An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)*†

STATEMENT ON TRAVELLERS' DIARRHEA

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PREAMBLE

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to tropical infectious disease and health risks associated with international travel. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

INTRODUCTION

Diarrhea is the most common medical problem affecting travellers to developing countries⁽¹⁾. Episodes of travellers’ diarrhea usually begin abruptly, either during travel or soon after returning home, and are generally self-limited. The most important determinant of risk is the travel destination and the type of travel (five-star accommodations vs. backpacking). Although usually mild, travellers’ diarrhea can adversely affect the quality of a vacation or the success of a business trip. Concern about the incidence of diarrhea in high-risk destinations may also impose limitations on travellers’ itineraries. The estimated economic impact of travellers’ diarrhea is significant.

EPIDEMIOLOGY

Travellers’ diarrhea can be a debilitating illness, and may be particularly difficult to manage in remote or unfamiliar surroundings. Up to 50% of travellers from developed to developing countries can expect to have at least one episode of acute diarrhea during a 2-week stay, with 20% being confined to bed for a day^(2,3). The risk of travellers’ diarrhea is not uniform throughout the developing world. For example, in the Caribbean, Eastern and Southern Europe the risk varies from 15% to 20% whereas in Africa, Southeast Asia, and Latin America it ranges from 20% to 50%⁽³⁾. Although travellers’ diarrhea can be caused by both food- and waterborne pathogens, most cases are due to food contaminated with enterotoxigenic bacteria. Factors that may be associated with a higher probability of acquiring travellers’ diarrhea include adventurous eating habits, gastric hypochlorhydria^(4,5), immunodeficiency diseases, and the relative lack of gut immunity seen in younger individuals⁽¹⁾.

FOOD

Contaminated food is the common cause of travellers’ diarrhea, and enterotoxigenic Escherichia coli (ETEC), is most frequently associated with foodborne transmission. However, recent outbreaks of ETEC on cruise ships highlight the possibility of waterborne transmission as well⁽⁶⁾. There are numerous opportunities in developing countries for food to become contaminated including the fertilization of crops with human fecal material, inadequate storage and transport of food, unreliable refrigeration, lack of pasteurization, and unhygienic food handling practices. No food group can be regarded as “safe” and the sources of foodborne illness can be numerous including poorly cooked meat, contaminated raw vegetables, or unpasteurized dairy products. Even adequately cooked foods can become contaminated if allowed to stand for several hours at ambient temperatures, since many such foods are essentially ideal bacterial culture media. Flies may be important vectors of some foodborne enteric pathogens. The highest risk food items include custards^(7,8), mousses⁽⁹⁾, potato salads^(10,11), hollandaise sauce⁽¹²⁾, mayonnaise⁽¹³⁾, and seafood⁽¹⁴⁾. Although eating food purchased from street vendors can enhance cross-cultural experiences, the inadequate sanitary facilities and poor refrigeration typical of such food stalls carries an increased risk of travellers’ diarrhea⁽¹⁵⁾. Even compulsive peeling and washing of fruits and vegetables may not be a guarantee of safety, since they are sometimes injected with contaminated water to increase their weight and hence, their value.

WATER

Waterborne diarrheal illness usually results from the ingestion of viruses and parasites in water contaminated by human or agricultural fecal waste. The lesser importance of water as a cause of travellers’ diarrhea is likely due to the relatively lower concentration of contaminating organisms in liquid versus solid foods. Although commercially bottled water is generally safe, the unscrupulous practice of selling tap water as “safe, purified, bottled water” is not uncommon in some regions of the world. Carbonated beverages are generally too acidic
to sustain enteric pathogens and are therefore safe to drink⁽¹⁶⁾. The processes involved in the making of beer and other alcohol-containing drinks usually ensures that these beverages are also free of enteric pathogens⁽¹⁷⁾. However, the ice cubes that are frequently added to carbonated and alcoholic beverages are often made from potentially contaminated tap water⁽¹⁸⁾. Freezing water may in fact act as a preservative for some enteric pathogens. The risk of travellers’ diarrhea from brushing teeth with tap water is probably small due to the low inoculum of organisms and the possible antibacterial properties of toothpaste⁽¹⁹⁾. Swallowing water while taking showers or swimming in chlorinated pools likely carries a lower risk due, once again, to the low inoculum of organisms.

