycin against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 hours. The area-under-the-bacterial-kill-curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 (AUBKC<SUB>0-24</SUB>), 48 (AUBKC<SUB>0-48</SUB>) and 72 hours (AUBKC<SUB>0-72</SUB>). The rapid bactericidal activity of oritavancin and daptomycin contributed to lower AUBKC<SUB>0-24</SUB> for the three MRSA strains compared to vancomycin (ANOVA, P < 0.05). Oritavancin exposure also resulted in lower AUBKC<SUB>0-48</SUB> and AUBKC<SUB>0-72</SUB> against one MRSA strain and lower AUBKC<SUB>0-48</SUB> for another strain when compared to vancomycin exposure (ANOVA, P<0.05). Furthermore, daptomycin exposure resulted in lower AUBKC<SUB>0-48</SUB> and AUBKC<SUB>0-72</SUB> for one of the MRSA isolates compared to vancomycin exposure (ANOVA, P<0.05). Lower AUBKC<SUB>0-24</SUB> for two of the MRSA strains (ANOVA, P<0.05) were obtained for oritavancin exposure compared to daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 hours. These results provide further justification to assess the single 1200 mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.
FOOTNOTES
Corresponding author: Adam Belley, PhD., The Medicines Company. 7170 Frederick Banting, St. Laurent, Quebec, Canada, H4S 2A1., Tel: 514-332-1008 x 1701, Fax: 514-332-6033, Email: adam.belley@themedco.com
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Author Affiliations: <SUP>1</SUP>The Medicines Company. 7170 Frederick Banting, Second floor, St. Laurent, Quebec, Canada, H4S 2A1; <SUP>2</SUP>Laboratoires de la qualit? et conformit?, 6100 Royalmount, Montr?al, Quebec, Canada, H4P 2R2; <SUP>3</SUP>Pharmacy Practice Division, University of Wisconsin-Madison, School of Pharmacy. 777 Highland Avenue, Madison, WI 53705-2222
ABSTRACT
The safety and efficacy of a single 1200 mg dose of the lipoglycopeptide oritavancin is currently being investigated in two global Phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1200 mg dose of oritavancin to once-daily dosing with 6 mg/kg daptomycin and twice-daily dosing with 1000 mg vancomycin against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 hours. The area-under-the-bacterial-kill-curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 (AUBKC<SUB>0-24</SUB>), 48 (AUBKC<SUB>0-48</SUB>) and 72 hours (AUBKC<SUB>0-72</SUB>). The rapid bactericidal activity of oritavancin and daptomycin contributed to lower AUBKC<SUB>0-24</SUB> for the three MRSA strains compared to vancomycin (ANOVA, P < 0.05). Oritavancin exposure also resulted in lower AUBKC<SUB>0-48</SUB> and AUBKC<SUB>0-72</SUB> against one MRSA strain and lower AUBKC<SUB>0-48</SUB> for another strain when compared to vancomycin exposure (ANOVA, P<0.05). Furthermore, daptomycin exposure resulted in lower AUBKC<SUB>0-48</SUB> and AUBKC<SUB>0-72</SUB> for one of the MRSA isolates compared to vancomycin exposure (ANOVA, P<0.05). Lower AUBKC<SUB>0-24</SUB> for two of the MRSA strains (ANOVA, P<0.05) were obtained for oritavancin exposure compared to daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 hours. These results provide further justification to assess the single 1200 mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.
FOOTNOTES
Corresponding author: Adam Belley, PhD., The Medicines Company. 7170 Frederick Banting, St. Laurent, Quebec, Canada, H4S 2A1., Tel: 514-332-1008 x 1701, Fax: 514-332-6033, Email: adam.belley@themedco.com
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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