title: Vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations: study protocol for a phase IIB randomized controlled trial.
abstract: BACKGROUND
  Vancomycin is the standard first-line treatment for methicillin-resistant Staphylococcus aureus bacteremia. However, recent consensus guidelines recommend that clinicians consider using alternative agents such as daptomycin when the vancomycin minimum inhibitory concentration is greater than 1 ug/ml. To date however, there have been no head-to-head randomized trials comparing the safety and efficacy of daptomycin and vancomycin in the treatment of such infections. The primary aim of our study is to compare the efficacy of daptomycin versus vancomycin in the treatment of bloodstream infections due to methicillin-resistant Staphylococcus aureus isolates with high vancomycin minimum inhibitory concentrations (greater than or equal to 1.5 ug/ml) in terms of reducing all-cause 60-day mortality.
  
  
  METHODS
  The study is designed as a multicenter prospective open label phase IIB pilot randomized controlled trial. Eligible participants will be inpatients over 21-years-old with a positive blood culture for methicillin-resistant Staphylococcus aureus with vancomycin minimum inhibitory concentration of greater than or equal to 1.5 ug/ml. Randomization into intervention or active control arms will be performed with a 1:1 allocation ratio. We aim to recruit 50 participants over a period of two years. Participants randomized to the active control arm will receive vancomycin dose-while those randomized to the intervention arm will receive daptomycin. Participants will receive a minimum of 14 days study treatment.The primary analysis will be conducted on the intention-to-treat principle. The Fisher's exact test will be used to compare the 60-day mortality rate from index blood cultures (primary endpoint) between the two treatment arms, and the exact two-sided 95% confidence interval will be calculated using the Clopper and Pearson method. Primary analysis will be conducted using a two sided alpha of 0.05.
  
  
  CONCLUSIONS
  If results from this pilot study suggest that daptomycin shows significant efficacy in the treatment of bloodstream infections due to methicillin-resistant Staphylococcus aureus isolates with high vancomycin minimum inhibitory concentrations, we aim to proceed with a larger scale confirmatory study. This would help guide clinicians and inform practice guidelines on the optimal treatment for such infections.
  
  
  BACKGROUND
  The trial is listed on clinicaltrials.gov (NCT01975662, date of registration: 29 October 2013).
authors.forename: Shirin
authors.initials: S
authors.lastname: Kalimuddin
authors.forename: Rachel
authors.initials: R
authors.lastname: Phillips
authors.forename: Mihir
authors.initials: M
authors.lastname: Gandhi
authors.forename: Nurun Nisa
authors.initials: NN
authors.lastname: de Souza
authors.forename: Jenny G H
authors.initials: JG
authors.lastname: Low
authors.forename: Sophia
authors.initials: S
authors.lastname: Archuleta
authors.forename: David
authors.initials: D
authors.lastname: Lye
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore. tan.thuan.tong@sgh.com.sg.
authors.forename: Thuan Tong
authors.initials: TT
authors.lastname: Tan
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects; D016470:Bacteremia / Q000188:drug therapy*; D017576:Daptomycin / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010865:Pilot Projects; D011446:Prospective Studies; D012107:Research Design; D013203:Staphylococcal Infections / Q000188:drug therapy*; D014640:Vancomycin / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D017576:Daptomycin