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Chapter 2 The Pre-Travel Consultation Self-Treatable Conditions

Travelers’ Diarrhea

TRAVELERS’ DIARRHEA

Bradley A. Connor

Travelers’ diarrhea (TD) is the most predictable travel-related illness. Attack rates range from 30% to 70% of travelers, depending on the destination and season of travel. Traditionally, it was thought that TD could be prevented by following simple recommendations such as “boil it, cook it, peel it, or forget it,” but studies have found that people who follow these rules may still become ill. Poor hygiene practice in local restaurants is likely the largest contributor to the risk for TD.

TD is a clinical syndrome that can result from a variety of intestinal pathogens. Bacterial pathogens are the predominant risk, thought to account for 80%–90% of TD. Intestinal viruses usually account for 5%–8% of illnesses, although increasing use of improved diagnostics may increase recognition of norovirus infections in the future. Infections with protozoal pathogens are slower to manifest symptoms and collectively account for approximately 10% of diagnoses in longer-term travelers. What is commonly known as “food poisoning” involves the ingestion of preformed toxins in food. In this syndrome, vomiting and diarrhea may both be present, but symptoms usually resolve spontaneously within 12 hours.

INFECTIOUS AGENTS

Bacteria are the most common cause of TD. Overall, the most common pathogen is enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella spp., and Salmonella spp. Enteroadherent and other E. coli pathotypes are also common pathogens in TD. There is increasing discussion of Aeromonas spp. and Plesiomonas spp. as potential causes of TD as well. Viral diarrhea can be caused by a number of pathogens, including norovirus, rotavirus, and astrovirus.

Giardia is the main protozoal pathogen found in TD. Entamoeba histolytica is a relatively uncommon pathogen in travelers. Cryptosporidium is also relatively uncommon. The risk for Cyclospora is highly geographic and seasonal: the most well-known risks are in Nepal, Peru, Haiti, and Guatemala. Dientamoeba fragilis is a low-grade but persistent pathogen that is occasionally diagnosed in travelers. The individual pathogens are each discussed in their own sections in Chapter 3, and persistent diarrhea in returned travelers is discussed in Chapter 5.

OCCURRENCE

The most important determinant of risk is travel destination, and there are regional differences in both the risk for and etiology of diarrhea. The world is generally divided into 3 grades of risk: low, intermediate, and high.

  • Low-risk countries include the United States, Canada, Australia, New Zealand, Japan, and countries in Northern and Western Europe.
  • Intermediate-risk countries include those in Eastern Europe, South Africa, and some of the Caribbean islands.
  • High-risk areas include most of Asia, the Middle East, Africa, Mexico, and Central and South America.

RISK FOR TRAVELERS

TD occurs equally in male and female travelers and 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 may occur during a single trip. A cohort of expatriates residing in Kathmandu, Nepal, experienced an average of 3.2 episodes of TD per person in their first year. In more temperate regions, there may be seasonal variations in diarrhea risk. In south Asia, for example, much higher TD attack rates are reported during the hot months preceding the monsoon.

In environments where large numbers of people do not have access to plumbing or latrines, the amount of stool contamination in the environment will be higher and more accessible to flies. Inadequate electrical capacity may lead to frequent blackouts or poorly functioning refrigeration, which can result in unsafe food storage and an increased risk for disease. Lack of safe water may lead to contaminated foods and drinks prepared with such water; inadequate water supply may lead to shortcuts in cleaning hands, surfaces, utensils, and foods such as fruits and vegetables. In addition, handwashing may not be a social norm and could be an extra expense, thus there may be no handwashing stations in food preparation areas. In destinations in which effective food handling courses have been provided, the risk for TD has been demonstrated to decrease. However, even in developed countries, pathogens such as Shigella sonnei have caused TD linked to handling and preparation of food in restaurants.

CLINICAL PRESENTATION

Bacterial and viral TD presents with the sudden onset of bothersome symptoms that can range from mild cramps and urgent loose stools to severe abdominal pain, fever, vomiting, and bloody diarrhea, although with norovirus vomiting may be more prominent. Protozoal diarrhea, such as that caused by Giardia intestinalis or E. histolytica, generally has a more gradual onset of low-grade symptoms, with 2–5 loose stools per day. The incubation period of the pathogens can be a clue to the etiology of TD:

  • Bacterial and viral pathogens have an incubation period of 6–72 hours.
  • Protozoal pathogens generally have an incubation period of 1–2 weeks and rarely present in the first few weeks of travel. An exception can be Cyclospora cayetanensis, which can present quickly in areas of high risk.

