IMPORTANCE: Whether ß-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 ß-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 ß-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 ß-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.
| Discipline Area | Score |
|---|---|
| Infectious Disease |  |
| Intensivist/Critical Care | |
| Hospital Doctor/Hospitalists |  |
| Internal Medicine | |
Important article for highlighting that there may be clinical benefit of continuous infusion of antibiotics, but further study is needed.
This is the largest high-quality trial ever done on this subject. The primary and secondary outcomes, the pre-specified adjusted overall and subgroup analyses all showed consistent patient-centered benefits. Unfortunately, the conclusion is totally non-informative and does not do justice to the clearly positive results. Ironically, while the editors of these major journals frequently criticize the excessive emphasis on p-values, the JAMA editorial decision to have the conclusion “…did not meet statistical significance…however, the confidence interval…” was obviously due to the arbitrary p-value cut-off. This excessive emphasis on p-values without accounting for the entirety and consistency of the trial results continues to be a common misleading practice of editors. Despite the editorial mistake by reporting this trial as negative when it is in fact positive, the BLING III results will change both clinical practice and major guidelines.
A number of trials have evaluated continuous vs intermittent administration of beta-lactam antibiotics in ICU. This large well conducted clinical trial's adjusted analysis suggests a small reduction in mortality, and a higher rate of clinical cure with the continuous administration strategy. I suspect when combined with other trials in a meta-analysis, this will provide robust evidence supporting continuous infusions. As a clinician, this trial finally makes continuous infusions the preferred choice whenever feasible.
