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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Bacteremia Caused by Gram-Negative Bacteria

Intervention / Treatment
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* Drug: Ceftolozane-Tazobactam
* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |