Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus [PublishAheadOfPrint]

The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four S. aureus strains were included. The telavancin MIC ranged from 0.06 — 0.25 mg/L and vancomycin MIC from 1 — 4 mg/L. Plasma pharmacokinetics of escalating doses (1.25, 5, 20 and 80 mg/kg) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed penetration into the ELF mirrored the percent free fraction (not protein bound) in plasma for each drug. Telavancin (0.3125 — 80 mg/kg/6h) and vancomycin (0.3125 — 1280 mg/kg/6h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity was observed in both models against all four strains. A sigmoid Emax model was used to determine the AUC/MIC exposure associated with net stasis and 1 log₁₀ kill relative to the burden at the start of therapy. The 24 h plasma free drug AUC/MIC associated with stasis and 1 log kill were remarkably congruent. Net stasis for telavancin was noted at free drug AUC/MIC (fAUC/MIC) of 83 and 40.4 in the thigh and lung, respectively; and 1 log kill at 215 and 76.4, respectively. For vancomycin, the stasis fAUC/MIC was 77.9 and 45.3, respectively, and 1 log kill 282 and 113, respectively. Twenty-four h ELF total drug AUC/MIC targets in the lung model were very similar to 24 h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus.

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