Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection (MERINO III)

A Multicentre, Parallel Group Open-label Randomised Controlled Non-Inferiority Phase 3 Trial, of Ceftolozane-tazobactam Versus Meropenem for Definitive Treatment of Bloodstream Infection Due to Extended-Spectrum Beta-Lactamase (ESBL) and AmpC-producing Enterobacterales

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).

Study Overview

• Status: Withdrawn
• Conditions: Bacteremia Caused by Gram-Negative Bacteria
• Intervention / Treatment: Drug: Ceftolozane-Tazobactam; Drug: Meropenem

Detailed Description

Enterobacterales are common causes of bacteraemia, and may produce extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases. ESBL or AmpC producers are typically resistant to third generation cephalosporins such as ceftriaxone, but susceptible to carbapenems. In no study has the outcome of treatment for serious infections for ESBL producers been significantly surpassed by carbapenems. 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.

Ceftolozane-tazobactam is a combination of a new beta-lactam antibiotic with an existing beta-lactamase inhibitor, tazobactam, and is active against ESBL and most AmpC producing organisms. In a large sample of ESBL- and AmpC-producing Enterobacterales isolates from urinary tract and intra-abdominal specimens, ceftolozane-tazobactam was susceptible in over 80%. It has been FDA approved for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI), and more recently for hospital-acquired and ventilator-associated pneumonia (HAP/VAP). In addition, a pooled analysis of phase 3 clinical trials has shown favourable clinical cure rates with ceftolozane-tazobactam for cUTI and cIAI caused by ESBL-producing Enterobacterales. Given the issues of carbapenem resistant organisms, there is a need for establishing the efficacy of an alternative to carbapenems for serious infections.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Newcastle, New South Wales, Australia, 2305
      • John Hunter Hospital
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Sydney, New South Wales, Australia, 2050
      • Royal Prince Alfred
    • Wollongong, New South Wales, Australia, 2500
      • Woolongong Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3168
      • Monash Medical Centre
    • Melbourne, Victoria, Australia, 3000
      • Peter Maccallum Cancer Centre
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
    • Melbourne, Victoria, Australia, 3175
      • Dandenong Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
    • Perth, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Perth, Western Australia, Australia, 6009
      • Sir Charles Gairdner
• Italy
  • Bologna, Italy
    • Policlinico Sant'Orsola Malpighi
  • Milan, Italy
    • Dipartimento di Scienze Biomediche e Cliniche
  • Pisa, Italy
    • Università di Pisa
  • Roma, Italy
    • Policlinico Umberto
  • Sanremo, Italy
    • Sanremo Hospital
• Saudi Arabia
  • Dammam, Saudi Arabia
    • King Fahad Specialist Hospital
  • Jeddah, Saudi Arabia
    • King Abdulaziz Medical City - Jeddah
  • Riyadh, Saudi Arabia, 14611
    • King Abdulaziz Medical City
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
  • Singapore, Singapore, 119074
    • National University Hospital
  • Singapore, Singapore, 308433
    • Tan Tock Seng Hospital
• Spain
  • Barcelona, Spain
    • Hospital Clinic de Barcelona
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • Hospital Sant Pau
  • Barcelona, Spain
    • Bellvitge University Hospital
  • Barcelona, Spain
    • Mutua Terrassa University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftolozane-tazobactam; 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; 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.
Active Comparator: Meropenem; Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.	Drug: Meropenem; Meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins. Dose adjusted for renal function.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate at 30 days	To compare the 30-day mortality from day of randomisation of each regimen	30 days post randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate at 14 days	To compare the 14-day mortality from day of randomisation of each regimen	14 days post randomisation
Clinical and microbiological success	Defined as survival PLUS resolution of fever (temperature <38 degrees Celsius) PLUS improved SOFA score (as compared to baseline) PLUS sterilisation of blood cultures at Day 5	5 days post randomisation
Functional bacteraemia score (FBS)	To compare the functional bacteraemia score of patients treated with each regimen at baseline and Day 30 (scored 0-7, higher scores equal better outcomes)	0 and 30 days post randomisation
Microbiological relapse	To compare the rates of relapse of bloodstream infection (microbiological failure) with each regimen at Day 30	30 days post randomisation
Rates of new bloodstream infection	To compare the rates of new bloodstream infection (growth of a new organism from blood cultures - not a contaminant as determined by treating clinician) with each regimen	30 days post randomisation
Length of in-patient hospital and ICU stay	To compare lengths of in-patient hospital and ICU stay with each regimen (not including in-patient rehabilitation, long term acute care or hospital in the home)	30 days post randomisation
Serious adverse events	To compare the number of treatment emergent serious adverse events with each regimen	Day 1 to last dose plus 24 hours of treatment:
Clostridioides difficile infection	To compare rates of Clostridioides difficile infection with each regimen	30 days post randomisation
Colonisation and/or infection with multi-resistant bacterial organisms	To compare rates of colonisation and/or infection with multi-resistant bacterial organisms (MROs) including those newly acquired	30 days post randomisation
Desirability of Outcome Ranking (DOOR) with partial credit	To compare the Desirability of Outcome Ranking (DOOR) with partial credit with each regimen (scored 0-100, higher scores equal better outcomes)	30 days post randomisation

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: December 16, 2019
• First Submitted That Met QC Criteria: January 19, 2020
• First Posted (Actual): January 23, 2020

Study Record Updates

• Last Update Posted (Actual): May 19, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Meropenem; Tazobactam; Ceftolozane; Ceftolozane, tazobactam drug combination
• Other Study ID Numbers: UQCCR-DP-AS-2019-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No