Antibiotic Resistant Infection, Nosocomial Infection, Pathogen Transmission, Nutrition Disorders, Critical Illness, Sepsis
Conditions
Keywords
Microbiome, Antibiotic resistance, Intensive care unit, Sepsis, Nutrition, Pathogen colonization
Brief summary
Normal gut bacteria prevent colonization and subsequent infection with MDR organisms (MDROs) through competition for resources and other mechanisms. During critical illness, this function of the microbiome is lost and there are no current treatments to restore it. Preliminary data indicates that the prebiotic fiber inulin is safe and may alter the gastrointestinal microbiome to improve gut barrier function, decrease colonization with MDROs, and reduce downstream risk for intensive care unit (ICU)-acquired MDR infections. However, the impact of inulin during critical illness is unknown. This double-blind, randomized clinical trial will test inulin for the prevention of antibiotic resistant infections in the ICU. The trial's specific aims are to determine (1) the feasibility, tolerability, and safety of inulin in the intensive care unit; (2) the impact of inulin on gut colonization with antibiotic-resistant pathogens; and (2A/exploratory) the impact of inulin on ICU-acquired antibiotic-resistant infections.
Detailed description
The proposed trial hypothesizes that inulin maintains short-chain fatty acid (SCFA)-producing colonic anaerobes and that these bacteria are protective against multi-drug resistant organism (MDRO) colonization and subsequent MDR infection. Inulin, a vegetable-derived non-digestible polysaccharide is well established as the key nutrient source for SCFA-producing bacteria. Previous human studies have shown that (1) inulin increases levels of SCFA producers and SCFAs and (2) that this increase correlates with improved colonic mucosal integrity and resistance to MDR pathogens. In animal studies, inulin improves survival after pathogen challenge or injection with lipopolysaccharide. The overall aim of this clinical trial is to determine whether inulin improves gut colonization resistance against antibiotic-resistant pathogens and therefore prevents antibiotic-resistant infections in the setting of critical illness. To accomplish this, 90 critically ill adults who are receiving broad-spectrum antibiotics will be blindly randomized 1:1:1 to receive placebo, inulin 8 g twice daily, or inulin 16 g twice daily for a minimum of 7 days, with bedside follow-up extending to 30 days or hospital discharge.
Interventions
DRUGInulin Oral Suspension
Inulin powder, derived from chicory root and re-suspended in 250cc water Dosage will be either 8g twice a day or 16g twice a day - dissolved in 250cc sterile water, given oral or via enteric tube
250cc sterile water alone, given twice daily a sweetener is added to the water to create identical flavor
Standard of care treatment for infections
Sponsors
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double-blind, randomized
Intervention model description
placebo-controlled trial with 1:1:1 enrollment into three arms: inulin 32 g/day, inulin 16 g/day, and placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Hospitalized in an eligible medical ICU 2. Age ≥ 18 years old at the time of hospitalization 3. With sepsis as defined by the Sepsis-3 (2016) consensus as a known or suspected infection with a sequential organ failure assessment (SOFA) score of ≥2 points above baseline 4. Received broad-spectrum antibiotics within the last 24 hours or ordered and pending administration 5. Able to complete enrollment within 4 hours of ICU admission for administration of the intervention within 6 hours of ICU admission
Exclusion criteria
1. Inability to receive oral or enteric fluids 2. Inulin allergy 3. Hyponatremia (serum sodium ≤128 mEq/L) 4. Immunosuppression, defined as history of solid organ transplant or as receipt of ablative chemotherapy, steroids at the equivalent of ≥5 mg/day prednisone, antimetabolites, anti-tumor necrosis factor (TNF) α agents, calcineurin inhibitors, or mycophenolate 5. Surgery involving the intestinal lumen within 30 days or known intestinal strictures 6. Do Not Resuscitate (DNR) or Do Not Intubate (DNI) status, or no escalation of care orders 7. Lack capacity for consent and no appropriate Legally Authorized Representative (LAR)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Within-individual Change in SCFA Producer Level | Baseline and Day 3 | Relative abundance (i.e., proportion) of SCFA producing bacteria within each treatment group, will be assessed via 16S sequencing of rectal swabs. Modified intent-to-treat, comparing baseline vs Day 3 levels of SCFAs among those who receive one or more doses of the intervention and complete both assessments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Day 0 and at last sample collected, up to Day 30 | Proportion of patients who are MDRO-GNB colonized within each treatment group, with MDRO-GNB colonization status classified categorically based on the presence or absence of methicillin-resistant Staphylococcus aureus (MRSA) or Gram negative bacteria (GNB) with third-generation cephalosporins non-susceptibility |
