Loperamide

Acute diarrhea affects millions of persons who travel to developing countries each year. Food and water contaminated with fecal matter are the main sources of infection. Bacteria such as enterotoxigenic Escherichia coli, enteroaggregative E. coli, Campylobacter, Salmonella, and Shigella are common causes of traveler's diarrhea. Parasites and viruses are less common etiologies. Travel destination is the most significant risk factor for traveler's diarrhea. The efficacy of pretravel counseling and dietary precautions in reducing the incidence of diarrhea is unproven. Empiric treatment of traveler's diarrhea with antibiotics and loperamide is effective and often limits symptoms to one day. Rifaximin, a recently approved antibiotic, can be used for the treatment of traveler's diarrhea in regions where noninvasive E. coli is the predominant pathogen. In areas where invasive organisms such as Campylobacter and Shigella are common, fluoroquinolones remain the drug of choice. Azithromycin is recommended in areas with quinolone-resistant Campylobacter and for the treatment of children and pregnant women.

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Acute diarrhea is the most common illness among travelers. Up to 55 percent of persons who travel from developed countries to developing countries are affected. (1,2) A study3 of Americans visiting developing countries found that 46 percent acquired diarrhea. The classic definition of traveler's diarrhea is three or more unformed stools in 24 hours with at least one of the following symptoms: fever, nausea, vomiting, abdominal cramps, tenesmus, or bloody stools. Milder forms can present with fewer than three stools (e.g., an abrupt bout of watery diarrhea with abdominal cramps). Most cases occur within the first two weeks of travel and last about four days without treatment. (1,3) Although traveler's diarrhea rarely is life threatening, it can result in significant morbidity; one in five travelers with diarrhea is bedridden for a day and more than one third have to alter their activities. (1,3)

Destination is the most significant risk factor for developing traveler's diarrhea. (1-4) Regions with the highest risk are Africa, South Asia, Latin America, and the Middle East. Travelers who are immunocompromised and those with lowered gastric acidity (e.g., patients taking histamine [H.sub.2] blockers or proton pump inhibitors) are more susceptible to traveler's diarrhea. Recently, a genetic susceptibility has been demonstrated. 5 Younger age and adventurous travel increase the risk of developing traveler's diarrhea,3,6 but persons staying at luxury resorts or on cruise ships also are at risk. (7,8)

Food and water contaminated with fecal matter are the main reservoirs for the pathogens that cause traveler's diarrhea. Unsafe foods and beverages include salads, unpeeled fruits, raw or poorly cooked meats and seafood, unpasteurized dairy products, and tap water. Eating in restaurants increases the probability of contracting traveler's diarrhea6 and food from street vendors is particularly risky. (9,10) Cold sauces, salsas, and foods that are cooked and then reheated also are risky. (6,11)

In contrast to the largely viral etiology of gastroenteritis in the United States, diarrhea acquired in developing countries is caused mainly by bacteria (1,4,6,12) (Table 1). Enterotoxigenic Escherichia coli is the pathogen most frequently isolated, but other types of E. coli such as enteroaggregative E. coli have been recognized as common causes of traveler's diarrhea. (13) Invasive pathogens such as Campylobacter, Shigella, and nontyphoid Salmonella are relatively common depending on the region, while Aeromonas and non-cholera Vibrio species are encountered less frequently.

Protozoal parasites such as Giardia lamblia, Entamoeba histolytica, and Cyclospora cayetanensis are uncommon causes of traveler's diarrhea, but increase in importance when diarrhea lasts for more than two weeks. (14) Parasites are diagnosed more frequently in returning travelers because of longer incubation periods (often one to two weeks) and because bacterial pathogens may have been treated with antibiotics. Rotavirus and noroviruses are infrequent causes of traveler's diarrhea, although noroviruses have been responsible for outbreaks on cruise ships.

The prevalence of specific organisms varies with travel destination. (1,4,12,13,15) Available data suggest that E. coli is the predominant cause of traveler's diarrhea in Latin America, the Caribbean, and Africa, while invasive pathogens are relatively uncommon. Enterotoxigenic E. coli and enteroaggregative E. coli may be responsible for up to 71 percent of cases of traveler's diarrhea in Mexico. (13) In contrast, Campylobacter is a leading cause of traveler's diarrhea in Thailand (15-17) and also is common in Nepal.6 Regional variation also exists with parasitic causes of traveler's diarrhea (Table 2). (12,13) For example, Cyclospora is endemic in Nepal, Peru, and Haiti.

