Background: The lack of new therapies to treat infections caused by vancomycin-resistant Enterococcus (VRE) has led to clinical use of daily high-dose daptomycin (hd DAP QD) regimens (≥ 10 mg/kg) to optimize outcomes. The long-acting lipoglycopeptide oritavancin (ORI) exhibits in vitro activity against VRE, although its safety and efficacy in treating clinical VRE infections have not been established. This study tested simulated human dosing regimens of a single 1200 mg dose of ORI (ORI SD) and hd DAP QD against clinical isolates of vancomycin-resistant Enterococcus faecium (VREfm) in an in vitro pharmacokinetic/pharmacodynamic model (IVPM) over 72h.
Methods: Inocula (106 CFU/ml) of VREfm (VanA) clinical isolates B7181440 (ORI MIC= 0.06 µg/ml; DAP MIC= 1 µg/ml) and B7231527 (ORI MIC= 0.5 µg/ml; DAP MIC= 4 µg/ml) were exposed to simulated free drug (d) plasma concentrations associated with ORI SD (3h infusion targeting a free peak [Cmax] of 20.7 µg/ml based on 85% plasma protein binding [PPB]; α, β and γ T½ of 2.3h, 13.4h, and 245h, respectively) or hd DAP QD (12 mg/kg; bolus dose targeting a Cmax of 15.6 µg/ml based on 91.5% PPB and T½ of 8h) over 72h in one-compartment IVPMs. ORI and DAP concentrations in the IVPM were determined by fluorescence polarization and bioassay, respectively. Results presented are from two independent experiments performed in duplicate. MICs were determined by broth microdilution following CLSI M7-A10 guidelines.
Results: d levels associated with hd DAP QD exhibited rapid bactericidal activity (≥3-log reduction in CFU/ml) within 3h against both VREfm isolates whereas ORI SD exerted bactericidal activity over 24h (Figure). Sustained bactericidal activity was observed with hd DAP QD over 24h; however, both VRE isolates exhibited subsequent regrowth at 48h coincident with 2- to 16-fold increases in DAP MICs. In contrast, no regrowth of either VREfm isolate occurred with the ORI SD as bacterial counts remained below the limit of detection (< 67 CFU/ml) between 24 to 72h.
Conclusion: The sustained bactericidal activity of ORI SD against VanA VREfm at simulated human exposures in the IVPM warrants further study of ORI as a treatment option for clinical VRE infections.
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F. Arhin, The Medicines Company: Employee , Salary
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