By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A multicenter, randomized, placebo-controlled clinical trial found the use of prophylactic probiotics did not reduce the risk for developing ventilator-associated pneumonia or improve other outcomes for intensive care unit patients, compared to placebo.

SOURCE: Johnstone J, Meade M, Lauzier F, et al; Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group. Effect of probiotics on incident ventilator-associated pneumonia in critically ill patients: A randomized clinical trial. JAMA 2021;326:1024-1033.

The development of ventilator-associated pneumonia (VAP) leads to significant morbidity, mortality, and increased healthcare costs. Previous studies have shown that prophylactic probiotics may reduce the risk of VAP. Therefore, Johnstone and colleagues sought to determine whether the probiotic Lactobacillus rhamnosus GG reduced the risk for VAP and other detrimental outcomes in patients admitted to the intensive care unit (ICU), compared to placebo.

The study was a randomized, placebo-controlled clinical trial that included 44 ICUs from the United States, Canada, and Saudi Arabia. Inclusion criteria were age at least 18 years and the expectation of mechanical ventilation for at least 72 hours. Patients were excluded if they had been on mechanical ventilation for more than 72 hours, were immunocompromised, were at increased risk of endovascular infection, had severe pancreatitis, had plans for palliation, or if they had a percutaneous enteral feeding tube or were unable to receive enteral medication. Patients were randomized 1:1 to receive either Lactobacillus rhamnosus GG 1 × 1010 colony forming units or an identical enteral placebo twice daily. The study product was given for up to 60 days or until discharge from the ICU. Also, the probiotic was discontinued if Lactobacillus spp. was isolated from a sterile culture site or if it was the predominant organism isolated in a culture from a nonsterile site.

The primary endpoint of the study was the development of VAP. This was defined as the presence of a new, progressive, or persistent infiltrate on chest imaging after at least two days of mechanical ventilation, along with any two of the following: fever (temperature > 38°C) or hypothermia (temperature < 36°C); white blood cell count > 10 × 106/L or < 3 × 106/L; and purulent sputum. There were 20 secondary endpoints, including Clostridioides difficile infection, length of hospital stay, length of mechanical ventilation, and death occurring during the hospitalization. Any cultures that were positive for Lactobacillus then had strain genotyping to determine whether it was the strain of L. rhamnosus GG used in the study.

There were 1,318 patients who received the probiotic and 1,332 who received placebo. The average age of all the patients was 59 years, 1,063 (40%) were women, and 2,027 (76.5%) had a medical admitting diagnosis. The study product was administered for a median of nine days in both groups. In the probiotic group, 289 of 1,318 (21.9%) developed VAP compared to 284 of 1,332 (21.3%) in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], -2.5% to 3.7%; P = 0.73). Subgroup analysis did not find any effect modification based on age, frailty status, prior use of antibiotics, diagnosis category (medical, surgical, or trauma), or comorbid infection. There were no significant differences between the two groups regarding secondary outcomes, including the development of C. difficile infection (2.4% in probiotic group vs. 2.1% in the placebo group, P = 0.60). Sixteen patients had Lactobacillus spp. isolated in a culture, of which 12 isolates were available for sequencing. Of these, all 12 were confirmed as L. rhamnosus GG.

COMMENTARY

Using probiotics to prevent VAP and other adverse outcomes in the ICU is an appealing concept. Indeed, probiotics are relatively inexpensive and generally perceived to be a low-risk intervention for most ICU patients. Unfortunately, the study by Johnstone et al is another example of a clinical approach that appeared promising based on preliminary research, but did not hold up under the scrutiny of a rigorously designed randomized clinical trial. The authors should be commended for their pragmatic investigation, which is an important contribution to the scientific literature on VAP and answers a frequent clinical conundrum.

Although not useful in preventing VAP, probiotics appear the have the potential for patient harm. It is possible that the dysbiosis present in ICU patients is too advanced for probiotics, at least L. rhamnosus GG, to overcome. Impaired gut integrity likely is the central factor that allowed Lactobacillus to spread to sterile sites, such as the bloodstream. Notably, bacteremia due to Lactobacillus spp. can lead to increased mortality, especially in patients with underlying comorbidities.

There were some limitations to the study. First, it is uncertain whether the results would have been similar if a different probiotic was chosen. Second, no sampling of pulmonary or gastrointestinal microbiota was performed prior to the administration of the study product. Finally, VAP is an imprecise diagnosis with no universal reference definition. How this affected the results, if at all, is unclear.

Until further evidence emerges, clinicians should not prescribe L. rhamnosus GG to prevent VAP in patients admitted to the ICU. Whether there are other, as yet undetermined, benefits for probiotics in the ICU setting remains to be elucidated.