Food poisoning is part of the differential diagnosis of traveler's diarrhea. Gastroenteritis from preformed toxins (e.g., Staphylococcus aureus, Bacillus cereus) is characterized by a short incubation period (one to six hours), and symptoms typically resolve within 24 hours. (18) Seafood ingestion syndromes such as diarrhetic shellfish poisoning, ciguatera poisoning, and scombroid poisoning also can cause diarrhea in travelers. These syndromes can be distinguished from traveler's diarrhea by symptoms such as perioral numbness and reversal of temperature sensation (ciguatera poisoning) or flushing and warmth (scombroid poisoning). (19)

Prevention

Although travelers often are advised to "Boil it, cook it, peel it, or forget it," data on the effectiveness of dietary precautions in preventing traveler's diarrhea are inconclusive. (3,6,20) Many travelers find it difficult to adhere to dietary recommendations. (21) In a study (3) of American travelers, nearly one half developed diarrhea despite pre-travel advice on avoidance measures; even persons who strictly followed dietary recommendations developed diarrhea. Avoiding high-risk foods and adventuresome eating behaviors may reduce the inoculum of ingested pathogens or prevent the development of other enteric diseases such as typhoid and hepatitis A and E.

Boiling is the best way to purify water. Iodination or chlorination is acceptable but does not kill Cryptosporidium or Cyclospora, and increased contact time is required to kill Giardia in cold or turbid water. (22) Filters with iodine resins generally are effective in purifying water, although it is uncertain whether the contact time with the resin is sufficient to kill viruses. Bottled water generally is safe if the cap and seal are intact.

DRUG PROPHYLAXIS

Antibiotic prophylaxis is not recommended by the Centers for Disease Control and Prevention (CDC) even for high-risk travelers because it can lead to drug-resistant organisms and may give travelers a false sense of security. Although antibiotic prophylaxis does not prevent viral or parasitic infection, some health care professionals believe that it may be an option for travelers who are at high risk of developing traveler's diarrhea and related complications (e.g., immunocompromised persons). Prophylaxis with fluoroquinolones is up to 90 percent effective. (23) Rifaximin (Xifaxan) may prove to be the preferred antibiotic because it is not absorbed and is well tolerated, although data on its effectiveness for prophylaxis have not yet been published.

Bismuth subsalicylate (Pepto-Bismol) provides a rate of protection of about 60 percent against traveler's diarrhea. (24) However, it is not recommended for persons taking anticoagulants or other salicylates. Because bismuth subsalicylate interferes with the absorption of doxycycline (Vibramycin), it should not be taken by travelers using doxycycline for malaria prophylaxis. Travelers should be warned about possible reversible side effects of bismuth subsalicylate, such as a black tongue, dark stools, and tinnitus.

Probiotics are a more natural approach to prophylaxis of traveler's diarrhea. Probiotics colonize the gastrointestinal tract and theoretically prevent pathogenic organisms from infecting the gut. Studies (25,26) of Lactobacillus GG (Culturelle) have suggested protection rates of up to 47 percent. More studies are needed to confirm the efficacy of probiotic prophylaxis. Agents for the prophylaxis of traveler's diarrhea are summarized in Table 3.

Empiric Treatment

Counseling travelers about food precautions does not eliminate the risk of traveler's diarrhea, and nonantibiotic prophylaxis requires frequent dosing to achieve only a modest reduction in risk. In addition, the traveler with diarrhea may have difficulty accessing medical care, the quality of care may be poor, and the quality of medications purchased abroad may be substandard. (27) However, because antibiotics reduce the duration and severity of traveler's diarrhea and generally are well tolerated, (28) providing the traveler with the means for empiric self-treatment can effectively reduce morbidity from traveler's diarrhea.

