Travelers' Diarrhea

Epidemiology

Travelers' diarrhea (TD) is a syndrome characterized by a twofold or greater increase in the frequency of unformed bowel movements. Commonly associated symptoms include abdominal cramps, nausea, bloating, urgency, fever, and malaise. Episodes of TD usually begin abruptly, occur during travel or soon after returning home, and are generally self-limited. The most important determinant of risk is the destination of the traveler. Attack rates of 20%–50% are commonly reported. High-risk destinations include most of the low-income countries of Latin America, Africa, the Middle East, and Asia. Intermediate-risk destinations include most of the southern European countries and a few Caribbean islands. Low-risk destinations include Canada, northern Europe, Australia, New Zealand, the United States, and some of the Caribbean islands.

TD is slightly more common in young adults than in older people. The reasons for this difference are unclear, but could include a lack of acquired immunity, more adventurous travel styles, and different eating habits. Attack rates are similar in men and women. The onset of TD is usually within the first week of travel but can occur at any time during the visit and even after returning home.

TD is acquired through ingestion of fecally contaminated food or water or both. Both cooked and uncooked foods might be implicated if they have been improperly handled. Especially risky foods include raw or undercooked meat and seafood and raw fruits and vegetables. Tap water, ice, and unpasteurized milk and dairy products can be associated with increased risk of TD. Safe beverages include bottled carbonated beverages (especially flavored beverages), beer, wine, hot coffee or tea, or water boiled and appropriately treated with iodine or chlorine. The place food is prepared appears to be an important variable, with private homes, restaurants, and street vendors listed in order of increasing risk.

TD typically results in four to five loose or watery stools per day. The median duration of diarrhea is 3–4 days. Approximately 10% of cases persist >1 week, approximately 2% longer than 1 month, and <1% longer than 3 months. Persistent diarrhea is thus quite uncommon and can differ considerably from acute TD with respect to etiology and risk factors. Approximately 15% of ill people have vomiting, and 2%–10% have diarrhea accompanied by fever or bloody stools or both. Travelers can have more than one episode of TD during a single trip. Rarely is TD life threatening.

Causes of Travelers' Diarrhea

Infectious agents are the primary cause of TD. Travelers from industrialized countries to developing countries frequently experience a rapid, dramatic change in the type of organisms in their gastrointestinal tract. These new organisms often include potential enteric pathogens. Travelers with diarrhea have ingested an inoculum of virulent organisms sufficiently large to overcome individual defense mechanisms, resulting in symptoms.

Enteric Bacterial Pathogens

Enterotoxigenic Escherichia coli (ETEC) are among the most common causative agents of TD in all countries where surveys have been conducted. ETEC produce a watery diarrhea associated with cramps; fever may be low-grade or absent.

Salmonella gastroenteritis is a well-known disease that occurs throughout the world. In industrialized nations, this large group of organisms is the most common cause of outbreaks of food-associated diarrhea. In low-income countries, the proportion of cases of TD caused by nontyphoidal salmonellae varies, but is not high. Salmonellae also can cause dysentery characterized by small-volume stools containing bloody mucus.

Shigellae, which are well known as the cause of bacillary dysentery, are the cause of TD in up to 20% of travelers to developing countries.

Campylobacter jejuni is a common cause of diarrhea throughout the world; it is responsible for a small percentage of reported cases of TD, some with bloody diarrhea. Additional studies are needed to determine how frequently it causes TD.

Vibrio parahaemolyticus is associated with ingestion of raw or poorly cooked seafood and has caused TD in passengers on Caribbean cruise ships and in travelers in Asia. How frequently it causes disease in other areas of the world is unknown.

Less common bacterial pathogens include other diarrheogenic E. coli, Yersinia enterocolitica, Vibrio cholerae O1 and O139, non-O1 V. cholerae, Vibrio fluvialis, and possibly Aeromonas hydrophila and Plesiomonas shigelloides.

