Description

Travelers’ diarrhea (TD) is a clinical syndrome resulting from microbial contamination of ingested food and water; it occurs during or shortly after travel, most commonly affecting persons traveling from an area of more highly developed hygiene and sanitation infrastructure to a less developed one. Thus, TD is defined more by circumstances of acquisition than by a specific microbial agent. In fact, there is considerable diversity in etiologic agents, which include bacteria, parasites, or viruses. A similar but less common syndrome is toxic gastroenteritis, caused by ingestion of pre-formed toxins. In this syndrome, vomiting may predominate, and symptoms usually resolve within 12-18 hours.

Pathogen isolation rates among TD studies vary from 30% to 60%. Most cases in which no pathogen is identified respond to antibiotics, suggesting that most of these are bacterial in origin (1).

BACTERIAL ENTERIC PATHOGENS

Bacteria are the most common cause of TD. In studies of etiologic agents at various destinations, bacteria are responsible for approximately 80%-85% of TD cases, parasites about 10%, and viruses 5% (2).

Enterotoxigenic Escherichia coli (ETEC)

The most common cause of TD worldwide is ETEC (3). Ingestion of a large inoculum of this organism is necessary to produce disease. These high inoculums occur when there is a breakdown in sanitation, which is often the case in developing countries where ETEC infections are common. ETEC typically produces watery diarrhea associated with cramps. Fever may be low grade or absent.

Enteroaggregative E. coli (EAEC)

EAEC are increasingly recognized as a cause of TD and may be responsible for up to 25% of cases (4). EAEC resemble ETEC in clinical presentation and response to antibiotics.

Campylobacter jejuni

Campylobacter jejuni is a common cause of diarrhea in developed countries but is many times more prevalent in developing countries (5). The risk of acquiring infection with Campylobacter appears to vary by destination, with travel to Asia posing a higher risk in most studies. Campylobacter infections may be associated with bloody diarrhea as well as fever.

Salmonella spp.

Although nontyphoidal Salmonella infections are frequently associated with foodborne outbreaks in industrialized countries, they are an infrequent cause of TD worldwide (6).

Shigella spp.

The low infectious dose of this organism makes it one of the more commonly reported bacteria associated with TD (7). Shigella may cause a bloody diarrhea with constitutional symptoms and fever.

Vibrio spp.

Diarrhea caused by Vibrio parahaemolyticus and non-O-group 1 Vibrio cholerae may be associated with eating raw or partially cooked seafood. Vibrio cholerae O-group 1 has in general been a rare cause of TD, but recent reports suggest this organism may be associated with the typical TD clinical picture in Western travelers to developing countries (8).

Other Bacteria

Other organisms that have been isolated from patients with TD include Aeromonas hydrophila, Plesiomonas shigelloides, Yersinia enterocolitica, and enterotoxigenic Bacteroides fragilis (9).

PARASITIC ENTERIC PATHOGENS

Parasitic protozoan pathogens account for about 10% of cases of TD, which usually present with a more insidious onset (10). Travelers often complain of persistent symptoms, and the likelihood of recovery of a parasite rather than bacteria from stool specimens increases proportionately with duration of symptoms. The most common organisms in this category include Giardia intestinalis, Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica, and Dientamoeba fragilis.

VIRAL ENTERIC PATHOGENS

The contribution of viruses to the burden of TD appears to be quite small, although they can cause substantial morbidity from gastroenteritis, with primarily nausea and vomiting (11). Sporadic viral infections account for 5%-10% of cases of TD. Enteric viruses such as rotavirus and norovirus, which infect children in developing countries, may also infect travelers to developing countries. Outbreaks of norovirus have been reported on cruise ships (see Chapter 7). In such outbreaks, a high percentage of susceptible people are likely to become ill.

Occurrence

The most important determinant of risk is travel destination, and there are regional differences in both the risk and etiology of diarrhea (12). The world map is generally divided into three grades of risk: high, intermediate, and low. (See map 4-12). 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, and Central and South America. Some destinations that were previously considered high risk have now been classified as low or intermediate risk, including parts of Southern Europe and some of the Caribbean islands.

