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

NCT ID: NCT04238390

Last Updated: 2022-05-19

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-01-31
• Study Completion Date: 2024-12-31

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.

Conditions

Bacteremia Caused by Gram-Negative Bacteria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Ceftolozane-Tazobactam

Intervention Type: 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.

Meropenem

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

Group Type: ACTIVE_COMPARATOR

Meropenem

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DRUG

Meropenem

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

Intervention Type: DRUG

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

The University of Queensland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

John Hunter Hospital

Newcastle, New South Wales, Australia

Royal Prince Alfred

Sydney, New South Wales, Australia

Westmead Hospital

Sydney, New South Wales, Australia

Woolongong Hospital

Wollongong, New South Wales, Australia

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

Alfred Hospital

Melbourne, Victoria, Australia

Monash Medical Centre

Melbourne, Victoria, Australia

Dandenong Hospital

Melbourne, Victoria, Australia

Royal Perth Hospital

Perth, Western Australia, Australia

Sir Charles Gairdner

Perth, Western Australia, Australia

Fiona Stanley Hospital

Perth, Western Australia, Australia

Policlinico Sant'Orsola Malpighi

Bologna, , Italy

Dipartimento di Scienze Biomediche e Cliniche

Milan, , Italy

Università di Pisa

Pisa, , Italy

Policlinico Umberto

Roma, , Italy

Sanremo Hospital

Sanremo, , Italy

King Fahad Specialist Hospital

Dammam, , Saudi Arabia

King Abdulaziz Medical City - Jeddah

Jeddah, , Saudi Arabia

King Abdulaziz Medical City

Riyadh, , Saudi Arabia

National University Hospital

Singapore, , Singapore

Singapore General Hospital

Singapore, , Singapore

Tan Tock Seng Hospital

Singapore, , Singapore

Bellvitge University Hospital

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital del Mar

Barcelona, , Spain

Hospital Sant Pau

Barcelona, , Spain

Mutua Terrassa University Hospital

Barcelona, , Spain

Countries

Australia; Italy; Saudi Arabia; Singapore; Spain

References

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.

Reference Type: DERIVED

PMID: 33888139 (View on PubMed)

Other Identifiers

UQCCR-DP-AS-2019-001

Identifier Type: -

Identifier Source: org_study_id