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    A summary of studies of TD graphically showing the average percentage of ETEC isolation by region of the world studied.

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    Scatter plot of percentage isolation of ETEC in subjects with TD by year and region of study.

  • 1

    Kean BH, 1963. The diarrhea of travelers to Mexico. Summary of five-year study. Ann Intern Med 59 :605–614.

  • 2

    DuPont HL, Haynes GA, Pickering LK, Tjoa W, Sullivan P, Olarte J, 1977. Diarrhea of travelers to Mexico. Relative susceptibility of United States and Latin American students attending a Mexican University. Am J Epidemiol 105 :37–41.

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  • 3

    Steffen R, van der Linde F, Gyr K, Schar M, 1983. Epidemiology of diarrhea in travelers. JAMA 249 :1176–1180.

  • 4

    Hoge CW, Shlim DR, Rajah R, Triplett J, Shear M, Rabold JG, Echeverria P, 1993. Epidemiology of diarrhoeal illness associated with coccidian-like organism among travellers and foreign residents in Nepal. Lancet 341 :1175–1179.

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  • 5

    Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P, 1988. Etiology of diarrhea among travelers and foreign residents in Nepal. JAMA 260 :1245–1248.

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  • 6

    Varela G, Kean BH, Barrett EL, Keegan CJ, 1959. The diarrhea of travelers. II. Bacteriologic studies of U.S. students in Mexico. Am J Trop Med Hyg 8 :353–357.

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  • 7

    DuPont HL, Formal SB, Hornick RB, Snyder MJ, Libonati JP, Sheahan DG, LaBrec EH, Kalas JP, 1971. Pathogenesis of Escherichia coli diarrhea. N Engl J Med 285 :1–9.

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  • 8

    Butzler JP, Dekeyser P, Detrain M, Dehaen F, 1973. Related vibrio in stools. J Pediatr 82 :493–495.

  • 9

    Bishop RF, Davidson GP, Holmes IH, Ruck BJ, 1973. Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet 2 :1281–1283.

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  • 10

    Dolin R, Blacklow NR, DuPont H, Formal S, Buscho RF, Kasel JA, Chames RP, Hornick R, Chanock RM, 1971. Transmission of acute infectious nonbacterial gastroenteritis to volunteers by oral administration of stool filtrates. J Infect Dis 123 :307–312.

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  • 11

    Gorbach SL, Kean BH, Evans DG, Evans DJ Jr, Bessudo D, 1975. Travelers’ diarrhea and toxigenic Escherichia coli. N Engl J Med 292 :933–936.

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  • 12

    DuPont HL, Reves RR, Galindo E, Sullivan PS, Wood LV, Mendiola JG, 1982. Treatment of travelers’ diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone. N Engl J Med 307 :841–844.

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  • 13

    Guerena-Burgueno F, Hall ER, Taylor DN, Cassels FJ, Scott DA, Wolf MK, Roberts ZJ, Nesterova GV, Alving CR, Glenn GM, 2002. Safety and immunogenicity of a prototype enterotoxigenic Escherichia coli vaccine administered transcutaneously. Infect Immun 70 :1874–1880.

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  • 14

    Peltola H, Siitonen A, Kyronseppa H, Simula I, Mattila L, Oksanen P, Kataja MJ, Cadoz M, 1991. Prevention of travellers’ diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 338 :1285–1289.

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  • 15

    Yamada S, Matsushita S, Dejsirilert S, Kudoh Y, 1997. Incidence and clinical symptoms of Aeromonas-associated travellers’ diarrhoea in Tokyo. Epidemiol Infect 119 :121–126.

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  • 16

    Clemens JD, Sack DA, Harris JR, Chakraborty J, Neogy PK, Stanton B, Huda N, Khan MU, Kay BA, Khan MR, et al., 1988. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. J Infect Dis 158 :372–377.

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  • 17

    Glenn GM, Flyer DC, Ellingsworth LR, Frech SA, Frerichs DM, Seid RC, Yu J, 2007. Transcutaneous immunization with heat-labile enterotoxin: development of a needle-free vaccine patch. Expert Rev Vaccines 6 :809–819.

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  • 18

    McKenzie R, Bourgeois AL, Frech SA, Flyer DC, Bloom A, Kazempour K, Glenn GM, 2007. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Vaccine 25 :3684–3691.

