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ID
Source
Brief title
Health condition
Endotoxemia
Sponsors and support
Intervention
Outcome measures
Primary outcome
Cytokine production in blood
Secondary outcome
Activation of coagulation
Composition of gut microbiota
Background summary
Rationale: Sepsis ranks among the top ten leading causes of death worldwide. Most nonsurvivors die in a state of immunosuppression. The gut microbiota exerts numerous beneficial functions in the host response against infections. Gut flora components express microorganism-associated molecular patterns (MAMPs) such as lipopolysaccharide (LPS), which are recognized by pattern recognition receptors (PRRs) expressed by neutrophils and macrophages. MAMPs from the intestinal microbiota constitutively translocate to the circulation and prime bone marrow derived neutrophils via PRRs. Antibiotic treatment, which is standard of care for all patients with sepsis, depletes the gut microbiota and leads to a diminished release of MAMPs and other bacteria derived products. This causes diminished priming of systemic immunity, which may attribute to sepsis associated immunosuppression and an increased susceptibility to invading bacteria.
Objective: To investigate the role of the gut microbiota in the systemic priming of immune effector
cells during human endotoxemia
Study design: Randomized, between- and within-subject-controlled intervention study in human
volunteers
Study population: Sixteen healthy male subjects, 18-35 years of age
Intervention: All subjects will receive lipopolysaccharide (endotoxin; 2 ng/kg bodyweight)
intravenously to induce experimental endotoxemia. Eight subjects will be pretreated with broad
spectrum antibiotics (ciprofloxacin, vancomycin, metronidazole) for seven days (washout period of 36 hours before endotoxemia), in order to deplete the gut microbiota. Blood and faeces will be sampled before, during and after endotoxemia.
Main study parameters/endpoints: Laboratory parameters for inflammatory responses, functional
assays and gut microbiota composition.
Study objective
Broad-spectrum antibiotics, which many patients with infectious diseases receive, deplete the gut microbiota. Several studies suggest that the gut microbiota may have a "priming" effect on the innate immune system. Broad- spectrum antibiotics would thus lead to a decreased innate immune response in disease states such as sepsis or endotoxemia.
Study design
Day 0
Day 9: t = 0 and at 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours after LPS injection
Intervention
The control group receives no antibiotics
The antibiotics group receives ciprofloxacin 500mg 2dd1, vancomycin 250mg 3dd2 and metronidazole 500mg 3dd1; all during 7 days
Both groups receive (on day 9) LPS (endotoxin) 2 ng/kg intravenously
Academic Medical Center<br>
University of Amsterdam<br>
Meibergdreef 9
J.M. Lankelma
Amsterdam 1105 AZ
The Netherlands
+31 (0)20 5665247
Academic Medical Center<br>
University of Amsterdam<br>
Meibergdreef 9
J.M. Lankelma
Amsterdam 1105 AZ
The Netherlands
+31 (0)20 5665247
Inclusion criteria
1. Healthy, as determined by a responsible physician, based on a medical evaluation
including medical history, physical examination and laboratory tests
2. Male between 18 and 35 years of age
3. Capable of giving written informed consent
4. Chemistry panel, including renal and liver function tests, without any clinically relevant abnormality as judged by the investigator
5. Normal defecation pattern
Exclusion criteria
1. Subject has had a major illness in the past 3 months or any significant chronic
medical illness
2. Subjects with a history of any type of malignancy
3. Subject has a past or current gastrointestinal disease
4. The subject has a known positive test for hepatitis C antibody, hepatitis B surface
antigen or human immunodeficiency virus (HIV) antibody 1 or 2
5. Current or chronic history of liver disease
6. Subject uses tobacco products
7. Subject has a history, within 3 years, of drug abuse
8. History of alcoholism
9. Any clinically relevant abnormality noted on the 12-lead ECG as judged by the
investigator or an average QTc > 450 msec
10. The subject has received an investigational product within three months
11. Use of prescription or non-prescription drugs and herbal and dietary supplements
12. Recent (< 12 months) use of antibiotics
13. Known allergy to antibiotics (any kind)
14. Subject has difficultly in donating blood or accessibility of a vein in left or right arm.
15. Subject has donated more than 350 mL of blood in last 3 months
16. Difficulty swallowing pills
17. Body mass index >28 kg/m2
Design
Recruitment
Followed up by the following (possibly more current) registration
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL4425 |
| NTR-old | NTR4549 |
| CCMO | NL45198.018.13 |
| OMON | NL-OMON38933 |