Do probiotics reduce the risk of Clostridioides difficile colitis?

"Health Care-Associated Infections: Best Practices for Prevention" published by AFP online ahead of print last week reviews evidence-based recommendations to reduce the risk of hospitalized patients acquiring SARS-CoV-2, catheter-associated urinary tract infections (CAUTIs), central line-associated bloodstream infections (CLABSIs), ventilator-associated pneumonia (VAP), surgical site infections, and Clostridioides difficile (C diff) colitis. Of the authors' key recommendations for practice, the one that might be the most unexpected is the use of probiotics to prevent C diff colitis.

Clostridioides difficile colitis, also referred to as Clostridioides difficile-associated diarrhea (CDAD), caused "an estimated 223,900 cases in hospitalized patients and 12,800 deaths in the United States" in 2017, the latest year for which data is available per the Centers for Disease Control and Prevention (CDC); a 2020 study estimated the incidence of CDAD at 8.3 cases per 10,000 patient-days, increasing the length of hospital stays by at least 3 days and as much as 21.6 days. Given this morbidity and mortality burden, several studies have examined the use of probiotics to reduce the risk of acquiring CDAD, especially in hospitalized patients receiving antibiotics. 

In 2017, a Cochrane meta-analysis assessed the literature to date on the use of probiotics to prevent CDAD. The authors ended up including 39 studies:

 A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate)....However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). 

The Cochrane authors found a number needed to treat (NNT) of 42 among all study participants, and a NNT among participants at high risk of CDAD of 12. The definitions of "high risk" varied a bit among studies, but most were close to the CDC's parameters of age 65 years and older, hospital or nursing facility admission, immunocompromise, and/or a previous history of CDAD. The Cochrane reviewers acknowledged that, of the 39 included studies, "27 studies were rated as either high or unclear risk of bias."

A 2021 letter in the Journal of the American Board of Family Medicine argues further for the routine use of probiotics for all hospitalized persons receiving antibiotics. In addition to reviewing the 2017 Cochrane review's findings, the authors of this letter also discuss the findings of a 2020 systematic review regarding the cost reduction associated with use of probiotics to reduce CDAD and state that even though "[l]ack of standardization and heterogeneity of treatment remain challenges to implementing probiotic therapies," "the positive results and favorable safety profiles across studies are reassuring." The authors of this AFP article on "Probiotics for Gastrointestinal Conditions: A Summary of the Evidence" also conditionally recommend the use of probiotics to prevent CDAD and other forms of antibiotic-associated diarrhea.

As noted in this 2020 AFP article on "Clostridioides difficile Infection: Update on Management," the Infectious Disease Society of America (IDSA) does not currently recommend the use of probiotics to prevent CDAD, citing the limitations of studies done to date and the potential risks of prescribing probiotics for immunocompromised persons. It remains to be seen when the IDSA might update their 2018 guideline, but one thing the IDSA and the AFP authors agree on is the importance of antibiotic stewardship in reducing CDAD. 

While we await that guideline update and, hopefully, more robust studies, it may be reasonable to consider patient-centered decision making regarding probiotics' potential risks and benefits for our hospitalized patients who need antibiotics and are at high risk of CDAD.