Use of translational PKPD infection models to understand impact of neutropenia on efficacy of tedizolid phosphate. (4th October 2017) - Xiao, Jianying
Abstract: Background: Tedizolid phosphate (TZD), an oxazolidinone antibiotic, has been approved in the United States, Europe, and other countries to treat adults with acute bacterial skin and skin structure infections (ABSSSI). Translational PKPD studies in neutropenic mouse infection models demonstrated improved potency and PKPD relative to first-in-class linezolid (LZD). 1 Follow-up studies in immune competent mice showed improved efficacy of TZD in the presence of granulocytes. 2 The TZD label contains a warning regarding use in neutropenic patients based on mouse studies. Previous studies reported a large contribution of neutrophils in the antibacterial activity of TZD. To re-evaluate earlier observations we examined the PKPD of TZD in the mouse thigh infection model in both immune competent (IC) and neutropenic (IS) mice using both methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA and MSSA) strains. Methods: The pharmacodynamics of TZD was assessed across a broad range of daily doses in IC and IS mice. Daily exposures resulting in static bacterial effect and 1- and 2-log reduction in burden relative to start of antibacterial therapy were compared at 24, 48, and 72h. Results: In IC mice, bacterial burden was reduced at all three time points through immune mediated clearance in the absence of drugs; TZD further reduced burden beyond static effect. Maximal efficacy (~2-log CFU reduction) was achieved at exposures equivalent to clinical doses of 200 mg QD. A more robust reduction of burden was seen with increased treatment time. In IS mice, treatment with TZD resulted in significantly greater reduction in bacterial burden compared with normal mice at doses ≥10 mg/kg, with higher doses required for maximal efficacy (up to ~6-log CFU reduction). TZD achieved a static effect at the human clinical dose of 200 mg at 72h. Stasis was achieved at doses lower than those reported in earlier studies. 2 Conclusion: The efficacy of TZD was evident in neutropenic mice and our studies suggest that efficacy may be achieved in neutropenic patients at the clinical dose of TZD. Reduction in bacterial burden was 2- to 3-fold greater in IS vs. IC mice. (1) A Louie; et al. Antimicrob . A gents and Chemother . 2011, 55: 3453–3460 (2) G.L.Drusano, et al. Antimicrob . A gents and Chemother . 2011, 55: 5300–5305. Disclosures: J. Xiao, Merck: Employee, Salary. C. Gill, Merck: Employee, Salary. L. Liang, Merck: Employee, Salary. J. Liu, Merck: Employee, Salary. J. Wu, Merck: Employee, Salary. C. M. Tan, Merck: Employee, Salary. A. Flattery, Merck: Employee, Salary.