title: Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial.
abstract: BACKGROUND
  New antibiotics are needed to treat infections caused by drug-resistant bacteria. Tedizolid is a novel oxazolidinone antibacterial drug designed to provide enhanced activity against Gram-positive pathogens. We aimed to assess the efficacy and safety of intravenous to oral tedizolid for treatment of patients with acute bacterial skin and skin-structure infections.
  
  
  METHODS
  ESTABLISH-2 was a randomised, double-blind, phase 3, non-inferiority trial done between Sept 28, 2011, and Jan 10, 2013, at 58 centres in nine countries. Patients (aged ≥12 years) with acute bacterial skin and skin-structure infections (cellulitis or erysipelas, major cutaneous abscess, or wound infection) that had a minimum lesion area of 75 cm(2) and were suspected or documented to be associated with a Gram-positive pathogen, were randomly assigned (1:1), via an interactive voice-response system with block randomisation, to receive intravenous once-daily tedizolid (200 mg for 6 days) or twice-daily linezolid (600 mg for 10 days), with optional oral step-down. Randomisation was stratified by geographic region and type of acute bacterial skin and skin-structure infection. The primary endpoint was early clinical response (≥20% reduction in lesion area at 48-72 h compared with baseline), with a non-inferiority margin of -10%. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01421511.
  
  
  RESULTS
  666 patients were randomly assigned to receive tedizolid (n=332) or linezolid (n=334). 283 (85%) patients in the tedizolid group and 276 (83%) in the linezolid group achieved early clinical response (difference 2·6%, 95% CI -3·0 to 8·2), meeting the prespecified non-inferiority margin. Gastrointestinal adverse events were less frequent with tedizolid than linezolid, taking place in 52 (16%) of 331 patients and 67 (20%) of 327 patients in the safety population. Treatment-emergent adverse events leading to discontinuation of study drug were reported by one (<1%) patient in the tedizolid group and four (1%) patients in the linezolid group.
  
  
  CONCLUSIONS
  Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with acute bacterial skin and skin-structure infections. Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings.
  
  
  BACKGROUND
  Cubist Pharmaceuticals.
authors.affiliation: Department of Emergency Medicine and Division of Infectious Diseases, Olive View-UCLA Medical Center, CA, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Moran
authors.affiliation: Clinical Development, Cubist Pharmaceuticals, CA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Fang
authors.affiliation: Division of Infectious Diseases, Duke University Medical Center, NC, USA.
authors.forename: G Ralph
authors.initials: GR
authors.lastname: Corey
authors.affiliation: Biometrics, InClin, CA, USA.
authors.forename: Anita F
authors.initials: AF
authors.lastname: Das
authors.affiliation: Clinical Development, Cubist Pharmaceuticals, CA, USA.
authors.forename: Carisa
authors.initials: C
authors.lastname: De Anda
authors.affiliation: Clinical Development, Cubist Pharmaceuticals, CA, USA. Electronic address: philippe.prokocimer@cubist.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Prokocimer
mesh_terms: D000081:Acetamides / Q000008:administration & dosage*; D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000008:administration & dosage*; D010080:Oxazoles / Q000008:administration & dosage*; D023303:Oxazolidinones / Q000008:administration & dosage*; D017192:Skin Diseases, Bacterial / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; D000069349:Linezolid; C515040:tedizolid phosphate