By Nadia Khosrodad, MD; Justin Khine, MD; and Nancy J. Selfridge, MD
Dr. Khine is a Clinical Teaching Fellow in the Department of Clinical Medicine at Ross University School of Medicine, Bridgetown, Barbados, West Indies.
Dr. Khosrodad is a PGY1 Internal Medicine Resident at St. Joseph Mercy Oakland Hospital, Pontiac, MI.
Dr. Selfridge is Chair of the Department of Clinical Foundations, Ross University School of Medicine, Bridgetown, Barbados, West Indies.
Dr. Khine, Dr. Khosrodad, and Dr. Selfridge report no financial relationships relevant to this field of study.
- In this Cochrane Review of 31 studies, probiotic treatment appears to confer up to 70% risk reduction for Clostridium difficile-associated diarrhea in high-risk patients without associated adverse effects and with an apparent reduction in adverse events compared to either placebo or no treatment.
In a systematic review of probiotic use for reducing Clostridium difficile-associated diarrhea (CDAD), probiotics appear to be most beneficial in populations with high baseline risk of CDAD (> 5%).
Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children (review). Cochrane Database Syst Rev 2017:12:CD006095.
A causal link between gut microflora perturbation by antibiotics and Clostridium difficile-associated diarrhea (CDAD) has long been established. However, therapeutic or prophylactic use of probiotics for CDAD has been viewed skeptically because of inconsistent reports of treatment efficacy. C. difficile infection (CDI) is an expensive disease with total annual attributable costs estimated at $6.3 billion and total annual inpatient management days estimated at 2.4 million in the United States.1 Effective prophylactic therapy potentially could decrease hospital length of stay, mitigate associated complications and patient suffering, and reduce the financial burden of CDI significantly.
In this meta-analysis, Goldenberg et al identified 39 clinical trials that met inclusion criteria for assessing probiotic efficacy in reducing a primary outcome of incidence of CDAD or antibiotic-associated diarrhea. They chose 31 trials assessing CDAD outcomes for data collation and analyses, which included probiotic dose, species/strains, adult vs. pediatric patients, inpatients vs. outpatients, risk of bias, and baseline risk of CDAD. The quality of evidence was assessed independently using the GRADE criteria.2
Twenty-two of the 31 studies had missing data for the outcome ranging from 2-45%. Thus, the authors performed a complete case analysis for the 8,672 participants who completed the study. The risk of CDAD in this group was 1.5% in the probiotic treatment group compared to 4% in the placebo or no treatment control group (relative risk [RR], 0.40; 95% confidence interval [CI], 0.30-0.53), an estimated 60% risk reduction in the treatment group. In a post-hoc analysis, the authors noted one large study comprising nearly 2,810 participants and several other smaller studies that failed to find a statistically significant effect of probiotics on reducing CDAD outcomes. They determined that the baseline risk of CDAD in these study populations was very low (< 5%). The overall risk reduction estimate of probiotic therapy in this analysis is heavily influenced by a number of studies with high baseline risk, including five trials showing a CDAD baseline risk > 15%. Thus, the protective effect of probiotics may not be applicable to low-risk populations. An increased baseline risk of CDAD is widely accepted as associated with advanced age, severity of comorbidities, prolonged hospitalization, and antibiotic use. Antibiotic exposure further stratifies the risk depending on the antibiotic used: High risk is associated with second- and third-generation cephalosporins, fluoroquinolones, and clindamycin; moderate risk with amoxicillin-clavulanic acid and macrolides; and low risk with all others.3
The authors found no association in subgroup analyses to determine if probiotic species, strain, or dose influenced CDAD outcome. Many of the included trials demonstrated high or indeterminate risk of bias, and many had other significant methodological flaws reducing the quality of evidence, which was reported as moderate for the primary outcome according to GRADE criteria. There were no attributable adverse effects associated with probiotics, and overall adverse events were lower in the probiotic group vs. control groups. The risk reduction effect of probiotics on adverse events was estimated at 17% (RR, 0.83; 95% CI, 0.71-0.97), although the quality of evidence (GRADE) for this effect was very low, primarily because of nonstandardized, clear event reporting across studies. Further, results of these trials cannot be generalized to immunocompromised patients.
Despite the need for additional high-quality research to confirm certainty of evidence and provide more detailed information concerning dosing and strains, informing immune-competent patients at high risk for CDAD of the large protective effect of probiotic therapy and encouraging probiotic prophylaxis is sound patient-centered care based on the results of this meta-analysis.
REFERENCES
- Zhang S, Palazuelos-Munoz S, Balsells EM, et al. Cost of hospital management of Clostridium difficile infection in the United States — a meta-analysis and modelling study. BCM Infectious Diseases 2016;16:447.
- Kavanaugh BP. The GRADE system for rating clinical guidelines. PLoS Med 2009;6:e1000094.
- Kuntz JL, Smith DH, Petrik AF, et al. Predicting the risk of Clostridium difficile infection upon admission: A score to identify patients for antimicrobial stewardship efforts. Perm J 2016;20:20-25.
