Secondary Outcomes and Clinical Implications of β-lactam Infusion Strategies in Critically Ill Patients with Sepsis

In the BLING III randomized clinical trial comparing continuous versus intermittent infusions of β-lactam antibiotics in critically ill patients with sepsis, the primary focus was on 90-day mortality. Secondary outcomes included clinical cure—defined as resolution of infection symptoms within 14 days post-randomization—and the incidence of new acquisition, colonization, or infection with multiresistant organisms or C difficile during the same period. Additionally, the trial assessed ICU mortality (deaths occurring while patients were still in intensive care) and in-hospital mortality (deaths throughout the hospital stay regardless of ICU discharge status).

While clinical cure rates significantly improved with continuous infusion compared to intermittent infusion, none of the secondary outcomes related to mortality demonstrated statistically significant differences between the two infusion methods. These findings underscore the multifaceted considerations in antibiotic administration for critically ill patients, highlighting both clinical efficacy and broader infection-related outcomes.

Given the secondary outcome of higher clinical cure rates with continuous infusion, how might these results influence current clinical guidelines or practices regarding the administration of β-lactam antibiotics in critically ill patients with sepsis? What further research or considerations are needed before recommending a change in practice?

Jason Roberts, PhD, from the BLING research program (Beta Lactam Infusion Group), highlights that a pivotal aspect of this successful study is its secondary outcomes,

“Most people are convinced by these results that giving the drug by intermittent infusion isn't as beneficial as giving it via a longer infusion. So I think that we will see quite a dramatic shift across most prescribing of these drugs for patients with sepsis to some form of prolonged infusion. It's something we are likely to see; there is a number of sites around the world that are very comfortable with using an extended infusion. So that's an infusion, which of course goes for about half of the dosing interval, as opposed to what a continuous infusion does, which runs throughout the entire dosing interval.”

Regarding the impact on clinical guidelines, the study suggests a potential revision in practice to favor prolonged infusions based on improved clinical cure rates. However, before definitively recommending a change, further research is warranted. Considerations should include cost-effectiveness analysis, long-term outcomes beyond 90 days, and identifying specific patient subgroups that may benefit more from one infusion method over the other.

“In terms of whether we need to wait for anything else before incorporating this into practice, I don't think that we do,” emphasizes Roberts. “Certainly within 24 hours of the publication of this study, there were ICUs around the world that had put onto Twitter exactly what their protocol would be and how from that moment forward patients with sepsis would all be receiving continuous infusions of piperacillin-tazobactam or meropenem.”

The findings of the study suggest a potential preference for prolonged infusions of β-lactam antibiotics due to observed improvements in clinical cure rates with continuous infusion compared to intermittent infusion.

Roberts finishes, “I think we don't necessarily need to wait. There are early adopters, and they'd be people that I agree with, certainly at our intensive care unit as well. Overall, it's been a great success for infectious diseases and critical care as a research program, providing strong evidence supporting a meaningful intervention for patients.”

Roberts acknowledges Professor Jeff Littman as his mentor and the program's originator three decades ago. He thanks the 104 ICUs and approximately 36,000 staff members worldwide for their dedicated efforts. Roberts recognizes the Georgia Institute for Global Health as the clinical trial methods center and appreciates ongoing support from the University of Queensland, emphasizing the collaborative effort that has propelled the research program

For further insights from Jason Roberts on BLING III, you can view Part 1 of his interview here: https://www.contagionlive.com/view/continuous--lactam-infusions-show-promise-in-the-battle-against-sepsis

Reference

Roberts, J, Dulhunty JM, Brett SJ, De Waele JJ, et al. Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis. JAMANetwork. Published June 12, 2024. Accessed June 24, 2024. doi:10.1001/jama.2024.9779