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

Overview

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).

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 1, 2024

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.

Interventions

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

Arms, Groups and Cohorts

  • 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
  • Active Comparator: Meropenem
    • Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.

Clinical Trial Outcome Measures

Primary Measures

  • Mortality rate at 30 days
    • Time Frame: 30 days post randomisation
    • To compare the 30-day mortality from day of randomisation of each regimen

Secondary Measures

  • Mortality rate at 14 days
    • Time Frame: 14 days post randomisation
    • To compare the 14-day mortality from day of randomisation of each regimen
  • Clinical and microbiological success
    • Time Frame: 5 days post randomisation
    • 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
  • Functional bacteraemia score (FBS)
    • Time Frame: 0 and 30 days post randomisation
    • 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)
  • Microbiological relapse
    • Time Frame: 30 days post randomisation
    • To compare the rates of relapse of bloodstream infection (microbiological failure) with each regimen at Day 30
  • Rates of new bloodstream infection
    • Time Frame: 30 days post randomisation
    • 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
  • Length of in-patient hospital and ICU stay
    • Time Frame: 30 days post randomisation
    • 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)
  • Serious adverse events
    • Time Frame: Day 1 to last dose plus 24 hours of treatment:
    • To compare the number of treatment emergent serious adverse events with each regimen
  • Clostridioides difficile infection
    • Time Frame: 30 days post randomisation
    • To compare rates of Clostridioides difficile infection with each regimen
  • Colonisation and/or infection with multi-resistant bacterial organisms
    • Time Frame: 30 days post randomisation
    • To compare rates of colonisation and/or infection with multi-resistant bacterial organisms (MROs) including those newly acquired
  • Desirability of Outcome Ranking (DOOR) with partial credit
    • Time Frame: 30 days post randomisation
    • To compare the Desirability of Outcome Ranking (DOOR) with partial credit with each regimen (scored 0-100, higher scores equal better outcomes)

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • The University of Queensland
  • Collaborator
    • Merck Sharp & Dohme (Australia) Pty Limited
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Adam G Stewart, MBBS, +61733465555, merino3@uq.edu.au

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