Regions of the world can be divided into various levels. Epidemiology of Travelers Diarrhea in Thailand

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1 179 Epidemiology of Travelers Diarrhea in Thailand Virasakdi Chongsuvivatwong, MD, PhD, * Suwat Chariyalertsak, MD, DrPH, Edward McNeil, MSc, * Somboon Aiyarak, MSc, Songwut Hutamai, MD, Herbert L. DuPont, MD, # Zhi-Dong Jiang, PhD, Thareerat Kalambaheti, PhD, ** Wittavat Tonyong, BSc, ** Sumit Thitiphuree, MD, and Robert Steffen, MD * Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand ; Research Institute for Health Science, Chiang Mai University, Chiang Mai, Thailand ; Phuket Provincial Health Office, Phuket, Thailand ; Office of Disease Control, Chiang Mai, Thailand ; University of Texas, Houston School of Public, Houston, TX, USA ; St. Luke s Episcopal Hospital, Houston, TX, USA ; # Baylor College of Medicine, Houston, TX, USA ; ** Mahidol University, Bangkok, Thailand ; Phuket International Hospital, Phuket, Thailand ; Center for Travel Medicine WHO Collaborating Center for Travelers Health, Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland DOI: /j x Background. Current data on risk of travelers diarrhea (TD) among visitors to Thailand largely comes from US military personnel, Peace Corps volunteers, or expatriates. We performed a 14-month systematic study of the incidence rate and characteristics of TD and a smaller study of etiology of the disease among visitors to Phuket and Chiang Mai. Methods. One randomly selected day each week from August 2005 until October 2006, data were collected from foreign tourists departing from airports serving Phuket and Chiang Mai. A separate subgroup of subjects with TD acquired in Phuket were invited to submit a stool sample for enteropathogens. Results. Based on 22,401 completed questionnaires, the attack rate for TD was highest among residents from Australia or New Zealand (16%), while those from the United States and Europe had attack rates of 7% to 8%. Independent risk factors for the development of TD were eating outside the hotel and eating meat. In contrast, a history of drinking tap water and consuming ice cream were protective. In 56 subjects studied for etiology, Aeromonas spp were found in 8 subjects (14%), enterotoxigenic Escherichia coli (ETEC) or Vibrio spp each was found in 7 (13%) with O1 V. cholera (cholera) seen in one, mixed pathogens were found in 3 (5%), with no pathogen being detected in 33 (59%). Conclusions. Phuket and Chiang Mai should not be considered high-risk destinations for development of TD among US and European travelers to Thailand. In the study, Aeromonas, ETEC, and Vibrio spp were the most frequent enteropathogens identified. Regions of the world can be divided into various levels of diarrhea risk for persons originating from industrialized countries during international travel with rates ranging from 4% to higher than 40%. 1 Most of the studies of travelers diarrhea (TD) have taken place in Latin America, Africa, and South Asia, with limited or older information available about rates of TD among international visitors to many parts of Southeast Asia including Thailand. 1 TD is a common cause of illness and suffering among international travelers with important cost. 2 The limited studies of the etiology of TD among US military personnel in Thailand have suggested that fluoroquinolone-resistant Campylobacter is the most important pathogen causing illness in international visitors Corresponding Author: Prof Virasakdi Chongsuvivatwong, MD, PhD, Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hatyai, 110 Thailand. cvirasak@ medicine.psu.ac.th Guest Editor: Charles D. Ericsson to this country. 3,4 It is not known how the daily doxycycline being taken by these subjects for malaria prevention influences diarrhea rates and the infecting pathogens. Importantly, there have been few reports from Thailand on the frequency of the illness among nonmilitary travelers. Information on antibiotic resistance patterns of the organisms responsible for such TD is lacking. Additional studies of TD etiology have been carried out in Peace Corps volunteers 5,6 and expatriates 7 living in Thailand. The present study was designed to determine the incidence of TD in international visitors to two popular tourist locations of Thailand and to assess: (1) seasonal and regional variations; (2) severity and disability associated with enteric disease; and (3) selected tourist-behavior risk-factors contributing to the occurrence of TD. Phuket and Chiang Mai were the two study sites chosen as they serve high volumes of international tourists. Methods The study protocol was approved by the Ethics Committee at the Prince of Songkla University and Ministry of 2009 International Society of Travel Medicine, Journal of Travel Medicine 2009; Volume 16 (Issue 3):