ETIOLOGY

Bacterial pathogens, with incubation periods measured in days, cause > 80% of cases of travellers’ diarrhea⁽²⁰⁾. The most commonly isolated organisms include Escherichia coli, primarily enterotoxigenic strains (ETEC), Campylobacter jejuni, Salmonella species, and Shigella species. A variety of other less commonly isolated bacteria include Aeromonas, Plesiomonas, and Yersinia species as well as non-cholera vibrios, and rarely Vibrio cholerae⁽²¹⁾. Clostridium difficile is an infrequent cause of travellers’ diarrhea that must always be considered in those taking doxycycline for malaria prophylaxis or using antibiotics for other reasons⁽²²⁾. Although rarely identified, parasitic pathogens that can cause travellers’ diarrhea with incubation periods of up to 1 to 2 weeks, include Giardia lamblia, Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica and rarely Microspora species, primarily Enterocytozoon bieneusi^(23-25). Viruses, notably Norwalk and rotavirus, can also cause travellers’ diarrhea, sometimes with onset within hours of exposure⁽²³⁾.

Certain etiologies have strong epidemiologic associations such as ETEC in Latin America⁽²⁶⁾, Campylobacter jejuni in Southeast Asia and North Africa⁽²⁷⁾, Vibrio cholerae in India, Bangladesh, Ecuador, Peru, and Bali⁽²⁸⁾, Giardia lamblia in mountainous areas of North America, Russia and Nepal⁽²⁹⁾, Cryptosporidium parvum in Russia, and Cyclospora cayetanensis in Nepal⁽²⁹⁾. Such information is important to consider when recommending antimicrobial prophylaxis or empiric treatment of travellers’ diarrhea. Seasonality is also an important factor; for example, cyclosporiasis is found primarily during the summer months in Nepal and campylobacteriosis occurs more frequently in North Africa and Mexico in winter months, whereas ETEC is a summer disease in these countries.

Resistance to antimicrobial agents is an increasingly common problem in enteric bacterial isolates from developing countries. Resistance to tetracyclines and sulfonamides is almost universal⁽³⁰⁾. Resistance to fluoroquinolones is rapidly increasing, especially among Campylobacter species isolated from Southeast Asia^(31-33).

PREVENTION

Prevention strategies for travellers’ diarrhea include 1) education about the ingestion of safe food and beverages, 2) water purification, 3) chemoprophylaxis with nonantibiotic drugs or antibiotics, and
4) vaccines. Often ignored is the importance of frequent handwashing while travelling in developing countries. Although soap and water are not always available, commercially available waterless hand sanitizing agents are suitable, convenient alternatives.

FOOD CHOICES

The judicious choice of food and water with the adage to “boil it, cook it, peel it, or forget it” seems reasonable, but may often not be practical. Several studies have shown that few travellers are able to comply with strict dietary recommendations and some evidence has recently revealed no association between dietary mistakes and the incidence of travellers’ diarrhea⁽³⁴⁾. On the other hand, common sense would dictate that avoidance of potentially contaminated food and water should reduce exposure to large inocula of organisms. As foodborne illness is more prevalent than waterborne disease, particular attention should be given to the choice of foods. Foods that have been well cooked, recently cooked, and served piping hot are best. Salad bars, raw vegetables, fruits that cannot be easily cleaned (e.g., grapes, strawberries, raspberries), custards, mousses, mayonnaise, hollandaise sauce, and raw seafood are best avoided. Fruits and vegetables should be either freshly peeled or freshly cooked. Non-bottled fruit and vegetable juices, which may be diluted with contaminated water, should also be avoided. Raw lettuce, the main ingredient of most salads, is nearly impossible to clean properly and should not be eaten. Only pasteurized and properly refrigerated dairy products should be eaten. Raw and incompletely cooked fish and meat should be avoided. In the Caribbean and the South Pacific, care should also be taken with the ingestion of large reef fish such as snapper, barracuda, grouper, jack, and moray eel which carry the additional risk of Ciguatera poisoning^(35,36). Ciguatera toxin is heat stable and therefore not neutralized by cooking.

