Continuous or intermittent Beta-lactam antibiotic infusions: Which is better for reducing mortality in ICU patients with sepsis?

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

"The randomized clinical trial comprising 7031 adult patients with sepsis revealed no statistically significant difference in the proportion of patients who died within 90 days who received continuous (24.9%) versus intermittent (26.8%) β-lactam antibiotic infusions (odds ratio, 0.91)," the researchers reported. The findings were published online in the Journal of the American Medical Association (JAMA).

Sepsis, a life-threatening condition characterized by systemic inflammation in response to infection, remains a significant challenge in critical care medicine. Antibiotic therapy is a cornerstone of sepsis management, yet the optimal dosing strategy has been a subject of debate. Traditionally, antibiotics have been administered intermittently, but recent evidence has suggested that continuous infusion may offer advantages regarding pharmacokinetics and clinical outcomes.

Joel M. Dulhunty, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia, and colleagues aimed to evaluate whether continuous versus intermittent infusion of a β-lactam antibiotic (meropenem or piperacillin-tazobactam) results in reduced all-cause mortality at 90 days in critically ill patients with sepsis.

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

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

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

The study led to the following findings:

• Among 7202 randomized participants, 7031 (mean age, 59 years; 35% women) met consent requirements for inclusion in the primary analysis (97.6%).
• Within 90 days, 24.9% of patients assigned to receive continuous infusion had died compared with 26.8% assigned intermittent infusion (absolute difference, −1.9%; odds ratio, 0.91).
• Clinical cure was higher in the continuous vs intermittent infusion group (55.7% and 50.0%, respectively; absolute difference, 5.7%).
• Other secondary outcomes were not statistically different.

"The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics failed to meet statistical significance in the primary analysis," the researchers wrote. "However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in continuous infusions use in this group of patients."

Reference:

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