Author(s): Bradley Connor

Travelers’ diarrhea (TD) is the most predictable travel-related illness. Attack rates range from 30%–70% of travelers during a 2-week period, depending on the destination and season of travel. Traditionally, TD was thought to be prevented by following simple dietary recommendations (e.g., “boil it, cook it, peel it, or forget it”), but studies have found that people who follow these rules can still become ill. Poor hygiene practices in local restaurants and underlying hygiene and sanitation infrastructure deficiencies are likely the largest contributors to the risk for TD.

TD is a clinical syndrome that can result from a variety of intestinal pathogens. Bacteria are the predominant enteropathogens and are thought to account for ≥80%–90% of cases. Intestinal viruses account for at least 5%–15% of illnesses, although the use of multiplex molecular diagnostic assays demonstrates that their contribution to the overall burden of TD disease is probably greater than previously estimated. Infections with protozoal pathogens are slower to manifest symptoms and collectively account for ≈10% of diagnoses in longer-term travelers (see Sec. 11, Ch. 7, Persistent Diarrhea in Returned Travelers).

What is commonly known as “food poisoning” involves the ingestion of infectious agents that release toxins (e.g., Clostridium perfringens) or consumption of preformed toxins (e.g., Staphylococcal food poisoning). In toxin-mediated illness, both vomiting and diarrhea can be present; symptoms usually resolve spontaneously within 12–24 hours.

Infectious Agents

Bacteria

Bacteria are the most common cause of TD. Overall, the most common pathogen identified is enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella spp., and Salmonella spp. Enteroaggregative and other E. coli pathotypes also are commonly found in cases of TD. Surveillance also points to Aeromonas spp., Plesiomonas spp., and newly recognized pathogens (Acrobacter, enterotoxigenic Bacteroides fragilis, Larobacter) as potential causes of TD.

Viruses

Viral diarrhea can be caused by several pathogens, including astrovirus, norovirus, and rotavirus.

Protozoal Parasites

Giardia is the main protozoal pathogen found in TD. Entamoeba histolytica and Cryptosporidium are relatively uncommon causes of TD. The risk for Cyclospora is highly geographic and seasonal: the most well-known risks are in Guatemala, Haiti, Nepal, and Peru. Dientamoeba fragilis is a flagellate occasionally associated with diarrhea in travelers. Several pathogens are discussed in their own chapters in Section 5.

Risk for Travelers

TD occurs equally in male and female travelers; it is more common in young adult travelers than in older travelers. In short-term travelers, bouts of TD do not appear to protect against future attacks, and >1 episode of TD can occur during a single trip. A cohort of expatriates residing in Kathmandu, Nepal, experienced an average of 3.2 episodes of TD per person during their first year. In more temperate regions, seasonal variations in diarrhea risk can occur. In South Asia, for example, much higher TD attack rates are reported during the hot months preceding the monsoon.

Particularly in locations where large numbers of people lack plumbing or latrine access, stool contamination in the environment will be greater and more accessible to disease-transmitting vectors (e.g., flies). Inadequate electrical capacity leading to frequent blackouts or poorly functioning refrigeration can result in unsafe food storage and an additional increased risk for disease. Lack of safe, potable water contributes to food and drink contamination, as do unhealthful shortcuts in cleaning hands, countertops, cutting boards, utensils, and foods (e.g., fruits and vegetables). In some places, handwashing might not be a social norm and could represent an extra expense; thus, adequately equipped handwashing stations might not be available in food preparation areas.

Where provided, effective food handling courses have been shown to decrease the risk for TD. However, even in high-income countries, food handling and preparation in restaurants has been linked to TD caused by pathogens such as Shigella sonnei.

Clinical Presentation

The incubation period between exposure and clinical presentation can provide clues to etiology. Toxin-mediated illness, for example, generally causes symptoms within a few hours. By contrast, bacterial and viral pathogens have an incubation period of 6–72 hours. In general, protozoal pathogens have longer incubation periods (1–2 weeks), rarely presenting in the first few days of travel. An exception is Cyclospora cayetanensis, which can present quickly in areas of high risk.

