The combination of tedizolid and daptomycin against methicillin-resistant Staphylococcus aureus in an in vitro model of simulated endocardial vegetations [PublishAheadOfPrint]

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for healthcare-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 + DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs).

Methods: TZD simulations of 200 mg once daily and DAP simulations of 6-mg/kg and 10-mg/kg once daily were tested alone and in the combinations of TZD + DAP 6-mg/kg or DAP 10-mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents.

Results: Against both 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 hours. In all cases, DAP alone was statistically superior to DAP + TZD. When the combination was stopped after 96 hours, transitioning to DAP 6-mg/kg or DAP 10-mg/kg alone resulted in better antibacterial activity than either of the TZD + DAP combinations, further demonstrating antagonistic effects.

Conclusions: Against MRSA, we have demonstrated that TZD and DAP have antagonistic activity that hinders overall antimicrobial efficacy. The exact nature of this antagonistic relationship is as of yet undetermined, but its presence warrants further study into the potentially harmful grouping of these two antibiotics in clinical use.

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