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

• Growth of Gram-negative bacilli identified from blood culture(s)
• Receiving or planning to receive intravenous antibiotics
• 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:

• temperature > 38 °C
• 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)
• 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:

• 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:

• new onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased in suctioning requirements
• new onset or worsening tachypnoea or dyspnoea
• rales or bronchial breath sounds
• 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

• Treating team deems enrolment in the study is not in the best interest of the patient
• Patient is on end-of-life care
• Patient is incarcerated in a correctional facility
• Participation in any interventional study activities outlined in the TREAT-GNB study within the last 90 days
• Pregnant women and children

OR

• Polymicrobial bloodstream infection