Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

Abstract

The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model of Staphylococcus aureus necrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P = 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P = 0.003) and 17% for rabbits treated with saline (P = 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. The in vivo bacterial production of alpha-toxin and Panton-Valentine leukocidin, two key S. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment of S. aureus necrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.

Keywords: PVL; alpha-toxin; linezolid; pneumonia; rabbit model; tedizolid; vancomycin.

FIG 1

Treatment efficacy of tedizolid phosphate compared to that of linezolid, vancomycin, and saline in a rabbit model of USA300 necrotizing pneumonia. (A) Kaplan-Meier survival curves for animals treated with 6 mg/kg tedizolid phosphate intravenously at 1.5, 13, 25, and 37 h postinfection (hpi; n = 12 rabbits), 50 mg/kg linezolid subcutaneously at 1.5, 10, 18, and 26 h postinfection (n = 12 rabbits), 30 mg/kg vancomycin intravenously at 1.5, 13, 25, and 37 h postinfection (n = 12 rabbits), or saline intravenously at 1.5, 13, 25, and 37 h postinfection. A two-sided log-rank (Mantel-Cox) test was used to test the hypothesis that the rate of survival of animals treated with tedizolid phosphate is not different from the rate of survival of those treated with linezolid, vancomycin, or saline; a P value of <0.0167 (a significance level of 0.05 divided by 3 for three different comparisons), determined using the Bonferroni method to account for multiple comparisons, was considered statistically significant. (B, C) The lung weight-to-body weight (LW/BW [10³]) ratio (B) and bacterial densities (in log₁₀ number of CFU per lung) (C) for saline-treated animals were compared to those for animals in each of the other three treatment groups by a nonparametric one-way ANOVA with the Kruskal-Wallis test followed by Dunn's multiple-comparison test. Filled symbols, data from dead animals; open symbols, data from surviving animals that were euthanized at 48 h after infection. (D) Representative images of lungs from rabbits in the four treatment groups.

FIG 2

Concentrations of the key lung-damaging toxins PVL and Hla in the lungs of rabbits. The LukF (A), LukS (B), and Hla (C) concentrations (in micrograms per lungs) of rabbits treated with tedizolid phosphate, linezolid, vancomycin, and saline were compared by a nonparametric one-way ANOVA with the Kruskal-Wallis test followed by Dunn's multiple-comparison test. Filled symbols, data from dead animals; open symbols, data from surviving animals that were euthanized at 48 h after infection.