title: In vitro activity of the new multivalent glycopeptide-cephalosporin antibiotic TD-1792 against vancomycin-nonsusceptible Staphylococcus isolates.
abstract: 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 microg/ml), followed by quinupristin-dalfopristin and daptomycin (MIC(90) = 1 microg/ml) and then linezolid (MIC(90) = 2 microg/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.
authors.affiliation: Anti-Infective Research Laboratory, Department of Pharmacy Practice-4148, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Leuthner
authors.forename: Celine
authors.initials: C
authors.lastname: Vidaillac
authors.forename: Chrissy M
authors.initials: CM
authors.lastname: Cheung
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology*; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000494:pharmacology; D013210:Staphylococcus / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000187:drug effects*; D014769:Virginiamycin / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D017576:Daptomycin; D006020:Glycopeptides; D000069349:Linezolid; D023303:Oxazolidinones; D014640:Vancomycin; D014769:Virginiamycin; C539430:cefilavancin; C062940:quinupristin-dalfopristin