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Randomized Controlled Trial
. 2024 Aug 27;332(8):629-637.
doi: 10.1001/jama.2024.9779.

Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial

Joel M Dulhunty  1   2   3 , Stephen J Brett  4   5 , Jan J De Waele  6 , Dorrilyn Rajbhandari  7 , Laurent Billot  7 , Menino O Cotta  1   3 , Joshua S Davis  8   9 , Simon Finfer  7   10 , Naomi E Hammond  7   11 , Serena Knowles  7 , Xiaoqiu Liu  7 , Shay McGuinness  12   13 , Jayanthi Mysore  7 , David L Paterson  1   3   14 , Sandra Peake  15   16   17 , Andrew Rhodes  18   19 , Jason A Roberts  1   3   20   21 , Claire Roger  21   22 , Charudatt Shirwadkar  23 , Therese Starr  1   24 , Colman Taylor  7 , John A Myburgh  7   25 , Jeffrey Lipman  1   3   21 ; BLING III Study Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial

Joel M Dulhunty et al. JAMA. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Brett reported receiving consultancy fees from GSK to the university account for a project on real-world effectiveness of sotrovimab outside the submitted work. Dr De Waele reported receiving grants from Flanders Research Foundation Senior Clinical Investigator Fellowship during the conduct of the study and speaker activities and honoraria paid to the institution from Pfizer, MSD, Menarini, and Viatris outside the submitted work. Dr Davis reported receiving a National Health and Medical Research Council Career Development Award (salary funding) during the conduct of the study. Dr Finfer reported receiving consulting fees from RevImmune Inc paid to his institution during the conduct of the study, stock options from Sepsis Scout outside the submitted work, and support from the National Health and Medical Research Council of Australia with a Leadership Fellowship. Dr Hammond reported receiving consulting fees from RevImmune Inc paid to her institution outside the submitted work and support from the National Health and Medical Research Council of Australia with an Emerging Leader grant. Dr Paterson reported receiving grants from Shionogi, Pfizer, Merck, BioVersys, bioMerieux, and Gilead and personal fees from Shionogi, Merck, GSK, bioMerieux, Cepheid, Aurobac, Arrepath, CARB-X, and AMR Action Fund outside the submitted work. Dr Rhodes reported receiving nonfinancial support from St George’s University NHS Foundation Trust during the conduct of the study and serving as past chair of the sepsis guidelines committee and executive member of the Surviving Sepsis Campaign. Dr Roberts reported receiving personal fees from Qpex, Gilead, Advanz Pharma, Pfizer, Sandoz, MSD, Cipla, and bioMerieux and grants from Qpex, Pfizer, bioMerieux (provided e-Tests for bacterial susceptibility testing within the BLING III pharmacokinetic-pharmacodynamic substudy), and the British Society for Antimicrobial Chemotherapy outside the submitted work; Dr Roberts was supported by a Leadership Fellowship from the National Health and Medical Research Council of Australia and an Advancing Queensland Clinical Fellowship. He is also in receipt of a Centre of Research Excellence from the National Health and Medical Research Council of Australia. Dr Roger reported receiving personal fees from Shionogi, bioMerieux, AOP Orphan, MSD, Viatris, Pfizer, Fresenius, and Advanz Pharma outside the submitted work. Dr Taylor reported being part owner of Health Technology Analysts Pty Ltd, which provides consulting services to pharmaceutical companies, medical device companies, and the Australian government. Dr Myburgh reported receiving support from a Leadership Fellowship from the National Health and Medical Research Council of Australia outside the submitted work. No other disclosures were reported.

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