FLUID CHOICES

Safe beverages are readily available in developing countries and include carbonated soft drinks, carbonated bottled water, bottled fruit juices, alcoholic beverages without ice, and hot beverages such as tea and coffee. Commercially carbonated beverages are safe by virtue of their bactericidal acidic environment⁽¹⁶⁾. Noncarbonated commercially bottled water should be safe as long as the cap seal is intact. Beer is free of enteric pathogens⁽¹⁷⁾. Ice cubes should be regarded as potentially contaminated and best avoided⁽¹⁸⁾. Properly collected and stored rain water is usually safe to drink.

WATER PURIFICATION

Water purification may be achieved by heat, filtration, or chemical disinfection. Boiling is the most effective way of producing water that is safe to drink. Simply bringing water to a boil, irrespective of altitude, is sufficient to kill all of the common organisms that cause travellers’ diarrhea^(37,38). Small portable heater coils may be a practical way for travellers to boil small quantities of water for tea or coffee. Alternatively, carrying a water bottle along with a portable 0.5 - 1.0 litre traveller’s kettle with electrical outlet and current flexibility, is another inexpensive way to ensure a constant supply of purified water. If no other choices are available, tap water that is too hot to touch should also be relatively safe to drink once it has cooled.

Filters that exclude particles above a specified size (e.g., 0.2 microns) are effective against most bacteria and parasites, but do not protect against viral pathogens. Therefore, water filtration should, if possible, be followed by chemical decontamination with a halogen. Some water purification products combine a 0.2 micron filter with iodine-impregnated resins, although there is limited evidence to confirm their efficacy and they are expensive. Another purification method is the direct addition of a halogen such as iodine or chlorine. Adding iodine as a liquid or crystal to water rapidly eliminates bacterial, protozoal, and viral pathogens. Iodine treated water is often unpalatable, however the addition of orange juice crystals may improve the taste. Dehalogenation with vitamin C should be performed only after 30 minutes contact-time has elapsed. Chlorine, available as tablets or simply in commercial household bleach, is relatively ineffective against the cysts of Giardia lamblia and Cryptosporidium parvum^(39-41).

The choice of water purification method will vary according to the traveller’s itinerary and personal preferences. Travellers who are on long-term postings may prefer to boil their water as filters have finite life spans and chemically-treated water is often unpalatable. Most short-term travellers on business trips or resort holidays may prefer limiting themselves to commercially bottled beverages and portable, halogen-containing, water filters.

CHEMOPROPHYLAXIS

Chemoprophylaxis using bismuth subsalicylate and antimicrobials has been shown to be effective in preventing travellers’ diarrhea^(42,43). However, important issues deserving consideration include cost, drug interactions, drug side effects, antibiotic resistance, and alteration of normal bowel and vaginal flora. Although the use of prophylactic antibiotics in travellers can be cost-effective because of the expense incurred in changing travel plans⁽⁴⁴⁾, other investigators have concluded that self-treatment options have a more favourable cost:benefit ratio than antimicrobial prophylaxis except in selected high risk travellers⁽⁴⁵⁾ (see Therapy section below). Furthermore, when prescribing prophylactic antimicrobials, significant drug-induced adverse events must be considered, including severe allergic reactions such as Stevens-Johnson syndrome or anaphylaxis, as well as, photosensitivity reactions, candidal vaginitis, Clostridium difficile-associated diarrhea, and the emergence of antibiotic-resistant flora.

Prophylactic bismuth subsalicylate (Pepto-Bismol^®) has an efficacy of approximately 60% but must be administered four times daily⁽⁴⁶⁾ (Table 1). Bismuth subsalicylate should be avoided by persons with aspirin allergy, renal insufficiency, and gout, and by those taking anticoagulants, probenecid, or methotrexate. Caution should be exercised when using bismuth subsalicylate in children due to the potential risk of Reye syndrome. Bismuth subsalicylate has not been approved for children < 2 years of age.

Antibiotic prophylaxis is typically administered once daily (od) (Table 1), and although 70% - 95% efficacious^(47-49), it should only be considered in selected high risk short-term travellers such as:

• those for whom a brief illness cannot be tolerated (i.e., elite athletes, business or political travellers);
  
  
• those with increased susceptibility to travellers’ diarrhea due to achlorhydria, gastrectomy, or history of repeated severe travellers’ diarrhea;
  
  
• those who are immunosuppressed due to HIV infection with depressed CD4 count or other immunodeficiency states;
  
  
• those with chronic illnesses for whom there is an increased risk of serious consequences from travellers’ diarrhea (e.g., chronic renal failure, congestive heart failure, insulin dependent diabetes mellitus, inflammatory bowel disease).

