The use of preventive measures and self-treatment for travelers' diarrhea is routine in regions where the occurrence of diarrhea is predictably high. People traveling to these areas who do not exercise care in their selection of consumed foods and beverages will suffer high rates of illness. Such diarrhea normally affects the traveler for a day, although it can result in chronic postinfectious irritable bowel syndrome. Although systemic antibacterial drugs are effective in preventing diarrhea, their use is not routinely recommended because of side effects and their importance as a therapy for extra-intestinal infections. This review focuses on current and future uses of antibacterial drugs in the prevention and therapy of travelers' diarrhea. Minimally absorbed (<0.4%) rifaximin can effectively reduce the occurrence of travelers' diarrhea without side effects. Bismuth subsalicylate is a useful alternative, although it is less effective than rifaximin for the prevention of travelers' diarrhea and the required doses are less convenient. All people who travel to high-risk areas should take curative antimicrobial agents with them for self-treatment of illness: rifaximin 200 mg three times a day for 3 days, or an absorbable agent such as a fluoroquinolone or azithromycin taken in a single dose initially, with the need for a second or third dose determined by clinical response. Loperamide (up to 8 mg per day for =2 days) can be given with the antibiotic to offer rapid symptomatic improvement. In the future, the ability to evaluate the genetic risk of illness acquisition might allow person-specific recommendations to be made.
Approximately 20 million episodes of diarrhea occur annually in people traveling from industrialized regions to developing countries. The world can be divided into three regions depending upon the risk of acquiring travelers' diarrhea for visitors from industrialized and low-risk regions.
The success of antibacterial chemoprophylaxis in treating diarrhea provided the first evidence that bacteria are responsible for most episodes of the illness. Studies demonstrating that antibacterial drugs were effective in the treatment of travelers' diarrhea were first carried out in 1980 and 1981, with each study published 2 years later.
Thanks to microbiology studies and the response of patients to antibacterial treatment, we now know that about 80% of cases of travelers' diarrhea are due to bacterial agents. There are three main causes of diarrhea. Diarrheogenic Escherichia coli, including enterotoxigenic E. coli and enteroaggregative E. coli, is responsible for ~50% of cases. The invasive bacterial pathogens Campylobacter jejuni, Shigella, Salmonella and invasive E. coli cause ~10-25% of cases, with the highest frequencies in southern Asia. In ~20% of cases no pathogen is detectable; because they seem to be both treated and prevented by antibacterial drugs, most of these cases are caused by undefined bacterial pathogens. In coastal areas of the world, non-cholera Vibrio species cause a small percentage of diarrhea. V. cholerae can cause travelers' diarrhea in epidemic areas but cholera is rare in international travelers.
Regardless of cause, most cases of travelers' diarrhea have a similar clinical appearance, with patients complaining of watery diarrhea with abdominal pain or cramps of variable severity. Fever and dysentery (gross blood in stool) are infrequent and are documented in 1-3% of cases. Illness generally incapacitates the traveler for about 1 day. Diarrhea persists for more than 2 weeks in ~2-10% of cases and as many as 10% of patients develop what is now recognized as postinfectious irritable bowel syndrome (IBS). With postinfectious IBS, chronic gastrointestinal complaints occur with abdominal discomfort or pain that can be relieved by defecation and/or a change in bowel pattern and stool form (intermittent diarrhea and constipation), bloating, abdominal distention, passage of mucus, fecal straining, urgency or feeling of incomplete evacuation.
Prevention of Illness
The objectives of disease prevention are to eliminate the incapacitation that is associated with diarrhea and the possibility of chronic enteric complications post-diarrhea. Success in these areas will help reduce the fear of acquiring diarrhea, which can often lead to failed travel plans, preventing business development with economic implications for all concerned.
Food and Beverage Selection
More research is needed to determine how to motivate travelers to select safer food and beverage items, which would reduce the rates of developing diarrhea. The frequently safe foods include those served steaming hot (=59 °C), dry items such as bread, those with high sugar content such as syrups, jellies and honey, and fruit that can be peeled. The often unsafe foods include moist foods served at near room temperature.
A study carried out in 1957 that was published in 1959 showed that 35% of US travelers regularly took preventive drugs during visits to Mexico and that this was the recommended approach at the time. Although there are no recent studies of the use of prophylaxis because of current travel medicine recommendations, antimicrobial chemoprophylaxis appears to be less common.
