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

NCT ID: NCT02176122

Last Updated: 2017-11-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 391 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2017-08-07

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).

Conditions

Bloodstream Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Meropenem

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

Group Type: ACTIVE_COMPARATOR

Meropenem

Intervention Type: DRUG

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

Piperacillin-tazobactam combination product

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

Group Type: EXPERIMENTAL

Piperacillin-tazobactam combination product

Intervention Type: DRUG

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

Interventions

Meropenem

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

Intervention Type: DRUG

Piperacillin-tazobactam combination product

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

Intervention Type: DRUG

Other Intervention Names

Merrem; Meronem; Zosyn; Tazocin

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

International Society of Chemotherapy

UNKNOWN

Sponsor Role: collaborator

Australian Society for Antimicrobials

UNKNOWN

Sponsor Role: collaborator

Queensland Clinical Trials & Biostatistics Centre

UNKNOWN

Sponsor Role: collaborator

Australasian Society for Infectious Diseases

OTHER

Sponsor Role: collaborator

The University of Queensland

OTHER

Sponsor Role: lead

Responsible Party

Professor David L. Paterson

Professor of Medicine, Infectious Diseases Consultant and Clinical Microbiologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David L Paterson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UQCCR, RBWH

Locations

Shellharbour Hospital (Illawarra Shoalhaven Local Health District)

Shellharbour, New South Wales, Australia

Westmead Hospital

Westmead, New South Wales, Australia

Wollongong Hospital

Wollongong, New South Wales, Australia

Brisbane Private Hospital

Brisbane, Queensland, Australia

St. Andrew's War Memorial Hospital

Brisbane, Queensland, Australia

Mater Misericordiae Health Services Brisbane Ltd.

Brisbane, Queensland, Australia

Royal Brisbane and Women's Hospital

Herston, Queensland, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Monash Health

Clayton, Victoria, Australia

Peter MacCallum Cancer Centre

East Melbourne, Victoria, Australia

Barwon Health

Geelong, Victoria, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Royal Perth Hospital

Perth, Western Australia, Australia

Fiona Stanley Hospital

Perth, , Australia

Sunnybrook Research Institute

Toronto, , Canada

Teaching Hospital - Sant'Orsola Malpighi

Bologna, , Italy

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

Milan, , Italy

"Sapienza" University of Rome

Rome, , Italy

Catholic University Rome

Rome, , Italy

Sanremo Hospital

Sanremo, , Italy

Santa Maria Misericorida University Hospital

Udine, , Italy

The American University of Beirut

Beirut, , Lebanon

Middlemore Hospital

Papatoetoe, , New Zealand

The North Shore Hospital

Westlake, , New Zealand

King Fahad Specialist Hospital

Dammam, , Saudi Arabia

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

Riyadh, , Saudi Arabia

National University Hospital

Singapore, , Singapore

Tan Tock Seng Hospital

Singapore, , Singapore

Groote Schuur Hospital

Cape Town, , South Africa

Charlotte Maxeke Johannesberg Academic Hospital

Johannesburg, , South Africa

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

Istanbul, , Turkey (Türkiye)

Countries

Malaysia; Australia; Canada; Italy; Lebanon; New Zealand; Saudi Arabia; Singapore; South Africa; Turkey (Türkiye)

References

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.

Reference Type: DERIVED

PMID: 30208454 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25623485 (View on PubMed)

Other Identifiers

ACTRN12613000532707

Identifier Type: -

Identifier Source: org_study_id