2 180 Public Health. After pilot studying a questionnaire developed for the study and making modifications on wording to be better understood, the modified questionnaires were distributed to international tourists and collected at the airport departure halls of the two airports for 14 months, from August 2005 until October 2006 as performed in other world regions. 8 The study populations included persons aged 16 years willing to sign a consent form and able to understand the questions printed in Chinese, English, French, German, Italian, Japanese, Korean, or Spanish. Age, gender, health preparations before travel, duration of stay in Thailand, food and beverage consumption behavior during the stay, development of and severity of TD experienced while in Thailand were investigated; also, it was determined if subjects sought medical help and what medications were taken for their illnesses. The total sample size was aimed at 20,000 to allow detailed analyses of effects of various risk factors stratified by site and season. Data were collected on one randomly selected day each week of the study period, beginning at 8:30 AM until the required sample size for each day was achieved. The schedule of data collection was preset to ensure that the number of subjects enrolled into the study was uniformly distributed throughout the year. The questionnaires from both airports were shipped to Prince of Songkla University in Hatyai where the data were rechecked and double entered using Epidata version 3.0. Data from the questionnaires were entered into a database including data entry checks. All statistical analyses were done with R software (R Foundation for Statistical Computing, Vienna, Austria, ISBN , ORL ). Since the subjects stayed in study areas for different time periods, the denominator used was person-days. The distribution of background information and related behavior of respondents were grouped by geographic region of country of origin. Kaplan Meier values were plotted using package survival or R software 9 to display survival probability, and hazard rate changes over time of stay. Cox regression was used to study the hazard ratios of the putative risk factors that included variables related to personal characteristics and food consumption behaviors adjusted for one another since all subjects had 0 or 1 episodes of classical TD. For independent variables with more than two levels, likelihood ratio test was employed to check for the effect of that variable as a whole in addition to Wald s test, which examined each level against the reference. A value with 95% confidence interval above unity indicated that the variable was a possible risk factor. Significance level was set at <0.05. Before reporting, the final model was checked under global test to make sure the assumption of proportional hazard was not violated. During 2006 and early 2007, a sample of European, American, and Australia/New Zealand (ANZ) patients with TD presenting themselves to the Phuket International and Patong Hospitals were invited to submit a stool sample for detailed microbiological investigation. All subjects were studied within the first 72 hours of Chongsuvivatwong et al. their diarrhea and receipt of antibiotics in the preceding week was an exclusion to enrollment. The methods employed for evaluation of bacterial and parasitic enteropathogens have been published. 10 Bacterial agents were sought by culture, and Giardia, Entamoeba histolytica, and Cryptosporidum were sought by commercial enzyme immunoassay. Viral pathogens were not sought. Mild TD was the passage of 1 to 2 unformed stools in a 24-hour period. Moderate TD was defined as passage of 1 to 2 unformed stools together with a symptom or sign of an enteric infection including excessive intestinal gas related symptoms, abdominal cramps or pain, nausea, vomiting, fever, or dysentery (passage of grossly bloody stools). Classic TD was defined as passage of 3 unformed stools plus one of the above signs or symptoms of enteric infection. 8 In the text when we report rates of TD, we are considering only the classic TD definition, except when overall rates are mentioned and in Table 1 we also give data on mild and moderate TD. Results The number of questionnaires obtained for analysis was 12,014 from Phuket and 10,387 from Chiang Mai, totaling 22,401 subject evaluations. Breakdown of means (with SD) and percentage of key variables by regions of origin of the tourists are summarized in Table 1. Europeans, East Asians, Southeast Asians, and the combination of ANZ and North Americans each contributed approximately a quarter of the respondents. A majority of visitors from ANZ came to Thailand during September to December. The European travel peak was from December to February. The North Americans showed a small peak in January but were uniformly seen throughout the 14 months of study. The most uniform distribution timewise was seen for the Asian visitors. Visitors from the various areas of the world showed similar mean age, from