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Protocol Details

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

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

16-I-0078

Sponsoring Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: 49 Years

Referral Letter Required

No

Population Exclusion(s)

Children

Keywords

Microbiome;
Amoxicillin;
Azithromycin;
Stool;
Healthy

Recruitment Keyword(s)

None

Condition(s)

Normal Physiology;
Healthy

Investigational Drug(s)

None

Investigational Device(s)

None

Intervention(s)

Drug: Amoxicillin
Drug: Azithromycin
Other: Control

Supporting Site

National Institute of Allergy and Infectious Diseases

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.

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Eligibility

SUBJECT INCLUSION CRITERIA:

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.

SUBJECT EXCLUSION CRITERIA:

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.

-Illicit drug use, including amphetamines, cocaine, or heroin, within the last 6 months. Marijuana use is not exclusionary.

-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.

-Use of laxatives or enemas within the last 3 months.

-Diagnostic colonoscopy within the last 6 months.

-Use of topical antibiotics or topical steroids on the face, scalp, or neck, or on arms, forearms, or hands within the previous 30 days.

-Use of vaginal/vulvar medications, including antifungals, within the previous 30 days. Subjects may continue to use permitted vaginal contraceptives (spermicides and female condoms) until 24 hours prior to sampling

-Use of isotretinoin within the past 5 years.

-Intranasal influenza vaccination within the last 6 months due to effects on mucosal immunity.

-Acute disease at the time of enrollment (defer enrollment until subject recovers). Acute disease is defined as the presence of a moderate or severe illness with or without fever.

-Chronic, clinically significant (unresolved, requiring ongoing medical management or medication) pulmonary, cardiovascular, dermatologic, endocrine, GI, hepatic, or renal functional abnormality, as determined by medical history, physical examination, and/or laboratory testing. Includes, but not limited to:

--A history of diabetes mellitus (Type 1 or 2), pituitary disease, hypothyroidism, hyperthyroidism

--A history of physician-diagnosed asthma

--A history of allergy to any antibiotic medications, including amoxicillin (penicillin) and/or azithromycin (macrolide)

-- A history of food allergy requiring dietary accommodation

--Lactose-intolerance requiring dietary accommodation

--A history of a bleeding disorder

--Mononucleosis

--Liver disease, including non-alcoholic fatty liver disease, AST or ALT > 1.5 times normal value, cirrhosis

--Renal disease, as defined by serum creatinine concentrations > 1.5 mg/dL and/or overt proteinuria

--Central nervous system disease, including previous history of cerebrovascular accidents, dementia, and neurodegenerative disorders

--Clinically significant abnormal results on electrocardiogram (ECG) that in the opinion of the PI, would place the patient at increased risk of QT-prolongation or other cardiac event

-Genitourinary/Gynecologic conditions, including:

--Treatment for or suspicion of ever having had toxic shock syndrome

--History of hysterectomy or oophorectomy

--History of condyloma or human papillomavirus diagnosed within the previous 2 years

--History of candidiasis, urinary tract infection, or sexually transmitted disease (specifically chlamydia, gonorrhea, syphilis, genital herpes, trichomoniasis) diagnosed within the previous 6 months

--Evidence (by history or physical exam) of vulvar or vaginal irritation at screening

--History of vulvar, vaginal, or cervical dysplasia within the previous 5 years

-History of cancer except for squamous or basal cell carcinomas of the skin that have been medically managed by local excision.

-Unstable dietary history as defined by major changes in diet during the previous month, where the subject has eliminated or significantly increased a major food group in the diet.

-Recent history of excessive alcohol consumption defined as more than five 1.5-ounce servings of 80-proof distilled spirits, five 12-ounce servings of beer, or five 5-ounce servings of wine at one sitting over the last 30 days.

-Positive test for HIV, hepatitis B virus, or hepatitis C virus indicating infection (hepatitis B seropositivity conferred by vaccination is not exclusionary).

-Any confirmed or suspected condition/state of immunosuppression or immunodeficiency (primary or acquired).

-Major surgery of the GI tract, including cholecystectomy or appendectomy, in the past 5 years. Any major bowel resection at any time.

-History of gastric stapling, lap band, or surgical procedure for treatment of obesity.

-History of GI disorders or diseases including:

--inflammatory bowel disease (IBD) including ulcerative colitis, Crohn s disease (of any severity), or indeterminate colitis;

--irritable bowel syndrome (IBS);

--persistent, infectious gastroenteritis, colitis or gastritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent), gastric or duodenal ulcer;

--Celiac disease;

--chronic constipation.

-Active behavioral or psychiatric conditions that would be incompatible with a safe and successful participation in the study, including major depression, anxiety disorder, schizophrenia, and presence of psychotic symptoms.

-Active eating disorders, including anorexia nervosa, bulimia, or binge eating syndrome.

-Use of weight-loss drugs within the past 5 years.

-Weight change (intended or unintended; loss or gain) of more than 10% of total body weight in the 3 months before admission.

-Regular urinary incontinence necessitating use of incontinence protection garments.

-Female who is pregnant, intending to become pregnant, or lactating.

-History of recurrent rashes within the past 6 months.

-At the time of the screening visit:

--multiple blisters, pustules, boils, abscesses, erosions or ulcers on the scalp, face, neck, arms, forearms, or hands;

--uniformly thickened, cracking, dry skin on bilateral palms and/or soles;

--disseminated rash (at multiple body sites or extending throughout a broad body area).

-Subjects who are unable to complete required study visits per allotted visit windows.

-Any condition that, in the opinion of the investigator, contraindicates participation in this study.


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Citations:

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. Erratum in: Emerg Infect Dis. 2003 May;9(5):609.

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. Erratum in: JAMA 1998 Feb 11;279(6):434.

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.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Christa S. Zerbe, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 10 - CLINICAL CENTER BG RM 12C110
10 CENTER DR
BETHESDA MD 20892
(301) 594-5932
zerbech@niaid.nih.gov

Carla D. Williams, R.N.
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health
Building 10
Room 4-1479
10 Center Drive
Bethesda, Maryland 20892
(240) 702-6344
carla.williams@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT02707042

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