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

NCT02176122 | Terminated Phase 4 DMC

• 1 other identifier: ACTRN12613000532707
• Study Type: interventional
• Target: 391
• Locations: 9 countries
• Sites: 31

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.

Conditions

Bloodstream Infections

Outcome Measures

Primary Outcomes (1)

• Mortality at 30 days

  To compare the 30-day mortality post bloodstream infection of piperacillin/tazobactam and meropenem.

  30 days

Secondary Outcomes (5)

• Time to clinical and microbiologic resolution of infection

  on or before study day 4

• Clinical and microbiologic success

  day 4

• Microbiologic resolution of infection

  day 4

• Microbiologic relapse

  day 30

• Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium Difficile

  day 30

Study Arms (2)

Meropenem

ACTIVE COMPARATOR

Meropenem 1g adm every 8 hours IV up to study day 4.

Drug: Meropenem

Piperacillin-tazobactam combination product

EXPERIMENTAL

Piperacillin/tazobactam 4.5g adm every 6 hours IV up to study day 4.

Drug: Piperacillin-tazobactam combination product

Interventions

Meropenem DRUG

Meropenem is a carbapenem anti-bacterial used for the treatment of serious infections in patients.

Also known as: Merrem, Meronem

Meropenem

Piperacillin-tazobactam combination product DRUG

Piperacillin-tazobactam is used for the treatment of patients with systemic and/or local bacterial infections.

Also known as: Zosyn, Tazocin

Piperacillin-tazobactam combination product

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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).

Sponsors & Collaborators

• The University of Queensland: lead
• International Society of Chemotherapy: collaborator
• Australian Society for Antimicrobials: collaborator
• Queensland Clinical Trials & Biostatistics Centre: collaborator
• Australasian Society for Infectious Diseases: collaborator

Study Sites (31)

Shellharbour Hospital (Illawarra Shoalhaven Local Health District)

Shellharbour, New South Wales, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Wollongong Hospital

Wollongong, New South Wales, 2500, Australia

Location

Brisbane Private Hospital

Brisbane, Queensland, 4000, Australia

Location

St. Andrew's War Memorial Hospital

Brisbane, Queensland, 4001, Australia

Location

Mater Misericordiae Health Services Brisbane Ltd.

Brisbane, Queensland, Australia

Location

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

Peter MacCallum Cancer Centre

East Melbourne, Victoria, 3002, Australia

Location

Barwon Health

Geelong, Victoria, 3220, Australia

Location

The Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Fiona Stanley Hospital

Perth, Australia

Location

Sunnybrook Research Institute

Toronto, Canada

Location

Teaching Hospital - Sant'Orsola Malpighi

Bologna, Italy

Location

Dipartimento di Scienze Biomediche e Cliniche "L. Sacco". Azienda Ospedaliera - Polo Universitario

Milan, Italy

Location

"Sapienza" University of Rome

Rome, Italy

Location

Catholic University Rome

Rome, Italy

Location

Sanremo Hospital

Sanremo, Italy

Location

Santa Maria Misericorida University Hospital

Udine, Italy

Location

The American University of Beirut

Beirut, Lebanon

Location

Middlemore Hospital

Papatoetoe, 2025, New Zealand

Location

The North Shore Hospital

Westlake, 0622, New Zealand

Location

King Fahad Specialist Hospital

Dammam, Saudi Arabia

Location

King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City

Riyadh, Saudi Arabia

Location

National University Hospital

Singapore, 119074, Singapore

Location

Tan Tock Seng Hospital

Singapore, 308433, Singapore

Location

Groote Schuur Hospital

Cape Town, South Africa

Location

Charlotte Maxeke Johannesberg Academic Hospital

Johannesburg, South Africa

Location

İstanbul Medipol Üniversitesi Medipol Mega Hastaneler Kompleksi (Medipol Mega Hospitals Complex)

Istanbul, Turkey (Türkiye)

Location

Related Publications (2)

• Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, Alenazi TH, Arabi Y, Falcone M, Bassetti M, Righi E, Rogers BA, Kanj S, Bhally H, Iredell J, Mendelson M, Boyles TH, Looke D, Miyakis S, Walls G, Al Khamis M, Zikri A, Crowe A, Ingram P, Daneman N, Griffin P, Athan E, Lorenc P, Baker P, Roberts L, Beatson SA, Peleg AY, Harris-Brown T, Paterson DL; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018 Sep 11;320(10):984-994. doi: 10.1001/jama.2018.12163.

  PMID: 30208454 DERIVED

• Harris PN, Peleg AY, Iredell J, Ingram PR, Miyakis S, Stewardson AJ, Rogers BA, McBryde ES, Roberts JA, Lipman J, Athan E, Paul SK, Baker P, Harris-Brown T, Paterson DL. 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. 2015 Jan 27;16:24. doi: 10.1186/s13063-014-0541-9.

  PMID: 25623485 DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

Meropenem; Piperacillin, Tazobactam Drug Combination

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Tazobactam; Penicillanic Acid; Penicillins; Piperacillin; Ampicillin; Penicillin G; Sulfur Compounds; Sulfones; Drug Combinations; Pharmaceutical Preparations

Study Officials

• David L Paterson, MD, PhD

  UQCCR, RBWH

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine, Infectious Diseases Consultant and Clinical Microbiologist

Study Record Dates

• First Submitted: June 24, 2014
• First Posted: June 26, 2014
• Study Start: February 1, 2014
• Primary Completion: July 7, 2017
• Study Completion: August 7, 2017
• Last Updated: November 27, 2017

Record last verified: 2017-11

Locations

NZ (2); LE (1); TU (1); ZA (2); SA (2); CA (1); SG (2); IT (6); AU (14)