Comparative in vitro activity of oritavancin against Staphylococcus aureus strains that are resistant, intermediate or heteroresistant to vancomycin

Sir, Widespread use of vancomycin has led to the emergence of isolates that show reduced susceptibility to vancomycin; vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-resistant S. aureus (VRSA) and heteroresistant VISA (hVISA) have been described.1 The emergence of such strains with concomitant vancomycin therapeutic failures2 has necessitated the development of other therapeutic agents. Newer drugs of the glycopeptide class, such as oritavancin, with activity against isolates with reduced susceptibility to vancomycin are currently in development. Additional mechanisms exhibited by oritavancin help explain its rapid, concentration-dependent bactericidal activity in vitro3 and distinguish it from vancomycin. In surveillance studies, oritavancin activity was demonstrated against vancomycin-susceptible S. aureus isolates that are susceptible and resistant to methicillin.4 This study examined the in vitro activity of oritavancin against clinical isolates of VRSA, VISA and hVISA using recently updated broth microdilution methodology.5 MICs and MBCs of oritavancin were determined for these groups of organisms and compared with those of seven clinically used antimicrobial agents. MICs of antimicrobial agents were determined by broth microdilution according to CLSI (formerly NCCLS) guidelines.5 Polysorbate-80 was included when testing oritavancin, so as to limit losses of oritavancin to the surfaces of test vessels as recommended in CLSI guidelines.5 MBCs were also determined according to CLSI guidelines.6 Aliquots (50 µL) were plated onto brain heart infusion agar (BHIA) plates for the VISA and hVISA isolates, or BHIA plates containing 4 mg/L vancomycin for the VRSA isolates to maintain selection for vancomycin, and incubated at 35°C for 24 h. The MBC was defined as the lowest concentration killing >99.9% of the original inoculum.6 Oritavancin showed good in vitro activity against the hVISA isolates (MIC range of 0.12–2 mg/L and MIC90 of 1 mg/L; Table 1). The oritavancin MIC90 was identical to those of linezolid and quinupristin/dalfopristin, and one doubling dilution higher than that of tigecycline. The oritavancin MIC90 was 2- to 8-fold lower than those of the rest of the comparators. The oritavancin MBC range and MBC90 against hVISAs were 0.25–2 and 1 mg/L, respectively. The oritavancin MBC90 against the hVISA isolates was identical to that of tigecycline and 2- to 64-fold lower than those of the rest of the comparators. The oritavancin MBC90/MIC90 ratio of 1 indicates that oritavancin is bactericidal against hVISA. The oritavancin MBC90/MIC90 ratio was identical to that of daptomycin and 2- to 16-fold lower than those of the rest of the comparators. Comparative in vitro activity of oritavancin against hVISA, VISA and VRSA isolates NA, not applicable; ORI, oritavancin; VAN, vancomycin; MIN, minocycline; DAP, daptomycin; TEC, teicoplanin; LZD, linezolid; Q/D, quinupristin/dalfopristin; TGC, tigecycline. Comparative in vitro activity of oritavancin against hVISA, VISA and VRSA isolates NA, not applicable; ORI, oritavancin; VAN, vancomycin; MIN, minocycline; DAP, daptomycin; TEC, teicoplanin; LZD, linezolid; Q/D, quinupristin/dalfopristin; TGC, tigecycline. Oritavancin showed good in vitro activity against the VISA isolates (MIC range of 0.5–4 mg/L and MIC90 of 2 mg/L; Table 1). The MIC90 was identical to that of quinupristin/dalfopristin and was two doubling dilutions higher than that of tigecycline. The oritavancin MIC90 was 2- to 8-fold lower than those of the rest of the comparators. The oritavancin MBC range and MBC90 against VISAs were 0.5–8 and 4 mg/L, respectively. The oritavancin MBC90 for the VISA isolates was 4-fold higher than that of tigecycline and 2- to 8-fold lower than those of the rest of the comparators. The oritavancin MBC90/MIC90 ratio of 2 indicates that oritavancin is bactericidal against VISA. The oritavancin MBC90/MIC90 ratio was identical to, or within a dilution of, those of the comparators. Oritavancin showed good in vitro activity against the VRSA isolates (MIC range of 0.12–1 mg/L and MIC90 of 0.5 mg/L; Table 1). The MIC90 was identical to that of daptomycin and was a doubling dilution higher than that of tigecycline. The oritavancin MIC90 was 2- to >1024-fold lower than those of the rest of the comparators. The oritavancin MBC range and MBC90 against VRSAs were 0.25–1 and 1 mg/L, respectively. The oritavancin MBC90 for the VRSA isolates was 2- to >512-fold lower than those of the comparators. The oritavancin MBC90/MIC90 ratio of 2 indicates that oritavancin is bactericidal against VRSA. The oritavancin MBC90/MIC90 ratio was at least 2-fold lower than those of the comparators. Against the 35 isolates of S. aureus tested in this study, the oritavancin MIC range and MIC90 were 0.12–4 and 1 mg/L, respectively (Table 1). The oritavancin MIC90 was identical to that of quinupristin/dalfopristin and was a doubling dilution higher than that of tigecycline. The oritavancin MIC90 was ≥2-fold lower than those of the rest of the comparators. The oritavancin MBC range and MBC90 were 0.25–8 and 4 mg/L, respectively. The oritavancin MBC90 against the 35 isolates was 2-fold higher than that of tigecycline. Oritavancin MBC90 was at least 2-fold lower than those of the other comparators (Table 1). The in vitro data in this study suggest that oritavancin could be an attractive candidate in the treatment of infections caused by S. aureus strains that have challenges with vancomycin therapy. These studies were generated as part of the routine work of Targanta Therapeutics Inc. (now a fully owned subsidiary of The Medicines Company) and have received no external funding. All authors were full-time employees of Targanta Therapeutics Inc., Ville Saint Laurent, Canada at the time this work was performed and had no significant declarations to make with respect to external funding, ownership of company stocks or shares and reimbursement for preparing this article. Targanta Therapeutics is now a fully owned subsidiary of The Medicines Company. Parts of this work were presented at the Seventeenth European Congress of Clinical Microbiology and Infectious Diseases, Barcelona, Spain, 2008 (Poster P 584).