Enteroaggregative E.Coli (EAEC)

• Status: Terminated
• Trial end date: 2008-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Enteroaggregative E. coli (EAEC) is a bacterium that can cause diarrhea. The purposes of this study are to: determine how much EAEC is needed to cause diarrhea in a healthy person, determine if a genetic factor is important in causing diarrhea, and to see how the body's defenses control EAEC. Participants include 25 healthy adults, ages 18-40. Volunteers will be assigned to 1 of 4 dose levels in groups of 5 volunteers each. One volunteer in each group will receive a sodium bicarbonate placebo solution. Volunteers will be admitted to the University Clinical Research Unit for up to 8 days. Volunteers will receive therapy with levofloxacin to treat the infection either once they develop diarrhea or at Day 5 if they remain asymptomatic. Study procedures will include saliva, blood, and fecal sample collection. An optional study procedure will include an intestinal biopsy. Participants will be involved in study related procedures for up to 223 days.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Levofloxacin; Ofloxacin; Pharmaceutical Solutions

Criteria

Inclusion Criteria:

• Sign an Institutional Review Board-approved consent prior to any study-related activities.

• Initiate screening 21± 7 days prior to admission or enrollment.

• Must accomplish all laboratory and diagnostic examinations at 21± 7 days prior to admission or enrollment.

• Be at least 18 years of age but not older than 40 years of age at the time of enrollment.

• Be otherwise healthy with a stable address and telephone where the volunteer can be contacted.

• Be able to read and write English.

• Possess a social security number in order to receive compensation.

• Female participants must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the morning of the challenge and use effective birth control during the entire study period. Methods of effective birth control include: complete abstinence, the use of a licensed hormonal method, intrauterine device, barrier method plus spermicide, or having sexual relations exclusively with a vasectomized partner. Appropriate barrier methods include condoms, cervical sponge, and diaphragm. Females who are not of childbearing potential are defined as those who are physiologically incapable of becoming pregnant, including any female with tubal ligation or who is postmenopausal. For purposes of this study, postmenopausal status will be defined as absence of menses for at least 1 year.

• Be seronegative for antibodies to dispersin.

• Have normal laboratory screening values including a white blood cell (WBC) count, hemoglobin, hematocrit, platelets, blood urea nitrogen, glucose, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), quantitative immunoglobulins, T cell subsets (CD4 and CD8), urinalysis.

• Have normal chest x-ray and electrocardiogram.

• Have negative serologies for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), and a negative rapid plasma reagin (RPR).

• Have a negative stool examination for pathogenic ova and pathogenic parasites, and bacterial enteropathogens (EAEC, Salmonella, Shigella, Campylobacter).

• Have the -251 AA IL-8 genotype.

Exclusion Criteria:

• Has acute or chronic medical illness (i.e., renal or hepatic disease, hypertension, diabetes mellitus, coronary artery disease, malnutrition, obesity (body mass index >30 kg/m2), HIV, corticosteroid use, cancer or receiving chemotherapy, chronic debilitating illness, syphilis).

• Has used antibiotics within 7 days of challenge.

• Has used medications or drugs, including over-the-counter medications such as decongestants, antacids (calcium carbonate or aluminum-based antacids, H2 blockers), anti-diarrheal medications (such as bismuth subsalicylate or loperamide), antihistamines within 7 days of challenge.

• Has a history of chronic gastrointestinal illness, intra-abdominal surgery, chronic functional dyspepsia, chronic gastroesophageal reflux, documented peptic ulcer disease, gastrointestinal hemorrhage, gallbladder disease, inflammatory bowel disease (Crohn's and ulcerative colitis), diverticulitis, irritable bowel syndrome or frequent diarrhea.

• Has a history any of the following psychiatric illness(es):

• Depression not controlled with current drug therapy or involving institutionalization

• Schizophrenia or psychosis

• Suicide attempt.

• Has a history of or current alcohol or illicit drug abuse.

