title: Use of pharmacokinetic/pharmacodynamic systems analyses to inform dose selection of tedizolid phosphate.
abstract: In the Staphylococcus aureus neutropenic murine thigh-infection model, the ratio of the free area under the 24-hour concentration-time curve to the minimum inhibitory concentration (fAUC/MIC) was found to be the pharmacodynamic index most closely linked to bacterial effect, with a ratio of approximately 50 producing a static effect. Further work was undertaken in neutropenic versus non-neutropenic animals. The presence of granulocytes increased the activity of tedizolid considerably, 25-fold on average, and maximal effect was achieved at an exposure equivalent to approximately 200 mg tedizolid phosphate per day in humans (dosing regimen used in phase 2 and 3 clinical trials). The fAUC/MIC was also found to be the pharmacodynamically linked variable in the S. aureus neutropenic murine pneumonia model; the fAUC/MIC ratio required for a static effect was approximately 20. Pharmacokinetic (PK) data demonstrate that tedizolid penetrates well into the epithelial lining fluid (ELF) of the lung. Data from the pneumonia infection model and ELF penetration PK study support exploring its use in pneumonia.
authors.affiliation: Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D004195:Disease Models, Animal; D006801:Humans; D008826:Microbial Sensitivity Tests; D010755:Organophosphates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010080:Oxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; C515040:tedizolid phosphate