Prophylactic antibiotics or bismuth subsalicylate should only be considered for short-term travel to a maximum of 3 weeks, with the possible exception of HIV positive persons who may require long-term prophylaxis for prolonged travel. Long-term travellers and those living in developing countries gradually develop immunity to some enteropathogens (over 12 to 24 months) and subsequently have fewer episodes of diarrhea. There is little convincing evidence that Lactobacillus or Saccharomyces boulardii preparations are useful for the prevention of travellers’ diarrhea^(50,51).

VACCINES

Although there are currently no effective vaccines available for the prevention of travellers’ diarrhea, immunoprevention for the most frequent cause, namely ETEC, could significantly reduce the incidence of disease. A killed, whole-cell vaccine against ETEC appears to be safe and efficacious^(52,53), but is not yet available. As well, a vaccine against Campylobacter jejuni is under development and may prove useful for travellers to Southeast Asia⁽⁵⁴⁾. Typhoid vaccine has a probable protective efficacy of 50% to 75% and is recommended for travellers who will have significant exposure to contaminated food and water, in smaller cities and villages or rural areas off the usual tourist routes. Two typhoid vaccines are currently available; a parenteral, inactivated Vi capsular polysaccharide vaccine and an oral (liquid or enteric-coated capsules) attenuated live vaccine Ty21a⁽⁵⁵⁾. Travellers who may be at increased risk for acquiring cholera such as health care professionals working in endemic areas, aid workers in refugee camps, and perhaps those travelling in remote areas where health care is not readily available may benefit from the live attenuated oral cholera vaccine. However, the risk of cholera for the vast majority of travellers is so low that cholera vaccination is not generally recommended⁽⁵⁶⁾.

THERAPY

Although life-threatening dehydration is rarely seen in adults with travellers’ diarrhea, fluid replacement is still of primary importance in managing all cases. Diarrhea-induced dehydration is more of a concern in children and elderly individuals but can usually be managed with oral rehydration solutions⁽⁵⁷⁾, either those widely available in developing countries or homemade (Table 2). Children < 2 years of age are at high risk of acquiring travellers’ diarrhea and of suffering subsequent dehydration⁽⁵⁸⁾. Instructions for commercially available oral rehydration salts, prepared using boiled or treated water, should be carefully followed. Oral rehydration solutions should be consumed or discarded within 12 hours if held at room temperature or 24 hours if kept refrigerated. The dehydrated child should continue to breast-feed on demand or, if bottle-fed, should be given full-strength lactose-free or lactose-reduced formulas. Recommended foods for older children with dehydration include starches (e.g., rice, noodles, potatoes), cereals, yogurt, fruits, and vegetables. Immediate medical attention is required for the infant with diarrhea who develops signs of moderate to severe dehydration such as sunken eyes, absence of tears, reduced amount of or concentrated urine, or > 5% loss in body weight. As well, infants with bloody diarrhea, fever > 38.9° C, or persistent vomiting should receive immediate medical attention.

For most adults with otherwise uncomplicated travellers’ diarrhea, hydration can be maintained with canned juices, carbonated soft drinks, purified water, or clear salty soups. Beverages containing caffeine are discouraged as they may increase gastrointestinal motility and fluid secretion. Dairy products, prune juice, orange juice, and apple juice may also aggravate diarrhea. Fluids should be consumed at a rate to allay thirst and maintain pale-coloured urine.

Adjunctive therapy may be aimed at reducing bowel motility or may be directed against bacterial toxins and/or against bacterial pathogens (Table 3). Antimotility agents are both safe and efficacious if judiciously used. Loperamide (Imodium^®) is probably the most effective antimotility agent available to reduce the duration and severity of diarrhea in mild to moderate cases of travellers’ diarrhea (i.e., minimal cramps, no fever, and no blood in the stools) in adults and children > 2 years of age⁽⁵⁹⁾. However, caution should be exercised when using antimotility agents in children as there is an increased risk of severe complications including toxic megacolon in infants < 2 years of age⁽⁶⁰⁾ and hemolytic uremic syndrome in children infected with Escherichia coli O157:H7⁽⁶¹⁾. Diphenoxylate (Lomotil^®) is not recommended as it may be habit-forming and has been associated with toxic megacolon in patients with bacterial dysentery⁽⁶²⁾.