Risk for Travelers

Travelers’ diarrhea occurs equally in males and females and is more common in young adults than in older people. In short-term travelers, bouts of TD do not appear to protect against future attacks, and more than one episode of TD may occur during a single trip. On average, 30%-50% of travelers to high-risk areas will develop TD during a 1- to 2-week stay. Based on the annual figure of 50 million travelers to developing countries, this estimate translates to approximately 50,000 cases of TD each day. In more temperate regions, there may be seasonal variations in diarrhea risk. In South Asia, for example, during the hot months preceeding the monsoon, much higher TD attack rates are commonly reported.

Clinical Presentation

Definitions of TD that rely on rigid criteria for frequency of loose stools in a 24-hour period are commonly used in clinical research studies but are not relevant to the clinical syndrome as it affects travelers. Travelers’ diarrhea is characterized by the fairly abrupt onset of loose, watery or semi-formed stools associated with abdominal cramps and rectal urgency. Symptoms may be preceded by a prodrome of gaseousness and abdominal cramping, and additional symptoms, such as nausea, bloating, and fever, may be associated. Vomiting may occur in up to 15% of those affected. Travelers’ diarrhea is generally self-limited and lasts 3-4 days even without treatment, but persistent symptoms may occur in a small percentage of travelers. Medical attention should be sought for diarrhea accompanied by a high fever or blood. Postinfectious sequelae have been described, including reactive arthritis, Guillain-Barré syndrome, and postinfectious irritable bowel syndrome (PI-IBS). PI-IBS may occur in up to 3% of persons who contracted travelers’ diarrhea (13).

Prevention

For travelers to high-risk areas, several approaches may be recommended, which can minimize but never completely eliminate the risk of TD. These include 1) instruction regarding food and beverage selection, 2) use of agents other than antimicrobial drugs for prophylaxis, and 3) use of prophylactic antibiotics. Travelers should also be reminded to wash their hands with soap and water prior to eating or meal preparation.

Care in selecting food and beverages for consumption may minimize the risk for acquiring TD (12). Travelers should be advised to eat foods that are freshly cooked and served piping hot and to avoid water and beverages diluted with non-potable water (reconstituted fruit juices, ice, and milk) and foods washed in non-potable water, such as salads. Other risky foods include raw or undercooked meat and seafood and raw fruits and vegetables. Safe beverages include those that are bottled and sealed or carbonated. Boiled beverages and those appropriately treated with iodine or chlorine might also be safely consumed. Studies of TD risk at high-risk destinations show that consumption of food or beverages from street vendors poses a particularly high risk, and some studies suggest certain food items, such as reheated prepared foods or buffet items are also high risk.

Although food and water precautions continue to be recommended, travelers may have difficulty following this advice. Furthermore, many of the factors that ensure food safety are out of the traveler’s control.

The primary agent other than antimicrobial drugs studied for prevention of TD is bismuth subsalicylate (BSS), which is the active ingredient in Pepto-Bismol. Studies from Mexico have shown this agent (taken on arrival at the destination as either 2 oz of liquid or two chewable tablets four times per day) reduces the incidence of TD from 40% to 14% (14). 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. Caution should be used in administering BSS to children with viral infections, such as varicella or influenza, because of the risk of Reye syndrome. BSS is not recommended for children younger than 3 years of age. Studies have not established the safety of BSS use for periods longer than 3 weeks.

The use of probiotics, such as Lactobacillus GG and Saccharomyces boulardii, has been studied in the prevention of TD in limited numbers of subjects. Results are inconclusive (15).

Travelers should be cautioned that other nonantimicrobial agents, such as enterovioform and related halogenated hydroxyquinoline derivatives, are sometimes available to travelers at their destination. These substances are not useful in preventing TD, may cause serious neurologic adverse events, and should never be used for prophylaxis.