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  • 19

    Frech SA, DuPont HL, Bourgeois AL, McKenzie R, Belkind-Gerson J, Figueroa JF, Okhuysen PC, Guerrero NH, Martinez-Sandoval FG, Melendez-Romero JH, Jiang ZD, Asturias EJ, Halpern J, Torres OR, Hoffman AS, Villar CP, Kassem RN, Flyer DC, Andersen BH, Kazempour K, Breisch SA, Glenn GM, 2008. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 371 :2019–2025.

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  • 20

    Huang DB, Mohamed JA, Nataro JP, DuPont HL, Jiang ZD, Okhuysen PC, 2007. Virulence characteristics and the molecular epidemiology of enteroaggregative Escherichia coli isolates from travellers to developing countries. J Med Microbiol 56 :1386–1392.

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  • 21

    Nataro JP, 2005. Enteroaggregative Escherichia coli pathogenesis. Curr Opin Gastroenterol 21 :4–8.

  • 22

    Adachi JA, Jiang ZD, Mathewson JJ, Verenkar MP, Thompson S, Martinez-Sandoval F, Steffen R, Ericsson CD, DuPont HL, 2001. Enteroaggregative Escherichia coli as a major etiologic agent in traveler’s diarrhea in 3 regions of the world. Clin Infect Dis 32 :1706–1709.

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  • 23

    Hoge CW, Gambel JM, Srijan A, Pitarangsi C, Echeverria P, 1998. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 26 :341–345.

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  • 24

    Kuschner RA, Trofa AF, Thomas RJ, Hoge CW, Pitarangsi C, Amato S, Olafson RP, Echeverria P, Sadoff JC, Taylor DN, 1995. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 21 :536–541.

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  • 25

    Tribble DR, Sanders JW, Pang LW, Mason C, Pitarangsi C, Baqar S, Armstrong A, Hshieh P, Fox A, Maley EA, Lebron C, Faix DJ, Lawler JV, Nayak G, Lewis M, Bodhidatta L, Scott DA, 2007. Traveler’s diarrhea in Thailand: randomized, double-blind trial comparing single-dose and 3-day azithromycin-based regimens with a 3-day levofloxacin regimen. Clin Infect Dis 44 :338–346.

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  • 26

    DuPont HL, Ericsson CD, Mathewson JJ, DuPont MW, 1992. Five versus three days of ofloxacin therapy for traveler’s diarrhea: a placebo-controlled study. Antimicrob Agents Chemother 36 :87–91.

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  • 27

    DuPont HL, Haake R, Taylor DN, Ericsson CD, Jiang ZD, Okhuysen PC, Steffen R, 2007. Rifaximin treatment of pathogen-negative travelers’ diarrhea. J Travel Med 14 :16–19.

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  • 28

    Caeiro JP, Estrada-Garcia MT, Jiang ZD, Mathewson JJ, Adachi JA, Steffen R, DuPont HL, 1999. Improved detection of enterotoxigenic Escherichia coli among patients with travelers’ diarrhea, by use of the polymerase chain reaction technique. J Infect Dis 180 :2053–2055.

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  • 29

    Iijima Y, Tanaka S, Miki K, Kanamori S, Toyokawa M, Asari S, 2007. Evaluation of colony-based examinations of diarrheagenic Escherichia coli in stool specimens: low probability of detection because of low concentrations, particularly during the early stage of gastroenteritis. Diagn Microbiol Infect Dis 58 :303–308.

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  • 30

    Meraz IM, Jiang ZD, Ericsson CD, Bourgeois AL, Steffen R, Taylor DN, Hernandez N, DuPont HL, 2008. Enterotoxigenic Escherichia coli and diffusely adherent E. coli as likely causes of a proportion of pathogen-negative travelers’ diarrhea: a PCR-based study. J Travel Med 15 :412–418.

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  • 31

    Vargas M, Gascon J, Gallardo F, Jimenez De Anta MT, Vila J, 1998. Prevalence of diarrheagenic Escherichia coli strains detected by PCR in patients with travelers’ diarrhea. Clin Microbiol Infect 4 :682–688.

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  • 32

    Ko G, Garcia C, Jiang ZD, Okhuysen PC, Belkind-Gerson J, Glass RI, DuPont HL, 2005. Noroviruses as a cause of traveler’s diarrhea among students from the United States visiting Mexico. J Clin Microbiol 43 :6126–6129.

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  • 33

    Black RE, 1990. Epidemiology of travelers’ diarrhea and relative importance of various pathogens. Rev Infect Dis 12 (Suppl 1):S73–S79.

