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Cited by 550Clostridium difficile and Clostridium perfringens researchProbiotics and Fermented FoodsGut microbiota and health

Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children

Goldenberg, Joshua Z, Yap, Christina, Lytvyn, Lyubov, Lo, Calvin Ka-Fung, Beardsley, Jennifer, Mertz, Dominik, Johnston, Bradley C·2017·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd006095.pub4
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Abstract

Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies.To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children.We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search.Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion.Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group, we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria.Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. 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). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. 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). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance.Based on this syst

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  • Gastrointestinal disturbances including vomiting, cramps, bloating, nausea, diarrhea, thirst, and taste disturbances occur with probiotic use.

    “Such disturbances in gastrointestinal activity include vomiting, cramps, bloating, nausea, diarrhea, thirst, and taste disturbances that occur with the use of probiotics [98,99].”

    From Current Concepts in Probiotic Safety and Efficacy (2026) · cites this paper as [99]

  • Among the general population and in patients who are not immunocompromised or severely debilitated, acute safety issues appear to be minor, especially when considering the large global use of probiotics in foods and nutritional supplements.

    “Among the general population and in patients who are not immunocompromised or severely debilitated, acute safety issues appear to be minor, especially when considering the large global use of probiotics in foods and nutritional supplements.2–5”

    From Emerging issues in probiotic safety: 2023 perspectives (2023) · cites this paper as [3]

  • While probiotics significantly reduce incidence of CDAD, they do not appear to reduce C. difficile infection.

    “Furthermore, while probiotics significantly reduce incidence of CDAD they do not appear to reduce C. difficile infection.21”

    From Probiotics for the prevention of antibiotic-associated diarrhoea: A systematic review and meta-analysis (2021) · cites this paper as [21]

  • A Cochrane review found moderate quality evidence for a large protective effect of probiotics against C. difficile-associated diarrhoea (RR 0.40, 95% CI 0.30 to 0.52).

    “In a Cochrane review21 authors found moderate quality evidence for a large protective effect of probiotics against C. difficile-associated diarrhoea (CDAD) (RR 0.40, 95% CI 0.30 to 0.52).”

    From Probiotics for the prevention of antibiotic-associated diarrhoea: A systematic review and meta-analysis (2021) · cites this paper as [21]

  • The initial search was a title search as opposed to a keyword search, which may explain the lower number of studies initially identified compared with the recent Cochrane review.

    “Additionally, the initial search was a title search as opposed to keyword search, which may explain the lower number of studies initially identified, compared with the recent Cochrane review.21”

    From Probiotics for the prevention of antibiotic-associated diarrhoea: A systematic review and meta-analysis (2021) · cites this paper as [21]

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Authors
Goldenberg, J. Z., Yap, C., Lytvyn, L., Lo, C. K.-F., Beardsley, J., Mertz, D., & Johnston, B. C.
Affiliations
  • University of Technology Sydney (AU)
  • Bastyr University (US)
  • McMaster University (CA)
  • University of British Columbia (CA)
  • Juravinski Cancer Centre (CA)
  • Dalhousie University (CA)
ORCID
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2017-12-19
Volume
2017
Issue
12
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd006095.pub4
OpenAlex
W3174485034
Cited by
550
References
162
Citations by year
2026: 19 · 2025: 49 · 2024: 62 · 2023: 81 · 2022: 81 · 2021: 75 · 2020: 69 · 2019: 74 · 2018: 39 · 2013: 1
FWCI
7.59
Type
journal article
Language
en
Update notices
new_version (2025-09-11)
Open access
closed
Locations
Cochrane Database of Systematic Reviews (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Clostridium difficile and Clostridium perfringens research
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
probiotics, Clostridium difficile-associated diarrhea, Clostridium difficile infection, antibiotic-associated diarrhea, probiotic prophylaxis, gut microbiota, length of hospital stay, adverse events, pediatric patients, adults, risk of bias, subgroup analysis, number needed to treat, quality of evidence, number needed to harm, number needed to benefit

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