| Vancomycin-resistant Enterococcus (VRE) Colonization Status | Day 0 and at last sample collected, up to Day 30 | Proportion of patients who are VRE colonized within each treatment group, with VRE colonization status classified categorically based on the presence or absence of vancomycin-resistant Enterococcus (VRE) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fecal Short Chain Fatty Acid (SCFA) Levels | Days 3 and 7 | The SCFAs butyrate, acetate, and propionate will be measured from whole stools on a 6490 triple quadrupole mass spectrometer and compared between intervention groups using the first stool sample produced after the Day 3 assessment. Patients who fail to produce a stool from Day 3 to 7 will be excluded from this analysis. |
| Mortality | Day 90 | Death data will be extracted from the hospital electronic medical record (EMR) which immediately captures in-hospital death and receives monthly mortality updates from the National social security death index. |
| ICU Length of Stay (LOS) | through ICU Day 30 | compared between groups, after adjusting for death as a competing risk |
| Multidrug Resistant (MDR) Infections | through 30 days | proportion of patients with culture-proven infections within each treatment group, with culture-proven infections defined as those that have (1) an organism meeting MDRO criteria from a clinical culture, (2) signs and symptoms of infection by Centers for Disease Control (CDC)/National Health and Safety Network (NHSN) guideline definitions, and (3) receive appropriate antibiotics from the treating team |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Critically ill adults who are receiving broad-spectrum antibiotics will also receive placebo oral suspension for a minimum of 7 days.
Placebo Oral Suspension: 250cc sterile water alone, given twice daily a sweetener is added to the water to create identical flavor
Broad-spectrum antibiotics: Standard of care treatment for infections | 30 |
| Inulin 16 g/Day Critically ill adults who are receiving broad-spectrum antibiotics will also receive inulin oral suspension (8g twice daily) for a minimum of 7 days.
Inulin Oral Suspension: Inulin powder, derived from chicory root and re-suspended in 250cc water Dosage will be either 8g twice a day or 16g twice a day - dissolved in 250cc sterile water, given oral or via enteric tube
Broad-spectrum antibiotics: Standard of care treatment for infections | 30 |
| Inulin 32 g/Day Critically ill adults who are receiving broad-spectrum antibiotics will also receive inulin oral suspension (16g twice daily) for a minimum of 7 days.
Inulin Oral Suspension: Inulin powder, derived from chicory root and re-suspended in 250cc water Dosage will be either 8g twice a day or 16g twice a day - dissolved in 250cc sterile water, given oral or via enteric tube
Broad-spectrum antibiotics: Standard of care treatment for infections | 30 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Inulin 16 g/Day | Inulin 32 g/Day | Total |
|---|---|---|---|---|
| Age, Continuous | 66 years | 62 years | 65 years | 62 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 11 Participants | 13 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 19 Participants | 17 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 7 Participants | 7 Participants | 19 Participants |
| Race/Ethnicity, Customized Other | 15 Participants | 11 Participants | 10 Participants | 36 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 12 Participants | 13 Participants | 35 Participants |
| Region of Enrollment United States | 30 participants | 30 participants | 30 participants | 90 participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 13 Participants | 40 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 17 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 30 | 7 / 30 | 9 / 30 |
| other Total, other adverse events | 15 / 30 | 11 / 30 | 15 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 30 |
Outcome results
Primary
Within-individual Change in SCFA Producer Level
Relative abundance (i.e., proportion) of SCFA producing bacteria within each treatment group, will be assessed via 16S sequencing of rectal swabs. Modified intent-to-treat, comparing baseline vs Day 3 levels of SCFAs among those who receive one or more doses of the intervention and complete both assessments.
