High-dose Probiotic Mix of Lactobacillus spp., Bifidobacterium spp., Bacillus coagulans, and Saccharomyces boulardii to Prevent Antibiotic-associated Diarrhea in Adults: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial (SPAADA)

Abstract

Background: Probiotics have been used to prevent antibiotic-associated diarrhea (AAD), but practical guidelines are sparse. This trial evaluated the efficacy and safety of a high-dose, multistrain probiotic mix (Sinquanon), specially designed for prevention of AAD in adults.

Methods: A phase IV, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted over 5 months. Participants receiving broad-spectrum antibiotics were administered the specialized probiotic mix or placebo from the first dose of antibiotics until 14 days after the last antibiotic dose. The primary outcome measure was the incidence of AAD.

Results: In total, 564 participants were randomized (probiotic mix: 285; placebo: 279), of which 9 participants discontinued the trial early (probiotic mix: 3; placebo: 6), had no efficacy data, and were excluded from the efficacy analysis. The 555 remaining participants completed the trial and were included in the efficacy analysis (probiotic mix: 282; placebo: 273). AAD occurred less frequently in the studied probiotic mix versus placebo group (9.2% vs 25.3%, P < .001), resulting in an absolute risk reduction of 16% and a number needed to treat of 6 (95% confidence interval, 4.55-10.49). A significant improvement in the average gastrointestinal quality of life in the studied probiotic mix versus placebo group was also observed. There were no clinically relevant differences in the incidence of adverse events between the studied probiotic mix and the placebo group.

Conclusions: The specially designed high-dose, multistrain probiotic mix (Sinquanon) demonstrated to be beneficial compared with placebo in the prevention of AAD in adults who received broad-spectrum antibiotics.

Clinicaltrialsgov identifier and url: NCT05607056; https://classic.clinicaltrials.gov/ct2/show/NCT05607056.

Keywords: antibiotic-associated diarrhea; high-dose; multi-strain; probiotic; randomized controlled trial.

Graphical abstract

Figure 1.

Flowchart of participant disposition. Screening failures included use of antibiotics within 60 d before screening, planned intake of antibiotics >10 d, and use of antidiarrheal medications. Although 1 AE of constipation in the studied probiotic mix group and 1 in the placebo group led to discontinuation of the trial intervention, these participants were not excluded from the efficacy analysis because they received more than 75% of the trial intervention. Nine participants discontinued the trial early (3 on the studied probiotic mix and 6 on placebo), had no efficacy data, and were excluded from the efficacy analysis. The clinical trial was conducted between 27 November 2022 and 25 April 2023. Abbreviation: AE, adverse event.

Figure 2.

Frequency of participants with AAD (primary outcome) overall and by antibiotic treatment. Total n = 555 (probiotic mix/placebo: 282/273). RRs and ORs are accompanied by corresponding 95% CIs. P-values were calculated using the Pearson χ² test (2-sided). Abbreviations: AAD, antibiotic-associated diarrhea; CI, confidence interval; OR, odds ratio; RR, relative risk.

Figure 3.

Secondary outcomes by trial intervention group. A, Severity of AAD: frequency of participants with mild, moderate, and severe AAD. Participants without AAD are not shown on the graph. P-values were calculated using the Z-test (2-sided). B, Duration of AAD in days: frequency of participants with an AAD duration of ≤2, 3–5, or ≥6 d. P-values were calculated using the Z-test (2-sided). C, Gastrointestinal complaints: frequency of participants with nausea, abdominal pain, abdominal swelling, and gas formation. P-values were calculated using the Pearson χ² test (2-sided). D, VAS-QoL per visit: visit 1 on day 1 and visits 2, 3, and 4 on 1 ± 2, 14 ± 2, and 21 ± 2 d after completion of antibiotic treatment, respectively. A lower VAS-QoL score indicates a better gastrointestinal QoL. P-values were calculated using the Student t-test (2–sided). Total n = 555 (probiotic mix/placebo: 282/273), note that in (B) only participants with AAD were included (n = 95 [probiotic mix/placebo: 26/69]). RRs and ORs are accompanied by corresponding 95% CIs. Abbreviations: AAD, antibiotic-associated diarrhea; CI, confidence interval; OR, odds ratio; QoL, quality of life; RR, relative risk; VAS–QoL, visual-analogue scale for the gastrointestinal quality of life.