Viral Enteric Pathogens—Rotaviruses and Norwalk-Like Virus

The traveler may also acquire many viruses. Studies have shown that as much as 36% of diarrheal illnesses in travelers (median 22%) was associated with rotaviruses in the stool. However, a comparable number of asymptomatic travelers also had rotaviruses, and up to 50% of symptomatic people with rotavirus infections also had nonviral pathogens. Approximately 10%–15% of travelers have serologic evidence of infection with Norwalk-like viruses. The roles of adenoviruses, astroviruses, coronaviruses, enteroviruses, or other viral agents in causing TD are even less clear. Although travelers commonly acquire viruses, they do not appear to be frequent causes of TD in adults.

Parasitic Enteric Pathogens

While less commonly implicated as the cause of TD than bacteria, enteric protozoa are recognized etiologic agents of TD. In the small number of studies that have included appropriate testing for these parasites in travelers or expatriates in developing countries, a variable proportion of TD, from 0% to 12%, has been attributed to Giardia intestinalis, Entamoeba histolytica, Cryptosporidium parvum, and Cyclospora cayetanensis. The likelihood of a parasitic etiology is higher when diarrheal illness is prolonged. E. histolytica should be considered when the patient has dysentery or invasive diarrhea (bloody stools); however, E. histolytica infection can also have mild, nonspecific symptoms. Specific diagnostic testing is required to identify E. histolytica, C. parvum, and C. cayetanensis. Dientamoeba fragilis, Isospora belli, Balantidium coli, and Strongyloides stercoralis can cause occasional cases of TD. While not common causes of TD, these parasites should be considered in persistent, unexplained cases, and the possibility of these agents should be discussed with the laboratory before requesting evaluation.

Unknown Causes

No data have been published to support noninfectious causes of TD, such as changes in diet, jet lag, altitude, and fatigue. Existing evidence indicates that in all but a few instances, such as drug-induced or preexisting gastrointestinal disorders, an infectious agent or agents is the cause of diarrhea in travelers. However, even with the application of the best existing methods for detecting bacteria, viruses, and parasites, 20%–50% of cases of TD remain without identified causes.

Prevention

There are four possible approaches to prevention of TD: 1) instruction regarding food and beverage consumption, 2) immunization, 3) use of nonantimicrobial medications, and 4) use of prophylactic antimicrobial drugs. Data indicate that meticulous attention to food and beverage consumption, as mentioned previously, can decrease the likelihood of developing TD. Most travelers, however, encounter difficulty in observing the requisite dietary restrictions 100% of the time.

No available vaccines and none that are expected to be available in the next 3 years are effective against TD. Several nonantimicrobial agents have been advocated for prevention of TD. Controlled studies indicate that prophylactic use of difenoxine, the active metabolite of diphenoxylate (Lomotil), actually increases the incidence of TD, in addition to producing other undesirable side effects. Antiperistaltic agents (e.g., Lomotil and Imodium) are not effective in preventing TD. No data support the prophylactic use of activated charcoal.

Bismuth subsalicylate, taken as the active ingredient of Pepto-Bismol (2 oz four times a day, or two tablets four times a day), has decreased the incidence of diarrhea by about 60% in several placebo-controlled studies. Side effects include temporary blackening of the tongue and stools; occasional nausea and constipation; and, rarely, tinnitus. Whether there is risk to the traveler from the use of such large doses of bismuth subsalicylate for a period of >3 weeks has not been sufficiently evaluated. Bismuth subsalicylate should be avoided by travelers with aspirin allergy, renal insufficiency, and gout, and by those who are taking anticoagulants, probenecid, or methotrexate. In travelers already taking aspirin or related salicylates for arthritis, large concurrent doses of bismuth subsalicylate can produce toxic serum concentrations of salicylate. Caution should be used in giving bismuth subsalicylate to children and adolescents with chickenpox or influenza because of a potential risk of Reye syndrome. Bismuth subsalicylate has not been approved for infants and children <3 years of age. Bismuth subsalicylate appears to be an effective prophylactic agent for TD but is not recommended for periods of >3 weeks. Further studies of the efficacy and side effects of lower-dose regimens are needed.

Controlled data are available on the prophylactic value of several other nonantimicrobial drugs. Enterovioform and related halogenated hydroxyquinoline derivatives (e.g., clioquinol, iodoquinol, Mexaform, and Intestopan) are not helpful in preventing TD, can have serious neurologic side effects, and should never be used for prophylaxis of TD.

