Expert Review of the Evidence Base for Prevention of Travelers’ Diarrhea

Herbert L. DuPont MD, Charles D. Ericsson MD, Michael J. G. Farthing MD, Sherwood Gorbach MD, Larry K. Pickering MD, Lars Rombo MD, PhD, Robert Steffen MD, Thomas Weinke MD, PD
DOI: http://dx.doi.org/10.1111/j.1708-8305.2008.00299.x 149-160 First published online: 1 May 2009

Abstract

The most frequent illness among persons traveling from developed to developing countries is travelers’ diarrhea. Travelers to high‐risk regions traditionally have been educated to exercise care in food and beverage selection. Innovative research is needed to identify ways to motivate people to exercise this care and to determine its value. Chemoprophylaxis can be recommended for certain groups while monitoring for safety, drug resistance, and efficacy against all forms of bacterial diarrhea. Research to evaluate the value of immunoprophylaxis is recommended. In the following document, the authors used an evidence base when available to determine strength and quality of evidence and when data were lacking, the panel experts provided consensus opinion.

Major findings

Although unproven, the panel recommends pretravel education about safe foods and beverages and the often unsafe items, which may depend upon travel destination. Creative hypothesis‐driven research is needed to determine the effectiveness of dietary and beverage restriction in prevention of travelers’ diarrhea (TD). In addition, the travel health research community should develop effective ways to motivate travelers to carefully select food and beverage items during international travel. While all travelers going from low‐risk to high‐risk regions cannot be recommended to take chemoprophylaxis designed to prevent TD, the effectiveness of a limited number of drugs makes chemoprophylaxis a valuable approach for travelers at greatest risk of disease or its complications. Daily rifaximin meets the criteria as safe and effective agents for TD prevention. Many authorities in North America believe that bismuth subsalicylate (BSS) also should be considered as safe and effective. Many European experts feel that potential bismuth toxicity prevents general use of BSS. The fluoroquinolones taken daily are highly effective but may produce adverse effects including tendon rupture and development of antibacterial resistance among extraintestinal as well as intestinal flora. Many travel medicine authorities less supportive of the concept of chemoprophylaxis prefer instead to use known effective antimicrobial agents to treat TD after gastrointestinal illness develops. Unproven approaches to prevention of TD needing additional studies include probiotics and immunoprophylaxis with vaccines directed against enteric pathogens including enterotoxigenic Escherichia coli.

Purpose

The purposes of this review are to provide available evidence for effectiveness of beverage and food selection patterns, chemoprophylaxis and immunoprophylaxis in prevention of TD, and to determine their impact in reducing the occurrence of enteric disease in international travelers. This area is controversial with differing support among specialists and in various regions of the world. The risks and benefits of the available approaches are highlighted along with regional views. When evidence is available, recommendations are graded by the strength and quality of evidence (Table 1). When evidence is lacking, the quality of evidence is graded as category III, representing a consensus of expert authors (Table 1).

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Table 1

Strength and quality of evidence, grading, and definitions in studies aimed at prevention of travelers’ diarrhea 1

CategoryGradeDefinition
Strength of evidenceAGood evidence to support a recommendation for use
BModerate evidence to support a recommendation for use
CPoor evidence to support a recommendation
DModerate evidence to support a recommendation against use
EGood evidence to support a recommendation against use
Quality of evidenceIEvidence from ≥1 properly randomized, controlled trial
IIEvidence from ≥1 well‐designed clinical trial without randomization, from case‐controlled analysis of cohort study
IIIConsensus evidence, evidence from one authority or reports of expert committees

Target population

These recommendations are made for travel populations originating from an industrialized country and visiting destinations with suboptimal hygienic conditions, usually in the tropics or subtropics. The travel populations include healthy adult travelers, children, pregnant women, people with underlying illness and immunosuppression, and the elderly. The target audience for receipt of the material includes nurse– and physician–travel medicine practitioners, primary care physicians and general practitioners, medical students and residents in training, and infectious diseases and tropical medicine specialists.

Desired outcome

The panel was asked to consider the current status of diet and beverage restrictions, recommendations for use of chemoprophylaxis among travelers to high‐risk areas, and the potential value of pursuing new vaccines against prevalent enteric pathogens that are important causes of TD.

Details of the review process including selection of literature considered by the panel, and plans for periodic updating of the evidence base can be found athttp://www.istm.org; click on “ISTM Committees” and then “Publications.”

