Prophylactic antibiotics have been demonstrated to be quite effective in the prevention of TD. Controlled studies have shown that diarrhea attack rates are reduced from 40% to 4% by the use of antibiotics. The prophylactic antibiotic of choice has changed over the past few decades as resistance patterns have evolved. Agents such as trimethoprim-sulfamethoxazole and doxycycline are no longer considered effective antimicrobial agents against enteric bacterial pathogens. The fluoroquinolones have been the most effective antibiotics for the prophylaxis and treatment of bacterial TD pathogens, but increasing resistance to these agents, mainly among Campylobacter species, may limit their benefit in the future. A nonabsorbable antibiotic, rifaximin, is being investigated for its potential use in TD prophylaxis. In the only study published to date, rifaximin reduced the risk for TD in travelers to Mexico by 77%. At this time, prophylactic antibiotics should not be recommended for most travelers. In addition to affording no protection against nonbacterial pathogens, the use of antibiotics may be associated with allergic or adverse reactions in a certain percentage of travelers. The use of prophylactic antibiotics should be weighed against the result of using prompt, early self-treatment with antibiotics when TD occurs, which can limit the duration of illness to 6–24 hours in most cases.

Prophylactic antibiotics may be considered for short-term travelers who are high-risk hosts (such as those who are immunosuppressed) or are taking critical trips during which even a short bout of diarrhea could impact the purpose of the trip.

As bacterial causes of TD far outnumber other microbial etiologies, empiric treatment with an antibiotic directed at enteric bacterial pathogens remains the best therapy for TD. The benefit of treatment of TD with antibiotics has been proven in numerous studies. The effectiveness of a particular antimicrobial depends on the etiologic agent and its antibiotic sensitivity. Both as empiric therapy or for treatment of a specific bacterial pathogen, first-line antibiotics include those of the fluoroquinolone class, such as ciprofloxacin or levofloxacin. Increasing microbial resistance to the fluoroquinolones, especially among Campylobacter isolates, may limit their usefulness in some destinations such as Thailand, where Campylobacter is prevalent. Isolated anecdotal case reports of resistant Campylobacter diarrhea occur periodically from other destinations. An alternative to the fluoroquinolones in this situation is azithromycin. Rifaximin has been approved for the treatment of TD caused by noninvasive strains of E. coli. However, since it is often difficult for travelers to distinguish between invasive and noninvasive diarrhea and since they would have to carry a back-up drug in the event of invasive diarrhea, the overall usefulness of rifaximin as empiric self-treatment remains to be determined.

Single-dose or 1-day therapy for TD with a fluoroquinolone is well established, both by clinical trials and clinical experience. The best regimen for azithromycin treatment is not yet established. One study used a single dose of 1,000 mg, but side effects (mainly nausea) may limit the acceptability of this large dose. Azithromycin, 500 mg per day for 1–2 days, appears to be effective in most cases of TD.

Antimotility agents provide symptomatic relief and serve as useful adjuncts to antibiotic therapy in TD. Synthetic opiates, such as loperamide and diphenoxylate, can reduce bowel movement frequency and enable travelers to ride on an airplane or bus while awaiting the effects of antibiotics. Loperamide appears to have antisecretory properties as well. The safety of loperamide when used along with an appropriate antibiotic has been well established, even in cases of invasive pathogens. Loperamide can be used in children, and liquid formulations are available. In practice, however, these drugs are rarely given to small children.