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  • 34

    DuPont HL, Jiang ZD, Okhuysen PC, Ericsson CD, de la Cabada FJ, Ke S, DuPont MW, Martinez-Sandoval F, 2005. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 142 :805–812.

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  • 35

    Sack DA, Kaminsky DC, Sack RB, Itotia JN, Arthur RR, Kapikian AZ, Orskov F, Orskov I, 1978. Prophylactic doxycycline for travelers’ diarrhea. Results of a prospective double-blind study of Peace Corps volunteers in Kenya. N Engl J Med 298 :758–763.

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  • 36

    Salam I, Katelaris P, Leigh-Smith S, Farthing MJ, 1994. Randomised trial of single-dose ciprofloxacin for travellers’ diarrhoea. Lancet 344 :1537–1539.

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  • 37

    Jiang ZD, Lowe B, Verenkar MP, Ashley D, Steffen R, Tornieporth N, von Sonnenburg F, Waiyaki P, DuPont HL, 2002. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay). J Infect Dis 185 :497–502.

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  • 38

    Bolivar R, Conklin RH, Vollet JJ, Pickering LK, DuPont HL, Walters DL, Kohl S, 1978. Rotavirus in travelers’ diarrhea: study of an adult student population in Mexico. J Infect Dis 137 :324–327.

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  • 39

    DuPont HL, Evans DG, Rios N, Cabada FJ, Evans DJ Jr, DuPont MW, 1982. Prevention of travelers’ diarrhea with trimethoprim-sulfamethoxazole. Rev Infect Dis 4 :533–539.

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  • 40

    DuPont HL, Olarte J, Evans DG, Pickering LK, Galindo E, Evans DJ, 1976. Comparative susceptibility of Latin American and United States students to enteric pathogens. N Engl J Med 295 :1520–1521.

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  • 41

    DuPont HL, Sullivan P, Evans DG, Pickering LK, Evans DJ Jr, Vollet JJ, Ericsson CD, Ackerman PB, Tjoa WS, 1980. Prevention of traveler’s diarrhea (emporiatric enteritis). Prophylactic administration of subsalicylate bismuth). JAMA 243 :237–241.

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  • 42

    Merson MH, Morris GK, Sack DA, Wells JG, Feeley JC, Sack RB, Creech WB, Kapikian AZ, Gangarosa EJ, 1976. Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress. N Engl J Med 294 :1299–1305.

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  • 43

    DuPont HL, Ericsson CD, Galindo E, Wood LV, Morgan D, Bitsura JA, Mendiola JG, 1984. Furazolidone versus ampicillin in the treatment of traveler’s diarrhea. Antimicrob Agents Chemother 26 :160–163.

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  • 44

    Ericsson CD, DuPont HL, Sullivan P, Galindo E, Evans DG, Evans DJ Jr, 1983. Bicozamycin, a poorly absorbable antibiotic, effectively treats travelers’ diarrhea. Ann Intern Med 98 :20–25.

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  • 45

    Mathewson JJ, Johnson PC, DuPont HL, 1988. Enteroadherent Escherichia coli as a cause of travelers’ diarrhea. Advances in Research on Cholera and Related Diarrheas. Kuwahara S, Pierce NF, eds. Tokyo: KTK Scientific Publishers, 15–20.

  • 46

    Sack RB, Santosham M, Froehlich JL, Medina C, Orskov F, Orskov I, 1984. Doxycycline prophylaxis of travelers’ diarrhea in Honduras, an area where resistance to doxycycline is common among enterotoxigenic Escherichia coli. Am J Trop Med Hyg 33 :460–466.

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  • 47

    Steffen R, Mathewson JJ, Ericsson CD, DuPont HL, Helminger A, Balm TK, Wolff K, Witassek F, 1988. Travelers’ diarrhea in West Africa and Mexico: fecal transport systems and liquid bismuth subsalicylate for self-therapy. J Infect Dis 157 :1008–1013.

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  • 48

    Bouckenooghe AR, Jiang ZD, De La Cabada FJ, Ericsson CD, DuPont HL, 2002. Enterotoxigenic Escherichia coli as cause of diarrhea among Mexican adults and US travelers in Mexico. J Travel Med 9 :137–140.

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  • 49

    DuPont HL, Ericsson CD, Mathewson JJ, de la Cabada FJ, Conrad DA, 1992. Oral aztreonam, a poorly absorbed yet effective therapy for bacterial diarrhea in US travelers to Mexico. JAMA 267 :1932–1935.

