The purpose of this study is to compare a single dose of rifaximin with loperamide to the current standard approach of single dose azithromycin with loperamide for the treatment of acute watery traveler's diarrhea (TD).

The study requires 1) taking a single dose antibiotic plus loperamide to treat TD, 2) providing blood and stool samples at different time points to evaluate infection and immune responses, 3) completing a daily symptom diary following treatment, 4) being seen by the study doctor to monitor illness and recovery, and 5) completing a brief electronic questionnaire at 3 months.

Participants will be randomly assigned to one of the two treatment groups. The two groups are 1) rifaximin 550 mg as a single dose with loperamide 4 mg initially followed by 2 mg after each unformed stool or 2) azithromycin 500 mg as a single dose with loperamide 4 mg initially followed by 2 mg after each unformed stool. Both groups will take the antibiotic dose and 4 mg of loperamide.

Inclusion Criteria:

1. Active duty military, 18-60 years old
2. Presence of acute watery diarrhea (3 or more loose/liquid stools in 24 hours or 2 loose/liquid stools in 24 hours and associated symptoms such as nausea, vomiting, abdominal cramps or tenesmus) lasting <96 hours in duration that impacts function in activities and/or performance of primary duties. Refer to recruitment decision tree below.
3. Eligible for ambulatory management. (Note: Ambulatory management in this study means that the patient can be treated on an outpatient basis to include up to 23 hours of medical observation and IV therapies.)
4. Able to comply with follow-up procedures.
5. Will remain in country for at least 7 days or an assurance that follow-up can be arranged elsewhere.

Exclusion Criteria:

1. Allergy to rifamycins, macrolides, or loperamide (not including mild gastrointestinal upset).
2. Antibiotic therapy in the 72 hours prior to presentation (excluding malaria prophylaxis with mefloquine, malarone, chloroquine/proguanil, tafenoquine, or doxycycline).
3. Concomitant medications with known drug-drug interactions with any of the study drugs (includes theophylline, digoxin, warfarin, chloroquine and hydroxychloroquine).
4. Current or history of liver disease or other serious health conditions based on review by study physician.
5. Acute dysentery and/or febrile illness (temperature > 100.4°F [38.1°C]).
6. Presence of symptoms >96 hours prior to initiating treatment.
7. Use of >4 mg loperamide or use of any amount of loperamide for greater than 24 hours prior to enrollment. Prior use of bismuth subsalicylate or other anti-diarrheal, non-antibiotic therapy in the 48 hours prior to enrollment.
8. Positive pregnancy test at presentation (unknown effects with rifaximin). All female participants will be administered a urine pregnancy test prior to enrollment.
9. Previously screened or randomized in this study.