Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017 Dec 19;12:CD006095. doi: 10.1002/14651858.CD006095.pub4.
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BACKGROUND: 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.

OBJECTIVES: To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children.

SEARCH METHODS: 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.

SELECTION CRITERIA: 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.

DATA COLLECTION AND ANALYSIS: 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.

MAIN RESULTS: 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.

AUTHORS' CONCLUSIONS: Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk =5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.

Comments from MORE raters

Gastroenterology rater

This systematic review is well done. There are other previous systematic reviews that have shown similar findings. It is good to have a rigorous Cochrane review that confirms this but I would imagine most practitioners already know this information.

General Internal Medicine-Primary Care(US) rater

NOTE: From Wikipedia - "Bastyr Univ is an alternative medicine university ... Programs include naturopathy, acupuncture and Oriental medicine, nutrition, herbal medicine, ayurvedic medicine, psychology, and midwifery. Bastyr's programs teach and research topics that are considered pseudoscience and quackery by the scientific and medical communities. Quackwatch, a group against health fraud, put Bastyr University on its list of 'questionable organizations' as a school which is 'accredited but not recommended'. Bastyr University and similar naturopathic programs are not accredited as medical schools but as special programs that are overseen by a naturopathic council which is not required to be scientific." Also of concern: Disraeli-Twain statistics (a hazard of every meta-analysis), and that I do not see the breakdown on the rate of admission of the IV antibiotic. This has been going on for decades, and I doubt we've heard the end of it. Let's CUT antibiotic use instead.

General Internal Medicine-Primary Care(US) rater

This is a common question among patients, and the data have been mixed, so it is helpful to see a systematic review.

Hospital Doctor/Hospitalists rater

The meta-analysis highlights the effectiveness of probiotics among patients at an elevated (>5%) risk of developing Clostridium difficile-associated diarrhea. The article quantifies the expected benefit of using probiotics along with the risks for developing side effects. The article might help clinicians have more detailed conversations with patients who are particularly concerned about the risks of probiotics.

Hospital Doctor/Hospitalists rater

Prevention of C difficile colitis is a very important goal. This meta-analysis suggests probiotics work for this goal.

Hospital Doctor/Hospitalists rater

Useful review. Clearly delineating high-risk patients with CDAD benefit with probiotics.

Infectious Disease rater

The dialog about probiotics and various gut dysbioses has been going on for quite a while. This is one of a number of systematic reviews that concludes that there is a likely benefit to probiotics with a number-needed-to-benefit of around 40. The famous "devil in the details" is the variability among probiotics, and the possibility that some may be much more beneficial than others. The good news in these studies is the consistency of the message that probiotics are safe (perhaps even safer than placebo). Why has there been relatively little uptake of these findings? Perhaps clinicians cannot see the small benefit in their practice? Perhaps adding another medication seems burdensome? Perhaps doctors are unaware of this research? Perhaps doctors feel that there are hidden biases in favor of probiotics because of the sponsorship of research? Would I try this in a high-risk group? Yes, because there is little to lose, but I would convey little confidence in the outcome.

Infectious Disease rater

A potentially impactful synthesis as the current (2010) IDSA guidelines do not recommend use of probiotics due to limited data.

Internal Medicine rater

We have been doing this in our hospital for well over a year now.

Pediatric Hospital Medicine rater

This is a recent updated Cochrane on use of probiotics to prevents CDAD. It's always great to see a Cochrane, particularly centered around something we see very commonly on IM and Peds floors. This should inform practice.