Untreated bacterial diarrhea 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 gastroenteritis can lead to persistent gastrointestinal symptoms, even in the absence of continued infection (see Chapter 5, Persistent Travelers’ Diarrhea). Other postinfectious sequelae may include reactive arthritis and Guillain-Barré syndrome.

PREVENTION

For travelers to high-risk areas, several approaches may be recommended that can reduce, but never completely eliminate, the risk for TD. These include instruction regarding food and beverage selection, use of agents other than antimicrobial drugs for prophylaxis, and use of prophylactic antibiotics. Carrying small containers of alcohol-based hand sanitizers (containing ≥60% alcohol) may make it easier for travelers to clean their hands before eating. No vaccines are available for most pathogens that cause TD, but travelers should refer to the Hepatitis A and Typhoid & Paratyphoid Fever sections in Chapter 3 regarding vaccines that can prevent other foodborne or waterborne infections to which travelers are prone.

Food and Beverage Selection

Care in selecting food and beverages for consumption helps to minimize the risk for acquiring TD. See the Food & Water Precautions section later in this chapter for CDC’s detailed food and beverage recommendations. Although food and water precautions continue to be recommended, travelers may not always be able to adhere to the advice. Furthermore, many of the factors that ensure food safety, such as restaurant hygiene, are out of the traveler’s control.

Nonantimicrobial Drugs for Prophylaxis

The primary agent studied for prevention of TD, other than antimicrobial drugs, is bismuth subsalicylate (BSS), which is the active ingredient in Pepto-Bismol. Studies from Mexico have shown that this agent (taken daily as either 2 oz of liquid or 2 chewable tablets 4 times per day) reduces the incidence of TD by approximately 50%. BSS commonly causes blackening of the tongue and stool and may cause nausea, constipation, and rarely tinnitus. BSS should be avoided by travelers with aspirin allergy, renal insufficiency, and gout and by those taking anticoagulants, probenecid, or methotrexate. In travelers taking aspirin or salicylates for other reasons, the use of BSS may result in salicylate toxicity. BSS is not generally recommended for children aged <12 years; however, some clinicians use it off-label with caution in certain circumstances. Caution should be taken in administering BSS to children with viral infections, such as varicella or influenza, because of the risk for Reye syndrome. BSS is not recommended for children aged <3 years. Studies have not established the safety of BSS use for periods >3 weeks. Because of the number of tablets required and the inconvenient dosing, BSS is not commonly used as prophylaxis for TD.

The use of probiotics, such as Lactobacillus GG and Saccharomyces boulardii, has been studied in the prevention of TD in small numbers of people. Results are inconclusive, partially because standardized preparations of these bacteria are not reliably available. Some people report beneficial outcomes using bovine colostrum as a daily prophylaxis agent for TD. However, commercially sold preparations of bovine colostrum are marketed as dietary supplements that are not Food and Drug Administration (FDA) approved for medical indications. Because no data from rigorous clinical trials demonstrate efficacy in controlled trials, there is insufficient information to recommend the use of bovine colostrum to prevent TD.

Although not available in the United States, a cholera vaccine that provides partial protection against enterotoxigenic E. coli is available in some other countries. Several clinical trials of new vaccines against TD pathogens are in progress.

Prophylactic Antibiotics

Prophylactic antibiotics are effective in the prevention of some TD. Controlled studies have shown that diarrhea attack rates are reduced by 90% or more 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 and Shigella species, may limit their benefit in the future. A nonabsorbable antibiotic, rifaximin, is being investigated but is not currently approved by the FDA for its potential use in TD prophylaxis. In one study, rifaximin reduced the risk for TD in travelers to Mexico by 77%.

At this time, prophylactic antibiotics should not be recommended for most travelers. Prophylactic antibiotics afford no protection against nonbacterial pathogens and can remove normally protective microflora from the bowel, which could make a traveler more susceptible to infection with resistant bacterial pathogens. A traveler relying on prophylactic antibiotics will need to carry an alternative antibiotic to use in case diarrhea develops despite prophylaxis. Additionally, the use of antibiotics may be associated with allergic or adverse reactions in a certain percentage of travelers and may potentially contribute to drug resistance. 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 who are taking critical trips (such as engaging in a sporting event) during which even a short bout of diarrhea could affect the trip.

