Comparative efficacy of human-simulated epithelial lining fluid exposures of tedizolid, linezolid and vancomycin in neutropenic and immunocompetent murine models of staphylococcal pneumonia

Objectives: Few antibiotics are approved to treat Staphylococcus aureus pneumonia. Tedizolid is an oxazolidinone with potent in vitro activity against S. aureus and is currently under investigation for hospital-acquired and ventilator-associated bacterial pneumonia. Limited data exist on the comparative efficacy of tedizolid versus current first-line treatments vancomycin and linezolid in the compromised host. Our objective was to compare the efficacy of human-simulated epithelial lining fluid (ELF) exposures of tedizolid, linezolid and vancomycin against S. aureus in neutropenic and immunocompetent murine pneumonia models.

Methods: Eight S. aureus isolates (four MRSA and four MSSA) were studied. Neutropenic and immunocompetent mice were inoculated intranasally with bacterial suspensions of 107 and 109 cfu/mL, respectively, then treated for up to 72 h with model-specific regimens of tedizolid, linezolid and vancomycin simulating human ELF exposures after clinical doses. Mice were sacrificed at 24, 48 or 72 h and changes in log10 cfu/lungs were compared with 0 h controls.

Results: Mean bacterial burdens at 0 h were 5.81 and 8.17 log10 cfu/lungs for neutropenic and immunocompetent mice, respectively, and increased at 24 h in the absence of antibiotic treatment to 7.97 and 9.00 log10 cfu/lungs, respectively. In neutropenic and immunocompetent mice, tedizolid was associated with bacterial density changes of -2.69 ± 0.62 and -3.57 ± 0.88 log10 cfu/lungs at 72 h, respectively. In both models, tedizolid treatment produced greater bacterial reductions than vancomycin and was not statistically significantly different from linezolid.

Conclusions: Human-simulated ELF exposures of tedizolid demonstrated sustained efficacy in compromised and competent models of pneumonia. Validation of these findings in patients is warranted.