Prophylactic Antibiotics for the Prevention of Travelers' Diarrhea

Controlled studies have indicated that a variety of antibiotics, including doxycycline, trimethoprim-sulfamethoxazole (TMP/SMX), trimethoprim alone, and the fluoroquinolone agents ciprofloxacin and norfloxacin, when taken prophylactically have been 52%–95% effective in preventing TD in several areas of the developing world. The effectiveness of these agents, however, depends on the antibiotic resistance patterns of the pathogenic bacteria in each area of travel, and such information is seldom available. Resistance to fluoroquinolones is the least common but this situation is changing as use of these agents increases worldwide.

Although effective in preventing some bacterial causes of diarrhea, antibiotics have no effect on the acquisition of various viral and parasitic diseases. Prophylactic antibiotics can give travelers a false sense of security about the risk associated with consuming certain local foods and beverages.

The benefits of widespread prophylactic use of doxycyline, fluoroquinolones, TMP/SMX, or TMP alone in several million travelers must be weighed against the potential drawbacks. The known risks include allergic and other side effects (e.g., common skin rashes, photosensitivity of the skin, blood disorders, Stevens-Johnson syndrome, and staining of the teeth in children), as well as other infections that might be induced by antimicrobial therapy (e.g., antibiotic-associated colitis, Candida vaginitis, and Salmonella enteritis). Because of the uncertain risk involved in the widespread administration of these antimicrobial agents, their prophylactic use is not recommended. Although it seems reasonable to use prophylactic antibiotics in certain high-risk groups, such as travelers with immunosuppression or immunodeficiency, no data directly support this practice. There is little evidence that other disease entities are worsened sufficiently by an episode of TD to risk the rare undesirable side effects of prophylactic antimicrobial drugs. Therefore, CDC does not recommend prophylactic antimicrobial agents for travelers. Instead, available data support the recommendation that travelers be instructed in sensible dietary practices as a prophylactic measure. This recommendation is justified by the excellent results of early treatment of TD, as outlined in the following section. Some travelers might wish to consult with their physicians and might elect to use prophylactic antimicrobial agents for travel under special circumstances, once the risks and benefits are clearly understood.

Treatment

Travelers with TD have two major complaints for which they desire relief: abdominal cramps and diarrhea. Many agents have been proposed to control these symptoms, but few have been demonstrated to be effective in rigorous clinical trials.

Nonspecific Agents

A variety of “adsorbents” have been used in treating diarrhea. For example, activated charcoal has been found to be ineffective in the treatment of diarrhea. Kaolin and pectin have been widely used for diarrhea. While the combination appears to give the stools more consistency, it has not been shown to decrease cramps and frequency of stools or to shorten the course of infectious diarrhea. Lactobacillus preparations and yogurt have also been advocated, but no evidence supports use of these treatments for TD.

Bismuth subsalicylate preparation (1 oz of liquid or two 262.5-mg tablets every 30 minutes for eight doses) decreased the frequency of stools and shortened the duration of illness in several placebo-controlled studies. Treatment was limited to 48 hours at most, with no more than eight doses in a 24-hour period. There is concern about taking large amounts of bismuth and salicylate without supervision, especially for people who might be intolerant of salicylates, who have renal insufficiency, or who take salicylates for other reasons.

Antimotility Agents

Antimotility agents are widely used in treating diarrhea of all types. Natural opiates (paregoric, tincture of opium, and codeine) have long been used to control diarrhea and cramps. Synthetic agents, such as diphenoxylate and loperamide, come in convenient dosage forms and provide prompt symptomatic but temporary relief of uncomplicated TD. However, they should not be used by people with high fever or with blood in the stools. Use of these drugs should be discontinued if symptoms persist >48 hours. Diphenoxylate and loperamide should not be used in infants <2 years of age.