In studies carried out during the 1980s and 1990s, bismuth subsalicylate, PROBIOTICS and a variety of antibiotics were tried as a means of reducing the occurrence of enteric illness during travel to high-risk areas.
Bismuth Subsalicylate. Bismuth subsalicylate has antibacterial properties and prevents 65% of expected travelers' diarrhea cases when a total dose of 2.1 g per day is taken as four equally divided doses at meals and at bedtime. Bismuth subsalicylate causes harmless darkening of the tongue and stools and, on direct questioning, tinnitus in a small number of treated subjects. Compliance with this preventive approach is always a concern.
Probiotics. The use of probiotics, living bacterial cultures that inhibit potential colonizing bacteria, has been evaluated for the prevention of travelers' diarrhea. In a group of travelers to various international destinations, the probiotic Lactobacillus GG prevented travelers' diarrhea in 47% of those who would have been expected to develop the condition. Although the use of Lactobacillus GG or other probiotics is not currently recommended because of their low efficacies, the search for new and more effective probiotics is warranted in view of the intrinsic safety of these agents.
Antimicrobial Drugs. When enterotoxigenic E. coli was established as the main cause of travelers' diarrhea, antimicrobial agents were tested as preventive drugs. Despite well-documented concerns about the photosensitivity of treated patients, DOXYCYCLINE was successfully employed as a preventive therapy more than two decades ago. Because of current high levels of doxycycline resistance among enteric bacterial pathogens worldwide, this antibacterial drug is currently not recommended for the prevention of travelers' diarrhea. During the 1980s, before resistance to the drug became widespread, trimethoprim-sulfamethoxazole was found to be effective in preventing travelers' diarrhea. Despite an increase in bacterial resistance to many drugs, the fluoroquinolones have been shown to prevent most cases of travelers' diarrhea.
In 1985, an NIH Consensus Statement concluded that antibacterial chemoprophylaxis with absorbed drugs, such as trimethoprim-sulfamethoxazole or the fluoroquinolones, should not be routinely used because of the possible side effects and the potential for stimulating bacterial resistance to agents needed for the treatment of extraintestinal infections. Recommendations for the treatment of breakthrough diarrhea that might occur during fluoroquinolone prophylaxis, however, are unclear when the drug failing to prevent the initial diarrhea, presumably owing to a resistant microorganism, is also one of the recommended treatments. Seven years later in a meeting of specialists from Europe and the US it was concluded that use of prophylaxis with absorbed drugs should be considered (in spite of the possible side effects) for travelers to high-risk areas who would not adhere to strict guidelines for avoiding potentially contaminated food and drink. Although prophylaxis with absorbed drugs is not recommended for all travelers, this approach was felt by the group reviewing guidelines to be useful for people performing high-risk travel who also had higher risk of infection, such as those with advanced AIDS, the elderly, or in the presence of an unstable medical problem such as insulin-dependent diabetes, cancer or liver disease.
When studies demonstrated the value of nonabsorbed drugs for the treatment or prevention of travelers' diarrhea, a minimally absorbed (<0.4%) rifamycin-derivative being used in Italy, rifaximin, was evaluated. Rifaximin successfully prevented travelers' diarrhea in a placebo-controlled trial among more than 200 US college students during their first 2 weeks in Mexico, with diarrhea occurring in 15% of students taking rifaximin and 54% taking a placebo, which gives the drug a protection rate of 72-77%. Rifaximin 200 mg was equally effective when taken with meals once, twice or three times a day. Rifaximin was shown in this study and others to be free of detectable side effects, with minimal alteration of colonic flora.
A study to determine the effect of rifaximin in the prevention of diarrhea due to invasive pathogens is being planned for international travelers to Asia. As volunteers given rifaximin prophylaxis are protected against experimental Shigella challenge, rifaximin is likely to reduce the occurrence of invasive disease. My research group is also planning a study to evaluate prophylactic rifaximin in the prevention of postinfectious IBS. If chemoprophylaxis with rifaximin successfully prevents diarrhea from invasive pathogens and postinfectious IBS, recommendations for rifaximin chemoprophylaxis in international travelers should become routine.
Prophylaxis is a cost-effective way of reducing the occurrence of diarrhea. Use of a safe and effective poorly absorbed antimicrobial (such as rifaximin) is preferable because it will not cause systemic side effects and should not encourage the development of resistance in pathogenic bacteria outside the gut. This should encourage more liberal use of chemoprophylaxis in preventing illness among international travelers.
Options for Treatment
Fluids, Diet and Symptomatic Treatment
When otherwise healthy travelers develop diarrhea they should be encouraged to consume fluids and salty foods. Oral fluid treatment that is more active should be considered for very young or old travelers or for those with profuse cholera-like diarrhea. Antisecretory and antimotility drugs decrease the number of stools passed by patients with travelers' diarrhea but do not shorten the duration of illness. The ingestion of food while ill is recommended to facilitate enterocyte renewal and speed up recovery.
Showing the in vitro activity of antibacterial drugs against the likely causative bacteria of travelers' diarrhea is of use in predicting the value of the drug in shortening the duration of illness. The primary efficacy parameter in clinical trials evaluating antimicrobial agents for treatment is the time from initiation of therapy until the last unformed stool is passed (TLUS); wellness is declared at this point. Antibacterial drugs with in vitro activity have been shown to reduce TLUS in cases of travelers' diarrhea by 1-3 days compared with no therapy or placebo. A second clinical parameter in the evaluation of therapy is treatment failure or failure to achieve wellness after 5 days of observation. Active antibacterial drugs significantly reduce the treatment failure rate from 27-56% for placebo treatment, to 4-17%. Some of the illnesses that persist after treatment relate to the presence of nonbacterial or antimicrobial-resistant pathogens, especially Campylobacter.
Use of rifaximin 400 mg twice a day for 3 days and ciprofloxacin 500 mg twice a day for 3 days (the usual recommended dose) is associated with similar rates of TLUS (25.7 h and 25.0 h, respectively) and treatment failure (10% and 6%, respectively). In a multicenter, multidose, placebo-controlled study, rifaximin was effective in shortening the duration of diarrhea and in reducing the rate of treatment failure with a similar side-effect profile to placebo. The in vitro susceptibility of bacteria to rifaximin is moderately high (16-32 µg/ml) but, as rifaximin is minimally absorbed, fecal levels of the drug exceed 8,000 µg/g after 3 days of therapy, far exceeding inhibitory levels. Although rifaximin is as effective as the fluoroquinolones for the management of the watery diarrhea syndrome, the less common cases of febrile dysentery, usually caused by strains of Shigella or Campylobacter, are best treated with a systemic antibiotic, such as a fluoroquinolone or azithromycin, which is able to reach the organisms that have invaded the intestine. Nonabsorbed drugs are primarily active at the surface of the gut mucosa.
As a result of the widespread use of ciprofloxacin in humans and fluoroquinolone use in animal populations over the past few decades, antibacterial resistance to ciprofloxacin has become a growing problem, particularly among strains of Campylobacter. Unlike the related drug rifampin, rifaximin has a low potential for the development of resistance of colonic flora when used both for prophylaxis and therapy. This is probably related to the low aqueous colonic solubility of the drug.
As antimicrobial resistance increases with more widespread use of these drugs, newer drugs with less potential for the development of resistance should be sought. Encouragingly, rifaximin resistance is not thought to have emerged after nearly two decades of use in Italy. Rifaximin is currently licensed in 18 countries: Argentina, Bulgaria, China, Colombia, Czech Republic, Greece, Hungary, Italy, Korea, Lebanon, Mexico, Pakistan, Poland, Romania, Spain, Tunisia, United States and Venezuela. A pediatric suspension form is also available in a number of these countries.
The newer fluoroquinolones, gatifloxacin and moxifloxacin, have been shown to have high in vitro activity against enteric pathogens, and have shown greater activity against Campylobacter than ciprofloxacin in both a published study, and in an unpublished study of multi-resistant strains in our laboratory. These drugs offer another advantage in that they can be used by international travelers for the treatment of diarrhea as well as respiratory tract bacterial infections. Table 3 lists the newer drugs with potential value in the therapy and selective prophylaxis of travelers' diarrhea, with comments about their use. A program of monitoring for antibacterial resistance among prevalent bacterial pathogens in high-risk regions should be developed to help identify the drugs for which the least resistance develops.
