Diarrhea Travelers, Antibiotic Resistant Infection
Conditions
Brief summary
The purpose of this study is to determine if the use of prophylactic bismuth subsalicylate (BSS) has an effect on the acquisition of travelers' diarrhea (TD) or antimicrobial resistance (AMR) genes in fecal samples among international travelers who departed from the United States to South East Asia, South Central Asia, or Africa. Our hypotheses will be tested using a double-blinded, placebo controlled randomized clinical trial with participants from a pre-travel health clinic in the United States.
Detailed description
This study is a double-blind, placebo-controlled randomized clinical trial designed to evaluate the effectiveness of bismuth subsalicylate (BSS) in preventing travelers' diarrhea (TD) and its potential impact on the acquisition of antimicrobial resistance (AMR) genes and changes in the gut microbiome among international travelers. Adult participants (18-69 years) planning travel from the United States to high-risk regions, including South East Asia, South Central Asia, and Africa, will be recruited from a pre-travel health clinic. Eligible participants will be randomized to receive either BSS (4 tablets twice daily; total daily dose approximately 2.1 g) or a matching placebo. Study medication will begin prior to arrival at the destination and continue throughout the duration of travel (up to 21 days). Participants will complete standardized questionnaires before travel, daily during travel, and after returning to the United States. These questionnaires will capture information on medication adherence, gastrointestinal symptoms, development of TD, healthcare utilization, and adverse events. TD will be defined as three or more unformed stools within a 24-hour period, with or without associated symptoms. To evaluate secondary objectives, participants will provide stool samples within 7 days prior to departure and within 10 days after return. These samples will be analyzed to assess acquisition of AMR genes using molecular methods and to evaluate changes in the gut microbiome, including the presence of enteric pathogens. The primary objective is to determine whether prophylactic BSS reduces the incidence of TD among international travelers. Secondary objectives include assessing the impact of BSS on acquisition of AMR genes and evaluating changes in the gut microbiome associated with travel and intervention use. Participants will be followed from enrollment through completion of post-travel data collection, with a total participation duration of approximately 4-6 weeks. Safety will be monitored through participant-reported adverse events collected during and after travel. This study aims to provide evidence on a low-cost, widely available preventive strategy for TD and to better understand its potential role in reducing the spread of antimicrobial resistance associated with international travel.
Interventions
Bismuth subsalicylate administered orally as tablets (4 tablets twice daily; total daily dose approximately 2.1 g) beginning prior to arrival at the travel destination and continued throughout the duration of travel (up to 21 days).
DRUGPlacebo
Matching oral placebo tablets administered twice daily, identical in appearance, taste, and packaging to bismuth subsalicylate, given for the duration of travel (up to 21 days).
Sponsors
Centers for Disease Control and Prevention
Procter and Gamble
The New York Center for Travel and Tropical Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This study will be conducted as a double-blinded, placebo-controlled randomized clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
Yes
Inclusion criteria
1. Be ≥ 18 and \<70 years of age at the time of enrollment 2. Sign an informed consent stating willingness to participate and comply with the study protocol 3. Plan on leaving for an international trip ≥7 days after their pre-travel consultation 4. Plan on traveling in country for ≥7 days but ≤21 days (21 day limit due to BSS duration recommendations and a lack of data on longer-term BSS use) 5. Traveling to either South East Asia, South Central Asia, North Africa, or Sub-Saharan Africa for at least 7 days of their itinerary 6. Be willing to complete an initial eligibility screening 7. Be willing to complete questionnaires and provide biologic specimens (stool) within 7 days of departure and within 10 days after return 8. Be willing to refrain from taking any pre-biotics, probiotic, synbiotic and/or herbal supplements throughout their study period
Exclusion criteria
1. Are \<18 years of age or \>69 years of age 2. Are traveling in country for \<7 or \>21 days 3. Have known or suspected contraindications to taking BSS (including, but not limited to, travelers with kidney disease, diabetes, gout, a clotting disorder, or an allergy to any component of BSS) 4. Are pregnant (via self-report), are planning to become pregnant, or may become pregnant during travel (not actively using contraception and are sexually active), or are breastfeeding 5. Routinely take a medication known to interact with BSS (including, but not limited to, insulin, methotrexate, valproic acid, angiotensin-converting enzyme inhibitors, anticoagulants, or other salicylates) 6. Have taken an antibiotic in the 30 days before departure 7. Have taken any medications that may lower one's ability to fight infection (e.g., steroids, monoclonal antibodies, etc.) 8. Have previous diagnoses of immunocompromising conditions such as HIV/AIDS, complement deficiency, immunoglobulin deficiency, or undergoing active chemotherapy or participants with chronic gastrointestinal disorders, such as chronic diarrhea, irritable bowel syndrome (IBS), inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis), celiac disease, malabsorption syndromes, pancreatic insufficiency, gallbladder disease, or current gastrointestinal cancer 9. Have had diarrhea anytime in the previous 30 days, have diarrhea at the pre-travel consultation, or develop diarrhea before departure 10. Have been given doxycycline for malaria prophylaxis for the current trip (due to possible drug-drug interactions and decreased absorption of the doxycycline) 11. Have an allergy to any component of the placebo tablets
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Traveler's Diarrhea | Change from baseline through 10 days post-travel | Incidence of travelers' diarrhea, defined as self-reported occurrence of three or more unformed stools within a 24-hour period with or without associated gastrointestinal symptoms during travel or within 10 days after return. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gut AMR Genes | Once within 7 days (before travel); once within 10 days (after travel) | Pre- and post-travel stools will be tested for the presence/absence of AMR genes. Data for this outcome measure are not yet analyzed. Results will be submitted when analyses are complete. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBradley Connor, MD
The New York Center for Travel and Tropical Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Group Bismuth subsalicylate 4 tablets po bid (2.1 grams total of BSS)
Bismuth subsalicylate: We aim to determine if there is a biologic benefit to an intervention (BSS administration) in the acquisition of travelers diarrhea and the acquisition of antimicrobial resistance genes. | 136 |
| Placebo Placebo oral tablet 4 bid
Placebo Oral Tablet: Placebo manufactured to mimic pepto bismol | 134 |
| Total | 270 |
Baseline characteristics
| Characteristic | Intervention Group | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 32 years | 32 years | 32 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants | 123 Participants | 239 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 7 Participants | 15 Participants |
| History of travelers' diarrhea | 136 Participants | 134 Participants | 270 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 10 Participants | 23 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 32 Participants | 56 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 25 Participants | 21 Participants | 46 Participants |
| Race (NIH/OMB) White | 73 Participants | 71 Participants | 144 Participants |
| Region of Enrollment United States | 136 participants | 134 participants | 270 participants |
| Sex/Gender, Customized Female | 84 Participants | 85 Participants | 169 Participants |
| Sex/Gender, Customized Male | 51 Participants | 49 Participants | 100 Participants |
| Sex/Gender, Customized Missing | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 136 | 0 / 134 |
| other Total, other adverse events | 0 / 136 | 0 / 134 |
| serious Total, serious adverse events | 0 / 136 | 0 / 134 |
Outcome results
Primary
Traveler's Diarrhea
Self-reported TD
Time frame: Change from baseline through 10 days post-travel
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Group | Traveler's Diarrhea | 27 Participants |
| Placebo | Traveler's Diarrhea | 26 Participants |
Secondary
Gut AMR Genes
Pre- and post-travel stools will be tested for the presence/absence of AMR genes
Time frame: Once within 7 days (before travel); once within 10 days (after travel)