The cause and source of TD as a background for disease prevention

TD, the most common medical complication among travelers to destinations with suboptimal hygienic standards, is caused by a wide variety of enteropathogens of which enterotoxigenic E coli(ETEC), 2,3 enteroaggregative E coli(EAEC), 4 and norovirus 5–8 appear to be the most important. There are other bacterial causes of illness including Shigella spp,Salmonella spp,Campylobacter spp,Aeromonas spp,Plesiomonas spp, non‐cholera Vibrios, 9 Vibrio cholerae, 10,11 and possibly diffusely adherent E coli. 12 Less commonly, infection by protozoal parasites is associated with TD cases. 9 Parasites are more important in expatriates living for longer time periods in high‐risk regions. 13–15 In many cases of TD, an enteric pathogen is not identified. Enteropathogens encountered in Africa 9,16,17 and Latin America 9 appear to be similar, with diarrheagenic E coli identified as the most important agents in both settings. In Asia, diarrheagenic E coli occurs commonly, but the invasive bacterial enteropathogens occur with important frequency. 13,18–21

Prevention strategies are aimed at common bacterial causes of TD. Chemoprophylaxis strategies have been directed to the subgroup of bacterial causes of TD. Immunoprophylaxis has been aimed at a more restricted target, most importantly ETEC. It is understood that no one preparation, drug or vaccine, will be protective against all causes of the syndrome.

Education of travelers on food safety and food and beverage hygiene

For more than two decades, food has been known to be the principal source of enteric pathogens for travelers. 22–25 Tap water is less important in most urban settings with municipal water treatment facilities. Water remains a likely source of viral enteropathogens. 26,27 Knowledge of environmental risks has led to attempts to decrease the risk through careful selection of food and beverages.

Can high‐risk foods be identified?

That food is the source of most cases of TD is evidence based considering both strength and quality of evidence (see references cited in this document). Consumption of raw oysters and raw fish in many regions, particularly in Southeast Asia, is associated with risk of enteric infection by bacteria (V cholerae and Vibrio parahemolyticus) and parasites. 28–30 Although poorly studied, raw meat is likely to be unsafe for travelers to consume. Some unproven principles offered by the panel about likely safe food items include those that are served steaming hot and look, smell, and taste good; have reached 60°C, a temperature where bacterial enteropathogens are inactivated 31 ; have been peeled; or have been cleansed adequately and prepared by the traveler in his own apartment or room. 24 Moist foods as well as cold and raw items remaining for periods of time at room temperature before consumption are most likely to be unsafe. 32 Bottled beverages that require breaking a seal upon opening, especially if carbonated, should be considered safe. Tap water should be considered suspect for drinking even in hotels claiming adequate filtration and chlorination.

Can rates of TD be reduced by exercising care on food consumed?

In one study, the number of author‐defined errors made in selecting beverages, ice, and foods was related directly to rates of diarrhea. 33 However, seven retrospective and uncontrolled studies failed to show that caution in food and beverage selection would translate into reduced rates of TD. 34 Authors of one of the uncontrolled studies concluded that the harder travelers tried to avoid dangerous food items, the higher the rate of diarrhea, which they suggested was likely due to recall bias. 35 Another study indicated that while most people were careful in selecting food, they commonly experienced TD. 36 One study of BSS chemoprophylaxis noted that the highest protection against TD was realized by travelers who took the drug and ate less frequently at risky locations. 37 If overall reduction in hygiene is restaurant specific, then all food items served by that establishment should be considered unsafe. The panel feels that there is no clear information to say one way or another that being careful about what is eaten or drunk will or will not influence rates of diarrheal illness in travelers. However, common sense and reports of numerous food‐borne outbreaks of diarrhea support care in selection and preparation of food when traveling. 32 Future studies directed to this topic are needed.

Objectives of chemoprophylaxis

With a diarrhea rate of approximately 40% for people going from industrialized areas to developing tropical and semitropical regions, many travelers will develop an illness consisting of passage of a mean of 13 unformed stools over 5 days if untreated, 38 and each will experience a period of disability lasting approximately 24 hours. 39,40 Rapid initiation of antimicrobial therapy will reduce the duration of illness. Prodrome symptoms and post‐diarrhea ill health add to the overall illness. The illness, even if shortened by effective treatment can threaten the mission of a trip for people with little flexible time as occurs with politicians, lecturers, performers, and tourists on a tight schedule. Preventing such morbidity might be sufficient to consider use of chemoprophylaxis for disease prevention in selected groups. In addition, some people have sufficiently important underlying illnesses (eg, insulin‐dependent diabetes mellitus, Crohn’s disease, people with ileostomies, previous reactive arthritis, wheel‐chair bound persons) that diarrhea can be more complicated or an enteric infection may worsen their preexistent disease.

