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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

Journal Article


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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/Design

    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.

    Trial registration

    The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 webcite (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 webcite (registered 24 June 2014).

UOW Authors


  •   Narris, Patrick NA. (external author)
  •   Peleg, Anton Y. (external author)
  •   Iredell, Jon (external author)
  •   Ingram, Paul R. (external author)
  •   Miyakis, Spiros
  •   Stewardson, Andrew J. (external author)
  •   Rogers, Benjamin A. (external author)
  •   Mcbryde, Emma S. (external author)
  •   Roberts, Jason A. (external author)
  •   Lipman, Jeff (external author)
  •   Athan, Eugene (external author)
  •   Paul, Sanjoy K. (external author)
  •   Baker, Peter (external author)
  •   Harrisi-Brown, Tiffany (external author)
  •   Paterson, David L. (external author)

Publication Date


  • 2015

Published In


Citation


  • Narris, P. NA., Peleg, A. Y., Iredell, J., Ingram, P. R., Miyakis, S., Stewardson, A. J., Rogers, B. A., Mcbryde, E. S., Roberts, J. A., Lipman, J., Athan, E., Paul, S. K., Baker, P., Harrisi-Brown, T. & Paterson, D. L. (2015). 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. Trials, 16 (January), 24-1-24-8.

Scopus Eid


  • 2-s2.0-84938222503

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4642&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3619

Has Global Citation Frequency


Start Page


  • 24-1

End Page


  • 24-8

Volume


  • 16

Issue


  • January

Place Of Publication


  • United Kingdom

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/Design

    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.

    Trial registration

    The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 webcite (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 webcite (registered 24 June 2014).

UOW Authors


  •   Narris, Patrick NA. (external author)
  •   Peleg, Anton Y. (external author)
  •   Iredell, Jon (external author)
  •   Ingram, Paul R. (external author)
  •   Miyakis, Spiros
  •   Stewardson, Andrew J. (external author)
  •   Rogers, Benjamin A. (external author)
  •   Mcbryde, Emma S. (external author)
  •   Roberts, Jason A. (external author)
  •   Lipman, Jeff (external author)
  •   Athan, Eugene (external author)
  •   Paul, Sanjoy K. (external author)
  •   Baker, Peter (external author)
  •   Harrisi-Brown, Tiffany (external author)
  •   Paterson, David L. (external author)

Publication Date


  • 2015

Published In


Citation


  • Narris, P. NA., Peleg, A. Y., Iredell, J., Ingram, P. R., Miyakis, S., Stewardson, A. J., Rogers, B. A., Mcbryde, E. S., Roberts, J. A., Lipman, J., Athan, E., Paul, S. K., Baker, P., Harrisi-Brown, T. & Paterson, D. L. (2015). 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. Trials, 16 (January), 24-1-24-8.

Scopus Eid


  • 2-s2.0-84938222503

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4642&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3619

Has Global Citation Frequency


Start Page


  • 24-1

End Page


  • 24-8

Volume


  • 16

Issue


  • January

Place Of Publication


  • United Kingdom