Anti-Staphylococcal Effects of Telavancin and Vancomycin in In Vitro Simulations of the Antibiotic Pharmacokinetics

Abstract

Telavancin (TLV) is an investigational lipoglycopeptide with multiple mechanism of action. It exhibits rapid bactericidal activity against gram-positive bacteria, including methicillin-susceptible and -resistant, glycopeptide-intermediate and -resistant strains of Staphylococcus aureus. To predict the efficacies of TLV and vancomycin (VAN), the killing kinetics of two strains of S. aureus were exposed to in vitro simulated pharmacokinetics of once-daily TLV and twice-daily VAN given for five consecutive days. The simulated ratios of the 24-hour area under the curve (AUC24) to the MIC varied from 30-50 to 1700-3400 h. With both S. aureus ATCC 43300 and ATCC 700699 (Mu50), concentration-dependent reduction of the starting inoculum was observed at AUC24/MICs from 100 to 800 h, without further lowering the minimal numbers of surviving organisms at the larger AUC24/MICs (up to 1700 h with S. aureus ATCC 700699 and up to 3400 h with S. aureus ATCC 43300). At a given AUC24/MIC ratio, the cumulative anti-staphylococcal effects of TLV and VAN expressed by the area between the baseline and the time-kill curve (ABBC) were similar. However, TLV was more efficient against S. aureus ATCC 700699 than VAN at close to clinically attainable AUC24/MIC ratios (1700 h for TLV and 100 h for VAN). Neither TLV-, nor VAN-resistant mutants of S. aureus ATCC 700699 were enriched in the simulated treatments. Mutants of S. aureus ATCC 43300 resistant to 2× and 4×MIC of VAN were amplified at AUC24/MIC ratios of 60 and 120 h. There were no TLV-resistant mutants of S. aureus ATCC 43300 exposed to TLV. As ABBC exhibited more tight correlations with the AUC24/MIC than the conventional indices, it may be useful in the comparative pharmacodynamic studies with antibiotics.