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  • 50

    DuPont HL, Ericsson CD, Mathewson JJ, Marani S, Knellwolf-Cousin AL, Martinez-Sandoval FG, 1993. Zaldaride maleate, an intestinal calmodulin inhibitor, in the therapy of travelers’ diarrhea. Gastroenterology 104 :709–715.

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  • 51

    DuPont HL, Ericsson CD, Mathewson JJ, Palazzini E, DuPont MW, Jiang ZD, Mosavi A, de la Cabada FJ, 1998. Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers’ diarrhea. Digestion 59 :708–714.

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  • 52

    Ericsson CD, DuPont HL, Mathewson JJ, 1997. Single dose ofloxacin plus loperamide compared with single dose or three days of ofloxacin in the treatment of traveler’s diarrhea. J Travel Med 4 :3–7.

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  • 53

    Ericsson CD, DuPont HL, Mathewson JJ, West MS, Johnson PC, Bitsura JA, 1990. Treatment of traveler’s diarrhea with sulfame-thoxazole and trimethoprim and loperamide. JAMA 263 :257–261.

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  • 54

    Gascon J, Vila J, Valls ME, Ruiz L, Vidal J, Corachan M, Prats G, Jimenez de Anta MT, 1993. Etiology of traveller’s diarrhea in Spanish travellers to developing countries. Eur J Epidemiol 9 :217–223.

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  • 55

    Paredes P, Campbell-Forrester S, Mathewson JJ, Ashley D, Thompson S, Steffen R, Jiang ZD, Svennerholm AM, DuPont HL, 2000. Etiology of travelers’ diarrhea on a Caribbean island. J Travel Med 7 :15–18.

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  • 56

    Taylor DN, Bourgeois AL, Ericsson CD, Steffen R, Jiang ZD, Halpern J, Haake R, DuPont HL, 2006. A randomized, double-blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers’ diarrhea. Am J Trop Med Hyg 74 :1060–1066.

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  • 57

    Sack DA, Kaminsky DC, Sack RB, Wamola IA, Orskov F, Orskov I, Slack RC, Arthur RR, Kapikian AZ, 1977. Enterotoxigenic Escherichia coli diarrhea of travelers: a prospective study of American Peace Corps volunteers. Johns Hopkins Med J 141 :63–70.

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  • 58

    Sack RB, Froehlich JL, Zulich AW, Hidi DS, Kapikian AZ, Orskov F, Orskov I, Greenberg HB, 1979. Prophylactic doxycycline for travelers’ diarrhea: results of a prospective double-blind study of Peace Corps volunteers in Morocco. Gastroenterology 76 :1368–1373.

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  • 59

    Bourgeois AL, Gardiner CH, Thornton SA, Batchelor RA, Burr DH, Escamilla J, Echeverria P, Blacklow NR, Herrmann JE, Hyams KC, 1993. Etiology of acute diarrhea among United States military personnel deployed to South America and west Africa. Am J Trop Med Hyg 48 :243–248.

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  • 60

    Haberberger RL, Scott DA, Thornton SA, Hyams KC, 1994. Diarrheal disease aboard a U.S. Navy ship after a brief port visit to a high risk area. Mil Med 159 :445–448.

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  • 61

    Mattila L, Siitonen A, Kyronseppa H, Simula I, Oksanen P, Stenvik M, Salo P, Peltola H, 1992. Seasonal variation in etiology of travelers’ diarrhea. Finnish-Moroccan Study Group. J Infect Dis 165 :385–388.

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  • 62

    Sharp TW, Thornton SA, Wallace MR, Defraites RF, Sanchez JL, Batchelor RA, Rozmajzl PJ, Hanson RK, Echeverria P, Kapikian AZ, et al., 1995. Diarrheal disease among military personnel during Operation Restore Hope, Somalia, 1992–1993. Am J Trop Med Hyg 52 :188–193.

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  • 63

    Echeverria P, Jackson LR, Hoge CW, Arness MK, Dunnavant GR, Larsen RR, 1993. Diarrhea in U.S. troops deployed to Thailand. J Clin Microbiol 31 :3351–3352.

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  • 64

    Murphy GS Jr, Echeverria P, Jackson LR, Arness MK, LeBron C, Pitarangsi C, 1996. Ciprofloxacin- and azithromycin-resistant Campylobacter causing traveler’s diarrhea in U.S. troops deployed to Thailand in 1994. Clin Infect Dis 22 :868–869.

