Reference: JAMA Pediatr. 2022 Sep 1;176(9):860-866
Practice Point: Continue to consider certain probiotics for certain children getting certain antibiotics. No change of practice is indicated based on a new study.
EBM Pearl: Heterogeneity in study populations, particularly combined with flawed randomization, allows for uncontrolled variables which undermine confidence in the results.
A new study published in JAMA Pediatrics calls into question what effect the “strict” definition of antibiotic-associated diarrhea (AAD) has on clinical trial results and their interpretation, and reports a benefit of probiotics for prevention of diarrhea due to any cause. We question this study more than the definition of AAD, however.
Study investigators enrolled 350 children who were started on broad-spectrum oral or intravenous antibiotics within the past 24 hours in either the inpatient or outpatient setting and randomized them to receive either daily high-dose multispecies probiotics or placebo for the duration of antibiotics plus 7 days. Using a quasi-intention-to-treat analysis, investigators analyzed data from 313 of the 350 children and found no difference in AAD, defined as ≥ 3 loose or watery stools in a 24-hour period caused either by Clostridioides difficile or of otherwise unexplained etiology after testing for common diarrheal pathogens. A second analysis used a broader definition and found a significant reduction in diarrhea due to any cause in children treated with probiotics (relative risk 0.65). However, flaws in the design and execution of this study make the data difficult to interpret or apply, no matter how you define diarrhea.
First, the study population was heterogeneous. Enrolled children got a variety of antibiotic regimens in different treatment settings (77% were inpatient). Hospitalized children are generally sicker than those treated at home, and some antibiotics tend to cause more diarrhea than others, namely amoxicillin-clavulanate. This leads us to the second issue: significant baseline differences between groups, which is indicative of flawed randomization. Fewer children in the probiotic group were being treated with amoxicillin-clavulanate or with a single-(as opposed to multiple-) antibiotic regimen. This heterogeneity introduces confounding at multiple levels, making it impossible to conclude whether any reduction in diarrhea was due to the probiotics or other variable(s) not accounted for.
It’s also possible that the lack of true intention-to-treat analysis actually underestimated the benefit of the intervention. Thirteen percent of patients in the placebo group who had diarrhea did not provide stool samples. These were attributed to diarrhea from any cause, thereby diluting the potential benefit for preventing AAD (or overestimating the benefit for prevention of diarrhea due to any cause).This could be a big part of why it doesn't appear that probiotics reduced AAD, but did reduce diarrhea as a whole.
The bottom line here is that threats to validity in this study are more significant than any potential conclusions that can be made about the benefits of probiotics for the prevention of antibiotic-associated diarrhea.
For more information, see the topic Probiotics to Prevent Antibiotic-associated Diarrhea in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.