Optimising TREATment for Severe Gram-Negative Bacterial Infections

Inclusion Criteria: A: Bloodstream infections a) Suitable for at least 2 antibiotic regimens in the site randomisation list 1. Growth of Gram-negative bacilli identified from blood culture(s) 2. Receiving or planning to receive intravenous antibiotics 3. Expected time from blood culture sampling to randomisation is ≤ 96 hours. OR B: Ventilator-associated pneumonia / hospital-acquired pneumonia a) Suitable for at least 2 antibiotic regimens in the site randomisation list b) Infection syndrome definitions\^( (US Centers for Disease Control and Prevention National Healthcare Safety Network)3: i) At least one of the following: 1. temperature \> 38 °C 2. white blood cell count ≥ 12,000 cells/mm3 (12 x 109/L, 12 x 103/µL) or ≤ 4,000 cells/mm3 (4 x 109/L, 4 x 103/µL) 3. altered mental status with no other causes in \> 70 years old; AND ii) Two or more chest imaging tests demonstrating at least one of the following: 1\) new and progressive OR progressive and persistent infiltrate 2) new and persistent OR progressive and persistent consolidation 3) new and persistent OR progressive and persistent cavitation; AND iii) At least two of the following: 1. new onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased in suctioning requirements 2. new onset or worsening tachypnoea or dyspnoea 3. rales or bronchial breath sounds 4. worsening gas exchange defined by oxygen desaturations (e.g., PaO2/FiO2 \< 240), increased oxygen requirements or increased ventilation demand. c) Hospital admission \> 48 hours d) Predominant growth of Gram-negative bacilli identified from respiratory tract specimen(s)\*; e) Receiving or planning to receive intravenous antibiotics f) Expected time from respiratory culture sampling to randomisation is ≤ 96 hours AND C: CR-GNB antibiotic backbone domain a) Gram-negative bacilli belonging to Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa or Enterobacterales b) Carbapenem resistance in isolate detected - i) Phenotypically via conventional microbiology testing: meropenem / imipenem / ertapenem resistance; OR ii) Genotypically via PCR or next generation sequencing: presence of genes associated with carbapenemase production (eg. blaNDM, blaKPC, blaIMP, blaIMI, blaVIM, blaOXA-48-like). Exclusion Criteria: 1. Treating team deems enrolment in the study is not in the best interest of the patient 2. Patient is on end-of-life care 3. Patient is incarcerated in a correctional facility 4. Participation in any interventional study activities outlined in the TREAT-GNB study within the last 90 days 5. Pregnant women and children OR 6. Polymicrobial bloodstream infection