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  • 65

    Petruccelli BP, Murphy GS, Sanchez JL, Walz S, DeFraites R, Gelnett J, Haberberger RL, Echeverria P, Taylor DN, 1992. Treatment of traveler’s diarrhea with ciprofloxacin and loperamide. J Infect Dis 165 :557–560.

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  • 66

    Echeverria P, Ramirez G, Blacklow NR, Ksiazek T, Cukor G, Cross JH, 1979. Travelers’ diarrhea among U.S. Army troops in South Korea. J Infect Dis 139 :215–219.

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  • 67

    Sriratanaban A, Reinprayoon S, 1982. Vibrio parahaemolyticus: a major cause of travelers’ diarrhea in Bangkok. Am J Trop Med Hyg 31 :128–130.

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  • 68

    Echeverria P, Sack RB, Blacklow NR, Bodhidatta P, Rowe B, McFarland A, 1984. Prophylactic doxycycline for travelers’ diarrhea in Thailand. Further supportive evidence of Aeromonas hydrophila as an enteric pathogen. Am J Epidemiol 120 :912–921.

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  • 69

    Guerrant RL, Rouse JD, Hughes JM, Rowe B, 1980. Turista among members of the Yale Glee Club in Latin America. Am J Trop Med Hyg 29 :895–900.

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  • 70

    Shore EG, Dean AG, Holik KJ, Davis BR, 1974. Enterotoxin-producing Escherichia coli and diarrheal disease in adult travelers: a prospective study. J Infect Dis 129 :577–582.

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  • 71

    Black FT, Gaarslev K, Orskov F, Orskov I, Stenderup A, Stenderup J, Christensen O, 1983. Mecillinam, a new prophylactic for travellers’ diarrhoea. A prospective double-blind study in tourists travelling to Egypt and the Far East. Scand J Infect Dis 15 :189–193.

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  • 72

    Jertborn M, Svennerholm AM, Iwarson S, 1988. A prospective study of serum antibody responses to enterotoxinogenic Escherichia coli in Swedish travellers. Scand J Infect Dis 20 :69–75.

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  • 73

    Pitkanen T, 1982. Travellers’ diarrhoea caused by Campylobacter jejuni. Ann Clin Res 14 :111–113.

  • 74

    DuPont HL, Jiang ZD, Ericsson CD, Adachi JA, Mathewson JJ, DuPont MW, Palazzini E, Riopel LM, Ashley D, Martinez-Sandoval F, 2001. Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 33 :1807–1815.

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  • 75

    Gallardo F, Gascon J, Ruiz J, Corachan M, Jimenez de Anta M, Vila J, 1998. Campylobacter jejuni as a cause of traveler’s diarrhea: clinical features and antimicrobial susceptibility. J Travel Med 5 :23–26.

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  • 76

    Hyams KC, Bourgeois AL, Merrell BR, Rozmajzl P, Escamilla J, Thornton SA, Wasserman GM, Burke A, Echeverria P, Green KY, et al., 1991. Diarrheal disease during Operation Desert Shield. N Engl J Med 325 :1423–1428.

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  • 77

    Jelinek T, Lotze M, Eichenlaub S, Loscher T, Nothdurft HD, 1997. Prevalence of infection with Cryptosporidium parvum and Cyclospora cayetanensis among international travellers. Gut 41 :801–804.

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  • 78

    Vila J, Ruiz J, Gallardo F, Vargas M, Soler L, Figueras MJ, Gascon J, 2003. Aeromonas spp. and traveler’s diarrhea: clinical features and antimicrobial resistance. Emerg Infect Dis 9 :552–555.

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Global Etiology of Travelers’ Diarrhea: Systematic Review from 1973 to the Present

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  • 1 School of Public Health and School of Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; Baylor College of Medicine, Houston, Texas; St Luke’s Episcopal Hospital, Houston, Texas

Fifty-one published studies of travelers’ diarrhea (TD) were examined to look for regional differences in pathogens identified. Enterotoxigenic E. coli was detected in 1,678/5,518 (30.4%) of TD cases overall, with rates in Latin America/Caribbean (L. America), Africa, south Asia, and Southeast Asia of 1,109/3,302 (33.6%), 389/1,217 (31.2%), 153/499 (30.6%), and 36/500 (7.2%), respectively (P < 0.001). Enteroaggregative E. coli was the second most common agent in L. America, found in 166/689 (24.1%), compared with 3/165 (1.8%) in Africa and 33/206 (16%) in south Asia (P < 0.001). Other significantly regional differences were seen for enteropathogenic E. coli, diffusely adherent E. coli, Campylobacter, Shigella spp., Salmonella, Aeromonas spp., Plesiomonas, Vibrios, rotavirus, noroviruses, Giardia, and Entoamoeba histolytica. The regional differences in pathogen identification identified will serve as a baseline for antimicrobial therapy recommendations and vaccines strategies.

