Comparative<i>in vitro</i>activity of oritavancin and other agents against vancomycin-susceptible and -resistant enterococci

Sir, Antibiotic research has focused on discovering agents with activity against MDR pathogens (e.g. ESKAPE pathogens1), including VRE, which along with Staphylococcusaureus are commonly isolated from healthcare-associated infections.2 Several new agents have been approved for the treatment of skin and skin structure infections caused by MRSA and enterococci, including oxazolidinones (linezolid and tedizolid), lipoglycopeptides (oritavancin, dalbavancin and telavancin), a cyclic lipopeptide (daptomycin), a glycylcycline (tigecycline) and an anti-MRSA cephalosporin (ceftaroline). Lipoglycopeptides, though active against vancomycin-susceptible enterococci (VSE), have variable activity against VRE, with oritavancin being the sole agent maintaining potent activity against VanA-type VRE.3 We report here a direct comparison of the in vitro activity of lipoglycopeptides and other skin agents against vancomycin-susceptible and -resistant Enterococcusfaecalis (VSEfa and VREfa) and Enterococcusfaecium (VSEfm and VREfm). Comparative evaluations included MIC and MBC determinations and time–kill kinetics. Since variation in inoculum density has been shown to impact the activity of several of these agents against S. aureus,4,5 time–kill kinetics were assessed at both standard and high inoculum densities. The evaluated isolates consisted of 74 random non-duplicate clinical isolates of VSEfa, VREfa, VSEfm and VREfm from the Micromyx repository (Kalamazoo, MI, USA) and The Medicines Company (Ville Saint Laurent, Quebec, Canada). VanA-phenotype (vancomycin and teicoplanin resistant) and VanB-phenotype (vancomycin resistant and teicoplanin susceptible) VRE were selected based on prior glycopeptide susceptibility test history. Agents were handled per CLSI (formerly NCCLS) guidelines and had results within CLSI quality control ranges during testing.6 Evaluations of lipoglycopeptides incorporated polysorbate 80 at a final concentration of 0.002% (v/v). MIC and MBC values were determined in accordance with standard CLSI methods.6–8 The time–kill kinetics of select isolates (one per phenotype evaluated) at standard inoculum (∼5 × 105 cfu/mL) and high inoculum (∼5 × 107 cfu/mL) were determined as described by Arhin et al.9 using a method derived from the CLSI8 for agents at their fCmax (calculated from the respective prescribing information as 16 mg/L for oritavancin, dalbavancin, linezolid, vancomycin and ceftaroline, 8 mg/L for telavancin, 4 mg/L for daptomycin and 1 mg/L for tedizolid). The activity of the tested agents against enterococci is summarized by species and phenotype in Table 1. Among E. faecalis, VSEfa were susceptible to all agents with the lipoglycopeptides having the most potent activity by MIC90. Ceftaroline and oritavancin were the only consistently bactericidal agents against VSEfa based on the proportion of isolates with MBC:MIC ratios of ≤4. Based on MIC90, oritavancin, daptomycin, linezolid, tedizolid and ceftaroline maintained potent activity against VanA VREfa. Ceftaroline maintained bactericidal activity against VanA VREfa, while the other agents typically had MBC:MIC ratios >4. Summary of the in vitro activity of evaluated agents against enterococci by species and vancomycin phenotype (n = 74) MBC:MIC ratio only reported for isolates where defined MBC and MIC values allowed for determination of whether the MBC:MIC ratio was either ≤4 or >4. Time to 3 log kill in hours for standard/high inoculum density (n = 1 isolate/phenotype); a dash indicates that a 3 log kill was not observed during the course of the experiment (24 h). For the evaluated VSEfm isolate at standard inoculum density, time to 2.9 log kill was reported (based on the starting inoculum of 4.9 log cfu/mL and a lower limit of detection of 2 log cfu/mL for the assay). Summary of the in vitro activity of evaluated agents against enterococci by species and vancomycin phenotype (n = 74) MBC:MIC ratio only reported for isolates where defined MBC and MIC values allowed for determination of whether the MBC:MIC ratio was either ≤4 or >4. Time to 3 log kill in hours for standard/high inoculum density (n = 1 isolate/phenotype); a dash indicates that a 3 log kill was not observed during the course of the experiment (24 h). For the evaluated VSEfm isolate at standard inoculum density, time to 2.9 log kill was reported (based on the starting inoculum of 4.9 log cfu/mL and a lower limit of detection of 2 log cfu/mL for the assay). Against VSEfm and VREfm (VanA and VanB phenotypes), oritavancin was the most potent agent evaluated based on MIC90. All agents, excluding ceftaroline, which was largely inactive against E. faecium, had potent activity against VSEfm by MIC90. Oritavancin, daptomycin, linezolid and tedizolid maintained potent activity against VREfm. Oritavancin was ≥16-fold more potent by MIC90 than the comparator lipoglycopeptides against VREfm. Against VSEfm, oritavancin and daptomycin were the only consistently bactericidal agents based on the proportion of isolates with MBC:MIC ratios of ≤4. Daptomycin maintained bactericidal activity by MBC:MIC ratio against VanA and VanB VREfm. Consistent trends in bactericidal activity were apparent for each agent by time–kill at fCmax across the evaluated E. faecalis (one isolate each of VSEfa and VanA VREfa) and E. faecium (one isolate each of VSEfm, VanA VREfm and VanB VREfm) isolates. At the standard inoculum density, oritavancin and daptomycin were rapidly bactericidal with 3 log killing typically achieved within 0.25 and 4 h, respectively, with singular exceptions (4 h for oritavancin and 1 h for daptomycin against the VanA VREfa isolate). Telavancin was typically bactericidal, with 3 log killing observed at 24 h at the standard inoculum density with the exception of the VanB VREfm isolate, as was ceftaroline for E. faecalis but not E. faecium. Vancomycin, dalbavancin, tedizolid and linezolid did not achieve 3 log killing at the standard inoculum density for any of the evaluated E. faecalis or E. faecium isolates. Only oritavancin maintained bactericidal activity at the high inoculum density, with similar kill kinetics to those observed at the standard inoculum density. Few available agents exist for treating VRE infections despite their prevalence and associated mortality and morbidity.10 Among agents with activity against enterococci, oritavancin, daptomycin, linezolid and tedizolid maintained potent activity against VanA/VanB VRE isolates. Both daptomycin and oritavancin exhibited rapid bactericidal activity at fCmax against VSE and VRE at standard inoculum densities, but only oritavancin maintained rapid bactericidal activity at high inoculum densities. Maintaining bactericidal activity at high inoculum density may be relevant in the context of enterococcal infections where dense foci of pathogens may be present locally (e.g. endocarditis and osteomyelitis). Thus, further investigation into the clinical utility of both daptomycin and oritavancin against VRE infections is warranted. This work was supported by The Medicines Company. F. A., A. B. and G. M. participated in the design and reporting of this research and are salaried employees and stockholders at The Medicines Company, which funded this research and markets oritavancin. All other authors: none to declare.

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