late 30s to early 40s, and each showed a predominantly male orientation, except among visitors from East Asia who had a higher proportion of females. Nearly % of persons surveyed visited Thailand as tourists. Western travelers stayed longer than those from other Asian locations. A higher percentage of ANZ and European respondents visited Phuket, while North American and the Asian travelers more often went to Chiang Mai. Over two thirds of the hotels in which respondents stayed provided the visitors with a free breakfast. An equal proportion of travelers ate at hotels or took their food and beverages outside the hotel. Tap water was relatively rarely consumed, while eating raw oyster/fish and rare meat occurred commonly. Not counting the Asian travelers, over half of all groups consumed ice cream during their visit. Overall, diarrhea attack rate and also the attack rate of classic TD were highest among the travelers from ANZ, which was more than double the rate seen among Europeans and those from the United States. People

3 Travelers Diarrhea in Thailand 181 Table 1 Characteristics of subjects enrolled during stay in Thailand and diarrhea rates according to region of origin Australia and New Zealand Europe North America Eastern Asia Others Southeast Asia Number studied 2,268 4,886 1,102 5,897 1,128 5,311 Mean age (SD) 37.8 (14.1) 40.3 (13.9) 41.4 (14.9) 35.9 (12.1) 38.3 (12.4) 38.7 (11.6) Days stayed/mean (SD) 10 (24.6) 11.8 (20.9) 11.9 (29) 6.3 (20.6) 9.9 (30.3) 4.7 (8.2) % female % tourists % in Phuket % often ate out % drank tap water daily % ate oyster or fish daily % ate rare meat daily % eating ice cream daily Travelers diarrhea severity * None Mild Moderate Classic Days stayed = days remaining in Thailand; Travelers diarrhea severity: mild = passage of 1 2 unformed stools per day; moderate = passage of 1 2 unformed stools per day with one or more signs or symptoms of enteric infection (see text for list); and classic = passage of 3 unformed stools/24 hours plus a sign or symptom of enteric infection (see text for list). * See references for definitions of Travelers Diarrhea. from Southeast and East Asia and those originating in other parts of the world had the lowest TD rates ( Table 1 ). When length of stay was used as a denominator, the level of risk (incidence density) difference between groups was only slightly reduced. The overall attack rates varied between 6% in June to 10% in December. The seasonal or monthly differences were not significant. With time in country, the diarrhea attack rate decreased, providing evidence of the development of natural immunity with exposure to pathogens. 11 In Figure 1, Kaplan Meier plots are depicted showing the cumulative percentage of subjects remaining well from classic TD over time. Through the period of stay, the six curves could be grouped into three as mentioned earlier. By the end of the second week, the curves were relatively flat with cumulative hazard rates (not shown) indicating reduction of susceptibility after this period. For multivariate analysis, the results of Cox regression predicting relative hazard of classic TD related with the various risk factors are given in Table 2. The assumption of proportional hazard by global test was nonsignificant, indicating there was no violation of the assumption. Using Southeast Asian visitors as the reference group, ANZ travelers had an increased risk by factor 6.2 compared to factors of 2.8 for North Americans and of 2.3 for Europeans. While ANZ subjects more often visited Phuket than Chiang Mai, the higher risk of diarrhea in this group was adjusted in the regression analysis and site preference did not explain their increased risk. An important risk factor for TD was the visitor s meal arrangement. With increasing frequency of meals eaten outside the hotel, there was a dose-response relationship for development of diarrhea. Drinking tap water was protective while other putative eating behaviors such as eating cooked meat, raw oysters/fish, salads, and vegetables did not show statistical significance. Microbiological assessment for etiology of TD included 56 subjects seen in Phuket. The mean age of this subpopulation was 37 years (range years). Aeromonas sobria was identified in 8 (14%) and enterotoxigenic Escherichia coli (ETEC) was identified in 7 (13%) with a breakdown of heat-labile toxin (LT) producing ETEC found in 4 (7%), heat-stable toxin (ST) producing ETEC in one (2%), and LT/ST ETEC identified in 2 (5%). The breakdown of other pathogens were Campylobacter in 2 (4%), Salmonella spp in 2 (4%), Vibrio cholerae in 2 (4%; one had O1 Ag, the other did not agglutinate to O1 or to O139 antiserum), and Vibrio parahaemolyticus in 5 (9%). Figure 1 Kaplan Meier plots of the cumulative frequency of remaining well from classic travelers diarrhea by day of study, from day 0 to day 30 after arrival in Thailand for various groups differing by country of origin.

