In the recent publication of the American College of Gastroenterology (ACG) guidelines for Clostridioides difficile infections (CDI), Kelly et al. (1) recommended against probiotics for primary prevention of CDI (conditional recommendation, moderate quality of evidence) and probiotics for preventing CDI recurrences (strong recommendation, very low quality of evidence). These ACG guidelines failed to account for the strain specificity associated with probiotic efficacy by basing their conclusions on data pooling disparate types of probiotics together, which often results in a biased efficacy measurement. When different probiotics are analyzed accounting for strain specificity, some strains show significant efficacy, whereas others do not (2). In addition, Kelly et al. based their recommendations on only 1 underpowered randomized trial (RCT) to detect a significant effect on CDI and several meta-analyses that did not account for strain specificity. When the American Gastroenterology Association published their guidelines for CDI, they reviewed 39 RCTs, accounted for strain specificity in their analysis, and determined 4 different types of probiotics could be recommended for CDI (3). Both guidelines point out the need for more RCTs of probiotics for CDI to increase the strength of the evidence for both primary and secondary prevention of CDI.
Challenges for doing RCTs include the sporadic nature of CDI outbreaks and varying incidence of CDI at different healthcare facilities, leading to underpowered trials when the incidence of CDI is <5%. In an effort to test whether probiotics can be an effective adjunct to infection prevention programs, several studies have performed quasiexperimental studies where a specific probiotic is offered to inpatients at high risk of CDI (receiving antibiotics) and given for the duration of the patient's stay. Then, healthcare facility-level CDI rates are compared for periods before and during the probiotic intervention. Although not an RCT and lacking a concurrent control group, this approach has been successful in some programs for reducing CDI rates (4).
The guidelines from ACG also recommended fecal microbial transplants (FMT) for severe/fulminant CDI (strong recommendation, low quality of evidence) (1). However, instead of the recommendations being based on the gold standard (RCT), they are based on 7 studies: case reports/series and phase 2 formulation studies. These studies were not included as evidence for their analysis of probiotics and are typically excluded from efficacy analyses altogether, so it is unclear why these were included just for FMT. In addition, to prevent recurrent CDI, Kelly et al. based their positive recommendation on 12 studies, but only 3 are phase 3 RCTs. The authors concluded that there are “ample data demonstrating the safety and efficacy of FMT…,” but the ample data do not include phase 3 efficacy RCTs. There seem to be different degrees of evidence required for the efficacy of probiotics and FMT.
The differing conclusions of these 2 guidelines highlight the effect of applying different types of evidence to evaluate distinct interventions and the impact of not accounting for probiotic strain specificity.
CONFLICTS OF INTEREST
Guarantor of the article: Lynne V. McFarland, PhD.
Specific author contributions: L.V.M., R.K., S.J., J.C.S., K.W., and E.J.C.G.: helped in writing the letter and each author has approved the final draft submitted.
Financial support: Sponsor (Bio-K Plus, Canada) paid for the publication fees but was not involved in writing the Letter or decision to publish. The Letter was independent of funding sponsor.
Potential competing interests: L.V.M., R.K., S.J., J.C.S., and E.J.C.G. serve for the Scientific Advisory Board for Bio-K Plus International, Inc.
1. Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, diagnosis, and treatment of Clostridiodides difficile
infections. Am J Gastroenterol 2021;116:1124–47.
2. McFarland LV, Evans CT, Goldstein EJC. Strain-specificity and disease-specificity of probiotic efficacy: A systematic review and meta-analysis. Front Med (Lausanne) 2018;5(124):124–14.
3. Su GL, Ko CW, Bercik P, et al. AGA clinical practice guidelines on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology 2020;159(2):697–705.
4. Kullar R, Johnson S, McFarland LV, et al. Bundling probiotics with antimicrobial stewardship programs for the prevention of Clostridioides difficile
infections in acute care hospitals. Infect Dis Clin Pract 2020;28(3):123–9.