Probiotics for primary prevention of Clostridioides difficile infection: revisiting the evidence

Abstract

Prophylactic probiotics have been shown to be effective in preventing Clostridioides difficile infection (CDI), according to multiple meta-analyses. However, different medical societies have varying recommendations on their use for preventing CDI. In this commentary, we discuss current evidence for probiotic use in primary prevention of CDI and the issues raised by professional societies when evaluating the evidence. We highlight four areas for future improvement: considering baseline risk for CDI, timing of probiotics with antibiotics, combining efficacy data from different probiotic strains, and safety. All societies agree on the need for more high-quality and adequately powered randomized controlled trials to further strengthen the evidence.

Keywords:

• Healthcare-associated infections
• probiotics
• Clostridioides difficile infection
• Clostridioides difficle prevention

Introduction

Clostridioides difficile is the leading cause of healthcare-associated diarrhea and has a significant mortality burden in the United States¹. Despite the advancements in both preventative and curative strategies, further reducing the incidence of C. difficile infection (CDI) remains a priority². Prophylactic probiotic treatment is a promising strategy for preventing CDI. Multiple randomized controlled trials (RCTs) have evaluated the efficacy of various probiotic compositions for primary and secondary prevention of CDI. Several recent meta-analyses of these RCTs have suggested that prophylactic use of probiotics can reduce the risk of CDI^3–6.

Based on this evidence, professional medical societies in gastroenterology (the American Gastroenterology Association (AGA)⁷ and the American College of Gastroenterology (ACG)⁸) and infectious diseases (the Infectious Diseases Society of America (IDSA)⁹ and the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID)¹⁰) have published clinical guidelines for using prophylactic probiotics to prevent CDI. However, these four professional societies do not provide the same recommendation, nor agree on the strength of evidence. This raises the question of how these societies arrived at different conclusions while evaluating the same body of evidence. We review current evidence on probiotics for primary prevention of CDI and make recommendations to increase confidence in future studies.

Discussion

Despite evaluating identical trials, professional societies arrive at disparate conclusions on the efficacy of probiotics. Some of the concerns raised by the professional societies include a high base-line risk of CDI, sample size, trial size and quality, heterogeneity of probiotic microorganisms, and potential harm of probiotics. While the AGA recommends prophylactic probiotics, the ACG, IDSA, and ECCMID do not (Table 1)^7–10. Interestingly, the ACG’s⁸ recommendation is largely based on the negative result published in the PLACIDE trial¹¹, which has limitations discussed below¹².

Table 1. Probiotic administration recommendation and strength by medical society.

Society	Recommendation	Strength
AGA	“In adults and children on antibiotic treatment, we suggest the use of S boulardii; or the 2-strain combination of L acidophilus CL1285 and L casei LBC80R; or the 3-strain combination of L acidophilus, L delbrueckii subsp bulgaricus, and Bifidobacterium bifidum; or the 4-strain combination of L acidophilus, L delbrueckii subsp bulgaricus, B bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of C difficile infection”^7.	Conditional recommendation, low quality of evidence
ACG	“We recommend against probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention)”^8.	Conditional recommendation, moderate quality of evidence
IDSA	“There are insufficient data at this time to recommend administration of probiotics for primary prevention of CDI outside of clinical trials”^9.	No recommendation
ECCMID	“Routine administration of probiotics to prevent CDI when on antibiotic treatment is not recommended”^10.	Strong recommendation, low quality of evidence

Baseline risk of CDI in the population being studied

A 2017 Cochrane Collaboration meta-analysis³ examined 31 RCTs (8672 subjects) that assessed the efficacy of probiotics in preventing CDI in subjects taking antibiotics, concluding that co-administration reduced the risk of developing CDI by 60%. However, the meta-analysis has been critiqued for including studies with a high baseline risk of CDI (>5%) and inconsistency in weighing studies, both potentially leading to an overestimation of prophylactic probiotics efficacy¹³. Interestingly, three other meta-regressions using a subset of the studies included in the Cochrane analysis demonstrated similar point estimates (58–66%), despite weighing studies differently^4–6. The PLACIDE trial¹¹, the largest prophylactic probiotic RCT to date (n = 2500), was included in the two most recent meta-analyses and was powered to detect a 50% reduction in CDI incidence, assuming a 4% baseline risk. However, the actual incidence of CDI during the study was ∼1%, making the study underpowered to detect their primary endpoint¹¹. Therefore, a larger RCT (n = ∼9000) is needed to assess efficacy of prophylactic probiotics given the low baseline incidence of CDI.

Timing of probiotic initiation with respect to antibiotics

A meta-analysis by Shen et al.⁴ highlighted the importance of probiotic timing with antibiotics. Those given probiotics within two days of starting antibiotics had the greatest magnitude of CDI risk reduction. Furthermore, the odds of developing CDI increased by 18% for each additional day of delay in receiving probiotics. Of note, the PLACIDE trial¹¹ included patients who were administered probiotics up to seven days after their first antibiotic dose which could have impacted its efficacy. In a sensitivity analysis where the PLACIDE trial was excluded, the risk of developing CDI increased to 54% per day-delay of probiotic administration⁴. Therefore, future RCTs assessing the efficacy of prophylactic probiotics should consider administering probiotics alongside antibiotics to ensure optimal timing.

Probiotic microorganism specificity

A 2018 meta-analysis of 18 RCTs found that while prophylactic probiotics can reduce the risk of CDI by 40%, the benefit was greater from multispecies probiotics compared with single-species probiotics¹⁴. Additionally, a meta-analysis by McFarland et al.¹⁵ demonstrated that different probiotic strains have different efficacies for disease prevention. However, three of the four society guidelines evaluated the efficacy of probiotics as a single entity, which has the potential to produce biased results from pooling studies using different strains of probiotics^8–10. Only the AGA⁷ guidelines describe 4 different types of probiotics that can reduce the risk of CDI. Therefore, future randomized studies assessing the efficacy of prophylactic probiotics must account for strain specificity and combinations to ensure the validity of the results.

Safety of probiotics

The magnitude of probiotic risk is unclear with some studies suggesting that probiotics delay the restoration of the host’s native microbiome following antibiotic exposure^16,17, while others suggest the opposite^18,19. Nevertheless, published case reports of bacteremia/fungemia, particularly in immunocompromised and critically-ill patients have been reported²⁰. While RCTs to date have found no significant increase in adverse events, it is important to view these results with caution as high-risk patients were likely excluded from these studies. Therefore, probiotics should be used with extreme caution in high-risk patients, and further studies are needed to fully describe potential adverse events.

Conclusions

Current meta-analyses suggest that prophylactic probiotics are effective in reducing the risk of CDI. However, issues with meta-analytic study design such as trial weighting, unresolved subgroup effects, low power, and heterogeneity of probiotic microorganisms threaten the validity of these findings. All the professional societies agree that there is a need for more high-quality and adequately powered RCTs to definitively conclude the efficacy of prophylactic probiotics.

Transparency

Declaration of funding

This paper was not funded.

Author contributions

JF and WP contributed equally to the research and writing. AD was involved in the conception of the work.

Acknowledgements

None.

Declaration of financial/other relationships

All authors report no conflicts of interest relevant to this article. AD has received research support from The Clorox Company and Seres Therapeutics; and is a consultant for Merck. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.