Bismuth subsalicylate has antisecretory, antibacterial, and anti-inflammatory properties, and may reduce the severity and duration of travellers’ diarrhea when used as treatment⁽⁶³⁾. The principle disadvantages of bismuth subsalicylate therapy include delayed onset of action, frequent dosing, and interference with the absorption of doxycycline, sometimes taken by travellers as an antimalarial agent.

Self-administered antibiotic therapy with a fluoroquinolone or extended-spectrum macrolide (e.g., azithromycin) may be indicated for those with moderate to severe travellers’ diarrhea (Table 3).

Therefore, with few exceptions, travellers should carry a single dose or 3-day course of antibiotic as well as loperamide and a thermometer. Loperamide may be used as an adjunct to antibiotics in the treatment of moderate to severe travellers’ diarrhea. When given in combination with an antibiotic, loperamide may reduce the duration of diarrhea without increasing toxicities in patients with bacterial dysentery^(64-66).

Fluoroquinolones are currently the drugs of choice for the empiric treatment of travellers’ diarrhea⁽⁶⁷⁾ (Table 3). Ciprofloxacin has been shown to reduce the duration of diarrhea, relieve associated symptoms such as cramps, and reduce the number of liquid stools passed⁽⁶⁸⁾. Although single-dose regimens of fluoroquinolones can often provide equivalent relief compared to the standard 3-day regimens, significant failure rates have been documented with Shigella dysenteriae and Campylobacter-induced disease^(65,69). In countries such as Thailand, where fluoroquinolone resistance among Campylobacter species is almost universal, azithromycin is a more effective alternative⁽³²⁾. In unique circumstances where Cyclospora species are prevalent, such as Nepal during the summer months, and symptoms are suggestive of this infection, a more rational choice for empiric antimicrobial therapy for travellers’ diarrhea might be TMP-SMX (trimethoprim and sulfamethoxazole)⁽²⁹⁾. For children < 16 years of age, in whom fluoroquinolones are generally not recommended, azithromycin and cefixime^(70,71) are more appropriate agents of choice. However, in children with severe travellers’ diarrhea, the benefits of a quinolone antibiotic used for a 1 to 3-day course far outweigh the risks⁽⁷²⁾. In pregnancy, appropriate choices would include cefixime, and azithromycin. However, cefixime may not be ideal for the treatment of shigellosis in adults⁽⁷³⁾ and experience with the use of azithromycin in pregnancy is limited.

Any febrile traveller with diarrhea who has visited a malaria endemic area must have blood films performed immediately to rule out malaria. Patients with severe travellers’ diarrhea not responding to empiric therapy and those with severe underlying medical conditions, immunosuppression, or grossly bloody stools should be referred to a specialist for further evaluation. Travellers’ with persistent diarrhea lasting > 14 days, despite therapy, should be managed according to the CATMAT statement of persistent diarrhea in the returned traveller⁽⁷⁴⁾.

RECOMMENDATIONS

Table 4 presents evidence-based medicine categories for the strength and quality of the evidence for the recommendations that follow (Table 5).

EXPIRATION

This document will be updated every 3 years, or when new information becomes available.

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74. Committee to Advise on Tropical Medicine and Travel. Persistent diarrhea in the returned traveller. CCDR 1998;24(ACS-1):1-4.

* Members: Dr. B. Ward (Chairman); H. Birk; M. Bodie-Collins (Executive Secretary); Dr. S.E. Boraston; Dr. H.O. Davies; Dr. K. Gamble; Dr. L. Green; Dr. J.S. Keystone; Dr. P.J. Plourde; Dr. J.R. Salzman; Dr. D. Tessier.

Liaison Representatives: Dr. R. Birnbaum (CSIH); L. Cobb (CUSO); Dr. V. Marchessault (CPS and NACI); Dr. H. Onyette (CIDS); Dr. R. Saginur (CPHA); Dr. F. Stratton (ACE).

Ex-Officio Members: Dr. E. Callary (HC); Dr. M. Cetron (CDC); R. Dewart (CDC);
Dr. E. Gadd (HC); Dr. H. Lobel (CDC); Dr. A.E. McCarthy (DND); Dr. M. Parise (CDC).

Member Emeritus: Dr. C.W.L. Jeanes.

* This statement was prepared by Dr. P. Plourde and approved by CATMAT.

[Canada Communicable Disease Report]