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 ideal antibiotic is one to which the pathogenic bacteria are sensitive, which has changed over the past few decades as resistance patterns have evolved (16). Agents such as TMP-SMX and doxycycline are no longer considered effective antimicrobial agents against enteric bacterial pathogens. The fluoroquinolones have been the most popular and effective antibiotics for the prophylaxis and treatment of bacterial TD pathogens, but increasing resistance to these agents, initially among Campylobacter species and now among other TD pathogens, may limit their benefit in the future. A newly approved nonabsorbable antibiotic, rifaximin, is being investigated for its potential use in TD prophylaxis (17). At this time prophylactic antibiotics should not be recommended for most travelers. In addition to affording no protection against nonbacterial pathogens, they may also give the traveler a false sense of security, leading to neglect of the food and water precautions that might protect against other enteric diseases. In addition, the use of antibiotics may be associated with allergic or adverse reactions in a certain percentage of travelers, an unnecessary occurrence, as early self-treatment with antibiotics for established TD is still quite effective.

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 their trip.

Treatment

Antibiotics are the principal element in the treatment of TD. Adjunctive agents used for symptomatic control may also be recommended.

ANTIBIOTICS

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 (12). The benefit of treatment of TD with antibiotics has been proven in a number of 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 and Nepal. 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 (17).

The standard treatment regimens consist of 3 days of antibiotic, although when treatment is initiated promptly, shorter courses, including single-dose therapy, may reduce the duration of the illness to a few hours.

NONSPECIFIC AGENTS

Bismuth subsalicylate (BSS or Pepto-Bismol), taken as 1 oz of liquid or two chewable tablets every 30 minutes for eight doses, has been shown to decrease stool frequency and shorten the duration of illness in several placebo-controlled studies (14). This agent has both antisecretory and antimicrobial properties. BSS should be used with caution in travelers on aspirin therapy or anticoagulants or those who have renal insufficiency. In addition, BSS should be avoided in children with viral infections, such as varicella or influenza, because of the risk of Reye syndrome.

Other nonspecific agents, such as kaolin pectin, activated charcoal, and probiotics, have had a limited role in the treatment of TD.

ANTIMOTILITY AGENTS

Antimotility agents provide symptomatic relief and serve as useful adjuncts to antibiotic therapy in TD (12). Synthetic opiates, such as loperamide and diphenoxylate, can reduce bowel movement frequency and enable travelers to resume their activities while awaiting the effects of antibiotics. Loperamide appears to have antisecretory properties as well. These agents should not be used by travelers in diarrheal illness associated with high fever or blood in the stool, rather they should seek medical attention. Loperamide and diphenoxylate are not recommended for children <12 years of age.

ORAL REHYDRATION THERAPY

Fluid and electrolytes are lost in cases of TD, and replenishment is important, especially in young children or adults with chronic medical illness (18). In adult travelers who are otherwise healthy, severe dehydration resulting from TD is unusual unless vomiting is present. Nonetheless, replacement of fluid losses remains an important adjunct to other therapy. Travelers should remember to use only beverages that are sealed or carbonated. For more severe fluid loss, replacement is best accomplished with oral rehydration solutions (ORS), such as World Health Organization ORS solutions, which are widely available at stores and pharmacies in most developing countries. (See Table 4-20 for details.) ORS is prepared by adding one packet to the appropriate volume of boiled or treated water. Once prepared, solutions should be consumed or discarded within 12 hours (24 hours if refrigerated).

TREATMENT OF TD CAUSED BY PROTOZOA

The most common parasitic cause of TD is Giardia intestinalis, and treatment options include metronidazole, tinidazole, and nitazoxanide (10). Although cryptosporidiosis is usually a self-limited illness in immunocompetent persons, nitazox-anide can be considered as a treatment option. Cyclosporiasis is treated with TMP-SMX. 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 may be expected to have TD as well (19). There is no reason to withhold antibiotics from children who contract TD. In older children and teenagers, treatment recommendations for TD follow those for adults, with possible adjustments in dose of medication. Macrolides such as azithromycin are considered first-line antibiotic therapy in children, although some experts are using short-course fluoroquinolone therapy with caution for travelers younger than 18 years of age. Rifaximin is approved for use starting at age 12. Loperamide and diphenoxylate are not recommended for children younger than 12 years of age.

