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).