Bacterial and viral TD present with the sudden onset of bothersome symptoms that can range from mild cramps and urgent loose stools to severe abdominal pain, bloody diarrhea, fever, and vomiting; with norovirus, vomiting can be more prominent. Diarrhea caused by protozoa (e.g., E. histolytica, Giardia duodenalis) generally has a more gradual onset of low-grade symptoms, with 2–5 loose stools per day.

Untreated, bacterial diarrhea usually lasts 3–7 days. Viral diarrhea generally lasts 2–3 days. Protozoal diarrhea can persist for weeks to months without treatment. An acute bout of TD can lead to persistent enteric symptoms, even in the absence of continued infection. This presentation is commonly referred to as postinfectious irritable bowel syndrome (see Sec. 11, Ch. 7, Persistent Diarrhea in Returned Travelers). Other postinfectious sequelae can include reactive arthritis and Guillain-Barré syndrome.

Prevention

Vaccines are not available in the United States for pathogens that commonly cause TD. Traveler adherence to recommended approaches can, however, help reduce, although never fully eliminate, the risk for illness. These recommendations include making careful food and beverage choices, using agents other than antimicrobial medications for prophylaxis, and carefully washing hands with soap whenever available. When handwashing is not possible, small containers of hand sanitizer containing ≥60% alcohol can make it easier for travelers to clean their hands before eating. Refer to the relevant chapters in Section 5 (Cholera, Hepatitis A, and Typhoid & Paratyphoid Fever) for details regarding vaccines to prevent other foodborne and waterborne infections to which travelers are susceptible.

Food & Beverage Selection

Care in selecting food and beverages can help minimize the risk for acquiring TD. See Sec. 2, Ch. 8, Food & Water Precautions, for detailed food and beverage recommendations. Although food and water precautions are recommended, travelers are not always able to adhere to the advice. Furthermore, food safety factors (e.g., restaurant hygiene) are out of the traveler’s control.

Non-Antimicrobial Drugs for Prophylaxis

Bismuth Subsalicylate

The primary agent studied for prevention of TD, other than antibiotics, is bismuth subsalicylate (BSS). Studies from Mexico have shown that this agent reduces the incidence of TD by approximately 50%. BSS commonly causes blackening of the tongue and stool and can cause constipation, nausea, and rarely tinnitus.

Contraindications & Safety

Travelers with aspirin allergy, gout, or renal insufficiency, and those taking anticoagulants, methotrexate, or probenecid should not take BSS. In travelers taking aspirin or salicylates for other reasons, concomitant use of BSS can increase the risk of developing salicylate toxicity.

BSS is not generally recommended for children aged <12 years; some clinicians use it off-label, however, with caution to avoid administering BSS to children aged ≤18 years with viral infections (e.g., influenza, varicella), because of the risk for Reye’s syndrome. BSS is not recommended for children aged <3 years or pregnant people.

Studies have not established the safety of BSS use for >3 weeks. Because of the number of tablets required and the inconvenient dosing, BSS is not commonly used as TD prophylaxis.

Probiotics

Probiotics (e.g., Lactobacillus GG, Saccharomyces boulardii) have been studied in small numbers of people as TD prevention, but results are inconclusive, partly because standardized preparations of these bacteria are not reliably available. Studies of probiotics to prevent TD are ongoing, but data are insufficient to recommend their use (see the Sec. 2, Ch. 14, Complementary & Integrative Health Approaches to Travel Wellness).

Anecdotal reports claim beneficial outcomes after using bovine colostrum as a daily prophylaxis agent for TD. However, commercially sold preparations of bovine colostrum marketed as dietary supplements are not approved by the US Food and Drug Administration (FDA). Because no data from rigorous clinical trials demonstrate efficacy, insufficient information is available to recommend the use of bovine colostrum to prevent TD.

Prophylactic Antibiotics

Older controlled studies showed that use of antibiotics reduced diarrhea attack rates by 90%. For most travelers, though, the risks associated with the use of prophylactic antibiotics (see below) do not outweigh the benefits. Prophylactic antibiotics might rarely be considered for short-term travelers who are high-risk hosts (e.g., immunocompromised people or people who have significant medical comorbidities).