INTRODUCTION

Travelers’ diarrhea (TD) is the most common illness of international travelers bound for developing regions of the world where substandard hygienic conditions exist. The average rate of TD among persons entering into the high-risk regions of Latin America, Southern Asia, and Africa from industrialized countries is 40%, a rate unchanged in > 50 years.15 A potential key to developing a strategy for disease control and prevention is determination of cause of enteric illness. Until 1970, the etiology of TD was obscure.6 During a remarkable 2-year time period in the early 1970s, major advances in the microbiology of acute diarrhea occurred when enterotoxigenic Escherichia coli,7 Campylobacter,8 rotavirus,9 and Norwalk virus 10 were identified as causes of human illness. Soon thereafter, it was shown that bacterial enteropathogens were the most common class of agents causing TD, with enterotoxigenic Escherichia coli (ETEC) being the most common etiologic agent. 11 It was also shown that antibacterial drugs shortened the illness related to TD. 12 In the modern era, vaccines are in development against ETEC to prevent TD. 13,14

We review published studies on the cause of TD, carried out since the important bacterial and viral agents were identifiable. The aim of the review was to look at the etiology of TD by region of the developing world and to determine changes in frequency of enteropathogens causing TD over the three decades of study. The review was designed to provide baseline information that would allow identification of treatment and chemoprophylaxis strategies and to help determine the potential value of ETEC vaccines based on the frequency and geographic distribution of ETEC diarrhea within the larger group of TD.

MATERIALS AND METHODS

All studies on the etiology of TD listed by PubMed and Medline Ovid and published since 1973 were reviewed using the following key words: etiology of traveler’s diarrhea; travelers’ diarrhea; and acute diarrhea of travelers. Additionally, the extensive files maintained by the corresponding author were reviewed. The definition of TD was passage of one or more unformed stools in 24 hours with at least one sign or symptom of enteric infection, including fever, abdominal cramps or pain, nausea, vomiting, tenesmus, or fecal urgency. In most of the studies, enrollment criteria included passage of at least three unformed stools in 24 hours together with an enteric sign or symptom. The study divided the cases into geographic settings where the TD occurred including 1) Latin America and the Caribbean (L. America); 2) Africa; 3) South Asia; 4) Southeast Asia; and 5) multiple or unspecified developing regions (unspecified).

Inclusion criteria of the articles reviewed: 1) studies of the etiology of TD when microbiology methods seemed to be appropriate for the organism(s) under study; 2) when travelers were studied for multiple bouts of diarrhea, etiology information only for the first episode of illness was included; and 3) studies of TD where the duration of stay of travelers was 40 days or less.

During the review of published literature, the data extracted included country of origin of the travelers, the regions being visited, the year of data collection for the study, the age of the traveler, the number of study participants, the duration of stay, the number of persons acquiring TD, and identification of enteropathogens.

The statistical analyses were performed using StataCorp 2007 (Stata Statistical Software Release 10; StataCorp, College Station, TX). Regional differences for pathogens were compared using the Fisher exact test. We studied variation in ETEC isolation rate in each group over a period of time from 1970 to 2004 using two-way scatterplots. We tested correlation between ETEC and year of study in each group separately.

RESULTS

In 51 published studies between 1973 and 2008, 57 different groups of travelers were evaluated for etiology of diarrhea. In one study, four different travel groups were evaluated, and in four, two travel groups each were included. In Table 1, the various studies and references are identified by decade carried out. For studies bridging a time period (e.g., 1989–1990), they are included in the later time period (e.g., 1990–1999). In Table 1, the number of studies carried out and the number of subjects included per time period of review are provided.

