Background: antibiotic-associated diarrhoea (AAD) is defined as an acute inflammation of the intestinal mucosa associated to the administration of antibiotics. Its aetiology seems to be linked to the impact of antibiotics on the normal digestive microbiota. Acute otitis media (AOM) is a common paediatric condition and it is one of the most commonly cited indication for antimicrobial therapy in children (amoxicillin + clavulanic acid).

Treatment modalities for AAD are limited because no established treatment exists for non-Clostridium difficile associated AAD, except for discontinuing antibiotic therapy. Measures to prevent AAD include the use of probiotics. The rationale for the use of probiotics in AAD assumes that, considering the pathogenesis of AAD, AAD is associated with disturbance in the normal intestinal microbiota; administrating specific probiotic strains it is possible to normalize unbalanced indigenous microbiota.

Scientific evidence suggests that prebiotics could be beneficial too. Prebiotics can act in synergy with probiotics, being efficacious in suppressing the growth of pathogenic bacteria that may occur during antibiotic therapy.

Study rationale: the principal side effects of treatment with amoxicillin-clavulanate include diarrhoea, vomiting and allergic reactions. Aim of this study is to evaluate the effectiveness of the administration of a synbiotic product, Bio-Kult Infantis®, in the prevention of AAD during a standard therapy with amoxicillin-clavulanate to treat AOM.

Objective: to evaluate the effectiveness of a synbiotic product in the prevention of Antibiotics-Associated Diarrhoea (AAD) during a concomitant standard therapy with amoxicillin / clavulanic acid, also known as co-amoxiclav, to treat Acute Otitis Media (AOM).

Study design: this is a multicenter, double blind, parallel group, placebo controlled, randomized clinical study. 276 children 6 - 35 months old will be enrolled and then randomized into one of the two study groups (Bio-Kult Infantis® + co-amoxiclav standard treatment for AOM / placebo + co-amoxiclav standard treatment for AOM). A comparison will be performed to evaluate the effectiveness of a synbiotic product in the prevention of AAD during the concomitant standard therapy with co-amoxiclav.

During the study 4 visits will have to be performed at the study centre, and extra visits will be performed in case of AOM relapse after recovery. The study will last for each patient 38 ± 6 days.

Inclusion Criteria:

• 1. Parents / legal guardians signed written informed consent to participate in the study.

• 2. Male and female infants aged 6 - 35 months (6 and 35 inclusive).

• 3. Infants eligible to receive co-amoxiclav to treat AOM according to current Italian guidelines, edited by Società Italiana di Pediatria, 2012.

• 4. Outpatients infants (not hospitalized).

• 5. Infants who have received at least 2 doses of pneumococcal conjugate vaccine.

• 6. Infants diagnosed with Acute Otitis Media (AOM) based on the following three criteria:

  1. onset, within the preceding 48 hours, of symptoms that parents or legal guardians rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms (AOM - SOS);
  2. presence of middle-ear effusion;
  3. moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane

• 7. Infants already exposed to formula milk without Cow Milk Protein Allergy (CMPA) (not requiring a formal diagnosis of CMPA).

Exclusion Criteria:

• 1. Infants with any other acute illness apart from AOM (e.g. pneumonia) or with any other chronic illness (e.g. cystic fibrosis).
• 2. Infants with a clinical history positive for any allergy or intolerance to amoxicillin, clavulanic acid or any component of the active product, the placebo or of the rescue medication (acetaminophen).
• 3. Infants presenting contraindications to the study products, to co-amoxiclav or to the rescue medication, according to concerning Summaries of Product Characteristics (SPC).
• 4. Infants being treated with any drug whose pharmacokinetics can interfere with the intake of amoxicillin, clavulanic acid, the study products or the rescue medication or with any drug with which amoxicillin, clavulanic acid, the study products or the rescue medication can interact, according to concerning Summaries of Product Characteristics (SPC).
• 5. Infants with a clinical history positive for allergy to any other antibiotics.
• 6. Infants who have received antibiotics within 8 weeks prior to enrollment.
• 7. Infants who have had otalgia for longer than 48 hours or perforation of the tympanic membrane.
• 8. Infants suffering from active diarrhoea at time of enrollment or chronic diarrhoea.
• 9. Infants who consumed a probiotic product for medicinal purposes within 7 days prior to enrollment.
• 10. Unwillingness on the part of the parents or legal guardians to interrupt any regular intake of other probiotics during the study period
• 11. Diagnosis of Clostridium difficile-associated diarrhoea (CDAD) within the previous three months from enrolment

A multicenter, double blind, parallel group, placebo controlled, randomized study.