Antimicrobial Treatment

Travelers who have diarrhea with three or more loose stools in an 8-hour period, especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in the stools, might benefit from antimicrobial treatment. A typical 3- to 5-day illness can often be shortened to 1 to 1 1/2 days by effective antimicrobial agents. The effectiveness of antibiotic therapy will depend on the etiologic agent and its antibiotic sensitivity. The antibiotic regimen most likely to be effective is ciprofloxacin (500 mg) taken twice a day. Other fluoroquinolones, such as norfloxacin, ofloxacin, or levofloxacin, might be equally effective. Fewer side effects and less widespread antibiotic resistance have been reported with the fluoroquinolones than with TMP/SMX. Three days of treatment is recommended, although less than three days might be sufficient. Nausea and vomiting without diarrhea should not be treated with antimicrobial drugs. There is no contraindication to using an antimotility agent along with an antibiotic for TD, as long as there is no high fever or blood in the stool.

Travelers should be advised to consult a physician rather than attempt self-medication if the diarrhea is severe or does not resolve within several days; if there is blood or mucus, or both, in the stools; if fever occurs with shaking chills; or if there is dehydration with persistent diarrhea.

Oral Fluids

Most cases of diarrhea are self-limited and require only simple replacement of the fluids and salts lost in diarrheal stools. Fluid replacement is best achieved by use of an oral rehydration solution such as World Health Organization oral rehydration salts (ORS) solution (Table 4–2). This solution is appropriate for treating as well as preventing dehydration. Travelers should be advised that ORS packets are available at stores or pharmacies in almost all developing countries. ORS is prepared by adding one packet to boiled or treated water. Packet instructions should be checked carefully to ensure that the salts are added to the correct volume of water. ORS solution should be consumed or discarded within 12 hours if held at room temperature or 24 hours if kept refrigerated.

Travelers should be advised to avoid iced drinks and noncarbonated bottled fluids made from water of uncertain quality. Dairy products aggravate diarrhea in some people, and travelers with diarrhea should be advised to avoid them.

Infants with Diarrhea

Infants 2 years of age or younger are at high risk for acquiring TD. The greatest risk to the infant with diarrhea is dehydration (Table 4–3). Travelers should be advised that dehydration is best prevented by use of the WHO ORS solution in addition to the infant's usual food. ORS packets are available at stores or pharmacies in almost all developing countries. ORS is prepared by adding one packet to boiled or treated water. Travelers should be advised to check packet instructions carefully to ensure that the salts are added to the correct volume of water. ORS solution should be consumed or discarded within 12 hours if held at room temperature or 24 hours if kept refrigerated. A dehydrated child will drink ORS avidly; travelers should be advised to give it to the child as long as the dehydration persists. An infant who vomits the ORS will usually keep it down if it is offered by spoon in frequent small sips. Breast-fed infants should continue nursing on demand. For bottle-fed infants, full-strength, lactose-free or lactose-reduced formulas should be administered. Older infants and children receiving semisolid or solid foods should continue to receive their usual diet during the illness. Recommended foods include starches, cereals, yogurt, fruits, and vegetables. Immediate medical attention is required for the infant with diarrhea who has signs of moderate to severe dehydration (Table 4–3), bloody diarrhea, >30° C (>102° F) fever, or persistent vomiting. While medical attention is being obtained, the infant should be offered ORS.

More information is available from CDC in a publication entitled “The Management of Acute Diarrhea in Children: Oral Rehydration, Maintenance, and Nutritional Therapy” (MMWR No. RR-16, October 16, 1992). ORS packets are available in the United States from Jianas Brothers Packaging Company, 2533 Southwest Boulevard, Kansas City, Missouri 64108 (1-816-421-2880).

In addition, Cera Products, 8265 I Patuxent Range Road, Jessup, Maryland 20794 (1-410-997-2334 or 1-888-CERALYTE), markets a cereal- rather than glucose-based product, Ceralyte, in several flavors.

Precautions for Children and Pregnant Women

Although infants and children do not make up a large proportion of travelers to high-risk areas, some children do accompany their families. Teenagers should follow the advice given to adults, with possible adjustments of doses of medication. Physicians should be aware of the risks of tetracyclines for infants and children <8 years of age. Few data are available about the use of antidiarrheal drugs in infants and children. Drugs should be prescribed with caution for pregnant women and nursing mothers.

— Caryn Bern, Barbara Herwaldt, Phyllis Kozarsky, Stephen Luby, James Maguire