Microbial, Immune, and Metabolic Perturbations by Antibiotics (MIME Study)

NCT02707042 | Completed Phase 1 FDA Drug

• 2 other identifiers: 16007816-I-0078
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 1

Brief Summary

More than 250 million courses of antibiotics are prescribed annually in the ambulatory care setting in the United States alone, including more than 40 million in children under 18 years of age. The perception that antibiotic use has minimal attendant adverse side effects contributes to the over-utilization of antibiotics in clinical circumstances when they are not strictly indicated. We have learned much about the human microbiome. The emerging view is of profound life-long bi-directional interactions between our microbiota and our cells. Perturbations in the microbiota affect metabolic, immune, and cognitive physiology in experimental animal models. When a person takes an antibiotic, the antibiotic diffuses via the blood into all body compartments, selecting for resistance. We propose to examine the effects of two commonly used antibiotics (the beta-lactam, amoxicillin and the macrolide azithromycin) on human microbial populations and on metabolic and immune physiology, studying healthy human volunteers in a randomized controlled clinical trial at the NIH Clinical Center. Our hypothesis is that in addition to acutely perturbing the human microbiome, these agents will have measurable metabolic and immunologic effects, with residual effects in the weeks that follow. To test this hypothesis, we will assess the effects of a brief therapeutic course of antibiotics on microbiome and metagenome composition. After an initial evaluation period, antibiotics will be given for 7 days or 5 days (depending on the antibiotic), and there will be a post-treatment evaluation. A control group will receive no drug intervention. Specimens will be obtained from multiple sites at each of 10 time points occurring before, during, and after antibiotic administration, and used for estimating bacterial and fungal composition and gene content. We will also assess the effects of the antibiotic course on markers of innate and adaptive immunity as well as markers of metabolic and hormonal physiology. A subgroup of subjects will be studied in the clinical center metabolic chamber to assess 24-hour energy expenditure and its components (sleeping, diet-induced, and activity energy expenditure), as well as macronutrient oxidation rates (carbohydrate, fat, and protein), during 3 of the 10 study visits. In addition to the primary data analyses, we will build a model that integrates the temporal data to begin to understand the complex intertwined physiology between microbiome and host.

Conditions

Normal Physiology; Healthy

Keywords

Microbiome; Amoxicillin; Azithromycin; Stool; Healthy

Outcome Measures

Primary Outcomes (1)

• To determine whether antibiotic-induced perturbation of the microbiome has measurable metabolic and immunologic effects during and after the treatment period.

  1\. Change in total EE of 5% from pre-treatment to post-treatment among the subjects receiving antibiotics (metabolic endpoint). 2. Average decrease of 500 cell/mm3 in the peripheral blood leukocyte count from pre-treatment to post-treatment among subjects receiving antibiotics (immunologic endpoint).

  Prior to, during, after antibiotic course

Secondary Outcomes (3)

• Changes in parameters of metabolic functioning, including measures of hormones relevant to metabolism.

  Prior to, during, after antibiotic course

• Changes in blood, cutaneous, intestinal, oral, salivary, urinary, vaginal bacterial microbiomes;

  Prior to, during, after antibiotic course

• Changes in parameters of immune function and response in samples of blood, serum/plasma; and

  Prior to, during, after antibiotic course

Study Arms (3)

Group A

OTHER

Control

Other: Control

Group B

OTHER

Amoxicillin

Drug: Amoxicillin

Group C

OTHER

Azithromycin

Drug: Azithromycin

Interventions

Amoxicillin DRUG

7-day therapeutic oral course of twice daily amoxicillin

Group B

Azithromycin DRUG

5-day oral course of once-daily azithromycin

Group C

Control OTHER

A group of volunteers will receive no antibiotics and will serve as study controls.

Group A

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy women and men will be eligible for study participation if they meet the following criteria:
• A participant will have passed his/her 18th birthday and will not have attained the age of 50 at the time of enrollment.
• Willing to allow storage of their biological samples.
• Able to comply with study procedures and swallow capsules.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from study participation:
• Body Mass Index (BMI) greater than or equal to 35 or less than or equal to 18 kg/M(2).
• Vital signs outside of acceptable range at Screening Visit, i.e., blood pressure \>160/100, oral temperature \>100 degrees F, pulse \>100.
• Use of any of the following drugs or devices within the last 6 months:
• systemic antibiotics, antifungals, antivirals, or antiparasitics (intravenous, intramuscular, or oral);
• oral, intravenous, intramuscular, nasal, or inhaled corticosteroids;
• cytokines;
• methotrexate or immunosuppressive cytotoxic agents;
• large doses of commercial probiotics consumed (greater than or equal to 10(8) cfu or organisms per day), including tablets, capsules, lozenges, chewing gum, or powders in which probiotic is a primary component. Ordinary dietary components such as fermented beverages/milks, yogurts, and foods do not apply.
• anabolic steroids;
• intrauterine device, combination hormone vaginal ring for contraception (due to unknown duration of local hormone effects), topical or systemic estrogens. Oral contraceptives with a standard 28-day cycle will be permitted if the subject has been consistently taking them for at least 1 month;
• oral, topical, intramuscular testosterone preparations.
• Chronic smokers and subjects who use smokeless tobacco products (due to known effects of tobacco on the oral microbiome).
• Claustrophobia.
• Use of antacids (proton pump inhibitors, sucralfate, H1 and H2 antagonists, and those containing aluminum magnesium) within the last 3 months.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• McCaig LF, Besser RE, Hughes JM. Antimicrobial drug prescription in ambulatory care settings, United States, 1992-2000. Emerg Infect Dis. 2003 Apr;9(4):432-7. doi: 10.3201/eid0904.020268.

  PMID: 12702222 BACKGROUND

• McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA. 1995 Jan 18;273(3):214-9.

  PMID: 7807660 BACKGROUND

• Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA. 2009 Aug 19;302(7):758-66. doi: 10.1001/jama.2009.1163.

  PMID: 19690308 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Amoxicillin; Azithromycin

Intervention Hierarchy (Ancestors)

Ampicillin; Penicillin G; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones

Study Officials

• Christa S Zerbe, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 8, 2016
• First Posted: March 14, 2016
• Study Start: March 22, 2017
• Primary Completion: May 14, 2025
• Study Completion: May 15, 2025
• Last Updated: September 11, 2025

Record last verified: 2025-09-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)