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

Bacteremia Caused by Gram-Negative Bacteria Clinical Trial

— MERINO III  

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04238390
• Other study ID #: UQCCR-DP-AS-2019-001
• Status: Withdrawn
• Phase: Phase 3
• Start date: January 2022
• Est. completion date: December 2024

Study information

• Verified date: October 2021
• Source: The University of Queensland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Bacteremia
• Bacteremia Caused by Gram-Negative Bacteria
• Sepsis

Intervention

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

Locations

Country	Name	City	State
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Dandenong Hospital	Melbourne	Victoria
Australia	Monash Medical Centre	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Fiona Stanley Hospital	Perth	Western Australia
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Sir Charles Gairdner	Perth	Western Australia
Australia	Royal Prince Alfred	Sydney	New South Wales
Australia	Westmead Hospital	Sydney	New South Wales
Australia	Woolongong Hospital	Wollongong	New South Wales
Italy	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
Saudi Arabia	King Fahad Specialist Hospital	Dammam
Saudi Arabia	King Abdulaziz Medical City - Jeddah	Jeddah
Saudi Arabia	King Abdulaziz Medical City	Riyadh
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
Spain	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

Sponsors (2)

Lead Sponsor	Collaborator
The University of Queensland	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

Australia,  Italy,  Saudi Arabia,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality rate at 30 days	To compare the 30-day mortality from day of randomisation of each regimen	30 days post randomisation
Secondary	Mortality rate at 14 days	To compare the 14-day mortality from day of randomisation of each regimen	14 days post randomisation
Secondary	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
Secondary	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
Secondary	Microbiological relapse	To compare the rates of relapse of bloodstream infection (microbiological failure) with each regimen at Day 30	30 days post randomisation
Secondary	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
Secondary	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
Secondary	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:
Secondary	Clostridioides difficile infection	To compare rates of Clostridioides difficile infection with each regimen	30 days post randomisation
Secondary	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
Secondary	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