Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection

NCT04238390 | Withdrawn Phase 3 DMC

• 1 other identifier: UQCCR-DP-AS-2019-001
• Study Type: interventional
• Target: N/A
• Locations: 5 countries
• Sites: 29

Brief Summary

The purpose of this study is to determine whether ceftolozane-tazobactam is as effective as meropenem with respect to 30 day mortality in the treatment of bloodstream infection due to third-generation cephalosporin non-susceptible Enterobacterales or a known chromosomal AmpC-producing Enterobacterales (Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens).

Conditions

Bacteremia Caused by Gram-Negative Bacteria

Outcome Measures

Primary Outcomes (1)

• Mortality rate at 30 days

  To compare the 30-day mortality from day of randomisation of each regimen

  30 days post randomisation

Secondary Outcomes (10)

• Mortality rate at 14 days

  14 days post randomisation

• Clinical and microbiological success

  5 days post randomisation

• Functional bacteraemia score (FBS)

  0 and 30 days post randomisation

• Microbiological relapse

  30 days post randomisation

• Rates of new bloodstream infection

  30 days post randomisation

Study Arms (2)

Ceftolozane-tazobactam

EXPERIMENTAL

Participants will receive ceftolozane-tazobactam 3 grams (comprising ceftolozane 2 grams and tazobactam 1 gram) administered, every 8 hours, three times a day, intravenously over 60 mins

Drug: Ceftolozane-Tazobactam

Meropenem

ACTIVE COMPARATOR

Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.

Drug: Meropenem

Interventions

Ceftolozane-Tazobactam DRUG

Ceftolozane-tazobactam 3 grams (comprising ceftolozane 2 grams and tazobactam 1 gram) administered, every 8 hours, three times a day, intravenously over 60 mins. Dose adjusted for renal function.

Ceftolozane-tazobactam

Meropenem DRUG

Meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins. Dose adjusted for renal function.

Meropenem

Eligibility Criteria

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

You may qualify if:

• Bloodstream infection defined as presence in at least one peripheral blood culture draw demonstrating Enterobacterales with proven non-susceptibility to third generation cephalosporins or cephalosporin susceptible species known to harbour chromosomal AmpC-beta-lactamases (Enterobacter spp., Klebsiella aerogenes, Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens) during hospitalisation
• Patient is aged 18 years and over (21 and over in Singapore)
• The patient or approved proxy is able to provide informed consent
• ≤72 hours has elapsed since the first positive qualifying (index) blood culture collection
• Expected to receive IV therapy for ≥5 days

You may not qualify if:

• Known hypersensitivity to a cephalosporin or a carbapenem, or anaphylaxis to beta-lactam antibiotics
• Participant with significant polymicrobial bloodstream infection (i.e. not a contaminant)
• Treatment is not with the intent to cure the infection (i.e. palliative intent) or the expected survival is ≤4 days
• Participant is pregnant or breast-feeding (tested for in women of child-bearing age only)
• Use of concomitant antimicrobials with known activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis and when adding metronidazole for suspected IAI) in the first 5 days post-randomisation
• Participant with CrCl \<15 mL/minute or on renal replacement therapy (in addition, participants will be withdrawn from the study if CrCl reaches this level)
• Previously randomised in the MERINO-3 trial or concurrently enrolled in another therapeutic antibiotic clinical trial
• Blood culture isolate with in-vitro resistance to either meropenem or ceftolozane-tazobactam (known either at time of enrolment or during the course of study treatment, in which case the participant will be withdrawn)

Sponsors & Collaborators

• The University of Queensland: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (29)

John Hunter Hospital

Newcastle, New South Wales, 2305, Australia

Location

Royal Prince Alfred

Sydney, New South Wales, 2050, Australia

Location

Westmead Hospital

Sydney, New South Wales, 2145, Australia

Location

Woolongong Hospital

Wollongong, New South Wales, 2500, Australia

Location

Royal Brisbane and Women's Hospital

Brisbane, Queensland, 4029, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, 4102, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Monash Medical Centre

Melbourne, Victoria, 3168, Australia

Location

Dandenong Hospital

Melbourne, Victoria, 3175, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Sir Charles Gairdner

Perth, Western Australia, 6009, Australia

Location

Fiona Stanley Hospital

Perth, Western Australia, 6150, Australia

Location

Policlinico Sant'Orsola Malpighi

Bologna, Italy

Location

Dipartimento di Scienze Biomediche e Cliniche

Milan, Italy

Location

Università di Pisa

Pisa, Italy

Location

Policlinico Umberto

Roma, Italy

Location

Sanremo Hospital

Sanremo, Italy

Location

King Fahad Specialist Hospital

Dammam, Saudi Arabia

Location

King Abdulaziz Medical City - Jeddah

Jeddah, Saudi Arabia

Location

King Abdulaziz Medical City

Riyadh, 14611, Saudi Arabia

Location

National University Hospital

Singapore, 119074, Singapore

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

Tan Tock Seng Hospital

Singapore, 308433, Singapore

Location

Bellvitge University Hospital

Barcelona, Spain

Location

Hospital Clinic de Barcelona

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Hospital Sant Pau

Barcelona, Spain

Location

Mutua Terrassa University Hospital

Barcelona, Spain

Location

Related Publications (1)

• Stewart AG, Harris PNA, Chatfield MD, Littleford R, Paterson DL. Ceftolozane-tazobactam versus meropenem for definitive treatment of bloodstream infection due to extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales ("MERINO-3"): study protocol for a multicentre, open-label randomised non-inferiority trial. Trials. 2021 Apr 22;22(1):301. doi: 10.1186/s13063-021-05206-8.

  PMID: 33888139 DERIVED

MeSH Terms

Interventions

ceftolozane, tazobactam drug combination; Meropenem

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2019
• First Posted: January 23, 2020
• Study Start: January 1, 2022
• Primary Completion: June 1, 2024
• Study Completion: December 1, 2024
• Last Updated: May 19, 2022

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

SG (3); SA (3); IT (5); AU (13); ES (5)