TREATMENT

Antibiotics are the principal element in the treatment of TD and are effective in cases caused by bacterial pathogens that are susceptible to the particular antibiotic prescribed. Adjunctive agents used for symptomatic control may also be recommended.

Antibiotics

As bacterial causes of TD far outnumber other microbial causes, empiric treatment with an antibiotic directed at enteric bacterial pathogens remains the best therapy for TD. The benefit of treating 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 fluoroquinolones, 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. Increasing cases of fluoroquinolone resistance have been reported from other destinations and in other bacterial pathogens, including Shigella and Salmonella. A potential alternative to the fluoroquinolones in these situations is azithromycin, although enteropathogens with decreased azithromycin susceptibility have been documented in several countries. Rifaximin has been approved to treat 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 1–3 days, appears to be effective in most cases of TD.

Antimotility Agents

Antimotility agents provide symptomatic relief and serve as useful adjuncts to antibiotic therapy in TD. Synthetic opiates, such as loperamide and diphenoxylate, can reduce frequency of bowel movements 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 antibiotic has been well established, even in cases of invasive pathogens. Antimotility agents are not generally 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 small children (aged <6 years).

Oral Rehydration Therapy

Fluids and electrolytes are lost during TD, and replenishment is important, especially in young children or adults with chronic medical illness. In adult travelers who are otherwise healthy, severe dehydration resulting from TD is unusual unless vomiting is prolonged. Nonetheless, replacement of fluid losses remains an adjunct to other 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. For severe fluid loss, replacement is best accomplished with oral rehydration solution (ORS), prepared from packaged oral rehydration salts, such as those provided by the World Health Organization. ORS is widely available at stores and pharmacies in most developing countries. ORS is prepared by adding 1 packet to the indicated volume of boiled or treated water—generally 1 liter. Travelers may find most ORS formulations to be relatively unpalatable, due to their saltiness. In mild cases, rehydration can be maintained with any palatable liquid (including sports drinks), although overly sweet drinks, such as sodas, can cause osmotic diarrhea if consumed in quantity.

Treatment of TD Caused by Protozoa

The most common parasitic cause of TD is Giardia intestinalis, and treatment options include metronidazole, tinidazole, and nitazoxanide (see Chapter 3, Giardiasis). Although cryptosporidiosis is usually a self-limited illness in immunocompetent people, nitazoxanide can be considered as a treatment option. Cyclosporiasis is treated with trimethoprim-sulfamethoxazole. Treatment of amebiasis is with metronidazole or tinidazole, followed by treatment with a luminal agent such as iodoquinol or paromomycin.

Treatment for Children

Children who accompany their parents on trips to high-risk destinations can contract TD as well. There is no reason to withhold antibiotics from children who contract TD unless they have drug allergies, are taking medications that may interact with the antibiotic, or there is a strong suspicion that the illness is viral. In older children and teenagers, treatment recommendations for TD follow those for adults, with possible adjustments in the dose of medication. Among younger children, macrolides such as azithromycin are considered first-line antibiotic therapy, although some experts now use short-course fluoroquinolone therapy (despite its not being FDA-approved for this indication in children) for travelers aged <18 years. Rifaximin is approved for use in children aged ≥12 years.

Infants and younger children with TD are at higher risk for developing dehydration, which is best prevented by the early initiation of oral rehydration. 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 may consume a regular diet. Children in diapers are at risk for developing diaper rash on their buttocks in response to the liquid stool. Barrier creams, such as zinc oxide or petrolatum, could be applied at the onset of diarrhea to help prevent and treat rash. More information about diarrhea and dehydration is discussed in Chapter 7, Traveling Safely with Infants & Children.

Tropical Sprue

Tropical sprue is a syndrome of persistent TD often associated with malabsorption, steatorrhea, and folate and vitamin B12 deficiency. Tropical sprue is rare in short-term travelers, and recent surveys of returned travelers suggest that it is occurring less frequently worldwide. Although exhaustive searches to identify the etiologic agent of tropical sprue have been futile, it bears all the hallmarks of an infectious disease. Exclusion of other diarrheal etiologies is required for diagnosis. Treatment with tetracycline 250 mg 4 times daily and folate 5 mg daily for at least 6 weeks is generally successful. Patients with concomitant vitamin B12 deficiency may require parenteral vitamin B12.

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