In vitro activity of oritavancin alone or in combination against vancomycin-susceptible and -resistant enterococci

Objectives: The optimal treatment for serious infections due to Enterococcus spp. is unknown although combination antimicrobial therapy is often recommended for invasive infections to achieve bactericidal activity and improve clinical outcomes. Oritavancin is a novel lipoglycopeptide agent with in vitro activity against enterococci, including vancomycin-resistant VanA-type Enterococcus faecium. Data on its activity in combination with other antibacterials are limited. The objective of this study was to evaluate the activity of oritavancin alone and in combination with ceftriaxone, daptomycin, gentamicin, linezolid and rifampicin against vancomycin-susceptible and -resistant enterococci in in vitro time-kill analyses. Methods: Five enterococcal strains were used for all experiments: three vancomycin-resistant VanA-type E. faecium clinical bloodstream isolates, vancomycin-resistant VanA-type E. faecium ATCC 700221 and vancomycin-susceptible Enterococcus faecalis ATCC 29212. Individual drugs were tested at 1/4, 1/2, 1, 2 and 4x MIC. Oritavancin combination experiments were performed with each agent at 1/4x MIC. Results: Daptomycin was the most active single agent and was bactericidal against all strains at 4x MIC, followed by oritavancin, which was bactericidal against all three clinical VRE strains at >= 2x MIC. In combination experiments at 1/4x MIC, oritavancin was synergistic with gentamicin against strains not displaying high-level aminoglycoside resistance. No other synergy against VRE strains was observed in any experiment. Strain-and drug-dependent antagonism was observed for many combinations. Conclusions: These in vitro data do not support the routine use of combination therapy with oritavancin in the treatment of infections due to VRE.