Infants and younger children are at higher risk for developing dehydration from TD, which is best prevented by the early use of ORS solutions. Breastfed infants should continue to nurse on demand, and bottle-fed infants should be offered full-strength lactose-free or -reduced formula. Older infants and children should continue their regular diets during the illness (see Chapter 8).

References

1. Steffen R. Epidemiology of travellers’ diarrhoea. Scand J Gastroenterol Suppl. 1983;84:5-17.
2. Black RE. Epidemiology of travelers’ diarrhea and relative importance of various pathogens. Rev Infect Dis. 1990;12(suppl 1):S73-S79.
3. Jiang ZD, Mathewson JJ, Ericsson CD, Svennerholm AM, Pulido C, DuPont HL. Characterization of enterotoxigenic Escherichia coli strains in patients with travelers’ diarrhea acquired in Guadalajara, Mexico, 1992-1997. J Infect Dis. 2000;181:779-82.  
4. Adachi JA, Jiang ZD, Mathewson JJ, Verenkar MP, Thompson S, Martinez-Sandoval F, et al. Enteroaggregative Escherichia coli as a major etiologic agent in traveler’s diarrhea in 3 regions of the world. Clin Infect Dis. 2001;32:1706-9.  
5. Allos BM. Campylobacter jejuni infections: update on emerging issues and trends. Clin Infect Dis. 2001;32:1201-6.  
6. von Sonnenburg F, Tornieporth N, Waiyaki P, Lowe B, Peruski LF Jr, DuPont HL, et al. Risk and aetiology of diarrhoea at various tourist destinations. Lancet. 2000;356:133-4.
7. Sharp TW, Thornton SA, Wallace MR, Defraites RF, Sanchez JL, Batchelor RA, et al. Diarrheal disease among military personnel during Operation Restore Hope, Somalia, 1992-1993. Am J Trop Med Hyg. 1995;52:188-93.  
8. Taylor DN, Rizzo J, Meza R, Perez J, Watts D. Cholera among Americans living in Peru. Clin Infect Dis. 1996;22:1108-9.  
9. Pathela P, Hasan KZ, Roy E, Alam K, Huq F, Siddique AK, et al. Enterotoxigenic Bacteroides fragilis-associated diarrhea in children 0-2 years of age in rural Bangladesh. J Infect Dis. 2005;191: 1245-52.
10. Shlim DR. Update in traveler’s diarrhea. Infect Dis Clin North Am. 2005;19:137-49.
11. Widdowson M, Monroe SS, Glass RI. Are noroviruses emerging? Emerg Infect Dis. 2005;11:735-7.
12. DuPont HL, Ericsson CD. Prevention and treatment of traveler’s diarrhea. N Engl J Med. 1993;328:1821-37.
13. Connor BA. Sequelae of traveler’s diarrhea: focus on postinfectious irritable bowel syndrome. Clin Infect Dis. 2005;41:S577-86.
14. DuPont HL. Prevention of travelers’ diarrhea by the tablet formulation of bismuth subsalicylate. JAMA. 1987;257:1347-50.
15. Hilton E, Kalakowski P, Singer C, Smith M. Efficacy of Lactobacillus GG as a diarrheal preventive in travelers. J Trav Med. 1997;4:41-3.
16. Hoge CW, Gambel JM, Srijan A, Pitarangsi C, Echeverria P. Trends in antimicrobial resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis. 1998;26:341-5.
17. DuPont HL, Jiang ZD, Ericsson CD, Adachi JA, Mathewson JJ, DePont MW, et al. Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized double blind clinical trial. Clin Infect Dis. 2001;33:1807-15.
18. Greenough WB. Oral rehydration therapy: something new, something old. Infect Dis Clin Pract. 1998;7:97-100.
19. Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of travelers’ diarrhea in infants and children. Pediatr Infect Dis J. 1991;10:719-23.

BRADLEY A. CONNOR

MAP 4-12 Areas of risk for travelers’ diarrhea.

TABLE 4-20. Composition of WHO Oral Rehydration Solution (ORS) for diarrheal illness