An unproven but likely benefit of antibacterial chemoprophylaxis is prevention of chronic gastrointestinal disease. The problem of postinfectious irritable bowel syndrome (PI‐IBS) has been shown to be especially common after enteric bacterial infection. 41 Three preliminary studies evaluated the occurrence of PI‐IBS in people acquiring diarrhea during international travel. 42–44 While more studies are needed to confirm the association, it appears that 3% to 10% of travelers acquiring diarrhea while in a tropical or semitropical region of the developing world will develop chronic abdominal complaints or new onset PI‐IBS, which rarely occurs in travelers not experiencing clinical illness. 43,44 Two studies have provided evidence that PI‐IBS will persist for many years. In one study, 57% of the cases were still suffering from IBS 6 years later, 45 and a second follow‐up study found that 76% of PI‐IBS continued with their illness 5 years later. 46 Studies are needed to determine if chemoprophylaxis will not only prevent diarrhea but also chronic complications.

Studies of cost benefit are needed to compare chemoprophylaxis with early initiation of therapy of TD. The cost of generic ciprofloxacin for 1‐ to 3‐day treatment is certainly less than the cost of 14 days of rifaximin used for chemoprophylaxis. Costs of treatment also include lost productivity or leisure enjoyment while awaiting the benefits of early therapeutic intervention. Such costs as well as costs of failing to prevent post‐diarrhea complications will need to be included in the equation in future studies.

Geographic considerations and antimicrobial resistance patterns

Widespread resistance among bacterial enteropathogens causing TD has occurred to trimethoprim/sulfamethoxazole (TMP/SMX), tetracyclines, and ampicillin. Fluoroquinolone resistance was seen among isolates of Shigella in Finnish foreign travelers, 47 in one limited area for diarrheagenic E coli strains important in TD, 48 and fluoroquinolone resistance has become common for Campylobacter in most areas of the world with highest rates being reported in Thailand and Spain. 49–51 Fluoroquinolone susceptibility can be expected currently for most non‐Campylobacter bacterial pathogens causing TD, but resistance rates are increasing in many areas of the world. In two published studies, important levels of rifaximin resistance were not reported among diarrheagenic E coli in travelers receiving rifaximin. 52,53 In a study by Taylor and colleagues 54 comparing pre‐ and post‐treatment stool specimens, greater than or equal to four‐fold rises in minimal inhibitory concentrations (MICs) of ETEC for rifaximin were seen in many patients; however, the MICs remained below the stool concentrations achieved. Rifaximin MICs of pathogens and intestinal flora will need to be monitored as the drug is used for chemoprophylaxis. The lack of resistance so far may relate to limited general use.

Chemoprophylaxis, Drugs to Consider, Clinical Trials and Concerns

SeeTable 2 for a summary of past trials.

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Table 2

Published placebo‐controlled studies of chemoprophylaxis in people traveling from industrialized countries to developing regions for 1 to 3 weeks

Year, country (reference)Number of subjects receiving active treatmentStudy drugProtection rate (%)
1975, Mexico 55 26Lactobacillus acidophilus and Lactobacillus bulgaricus0
1976, Kenya 56 39Doxycycline 100 mg qd86
1977, Morocco 57 40Doxycycline 100 mg qd83
1977, Mexico 58 62Bismuth subsalicylate liquid preparation, 4.2 g/d in four divided daily doses62
1979, Mexico 59 147TMP/SMX 160 mg of 800 mg bid71
1980, Mexico 60 87TMP/SMX 160 mg of 800 mg qd94
1980, Honduras 61 44Doxycycline 100 mg qd68*
1982, Mexico 62 30Bicozamycin 500 mg qid100
1984, Mexico 63 115Norfloxacin 400 mg qd88
1985, Mexico 64 51Bismuth subsalicylate tablet formulation, 2.1 g/d in four divided daily doses65
1986, Variety of countries 65 62Norfloxacin 200 mg bid75
1988, Egypt 66 222Norfloxacin 400 mg qd93
1988, Tunisia 67 54Ciprofloxacin 500 mg qd94
˜1992, various countries 68 ˜2,000Saccharomyces boulardii0–58
1993–1995, various countries 69 126Lactobacillus GG45
2001–2004, various countries 70 174Lactobacillus acidophilus0
2003, Mexico 53 156Rifaximin 200 mg/qd, bid, or tid72–77
2005, Mexico 71 106Rifaximin 600 mg once per day58
  • TMP/SMX = trimethoprim/sulfamethoxazole.

