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 found 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 co-administration of probiotics with antibiotics may reduce the risk for HO-CDI, at least in institutions where the rates are high (i.e., > 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.

The investigators 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 or older and had received at least one dose of antibiotics and had a length of stay longer than three days. The authors of the study 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.

During the study period of March 29, 2016, to Sept. 30, 2016, investigators evaluated 1,576 patients treated with IV antibiotics. Of those patients, 649 received antibiotics plus probiotics and 927 received antibiotics alone. The two groups were well matched in terms of age and intensive care unit (ICU) stay. However, patients who received probiotics had significantly longer length of stay (LOS), a higher Charleston Comorbidity Index (CCI), and a higher amount of antibiotics billed. 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; 8.2%) compared to the antibiotics alone group (63/927; 6.8%), 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, 1.8%; P = no significance).

COMMENTARY

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 strategy outside of clinical trials, citing insufficient data at the time of publication.1 Based on the results of the study by Box and colleagues, their institution removed all probiotics from the formulary. This decision seems rational from a quality standpoint, since probiotics did not demonstrate any benefit and have associated costs.

There were a few limitations to the study. 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 had higher CCIs and longer LOS and received more antibiotics likely indicates they 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 made to discern initial CDI from recurrent CDI. Whether probiotics had any benefit 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 study by Box and colleagues 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 further 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 utilization perspectives.

REFERENCES

  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: https://www.cdc.gov/antibiotic-use/stewardship-report/outpatient.html. Accessed March 2, 2019.