title: CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia.
  
  
  METHODS
  We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint.
  
  
  CONCLUSIONS
  Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015.
authors.affiliation: Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.|Royal Darwin Hospital, Darwin, NT, Australia.
authors.forename: Steven Y C
authors.initials: SY
authors.lastname: Tong
authors.affiliation: Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Nelson
authors.affiliation: University of Queensland, Centre for Clinical Research, Herston, QLD, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
authors.affiliation: Microbiological Diagnostic Unit Public Health Laboratory, The University of Melbourne, at The Doherty Institute, Melbourne, VIC, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Howden
authors.affiliation: Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Cheng
authors.affiliation: Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Chatfield
authors.affiliation: Burns, Trauma Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Department of Microbiology and Infectious Disease Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Van Hal
authors.affiliation: Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, NSW, Australia.|Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Sullivan
authors.affiliation: Department of Microbiology and Infectious Diseases, Pathwest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital, Perth, WA, Australia.|Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia.
authors.forename: James O
authors.initials: JO
authors.lastname: Robinson
authors.affiliation: Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.|Rabin Medical Center, Petah Tikvah, Israel.
authors.forename: Dafna
authors.initials: D
authors.lastname: Yahav
authors.affiliation: Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore, Singapore.|Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: David
authors.initials: D
authors.lastname: Lye
authors.affiliation: Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia. Joshua.Davis@menzies.edu.au.|John Hunter Hospital, Newcastle, NSW, Australia. Joshua.Davis@menzies.edu.au.
authors.forename: Joshua S
authors.identifier: http://orcid.org/0000-0001-9864-5699
authors.initials: JS
authors.lastname: Davis
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001315:Australia; D002437:Cefazolin / Q000627:therapeutic use; D002985:Clinical Protocols; D003023:Cloxacillin / Q000627:therapeutic use; D017576:Daptomycin / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005436:Floxacillin / Q000627:therapeutic use; D006801:Humans; D007557:Israel; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity; D009520:New Zealand; D012107:Research Design; D012846:Singapore; D013203:Staphylococcal Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome; D014640:Vancomycin / Q000627:therapeutic use; D047090:beta-Lactams / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D005436:Floxacillin; D014640:Vancomycin; D002437:Cefazolin; D017576:Daptomycin; D003023:Cloxacillin
keywords: Cefazolin; Cloxacillin; Combination; Daptomycin; Flucloxacillin; MRSA; Methicillin-resistant; Nafcillin; Randomised controlled trial; Staphylococcus aureus; Vancomycin