Combination of Tedizolid and Daptomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

Abstract

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for health care-associated infections, and treatment options are limited. Tedizolid (TZD) is a novel oxazolidinone antibiotic with activity against MRSA. Previously, daptomycin (DAP) has demonstrated synergy with other antibiotics against MRSA. We sought to determine the efficacy of the combination of TZD and DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs). TZD simulations of 200 mg once daily and DAP simulations of 6 mg/kg of body weight and 10 mg/kg once daily were tested alone and in the combinations TZD plus DAP at 6 mg/kg or DAP at 10 mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine the antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents. Against both strains 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 h. In all cases, DAP alone was statistically superior to DAP plus TZD. When the combination was stopped after 96 h, transitioning to DAP at 6 mg/kg or DAP at 10 mg/kg alone resulted in better antibacterial activity than either of the TZD-plus-DAP combinations, further demonstrating antagonistic effects. Against MRSA, we demonstrated that TZD and DAP have antagonistic activity that hinders their overall antimicrobial efficacy. The exact nature of this antagonistic relationship is still undetermined, but its presence warrants further study of the potentially harmful grouping of the two antibiotics in clinical use.