Travelers’ Diarrhea

Introduction

Travelers' diarrhea (TD) is the most predictable travel-related illness. Attack rates range from 30% to 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 ≥75%–90% of cases. Intestinal viruses account for at least 10%–25% of illnesses and are more commonly associated with vomiting. The use of multiplex molecular diagnostic assays has suggested that the contribution of viruses to the overall burden of TD disease is underestimated. Infections with protozoal pathogens are slower to manifest symptoms and collectively account for approximately 10% of diagnoses, predominantly in longer-term travelers (see Post-Travel Diarrhea chapter).

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 pathogens identified are diarrheagenic Escherichia coli (most prominently enterotoxigenic E. coli, but also including enteroaggregative E. coli and enteropathogenic E. coli), followed by Campylobacter jejuni, Shigella spp., and Salmonella spp. Surveillance also points to Aeromonas spp., Plesiomonas spp., and newly recognized pathogens (Aliarcobacter, enterotoxigenic Bacteroides fragilis, Larobacter) as potential causes of TD.

Viruses

Viral diarrhea can be caused by several pathogens, most notably norovirus, but also including astrovirus, sapovirus, and rotavirus (see Norovirus chapter).

Protozoal parasites

Giardia is the main protozoal pathogen found in TD, followed by Cryptosporidium. Entamoeba histolytica is a relatively uncommon cause 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.

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 diarrhea 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, illnesses caused by bacterial and viral pathogens have incubation periods of 6–96 hours. In general, illnesses due to protozoal pathogens have longer incubation periods (1–2 weeks), rarely presenting in the first few days of travel. An exception is Cyclospora cayetanensis infection, in which symptoms can present quickly (2–14 days).

Bacterial and viral TD present with the sudden onset of 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., Cryptosporidium, Giardia duodenalis) may have 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 (less than 2 weeks) bout of TD can lead to persistent enteric symptoms, even in the absence of continued infection. This presentation is commonly referred to as post-infectious irritable bowel syndrome (see Post-Travel Diarrhea chapter). Other post-infectious 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 the Travel-Associated Infections and Diseases section (see Cholera, Hepatitis A, and Typhoid and Paratyphoid Fever chapters) for details regarding vaccines to prevent other foodborne and waterborne infections to which travelers are susceptible.

Food and beverage selection

Care in selecting food and beverages can help lower the risk for acquiring TD (see Food and Water Precautions for Travelers chapter for detailed food and beverage recommendations). Although food and water precautions are recommended, travelers are not always able to adhere to the advice. Furthermore, some food safety factors (e.g., restaurant hygiene) are out of the traveler's control, and studies have demonstrated that risk behavior counseling on food and water hygiene may not decrease risk of diarrhea.

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 and 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 healthcare professionals 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 women.

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 Complementary and Integrative Health Approaches to Travel Wellness chapter).

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 U.S. 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 almost all travelers, though, the risks associated with the use of prophylactic antibiotics, including side effects, Clostridioides difficile infection, and increased risk of carriage of antimicrobial-resistant bacteria (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 and 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 acquisition of resistant bacterial pathogens. Travelers can become colonized with extended-spectrum beta lactamase-producing enterobacteriaceae (ESBL-PE), a risk that is increased by exposure to antibiotics while abroad.

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

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 Water Disinfection for Travelers chapter).

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 L. 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.

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 may be helpful to travelers embarking on long-distance travel, such as 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 co-administered.

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.

Antibiotics

The effectiveness of a particular standby antimicrobial drug for self-treatment depends on the etiologic agent and its antibiotic sensitivity (Table 1.6.1). If tolerated, single-dose regimens are equivalent to multidose regimens and might be more convenient for the traveler.

Table 1.6.1: Acute diarrhea antibiotic treatment recommendations¹

Azithromycin

Azithromycin is an alternative to fluoroquinolones (see below), although enteropathogens with decreased azithromycin susceptibility, especially isolates of Shigella sonnei, 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; other options include taking the 1,000 mg as 2 divided doses on the same day, or 500 mg a day for 3 days.

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 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.

Rifaximin and rifamycin

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 either seek medical care or carry a backup drug in the event of invasive diarrhea, the overall usefulness of rifaximin as empiric self-treatment remains undetermined. Nevertheless, for those who have a contraindication (e.g., due to drug-drug interactions) to fluoroquinolones or azithromycin, this remains a potential option for self-treatment. Another therapeutic option is rifamycin, approved to treat TD caused by noninvasive strains of E. coli in adults. Like rifaximin, this compound is a nonabsorbable antibiotic 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 noninferior to ciprofloxacin in the treatment of TD. As with rifaximin, travelers taking rifamycin would need to seek medical care or carry a separate antibiotic (e.g., azithromycin) in case of infection due to an invasive pathogen.

Antimicrobial resistance and other adverse consequences

Antibiotics are effective in reducing the duration of diarrhea by approximately 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 post-infectious 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 rather than the frequency-based algorithm used traditionally (Table 1.6.2). The guidelines suggest an approach that matches therapeutic intervention with severity of illness, in terms of both safety and effectiveness.

Table 1.6.2: Acute travelers’ diarrhea, functional definitions

Travelers' diarrhea caused by protozoa

Protozoa are the pathogens more likely to be isolated from patients with persistent diarrhea (i.e., diarrhea lasting >2 weeks). For travelers on shorter trips, symptoms may occur after returning home, often allowing for easier access to more comprehensive diagnostic evaluation and specific treatment (see Post-Travel Diarrhea chapter). The most common parasitic cause of TD is Giardia duodenalis, and treatment options include metronidazole, nitazoxanide, and tinidazole. Amebiasis (Entamoeba histolytica) 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 persons, healthcare professionals can consider nitazoxanide as a treatment option. Cyclosporiasis should be treated with trimethoprim-sulfamethoxazole but not trime­thoprim alone.

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 empiric antibiotic therapy for severe watery diarrhea or evidence of systemic infection. In children with bloody diarrhea, empiric antibiotic therapy must be weighed against the risk of hemolytic uremic syndrome in association with Shiga-toxin producing E. coli 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 ≥18 years.

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 be offered 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 provided in Traveling Safely with Infants and Children chapter).