BLING III: Beta-Lactam Infusion in Sepsis (2024)

“Among critically ill patients with sepsis, the administration of beta-lactam antibiotics as a continuous infusion, compared with intermittent infusion, did not result in a lower risk of death at 90 days.”

  • The BLING III Investigators

1. Publication Details

  • Trial Title: Continuous versus Intermittent Beta-Lactam Antibiotic Infusions in Critically Ill Patients (BLING III): A Multicentre, Open-label, Randomised Controlled Trial
  • Citation: Lipman J, Brett SJ, De Waele JJ, et al. Continuous versus intermittent beta-lactam antibiotic infusions in critically ill patients (BLING III): a multicentre, open-label, randomised controlled trial. Lancet Infect Dis. 2024;S1473-3099(24)00139-3. DOI: 10.1016/S1473-3099(24)00139-3
  • Published: April 8, 2024, in The Lancet Infectious Diseases
  • Author: Jeffrey Lipman, M.B., B.Ch.
  • Funding: National Health and Medical Research Council of Australia; and others.

2. Keywords

  • Sepsis, Septic Shock, Beta-Lactam Antibiotics, Continuous Infusion, Pharmacokinetics, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with sepsis or septic shock receiving a beta-lactam antibiotic (Population), does administration via continuous infusion (Intervention) compared to standard intermittent infusion (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Beta-lactam antibiotics are time-dependent killers, meaning their efficacy is related to the amount of time the drug concentration remains above the minimum inhibitory concentration (MIC) for the pathogen. In critically ill patients, altered physiology can lead to lower-than-expected drug concentrations. Continuous infusion was hypothesized to be a superior method for maintaining target drug concentrations compared to intermittent bolus dosing.
  • Knowledge Gap: While physiologically plausible and supported by smaller studies, there was no definitive evidence from a very large, multicenter randomized trial to determine if this pharmacokinetic advantage translated into improved patient-centered outcomes like survival.
  • Proposed Hypothesis: The authors hypothesized that continuous infusion of beta-lactam antibiotics would be superior to intermittent infusion in reducing 90-day mortality in critically ill patients with sepsis.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 104 intensive care units (ICUs) in 7 countries.
  • Trial Period: Enrollment ran from June 2018 to December 2022.
  • Population:
    • Inclusion Criteria: Critically ill adult patients (≥18 years) with sepsis or septic shock who were prescribed piperacillin-tazobactam or meropenem.
    • Exclusion Criteria: Included patients not expected to survive for 96 hours or those who had received the study drug for more than 24 hours before enrollment.
  • Intervention: The study beta-lactam antibiotic was administered as a continuous infusion over 24 hours (after an initial loading dose).
  • Control: The study beta-lactam antibiotic was administered as a standard intermittent infusion over 30-60 minutes every 6-8 hours.
  • Management Common to Both Groups: All other aspects of sepsis management, including the choice and duration of antibiotic therapy, were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 7000 patients would provide 90% power to detect a 4.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included clinical cure at day 14, ICU-free days at day 28, and the incidence of antibiotic-related adverse events.

6. Key Results

  • Enrollment and Baseline: 6078 patients were randomized and included in the primary analysis (3034 to continuous infusion and 3044 to intermittent infusion). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned, though it did not reach the original target of 7000 patients.
  • Primary Outcome: There was no significant difference in 90-day mortality. 859 of 3034 patients (28.3%) in the continuous infusion group died, compared with 891 of 3044 patients (29.3%) in the intermittent infusion group (p=0.43).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including clinical cure at day 14 or ICU-free days.
  • Adverse Events: The incidence of adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Adjusted Odds Ratio (OR) for death at 90 days: 0.96 (95% CI, 0.86 to 1.08; P-value: 0.55).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the adjusted result as 0.96.
      • Clinical Meaning: An OR of 0.96 suggests a non-significant 4% lower odds of death in the continuous infusion group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.86 to 1.08.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 14% benefit to an 8% harm.
    • P-value: The p-value of 0.55 is much higher than the 0.05 threshold, indicating the result is not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized controlled design provides a high level of evidence.
  • Generalizability: The pragmatic design and inclusion of 104 diverse ICUs across seven countries make the findings highly generalizable to real-world practice.
  • Statistical Power: The study was very large and adequately powered to confidently rule out a modest but clinically important mortality benefit.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias, as clinicians’ knowledge of the infusion method could have influenced other aspects of care.
  • External Validity (Generalizability): The findings are specific to piperacillin-tazobactam and meropenem and may not apply to other beta-lactam antibiotics.
  • Other: The study did not routinely measure drug concentrations, so it is unknown if the continuous infusion arm consistently achieved higher time above MIC.

10. Conclusion of the Authors

  • Among critically ill patients with sepsis or septic shock, the use of continuous infusion of beta-lactam antibiotics did not result in a lower 90-day mortality than standard intermittent infusion.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provides strong evidence that the routine use of continuous beta-lactam infusions does not improve survival in a general population of critically ill patients with sepsis.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with sepsis receiving piperacillin-tazobactam or meropenem.
    • Actionable Intervention: The results suggest that either continuous or intermittent infusion is an acceptable administration strategy, with no evidence of superiority for the more complex continuous infusion method.
  • What This Trial Does NOT Mean: This trial does NOT mean that pharmacokinetic principles are unimportant. It is possible that continuous infusion may still be beneficial in specific situations not captured in this broad trial, such as in patients with infections caused by less susceptible organisms.
  • Implementation Caveats: Given the lack of demonstrated benefit, the additional logistical complexity and potential for error associated with continuous infusions may not be justified for routine use.

12. Context and Related Studies

  • Building on Previous Evidence: The BLING III trial (2024) was designed to be the definitive, large-scale trial to answer a question that had been debated for years and explored in many smaller, often conflicting, studies and meta-analyses.
  • Influence on Subsequent Research: The definitive neutral finding of this very large trial will likely be practice-affirming for most clinicians and will be highly influential in future sepsis and antimicrobial stewardship guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether there are specific subgroups of patients (e.g., those with augmented renal clearance, or those infected with pathogens with higher MICs) who might still benefit from continuous infusion.
  • Future Directions: Future research may focus on using therapeutic drug monitoring to individualize antibiotic dosing, rather than relying on a “one-size-fits-all” infusion strategy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common clinical practice that was based on strong physiological theory but lacked definitive evidence.
  • Methods: The very large, multicenter RCT design was a major strength. The main methodological weakness is the open-label design. The pragmatic nature of the trial, however, increases its generalizability.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that was narrow and centered on the null value. This provides strong evidence against a meaningful clinical benefit of continuous infusion in this population.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to most ICUs. This trial is a classic example of a high-quality “negative” trial that is practice-changing by providing strong evidence that a more complex intervention is not superior to standard care.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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