By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: A retrospective cohort study from a single California hospital revealed the administration of probiotics to patients receiving antibiotics did not reduce the incidence of healthcare facility-onset Clostridioides difficile infection.

SOURCE: Box MJ, Ortwine KN, Goicoechea M, Scripps Antimicrobial Stewardship Program (SASP). No impact of probiotics to reduce Clostridium difficile infection in hospitalized patients: A real-world experience. Open Forum Infect Dis 2018;5:ofy192.

Healthcare facility-onset Clostridioides difficile infection (HO-CDI), formerly known as Clostridium difficile, is detrimental to patients and healthcare institutions alike. Some data suggest the coadministration of probiotics with antibiotics may reduce the risk for HO-CDI, at least in institutions where the rates are high (> 20%).

As part of a care bundle to reduce HO-CDI, a specific probiotic formulation was recommended for administration to patients receiving antibiotics and judged to be at high risk for HO-CDI at the authors’ institution. Thereafter, the researchers sought to determine whether probiotics are beneficial in a hospital with a lower rate of HO-CDI, what they describe as a “real-world” environment.

Box et al conducted a retrospective cohort study at a 400-bed community hospital in La Jolla, CA. Patients were included if they were ≥ 18 years of age, had received at least one dose of antibiotics, and had been in the hospital more three days. The authors excluded patients whose CDI was community-acquired or who had received cefazolin or cefoxitin for surgical prophylaxis. The primary outcome was the incidence of HO-CDI in patients who received IV antibiotics plus probiotics compared to those who received IV antibiotics alone.

Between March 29, 2016, and Sept. 30, 2016, investigators evaluated 1,576 patients treated with IV antibiotics. Of those, 649 received antibiotics plus probiotics and 927 received antibiotics alone. The two groups were well matched in terms of age and ICU stay. However, patients who received probiotics were in the hospital longer, scored higher on the Charleston Comorbidity Index (CCI), and paid more money for antibiotics. The use of acid-suppressing agents was not significantly different between the two groups. HO-CDI occurred in 11 of 649 patients who received antibiotics plus probiotics and in eight of 927 patients who received antibiotics alone (1.8% vs. 0.9%, respectively; P = 0.16). The median duration of probiotic use was 8.1 days. Furthermore, in-house mortality was higher in the antibiotics plus probiotics group (53/649) compared to the antibiotics alone group (63/927), although this difference was not significant (P = 0.32).

The authors conducted a subgroup analysis to determine if greater exposure to antibiotics in the probiotic group offset a potential benefit. They compared HO-CDI rates in the probiotic group with rates in the top 30% of patients by antibiotic exposure (billed grams of antibiotics) in the group that received antibiotics alone. There was no observed difference in HO-CDI rates between the two groups (five of 284 patients; P = no significance).


This large, retrospective cohort study revealed no benefit for probiotics in preventing HO-CDI. The use of probiotics for CDI prevention has been controversial. The most recent Infectious Diseases Society of America guidelines decline to endorse probiotics as a CDI prevention approach outside clinical trials. The guideline authors cited insufficient data at the time of publication.1 Based on the results of the Box et al study, their institution removed all probiotics from the formulary. This decision seems rational from a quality standpoint, since probiotics did not demonstrate any benefit and carry associated costs.

There were a few limitations. First, it was conducted at a single community hospital, which may limit its generalizability to other healthcare settings, such as nursing homes, or for outpatients. Second, the authors did not explore the association and outcomes between probiotics and specific antibiotics, including those that are more prone to cause CDI. Third, the retrospective design may have led to bias from unmeasured confounding factors, such as differences in probiotic prescribing by physicians. Fourth, the finding that the probiotic recipients scored higher on the CCI, stayed in the hospital longer, and received more antibiotics likely indicates these patients were more ill and at higher risk for CDI. This could have skewed the results and led to a type II error. Finally, there was no attempt to discern initial CDI from recurrent CDI. Whether probiotics were beneficial in cases of recurrence is unclear from the study data.

Antibiotic use is the most important modifiable risk factor for CDI. The CDC estimates that 30% of antibiotics are prescribed unnecessarily.2 Thus, the Box et al study is another nail in the coffin for the idea that probiotics prevent CDI. Instead, it reaffirms that the best way forward to reduce the risk for CDI is through prudent and aggressive antibiotic stewardship efforts.

Rather than conducting more studies on probiotics, it would be more pragmatic if investigators focused on ways to reduce antibiotic use that still leads to successful eradication of infections and positive outcomes. For example, studies that elucidate the least amount of time that antibiotics can be given for a particular infection to result in a cure would be valuable from clinical, quality, safety, and resource use perspectives.


  1. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66:987-994.
  2. Centers for Disease Control and Prevention. Antibiotic use in the United States, 2017: Progress and opportunities. Available at: Accessed April 4, 2019.