Clinical trial NCT04238390: Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection
Official title: 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: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Bacteremia Caused by Gram-Negative Bacteria
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2020-01-23
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Mortality rate at 30 days
timeFrame: 30 days post randomisation
Secondary outcomes:
measure: Mortality rate at 14 days
timeFrame: 14 days post randomisation
measure: Clinical and microbiological success
timeFrame: 5 days post randomisation
measure: Functional bacteraemia score (FBS)
timeFrame: 0 and 30 days post randomisation
measure: Microbiological relapse
timeFrame: 30 days post randomisation
measure: Rates of new bloodstream infection
timeFrame: 30 days post randomisation
measure: Length of in-patient hospital and ICU stay
timeFrame: 30 days post randomisation
measure: Serious adverse events
timeFrame: Day 1 to last dose plus 24 hours of treatment:
measure: Clostridioides difficile infection
timeFrame: 30 days post randomisation
measure: Colonisation and/or infection with multi-resistant bacterial organisms
timeFrame: 30 days post randomisation
measure: Desirability of Outcome Ranking (DOOR) with partial credit
timeFrame: 30 days post randomisation
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Woolongong Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Melbourne
country: Australia
facility: Dandenong Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola Malpighi
city: Milan
country: Italy
facility: Dipartimento di Scienze Biomediche e Cliniche
city: Pisa
country: Italy
facility: Università di Pisa
city: Roma
country: Italy
facility: Policlinico Umberto
city: Sanremo
country: Italy
facility: Sanremo Hospital
city: Dammam
country: Saudi Arabia
facility: King Fahad Specialist Hospital
city: Jeddah
country: Saudi Arabia
facility: King Abdulaziz Medical City - Jeddah
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Barcelona
country: Spain
facility: Bellvitge University Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: Barcelona
country: Spain
facility: Mutua Terrassa University Hospital
Study officials:
References:
citation: 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.