Prolonged β-Lactam Infusions and Patients Outcomes: Insights From the BLING III Trial

Most β lactams have a half-life of 1 to 2 hours, and it has been theorized that prolonged β-lactam infusions would improve pharmacokinetic target attainment. This is important especially in the intensive care population where many physiologic changes have pharmacokinetic consequences, including possible increased drug clearance and increased volume of distribution.

Most β lactams have a half-life of 1 to 2 hours, and it has been theorized that prolonged β-lactam infusions would improve pharmacokinetic target attainment. Image Credit: © ShannonK - stock.adobe.com

The highly awaited BLING III trial (NCT03213990) was published in JAMA on June 12, 2024.¹ It investigated the efficacy and safety of continuous vs intermittent administration of β-lactam antibiotics in critically ill patients with sepsis.¹ This international, multicenter, open-label, randomized controlled trial included 7202 patients who were assigned to receive β-lactam antibiotics either continuously or intermittently.¹ This trial was conducted in multiple sites across 3 continents with almost 800 local study investigators. This makes it one of the largest randomized control trials in the field of intensive care medicine in recent years.¹

The primary outcome assessed was 90-day all-cause mortality. Results showed no significant difference between the continuous and intermittent groups, with mortality rates of 24.9% and 26.8%, respectively.¹ Secondary outcomes were clinical cure up to 14 days after randomization and new acquisition, colonization, or infection with a multidrug resistant organism or Clostridioides difficile infection up to 14 days after randomization.¹ Feasibility and cost-effectiveness were not considered, but the total daily antibiotic dose was similar.¹ Less nursing time would be potentially beneficial and interesting to consider in future trials.¹

Clinical cure was higher in the continuous group compared to the intermittent group (1930/3467 [55.7%] vs 1744/3491 [50.0%]).¹ This leads to an absolute difference of 5.7% [95% CI, 2.4% to 9.1%].¹ Other secondary outcomes were not statistically different.¹

While these findings suggest that continuous infusion of β-lactam antibiotics does not provide a mortality benefit over intermittent, there are still many questions to be answered.² JAMA also released a systematic review on prolonged vs intermittent infusions of β-lactam antibiotics that used data from this trial.² This review concluded prolonged infusions of β-lactam antibiotics are associated with a reduced risk of death in critically ill adult patients with sepsis or septic shock.² There was also not a subgroup analysis breaking down effectiveness per MIC of the bacteria.² Hopefully, this information will be reviewed and released soon. It would be interesting to see how resistant bacteria respond to prolonged infusions of β lactams.

Pharmacists should consider these results and questions when developing antibiotic protocols and advising on antibiotic administration strategies. These results reinforce the need for individualized patient care and further research to optimize antibiotic use. Having a dedicated line for only continuous infusion is not easy, especially in the intensive care unit. Intravenous compatibility has to be reviewed before administering medications through via Y-site infusion. Nevertheless, the benefit on cure rate and unresolved questions regarding treatment of more resistant organisms should be considered. The use of prolonged/extended infusions is still recommended per the Surviving Sepsis Campaign guidelines; however, this is only a weak recommendation based on moderate quality of evidence.³ Extended infusions are also endorsed by the American College of Clinical Pharmacy, the British Society for Antimicrobial Chemotherapy, the Cystic Fibrosis Foundation, the European Society of Clinical Microbiology and Infectious Diseases, the Infectious Diseases Society of America, the Society of Critical Care Medicine, and the Society of Infectious Diseases Pharmacists.³

REFERENCES

1. 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. June 12, 2024. doi:10.1001/jama.2024.9779
2. Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA. June 12, 2024. doi:10.1001/jama.2024.9803
3. Hong LT, Downes KJ, FakhriRavari A, et al. International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2023;43(8):740-777. doi:10.1002/phar.2842