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

Abstract

Methicillin-resistant (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 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.

Treatment strategies for persistent methicillin‐resistantStaphylococcus aureusbacteraemia

“…In vitro data assessing the combinations with linezolid and daptomycin and vancomycin have shown mixed results with some studies observing antagonism whereas others showing indifference . Smith et al evaluated daptomycin combined with tedizolid, a novel oxazolidinone antibiotic, in an in vitro simulated endocardial vegetation model using two clinical strains of MRSA. In both tested strains, combination of daptomycin plus tedizolid demonstrated antagonism at 192 hours.…”

“…In vitro data assessing the combinations with linezolid and daptomycin and vancomycin have shown mixed results with some studies observing antagonism whereas others showing indifference. [84][85][86][87] Smith et al 88 and animal models of both endocarditis and osteomyelitis also demonstrating no benefit with combination. [89][90][91] Daptomycin plus vancomycin combination has not demonstrated synergy in vitro, but has been shown, in combination with rifampin to be effective in two cases of MRSA orthopaedic infections that relapsed after initial vancomycin and rifampin therapy.…”

The FICI paradigm: Correcting flaws in antimicrobial in vitro synergy screens at their inception

“…Biofilms are responsible of increased antimicrobial resistance and poor antimicrobial penetration at the site of infection, resulting in low rates of bacterial eradication and therapeutic failure [81]. Several in vitro biofilm models have been developed simulating a restricted nutrient and oxygen environment to allow biofilm formation [82][83][84]. Different parameters such as the Minimal Biofilm Inhibitory Concentration (MBIC) and the Minimal Biofilm Eradicative Concentrations (MBEC) could be better predictors of antimicrobial activity [78].…”

An update on Staphylococcus aureus infective endocarditis from the International Society of Antimicrobial Chemotherapy (ISAC)

“…Tedizolid had modest bactericidal in vivo activity but was less active than the other two drugs [42]. Also, the combination of tedizolid and daptomycin in simulated endocardial vegetations suggested an antagonistic relationship that impeded antimicrobial activity [43]. Additional investigation is thus needed before tedizolid is used to treat IE.…”