Travel to destinations such as Latin America, Asia, Africa and the Middle East has never been more popular, with over 20 million travelers visiting a less developed country each year.1 Approximately one third (20 to 50 percent) of travelers to less developed areas of the world become ill from ingesting fecally contaminated food or water.2,3 In 10 to 20 percent of cases, fever and bloody stools (dysentery) occur.2
Although traveler's diarrhea usually resolves within three to five days (mean duration: 3.6 days), in about 20 percent of persons the illness is severe enough to cause bed confinement and in 10 percent of cases the illness lasts more than one week.3,4 In the very young and the very old, as well as in those who are immunocompromised, traveler's diarrhea can occasionally be life-threatening. It is important to realize, however, that traveler's diarrhea can be minimized by education about ways to prevent the disease. Physicians can do a great deal to ensure that their patients have a safe and enjoyable trip abroad.
Traveler's diarrhea is defined as three or more unformed stools in 24 hours in a person from an industrialized nation traveling in a less developed country. Unlike in the United States, where most diarrheal disease is viral in origin, in developing countries, bacterial infection is the cause of diarrhea in at least 80 percent of cases. Viral, protozoal or undetermined etiologies account for the remainder of cases. Enterotoxigenic Escherichia coli is the chief pathogen, accounting for 40 to 50 percent of cases.5 Other common bacterial causes include Campylobacter jejuni, Shigella, Salmonella, Aeromonas and Yersinia species, Plesiomonas shigelloides and Vibrio parahaemolyticus (Table 1). All of these agents are efficiently spread by the fecal-oral route and, in some cases, such as Shigella infections, a minute inoculum (as few as 10 to 100 organisms) is all that is necessary to produce disease.
|Enterotoxigenic Escherichia coli|
|Salmonella (non-typhoid) species|
|Vibrio (non-cholera) species|
Without stool cultures for identifying the pathogen in diarrheal illness, it is easy to confuse the symptoms of traveler's diarrhea with those of food poisoning produced by heat-stable, toxin-forming bacteria such as Staphylococcus aureus and Bacillus cereus or by the heat-labile toxin of Clostridium perfringens. In general, however, preformed toxins (Staphylococcus and Bacillus) produce symptoms within one to six hours, whereas infections (such as from Clostridium) that result in toxin formation in vivo cause symptoms within eight to 16 hours. Most invasive bacterial infections, on the other hand, become symptomatic after 16 hours.6
Viruses that are responsible for traveler's diarrhea in the tropics include rotavirus and Norwalk agents. Diarrhea caused by viral agents is usually self-limited.
The three major protozoal causes of traveler's diarrhea are Entamoeba histolytica, Giardia duodenalis and Cryptosporidium parvum. Diarrheal disease caused by these organisms is notable for its longer duration and failure to respond to routine antibiotic therapy.
Risk factors for traveler's diarrhea are listed in Table 2. Persons from a developing region who have relocated to an industrialized country and who then return to their country of origin are also at increased risk, especially since they seldom take precautions. Any “native resistance” is soon lost after relocation and subsequent alteration of the intestinal flora.
|Age <30 years|
|Unhygienic primitive environment|
|Reduced gastric acidity (i.e., resulting from histamine H2 blocker or proton pump inhibitor therapy)|
|Prior (> 6 months previously) residence in an undeveloped country|
Traveler's diarrhea is fundamentally a sanitation failure, leading to bacterial contamination of food and water. It is best prevented through proper sewage treatment and water disinfection. In the absence of these amenities, the next best option is for the educated traveler to take precautions to prevent the disease.
Preventive measures include not drinking tap water, not using ice in beverages (even alcoholic drinks), not eating salads and other forms of raw vegetables, not eating fruits that can't be peeled on the spot and not eating mayonnaise, pastry icing, unpasteurized dairy products and undercooked shellfish.
Tying a ribbon around the faucet and keeping purified bottled water near the sink may serve as memory aids for travelers to remind them not to use tap water, even for tooth brushing. Hot cooked food, fresh bread, dry foods such as crackers, bottled carbonated beverages, coffee, tea and beer are usually safe, provided such food items are not obtained from street vendors. Helpful maxims to keep in mind include “boil it, cook it, peel it or forget it” and the “rule of P's”: food is safe if it is peelable, packaged, purified or piping hot.3 Careful handwashing, most conveniently achieved with packaged wipes or antiseptic gel, is essential.
