NASHVILLE, Tenn — Supported by several cases series, a large cohort analysis has associated exposure to probiotics in the intensive care unit (ICU) with a measurable increase in bacteremia and bacteremia-related mortality due to organisms in these preparations, according to new findings presented at the American College of Chest Physicians (CHEST) 2022 Annual Meeting.

According to data presented by Scott Mayer, MD, chief resident at HealthONE Denver, Colorado, which is part of the HCA Healthcare chain of hospitals, the risk is increased by any probiotic exposure. However, the risk is particularly acute for powdered formulations, presumably because powder more easily disseminates to contaminate central venous catheters.

“We think that probiotics should be eliminated entirely from the ICU. If not, we encourage eliminating the powder formulations,” said Mayer, who led the study.

The data linking probiotics to ICU bacteremia were drawn from 23,533 ICU admissions over a 5-year period in the HCA hospital database. Bacteremia proven to be probiotic-related was uncommon (0.37%), but the consequences were serious.

For those with probiotic-related bacteremia, the mortality rate was 25.6% or essentially twofold greater than the 13.5% mortality rate among those without probiotic bacteremia. An odds ratio (OR) drawn from a regression analysis confirmed a significant difference (OR, 2.23; 95% CI, 1.30 – 3.71; P < .01).

“The absolute risk of mortality is modest but not insignificant,” said Mayer. This suggests one probiotic-related mortality for about every 200 patients taking a probiotic in the ICU.

These deaths occur without any clear compensatory benefit from taking probiotics, according to Mayer. There is a long list of potential benefits from probiotics that might be relevant to patients in the ICU, particularly prophylaxis for Clostridium difficile infection, but also including a variety of gastrointestinal disorders, such as irritable bowel syndrome; however, none of these are firmly established in general, and particularly for patients in the ICU.

“The American College of Gastroenterology currently recommends against probiotics for the prevention of C difficile,” Mayer said. Although the American Gastroenterological Association has issued a “conditional recommendation” for prevention of C difficile infection with probiotics, Mayer pointed out this is qualified by a “low quality of evidence” and it is not specific to the ICU setting.

“The evidence for benefit is weak or nonexistent, but the risks are real,” Mayer said.

To confirm that probiotic-associated ICU bacteremias in the HCA hospital database were, in fact, related to probiotics being taken by patients at time of admission, Mayer evaluated the record of each of the 86 patients with probiotic bacteremia-associated mortality.

“I identified the organism that grew from the blood cultures to confirm that it was contained in the probiotic the patient was taking,” explained Mayer, who said this information was available in the electronic medical records.

The risk of probiotic-associated bacteremia in ICU patients was consistent with a series of case series that prompted the study. Mayer explained that he became interested when he encountered patients on his ICU rounds who were taking probiotics. He knew very little about these agents and explored the medical literature to see what evidence was available.

“I found several case reports of ICU patients with probiotic-associated infections, several of which were suspected of being associated with contamination of the central lines,” Mayer said. In one case, the patient was not taking a probiotic but a patient in an adjacent bed was receiving a powdered probiotic that was implicated. This prompted suspicion that the cause was central-line contamination.

This was evaluated in the HCA ICU database and also found to be a significant risk. Among the 67 patients in whom a capsule or tablet was used, the rate of probiotic-associated bacteremia was 0.33%. For those in which the probiotic was a powdered formulation, the rate was 0.76%, a significant difference (P < .01).

Mayer acknowledged that these data do not rule out all potential benefits from probiotics in the ICU. He believes an obstacle to proving benefit has been the heterogeneity of available products, which are likely to be relevant to any therapeutic role, including prevention of C difficile infection.

“There are now a large number of products available and they contain a large variety of strains of organisms, so this has been a difficult area to study,” he said. However, he maintains it is prudent at this point to avoid probiotics in the ICU because the risks are not confined to the patient making this choice.

“My concern is not just the lack of evidence of benefit relative to the risk for the patient, but the potential for probiotics in the ICU to place other patients at risk,” Mayer said.

Others have also noted the potential benefits of probiotics in the ICU, but the promise remains elusive. In a 2018 review article published in the Journal of Emergency and Critical Care Medicine, the authors evaluated a series of potential applications of probiotics in critically ill patients. These included treatment of ventilator-associated pneumonia (VAP), catheter-associated urinary tract infections (CAUTI), and surgical-site infections (SSI). For each, the data were negative or inconclusive.

Over the 4 years that have passed since the review was published, several trials have further explored the potential benefits of probiotics in the ICU but not have changed this basic conclusion. For example, a 2021 multinational trial published in The Lancet randomized more than 2600 patients to probiotics or placebo and showed no effect on VAP incidence (21.9% vs 21.3%).

The lead author of the 2018 review, Heather A. Vitko, PhD, an associate professor in the Department of Acute and Tertiary Care, University of Pittsburgh School of Nursing, Pennsylvania, also emphasized that the potential for benefit cannot be considered without the potential for risk. She, like Mayer, cited the case studies implicating probiotics in systemic infections.

For administration, probiotic capsules or sachets “often need to be opened for administration through a feeding tube,” she noted. The risk of contamination comes from both the air and contaminated hands, the latter of which “can cause a translocation to a central line catheter where the microbes have direct entry into the systemic circulation.”

She did not call for a ban of probiotics in the ICU, but she did recommend “a precautionary approach,” encouraging clinicians to “distinguish between reality [of what has been proven] and what is presented in the marketing of antibiotics.”

Mayer and Vitko have reported no relevant financial relationships.

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