Ceftolozane-tazobactam Versus Meropenem for ESBL and AmpC-producing Enterobacterales Bloodstream Infection
- Conditions
- Bacteremia Caused by Gram-Negative Bacteria
- Interventions
- Drug: Ceftolozane-Tazobactam
- Registration Number
- NCT04238390
- Lead Sponsor
- The University of Queensland
- 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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
- 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
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ceftolozane-tazobactam 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 Meropenem Meropenem Participants will receive meropenem 1 gram, every 8 hours, three times a day, intravenously over 30 mins.
- Primary Outcome Measures
Name Time Method Mortality rate at 30 days 30 days post randomisation To compare the 30-day mortality from day of randomisation of each regimen
- Secondary Outcome Measures
Name Time Method Clinical and microbiological success 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
Serious adverse events 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 30 days post randomisation To compare rates of Clostridioides difficile infection with each regimen
Colonisation and/or infection with multi-resistant bacterial organisms 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 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)
Mortality rate at 14 days 14 days post randomisation To compare the 14-day mortality from day of randomisation of each regimen
Functional bacteraemia score (FBS) 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 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 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 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)
Trial Locations
- Locations (29)
Sir Charles Gairdner
🇦🇺Perth, Western Australia, Australia
Fiona Stanley Hospital
🇦🇺Perth, Western Australia, Australia
King Abdulaziz Medical City
🇸🇦Riyadh, Saudi Arabia
Policlinico Umberto
🇮🇹Roma, Italy
Hospital Sant Pau
🇪🇸Barcelona, Spain
Dipartimento di Scienze Biomediche e Cliniche
🇮🇹Milan, Italy
National University Hospital
🇸🇬Singapore, Singapore
Singapore General Hospital
🇸🇬Singapore, Singapore
Sanremo Hospital
🇮🇹Sanremo, Italy
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
King Fahad Specialist Hospital
🇸🇦Dammam, Saudi Arabia
Mutua Terrassa University Hospital
🇪🇸Barcelona, Spain
Tan Tock Seng Hospital
🇸🇬Singapore, Singapore
Hospital del Mar
🇪🇸Barcelona, Spain
Bellvitge University Hospital
🇪🇸Barcelona, Spain
King Abdulaziz Medical City - Jeddah
🇸🇦Jeddah, Saudi Arabia
Università di Pisa
🇮🇹Pisa, Italy
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Westmead Hospital
🇦🇺Sydney, New South Wales, Australia
Royal Prince Alfred
🇦🇺Sydney, New South Wales, Australia
John Hunter Hospital
🇦🇺Newcastle, New South Wales, Australia
Princess Alexandra Hospital
🇦🇺Brisbane, Queensland, Australia
Woolongong Hospital
🇦🇺Wollongong, New South Wales, Australia
Royal Brisbane and Women's Hospital
🇦🇺Brisbane, Queensland, Australia
Monash Medical Centre
🇦🇺Melbourne, Victoria, Australia
Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Dandenong Hospital
🇦🇺Melbourne, Victoria, Australia
Policlinico Sant'Orsola Malpighi
🇮🇹Bologna, Italy