Waiting 24 hours to confirm the diagnosis of traveler's diarrhea results in unnecessary discomfort and time away from activities. Therapy can be initiated after the first episode of "distressing" diarrhea (i.e., diarrhea that is uncomfortable or interferes with activities). (29,30) If symptoms resolve within 24 hours, no further treatment is necessary. (31,32) If diarrhea persists after one day, treatment should be continued for one or two more days. An algorithm for the treatment of traveler's diarrhea is presented in Figure 1. (33,34)

[FIGURE 1 OMITTED]

Antibiotic selection is based on the likelihood that an invasive organism is present and on antibiotic resistance patterns. These factors are determined largely by travel destination. Although blood in the stool suggests invasive disease, fever is not a sensitive indicator of dysentery. Fluoroquinolones have been the drug of choice for traveler's diarrhea in most parts of the world because of their efficacy against most enteropathogens. Rifaximin recently became available for the treatment of noninvasive diarrhea caused by E. coli. For persons traveling to destinations where noninvasive E. coli is the predominant pathogen (e.g., Mexico), rifaximin is a good choice. (35,36)

In regions where invasive pathogens are responsible for a significant proportion of traveler's diarrhea, quinolones should be used. Azithromycin (Zithromax) is recommended in places where quinolone-resistant Campylobacter is prevalent (e.g., Thailand). (15,16) Antibiotics used for the treatment of traveler's diarrhea are listed in Table 4. (16,32,37) Trimethoprim-sulfamethoxazole (Bactrim, Septra) and doxycycline are no longer recommended because of the development of widespread resistance. (12)

Therapy that involves an antibiotic with loperamide (Imodium) often limits symptoms to one day. (38,39) Loperamide has antimotility and antisecretory effects and is taken as two 2-mg tablets after the first loose stool, followed by one tablet after each subsequent loose stool (maximum of 8 mg in 24 hours for two days). The use of loperamide in dysentery has been controversial because of concerns about prolonging illness, but it is now considered safe when combined with an antibiotic. (29,34,38) A conservative approach would be to use loperamide for dysentery only if combined with an antibiotic and if the traveler has a long trip or will have no toilet access.

Oral rehydration solutions generally are unnecessary in adults younger than 65 years. (40) However, all travelers with diarrhea should be encouraged to drink plenty of fluids and to replace lost electrolytes using foods such as salt crackers or broth.

Traveler's Diarrhea in Infants, Children, and Pregnant Women

Traveler's diarrhea is more common in young children than in adults, and they have a higher risk of dehydration and severe illness. (41) Parents should seek immediate medical attention if their child shows signs of moderate to severe dehydration, bloody diarrhea, a temperature higher than 39[degrees]C (102[degrees]F), or persistent vomiting. Few data exist on the treatment of diarrhea in children. The use of oral rehydration solutions is essential, and parents should include prepackaged packets (to be mixed with safe water) in their travel kits. These packets are available in camping stores in the United States or in pharmacies in other countries.

Because infants and toddlers normally can have three or more loose stools, an alternate definition of diarrhea in this age group is a twofold increase in the frequency of unformed stool. (37) Nursing infants should continue to breastfeed on demand, and infants and older children should be offered their usual food.

Fluoroquinolones are not approved by the U.S. Food and Drug Administration (FDA) for use in children, and rifaximin is approved only for children 12 years and older. Therefore, azithromycin is the drug of choice for most children with traveler's diarrhea. (37) Another option is nalidixic acid (Neggram) in a dosage of 55 mg per kg per day divided into four doses, not to exceed 1 g in 24 hours. (37) Loperamide is approved for children older than two years, but should not be used in children with dysentery. Bismuth subsalicylate should be avoided for prophylaxis in children because of the possible risk of Reye's syndrome.

Pregnant women may be at higher risk of traveler's diarrhea than nonpregnant women because of lowered gastric acidity and increased gastrointestinal transit time. (42) Quinolones (FDA pregnancy category C) generally are not advised during pregnancy, but azithromycin (FDA pregnancy category B) is safe. Oral rehydration should be emphasized. Although rifaximin is not absorbed, the safety of this medication in pregnant women has not been established. Loperamide (FDA pregnancy category B) may be used, but bismuth subsalicylate (FDA pregnancy category D) should be avoided. Being careful with food and water is particularly important during pregnancy because infections such as listeriosis can cause miscarriage, and hepatitis E can result in maternal mortality.

Complications

Dehydration is the main complication of traveler's diarrhea, especially in children and older adults. Because E. coli O157:H7 is a rare cause of traveler's diarrhea, there is little risk of hemolytic-uremic syndrome. Other complications include Guillain-Barre syndrome after Campylobacter enteritis, Reiter's syndrome (especially in persons who are HLA-B27 positive), Clostridium difficile colitis after antibiotic use, and postinfectious irritable bowel. These conditions may appear after the traveler has returned home.

