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RCT Meropenem vs Piperacillin-Tazobactam for Definitive Treatment of BSI's Due to Ceftriaxone Non-susceptible Escherichia Coli and Klebsiella Spp. (MERINO)

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ClinicalTrials.gov Identifier: NCT02176122
Recruitment Status : Terminated (Secondary to third interim analysis by the study DSMB.)
First Posted : June 26, 2014
Last Update Posted : November 27, 2017
Sponsor:
Collaborators:
International Society of Chemotherapy
Australian Society for Antimicrobials
Queensland Clinical Trials & Biostatistics Centre
Australasian Society for Infectious Diseases
Information provided by (Responsible Party):
Professor David L. Paterson, The University of Queensland

Tracking Information
First Submitted Date  ICMJE June 24, 2014
First Posted Date  ICMJE June 26, 2014
Last Update Posted Date November 27, 2017
Study Start Date  ICMJE February 2014
Actual Primary Completion Date July 7, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2014)
Mortality at 30 days [ Time Frame: 30 days ]
To compare the 30-day mortality post bloodstream infection of piperacillin/tazobactam and meropenem.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02176122 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2015)
  • Time to clinical and microbiologic resolution of infection [ Time Frame: on or before study day 4 ]
    defined as number of days from randomisation to resolution of fever (temperature > 38.0o C) and leucocytosis (white blood cell count >12x109/L) PLUS sterilisation of blood cultures.
  • Clinical and microbiologic success [ Time Frame: day 4 ]
    defined as survival PLUS resolution of fever and leucocytosis PLUS sterilisation of blood cultures
  • Microbiologic resolution of infection [ Time Frame: day 4 ]
    defined as sterility of blood cultures collected on or before day 4
  • Microbiologic relapse [ Time Frame: day 30 ]
    defined as growth of a meropenem resistant Gram negative bacillus from any clinical specimen collected or a positive stool test (according to local lab diagnostic procedures) for C. difficile, from day 4 of study drug administration to day 30
  • Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium Difficile [ Time Frame: day 30 ]
    To compare the risk of superinfection with a carbapenem resistant organism with each regimen.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2014)
  • Clinical and microbiologic resolution of infection [ Time Frame: on or before study day 4 ]
    To compare the time to clinical and microbiologic resolution of infection for each regimen.
  • Clinical and microbiologic success of intervention at study day 4 [ Time Frame: 4 days ]
    To compare the clinical and microbiologic success of each regimen at day 4 of the intervention.
  • Risk of relapse [ Time Frame: 30 days ]
    To compare the risk of relapse with each regimen.
  • Risk of superinfection of a carbapenem resistant organism [ Time Frame: 30 days ]
    To compare the risk of superinfection with a carbapenem resistant organism with each regimen.
  • Time to clinical and microbiologic resolution of infection [ Time Frame: 7 days ]
    To compare the number of days from randomization to resolution of fever (temperature > 38.0o C) and leucocytosis (white blood cell count >12x109/L) PLUS sterilization of blood cultures.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE RCT Meropenem vs Piperacillin-Tazobactam for Definitive Treatment of BSI's Due to Ceftriaxone Non-susceptible Escherichia Coli and Klebsiella Spp.
Official Title  ICMJE Randomized Controlled Trial of Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Due to Ceftriaxone Non-susceptible E. Coli and Klebsiella Species.
Brief Summary

No randomized controlled trials (RCTs) have yet been performed comparing different treatment options for AmpC or ESBL-producing Enterobacteriaceae. During the last 10 years we have seen an exponentially increasing rate of carbapenem resistance worldwide, including Australia and New Zealand. The investigators urgently need data from well-designed RCTs to guide clinicians in the treatment of antibiotic resistant Gram-negative infections. The investigators face a situation where a commonly used antibiotic for these infections (meropenem) may be driving carbapenem resistance. For this reason, the investigators are seeking to compare a carbapenem-sparing regimen with a carbapenem for the treatment of these infections. Formal evaluation of safety and efficacy of generic antibiotics in the treatment of infection is of immense clinical and public health importance, and no formal trial has yet been conducted to address these issues. The international collaboration between teams of clinician researchers, some of whom are leaders in their field, makes it highly likely that the outcomes of this trial will have a significant impact on clinical practice.

The investigators' hypothesis is that piperacillin/tazobactam (a carbapenem-sparing regimen) is non-inferior to meropenem (a widely used carbapenem) for the definitive treatment of bloodstream infections due to third-generation cephalosporin non-susceptible E. coli or Klebsiella species.

Detailed Description

Escherichia coli and Klebsiella spp. are common causes of bacteraemia, and may acquire genes encoding extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases (1). ESBL or AmpC producers are typically resistant to third generation cephalosporins such as ceftriaxone, but susceptible to carbapenems (1). Observational studies have been performed evaluating antibiotic choices for ESBL producers (2-9). In no study has the outcome of treatment for serious infections for ESBL producers been significantly surpassed by carbapenems (2-9).

