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More Cures and (Possibly) Less Mortality with Continuous than Intermittent ß-Lactam Infusion for Sepsis


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Continuous infusion of ß-lactam antibiotics for sepsis was associated with higher rate of clinical cure and lower, albeit not statistically significantly, 90-day mortality than intermittent infusion, in the latest and largest trial comparing outcomes from different schedules of the same 24-hour dose.1

Lead author Joel Dulhunty, MD, PhD, Intensive Care Services, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia and investigators of the Beta-Lactam Infusion Group (BLING) III trial point out that the confidence interval around the numerically lower 90-day mortality with continuous infusion (24.9% vs 26.8%) includes both the possibility of no important effect, as well as “a clinically important benefit in the use of continuous infusions in this group of patients.”

Learn more: Continuous β-Lactam Infusions Show Promise in the Battle Against Sepsis

In an accompanying editorial,2 W Joost Wiersinga, MD, PhD, MBA, and Michael A van Agtmael, MD, PhD, Department of Medicine, Division of Infectious Diseases, Amsterdam University Medical Center, Amsterdam, The Netherlands, also considered that the lower mortality rate, in a trial which also found more clinical cures with continuous infusion, could have clinical significance despite not having been statistically significant.

“Although nonsignificant, the observed reduction in mortality of around 2% with the use of a loading dose followed by continuous infusion represents a number needed to treat of 50 patients to prevent 1 death,” Wiesinga and van Agtmael point out.

“Despite the statistical nonsignificance of its primary end point, clinical guidelines are likely to use this new landmark study and accompanying metanalysis to strengthen their recommendation to use continuous ß-lactam antibiotics over intermittent dosing in adult patients with sepsis in the ICU,” they posited.

The BLING III trial randomized over 7,000 patients at 104 ICU units in 7 countries between October 26 2018 and January 11, 2023 on 1:1 ratio to receive the same total 24-hour ß-lactam antibiotic dose (14gm piperacillin-tazobactam or 3gm meropenem) in either continuous or intermittent infusions for the duration of the treatment or until ICU discharge.Each participant had been admitted with a documented site or strong suspicion of infection and one or more organ dysfunction criteria of sepsis; and had been treated with a ß-lactam antibiotic within the 24 hours prior to randomization.

The primary outcome was all-cause mortality at 90 day. The secondary outcome of clinical cure was defined as the completion of the antibiotic regimen by day 14 without requirement to recommence treatment within 48 hours of cessation for the same infectious episode. Additional secondary measures were new acquisition, colonization or infection with a multiresistant organism or Clostridioides difficle infection up to 14 days after randomization; all-cause ICU mortality; and all-cause hospital mortality.

What You Need to Know

The trial demonstrated that continuous infusion of β-lactam antibiotics significantly improved clinical cure rates compared to intermittent infusion. Specifically, 55.7% of patients in the continuous infusion group achieved clinical cure by day 14, versus 50.0% in the intermittent group.

Although the reduction in 90-day mortality with continuous infusion (24.9%) compared to intermittent infusion (26.8%) was not statistically significant, the trend suggests a possible benefit.

Despite the primary endpoint not being statistically significant, the trial’s findings are likely to influence clinical guidelines.

Dulhunty and colleagues reported that within 90 days, 864 of 3,474 patients (24.9%) assigned to receive continuous infusion and 939 of 3,507 (24.9%) receiving intermittent infusions had died (absolute difference -1.9% [95% CI, -4.9 to 1.1%]; odds ratio 0.91 [0.81 to 1.01]; p=0.08). Clinical cure was found in 1,930 of 3467 (55.7%) in the continuous infusion group, compared to 1,744 of 3,491 (50.0%) receiving intermittent infusion (absolute difference 5.7% [2.4 to 9.1%]. Differences between groups on other secondary measures were not statistically significant.

Wiersinga and van Agtmael explain that continuous infusion after loading dose should achieve sustained concentrations throughout the dosing interval, with longer time at levels above the minimum inhibitory concentration (MIC) than intermittent dosing.They acknowledge, however, that better pharmacokinetics does not necessarily mean better clinical outcomes.

“In those patients with a high renal clearance (in early phase of sepsis, before kidney failure, with increased cardiac output and intravenous fluids pushed to counteract leaky capillaries) and infected with a pathogen with a high MIC, increased exposure by continuous infusion could be convincingly superior,” Wiersinga and van Agtmael argue.

References
1.Dulhunty JM, Brett SJ, De Waele JJ, et al. Continuous vs intermittent ß-lactam antibiotic infusions in critically ill patients with sepsis.The BLING III randomized clinical trial. JAMA. Published June 12, 2024. doi:10.1001/jama.2024.9779.Accesssed June 14, 2024.
2.Wiersinga WJ, van Agtmael MA. Resolving the dilemma on continuous vs intermittent ß-lactam antibiotics in sepsis. JAMA. Published June 12, 2024.doi:10.1001/jama.2024.10168. Accessed June 14, 2024.



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