Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis (2024)

• ¹Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

• ²Redcliffe Hospital, Brisbane, Queensland, Australia

• ³The University of Queensland, Brisbane, Queensland, Australia

• ⁴Imperial College Healthcare NHS Trust, London, United Kingdom

• ⁵Department of Surgery and Cancer, Imperial College London, London, United Kingdom

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• ⁶Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium

• ⁷The George Institute for Global Health, The University of New South Wales, Sydney, New South Wales, Australia

• ⁸Infection Research Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

• ⁹Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia

• ¹⁰School of Public Health, Imperial College London, United Kingdom

• ¹¹Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, New South Wales, Australia

• ¹²Auckland City Hospital, Auckland, New Zealand

• ¹³Medical Research Institute of New Zealand, Wellington, New Zealand

• ¹⁴Saw Swee Hock School of Public Health and Yong Loo Lin School of Medicine, National University of Singapore, Singapore

• ¹⁵The Queen Elizabeth Hospital, Adelaide, South Australia, Australia

• ¹⁶School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia

• ¹⁷School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

• ¹⁸St George’s University Hospitals NHS Foundation Trust, London, United Kingdom

• ¹⁹St George’s University of London, London, United Kingdom

• ²⁰Herston Infectious Diseases Institute, Metro North Health, Brisbane, Queensland, Australia

• ²¹Department of Anesthesiology, Critical Care, Pain, and Emergency Medicine, University Hospital of Nîmes, Nîmes, France

• ²²University of Montpellier, Montpellier, France

• ²³Blacktown Hospital, Sydney, New South Wales, Australia

• ²⁴Metro North Health, Brisbane, Queensland, Australia

• ²⁵St George Hospital, Sydney, New South Wales, Australia

Key Points

Question Is there a difference in mortality between continuous and intermittent infusions of β-lactam antibiotics in critically ill patients with sepsis?

Findings In this randomized clinical trial that included 7031 adult patients with sepsis, there was not a statistically significant difference in the proportion of patients who died within 90 days who received continuous (24.9%) compared with intermittent (26.8%) β-lactam antibiotic infusions (odds ratio, 0.91).

Meaning In critically ill patients with sepsis, continuous vs intermittent β-lactam antibiotic infusions did not significantly reduce 90-day mortality in the primary analysis.

Importance Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain.

Objective To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis.

Design, Setting, and Participants An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis.

Intervention Eligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first.

Main Outcomes and Measures The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality.

Results Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, −1.9% [95% CI, −4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different.

Conclusions and Relevance The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients.

Trial Registration ClinicalTrials.gov Identifier: NCT03213990

Critical Care Medicine Antibiotic Use, Overuse, Resistance, Stewardship Sepsis Resuscitation Infectious Diseases

Citation

Dulhunty JM, Brett SJ, De Waele JJ, et al. Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. JAMA. Published online June 12, 2024. doi:10.1001/jama.2024.9779

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