The total population with TD included in this review was 30,884 persons studied in 57 separate travel groups. For L. America, there were 24 travel groups comprising 3,302 persons with TD studied over the years of the study. For Africa, the number of study groups was 10, with TD occurring in 1,217 persons (there were no studies carried out in the 2000s). For South Asia and Southeast Asia, we included 10 study groups with etiology data in 1,145 persons with TD. Finally, for the studies reporting travelers to unspecified developing regions, 13 study groups including 25,302 persons with TD provided information on enteropathogens. One of the studies to many but unspecified regions included 23,215 persons. 15

Table 2 shows the combined study groups by major host country region and by pathogen identified in cases of TD. To be included in this analysis, the agent had to have been sought in the study population in at least one study. Significant differences in geographic occurrence of the pathogen under study are provided in Table 2. The identification rate was significantly different when comparing the three major geographic regions for all pathogens other than enteroinvasive E. coli (EIEC), enterohemorrhagic (Shiga toxin-producing) E. coli (EHEC), and Cryptosporidium (see Table 2 for P values).

The most common pathogen identified overall was ETEC, which was found in 1,678/5,518 (30.4%) of the subjects studied. ETEC was most frequently identified in travelers to L. America and Africa, found in 1,109 of 3,302 (33.6%) and 380 of 1,217 (31.2%) subjects in the two locations, respectively. ETEC was found in 153/499 (30.6%) in south Asia and in 36/500 (7.2%) in Southeast Asia (P < 0.001; see Table 2 and Figure 1).

EAEC was the second most commonly identified enteropathogen found in 202/1,060 (19.0%) of the subjects studied. EAEC was isolated in 166 of 689 (24.1%) travelers with diarrhea while traveling in L. America. EAEC was identified in 33 of 206 (16.0%) of travelers with diarrhea developing while traveling in South Asia. EAEC was relatively infrequently encountered in subjects with TD acquired in Africa; it was found in 3 of 165 (1.8%; P < 0.001). Campylobacter was more often found in Asia compared with L. America and Africa. Shigella spp. were most commonly found in TD cases occurring in Africa compared with Asia, whereas Salmonella more often was identified in TD cases occurring in Asia than in Africa or L. America. Aeromonas spp. were more often found in Asia and Africa than L. America, and Plesiomonas spp. were more often found in Asia than the other study areas. Vibrios (non-cholera and cholera) were more common also in Asia than in the other study groups. Noroviruses and rotavirus were more often found in L. America and Africa and less common in Asia. Giardia and E. histolytica were found more commonly in Asia than the other study groups.

In Figure 2 the percentage isolation of ETEC by year and region of study is provided in a scatterplot. A decreasing ETEC rate for TD cases was observed for travelers to L. America (negative correlation coefficient, 0.41; P = 0.036) and Africa (negative correlation coefficient, 0.54; P = 0.10) over the years of the study. A non-significant increasing percentage of ETEC-associated diarrhea was seen among the cases of TD occurring in South Asia (negative correlation coefficient, 0.55; P = 0.09). Correlation testing showed a decreasing trend for Shigella identification rate (data not shown) during the years of the study in L. America (correlation coefficient = 0.46; P = 0.023). All the non-ETEC, non-Shigella pathogens failed to show significant trends (increases or decreases) over the years of the study.

DISCUSSION

This systematic review summarized what is known about the geographic variation of enteropathogens as etiologic agents of TD. The studies have taken place in a limited number of regions of the developing world. Insufficient studies of the incidence of TD and the relative importance of specific enteropathogens among international travelers to various world regions are presently available.

ETEC was found to be the most common organism isolated in all geographic regions in the review. The various studies suggest that the percentage isolation of ETEC may be decreasing over the years of the study in L. America and Africa. The rate of ETEC infection seems to be high in South Asia (India), whereas limited studies suggest that it remains low in Southeast Asia.

Two ETEC vaccines are being developed for use as a preventive against TD. The first is inactivated whole cells of Vibrio cholerae strains (WC) combined with recombinant binding subunit of cholera toxin (Dukoral, Oxford, UK). The binding subunit of cholera toxin is closely related to the binding portion of the heat labile enterotoxin (LT) of ETEC. The vaccine is given in two oral doses, providing short-term protection against ETEC diarrhea. 14,16 Dukoral is marketed in 50 countries including Canada and the European Union but not in the United States. The second vaccine being developed consists of purified LT that is administered transcutaneously as a patch, leading to brisk serum anti-IgG LT neutralizing antibodies 17 and protection against moderate to severe ETEC diarrhea 18 and clinically important TD. 13 Immunoprophylaxis aimed at ETEC infection seems to be a viable way to reduce enteric infection, and LT preparations may provide protection against TD, beyond that caused by LT-producing ETEC strains. 14,19 Based on this study, it would seem that an ETEC vaccine would have its greatest value for persons traveling to Latin America, Africa, and South Asia where ETEC is prevalent. Additional study is needed to determine the importance of ETEC in Southeast Asia.

