In the setting of Clostridioides difficile infection (CDI), the 2021 American College of Gastroenterology (ACG) guidelines recommend against probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention) and for the prevention of CDI recurrence (secondary prevention). Since probiotics are marketed as dietary supplements without strict oversight by the U.S. Food and Drug Administration required for drugs, the evidence for the use of probiotics is generally limited. Hence, manufacturers have little incentive to conduct clinical trials to support specific indications. Additionally, data based on case reports revealed several risks associated with the use of probiotics including bloodstream infections in critically ill patients. Microbiome analyses have also observed probiotics to impede normal recolonization of the colon after antibiotic courses. Evidence to support probiotics for CDI comes primarily from meta-analyses that pooled data from small trials of different probiotic formulations and methodologies. Overall, there is a paucity of high-quality clinical trial data on probiotic use in CDI, and most studies are underpowered, with CDI as a secondary outcome in studies performed to assess the prevention of antibiotic-associated diarrhea (AAD). [1]

The PLACIDE trial (N= 2,941) is the largest double-blind clinical primary prevention trial to date (see Table 2) and observed AAD or CDI occurred in 159 (10.8%) of patients in the probiotic group and 153 (10.4%) of patients in the placebo group (relative risk [RR] 1.04, 95% confidence interval [CI] 0.83 to 1.32, p= 0.72). Further, a 2017 Cochrane review of probiotics for the primary prevention of CDI in adults and children being treated with antibiotics (N= 8,672, 31 studies) observed a significant reduction in the risk of Clostridioides difficile-associated diarrhea (CDAD) with the use of probiotics compared to placebo or no treatment (1.5% vs. 4.0%; RR 0.40, 955 CI 0.30 to 0.52). However, there was not a favorable benefit for probiotics due to the relatively high number needed to treat of 42. Additionally, most of the studies included for analysis were deemed to be of high or unclear risk of bias with more than half having missing data. The external validity of this Cochrane review is low as only four of the 31 trials included observed benefits with probiotics, and results were heavily influenced by five studies with a baseline CDI risk > 15%, greater than the usual risk seen in any hospital setting. [1], [2], [3]

Additional data evaluating probiotics for primary prevention of CDI comes from a meta-analysis published in 2018 which specifically analyzed trials of a particular probiotic combination comprising three lactobacilli strains (Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus rhamnosus; Bio-K+) with in vitro activity against C. difficile. Of the three randomized controlled trials included in the analysis, only one trial from China with a relatively high incidence of CDI at baseline (approximately 24%), showed probiotic mixture can be efficacious for the primary prevention of CDI. However, a 2017 meta-analysis evaluated the efficacy of probiotics in preventing CDI in hospitalized adults receiving antibiotic therapy for another indication (N= 6,261, 19 randomized controlled trials). The four probiotic species studied were Lactobacillus, Saccharomyces, Bifidobacterium, and Streptococcus used either alone or in combination. The incidence of CDI in patients that used probiotics was lower than the control group (RR 0.42, 95% CI 0.30 to 0.57). When probiotics were administered closer to the first dose of antibiotics, they were more effective than a delayed start of probiotics (p= 0.04). Additionally, probiotics that were given within 2 days of the beginning of antibiotic therapy reduced the risk of CDI (RR 0.32, 95% CI 0.22 to 0.48) compared to later administration (RR 0.70, 95% CI 0.40 to 1.23; p= 0.02). There was no increased risk for adverse events among patients given probiotics. Of note, the studies included in the analysis had extensive exclusion criteria and the results may not be generalizable to many patients who would be using probiotics for primary prevention of CDI. [1,4-6]

For secondary prevention of CDI, the PICO trial, which was a phase 2 pilot randomized controlled trial published in 2017, randomized 33 patients with an initial mild-to-moderate CDI to 4-strain probiotics (Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and B. lactis Bl-04) or placebo for 28 days in addition to anti-CDI therapy. Probiotic adjunct therapy was associated with significant improvement in diarrhea outcomes compared to placebo including duration of diarrhea (0.0 versus 1.0 days; p= 0.039), total diarrhea days (3.5 vs. 12.0 days; p= 0.005), and rate of diarrhea (0.1 vs. 0.3 days of diarrhea/stool diary days submitted; p= 0.009). Additional data from randomized controlled trials and a Cochrane review evaluating probiotics for secondary prevention have generally not observed significant benefits with probiotics and are largely outdated and limited by small sample sizes. [1], [2], [3], [4], [5], [6], [7]

A 2019 network meta-analysis aimed to determine the most effective probiotic to prevent antibiotic-induced CDAD (N= 4,692, 10 randomized controlled trials). The nine probiotics studied were Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Bifidobacterium bifidum, Bifidobacterium lactis, Saccharomyces boulardii, and Streptococcus thermophilus. When compared to placebo, the incidence of CDAD (odds ratio [OR] 0.33, 95% CI 0.17 to 0.61) and AAD (OR 0.39, 95% CI 0.23 to 0.66) were reduced after probiotic intervention. No significant differences were found for the duration of diarrhea or the time to onset of diarrhea between the two groups. All probiotic interventions were more effective than placebo for decreasing the incidence rate of CDAD, with Lactobacillus casei (OR 0.19, 95% credible interval [CrI] 0.06 to 0.63) followed by Lactobacillus acidophilus (OR 0.26, 95% CrI 0.09 to 0.72) ranking superior to all other interventions. Lactobacillus casei also ranked the highest in reducing the incidence rate of AAD (OR 0.32, 95% CrI 0.14 to 0.74). Based on these outcomes, it suggested that patients treated with antibiotics should take probiotic supplements (50 billion-100 billion CFU once daily) or food containing Lactobacillus casei to prevent diarrhea. No safety outcomes were reported in this study. This network meta-analysis may be limited by the small number of direct comparisons between each probiotic and the high degree of heterogeneity observed among trials. [8]

A 2021 meta-analysis was conducted to determine which probiotics would be most effective in children (aged 18 years and younger) for treatment of acute diarrhea. Randomized controlled trials of children randomly assigned to receive probiotics versus placebo or no treatment were included for analysis (84 studies; N= 12,315 children; 21 interventions). Based on a Bayesian network meta-analysis, Saccharomyces boulardii (S. boulardii) was determined to have the highest evidence (moderate in quality) for reducing the duration of diarrhea compared to placebo (mean difference [MD] -1.25 day; 95%CI -1.59 to -0.91) or no treatment (MD -0.95; 95% CI -1.33 to -0.58). While Bifidobacterium lactis (B. lactis) demonstrated the highest probability of reducing diarrhea duration when compared with placebo or no treatment as a single category, the quality of evidence was low. Unfortunately, the meta-analysis was not an assessment of probiotic prophylaxis. [9]

While a 2021 guideline update from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) on the management of CDI in adults does not provide any guidance on the use of probiotics to prevent CDI, the 2017 IDSA, and SHEA guidelines do not recommend administration of probiotics for primary prevention of CDI. The guidelines state that there is insufficient data to recommend administration. However, it was noted that several meta-analyses indicated probiotics may be effective at preventing CDI in patients who were taking antibiotics and without a history of CDI. Overall, the studies with the greatest influence on the results of the meta-analyses had a CDI incidence 7-20 times higher in the placebo groups than would otherwise be expected based on the patient populations studied, potentially biasing the results to benefit the probiotic arms. [10], [11]

Aside from CDI, the 2020 American Gastroenterological Association (AGA) recommendations on the use of probiotics in gastrointestinal disorders more generally recommend probiotics, in specific strains, in patients for treatment of pouchitis, prevention of CDI, or preterm low-birth-weight infants. These recommendations are conditional, and patients who are concerned about potential harms due to comorbid illnesses or monetary costs of recommended probiotic strains may reasonably select no probiotics. [12]

The 2023 World Gastroenterology Organization Global Guidelines provide insights into the clinical applications for probiotics in gastroenterology. The effects of probiotics are strain-specific and dose-specific. For specific recommendations for different indications on the basis of levels of graded evidence please refer to Table 1. In terms of product safety, it was highlighted that most probiotics currently in use come from either fermented foods or the microbes found in a healthy human body, and have also been used in various products for many years. Due to the prevalence of lactobacilli in fermented foods and their natural presence in the human body, as well as their low association with infections, experts in the field generally consider them to have a low potential for causing harm. ​​Bifidobacterium species have a similarly positive safety record. Products are typically designed with the general healthy population in mind. Therefore, their use in individuals with compromised immune systems or serious underlying health conditions should be limited to specific strains and indications that have been proven safe and effective for these patient groups. Traditional lactic acid bacteria (LAB), which have a long history in food fermentation, are generally considered safe for oral consumption when included in foods and supplements for the typically healthy population, and at levels traditionally used. [13]

A search of the published medical literature revealed 2 studies investigating the researchable question:

Which probiotic (or strain) has the best data for inpatient prevention of diarrhea or C. diff?

B - One high-quality study or multiple studies with limitations  Read more→