Antibiotic-Associated Diarrhea and the Role of Microorganisms in the Gut
Condition: Antibiotic-associated Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 4

Summary: 
      Amoxicillin-clavulanate is an antibiotic commonly prescribed to treat a myriad of
      community-acquired infections. One of the most common adverse effects of
      amoxicillin-clavulanate is antibiotic-associated diarrhea (AAD). Studies have shown that
      administration of antibiotics can cause disruption and changes in the diversity of
      microorganisms within the gut (gut microbiome), with overgrowth of "harmful" bacteria as a
      possible driver for AAD. How antibiotics specifically affect the gut microbiome to cause AAD
      in humans, however, remains unknown. The overall goal of the study is to characterize the
      changes in the gut microbiome over time, in subjects who develop AAD after antibiotic
      ingestion, and to further demonstrate that resolution of AAD is due to return of "friendly,
      anti-diarrhea bacteria". The study investigators will also measure the proteins produced by
      the gut bacteria, as a potential tool to help predict which individuals are at risk of AAD.

      The investigators plan to recruit 30 healthy adult volunteers who will receive 3 days of oral
      amoxicillin-clavulanate, a very commonly prescribed antibiotic. Stool and blood samples will
      be collected throughout the study up to 28 days after antibiotic administration. The study
      investigators will measure and compare the changes in the gut microbiome and metabolic
      responses in order to identify the relationship between these changes and the onset of AAD.
      The results from this study will not only yield important scientific knowledge about the
      pathogenesis of AAD, but will also provide new leads to understand the interplay between the
      gut microbiome, immune-metabolism and AAD. These findings also have the potential to identify
      clinically important biomarkers to allow pre-identification of individuals at risk of AAD. If
      successful, this study could pave the way for personalized medicine for management of
      bacterial infections. This will help to prevent premature stoppage of antibiotic therapy due
      to diarrhea side effects, and reduce the risk of bacterial resistance from suboptimal
      treatment.
    

Detailed description: 
      All eligible subjects will proceed to Day 0, where they will receive study drug
      amoxicillin-clavulanate 1g twice a day for 3 days. Prior to administration of study drug on
      Day 0, stool sample and blood will be collected for microbiome and metabolomics & gene
      expression analysis respectively. Urine pregnancy test (for females subjects of child-bearing
      potential) will be performed prior to study drug administration. Baseline physical
      examination and vital signs will be done as well.

      Subsequently, stool and blood samples will be collected on day 1, day 2, day 3, day 7, day
      14, and day 28. Physical examination, vital signs, and review of adverse events will be done
      at each of the visits as well.

      Volunteers will be monitored for symptoms of AAD throughout this period. All study subjects
      will be asked to keep a standardised patient diary up to day 28 or until symptom resolution
      whichever is longer. All other potential AEs will also be solicited for throughout study
      period. Subjects who develop AAD will be graded according to CTCAE version 5.0 criteria for
      AEs. The study drug Augmentin will be discontinued in subjects who develop AAD, defined as a
      passage of loose or watery stool at least 3 times in a 24-hour period. Management of AAD is
      at the discretion of the study team PI and co-Is, guided by severity and clinical indication
      for intervention. All medication prescribed for the management of AAD or other AEs will be
      documented in the medication/concomitant medication clinical record form.
    

Intervention name(s): Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Intervention type(s): Drug
Intervention description(s): Oral amoxicillin-clavulanate 1 g twice a day for total of 6 doses
Other intervention name(s): Augmentin; Moxiclav
Intervention MeSH terms: Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: amoxicillin-clavulanate; diarrhea; Gut microbiome