Time-kill kinetics of oritavancin and comparator agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium.
OBJECTIVE
Oritavancin, a lipoglycopeptide, possesses bactericidal activity against Gram-positive bacteria including vancomycin-resistant Staphylococcus aureus and enterococci. To understand the time dependence of oritavancin activity, we have undertaken time-kill experiments against isolates of S. aureus, Enterococcus faecalis and Enterococcus faecium, including recent antibiotic-resistant strains.


METHODS
Six strains of S. aureus [methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA)] and five strains of enterococci [vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE; both VanA and VanB)] were tested in time-kill assays; oritavancin assays included 0.002% polysorbate-80 to ensure quantitative drug recovery. Oritavancin and comparators vancomycin, teicoplanin, linezolid and daptomycin were tested at static concentrations approximating their free peak (fC(max)) and free trough (fC(min)) in plasma when administered at standard doses for complicated skin and skin structure infections.


RESULTS
Oritavancin showed concentration-dependent killing of all strains tested: at its fC(max) predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (> or =3 log kill relative to starting inoculum) against MSSA, MRSA and VRSA within 1 h and against VSE between 11 and 24 h. At predicted fC(max) from an 800 mg dose, oritavancin was bactericidal against VISA strains at 24 h and against VRE at 10 h.


CONCLUSIONS
Oritavancin displayed concentration-dependent killing of MSSA, MRSA, VRSA, VISA, VSE and VRE. Oritavancin was more rapidly bactericidal against all strains tested than were vancomycin, teicoplanin, linezolid or daptomycin at physiologically relevant concentrations. These data support the conclusion that oritavancin exerts concentration-dependent bactericidal activity on recent, drug-resistant isolates of S. aureus and enterococci.
Targanta Therapeutics Inc., St Laurent, QC, Canada.
Geoffrey A
GA
McKay
Sylvain
S
Beaulieu
Francis F
FF
Arhin
Adam
A
Belley
Ingrid
I
Sarmiento
Thomas
T
Parr
Gregory
G
Moeck
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000302:isolation & purification; D016984:Enterococcus faecium / Q000187:drug effects* / Q000302:isolation & purification; D006020:Glycopeptides / Q000494:pharmacology*; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D006801:Humans; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013997:Time Factors; D014640:Vancomycin / Q000031:analogs & derivatives
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000077427:Lipoglycopeptides; C100708:oritavancin; D014640:Vancomycin