  • * Performed in an area of doxycycline resistance among bacterial enteric pathogens.

  • Depending upon destination.

Antibacterial drugs

The apparent practical inability to reduce enteric infection and diarrhea during international travel by exercising care in diet combined with the knowledge that most illnesses are caused by bacterial pathogens have encouraged evaluation of antimicrobial drugs to protect the traveler during high‐risk periods of travel.

During the late 1950s and early 1960s, Kean and colleagues 72,73 first demonstrated the value of antibacterial drugs in preventing TD. Later, doxycycline was shown to be effective when pathogens encountered were susceptible, 56,57 but not when the prevalent pathogens were resistant in vitro, 61 to doxycycline. Similarly, TMP/SMX were effective in preventing illness in US students in Mexico in the early 1980s when the drug showed in vitro activity against prevalent bacterial enteropathogens. 59,60 When TMP/SMX resistance emerged widely, 74 the emphasis moved to use of fluoroquinolones. 63,65–67 A Consensus Development Conference held in 1985 recommended against widespread use of antibacterial drugs for diarrhea prevention 75 because of potential drug adverse events, concern that widespread use might facilitate development of resistance among extraintestinal bacterial pathogens, inability to define the groups for which chemoprophylaxis should be recommended, and because self‐treatment was so effective. In making their recommendation, this group was considering the available systemically absorbed antibacterial drugs.

After the US Consensus Development Conference in 1985, a study evaluated the cost‐effectiveness of preventing TD through prophylaxis versus early initiation of empiric antibiotic therapy. 76 This study demonstrated a benefit to prophylaxis compared with treatment with an antibiotic alone and suggested that chemoprophylaxis be reexamined as a means of preventing TD. A second international working group was assembled in Rome 7 years after the National Institute of Health Consensus Conference to develop recommendations on the topic of TD. 77 This international group concluded that exercising care in what is eaten and drunk should be the basis of pretravel planning. The group further indicated that if such restriction in food and beverage intake was not followed, prophylaxis should be considered, particularly in travelers at high risk of diarrhea. At approximately the same time, a medical review article from the United States suggested that prophylaxis should not be recommended for all travelers but might be employed in travelers with higher risk of infection including people with AIDS, advanced disease, or for the elderly. 78

The availability of a poorly absorbed antibacterial drug with in vitro activity against prevalent enteric bacterial enteropathogens has renewed interest in pursuing this approach. In the early 1980s, poorly absorbed bicozamycin was evaluated in a group of US students attending classes in Mexico and found to be effective in preventing diarrhea compared with placebo in a randomized study, 62 providing scientific support for the use of a nonabsorbed antimicrobial agent to prevent TD. However, bicozamycin has not been marketed for human use at the time of this writing. The more recent availability of poorly absorbed rifaximin, an antibacterial drug with in vitro activity against prevalent enteric bacterial enteropathogens, has renewed interest in chemoprophylaxis. Rifaximin, a member of the rifampicin family approved in the United States for treatment of uncomplicated TD in adults, is being considered as a candidate for chemoprevention of TD in adults. Because of poor absorption (<0.4%), systemic reactions are rare. In a study carried out in Mexico in 2003, rifaximin was found to be 72% effective in prevention of TD and 77% effective in prevention of TD requiring antimicrobial therapy without apparent drug‐related adverse event. 53 A single daily dose of rifaximin was as effective as three times a day drug administration. A second study employing single daily dose rifaximin versus placebo was carried out in 2005, showing rifaximin efficacy in preventing TD. 71

Acquired resistance to rifampicin drugs occurs commonly and is the result of one of several single‐step mutations and is a well‐known problem with the absorbed rifamycin, rifampin. 79 Rifaximin may have a low potential for stimulation of resistance of enteric pathogens or gut flora 52,53,80 and modest rises in minimal inhibitory concentrations among enteropathogens should still be far exceeded by the high concentrations of rifaximin achieved in stool. Furthermore, concern about encouraging development of resistance is minimized in view of the drug’s lack of value for treatment of infections outside the intestine. Nevertheless, future monitoring of rifaximin and rifampin susceptibility of flora and pathogens will need to be performed if rifaximin becomes used more widely. One limitation of rifaximin use in chemoprophylaxis is that the drug is not licensed and available in many countries.