• Is unable to remain as an inpatient in the University Clinical Research Unit for up to 8 days.

• Has a known hypersensitivity to latex, heparin, opiates, antiemetics, benzodiazepines, lidocaine, magnesium citrate, or Fleet enema.

• Has a known hypersensitivity to antibiotics that could be used to treat EAEC infection including fluoroquinolones, amoxicillin, cephalosporins or rifaximin.

• Has serum antibodies to EAEC dispersin.

• Recently traveled to a developing country (within 6 months).

• Has household contacts who are less than 4 years of age or more than 80 years of age.

• Has household contacts that are infirmed or immunocompromised due to any of the following reasons:

• Corticosteroid therapy

• HIV infection

• Cancer chemotherapy

• Other chronic debilitating diseases.

• Works as health care personnel with direct patient care.

• Works in a day care center for children or the elderly.

• Is a food handler.

• Has factors that, in the opinion of the investigator or research personnel, would interfere with the study objectives or increase the risk to the volunteer or his contacts.

• Is currently participating in a clinical study or had receipt of an investigational drug in the past 30 days.

• Is pregnant or has a risk of pregnancy or is lactating.

• Has current excessive use of alcohol or drug dependence.

• Has evidence of impaired immune function.

• Has a new positive reaction to purified protein derivative (PPD) (volunteers who are known to be PPD positive that have a negative chest x-ray and have received isoniazid prophylaxis will be eligible).

• Has a stool culture that demonstrates the presence of pathogenic ova, pathogenic parasites, or bacterial enteropathogens (EAEC, Salmonella, Shigella, and Campylobacter), or that is devoid of normal flora.

• Has self-reported lactose or soy intolerance or allergy

• Is a smoker and cannot stop smoking for the duration of the inpatient study.

• Has abnormal lab results for screening beyond the normal range as defined below:

Hematology Hemoglobin: 13-15.0 gm/dL (Females) 14.5-17.0 gm/dL (Males) Hematocrit: 37-46 % (Females) 40-52 % (Males) Platelet count: 140,000-415,000 per mm3 WBC count: 4,000-10,500 per mm3 Neutrophils: 40-74 % or 1,800-7,800 per mm3 Lymphocytes: 14-26 % or 700-4,500 per mm3 Monocytes: 4-13 % or 100-1,000 per mm3 Eosinophils: 0-7 % or 0-400 per mm3 Basophils: 0-3 % or 0-200 per mm3

Chemistry BUN 5-25 mg/dL Creatinine 0.5-1.4 mg/dL Glucose (fasting) 69-99 mg/dL ALT 0-40 U/L AST 0-40 U/L

Immunology IgG: 596-1584 mg/dL IgA: 71-350 mg/dL IgM: 35-213 mg/dL CD4 T cells: 660-1500 cells/mcl CD8 T cells: 360-850 cells/mcl

Urinalysis Urine color: Yellow Turbidity: Clear pH: 5.0-8.0 Protein: Negative Sp. Gravity:

1.003-1.030 Glucose: Negative WBC: 0-2 Cells per HPF RBC: 0 Cells per HPF Bacteria: Rare Ketones: Negative The urinalysis will initially be evaluated for the quality of collection. If urinalysis is found to be poorly collected and demonstrates the presence of squamous epithelial cells and bacteria, results will not be used and a repeat urinalysis will be requested. In the case of menstruating women, the urinalysis collection will be postponed temporarily. A urinalysis may also be repeated once if traces of bile, protein, trace ketones, or Hb are identified. In the case of a properly collected urinalysis, the presence of leukocyte esterase glucose, or nitrates will exclude the participation of the subject.

• Occult blood (Hemoccult) positive stools on admission to the CRU.

• Develops gastrointestinal symptoms including nausea, vomiting, anorexia, abdominal pain, cramping, bloating, excessive gas or flatulence, diarrhea, constipation, urgency or tenesmus between the screening period and prior to challenge.

• Develops a febrile illness during the period of time screening period and prior to challenge.