Determination of Susceptibility Breakpoints for the Novel Oxazolidinone Tedizolid

Conference: ECCMID

Introduction

  • Tedizolid is a novel oxazolidinone antibacterial with potent in vitro activity against a wide range of Gram-positive pathogens, such as Staphylococcus aureus (including methicillin-resistant S. aureus), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group, and Enterococcus faecalis.1-3
  • The prodrug tedizolid phosphate is rapidly and extensively converted by phosphatases to its active moiety tedizolid after administration.4,5
  • The pharmacokinetic/pharmacodynamic (PK/PD) parameter that best predicts the efficacy of tedizolid is the free area under the concentration-time curve/minimum inhibitory concentration (fAUC/MIC); target ratio is 3 for S. aureus (including methicillin-resistant S. aureus [MRSA]).6
  • Tedizolid phosphate has been approved for the treatment of ABSSSI in the United States, the European Union, and Canada.7,8
  • Two Phase 3 trials, ESTABLISH-1 and ESTABLISH-2 , demonstrated the noninferior efficacy of tedizolid (200 mg once daily for 6 days) to linezolid (600 mg twice daily for 10 days) in patients with ABSSSI.9,10
  • Tedizolid phosphate is available in oral and intravenous (IV) formulations, and the approved dosage for treatment of ABSSSI with either formulation is 200 mg once daily for 6 days.7
  • The U.S. Food and Drug Administration approved the following tedizolid breakpoints: ≤0.5 mg/L (susceptible), 1 mg/L (intermediate), and ≥2 mg/L (resistant) for S. aureus (including MRSA); ≤0.5 mg/L (susceptible) for S. pyogenes, S. agalactiae, and E. faecalis; and ≤0.25 mg/L (susceptible) for S. anginosus Group.7
  • To establish breakpoints, current European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidance requires analysis of (1) PK/PD and Monte Carlo simulation data, (2) clinical data relating MIC to outcomes, and (3) in vitro MIC distributions.11
  • We present here the analyses conducted to establish antibacterial susceptibility breakpoints for tedizolid according to the current EUCAST guidelines.

25th European Congress of Clinical Microbiology and Infectious Diseases, April 25-28, 2015, Copenhagen, Denmark

By Paul Bien, Shawn Flanagan, Julie Passarell, Jill Fiedler-Kelly, Philippe Prokocimer