Rifaximin also needs to be evaluated more thoroughly in prevention of invasive forms of TD. A small volunteer study provided data to suggest that rifaximin may protect against Shigella infection providing the strain is susceptible to the drug. 81 Additional field studies are needed to determine the value of rifaximin in preventing invasive pathogens such as Shigella,Salmonella, and Campylobacter.

As listed inTable 2, a number of well‐controlled studies have shown that fluoroquinolones are effective in preventing TD when taken as one tablet per day. In published travel medicine guidelines, fluoroquinolones were indicated as the drug of choice if chemoprophylaxis was being considered, but this decision was based on the number of published studies documenting the efficacy of fluoroquinolones. 82 While it has not been studied, some travel medicine experts believe that intermittent doses of a fluoroquinolone could be employed to reduce enteric infection after a particularly high‐risk meal. Fluoroquinolones will effectively prevent enteric infection by diarrheagenic E coli(ETEC and EAEC) and many of the invasive pathogens encountered by travelers. Neither the fluoroquinolones nor the rifaximin at the doses used in prophylaxis are likely to be beneficial in the prevention of Campylobacter infection due to levels of resistance. 21,83 The International Society of Travel Medicine panel does not recommend fluoroquinolones as the first choice for chemoprophylaxis because of systemic absorption and the concern of development of drug‐related adverse events and encouragement of development of resistance by extraintestinal bacteria with potential importance in endogenous infection, although ciprofloxacin often represents the least expensive effective option available.

BSS has antibacterial activity. 84 When taken four times a day, BSS prevented 65% of disease that occurred in the placebo control group. 64 The dose of 2.1 g/d and the administration schedule, four times a day, with meals and at bedtime, are both important. Taking the same BSS dose twice a day or half the dose four times a day was not effective in reducing the occurrence of TD. 85 BSS is considered safe by many experts, although its use leads to potentially important levels of systemic salicylates. 86 It causes blackening of stools and tongues from the harmless bismuth sulfide salt metabolite. BSS generally is not available or used in Europe, Australia, or New Zealand because of concern about bismuth absorption with rare but serious toxic adverse events including encephalopathy. 87–90

Prebiotics and probiotics

A prebiotic is a nondigestible food ingredient that may benefit the host by stimulating growth of specific gut flora including Lactobacillus and Bifidobacterium spp. The prebiotic lactulose showed promise in reducing intestinal carriage of Shigella but was ineffective in treating shigellosis. 91 Prebiotic agents have not been tested for prevention of TD. Probiotics are dietary supplements of living bacteria or yeast providing health benefits through their capacity for intestinal colonization and a lowering of the pH of intestinal contents. A number of studies have evaluated probiotics in prevention of TD.

Lactobacillus spp and Saccharomyces boulardii

Several Lactobacillus species have been evaluated in travelers as chemoprophylactic agents.Lactobacillus acidophilus was studied in travelers and had no apparent effect on diarrhea prevention. 55,70 Lactobacillus GG provided 12% to 45% protection against TD. 69,92 Saccharomyces boulardii in a dose of 250 mg or 1,000 mg was used in 3,000 Austrian travelers to high‐risk regions and showed a dose‐related protection only for one group traveling to North Africa. 68 Significant protection was not seen for travel to other areas.

Future research should be directed toward evaluation of probiotic combinations 93 and toxin‐binding probiotics as prophylactic agents in TD 94 as well as establishing the optimal dose and administration schedule of Lactobacillus GG.

InTable 3, an assessment of strength of evidence for available prevention approaches, including informed food and beverage selection and chemoprophylaxis are provided.

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Table 3

Clinical evidence for efficacy of the various prevention approaches, informed food and beverage selection, and chemoprophylaxis in the prevention of travelers’ diarrhea (TD)

Approach or chemoprophylactic agentStrength of evidenceQuality of evidenceComments
Selection of likely safer foods and beveragesCIIIA randomized study would be difficult to design but could be helpful
Bismuth subsalicylateAIInexpensive; will turn stools and tongues black (harmless bismuth sulfide); leads to salicylate absorption, must take the drug four times a day; not to be used in persons with advanced AIDS or with chronic enteric disease where bismuth absorption may occur across the damaged mucosa
Lactobacillus GGBIMore study is needed, optimal dosage regimen uncertain
Saccharomyces boulardiiCIMore study is needed, optimal dosage regimen uncertain
DoxycyclineA I Expected worldwide resistance limits value of this drug
TMP/SMXA I Expected worldwide resistance limits value of this drug
Fluoroquinolones*AIEffective, side effects, and concern about stimulation of resistance prevents making recommendations for broad use
RifaximinAISafest available drug, it is not known if the drug will prevent invasive forms of the TD; close monitoring of antimicrobial resistance is needed if the drug is broadly used in travel medicine and gastroenterology
  • TMP/SMX = trimethoprim/sulfamethoxazole.

  • * Ciprofloxacin, norfloxacin, levofloxacin, ofloxacin.

  • When drugs were tested, bacterial pathogens causing TD generally were susceptible; if tested currently due to general resistance, the drugs would likely be classified as ineffective.

Objectives of immunoprophylaxis

For residents of many industrialized regions, immunization does not play a significant role in prevention of diarrhea since vaccines are not available for the vast majority of organisms associated with TD. Exceptions are rotavirus vaccines for infants 95 and a cholera vaccine with activity against ETEC, available in many countries (see below). The panel feels that vaccines should be pursued for prevention of TD. The evidence for vaccine prevention of TD is lacking and without additional information about cost of vaccine, protective efficacy achieved, duration of protection afforded, and adverse events, no meaningful cost‐effectiveness of this approach can be provided. Published trials with ETEC vaccines are summarized inTable 4.

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Table 4

Immunoprophylaxis trials in the vaccine prevention of travelers’ diarrhea

VaccinePopulation and protective efficacy (% protection)Reference
Vibrio cholerae whole cell/recombinant cholera toxin (CT) B subunit—oral cholera vaccine (Dukoral) and ETEC whole cell/recombinant CT B subunit—ETEC vaccineMorocco, 52% against ETEC diarrhea, 65% against mixed infections, and 82% for ETEC plus Salmonella enteric 97
Guatemala and Mexico, 77% against LT–ETEC strains with ETEC containing colonization factor antigens contained in the vaccine 104
37.5 μg LT administered by transcutaneous patch ETEC vaccine (Intercell Corporation) administered twiceGuatemala and Mexico, 76% for moderate to severe diarrhea (all causes), 66% for moderate to severe ETEC diarrhea 109
  • ETEC = Enteroaggregative Escherichia coli; LT = labile enterotoxin.

Whole Cell (WC) Vibrio cholerae/Recombinant B Subunit Cholera Toxin (CT) (WC/rBS)—Oral Cholera Vaccine

This vaccine has been evaluated in ETEC endemic areas in indigenous adults and children and has been found to be immunogenic, to provide short‐term (60%–67%) protection against ETEC diarrhea, 96–98 and to show 85% protective efficacy against cholera. 99,100 The vaccine, marketed as Dukoral or Ecoral, is available in more than 50 countries including countries in the European Union, Canada, Australia, Norway, and Switzerland.

Whole cell ETEC/Recombinant B subunit CT—Oral ETEC vaccine

This experimental vaccine has been developed for prevention of TD in view of the importance of ETEC as a cause of TD. 2,3,9 By providing the involved colonization factor antigens of prevalent ETEC strains, 101–103 the vaccine will reduce the occurrence of ETEC TD. 104

Heat‐labile enterotoxin (LT) ETEC transcutaneous patch vaccine

Colonization factor and antitoxin immunity were induced transcutaneously in animals 105 and with a patch in humans. 106 Physical disruption of the stratum corneum improved the efficiency of the transcutaneous delivery of the heat‐labile enterotoxin (LT) of ETEC. 107 The LT–ETEC patch vaccine was tested in volunteers producing a robust immune response with reduction in moderate to severe ETEC diarrhea following experimental ETEC challenge. 108 One report provided evidence that the patch vaccine administered twice before travel was both safe and effective in reducing the occurrence of moderate to severe diarrhea rates among 170 international travelers participating in a placebo‐controlled trial (59 vaccines and 111 placebo subjects). 109

Will vaccines go beyond ETEC prevention?

The WC/rBS oral cholera vaccine in one trial protected against ETEC diarrhea and diarrhea due to Salmonella. 97 The LT–ETEC patch vaccine was effective in reducing all cases of moderate to severe TD, not just those in which ETEC was isolated. There appear to be two potential explanations for the activity of the vaccines. First, it is likely that ETEC is more important as a cause of TD than is suggested by conventional methods of detection. 110,111 Second, ETEC LT–based vaccines may lead to protection against a variety of enteropathogens.

Prevention of TD in children

For children, the mainstay of prevention of TD while in developing regions should be diet and beverage restrictions, which will minimize the chance of consumption of the more likely contaminated items. For infants and toddlers, TD prevention should center on careful selection of foods and drinks, which will be microbiologically safe including foods purchased at reliable food stores and only bottled or previously boiled water. For infants, breast‐feeding should be encouraged to minimize contamination and possibly to provide protective factors. Chemoprophylaxis should never be used for infants ≤12 months of age.

Chemoprophylaxis with BSS is not recommended for young children because of the concern with excessive salicylate absorption. 86 Fluoroquinolones are not recommended for routine treatment or prevention of TD in children. Rifaximin is available in a small number of countries as a pediatric suspension. Rotavirus vaccine is part of the recommended immunization schedule for infants in the United States and many other countries throughout the world. 95

Performance and outcome measures

The following outcome measures will be important to examine as the areas of dietary/beverage restrictions, chemo‐ and immunoprophylaxis are evaluated in people planning trips to tropical and semitropical areas from industrialized regions.

  1. The proportion of people planning trips to high‐risk regions of developing tropical and semitropical areas who are aware of current characterization of the usually safe and often unsafe foods, the proportion of travelers complying with these principles during their travel, and the relationship between food and beverage consumption patterns and rates of diarrhea.

  2. The proportion of travelers to high‐risk regions electing to take preventive medications, rates of diarrhea in groups employing or not employing chemoprophylaxis, adverse drug effects, and antimicrobial susceptibility patterns of bacterial enteropathogens and intestinal flora to employed preventive drugs as well as related ones such as rifampicin in the case of rifaximin use.

  3. Safety and efficacy of immunoprophylactic measures and enteropathogens against which the vaccines provide protection.

To whom to offer chemoprophylaxis

Recommendations for chemoprophylaxis for TD differ by region of the world. Most European specialists and some US experts prefer to almost never recommend chemoprophylaxis in travelers. Some authorities from the United States and a minority of experts from Europe feel that subgroups can be identified where chemoprophylaxis could be considered. InTable 5, some of the subgroups identified by travel medicine specialists are identified along with references offering these indications.

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Table 5

Potential indications for recommending prevention strategies in international travelers to high‐risk regions of the developing world

Groups in whom to consider chemoprophylaxis or vaccinationIndividual subjects for whom the approach can be consideredReference
Short‐term illness could ruin purpose of tripAthletes, politicians, musicians, lecturers, travelers on a tight schedule 77,78,112
A diarrheal illness could importantly complicate an underlying conditionPersons with insulin‐dependent diabetes mellitus, congestive heart failure, advanced cancer or HIV infection, HLA‐B27 positive or reactive arthritis, inflammatory bowel disease (ulcerative colitis or Crohn’s disease), wheel chair confined person, ileostomy patients 77,112
Underlying condition or genetics making traveler more susceptible to enteric infectionReduced gastric acid by drugs, gastric disease, or surgery or genetic susceptibility (polymorphism in interleukin‐8 or lactoferrin gene) 113–118
Other healthy personsFuture travelers who have had TD before suggesting increased genetic risk and those who request chemoprophylaxis 112

Because the reservoir of enteric infections in TD is within the local host country and its food and water, use of antibiotics in travelers is unlikely to influence resistance patterns of the prevalent bacterial enteropathogens. Thus, as the infection is acquired exogenously by the traveler from the local environment and not from his or her own microbial flora, the duration of a positive drug effect in preventing diarrhea is likely to be quite long. However, the panel feels that the maximum length of time that preventive drugs should be used to prevent TD is 2 weeks. Giving the preventive drug for a 3‐week trip, while not recommended, should also be effective and safe. Prophylaxis is most beneficial for shorter trips based on drug cost and safety related to duration of drug administration and the possibility that natural immunity seen with medium‐ to long‐term stay in the country could be inhibited by preventive drugs. People remaining at risk for more than 3 weeks should not be offered the opportunity to take chemoprophylaxis.