Time frame: Baseline and Day 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Within-individual Change in SCFA Producer Level | -0.0 percentage of SCFA producers |
| Inulin 16 g/Day | Within-individual Change in SCFA Producer Level | -1.8 percentage of SCFA producers |
| Inulin 32 g/Day | Within-individual Change in SCFA Producer Level | 1.1 percentage of SCFA producers |
Secondary
Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status
Proportion of patients who are MDRO-GNB colonized within each treatment group, with MDRO-GNB colonization status classified categorically based on the presence or absence of methicillin-resistant Staphylococcus aureus (MRSA) or Gram negative bacteria (GNB) with third-generation cephalosporins non-susceptibility
Time frame: Day 0 and at last sample collected, up to Day 30
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Day 0 | 6 Participants |
| Placebo | Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Last Sample Collected, Up to Day 30 | 3 Participants |
| Inulin 16 g/Day | Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Day 0 | 4 Participants |
| Inulin 16 g/Day | Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Last Sample Collected, Up to Day 30 | 4 Participants |
| Inulin 32 g/Day | Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Day 0 | 3 Participants |
| Inulin 32 g/Day | Multidrug Resistant Organism (MDRO)-Gram Negative Bacteria (GNB) Colonization Status | Last Sample Collected, Up to Day 30 | 3 Participants |
Secondary
Vancomycin-resistant Enterococcus (VRE) Colonization Status
Proportion of patients who are VRE colonized within each treatment group, with VRE colonization status classified categorically based on the presence or absence of vancomycin-resistant Enterococcus (VRE)
Time frame: Day 0 and at last sample collected, up to Day 30
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Vancomycin-resistant Enterococcus (VRE) Colonization Status | Day 0 | 8 Participants |
| Placebo | Vancomycin-resistant Enterococcus (VRE) Colonization Status | Last Sample Collected, Up to Day 30 | 11 Participants |
| Inulin 16 g/Day | Vancomycin-resistant Enterococcus (VRE) Colonization Status | Day 0 | 6 Participants |
| Inulin 16 g/Day | Vancomycin-resistant Enterococcus (VRE) Colonization Status | Last Sample Collected, Up to Day 30 | 13 Participants |
| Inulin 32 g/Day | Vancomycin-resistant Enterococcus (VRE) Colonization Status | Day 0 | 4 Participants |
| Inulin 32 g/Day | Vancomycin-resistant Enterococcus (VRE) Colonization Status | Last Sample Collected, Up to Day 30 | 6 Participants |
Other Pre-specified
Fecal Short Chain Fatty Acid (SCFA) Levels
The SCFAs butyrate, acetate, and propionate will be measured from whole stools on a 6490 triple quadrupole mass spectrometer and compared between intervention groups using the first stool sample produced after the Day 3 assessment. Patients who fail to produce a stool from Day 3 to 7 will be excluded from this analysis.
Time frame: Days 3 and 7
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Fecal Short Chain Fatty Acid (SCFA) Levels | Day 3 | 0 mMol |
| Placebo | Fecal Short Chain Fatty Acid (SCFA) Levels | Day 7 | 0 mMol |
| Inulin 16 g/Day | Fecal Short Chain Fatty Acid (SCFA) Levels | Day 3 | 0.11 mMol |
| Inulin 16 g/Day | Fecal Short Chain Fatty Acid (SCFA) Levels | Day 7 | 0.29 mMol |
| Inulin 32 g/Day | Fecal Short Chain Fatty Acid (SCFA) Levels | Day 3 | 0 mMol |
| Inulin 32 g/Day | Fecal Short Chain Fatty Acid (SCFA) Levels | Day 7 | 0 mMol |
Other Pre-specified
ICU Length of Stay (LOS)
compared between groups, after adjusting for death as a competing risk
Time frame: through ICU Day 30
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | ICU Length of Stay (LOS) | 9.5 days |
| Inulin 16 g/Day | ICU Length of Stay (LOS) | 10.5 days |
| Inulin 32 g/Day | ICU Length of Stay (LOS) | 9 days |
Other Pre-specified
Mortality
Death data will be extracted from the hospital electronic medical record (EMR) which immediately captures in-hospital death and receives monthly mortality updates from the National social security death index.
Time frame: Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality | 7 Participants |
| Inulin 16 g/Day | Mortality | 7 Participants |
| Inulin 32 g/Day | Mortality | 9 Participants |
Other Pre-specified
Multidrug Resistant (MDR) Infections
proportion of patients with culture-proven infections within each treatment group, with culture-proven infections defined as those that have (1) an organism meeting MDRO criteria from a clinical culture, (2) signs and symptoms of infection by Centers for Disease Control (CDC)/National Health and Safety Network (NHSN) guideline definitions, and (3) receive appropriate antibiotics from the treating team
Time frame: through 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Multidrug Resistant (MDR) Infections | 15 Participants |
| Inulin 16 g/Day | Multidrug Resistant (MDR) Infections | 9 Participants |
| Inulin 32 g/Day | Multidrug Resistant (MDR) Infections | 12 Participants |