Effect of Limosilactobacillus reuteri DSM17938 to prevent antibiotic-associated diarrhea in children: prospective, multi-center, randomized, placebo-controlled clinical trial (PEARL Study)

Antibiotic-associated diarrhea (AAD) is one of the side effects that occur during and after antibiotic use. Some probiotics have strain-specific beneficial effects on AAD development when used in combination with antibiotics. The aim of this study was to evaluate the effect of Limosilactobacillus reuteri DSM 17938 on the prevention of AAD in children. This is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial in Türkiye between 2017–2019, among outpatient children with acute otitis media (AOM) or acute rhinosinusitis (ARS). Group 1 (n = 330) received amoxicillin-clavulanate and L. reuteri DSM 17938 (2 × 10⁸ CFU) and Group 2 (n = 324) received amoxicillin-clavulanate and a placebo during the antibiotic treatment or continued for 21 days after antibiotic cessation. The primary end point of this study was the percentage of children with AAD in the first 14, 21, and 56 days of follow-up. Secondary endpoints are the percentage of children with AAD regarding the AOM vs ARS, amoxicillin-clavulanate dose, age groups, and the comparison between 14- and 21-days use of L. reuteri. The percentage of children with AAD was significantly lower in the L. reuteri group compared to the placebo group at 14 days (7.9% vs. 16.7%; RR: 0.47, 95%CI 0.30–0.7; p < 0.001); at 21 days (8.8% vs. 17.9%; RR: 0.49, 95%CI 0.32–0.74;p < 0.001); and at 56 days (9.1% vs. 19.6%; RR: 0.46, 95%CI 0.30–0.69;p < 0.001). The incidence of AAD was also significantly lower in the L. reuteri group at 14, 21 and 56 days among children aged between 6–24 months (p < 0.01, p < 0.01, p < 0.001) or children with AOM (p = 0.0001,p < 0.0001,p < 0.0001). When AAD was observed, the mean duration of diarrhea was longer in the placebo group(p < 0.05). Conclusions: This first study with L. reuteri DSM 17938 in a large pediatric outpatient setting showed significant reduction of AAD during the first 14 days of antibiotic use and the 8-week follow-up period. Trial Registration: NCT02765217 (First Submitted 02.05.2016) (https://clinicaltrials.gov/study/NCT02765217?term=NCT02765217&rank=1). (Table presented.)