Despite the potential advantages of carbapenems for treatment of ceftriaxone non-susceptible organisms, widespread use of carbapenems may cause selection pressure leading to carbapenem-resistant organisms. This is a significant issue since carbapenem-resistant organisms are treated with "last-line" antibiotics such as colistin. Some new beta-lactam antibiotics and beta-lactamase inhibitors, which are active against ESBL, AmpC and some carbapenemase producing organisms, are in advanced clinical development (10). However, these antibiotics are likely to be expensive and may best be held in reserve for infections where there are no alternatives. Therefore, we see a need for establishing the efficacy of a generically available alternative to carbapenems for serious infections.

The susceptibility of ESBL producers and AmpC producers to piperacillin/tazobactam is less predictable than that of carbapenems. By definition, ESBLs are inhibited by beta-lactamase inhibitors such as tazobactam (1). However, E. coli or Klebsiella may produce multiple beta-lactamase types some of which are resistant to inhibition by tazobactam. Additionally, in some cases outer membrane protein loss may contribute to resistance to tazobactam. By definition, AmpC is not inhibited by beta-lactamase inhibitors such as tazobactam. However, despite these limitations, approximately 50% or more of ceftriaxone non-susceptible E. coli or Klebsiellae remain susceptible in vitro to piperacillin/tazobactam (1).

No randomised controlled trials have yet been performed comparing different treatment options for ceftriaxone resistant Enterobacteriaceae. The largest observational study with an analysis by treatment outcome was published in February 2012 by Rodriguez-Bano and colleagues (9). They performed a post-hoc analysis of six published cohorts of patients with bacteraemia due to ESBL producing E. coli. Two nonmutually exclusive cohorts (empirical therapy and definitive therapy) were constructed and analysed separately. In both cohorts, carbapenems were not superior to beta-lactam/beta-lactamase inhibitor combinations (BLBLIC). Specifically, in the definitive therapy cohort, mortality rates at 30 days were not significantly different - 9.3% for those who received a BLBLIC and 16.7% for those who received a carbapenem (p>0.20) (9).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bloodstream Infections
Intervention  ICMJE
  • Drug: Meropenem
    Meropenem is a carbapenem anti-bacterial used for the treatment of serious infections in patients.
    Other Names:
    • Merrem
    • Meronem
  • Drug: Piperacillin-tazobactam combination product
    Piperacillin-tazobactam is used for the treatment of patients with systemic and/or local bacterial infections.
    Other Names:
    • Zosyn
    • Tazocin
Study Arms  ICMJE
  • Active Comparator: Meropenem
    Meropenem 1g adm every 8 hours IV up to study day 4.
    Intervention: Drug: Meropenem
  • Experimental: Piperacillin-tazobactam combination product
    Piperacillin/tazobactam 4.5g adm every 6 hours IV up to study day 4.
    Intervention: Drug: Piperacillin-tazobactam combination product
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 22, 2017)
391
Original Estimated Enrollment  ICMJE
 (submitted: June 25, 2014)
100
Actual Study Completion Date  ICMJE August 7, 2017
Actual Primary Completion Date July 7, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Bloodstream infection with E. coli or Klebsiella spp. with proven non-susceptibility to third generation cephalosporins and susceptibility to meropenem and piperacillin-tazobactam from at least one blood culture draw. This will be determined in accordance with laboratory methods and susceptibility breakpoints defined by EUCAST standards (www. eucast.org). Bacterial identification to species level will be performed using standard laboratory methods (e.g. MALDI-TOF) and susceptibility testing (e.g. Vitek2)
  • No more than 72 hours has elapsed since the first positive blood culture collection.
  • Patient is aged 18 years and over
  • The patient or approved proxy is able to provide informed consent.

Exclusion Criteria:

  • Patient not expected to survive more than 4 days
  • Patient allergic to a penicillin or a carbapenem
  • Patient with significant polymicrobial bacteraemia (that is, a Gram positive skin contaminant in one set of blood cultures is not regarded as significant polymicrobial bacteraemia).
  • Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion).
  • Pregnancy or breast-feeding.
  • Use of concomitant antimicrobials in the first 4 days after enrolment with known activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole may be continued as Pneumocystis prophylaxis).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Italy,   Lebanon,   New Zealand,   Saudi Arabia,   Singapore,   South Africa,   Turkey
Removed Location Countries Malaysia
 
Administrative Information
NCT Number  ICMJE NCT02176122
Other Study ID Numbers  ICMJE ACTRN12613000532707
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Professor David L. Paterson, The University of Queensland
Study Sponsor  ICMJE The University of Queensland
Collaborators  ICMJE
  • International Society of Chemotherapy
  • Australian Society for Antimicrobials
  • Queensland Clinical Trials & Biostatistics Centre
  • Australasian Society for Infectious Diseases
Investigators  ICMJE
Principal Investigator: David L Paterson, MD, PhD UQCCR, RBWH
PRS Account The University of Queensland
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP