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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Background  Renewed interest in the use of antibiotics to prevent travellers’ diarrhoea has occurred with the availability of non-absorbed (<0.4%) rifaximin, and with evidence that a subgroup of travellers with diarrhoea have progression of their illnesses to postinfectious irritable bowel syndrome.

Aim  To summarize recently published information and make recommendations on travellers' diarrhoea prevention.

Methods  PubMed was reviewed on 2 January 2008 for 255 articles on the topic of ‘travellers diarrhoea’ published beginning with 2000 along with the author’s extensive file on prevention of travellers’ diarrhoea.

Results  Exercising care in food and beverage selection, while of unproven value, is recommended during travel to high-risk areas of Latin America, Southern Asia or Africa. An algorithm is presented to identify future travellers, for which chemoprophylaxis is appropriate. The preferred drug for prevention of travellers’ diarrhoea is rifaximin, with bismuth subsalicylate or a fluoroquinolone also being effective. Vaccines against the principal cause of travellers’ diarrhoea, enterotoxigenic Escherichia coli, are being developed.

Conclusions  Research is needed to determine the relative effectiveness of exercising care on food and beverage selection and chemoprophylaxis in preventing travellers’ diarrhoea and postinfectious irritable bowel syndrome during high-risk travel. Enterotoxigenic E. coli vaccines appear to be a promising addition to travel medicine.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

The frequency of travellers’ diarrhoea (TD) among international travellers has not importantly changed in the more than 50 years for which illness rates have been available.1–3 A majority of cases of TD are caused by bacterial enteropathogens,4–6 which explains the remarkable effectiveness of antibacterial drugs employed in chemoprophylaxis or therapy, providing prevalent bacterial aetiological agents are susceptible to the drugs employed.

Chemoprophylaxis was first shown to reduce the occurrence of TD effectively in the 1950s and early 1960s,3, 7 at which time more than one-third of international travellers returning to the US from Mexico were taking daily diarrhoea-preventive antibiotics during their trip.8 Because of the potential side effects expected from the available and known effective drugs, concern about development of resistance by extra-intestinal bacteria and difficulty of identifying populations for which preventive drugs should be recommended, chemoprophylaxis was discouraged for most travellers by consensus of experts in 1985.9 When they made their recommendations, the panel was considering the absorbed antibacterial drugs, trimethoprim/sulfamethoxazole (TMP/SMX) and the fluoroquinolones. With the availability of non-absorbed (<0.4%) rifaximin, over-the-counter bismuth subsalicylate (BSS) and probiotics with activity against prevalent bacterial enteropathogens and with the recent awareness of the occurrence of chronic gastrointestinal disease in those acquiring TD, the concept of chemoprophylaxis needs to be re-examined.10

Demonstration that strains of enterotoxigenic Escherichia coli (ETEC) are the major causes of TD,5, 11 coupled with the observation that persons develop anti-ETEC immunity as they remain in a high-risk region,12, 13 research teams have been encouraged to develop anti-ETEC vaccines.

This review will focus on the history and current approaches to TD prevention by exercising care in what is eaten or drunk, by employing chemoprophylaxis during high-risk travel, or for the future, employing protective vaccines pretravel.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

The 255 publications listed in PubMed, 2 January 2008, on the topic ‘travellers’ diarrhoea’ with a publication date since 1 January 2000 were reviewed along with the extensive file maintained on the topic of chemo- and immune-prophylaxis by the author. The article includes active websites from which data can also be accessed as new information is accumulated.

Reasons to consider strategies designed to prevent travellers’ diarrhoea

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Persons visiting high-risk regions of the developing world, including most countries of Latin America, Southern Asia and Africa, where food- and personal-hygiene standards are below those seen in the industrialized regions, are exposed to enteric pathogens in consumed food and beverages. Figure 1 divides the world into three regions depending upon the expected rate of diarrhoea among persons from low-risk regions (e.g. US and north-western Europe) during trips to one of the three regions.

image

Figure 1.  World map showing variation in risk of acquiring travellers’ diarrhoea among international visitors from low-risk regions.

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The rate of acquiring TD for persons going from low-risk to high-risk areas is approximately 40%14 with illness resulting in an average of 24 h of disability.15, 16 One day of TD can wreck the purpose of the trip depending upon timing of the illness and the nature of the trip. The postdiarrhoea consequences can be even more important for a subgroup of travellers. Approximately 10% of persons with TD will develop a chronic enteric disease best classified as postinfectious irritable bowel syndrome (PI-IBS).17, 18 Persons travelling to the same region without developing a diarrhoeal illness will develop PI-IBS with very low frequency suggesting that active diarrhoeal disease rather than enteric infection is a prerequisite for most of the cases of chronic functional bowel disease. PI-IBS has been extensively studied by the gastroenterology group from Nottingham, UK.19–21 This group has shown that PI-IBS is a chronic illness with a majority of cases still active after 6 years.22 Chronic reactive arthritis is also a complication of TD in susceptible persons.23

Approaches to prevent TD

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Considering the high rate of TD among international visitors to the developing world and because of the postdiarrhoea medical complications, a renewed interest in disease prevention is occurring. TD prevention strategies are divided into three areas: (i) prevention of exposure to pathogens present in contaminated foods and drinks; (ii) chemoprophylaxis and (iii) immunoprophylaxis. We will consider each separately.

Care in selection of food and beverages

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Knowledge that food is the major source of enteric pathogens in TD24–27 has led many to attempt to decrease diarrhoea by exercising care about what is eaten or drunk during high-risk travel. One prospective study found that the number of food hygiene errors made during selection of food and beverages predicted diarrhoea rates.28 Principles of food selection have been developed based on rates of recovery of coliforms and enteric pathogens from food.14 A number of retrospective studies have failed to show that diarrhoea rates were reduced in international travellers by exercising care about what they consumed, casting doubt on the value of this approach.29 Until prospective studies are performed, this author believes that it is worth pursuing safer foods and beverages while travelling to tropical and semi-tropical areas based on known food microbiology principles. In Table 1, a list of generally safe, often safe and often unsafe foods and beverages available in developing regions of world is provided. It is recommended that persons avoid exposure to often unsafe foods during travel to high-risk regions.

Table 1.   Foods and beverages in tropical and semi-tropical areas with expected travellers’ diarrhoea risk
Generally safeOften safeOften unsafe
  1. References from which recommendations are derived.24–27, 86, 87

Foods and beverages served steaming (>59 °C) hotTortillas and breads or toast containing butter or saucesFruits and vegetables with intact skins: berries, tomatoes
Bottled carbonated drinks including soft drinks and beerFruit juices which may have been augmented with tap waterHot sauces on tabletop
Bottled water with intact seal apparent on openingUse of tap water to rinse mouth and toothbrush without swallowing itMoist foods served at room temperature including vegetables and meats
Syrups, jellies, jams, honeyFoods serviced on airplanes in developing regionsAny food served buffet-style that is maintained at room temperature
Fruits that are peeledFew ice cubesTap water even in hotels claiming filtration systems
Dry items such as bread and rolls Large quantities of ice
Any foods carefully prepared in one’s own apartment or hotel Hamburgers not served hot or at fast food service restaurants with rapid turnover of prepared hamburgers (hamburger toppings are a major concern in these areas)

Chemoprophylaxis

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

It was the observations of B. H. Kean and colleagues in the 1950s and 1960s that antibacterial drugs prevented TD providing the early evidence that bacterial agents were responsible for a majority of the illness. During this time period, Olympic teams credited chemoprophylaxis for keeping them healthy during athletic competition in developing regions, including the international Olympic Games in Mexico City in 1968.30

Doxycycline was shown to be effective in preventing TD in Peace Corps volunteers during the 1970s31, 32 and TMP/SMX was found to reduce rates of illness in US students after arrival in Mexico in the 1980s.33, 34 Resistance to doxycycline35 and to TMP/SMX36 later limited value of these drugs. The antibacterial drugs listed in Table 2 are of historical interest in TD prevention and are no longer recommended for chemoprophylaxis for TD either because of adverse reactions or because of the development of widespread resistance among important pathogens.

Table 2.   The historically important but no longer used drugs in chemoprophylaxis of travellers’ (TD)
AgentFindingsReference
Various sulphonamidesResistance has occurred among prevalent causes of TD3
NeomycinHas potential for causing GI toxicity, has not been tested in recent years3, 88
EnterovioformMinimally to moderately effective, concern of neurotoxicity has prevented development89, 90
DoxycyclineResistance has occurred among prevalent causes of TD31, 32, 35
Trimethoprim–sulfamethoxazoleResistance has occurred among prevalent causes of TD33, 34

Other agents with potential value have been evaluated in the prevention of TD, including BSS, fluoroquinolones, non-absorbed rifaximin and probiotics. Following studies showing that BSS possessed antisecretory properties capable of neutralization of the toxins of ETEC,37 we successfully used the drug for therapy of TD.38 Our research team then demonstrated that both the liquid formulation39 and the tablet formulation of BSS40 were effective in preventing TD with protection rates of 62% and 65% respectively. While BSS was active in the treatment of acute diarrhoea through antisecretory salicylate,41 the drug moiety felt to be important in TD prevention was bismuth and bismuth intestinal reaction products with antimicrobial effects.42

Fluoroquinolones were shown to be even more effective in preventing TD than BSS with protection rates of >80%,43–46 although this class of drugs dramatically reduced colonic coliform flora during administration.43 This property of flora reduction is likely to be an important reason why fluoroquinolones have encouraged epidemic spread of Clostridium difficile in the US and Canada.47

In the 1980s, poorly absorbed bicozamycin was evaluated and found effective as a preventive drug for TD,48 although the drug has not since been developed for human use. Rifaximin, a poorly absorbed (<0.4%) rifamycin antibiotic with in vitro activity against enteric bacterial pathogens important in TD,36 was shown to be effective in treating TD.49 When studied as a chemoprophylactic agent among US students in Mexico in 2003, rifaximin prevented 72–77% of illness when given in a dose of one, two or three tablets a day during their first 2 weeks in country.2 A second study was carried out in the same setting in Mexico during the summer of 2005 providing similar results.50 Despite leading to very high drug concentrations in the gut,51 rifaximin alters colonic flora only minimally.2, 52 This probably relates both to low water solubility of the drug leading to low levels of free drug in the aqueous colon and to the relatively high minimal inhibitory concentrations of rifaximin for coliform flora. It is clear that rifaximin prevents illness caused by diarrhoeagenic E. coli including ETEC and enteroaggregative E. coli. Whether the drug prevents invasive forms of TD will need further evaluation. A volunteer study provided evidence that shigellosis was prevented by oral rifaximin.53 It is not known if rifaximin will prevent diarrhoea caused by other invasive organisms including Salmonella and Campylobacter, which may be encountered during travel, particularly in Asia.6, 54 If travellers have breakthrough diarrhoea while taking rifaximin prophylaxis, it is reasonable to assume that their illness is caused by an invasive enteropathogen, best treated with the azalide, azithromycin.55

Probiotics have been evaluated in the prevention of TD. A probiotics is a living culture of bacteria or yeast providing potential defence against ingested enteropathogens by colonization in the upper gut utilizing space and available nutrients and reducing lumenal pH to inhibitory levels. The probiotic, Lactobacillus GG, was shown to be modestly effective when evaluated as a preventive for TD.56 Two commercially available probiotics, L. acidophilus and L. bulgaricus, were evaluated for TD prevention and found to be ineffective.57, 58Saccharomyces boulardii was effective in preventing illness in a subset of subjects going to North Africa, but not for groups travelling to other regions in one published study.59

In Table 3, drugs with current value in preventing TD are listed along with dosage recommendations. Rifaximin has advantages over other effective preparations in view of convenience (single daily dosing), safety (side effect profile equivalent to placebo controls) and level of efficacy (protection rate >70%). BSS, while less convenient with its four daily dosing requirement, causes blackening of stools and tongues and may cause occasional tinnitus. Fluoroquinolones, while providing a high level of protection, are systemically absorbed and thus may produce systemic side effects,60 deplete colonic flora43 and lead to antimicrobial resistance by extra-intestinal flora, such as Streptococcus pneumoniae,61 possibly complicating later therapy of lower respiratory tract infection. The major safety issue with probiotics relates to the potential for organism dissemination in immunodeficient persons.62

Table 3.   The available drugs showing current value for chemoprophylaxis of travellers’ diarrhoea (TD)
Agent/recommended dosageProtective efficacy* and comments†Reference
  1. * Protection rate is determined by the equation: per cent of diarrhoea in the placebo control group minus per cent of diarrhoea in the drug group divided by per cent of diarrhoea in the placebo times 100.

  2. † All drugs are taken from the day of arrival in the developing region with the first meal consumed through the last meal taken on the returning air plane for trips no longer than 3 weeks.

Bismuth subsalicylate (2.1 g/day – 2 tablets chewed well with meals and at bedtime or eight – 262 mg tablets per day)65% effective in preventing TD; will turn stools and tongues black from harmless bismuth salt and occasional tinnitus. In Europe, there is concern about developing bismuth encephalopathy, a rare complication in healthy persons91–9440
Lactobacillus GG (2 × 109 bacteria/day in a single daily capsuleModestly effective (∼40%), not to be used in the elderly, debilitated and immunosuppressed for safety reasons (see text) 56
Fluoroquinolones (ciprofloxacin or levofloxacin, 500 mg tablet, once a day)>80% effective in preventing TD; being absorbed may produce systemic side effects60 and can encourage resistance among extra-intestinal bacterial flora and pathogens including Streptococcus pneumoniae6143–46
Rifaximin (one 200 mg tablet taken with major daily meals – most should take one tablet twice a day or 400 mg/day)72–77% effective, free of side effects, less a concern about development of resistance because the drug is not absorbed (<0.4%)2

Immunoprophylaxis (Table 4)

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References
Table 4.   Immunoprophylaxis approaches being taken in the prevention of ETEC, the major cause of travellers’ diarrhoea (TD)
VaccineFindingsReferences
  1. ETEC, enterotoxigenic Escherichia coli.

Inactivated whole cell Vibrio cholerae O1 strains (WC) plus recombinant cholera toxin B subunit (WC-rBSCT) marked as Dukoral in Canada and some European countriesProvides protection against cholera and short-term immunity against ETEC in endemic areas; may prevent diarrhoea due to non-ETEC, non-V. cholerae causes64, 95, 96
Inactivated WC ETEC strains plus recombinant cholera toxin B subunit (WC-rBSCT) in developmentExperimental vaccine which should include ETEC strains with colonization factor antigens important in the setting to be visited6765–67, 97
Purified heat labile enterotoxin (LT) of ETEC administered transcutaneouslyLT serves as an adjuvant, produces neutralizing antibodies against ETEC LT, protecting travellers against diarrhoea caused by LT-, ST/LT- and possibly ST-ETEC strains. The patch vaccine needs to be evaluated for potential protective effects against other non-ETEC pathogens68, 70–72

Vaccines for TD have been pursued for two reasons: (i) ETEC is the principal cause of TD and (ii) immunity to TD occurs naturally as persons live in endemic areas,1 which is best explained by the development of anti-ETEC immunity.12, 13 There are two vaccines in the later stages of development that look promising for prevention of TD (see Table 4). The first is inactivated whole cells of Vibrio cholerae strains (WC) combined with recombinant-binding subunit of cholera toxin (rBSCT). The binding subunit of cholera toxin is closely related to the binding portion of the heat labile enterotoxin (LT) of ETEC. The second vaccine under development is purified LT administered transcutaneously, leading to serum anti-IgG LT neutralizing antibodies and protective immunity against LT-producing ETEC.

WC-rBSCT oral cholera and ETEC vaccine (Dukoral)

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

The two-dose, orally administered WC-rBSCT vaccine has been evaluated in endemic areas in local populations and shown to provide short-term protection against ETEC diarrhoea63 and was shown to provide protective immunity to a group of Finnish travellers to Morocco.64 The vaccine is marketed as Dukoral in 50 countries including Canada and those in the European Union. An experimental ETEC vaccine is also under development, using inactivated WCs of ETEC containing important colonization factor antigens rather than strains of V. cholera, combined with the same rBSCT. This preparation was shown to be immunogenic and effective in preventing TD caused by stains of ETEC65, 66 if the inactivated ETEC WCs used in the vaccine contained important colonization factor antigens.67

Transcutaneous ETEC – heat labile enterotoxin patch vaccine

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

A novel ETEC vaccine is currently being developed that is delivered by the transcutaneous route.68, 69 Purified heat labile enterotoxin of ETEC (LT) serves as both an adjuvant and an immunizing antigen processed by Langerhans cells, antigen-presenting cells located in the superficial layers of skin. With minimal abrasion of the skin followed by cutaneous attachment of the LT antigen by patch, important levels of neutralizing antitoxic antibodies to LT result after a two-dose regimen.70 The LT patch vaccine was shown to be effective in preventing severe ETEC diarrhoea in volunteers after experimental ETEC challenge71 and to prevent naturally occurring ETEC diarrhoea among US travellers to Guatemala and Mexico.72

The value and limitations of immunoprophylaxis

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Assuming an ETEC vaccine is at least 80% effective in reducing the occurrence of ETEC infection, the attack rate of TD is 40% and that ETEC explains half of the illness, an immunizing agent can be expected to reduce rates of overall TD in travellers to high-risk areas by 16%. This protection rate could be increased, if the vaccine provided protection against non-LT-producing ETEC and other non-ETEC pathogens. The WC-rBSCT vaccine, Dukoral, was shown in one trial to protect against Salmonella as well as ETEC.64 The LT patch vaccine appeared to provide immunity against heat stable toxin (ST)-producing ETEC in the recently completed trial.72 Anti-LT immunity may be associated with nonspecific mucosal immunity or resistance to gut inflammation.73

Current recommendation for chemoprophylaxis

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Figure 2 offers an algorithm to help identify future travellers who might be encouraged to take chemoprophylaxis when trips to high-risk regions are planned. Chemoprophylaxis is not recommended when travel will be to a moderate risk region (e.g. China, Russia, Jamaica, the Middle East and Thailand) or to other low-risk regions. The first indication for chemoprophylaxis during high-risk travel is presence of unstable or important underlying conditions that could predispose the travellers to more severe illness or increase the complications of TD.14, 74 A second group where a preventive drug might be used includes travellers undergoing critical missions for which they cannot tolerate an 8–12 h illness. This might include lecturers, politicians, athletes, musicians or certain tourists on a tight schedule.14, 74, 75 A very high-risk setting for developing TD is seen with persons living in industrialized regions but travelling to a developing region to visit friends and relatives living under less hygienic conditions.76 A separate group where chemoprophylaxis may be indicated include those having experienced TD before, suggesting genetic susceptibility to the disease,77, 78 or those with reduced levels of gastric acid from drugs or prior surgery.79–81 One authority in travel medicine furthermore suggested that prophylaxis be provided to persons requesting use of a preventive drug for future travel if they are not in one of the other categories.75 Rifaximin should be considered the standard preventive drug for most persons in whom chemoprophylaxis will be employed. BSS or one of the fluoroquinolones may be recommended by some travel medicine experts for selected travellers.

image

Figure 2.  Algorithm to identify persons from industrialized countries planning a trip to a high-risk region of Latin America, Southern Asia or Africa who should be encouraged to take chemoprophylaxis (see text for references).

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Unanswered questions and needed research

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Additional studies are needed with rifaximin to determine the value of the drug in preventing invasive forms of TD caused by stains of Shigella, Salmonella and Campylobacter. Preventing an invasive organism from causing enteric infection is a far easier challenge for a non-absorbed antibiotic than treating enteric disease once the organisms have penetrated the mucosa and caused an inflammatory host response. Given the importance of diarrhoeagenic E. coli as causes of TD, rifaximin would still be of value, if not effective, in preventing invasive forms of enteric infection. Continued study of the occurrence of functional diarrhoea and other chronic gastrointestinal diseases82 is needed with an emphasis on the beneficial effects of prophylactic drugs on reducing these complications.10

In addition to evaluation of probiotics in TD prevention, studies should be carried out with prebiotics, nondigestible foods that encourage the growth of gut flora leading to release of protective organic acids. The prebiotic, lactulose was shown to eliminate the intestinal carriage of Shigella successfully, but was not effective in treating shigellosis.83 No prebiotic has yet been evaluated in the prevention of TD.

Azithromycin has been shown to be an effective treatment of TD.54, 84 This drug will likely be an effective chemoprophylactic agent. As this is the preferred treatment for invasive forms of TD including subjects with dysentery or important fever in international travellers,55 it is recommended that the drug not be developed for TD prevention. As most Campylobacter strains are resistant to fluoroquinolones,54, 85 we will need to depend upon azithromycin for the treatment of febrile or dysenteric TD.

More research is needed with ETEC vaccines in travel medicine. Additional studies should be designed to determine if LT-ETEC vaccines reduce the occurrence of diarrhoea due to non-LT-ETEC enteric pathogens important in TD. Also, as LT is a potent adjuvant, it may be combined with other non-ETEC antigens producing a multivalent vaccine.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

In view of the importance of TD in international travellers to developing regions and with the observation that TD may progress to PI-IBS or reactive arthritis, prevention of TD should be the objective of all persons venturing into high-risk areas. Studies are needed to determine the value of chemoprophylaxis in preventing TD and PI-IBS among persons travelling to a wide variety of high-risk areas. While of unproven benefit, these persons should focus on consumption of safe and likely safe food items, rejecting often unsafe foods and beverages.

Until we have more information about risks and benefits of the various methods of preventing travellers' diarrhoea, the following four categories of future travellers have been identified for possible chemoprophylaxis during travel to high-risk regions:

  • 1
    persons with presence of important underlying illness including an unstable medical condition or chronic gastrointestinal disease;
  • 2
    persons with previous bouts of TD during past international trips suggesting increased susceptibility to the disease;
  • 3
    those with reduced gastric hydrochloric acid because of antacid therapy or prior surgery and
  • 4
    future travellers who request preventive medication for their trip.

Rifaximin should be considered the standard preventive medication in travel medicine, while fluoroquinolones and BSS remain effective options.

The current TD vaccines, orally administered cholera/ETEC vaccine and the cutaneously applied patch vaccine against ETEC should be pursued as TD prevention approaches. How they will be used in the future will depend upon safety, cost and protective efficacy achieved.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References

Mr Ryan Craig of Salix Pharmaceuticals provided the world map of risk areas after consulting with the author on country-specific details. Declaration of personal interests: The author has served as a speaker, consultant and on advisory boards for the following companies: Salix Pharmaceuticals; Merck Vaccine Division; McNeil Consumer Healthcare; Romark Institute for Medical Research and IOMAI Corporation. Declaration of funding interests: The author's research has been funded through grants at the University of Texas from: Salix Pharmaceuticals; Romark Institute for Medical Research, IOMAI Corporation and Optimer Pharmaceuticals.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Reasons to consider strategies designed to prevent travellers’ diarrhoea
  6. Approaches to prevent TD
  7. Care in selection of food and beverages
  8. Chemoprophylaxis
  9. Immunoprophylaxis ()
  10. WC-rBSCT oral cholera and ETEC vaccine (Dukoral)
  11. Transcutaneous ETEC – heat labile enterotoxin patch vaccine
  12. The value and limitations of immunoprophylaxis
  13. Current recommendation for chemoprophylaxis
  14. Unanswered questions and needed research
  15. Websites for up-to-date travel medicine advice
  16. Conclusions
  17. Acknowledgements
  18. References
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