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Antibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates that are maintained in a nondividing state in vitro, whereas dalbavancin and the glycopeptide vancomycin do not., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Meticillin-resistant Staphylococcus aureus (MRSA) is routinely detected by amplification of the mecA gene. Recently, MRSA isolates harbouring a novel mec gene (mecC) that is not detected by mecA amplification have been reported. In this study, the activities of the lipoglycopeptide oritavancin as well as the comparators vancomycin, daptomycin and linezolid against 14 mecC MRSA isolates were studied by broth microdilution minimum inhibitory concentration (MIC) and time-kill assays at clinically relevant concentrations of each antibacterial agent. Oritavancin, vancomycin, daptomycin and linezolid MIC90 values (MIC required to inhibit 90% of the isolates) against the mecC isolates were 0.06, 1, 1 and 2mg/L, respectively. In time-kill assays, oritavancin at concentrations reflective of its free peak in plasma of patients receiving a single 1200 mg intravenous dose and the level 24h thereafter was bactericidal against all isolates tested, attaining 3 log kill relative to the starting inoculum between 5 min and 15 min. Vancomycin both at its free peak and free trough concentrations was also bactericidal against all isolates, attaining bactericidal activity between 6h and 24h. Daptomycin was bactericidal only at its free peak concentration, attaining bactericidal activity between 30 min and 4h against the tested isolates. Linezolid was bacteriostatic (<3 log kill relative to the starting inoculum) against the tested isolates. Oritavancin's in vitro activity against mecC MRSA isolates was indistinguishable from that against mecA MRSA isolates both in MIC and time-kill assays., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.

In this study, we assessed by broth microdilution the in vitro activity of oritavancin, a semisynthetic lipoglycopeptide currently under development, against selected meticillin-resistant Staphylococcus aureus (MRSA) bloodstream isolates (n=56) from Geneva University Hospital, Switzerland, displaying a wide range of vancomycin minimum inhibitory concentrations (MICs) (0.25-4 microg/mL). The MRSA resistance phenotype was confirmed by broth microdilution (oxacillin MIC > or = 4 microg/mL) for all isolates; 89% and 100% of the tested isolates were also resistant to erythromycin and ciprofloxacin, respectively. For 53 MRSA isolates for which vancomycin MICs were in the susceptible range (0.5-2.0 microg/mL), the oritavancin MICs ranged from 0.03 microg/mL to 0.5 microg/mL. For these 53 vancomycin-susceptible isolates, the cumulative distribution of oritavancin MICs was markedly different from those of vancomycin, teicoplanin, daptomycin and linezolid MICs, yielding an oritavancin MIC for 90% of the organisms (MIC(90)) (0.25 microg/mL) that was four times lower than the MIC(90) values (1 microg/mL) of comparators. For three MRSA isolates with a vancomycin-intermediate phenotype (vancomycin MIC=4 microg/mL), oritavancin MICs (0.5-1.0 microg/mL) were 2-4-fold lower than vancomycin, teicoplanin or daptomycin MICs, but were equivalent to linezolid MICs. Pairwise comparison for each bloodstream isolate showed that oritavancin was > or =4-fold more active than vancomycin, teicoplanin and daptomycin, against 86%, 75% and 59% of all MRSA isolates, respectively.

The ultrastructural effects of the lipoglycopeptide oritavancin on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) were examined by transmission electron microscopy. Oritavancin but not vancomycin induced aberrant septum formation and loss of staining of nascent septal cross walls in MRSA. Septal distortions were also observed in VRE exposed to oritavancin.