Active intervention involves boiling water for three to five minutes (depending on elevation), filtering water or using chlorine bleach (2 drops per quart) or tincture of iodine (5 drops per quart) in the water. Drawbacks with these methods of prevention include the need to allow sufficient time to disinfect the water, clogged filters, chlorine's incomplete effectiveness against some protozoal cysts and iodine's bad taste.7 Antibiotics (i.e., tetracyclines) added to the water may not destroy resistant bacteria and protozoal cysts. Fortunately, the wide availability of safe bottled water makes these cumbersome interventions unnecessary for all but the most remote destinations.
Table 3 summarizes the various drug therapies used for prophylaxis against traveler's diarrhea. Bismuth subsalicylate (Pepto-Bismol), in a dosage of two 262-mg tablets four times a day (taken with meals and in the evening) can prevent traveler's diarrhea. It has been shown to provide a 65 percent protection rate.8 Bismuth subsalicylate can be taken for up to three weeks. Such long-term use can, however, darken the tongue and stool, produce tinnitus and cause reactions in salicylate-sensitive patients. Bismuth subsalicylate also interferes with the absorption of doxycycline and certain other medications.8
|Bismuth subsalicylate (Pepto-Bismol), two 262-mg chewable tablets four times daily, taken with meals and once in the evening|
|Ciprofloxin (Cipro), 500 mg once daily|
|Norfloxacin (Noroxin), 400 mg once daily|
|Ofloxacin (Floxin), 300 mg once daily|
|Doxycycline (Vibramycin), 100 mg once daily|
|Trimethoprim-sulfamethoxazole (Bactrim DS), 160 mg/800 mg once daily|
Compared with bismuth subsalicylate, antibiotic prophylaxis with trimethoprim-sulfamethoxazole (Bactrim DS), in a dosage of 160 mg/800 mg daily, or doxycycline (Vibramycin), in a dosage of 100 mg daily, has been found to provide even better results for up to three weeks.8 Increasingly, however, resistance to these antibiotics has become such a problem that their routine use is not recommended. For instance, trimethoprim-sulfamethoxazole continues to be effective prophylaxis for summertime travel in inland Mexico, but it is unreliable in many other situations.2 Although fluoroquinolones such as ciprofloxacin (Cipro) may be the best alternatives to trimethoprim-sulfamethoxazole and doxycycline, resistance to fluoroquinolones is developing too rapidly to justify their continued use for prophylaxis against traveler's diarrhea.
Antibiotic prophylaxis for traveler's diarrhea, always a controversial topic, is now recommended only in specific situations, such as in the seriously immunocompromised patient or the seriously ill patient who would not be able to withstand a diarrheal illness. If antibiotic prophylaxis is used, the antibiotic should only be taken for a three-week period. Other exceptions may include persons who plan short-term critical travel, such as a diplomatic mission, or persons who are unable to practice prevention.
In most people, drug prophylaxis engenders a false sense of security. In addition, drug prophylaxis always carries the remote risk of a potentially life-threatening side effect such as pseudomembranous colitis or Stevens-Johnson syndrome. Nuisance side effects such as vaginal yeast infections and, with doxycycline, photosensitivity, are common. Therefore, the Centers for Disease Control and Prevention recommends preventive measures only and not drug prophylaxis for most travelers. If diarrhea occurs despite precautions, however, a self-treatment contingency plan is reasonable.
