Clinical trial NCT05258851: Ceftazidime-Avibactam Use in Critically Ill Patients With Carbapenem-Resistant Enterobacteriaceae Infections
Official title: Ceftazidime-Avibactam Versus Colistin in Critically Ill Patients With Carbapenem-Resistant Enterobacteriaceae Infections (AVI-ICU): A Non-Inferiority Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Carbapenem-Resistant Enterobacteriaceae Infection
Keywords: Carbapenem-Resistant Enterobacteriaceae
Critically ill
Ceftazidime-avibactam
Colistin
Lead sponsor: King Faisal Specialist Hospital & Research Center
Sponsor class: OTHER
First posted: 2022-02-28
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, multicenter, parallel-group, stratified, non-inferiority randomized controlled trial
Primary purpose: TREATMENT

Brief summary: Carbapenem-Resistant Enterobacteriaceae (CRE) infections are a growing national and international challenge in healthcare settings. This is not only due to the rapid spread of resistance and paucity of options of targeted-antimicrobial agents, but also owing to the high mortality of patients infected with CRE reaching up to 50% as per the Centers of Disease Control and Prevention.

Colistin-based combination regimens have been the mainstay for treating CRE-related infections. Ceftazidime-avibactam is a beta-lactamase inhibitor combination, a novel antibiotic, which recently showed a better clinical and microbiological cure against CRE along with the potential to reduce mortality and nephrotoxicity in comparison to colistin-based regimens in observational studies. However, randomized clinical trials are lacking.

This non-inferiority randomized controlled study aims to assess the efficacy and safety of ceftazidime-avibactam-based regimens in critically ill patients with CRE infections in comparison to colistin-based regimens.


Eligibility criteria: Inclusion Criteria:

1. Patients aged ≥ 18 years.
2. Admitted to an intensive care unit (ICU).
3. Patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), complicated urinary tract infection (cUTI), bacteremia, complicated intraabdominal infection (cIAI), and complicated skin and soft tissue infection (cSSTI).
4. Confirmed infection with CRE, based on a culture and sensitivity obtained within the past 72 hours of study enrollment.
5. Suspected CRE infection according to one of the following: (1) positive Xpert Carba-R test screening for blaKPC or blaOXA-48 or blaNDM or blaVIM or blaIMI assessed on the admission to the ICU, (2) positive culture for CRE obtained within 3 months from time of enrollment.

Exclusion Criteria:

1. Acute Physiology and Chronic Health Evaluation II (APACHE II) score more than 30
2. known significant hypersensitivity reaction to beta-lactam antibiotics or colistin
3. Positive culture for Stenotrophomonas maltophilia or Acinetobacter baumannii within the current hospitalization.
4. Patients received the study intervention or control for more than 24 hours before the intended randomization.
5. Patient/substitute decision-maker or caring physician's refusal to enroll in the study.
6. Patient with concomitant suspected or confirmed meningitis.
7. Pregnancy.
8. Cystic fibrosis.
9. Patients with Do Not Attempt to Resuscitate (DNAR) code status.
10. Prior knowledge that the index CRE pathogen was resistant to colistin (MIC \>2 μg/ml) or ceftazidime-avibactam (MIC \> 8 μg/ml) before randomization.
11. Objective clinical evidence for any of the following infections that necessitate study therapy for \>14 days: endovascular infection, including endocarditis, osteomyelitis, prosthetic joint infection, meningitis, and/or other central nervous system infections

Primary outcomes:
measure: 28-day mortality
timeFrame: 28 days from randomization
Secondary outcomes:
measure: 14-day mortality
timeFrame: 14 days from randomization
measure: Number of patients with clinical success at end of therapy (EOT) at day 7-14 from randomization and test of cure (TOC) 7 days after completion of treatment
timeFrame: EOT at 7-14 days from randomization and TOC 7 days after completion of treatment
measure: Number of patients with microbiological response at the EOT at days 7-14 from randomization and TOC 7 days after completion of treatment
timeFrame: EOT at 7-14 days from randomization and TOC 7 days after completion of treatment
measure: Time to weaning from mechanical ventilation at day 28
timeFrame: 28 days from randomization
measure: Requirement for renal replacement therapy at day 28
timeFrame: 28 days from randomization
measure: Intensive care unit (ICU) length of stay, censored at 28 days
timeFrame: 28 days from randomization
measure: Days alive and out of the ICU, censored at 28 days
timeFrame: 28 days from randomization
measure: Drug-related adverse events
timeFrame: 28 days from randomization
Other outcomes:
Locations:
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Centre
Study officials:
affiliation: King Faisal Specialist Hospital & Research Center
name: Zainab Al Duhailib
role: PRINCIPAL_INVESTIGATOR
affiliation: King Faisal Specialist Hospital & Research Center
name: Hakeam Hakeam
role: PRINCIPAL_INVESTIGATOR
References: