TOPIC: Should probiotics be used for prevention of Clostridium difficile infection?
Dr. Nicole T. Shen is a first year gastroenterology and hepatology fellow in the Division of Gastroenterology and Hepatology at Weill Department of Medicine, Weill Cornell Medicine (USA). She is first author of a recent systematic review with meta-analysis on the efficacy of probiotics for prevention of Clostridium difficile infection (CDI). In the US and other countries, CDI is the most common cause of infection in health care settings; administration of broad-spectrum antimicrobials is an important risk factor.
Question: What was the main clinical problem you were addressing with this meta-analysis?
NTS: Clinically, the question is: Are probiotics effective at preventing C. diff infection in hospitalized adults receiving antibiotics?
We were wondering why there was such a discrepancy in the recent large randomized multi-center trial, and then the systematic review with meta-analysis, and we wondered: what is the underlying answer to the two findings we’re observing? And why in practice are some hospitals using probiotics concurrently with antibiotics, and some hospitals not?
Question: What was unique about your meta-analysis?
NTS: For the first time we looked at the effect that the timing of initiation of the probiotic had on efficacy.
No other systematic review with meta-analysis thought to look at trials that allowed inclusion of patients up to a certain point after the first antibiotic dose. Trials that had more narrowed inclusion criteria—only allowing up to two days after the first antibiotic dose for the first probiotic dose—found significantly more benefit of probiotics than those that allowed later inclusion of subjects: those that were starting the probiotic three days or more after their first antibiotic dose.
We designed this before we went into the analysis, a priori, and we thought that was a good thing to investigate, because your gut flora changes so much right away with antibiotics.
Question: Based on what you found, what can you tell clinicians about probiotics for the prevention of C. difficile infection?
NTS: From our findings in this paper, we think that probiotics should be considered in any patient starting antibiotics that is hospitalized and an adult.
That’s to be done to reduce the risk of C. diff infection. Because we found a reduced risk of over 50%.
It’s important to remember that these trials did not see any bacteremia or fungemia, but it is a real risk because we hear of it case reported. The trials excluded the patients you see in those case reports. We didn’t study patients that were in the intensive care unit or pregnant, or have prosthetic heart valves—those are some of the main ones.
So you have to take the findings and make sure you use them in the appropriate clinical context.
But even if you take those people that were excluded, there’s still a large amount of people in the hospital that would benefit from starting a probiotic with the antibiotic.
Question: Were any particular probiotic strains more effective than others?
NTS: No particular strain showed significantly higher efficacy than another, but the ones that were more studied were Lactobacillus in combination with another species: Lactobacillus with Streptococcus, Lactobacillus with Bifidobacteria; whereas Saccharomyces was really only studied by itself.
Lactobacillus acidophilus in combination with Lactobacillus casei seemed to have the most support in the non-clinical settings. Lactobacillus casei in particular has a plausible pathophysiology for how it would attack C. diff.
Saccharomyces also has some good evidence, but the trials didn’t study enough of the same probiotic that you can really draw that conclusion. The same issue comes up with dosing too.
Question: How was your study different from the recent one by Vernaya & colleagues?
The study done by Vernaya and colleagues focused on papers investigating probiotic use with antibiotic use in hospitalized adults age greater than 60 on the outcome of CDAD (C. diff-associated diarrhea, also known as CDI or C. diff infection). Their search was much more limited as evidenced by finding only 5 papers to include. This limitation could be from the restriction to only papers published in English, age restriction of subjects to over 60, and the search being last conducted November 2015. Additionally, one of their included trials by Lewis et al. did not focus on CDAD. This trial was excluded from our analysis, given that Lewis et al. tested patients for C. diff regardless of whether the patient had the symptom of diarrhea; patients can be colonized with C. diff without active infection.
With our search, we were able to identify more randomized controlled trials, that when included, suggested probiotic efficacy, in meta-analysis with reduced heterogeneity. Additionally, we investigated the effect of probiotic timing on efficacy with meta-regression, which was found to be significant.
SUMMARY: Evidence supports the administration of probiotics close to the first antibiotic dose as a way to reduce the risk of CDI in hospitalized adults.
Shen NT, Maw A, Tmanova LL, et al. Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis. Gastroenterology. 2017; 152(8): 1889–1900.e9
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