In Vitro Activity of the New Multivalent Glycopeptide-Cephalosporin Antibiotic TD-1792 against Vancomycin-Nonsusceptible Staphylococcus Isolates

TD-1792 is a glycopeptide-cephalosporin heterodimer antibiotic with activity against a broad spectrum of Gram-positive pathogens that includes methicillin-susceptible and -resistant Staphylococcus aureus. The objective of the present study was to evaluate the in vitro activity of TD-1792 against a collection of clinical isolates of vancomycin-intermediate Staphylococcus spp. (VISS), heteroresistant VISS (hVISS), and vancomycin-resistant S. aureus (VRSA). The TD-1792, vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin MICs and minimum bactericidal concentrations (MBCs) were determined for 50 VISS/hVISS isolates and 3 VRSA isolates. Time-kill experiments (TKs) were then performed over 24 h with two vancomycin-intermediate S. aureus strains and two VRSA strains, using each agent at multiples of the MIC. TD-1792 and daptomycin were also evaluated in the presence and absence of 50% human serum to determine the effects of the proteins on their activities. Most of the VISS/hVISS isolates were susceptible to all agents except vancomycin. TD-1792 exhibited the lowest MIC values (MIC(90) = 0.125 mu g/ml), followed by quinupristin-dalfopristin and daptomycin (MIC(90) = 1 mu g/ml) and then linezolid (MIC(90) = 2 mu g/ml). The presence of serum resulted in a 2- to 8-fold increase in the TD-1792 and daptomycin MIC values. In TKs, QD demonstrated bactericidal activity at multiples of the MIC that simulated therapeutic levels, whereas linezolid was only bacteriostatic. Both TD-1792 and daptomycin demonstrated rapid bactericidal activities against all isolates tested. The presence of proteins had only a minimal impact on the activity of TD-1792 in TKs. TD-1792 exhibited significant in vitro activity against multidrug-resistant Staphylococcus isolates and represents a promising candidate for the treatment of infections caused by Gram-positive organisms.