Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics

Study Overview
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Brief Summary
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The focus of the study is to better understand the mechanisms causing antibiotic-associated diarrhea (AAD) and how probiotics may prevent some of the iatrogenic effects of antibiotic medications. One of the most common indications for probiotics is for prevention of antibiotic-associated diarrhea. Clinically, different probiotic strains have demonstrated the ability to prevent AAD; however, the mechanism of action behind this effect has not been elucidated. Data from several studies suggest that antibiotic-induced disruption of commensal bacteria in the colon results in a significant (up to 50%) reduction in short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption resulting in AAD. Probiotics have been shown to ameliorate a variety of gastrointestinal disease states and thus, the study investigators hypothesize that administration of a probiotic yogurt will protect against the development of AAD.

Detailed Description
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Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, the efficacy of many probiotic products used for AAD is not supported by rigorous independent research, and non-evidence-based clinical usage is common. Data from several studies are consistent with the notion that antibiotic-induced disruption of commensal bacteria in the colon results in a significant reduction of short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption resulting in AAD. The probiotic strain being studied, Bifidobacterium animalis subsp. lactis BB-12 (BB-12), has been shown to ameliorate a variety of gastrointestinal disease states and is known to produce acetate at concentrations up to 50 mM in vitro. Thus, the investigators hypothesize that administration of BB-12 at the same time as antibiotic consumption will protect against the development of AAD through its ability to generate acetate directly, and also increase other SCFAs through cross-feeding of certain bacteria in the Firmicutes phylum such Clostridium, Eubacterium and Roseburia, which use acetate to produce butyrate. The primary aim of the R61 phase (N=60) is to determine the ability of BB-12 to impact antibiotic-induced reduction in SCFA as reflected by the levels of acetate, the most abundant primary colonic SCFA. The primary hypothesis is that antibiotics will result in a reduction in fecal SCFA, but BB-12 supplementation will protect against antibiotic-induced SCFA reduction and/or be associated with a more rapid return to baseline SCFA levels as compared to controls. Antibiotics also result in a decrease in total microbial counts and diversity in the gut microbiota, disrupting the homeostasis of the gut ecosystem and allowing colonization by pathogens. The secondary aim will be to determine the ability of BB-12 to impact antibiotic-induced disruption of the gut microbiota with 16S (16 Svedberg) ribosomal ribonucleic acid (rRNA) profiling. The secondary hypothesis is that antibiotics will result in a decrease in the overall number and diversity of bacterial species present in the fecal microbiota, and further BB-12 supplementation will protect against antibiotic-induced shifts in the microbiota and/or will be associated with a more rapid return to a baseline microbiota composition as compared to controls. The long-term goal is to determine the impact of BB-12 on a variety of gastrointestinal disease states and ages, through high-level independent research. This mechanism elucidation is important for directing future translational and effectiveness research.

Official Title
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Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics

Conditions
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Antibiotic-associated Diarrhea

Intervention / Treatment
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* Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
* Biological: BB-12
* Other: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has the ability to read, speak, and write in English Has refrigerator (for proper storage of the study yogurt) Has reliable telephone access Is between ages of 18-65 years Agree to refrain from eating yogurts, yogurt drinks, and other foods specified in the provided What Not to Eat list Agree to collect stool samples and participate in follow-up calls as specified Exclusion Criteria: Diabetes or asthma that requires medication Allergy to strawberry Active diarrhea (three or more loose stools per day for two consecutive days) Any gastrointestinal (or digestive tract) medications, i.e. medicines for irritable bowel syndrome, gastroesophageal (acid) reflux disease, inflammatory bowel disease, etc. History of heart disease, including valvulopathies or cardiac surgery, any implantable device or prosthetic History of gastrointestinal surgery or disease Lactose intolerance that prevents participant from eating yogurt Allergy to milk-protein Allergy to any component of the product or the yogurt vehicle Allergy to penicillin or cephalosporin class antibiotics Allergy to any of the following medications: a) Penicillin; b) Erythromycin; c) Tetracycline; d) Trimethoprim; e) Ciprofloxacin Women who are breastfeeding, pregnant, or planning to become pregnant during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet | Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet<br>* Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet<br>* Other names: Augmentin;Other: Control<br>* Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12)<br>|
| Experimental: BB-12<br>Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet | Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet<br>* Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet<br>* Other names: Augmentin;Biological: BB-12<br>* Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of Fecal Short-chain Fatty Acid (SCFA) Acetate | Level of fecal short-chain fatty acid acetate (SCFA) after administration of amoxicillin clavulanate | day 0 (post run-in), 7, 14, 21, 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of Fecal SCFA Propionate | Level of fecal short-chain fatty acid propionate after administration of amoxicillin clavulanate | day 0 (post run-in), 7, 14, 21, 30 | 
| Level of Fecal SCFA Butyrate | Level of fecal short-chain fatty acid butyrate (μM) after administration of amoxicillin clavulanate | day 0 (post run-in), 7, 14, 21, 30 |