Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients

Importance

Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported.

Objective

To evaluate the effect ofLactobacillus rhamnosusGG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU).

Design, Setting, and Participants

Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020).

Interventions

EnteralL rhamnosusGG (1 × 10¹⁰colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU.

Main Outcomes and Measures

The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections includingClostridioides difficileinfection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality.

Results

Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22;P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event ofL rhamnosusin a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58;P < .001).

Conclusions and Relevance

Among critically ill patients requiring mechanical ventilation, administration of the probioticL rhamnosusGG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use ofL rhamnosusGG in critically ill patients.

Trial Registration

ClinicalTrials.gov Identifier:NCT02462590