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

Abstract

for the Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group 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 of Lactobacillus rhamnosus GG 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 Enteral L rhamnosus GG (1 × 10 10 colony-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 including Clostridioides difficile infection, 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 of L rhamnosus in 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 probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients.

Clinical Benefits From Administering Probiotics to Mechanical Ventilated Patients in Intensive Care Unit: A PRISMA-Guided Meta-Analysis

“…Recently, Johnstone et al completed the largest randomized trial to compare the effect of probiotics on preventing VAP in critically ill patients (16). In this multicenter and pragmatic study concerning 2,650 participates, as compared with placebo, the administration of 1 × 10 10 colony forming units of Lactobacillus rhamnosus GG two times daily for 9 days did not significantly reduce the risk of VAP.…”

“…Full texts of the remaining 37 articles were independently assessed by two investigators to determine inclusion and exclusion. After strict screening according to inclusion and exclusion criteria, 22 studies were excluded, 15 RCTs (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) were finally included in our meta-analysis (Figure 1 shows the study selection). Characteristics of included trials are shown in Table 1.…”

“…Furthermore, according to the new taxonomic description (35), the species and strain of probiotics administration varied in these studies. In six of the studies (16,19,23,24,27,30), a single probiotic was used, such as Lacticaseibacillus rhamnosus (35) (23). The rest of the nine studies used multiple probiotics.…”

Sepsis and the Human Microbiome. Just Another Kind of Organ Failure? A Review

“…It has been shown in vitro that Lactobacillus plantarum , Lactobacillus rhamnosus GG , and Lactobacillus casei have an anti-inflammatory effect on the epithelial tissue [ 51 ]. However, a large multicentre RCT could not demonstrate any impact between administering a probiotic with Lactobacillus rhamnosus GG compared to placebo on the incidence of ventilator-associated pneumonia and other infections such as bacteremia [ 60 ]. Therefore, it needs to be further investigated whether sepsis patients can also benefit from probiotics.…”

The role of the microbiota in the management of intensive care patients

“…Lactobacillus plantarum showed in this meta-analysis the most significant effect on the reduction of infections. A very recent large prospective, placebo-controlled trial, involving 2653 critically ill patients failed to demonstrate benefits of preventive administration of probiotics in these patients to avoid VAP [ 138 ]. However, these results need to be confirmed in other studies and notably probiotics should undergo precise safety evaluation: Lactobacillus spp.…”