BLING III

Population:

• Critically ill adults (≥18 years) with sepsis, treated with piperacillin-tazobactam or meropenem.

• Participants were enrolled from 104 ICUs across Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the UK.

• 7031 patients met the consent requirements for the primary analysis, with a mean age of 59 years and 35% being women.

Intervention:

• Continuous infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) for a clinician-determined duration or until ICU discharge.

• Total 24-hour dose determined by attending clinicians.

Comparison:

• Intermittent infusion of the same β-lactam antibiotics over 30 minutes for the same duration as the intervention group.

Outcome:

• Primary Outcome: All-cause mortality within 90 days of randomization. Continuous infusion: 24.9% mortality (864/3474 patients).
  Intermittent infusion: 26.8% mortality (939/3507 patients).
  Odds ratio (OR): 0.91 (95% CI, 0.81 to 1.01); P = 0.08.
  

• Secondary Outcomes: Clinical cure at 14 days was higher in the continuous infusion group (55.7% vs. 50.0%).
  No significant differences in the rates of new acquisitions, colonization, or infections with multiresistant organisms or Clostridioides difficile.
  No significant differences in ICU mortality or in-hospital mortality.
  

• Tertiary Outcomes: No significant differences in days alive and free of ICU stay, hospital stay, mechanical ventilation, and kidney replacement therapy.

Clinical Insights for Intensivists

The BLING III trial provides important insights into the administration of β-lactam antibiotics in critically ill patients with sepsis:

1. Mortality Impact: There was no statistically significant difference in 90-day mortality between continuous and intermittent infusions of β-lactam antibiotics. However, the study suggests a potential clinically important benefit with continuous infusion, indicated by a 2% absolute reduction in mortality, translating to a number needed to treat of 50 to prevent one death.
   

2. Clinical Cure Rates: Continuous infusion was associated with a higher rate of clinical cure at 14 days post-randomization compared to intermittent infusion, which may suggest better infection resolution with continuous infusion.
   

3. Secondary Infections and Adverse Events: No significant differences were observed in the rates of secondary infections or adverse events between the two administration methods.
   

4. Practical Considerations: Continuous infusion requires careful consideration of practical aspects such as drug stability, infusion pump use, and potential interruptions.
   Continuous infusion may have logistical advantages, including shorter preparation and administration times compared to intermittent dosing, although this may be offset by clinical interruptions.
   

5. Generalizability:The study's findings are primarily applicable to high-income ICU settings and may not directly translate to low- and middle-income environments.

Conclusion

The BLING III trial did not find a statistically significant reduction in 90-day mortality with continuous β-lactam infusion compared to intermittent infusion in critically ill patients with sepsis. Despite this, continuous infusion may offer benefits in clinical cure rates and presents a potential clinically important benefit that warrants further consideration in ICU settings. Intensivists should weigh these findings alongside practical and logistical factors when deciding on antibiotic administration strategies for patients with sepsis.