4 182 Chongsuvivatwong et al. Table 2 Hazard ratio (HR) of various risk factors for development of classic travelers diarrhea * employing Cox regression Adjusted HR (95% confidence interval) p (Wald s test) p (Likelihood ratio test) Age in decades (vs y) < y 1.26 ( ) y 0.87 ( ) y 0.79 ( ) y 0.57 ( ) y 0.5 ( ) >70 y 0.83 ( ) 0.7 Gender: Male vs Female 0.82 ( ) Purpose of stay (vs holiday) Business 1.18 ( ) 0.38 Medical 1.94 ( ) 0.26 Other 0.64 ( ) Region residence (vs Southeast Asia) <0.001 Australia and New Zealand 6.16 ( ) <0.001 Europe 2.29 ( ) <0.001 North America 2.78 ( ) <0.001 East Asia 0.89 ( ) 0.54 Others 0.96 ( ) 0.89 Place: Chiang Mai versus Phuket 1.13 ( ) 0.26 Hotel meal arrangements (vs none) Breakfast only 0.98 ( ) 0.85 Breakfast + dinner 0.59 ( ) 0.08 Breakfast + lunch + dinner 1.2 ( ) 0.56 Breakfast + lunch + dinner + drinks 0.94 ( ) 0.77 Consumption of food/beverages outside hotel (vs never) Occasionally 1.43 ( ) 0.22 Often 1.86 ( ) Consumption of ice cubes (vs never) Occasionally 1.37 ( ) Daily 1.41 ( ) Eating ice cream (vs never) Occasionally 0.97 ( ) 0.72 Daily 1.08 ( ) 0.63 Eaten rare cooked meat (vs never) Occasionally 1.04 ( ) 0.67 Daily 0.76 ( ) 0.2 Eaten raw oysters/fish (vs never) Occasionally 1.15 ( ) 0.13 Daily 1.12 ( ) 0.52 Eaten salads/vegetables (vs never) Occasionally 1.24 (1 1.55) Daily 1.16 ( ) 0.24 Drank tap water (vs never) <0.001 Occasionally 0.6 ( ) Daily 0.31 ( ) <0.001 * Passage of 3 unformed stools plus a sign or symptom of enteric infection (see text). No parasites were identified. More than one pathogen was found in 3 (5%): two patients had Aeromonas and Campylobacter, while a third was found to be infected by Aeromonas and ST/LT ETEC. No pathogen was identified in 22 (51%). In Table 3, the susceptibility of the bacterial isolates is provided. Trimethoprim sulfamethoxazole and ciprofloxacin showed low rates of activity against most of the isolated pathogens. Rifaximin was active against the ETEC, Vibrios, and Campylobacter but showed high minimal inhibitory concentrations against some of the strains of Salmonella spp and Aeromonas. Azithromycin showed the greatest in vitro activity against the various pathogens. Discussion The most striking epidemiological finding of the present study was the low rate of TD among visitors to two popular destinations in Thailand from the United States and Europe. Studies looking at US military personnel in Thailand 3,4 and Peace Corps volunteers 5,6 have given an impression that rates of TD remain as high as identified a quarter of a century earlier. 1 Possible explanations for the difference include: influence of doxycycline invariably used by US military in past studies, the different source of meals and beverages for the two populations, and the time difference in performing the studies with improvement

5 Travelers Diarrhea in Thailand 183 Table 3 Distribution of s ( g/ml) of antimicrobial agents by bacterial enteropathogens TMP SXT ( g/ml) CIP ( g/ml) AZM ( g/ml) RFX ( g/ml) Range Range Range Range Organism ETEC ( N = 7) < Vibrio spp ( N = 7) < Aeromonas sobria ( N = 8) < < < Campylobacte r spp ( N = 2) NA NA <0.01 NA NA 16 NA NA 4 NA NA Salmonella spp ( N = 2) 256 NA NA NA NA 4 32 NA NA NA NA = minimal inhibi- TMP/SXT = trimethoprim/sulfamethoxazole; CIP = ciprofloxacin; AZM = azithromycin; RFX = rifaximin; ETEC = enterotoxigenic Escherichia coli ; = minimal inhibitory concentration for % of isolates; tory concentration for % of isolates; NA = not applicable (too few strains tested to establish an or ). in overall hygiene in more recent years. Also, military populations and Peace Corps volunteers represent very different populations than short-term travelers included in this study. For unclear reasons, the two Thai cities studied remain a higher risk region for visitors from ANZ with an overall attack rate of 30% and an incidence rate of 22% per 14-day stay. This figure is comparable to attack rates among visitors to Brazil (20%) but less than that found in Jamaica (24%), India (61%), and Kenya (66%) reported in a previous study. 8,12 We are unable to say that Thailand as a whole will show a low rate of TD, but at least in these two most important tourist destinations, the rates were found to be lower than previously reported from smaller studies. TD rates varied importantly between groups of visitors depending upon their country of origin. The highest rate of TD was seen among the ANZ visitors. A recent report found a cluster of cases of TD among Cambodian students visiting Thailand showing regional differences in susceptibility. 13 There are three potential reasons for increased rate of illness in certain populations. First, these may have a greater proportion of genetically more susceptible persons, 14,15 which needs to be examined. Previous studies by our group demonstrated especially high rates of TD among British travelers to Jamaica and other destinations. 