title: Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.
  
  
  METHODS
  The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.
  
  
  BACKGROUND
  The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).
authors.affiliation: University of Queensland Centre for Clinical Research, Building 71/918 Royal Brisbane & Women's Hospital Campus, Herston, 4029, Brisbane, QLD, Australia. p.harris@uq.edu.au.
authors.forename: Patrick N A
authors.initials: PN
authors.lastname: Harris
authors.affiliation: Department of Infectious Diseases, The Alfred Hospital, Melbourne, VIC, Australia. anton.peleg@monash.edu.
authors.forename: Anton Y
authors.initials: AY
authors.lastname: Peleg
authors.affiliation: Westmead Millenium Institute for Medical Research, Westmead Hospital, Sydney, NSW, Australia. jon.iredell@swahs.health.nsw.gov.au.
authors.forename: Jon
authors.initials: J
authors.lastname: Iredell
authors.affiliation: Department of Microbiology and Infectious Diseases, Royal Perth Hospital, Perth, WA, Australia. paul.ingram@health.wa.gov.au.|School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia. paul.ingram@health.wa.gov.au.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Ingram
authors.affiliation: Department of Infectious Diseases, School of Medicine, University of Wollongong and The Wollongong Hospital, Wollongong, NSW, Australia. spiros_miyakis@uow.edu.au.
authors.forename: Spiros
authors.initials: S
authors.lastname: Miyakis
authors.affiliation: Department of Infectious Diseases, Austin Health, Melbourne, VIC, Australia. andrew.stewardson@gmail.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Stewardson
authors.affiliation: Monash Infectious Disease, Monash Health, Clayton, VIC, Australia. b.rogers1@uq.edu.au.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rogers
authors.affiliation: Victorian Infectious Diseases Unit, Royal Melbourne Hospital, Melbourne, VIC, Australia. emma.mcbryde@burnet.edu.au.
authors.forename: Emma S
authors.initials: ES
authors.lastname: McBryde
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia. j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia. j.lipman@uq.edu.au.
authors.forename: Jeff
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Department of Infectious Disease, Barwon Health, Deakin University, Geelong, VIC, Australia. eugene@barwonhealth.org.au.
authors.forename: Eugene
authors.initials: E
authors.lastname: Athan
authors.affiliation: Clinical Trials & Biostatistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Sanjoy.Paul@qimrberghofer.edu.au.
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Paul
authors.affiliation: Queensland Clinical Trials and Biostatistics Centre, University of Queensland, Brisbane, QLD, Australia. p.baker1@uq.edu.au.
authors.forename: Peter
authors.initials: P
authors.lastname: Baker
authors.affiliation: University of Queensland Centre for Clinical Research, Building 71/918 Royal Brisbane & Women's Hospital Campus, Herston, 4029, Brisbane, QLD, Australia. t.brown3@uq.edu.au.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Harris-Brown
authors.affiliation: University of Queensland Centre for Clinical Research, Building 71/918 Royal Brisbane & Women's Hospital Campus, Herston, 4029, Brisbane, QLD, Australia. david.antibiotics@gmail.com.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy*; D002443:Ceftriaxone / Q000627:therapeutic use*; D002985:Clinical Protocols; D004352:Drug Resistance, Microbial; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy*; D000077731:Meropenem; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010878:Piperacillin / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D018401:Sample Size; D013845:Thienamycins / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077725:Piperacillin, Tazobactam Drug Combination; D002443:Ceftriaxone; D010397:Penicillanic Acid; D000077731:Meropenem; D010878:Piperacillin