If diarrhea persists despite antibiotic treatment, medical attention should be sought. Parasitic causes should be suspected in travelers who return with prolonged diarrhea or who do not respond to antibiotics. For those traveling to remote areas for extended periods, it is reasonable to discuss empiric treatment of protozoal infections (e.g., metronidazole [Flagyl] 250 mg three times a day for five days or tinidazole [Fasigyn] in a single 2-g dose for Giardia). (43)

Resources such as the Travelers' Health section of the CDC Web site (http://www.cdc.gov/travel/diarrhea. htm) or commercial sites such as Travel Health Online (http://www.tripprep.com) can keep physicians up to date on the epidemiology and resistance patterns of traveler's diarrhea. Better preventive and prophylactic strategies will be needed until newer antibiotics become available and the sanitation and hygiene in developing countries improve.

The author thanks Prativa Pandey, M.D., for reviewing the manuscript.

This article reflects the views of the author and does not represent those of the CIWEC Clinic Travel Medicine Center.

The author indicates that he does not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

(1.) 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.

(2.) Castelli F, Pezzoli C, Tomasoni L. Epidemiology of travelers' diarrhea. J Travel Med 2001;8(suppl 2):S26-S30.

(3.) Hill DR. Occurrence and self-treatment of diarrhea in a large cohort of Americans traveling to developing countries. Am J Trop Med Hyg 2000;62:585-9.

(4.) Steffen R, Sack RB. Epidemiology. In: Ericsson CD, DuPont HL, Steffen R, eds. Travelers' diarrhea. Hamilton, Ont.: BC Decker, 2003:112-23.

(5.) Jiang ZD, Okhuysen PC, Guo DC, He R, King TM, DuPont HL, et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis 2003;188:506-11.

(6.) Hoge CW, Shlim DR, Echeverria P, Rajah R, Herrmann JE, Cross JH. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. JAMA 1996;275:533-8.

(7.) Hardie RM, Wall PG, Gott P, Bardhan M, Bartlett LR. Infectious diarrhea in tourists staying in a resort hotel. Emerg Infect Dis 1999;5:168-71.

(8.) Daniels NA, Neimann J, Karpati A, Parashar UD, Greene KD, Wells JG, et al. Traveler's diarrhea at sea: three outbreaks of waterborne enterotoxigenic Escherichia coli on cruise ships. J Infect Dis 2000;181:1491-5.

(9.) Ansdell VE, Ericsson CD. Prevention and empiric treatment of traveler's diarrhea. Med Clin North Am 1999;83:945-73,vi.

(10.) Mensah P, Yeboah-Manu D, Owusu-Darko K, Ablordey A. Street foods in Accra, Ghana: how safe are they? Bull World Health Organ 2002;80:546-54.

(11.) Adachi JA, Mathewson JJ, Jiang ZD, Ericsson CD, DuPont HL. Enteric pathogens in Mexican sauces of popular restaurants in Guadalajara, Mexico, and Houston, Texas. Ann Intern Med 2002;136:884-7.

(12.) Jiang ZD, Lowe B, Verenkar MP, Ashley D, Steffen R, Tornieporth N, et al. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay). J Infect Dis 2002;185:497-502.

(13.) 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.

(14.) Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P. Etiology of diarrhea among travelers and foreign residents in Nepal. JAMA 1988;260:1245-8.

(15.) Kuschner RA, Trofa AF, Thomas RJ, Hoge CW, Pitarangsi C, Amato S, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536-41.

(16.) Hoge CW, Gambel JM, Srijan A, Pitarangsi C, Echeverria P. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341-5.

(17.) Sanders JW, Isenbarger DW, Walz SE, Pang LW, Scott DA, Tamminga C, et al. An observational clinic-based study of diarrheal illness in deployed United States military personnel in Thailand: presentation and outcome of Campylobacter infection. Am J Trop Med Hyg 2002;67:533-8.

(18.) Tauxe RV, Swerdlow DL, Hughes JM. Foodborne disease. In: Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:1150-65.

(19.) Barbier HM, Diaz JH. Prevention and treatment of toxic seafoodborne diseases in travelers. J Travel Med 2003;10:29-37.

(20.) Kozicki M, Steffen R, Schar M. 'Boil it, cook it, peel it or forget it': does this rule prevent travellers' diarrhoea? Int J Epidemiol 1985;14:169-72.

(21.) Mattila L, Siitonen A, Kyronseppa H, Simula II, Peltola H. Risk behavior for travelers' diarrhea among Finnish travelers. J Travel Med 1995;2: 77-84.

(22.) Backer H. Water disinfection for international and wilderness travelers. Clin Infect Dis 2002;34:355-64.