The prophylactic antibiotic of choice has changed over the past few decades as resistance patterns have evolved. Historically, fluoroquinolones have been the most effective antibiotics for prophylaxis and treatment of bacterial TD pathogens, but resistance among Campylobacter and Shigella species globally now limits their use. In addition, fluoroquinolones are associated with tendinitis, concerns for QT interval prolongation, and an increased risk for Clostridioides difficile infection. Current guidelines discourage their use for prophylaxis. Alternative considerations include rifaximin and rifamycin SV.

Antimicrobial Resistance & Other Adverse Consequences

Prophylactic antibiotics are not recommended for most travelers. Prophylactic antibiotics afford no protection against nonbacterial pathogens and can remove normally protective microflora from the bowel, increasing the risk for infection with resistant bacterial pathogens. Travelers can become colonized with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), a risk that is increased by exposure to antibiotics while abroad (see Sec 2, Ch. 17, . . . perspectives: Antibiotics in Travelers’ Diarrhea—Balancing Benefit & Risk, and Sec. 11, Ch. 5, Antimicrobial Resistance).

Use of prophylactic antibiotics limits therapeutic options if TD occurs; a traveler relying on prophylactic antibiotics will need to carry an alternative antibiotic to use if severe diarrhea develops. Additionally, use of antibiotics has been associated with allergic and other adverse reactions.

Treatment

Antibiotics

The effectiveness of a particular antimicrobial drug depends on the etiologic agent and its antibiotic sensitivity (Table 2-09). If tolerated, single-dose regimens are equivalent to multidose regimens and might be more convenient for the traveler.

Azithromycin

Azithromycin is an alternative to fluoroquinolones (see below), although enteropathogens with decreased azithromycin susceptibility have been documented in several countries. The simplest azithromycin treatment regimen is a single dose of 1,000 mg, but side effects (mainly nausea) can limit the acceptability of this large dose; taking the medication as 2 divided doses on the same day can help.

Fluoroquinolones

Fluoroquinolones (e.g., ciprofloxacin, levofloxacin) have traditionally been the first-line antibiotics for empiric therapy of TD or to treat specific bacterial pathogens. Increasing microbial resistance to fluoroquinolones, however, especially among Campylobacter isolates, limits their usefulness in many destinations, particularly South and Southeast Asia, where both Campylobacter infection and fluoroquinolone resistance are prevalent. Increasing fluoroquinolone resistance has been reported from other destinations and in other bacterial pathogens, including in Salmonella and Shigella. Furthermore, fluoroquinolones now carry a black box warning from the FDA regarding multiple adverse reactions including aortic tears, hypoglycemia, mental health side effects, and tendinitis and tendon rupture.

Rifamycins

Rifamycin SV

A new therapeutic option is rifamycin SV, approved by the FDA in November 2018 to treat TD caused by noninvasive strains of E. coli in adults. Rifamycin SV is a nonabsorbable antibiotic in the ansamycin class of antibacterial drugs formulated with an enteric coating that targets delivery of the drug to the distal small bowel and colon. Two randomized clinical trials showed that rifamycin SV was superior to placebo and non-inferior to ciprofloxacin in the treatment of TD. As with rifaximin (see below), travelers would need to carry a separate antibiotic (e.g., azithromycin) in case of infection due to an invasive pathogen.

Rifaximin

Rifaximin has been approved to treat TD caused by noninvasive strains of E. coli. Since travelers likely cannot distinguish between invasive and noninvasive diarrhea, however, and since they would have to carry a backup drug in the event of invasive diarrhea, the overall usefulness of rifaximin as empiric self-treatment remains undetermined.

Antimicrobial Resistance & Other Adverse Consequences

Antibiotics are effective in reducing the duration of diarrhea by ≈1–2 days in cases caused by bacterial pathogens susceptible to the antibiotic prescribed. However, concerns about the adverse consequences of using antibiotics to treat TD remain. Travelers who take antibiotics are at risk of becoming colonized by drug-resistant organisms (e.g., ESBL-PE), resulting in potential harm to travelers—particularly immunocompromised people and people prone to urinary tract infections—and the possibility of introducing resistant bacteria into the community.

In addition, antibiotic use can affect the travelers’ own microbiota and increase the potential for C. difficile infection. These concerns must be weighed against the consequences of TD and the role of antibiotics in shortening the acute illness and possibly preventing postinfectious sequelae. Primarily because of these concerns, an expert advisory panel was convened in 2016 to prepare consensus guidelines on the prevention and treatment of TD. The advisory panel suggested a classification of TD using functional impact for defining severity (Box 2-03) rather than the frequency-based algorithm used traditionally. The guidelines suggest an approach that matches therapeutic intervention with severity of illness, in terms of both safety and effectiveness (Box 2-04).

Antimotility Agents

Antimotility agents provide symptomatic relief and are useful therapy in TD. Synthetic opiates (e.g., diphenoxylate, loperamide) can reduce frequency of bowel movements and therefore enable travelers to ride on an airplane or bus. Loperamide appears to have antisecretory properties as well. The safety of loperamide when used along with an antibiotic has been well established, even in cases of invasive pathogens; however, acquisition of ESBL-PE might be more common when loperamide and antibiotics are coadministered.

Antimotility agents alone are not recommended for patients with bloody diarrhea or those who have diarrhea and fever. Loperamide can be used in children, and liquid formulations are available. In practice, however, these drugs are rarely given to children aged <6 years.

Oral Rehydration Therapy

Fluids and electrolytes are lost during TD, and replenishment is important, especially in young children, older adults, and adults with chronic medical illness. In otherwise healthy adult travelers, severe dehydration from TD is unusual unless vomiting is prolonged. Nonetheless, replacement of fluid losses is key to diarrhea therapy and helps the traveler feel better more quickly. Travelers should remember to use only beverages that are sealed, treated with chlorine, boiled, or are otherwise known to be purified (see Sec. 2, Ch. 9, Water Disinfection).

For severe fluid loss, replacement is best accomplished with oral rehydration solution (ORS) prepared from packaged oral rehydration salts (e.g., those provided by the World Health Organization). ORS is widely available at stores and pharmacies in most low- and middle-income countries. ORS is prepared by adding 1 packet to the indicated volume of boiled or treated water—generally 1 liter. Due to their saltiness, travelers might find most ORS formulations relatively unpalatable. In mild cases, rehydration can be maintained with any preferred liquid (including sports drinks), although overly sweet drinks (e.g., sodas) can cause osmotic diarrhea if consumed in quantity.

Travelers’ Diarrhea Caused by Protozoa

The most common parasitic cause of TD is Giardia duodenalis, and treatment options include metronidazole, nitazoxanide, and tinidazole (see Sec. 5, Part 3, Ch.12, Giardiasis). Amebiasis (see Sec. 5, Part 3, Ch. 1, Amebiasis) should be treated with metronidazole or tinidazole, then treated with a luminal agent (e.g., iodoquinol or paromomycin). Although cryptosporidiosis is usually a self-limited illness in immunocompetent people, clinicians can consider nitazoxanide as a treatment option (see Sec. 5, Part 3, Ch. 3, Cryptosporidiosis). Cyclosporiasis should be treated with trimethoprim-sulfamethoxazole but not trimethoprim alone (see Sec. 5, Part 3, Ch. 5, Cyclosporiasis).

Travelers’ Diarrhea in Children

Children who accompany their parents on trips to high-risk destinations can contract TD, and their risk is elevated if they are visiting friends and family. Causative organisms include bacteria responsible for TD in adults, as well as viruses (e.g., norovirus, rotavirus). The main treatment for TD in children is ORS. Infants and younger children with TD are at greater risk for dehydration, which is best prevented by the early initiation of oral rehydration.

Consider recommending empiric antibiotic therapy for bloody or severe watery diarrhea or evidence of systemic infection. In older children and teenagers, treatment guidelines follow those for adults, with possible adjustments in the dose of medication. Among younger children, macrolides (e.g., azithromycin) are considered first-line antibiotic therapy. Rifaximin is approved for use in children aged ≥12 years. Rifamycin SV is approved for use only in adults.

Breastfed infants should continue to nurse on demand, and bottle-fed infants can continue to drink formula. Older infants and children should be encouraged to eat and should consume a regular diet. Children in diapers are at risk for developing diaper rash on their buttocks in response to liquid stool. Barrier creams (e.g., zinc oxide, petrolatum) could be applied at the onset of diarrhea to help prevent and treat rash; hydrocortisone cream is the best treatment for an established rash. More information about diarrhea and dehydration is discussed in Sec. 7, Ch. 3, Traveling Safely with Infants & Children.