12,16 Second, ANZ visitors may live in more hygienic environments at home compared to North America or Europeans, making them more susceptible to enteric pathogens. Finally, ANZ travelers may differ by the nature of their trips (adventure travel vs standard tours), living accommodations, or eating habits that were not identified by the study during international travel. Differences in attack rate between various tourist groups from industrialized areas need additional study and may provide important information about host risk factors for development of TD. Among the local Thai residents, the reported diarrhea rates had been stable over the past decade. The country crude incidence of diarrhea per 100,000 persons in 2005 was 1,837. The corresponding figures were 2,563 in Chiang Mai and 3,348 in Phuket (Bureau of Epidemiology, Department of Disease Control, Ministry of Public Health, accessed on April 14, 2008). The reported rates from the routine surveillance system are generally lower than in our study but the figures suggest higher risk among residents in Phuket than those in Chiang Mai. On the other hand, our data suggest that the risk for TD was not influenced by the place where they visited but by how they behaved during travel. The number of monthly visitors to Thailand varied little throughout the year based on Thai tourist statistics. In the present study, there was no evidence of seasonal variation in rates of TD. In Phuket, monthly rates of diarrhea in local populations fluctuated minimally throughout the year. In Chiang Mai, there was a peak in diarrhea among the locals during June, followed by a steady decline until reaching the lowest level in December, after which the rate rose once more. The difference between June and

6 184 December for diarrhea in local populations was 2.7-fold (Bureau of Epidemiology, Department of Disease Control, Ministry of Public Health, U surdata/y48/mcd_u Diarrhoea_48.rtf). Reasons for seasonal differences between travelers and residents are unknown. Eating behaviors influenced diarrhea rates among visitors to Thailand. The three western tourist groups generally stayed for longer time periods and ate more frequently outside the hotel than Asian visitors. While the visitors from ANZ were least likely to drink tap water and eat raw fish/oysters or rare cooked meat than other groups, they were less likely to consume ice cream than Western visitors. Interestingly, the East Asians had the most careful eating habits. Eating outside the hotel was identified to be a significant risk factor for acquisition of TD, whereas the aforementioned food items did not appear to importantly influence rates of illness. Surprisingly, drinking tap water in the two Thai cities was shown to be protective against severe TD showing a highly significant dose-response effect. Available evidence would suggest that water contamination is caused by leakage of peripheral water pipes with a drop in the pressure and introduction of microbes into the system. Most hotels in the study areas had their water supply directly attached to the major water distribution pipeline, decreasing the chance of microorganism introduction secondary to reduced water pressure. Thailand currently claims that tap water at the water plant is drinkable in 85 regions of the country including Chiang Mai (since 2000) and Phuket (since 2002) (Provincial Waterworks Authority, en.pwa.co.th/drinkable.htm, accessed on 14 April 2008). Our data suggest that where people eat was more important than what they eat as none of the food items under this study was shown to be at special risk, while eating outside the hotel was. The observation suggests that the level of hygiene inside the restaurants of the hotels was generally better than in eating establishments outside of the hotels. The pathogen data in the present study indicate that Aeromonas, ETEC, and Vibrio spp are important causes of diarrhea among travelers to Phuket, Thailand. Earlier reports from Peace Corps Volunteers in Thailand indicated that both ETEC and Aeromonas strains were important causes of TD. 17,18 In US military populations, Campylobacter had been detected in far greater proportions. 3,4 Of three other studies of etiology of TD in Thailand, Campylobacter strains accounted for 2% to 17% of cases. 