Evaluation of Telavancin Activity versus Daptomycin and Vancomycin against Daptomycin-Nonsusceptible Staphylococcus aureus in anIn VitroPharmacokinetic/Pharmacodynamic Model

Abstract

ABSTRACTDaptomycin-nonsusceptible (DNS)Staphylococcus aureusstrains have been reported over the last several years. Telavancin is a lipoglycopeptide with a dual mechanism of action, as it inhibits peptidoglycan polymerization/cross-linking and disrupts the membrane potential. Three clinical DNSS. aureusstrains, CB1814, R6212, and SA-684, were evaluated in anin vitropharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (starting inoculum, 108.5CFU/g) for 120 h. Simulated regimens included telavancin at 10 mg/kg every 24 h (q24h; peak, 87.5 mg/liter;t1/2, 7.5 h), daptomycin at 6 mg/kg q24h (peak, 95.7 mg/liter;t1/2, 8 h), and vancomycin at 1 g q12h (peak, 30 mg/liter;t1/2, 6 h). Differences in CFU/g between regimens at 24 through 120 h were evaluated by analysis of variance with a Tukey'spost hoctest. Bactericidal activity was defined as a ≥3-log10CFU/g decrease in colony count from the initial inoculum. MIC values were 1, 0.25, and 0.5 mg/liter (telavancin), 4, 2, and 2 mg/liter (daptomycin), and 2, 2, and 2 mg/liter (vancomycin) for CB1814, R6212, and SA-684, respectively. Telavancin displayed bactericidal activities against R6212 (32 to 120 h; −4.31 log10CFU/g), SA-684 (56 to 120 h; −3.06 log10CFU/g), and CB1814 (48 to 120 h; −4.9 log10CFU/g). Daptomycin displayed initial bactericidal activity followed by regrowth with all three strains. Vancomycin did not exhibit sustained bactericidal activity against any strain. At 120 h, telavancin was significantly better at reducing colony counts than vancomycin against all three tested strains and better than daptomycin against CB1814 (P< 0.05). Telavancin displayed bactericidal activityin vitroagainst DNSS. aureusisolates.