A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis: BLING III

Background and rationale: β-Lactam antibiotics display a time-dependent mechanism of action, with evidence suggesting improved outcomes when administering these drugs via continuous infusion compared with standard intermittent infusion. However, there is no phase 3 randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis. Design and setting: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 RCT to compare continuous infusion with standard intermittent infusion of β-lactam antibiotics in critically ill patients with sepsis. The study will be conducted in about 70 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Belgium and selected other countries, from 2018 to 2021. Participants and interventions: BLING III will recruit 7000 critically ill patients with sepsis being treated with one of two β-lactam antibiotics (piperacillin–tazobactam or meropenem) to receive the β-lactam antibiotic by either continuous or intermittent infusion. Main outcome measures: The primary outcome is allcause mortality within 90 days after randomisation. Secondary outcomes are clinical cure at Day 14 after randomisation, new acquisition, colonisation or infection with a multiresistant organism or Clostridium difficile diarrhoea up to 14 days after randomisation, all-cause ICU mortality and all-cause hospital mortality. Tertiary outcomes are ICU length of stay, hospital length of stay and duration of mechanical ventilation and duration of renal replacement therapy up to 90 days after randomisation. Results and conclusions: The BLING III study will compare the effect on 90-day mortality of β-lactam antibiotics administered via continuous versus intermittent infusion in 7000 critically ill patients with sepsis. Trial registration: ClinicalTrials.gov Registry (NCT03213990).