5 7 One 30-year-old British traveler to Phuket in the present study was found to be infected by a V. cholerae O1 (cholera) strain. The total number of reported cases of cholera in Thailand in 2005 was 279; one from Chiang Mai and none from Phuket ( y48/rate_cholera_48.rtf ). In 2007, the corresponding numbers for the country and the two cities were 986, 0, and 99, respectively. Among the 99 Phuket patients with cholera in 2007, eight were foreigners (five from Myanmar, one from Laos, and two from other countries) ( ). Chongsuvivatwong et al. We interpret the data to indicate that cholera is relatively rare among tourists but not uncommon among immigrant workers due to poor hygienic conditions, possibly that also may be associated with consumption of incompletely boiled shellfish. Additional studies of the current etiology of TD to Thailand are needed. From a population perspective, among the four commonly used antibiotics tested in this study, trimethoprim/ sulfamethoxazole and ciprofloxacin showed poor activities against a majority of pathogenic isolates. Azithromycin was the most active drug and may be the preferred agent for treatment of TD occurring in Thailand. Rifaximin showed activity against a majority of noninvasive bacteria encountered, although resistant strains of Aeromonas were encountered. Previously, we have found in a limited study of TD due to Aeromonas spp that the strains were often resistant to trimethoprim sulfamethoxazole 19 and susceptible to rifaximin. 20 Limitations of the present study include the lack of subjects with TD studied in both cities for enteric pathogens and the failure to identify reasons for the high rate of diarrhea among international visitors to Thailand from ANZ. In conclusion, the present study has provided strong evidence that TD rates among US and European visitors to Phuket and Chiang Mai are lower than expected. The finding of increased risk among visitors from ANZ requires additional study. Declaration of Interests R.S. has accepted fee for speaking, organizing and chairing education, consulting and/or serving on advisory boards, reimbursement for attending meetings, and/or funds for research from Astral, Baxter, Berna Biotech/ Crucell, GlaxoSmithKline, McDonalds, Novartis Vaccines, Optimer, Roche, Salix, Sanofi Pasteur MSD and/ or SBL Vaccin, also from Swiss International Air Lines. The other authors state that they have no conflicts of interest. References 1. Steffen R, van der Linde F, Gyr K, Schar M. Epidemiology of diarrhea in travelers. JAMA 1983 ; 249 : Wang M, Szucs TD, Steffen R. Economic aspects of travelers diarrhea. J Travel Med 2008 ; 15 : Kuschner RA, Trofa AF, Thomas RJ, 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 : Tribble DR, Sanders JW, Pang LW, et al. 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 2007 ; 44 : Taylor DN, Echeverria P. Etiology and epidemiology of travelers diarrhea in Asia. Rev Infect Dis 1986 ; 8 ( Suppl 2 ): S136 S141.

7 Travelers Diarrhea in Thailand 6. Taylor DN, Echeverria P, Blaser MJ, et al. Polymicrobial aetiology of travellers diarrhoea. Lancet 1985 ; 1 : Gaudio PA, Echeverria P, Hoge CW, et al. Diarrhea among expatriate residents in Thailand: correlation between reduced Campylobacter prevalence and longer duration of stay. J Travel Med 1996 ; 3 : von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhoea at various tourist destinations. Lancet 2000 ; 356 : Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977 ; 35 : Jiang ZD, Lowe B, Verenkar MP, 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 : Angst F, Steffen R. Update on the epidemiology of traveler s diarrhea in East Africa. J Travel Med 1997 ; 4 : Steffen R, Tornieporth N, Clemens SA, et al. Epidemiology of travelers diarrhea: details of a global survey. J Travel Med 2004 ; 11 : Johnson JY, McMullen LM, Hasselback P, et al. Travelers knowledge of prevention and treatment of travelers diarrhea. J Travel Med 2006 ; 13 : Jiang ZD, Okhuysen PC, Guo DC, et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis 2003 ; 188 : Mohamed JA, DuPont HL, Jiang ZD, et al. A novel singlenucleotide polymorphism in the lactoferrin gene is associated with susceptibility to diarrhea in North American travelers to Mexico. Clin Infect Dis 2007 ; 44 : Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of traveler s diarrhea in Jamaica. JAMA 1999 ; 281 : Echeverria P, Blacklow NR, Sanford LB, Cukor GG. Travelers diarrhea among American Peace Corps volunteers in rural Thailand. J Infect Dis 1981 ; 143 : Echeverria P, Sack RB, Blacklow NR, et al. Prophylactic doxycycline for travelers diarrhea in Thailand. Further supportive evidence of Aeromonas hydrophila as an enteric pathogen. Am J Epidemiol 1984 ; 120 : Vila J, Ruiz J, Gallardo F, et al. Aeromonas spp. and traveler s diarrhea: clinical features and antimicrobial resistance. Emerg Infect Dis 2003 ; 9 : Gomi H, Jiang ZD, Adachi JA, et al. In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing traveler s diarrhea in four geographic regions. Antimicrob Agents Chemother 2001 ; 45 :