Gregory J Moran1, Edward Fang2, G Ralph Corey3, Anita F Das4, Carisa De Anda2, Philippe Prokocimer5. 1. Department of Emergency Medicine and Division of Infectious Diseases, Olive View-UCLA Medical Center, CA, USA. 2. Clinical Development, Cubist Pharmaceuticals, CA, USA. 3. Division of Infectious Diseases, Duke University Medical Center, NC, USA. 4. Biometrics, InClin, CA, USA. 5. Clinical Development, Cubist Pharmaceuticals, CA, USA. Electronic address: philippe.prokocimer@cubist.com.
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. FINDINGS: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. INTERPRETATION: 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. FUNDING: Cubist Pharmaceuticals.
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Cubist Pharmaceuticals.
Authors: Taylor Sandison; Carisa De Anda; Edward Fang; Anita F Das; Philippe Prokocimer Journal: Antimicrob Agents Chemother Date: 2017-04-24 Impact factor: 5.191
Authors: Abraham Pulido-Cejudo; Mario Guzmán-Gutierrez; Abel Jalife-Montaño; Alejandro Ortiz-Covarrubias; Jose Luis Martínez-Ordaz; Héctor Faustino Noyola-Villalobos; Luis Mauricio Hurtado-López Journal: Ther Adv Infect Dis Date: 2017-08-31