Effect of Bifidobacterium Breve PRL2020 (an Amoxicillin-clavulanate-resistant Strain) on Gastrointestinal Symptoms and Gut Microbiota Composition in Children Treated With Amoxicillin or Amoxicillin/Clavulanate (PROACRE)

Effect of Bifidobacterium Breve PRL2020 (an Amoxicillin-Clavulanate-Resistant Strain) on Gastrointestinal Symptoms and Gut Microbiota Composition in Children Treated With Amoxicillin or Amoxicillin/Clavulanate: Results of a Pediatric, Multicenter, Randomized, Controlled, Prospective Study

Amoxicillin or Amoxicillin/Clavulanic acid antibiotic therapy has been shown to be associated with disrupting the microbiota population particularly Bifidobacterium, which may have further GI clinical implications.

The present randomized clinical trial is aimed to assess if probiotic Bifidobacterium breve PRL2020 (Brevicillin®) can help modulate the Bifidobacterium population and its clinical implications after antibiotic Amoxicillin or Amoxicillin/Clavulanic acid antibiotic therapy.

Study Overview

• Status: Completed
• Conditions: Bacterial Infections
• Intervention / Treatment: Drug: Antibiotic Treatment; Dietary supplement: Probiotic Bifidobacterium breve PRL2020 (Brevicillin®) treatment

Detailed Description

Treatment with Amoxicillin or Amoxicillin/Clavulanic acid is one of the most common antibiotic therapies used against various infections both in children and adults. These antibiotics can create an imbalance in the intestinal microbiota, altering its structure with a reduction in bacterial richness and, more specifically, in the abundance of bifidobacteria. This opened the window for further evaluations of the effect of this antibiotic combination on the composition of gut microbiota. The alteration can lead to intestinal symptoms such as pain, bloating, abdominal distension, flatulence, diarrhea, and constipation. In study by L. Mancabelli et al. (2021), Bifidobacterium breve PRL2020 has shown greatest resistance to Amoxicillin and Amoxicillin/Clavulanic acid. Currently available scientific data, however, have not yet analyzed the ability of B. breve PRL2020 to counteract the reduction of bifidobacteria that may occur in the human gut during the antibiotic therapy with Amoxicillin or Amoxicillin/Clavulanic acid, and neither its ability to avoid the consequent clinical relapse.

The purpose of this randomized, controlled (untreated group), prospective, multicentre, single-center, non-profit study will be to evaluate the efficacy and safety of the administration of Bifidobacterium breve PRL2020 (Brevicillin®) in pediatric patients (> 3 -12 years of age), treated with the antibiotic Amoxicillin or Amoxicillin/Clavulanic acid, in the improvement of the symptoms due to the pharmacological treatment and in the contrast of the fall of the Bifidobacterium cluster.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • PU (Pesaro E Urbino)
    • Urbino, PU (Pesaro E Urbino), Italy, 61029
      • Università di Urbino Carlo Bo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged between 3-12 years, of either gender, with a bacterial infection and the use of antibiotic therapy with Amoxicillin or Amoxicillin/clavulanic acid under a Physician's prescription.

Exclusion Criteria:

• Presence of neurological, oncological (also past), malformative, and/or autoimmune pathology
• Suspected or presumed allergy to the substance contained in the probiotic formula
• Using any type of probiotic product in the three months before the enrollment or during the trial
• Lack of parental consent to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Patients in this arm will receive only antibiotic Amoxicillin or Amoxicillin/Clavulanic acid.	Drug: Antibiotic Treatment; Antibiotic Amoxicillin or Amoxicillin/Clavulanic acid
Experimental: Probiotic Bifidobacterium breve PRL2020 (Brevicillin®); Patients in this arm will receive Probiotic Bifidobacterium breve PRL2020 (Brevicillin®) (20 billion CFU) 2 sticks/day for 7-10 days (according to antibiotic prescription)in addition to the antibiotic Amoxicillin or Amoxicillin/Clavulanic acid (antibiotic doses: 2-3/day according to physician prescription).	Drug: Antibiotic Treatment; Antibiotic Amoxicillin or Amoxicillin/Clavulanic acid; Dietary supplement: Probiotic Bifidobacterium breve PRL2020 (Brevicillin®) treatment; Probiotic Bifidobacterium breve PRL2020 (Brevicillin®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of antibiotic-associated diarrhea (AAD)	Assessment of diarrhea occurring during antibiotic treatment with amoxicillin or amoxicillin/clavulanic acid. AAD will be counted starting from a single episode of diarrhea and not only after three or more episodes in one day, differing from the standard AAD definition.	7-10 days (according to antibiotic prescription)
Incidence of gastrointestinal symptoms other than diarrhea	Evaluation of gastrointestinal symptoms related to antibiotic therapy, including constipation, nausea, vomiting, abdominal cramps, bloating, and loss of appetite. These will be recorded daily by parents or legal guardians during the antibiotic course.	7-10 days (according to antibiotic prescription)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in gut microbiota diversity following probiotic and antibiotic treatment	Change in gut microbiota composition and diversity assessed by 16S rRNA sequencing of stool samples collected during and after the treatment period. Alpha diversity (Shannon index) and relative abundance of Bifidobacterium genus will be calculated and compared between groups.	7-10 days (according to antibiotic prescription)
Tolerability of probiotic treatment	Number of participants rated as having "good" or "excellent" tolerability to probiotic treatment, as assessed by the physician at the end of antibiotic therapy. Tolerability will be evaluated based on clinical observation and parental report of side effects (e.g., nausea, abdominal discomfort, rash).	7-10 days (according to antibiotic prescription)
Adherence to probiotic treatment	Percentage of participants who completed ≥80% of the prescribed probiotic doses during the antibiotic treatment period, as assessed by returned product count and parental report.	7-10 days (according to antibiotic prescription)

Collaborators and Investigators

• Sponsor: Liaquat University of Medical & Health Sciences
• Collaborators: University of Urbino "Carlo Bo"

Publications and helpful links

General Publications

• Caron F, Ducrotte P, Lerebours E, Colin R, Humbert G, Denis P. Effects of amoxicillin-clavulanate combination on the motility of the small intestine in human beings. Antimicrob Agents Chemother. 1991 Jun;35(6):1085-8. doi: 10.1128/AAC.35.6.1085.
• Mancabelli L, Mancino W, Lugli GA, Argentini C, Longhi G, Milani C, Viappiani A, Anzalone R, Bernasconi S, van Sinderen D, Ventura M, Turroni F. Amoxicillin-Clavulanic Acid Resistance in the Genus Bifidobacterium. Appl Environ Microbiol. 2021 Mar 11;87(7):e03137-20. doi: 10.1128/AEM.03137-20. Print 2021 Mar 11.
• Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002 Jan 31;346(5):334-9. doi: 10.1056/NEJMcp011603. No abstract available.
• Salvo F, Polimeni G, Moretti U, Conforti A, Leone R, Leoni O, Motola D, Dusi G, Caputi AP. Adverse drug reactions related to amoxicillin alone and in association with clavulanic acid: data from spontaneous reporting in Italy. J Antimicrob Chemother. 2007 Jul;60(1):121-6. doi: 10.1093/jac/dkm111. Epub 2007 Apr 21.
• Yang L, Bajinka O, Jarju PO, Tan Y, Taal AM, Ozdemir G. The varying effects of antibiotics on gut microbiota. AMB Express. 2021 Aug 16;11(1):116. doi: 10.1186/s13568-021-01274-w.
• Liu L, Wang Q, Lin H, Das R, Wang S, Qi H, Yang J, Xue Y, Mao D, Luo Y. Amoxicillin Increased Functional Pathway Genes and Beta-Lactam Resistance Genes by Pathogens Bloomed in Intestinal Microbiota Using a Simulator of the Human Intestinal Microbial Ecosystem. Front Microbiol. 2020 Jun 4;11:1213. doi: 10.3389/fmicb.2020.01213. eCollection 2020.
• Duranti S, Lugli GA, Milani C, James K, Mancabelli L, Turroni F, Alessandri G, Mangifesta M, Mancino W, Ossiprandi MC, Iori A, Rota C, Gargano G, Bernasconi S, Di Pierro F, van Sinderen D, Ventura M. Bifidobacterium bifidum and the infant gut microbiota: an intriguing case of microbe-host co-evolution. Environ Microbiol. 2019 Oct;21(10):3683-3695. doi: 10.1111/1462-2920.14705. Epub 2019 Jun 20.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2023
• Primary Completion (Actual): March 31, 2025
• Study Completion (Actual): April 18, 2025

Study Registration Dates

• First Submitted: April 1, 2023
• First Submitted That Met QC Criteria: April 21, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Actual): November 21, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Anti-Infective Agents; Therapeutics
• Other Study ID Numbers: 77_6settembre2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No