(23.) Rendi-Wagner P, Kollaritsch H. Drug prophylaxis for travelers' diarrhea. Clin Infect Dis 2002;34:628-33.

(24.) Steffen R, Heusser R, DuPont HL. Prevention of travelers' diarrhea by nonantibiotic drugs. Rev Infect Dis 1986;8(suppl 2):S151-9.

(25.) Oksanen PJ, Salminen S, Saxelin M, Hamalainen P, Ihantola-Vormisto A, Muurasniemi-Isoviita L, et al. Prevention of travellers' diarrhoea by Lactobacillus GG. Ann Med 1990;22:53-6.

(26.) Hilton E, Kolakowski P, Singer C, Smith M. Efficacy of Lactobacillus GG as a diarrheal preventive in travelers. J Travel Med 1997;4:41-3.

(27.) World Health Organization. Substandard and counterfeit medicines. Fact sheet no. 275, November 2003. Accessed online April 6, 2005, at: http://www.who.int/mediacentre/factsheets/2003/fs275.

(28.) De Bruyn G, Hahn S, Borwick A. Antibiotic treatment for travellers' diarrhoea. Cochrane Database Syst Rev 2005;(1):CD002242.

(29.) Shlim DR. Self diagnosis and treatment of traveler's diarrhea. In: Keystone JS, Kozarsky PE, Freedman DO, Nothdurft HD, Connor BA, eds. Travel medicine. St. Louis: Mosby, 2003:201-4.

(30.) Ericsson CD. Travelers' diarrhea: epidemiology, prevention, and self-treatment. Infect Dis Clin North Am 1998;12:285-303.

(31.) Salam I, Katelaris P, Leigh-Smith S, Farthing MJ. Randomised trial of single-dose ciprofloxacin for travellers' diarrhoea. Lancet 1994;344: 1537-9.

(32.) Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Martinez-Sandoval F, Knirsch C, et al. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis 2003;37:1165-71.

(33.) DuPont HL, Mattila L. Antimicrobial treatment: an algorithmic approach. In: Ericsson CD, DuPont HL, Steffen R, eds. Travelers' diarrhea. Hamilton, Ont.: BC Decker, 2003:227-37.

(34.) Adachi JA, Ostrosky-Zeichner L, DuPont HL, Ericsson CD. Empirical antimicrobial therapy for traveler's diarrhea. Clin Infect Dis 2000;31: 1079-83.

(35.) DuPont HL, Jiang ZD, Ericsson CD, Adachi JA, Mathewson JJ, DuPont 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.

(36.) Steffen R, Sack DA, Riopel L, Jiang ZD, Sturchler M, Ericsson CD, et al. Therapy of travelers' diarrhea with rifaximin on various continents. Am J Gastroenterol 2003;98:1073-8.

(37.) Stauffer WM, Konop RJ, Kamat D. Traveling with infants and young children. Part III: travelers' diarrhea. J Travel Med 2002;9:141-50.

(38.) Murphy GS, Bodhidatta L, Echeverria P, Tansuphaswadikul S, Hoge CW, Imlarp S, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118:582-6.

(39.) Taylor DN, Sanchez JL, Candler W, Thornton S, McQueen C, Echeverria P. Treatment of travelers' diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. A placebo-controlled randomized trial. Ann Intern Med 1991;114:731-4.

(40.) Caeiro JP, DuPont HL, Albrecht H, Ericsson CD. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler's diarrhea. Clin Infect Dis 1999;28:1286-9.

(41.) Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler's diarrhea in infants and children. Pediatr Infect Dis J 1991;10: 719-23.

(42.) Samuel BU, Barry M. The pregnant traveler. Infect Dis Clin North Am 1998;12:325-54.

(43.) Drugs for parasitic infections. Med Lett Drugs Ther 2004;46:1-12.

JOHNNIE YATES, M.D., is on staff at the CIWEC Clinic Travel Medicine Center in Kathmandu, Nepal. He received his medical degree from Yale University School of Medicine, New Haven, Conn., completed an internship in family medicine at Ventura (Calif.) County Medical Center, and served a residency in family medicine at Middlesex Hospital, Middletown, Conn. Dr. Yates has a diploma in tropical medicine and hygiene and a certificate in travel health.

Address correspondence to Johnnie Yates, M.D., CIWEC Clinic Travel Medicine Center, P.O. Box 12895, Kathmandu, Nepal. Reprints are not available from the author.

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