Empiric Therapy Recommendations
Everyone who ventures into high-risk regions of the tropical and semi-tropical world should be encouraged to take an antibiotic with them for self-treatment if diarrhea should develop. When to initiate treatment is currently unclear; if treatment is delayed until illness is fully developed, valuable time is lost because it takes nearly a day for antibacterial drugs to cure the illness. On the other hand, if treatment is initiated with the passage of the first unformed stools, people might be exposed to antibiotics unnecessarily, because changes in stool form are not always indicative of illness. The advice given is to allow the traveler to determine when to initiate therapy based on how they feel. Many debilitating enteric illnesses are associated with excessive abdominal complaints including cramps and pain,with minimal degrees of diarrhea.
Loperamide can be given for the treatment of the watery diarrhea syndrome, along with antibacterial therapy for additive effects. Loperamide rapidly decreases the passage of diarrhea stools, while antibacterial drugs shorten or cure the enteric infection. There is sufficient concern about Campylobacter and other invasive pathogens that are present in Thailand, and possibly other parts of Southern Asia, to recommend that travelers take an absorbed drug with them in case they develop fever or dysentery with their illness. In these areas, however, watery E. coli -type diarrhea is still frequently encountered and rifaximin is usually appropriate for self-treatment. The absorbable drug can thus be reserved for treatment of nonresponsive illness.
In May 2004, the US FDA approved rifaximin for the treatment of travelers' diarrhea caused by noninvasive strains of diarrheogenic E. coli. In view of the fact that the overall treatment failure rate for absorbable drugs and rifaximin are equivalent (approximately 10%), and because of the prevalence of E. coli forms of diarrhea in international travelers, rifaximin is suitable as a single drug for self-treatment of diarrhea for travelers to destinations outside of Asia. Unless travelers take several drugs with them, it is not possible to provide coverage for all treatable forms of illness with a single drug. Also, all bacterial forms of travelers' diarrhea are self-limiting, which decreases the need for very broad coverage of all potential bacterial and parasitic pathogens.
Future Directions for Improved Treatment Strategies
In view of the lack of improvements in food hygiene in developing regions for more than a half a century, and with a current lack of attention to this area, it is unlikely that the risk of acquiring diarrhea in most high-risk areas will be altered in the foreseeable future. Thus, we must continue to educate the public about food and beverage safety and look at effective ways to improve peoples' selection of appropriate foods. As national programs have failed to improve food and beverage quality in most areas, universities or travel medicine organizations could work with industry or local governments to develop definable safe havens through education of hotel and restaurant employees and by monitoring local hygiene and food sanitation: this has occurred successfully in Jamaica. At present, all travelers to high-risk areas should be advised of the risk of illness and be armed with antibacterial therapy for self-treatment of resultant illness. Prophylaxis is a cost-effective means of reducing risk of illness for many travelers. Monitoring of antimicrobial susceptibility patterns worldwide will be needed to maintain the best contemporary recommendations for the traveling public. One of the exciting areas of research in this area is the definition of host genetic susceptibility to the bacterial pathogens that cause travelers' diarrhea. In the future it might be possible to develop an individual pre-travel strategy through which self-treatment and chemoprophylaxis would be tailored to individual genetic risk makeup.
At present, chemoprophylaxis with minimally absorbed rifaximin is recommended for travelers who are not likely to be careful about dietary restrictions and for those who are concerned about the temporary disability and postinfectious complications of diarrhea. If future studies confirm the high risk of postinfectious IBS in travelers' diarrhea and the effectiveness of chemoprophylaxis in this setting, broader use of preventive rifaximin should be pursued. All travelers to high-risk areas should be armed with antibacterial drugs to treat illness that occurs during international travel. Currently rifaximin 200 mg three times a day for 3 days is the safest treatment and is equally as effective as systemic antibiotics against most cases of travelers' diarrhea. Absorbed drugs are preferred for the less common symptoms of fever and dysentery. With bacterial resistance to ciprofloxacin increasing, one of the newer fluoroquinolones or the azalide, azithromycin, should become the preferred absorbed agent. The fluoroquinolones with broader activity, such as levofloxacin, gatifloxacin and moxifloxacin, offer advantages for a travel medicine kit, because a single agent might be appropriate for therapy of diarrhea, respiratory and bacterial urinary tract infections.