Comparative In Vivo Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models.

Abstract

Given that tedizolid exhibits substantial lung penetration, we hypothesize that it could achieve good efficacy against Streptococcus pneumoniae lung infections. We evaluated the pharmacodynamics of tedizolid for treatment of S. pneumoniae lung infections and compared the efficacies of tedizolid human-simulated epithelial lining fluid (ELF) exposures in immunocompetent and neutropenic murine lung infection models. ICR mice were rendered neutropenic via intraperitoneal cyclophosphamide injections and then inoculated intranasally with S. pneumoniae suspensions. Immunocompetent CBA/J mice were inoculated similarly. Single daily tedizolid doses were administered 4 h postinoculation (termed 0 h). Changes in log10 CFU at 24 h compared with 0-h controls were estimated. Ratios of area under the free-drug concentration-time curve to MIC (fAUC0-24/MIC) required to achieve various efficacy endpoints against each isolate were estimated using the Hill equation. Tedizolid doses in neutropenic and immunocompetent mice that mimic the human-simulated ELF exposure were examined. Stasis, 1-log reduction, and 2-log reduction were achieved at fAUC0-24/MIC of 8.96, 24.62, and 48.34, respectively, in immunocompetent mice and 19.21, 48.29, and 103.95, respectively, in neutropenic mice. Tedizolid at 40 mg/kg of body weight/day and 55 mg/kg/day in immunocompetent and neutropenic mice, respectively, resulted in ELF AUC0-24 comparable to that achieved in humans following a 200-mg once-daily clinical dose. These human-simulated ELF exposures were adequate to attain >2-log reduction in bacterial burden at 24 h in 3 out of 4 isolates in both models and 1.58- and 0.74-log reductions with the fourth isolate in immunocompetent and neutropenic mice, respectively. Tedizolid showed potent in vivo efficacy against S. pneumoniae in both immunocompetent and neutropenic lung infection models, which support its consideration for S. pneumoniae lung infections.