Non-ETEC diarrhea-producing E. coli may be responsible for an important proportion of TD. Unfortunately they have been sought in a limited number of studies. From this study, EAEC strains seem to be important causes of TD worldwide. This group of heterogeneous pathogens 20,21 have been found in all major regions of the world, 22 although there has been limited study outside L. America. Enteropathogenic E. coli (EPEC) have been detected in subjects with TD in each of the five studies in which they were examined. Diarrhea caused by diffusely adherent E. coli (DAEC) were sought in four studies (Table 2) and found to be associated with illness. Additional studies with DAEC are needed.

Campylobacter was most commonly associated with TD occurring in Asia. Not only has Campylobacter been found to be important as a cause of TD occurring in Asia, but ciprofloxacin-resistant strains seem to be commonly encountered in Asia. 2325 Other enteropathogens that seem to be more common in Asia include Vibrios (cholera and non-cholera), Giardia, and E. histolytica. Previous studies have identified Giardia and Cyclospora in travelers and expatriates to Nepal. 4,5

A remaining problem in TD is the high percentage (40–50%) of pathogen-negative diarrhea, despite thorough microbiology evaluation. Antibacterial therapy has been shown in multiple studies to shorten the illness associated with pathogen-negative TD, 12,26,27 suggesting that undetected bacterial enteropathogens are responsible for a large percentage of this illness. PCR-based detection methods have identified ETEC 2830 and other diarrhea-producing E. coli including DAEC 30,31 in the undetected pathogen group when conventional methods of detection were used. Noroviruses have not been routinely sought in TD studies and clearly explain a measure of this illness. 32 More research is needed on the subject of etiology of pathogen-negative diarrhea.

The major limitation of this review is that that the study depended on the existing published studies using different methods of organism detection and different definitions. Also, the review did not control for improving technologies for microbiological detection over the years of the study, limiting the validity of organism comparisons between regions. The methods of detection have steadily improved over the years of the study. Polymerase chain reaction–based methods used in more recent years have increased pathogen detection. However, the strength of the study is that a total review of published studies has not taken place in recent years. 33 This study confirms the importance of bacterial enteropathogens as causes of TD, explaining the remarkable effectiveness of antibacterial drugs in the prevention 34,35 and therapy 12,27,36 of TD.

We recommend more comprehensive studies of TD using the same diagnostic procedures in multiple geographic regions over the same time period as developed by Steffen and others during 1996–1998. 37 This is likely to be a dynamic field requiring that improved methods of surveillance be developed.

Table 1

Summary of 51 published studies providing data on the etiology of TD in 30,984 persons as part of 57 study populations by region visited and decade of study, 1973–2004

Table 1
Table 2

Identification of specific enteropathogens in studies of the etiology of TD carried out in Latin America/Caribbean, Africa, and Southern Asia, 1973–2004

Table 2
Figure 1.
Figure 1.

A summary of studies of TD graphically showing the average percentage of ETEC isolation by region of the world studied.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 4; 10.4269/ajtmh.2009.80.609

Figure 2.
Figure 2.

Scatter plot of percentage isolation of ETEC in subjects with TD by year and region of study.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 4; 10.4269/ajtmh.2009.80.609

*

Address correspondence to Herbert L. DuPont, 1200 Herman Pressler, Suite 733, Houston, TX 77030. E-mail: Herbert.l.Dupont@uth.tmc.edu

Authors’ addresses: Nipam Shah, 7900 Cambridge St., Apt. #7-2F, Houston, TX 77054. Herbert DuPont, University of Texas Health Science Center at Houston, 1200 Herman Pressler Dr. RAS-E743, Houston, TX 77030. David Ramsey, University of Texas Health Science Center at Houston, 1200 Herman Pressler Dr. RAS-E11, Houston, TX 77030.

Acknowledgment: The authors thank Judith Dunn, PhD, for providing statistical guidance.

Financial support: Discretionary funds from the University of Texas–Houston School of Public Health were used to support this study.

Disclaimer: The authors have no conflicts to declare.

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