title: 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 log10CFU 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 AUC0-24comparable 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.
authors: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors: Kamilia
authors: K
authors: Abdelraouf
authors: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA david.nicolau@hhchealth.org.|Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA.
authors: David P
authors: DP
authors: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D003520:Cyclophosphamide; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D006801:Humans; D007121:Immunocompetence; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D010755:Organophosphates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D003520:Cyclophosphamide; C515040:tedizolid phosphate
keywords: oxazolidinedione; pharmacodynamics; pneumonia