The human microbiome is a naturally diverse ecosystem of trillions of commensal bacteria. These bacteria outnumber human cells 10 to one and are largely under-studied and do not typically rise to the level of causing infections (1). Were you to contemplate the ecology of your navel, you might find that more than 60% of phylotypes detected were not previously reported to science, and the diversity of phylotypes is incredible (2). Bringing this to a more clinically relevant context, character and diversity of microbiota is associated with increased health and reduced risk of adverse outcomes (3). Carriage of antibiotic resistant bacteria is inversely associated with microbiome diversity and harbors certain dysbiotic changes, perhaps as a diverse microbiota is able to out-compete any encountered opportunistic pathogenic bacteria (4,5). Specifically, loss of Bacteroidetes has been associated with carbapenem-resistant Enterobacteriaceae carriage (6).

Knowing this, it makes intuitive sense that the forward-thinking intensivist might want to use any available tools to maintain the particular bacteria associated with the healthy state in patients at risk of microbiota dysbiosis during their stay in the ICU. Patients admitted to the ICU find their usual microbes are targets (or innocent bystanders) of antimicrobial warfare. Even with superb antimicrobial stewardship, the majority of ICU patients will receive antibiotic treatment (7). Additional impacts on the microbiome may come from protocolized disinfection procedures (such as chlorhexidine bathing), and indirectly from measures such as acid suppression, withholding gastrointestinal nutrition, and exposure to and acquisition of the local ICU bacterial milieu (8). Dysbiosis may negatively impact a patient’s clinical course, dose-dependent on their length of exposure to the ICU (9). Why not then, take a page from the tribe of wellness and focus on recreating and amplifying the healthy normal, rather than reactively treating the pathologic state? Probiotics claim to replenish the vibrant and diverse microbiota of the natural unmolested body. What could go wrong?

There is only a modest amount of literature reporting a small potential benefit of probiotics on clinically important ICU outcomes. A recent meta-analysis suggested a small reduction in healthcare-associated infections with probiotics. Notably, they saw no impact on mortality (10). There is even less published identifying safety concerns with this practice.

In this issue of Critical Care Medicine, Mayer et al (11) retrospectively analyzed a cohort of 23,015 adult patients admitted over 5 years to a large multihospital healthcare network. Patients with central venous catheters receiving probiotics while in the ICU who had blood cultures obtained during their stay were reviewed, and 86 potentially probiotic-associated central venous catheter infections were identified (0.37%). These probiotic-associated infections occurred with pathogens found in probiotic supplements the patients were receiving. Probiotic-associated catheter-associated bloodstream infections were associated with increased mortality (odds ratio = 2.23). Noting that it was unclear why, powder formulations were associated with increased risk as compared with nonpowder formulations of probiotic, hinting at a potential mechanical inoculation risk (11). The study by Mayer et al (11) is an admirable example of utilizing a large real-world dataset to answer a practical, clinical question. Notably, studies designed to detect efficacy of an intervention like probiotic treatment are typically under-powered to detect safety concerns. Rare safety concerns may be significant enough to determine a treatment unusable. Until very recently, with the Food and Drug Administration (FDA) approval of SER109 in late 2022 and RBX2660 in 2023 (both for prevention of recurrent Clostridioides difficile infection) (12), there were no FDA approved probiotic treatments. Previously available probiotic treatments used in the study by Mayer et al (11) were marketed as dietary supplements, with significantly less stringent safety requirements and little regulation. Furthermore, the results found by Mayer et al (11) provide a sobering reminder that “dietary supplements” whether “natural” or “whole health” harbor potential risk.

Real-world data studies have limitations. The study by Mayer et al (11) was not designed or powered to evaluate between types of probiotic formulations. The number of infections by organism are few, such that it is unclear what to make of higher (Saccharomyces boulardii) versus lower (Bifidobacterium longum) frequency infection-causing probiotic pathogens (11). The authors also postulate the differences between inside-out and outside-in infections, although it is unclear how this could reliably be differentiated in clinical practice. Inside sources of bacteria such as fecal matter are excreted and inadequate hand hygiene of healthcare workers when transitioning between clean and dirty tasks and sites would result in external contamination of catheters with formerly internal organisms.

History has shown that seemingly beneficial interventions can cause harm. Even benign sounding interventions, and especially interventions that have not been vetted with vigorous peer-reviewed science, should be left to well-designed experimental use only. We should not invite additional risk into the already precarious critically ill patient. Low-virulence anaerobic gut bacteria may only be useful… in moderation.

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