Conclusions

The available information about chemoprophylaxis comes largely from the limited number of studies supported by the pharmaceutical industry. Without financial support for such studies from federal or industrial sources, insufficient attention has been given to a prospective study of behavior change evaluating the effect of improved food and beverage selection on rates of subsequent illness. The International Society of Travel Medicine encourages innovative studies looking at nondrug approaches to reduce diarrhea. The efforts seen in Jamaica are particularly important. With governmental support, a Hazard Analysis and Critical Control Point program was instituted on resort properties aimed to improve hygiene. This program resulted in a 72% reduction in diarrhea rate. 119,120 Other countries should develop programs designed to improve general hygienic conditions in restaurants and on resorts.

Future research

Because of the significant health burden and economic implications associated with TD, more effective prevention measures are needed. In the following list, the panel highlights areas of special concern that need to be addressed as strategies are being developed to prevent TD.

  1. Studies should be designed to scientifically identify the high‐ and low‐risk foods and beverages encountered in developing regions.

  2. Studies should be pursued to determine how to modify behavior so that travelers follow food and beverage selection recommendations.

  3. Prospective studies are needed to determine the value of dietary and beverage selection principles in prevention of TD.

  4. Studies are needed to determine whether chemoprophylaxis (or aggressive early empiric treatment) with one of the evaluated drugs prevents PI‐IBS.

  5. Cost‐effectiveness studies should be performed to determine the optimal length and maximum length of time, which chemoprophylactic drugs should be employed while people are in high‐risk regions.

  6. Effectiveness of available agents including rifaximin, azithromycin, BSS, and probiotics in preventing TD due to both diarrheagenic E coli and invasive bacterial enteropathogens should be determined in multiple regions of the world.

  7. Surveillance of rifaximin and rifampicin resistance patterns should be established and maintained as rifaximin is more broadly used in chemoprophylaxis in travel medicine.

  8. Additional efficacy trials with immunoprophylaxis regimens in prevention of TD should be conducted. Today, the single available immunoprophylactic vaccine is the WC/rBS vaccine, Dukoral. The potential of this vaccine as well as its descendant, the WC ETEC–binding/rBS CT oral ETEC vaccine need to be fully explored. The ETEC transcutaneously administered patch vaccine looks promising and a large phase III clinical trial is being planned by the sponsor. Cost benefit studies are needed with future vaccines to place them in perspective with other options including chemoprophylaxis and early self‐therapy of illness.

Declaration of interests

H.L.D has consulted with, received honoraria for speaking and has received research grants administered through his university from Salix Pharmaceutical Company; has received a consulting fee from Romark Institute for Medical Research; has received research grants administered through his university from Optimer Pharmaceuticals and IOMAI Corporation; has received an honorarium for consulting and/or speaking with McNeil Consumer Healthcare and Merck Vaccine Division.

C.D.E has received speaking honoraria from and is on an advisory board for Salix.

S.G. is a part‐time employee of a pharmaceutical company (Optimer Pharmaceuticals, Inc., San Diego, CA, USA) that is currently in a phase 3 trial to test a drug to treat TD.

L.R. gave lectures and participated in advisory boards and phase II‐II studies SBL vaccine, Sanofi Pasteur MSD, and Glaxo Smith Kline.

R.S. has accepted fee for speaking, organizing and chairing education, consulting and/or serving on advisory boards, also reimbursement for attending meetings and funds for research from Astral, Baxter, Berna Biotech/Crucell, GlaxoSmithKline, Novartis Vaccine, Optimer, Roche, Salix, Sanofi Pasteur MSD, and/or SBL Vaccine.

T.W. receives fee for speaking from Sanofi Pasteur, GSK, UCB, and Novartis Vaccines.

M.J.G.F. and L.K.P. state that they have no conflicts of interest.

Acknowledgments

The authors wish to thank and acknowledge, with each person’s permission, Bradley A. Connor, MD for his excellent work as guest editor, David R Shlim, MD for his valuable advice in the preparation of this article, and Davidson H. Hamer, MD for his critical review.

References

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