Mild traveler's diarrhea can usually be managed with the judicious use of antimotility agents such as loperamide (Imodium A-D), in a dosage of two 2-mg tablets initially, then one tablet after each loose stool (maximum 24-hour dosage: 8 mg). Additionally, a single dose of ciprofloxacin—750 mg; levofloxacin (Levaquin)—500 mg; or ofloxacin (Floxin)—400 mg, usually relieves mild cases of traveler's diarrhea in less than 24 hours.9
The use of antimotility agents has traditionally been avoided in patients with dysentery, where decreased gut motility would be inadvisable. Moderate to severe traveler's diarrhea, including dysentery, can be empirically treated with a three-day course of a fluoroquinolone such as ciprofloxacin, norfloxacin (Noroxin) or ofloxacin (Table 4). Loperamide may also be taken if the patient does not have dysentery. Before beginning antibiotic therapy, however, patients should first take a dose of loperamide to see if the antimotility agent stops the diarrhea. Antibiotic therapy should be deferred until it is clear that the diarrheal illness requires antibiotic therapy, since dietary change and stress can cause transient gastrointestinal upset.2 A single antibiotic dose may be effective for mild traveler's diarrhea, and patients should reassess their condition in 12 hours to determine if further doses are necessary.10
|Ciprofloxacin (Cipro), 500 mg twice daily for one to three days, or one 750-mg dose (if diarrhea resolves)|
|Norfloxacin (Noroxin), 400 mg twice daily for one to three days|
|Ofloxacin (Floxin), 300 mg twice daily for one to three days|
|Trimethoprim-sulfamethoxazole (Bactrim DS), 160 mg/800 mg twice daily for three days|
|Doxycycline (Vibramycin), 100 mg twice a day for three days|
Ciprofloxacin is not recommended in patients with seizure disorders, in patients who are pregnant and in children under 18 years of age. Children older than two years of age can be given trimethoprim-sulfamethoxazole. Children under two years of age and pregnant women can be treated with an oral rehydration solution. Older children and other adults with traveler's diarrhea also would benefit from oral rehydration, possibly supplemented with salted soda crackers. Commercially available packets of oral rehydration solution can be reconstituted with safe water.
If treatment with a fluoroquinolone fails to resolve the diarrhea, several other diagnostic possibilities should be considered. Protozoal infections and pseudomembranous colitis must be excluded. In addition, infection from an antibiotic-resistant organism is now a third and increasingly probable explanation for continued diarrhea. Azithromycin (Zithromax), in a dosage of 500 mg daily for three days, has been found to be very effective in treating resistant Campylobacter enteritis contracted in Thailand, and its usefulness in other situations of fluoroquinolone resistance merits investigation.11
Patients should be told to consult a physician if diarrhea does not respond to the planned regimen, especially if high fever or bloody stools are present. Patients should also be warned to avoid over-the-counter anti-diarrheals such as iodochlorhydroxyquinoline (Entero-Vioform), which has been withdrawn from the U.S. market because of its association with myelooptic atrophy. This agent, however, may still be available outside this country.
Public Health Issues
Even with the emphasis now placed on pre-cautionary measures to prevent traveler's diarrhea rather than drug prophylaxis, the treatment of traveler's diarrhea will be increasingly hampered by antibiotic resistance. Multidrug-resistant Shigella and Salmonella strains are now so common that it is only a matter of time until they also become resistant to fluoroquinolones. Some respite may be provided by the most recently developed fluoroquinolones and azithromycin, but eventually a new approach will be necessary.
One future option might be nonabsorbable antimicrobial drugs such as bicozamycin, furazolidone (Furoxone), aztreonam and rifaximin, which have already shown some benefit in the treatment of traveler's diarrhea. Bicozamycin might also be an effective prophylactic agent that would treat only the gastrointestinal tract and, therefore, be more acceptable from the standpoint of safety.2 Although not yet marketed in the United States, zaldaride, a new type of drug called a calmodulin inhibitor, is a promising treatment.10
Use of biotherapeutic agents made of microorganisms that suppress pathogenic infection is another option. Lactobacillus casei and Saccharomyces boulardii, a nonpathogenic yeast, have been studied as prophylactic agents in travel scenarios, but the results have been inconsistent. The use of these organisms to treat other types of diarrhea has been encouraging, and improvements in bioengineered forms of these organisms may in the future yield an alternative to antibiotics.12
Immunoprophylaxis by means of oral vaccines may become a third alternative to systemic antibiotics. Vaccines have already been developed for typhoid, enterotoxigenic E. coli and cholera (the latter two are not yet available in the United States). Shigella and Campylobacter vaccines are in the development stage, and a pediatric rotavirus vaccine has recently been labeled. A combination, or “super,” vaccine could be an effective way to reduce the most common types of traveler's diarrhea. The limiting factor is the vast array of potential pathogens that cannot be included in any single vaccine.3,10
The most sensible, yet most problematic, approach to preventing traveler's diarrhea is to eliminate the basic problem of poor hygiene and water contamination through sanitary engineering, public education and, most importantly, the development of a safe water supply. Unfortunately, much of the developing world is in a “Catch-22” situation: poverty and unclean water hinder the tourism and investment money needed to correct these problems. Progress through international aid and economic development is difficult, but in an increasing number of transitional nations, such as Thailand, economic growth has reduced the country's risk profile in less than a decade. Ultimately, the elimination of poverty, and not new drugs, will resolve the problem of traveler's diarrhea.