Chapter 2 Preparing International Travelers
Travelers’ diarrhea (TD) is the most predictable travel-related illness. Attack rates range from 30% to 70% of travelers, depending on the destination and season of travel. Traditionally, it was thought that TD could be prevented by following simple recommendations such as “boil it, cook it, peel it, or forget it,” but studies have found that people who follow these rules may still become ill. Poor hygiene practice in local restaurants is likely the largest contributor to the risk for TD.
TD is a clinical syndrome that can result from a variety of intestinal pathogens. Bacterial pathogens are the predominant risk, thought to account for up to 80%–90% of TD. Intestinal viruses may account for at least 5%–15% of illnesses, although multiplex molecular diagnostic assays increase their detection. Infections with protozoal pathogens are slower to manifest symptoms and collectively account for approximately 10% of diagnoses in longer-term travelers. What is commonly known as “food poisoning” involves the ingestion of preformed toxins in food. In this syndrome, vomiting and diarrhea may both be present, but symptoms usually resolve spontaneously within 12 hours.
Bacteria are the most common cause of TD. Overall, the most common pathogen identified is enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella spp., and Salmonella spp. Enteroaggregative and other E. coli pathotypes are also commonly found in cases of TD. There is increasing discussion of Aeromonas spp., Plesiomonas spp., and newly recognized pathogens (Acrobacter, Larobacter, enterotoxigenic Bacteroides fragilis) as potential causes of TD as well. Viral diarrhea can be caused by a number of pathogens, including norovirus, rotavirus, and astrovirus.
Giardia is the main protozoal pathogen found in TD. Entamoeba histolytica is a relatively uncommon cause of TD, and Cryptosporidium is also relatively uncommon. The risk for Cyclospora is highly geographic and seasonal: the most well-known risks are in Nepal, Peru, Haiti, and Guatemala. Dientamoeba fragilis is a flagellate occasionally associated with diarrhea in travelers. Most of the individual pathogens are discussed in their own sections in Chapter 4, and diarrhea in returned travelers is discussed in Chapter 11.
RISK FOR TRAVELERS
TD occurs equally in male and female travelers and is more common in young adult travelers than in older travelers. In short-term travelers, bouts of TD do not appear to protect against future attacks, and >1 episode of TD may occur during a single trip. A cohort of expatriates residing in Kathmandu, Nepal, experienced an average of 3.2 episodes of TD per person in their first year. In more temperate regions, there may be seasonal variations in diarrhea risk. In south Asia, for example, much higher TD attack rates are reported during the hot months preceding the monsoon.
In environments in warmer climates where large numbers of people do not have access to plumbing or latrines, the amount of stool contamination in the environment will be higher and more accessible to flies. Inadequate electrical capacity may lead to frequent blackouts or poorly functioning refrigeration, which can result in unsafe food storage and an increased risk for disease. Lack of safe water may lead to contaminated foods and drinks prepared with such water; inadequate water supply may lead to shortcuts in cleaning hands, surfaces, utensils, and foods such as fruits and vegetables. In addition, handwashing may not be a social norm and could be an extra expense; thus there may be no handwashing stations in food preparation areas. In destinations in which effective food handling courses have been provided, the risk for TD has been demonstrated to decrease. However, even in developed countries, pathogens such as Shigella sonnei have caused TD linked to handling and preparation of food in restaurants.
Bacterial and viral TD presents with the sudden onset of bothersome symptoms that can range from mild cramps and urgent loose stools to severe abdominal pain, fever, vomiting, and bloody diarrhea, although with norovirus vomiting may be more prominent. Protozoal diarrhea, such as that caused by Giardia intestinalis or E. histolytica, generally has a more gradual onset of low-grade symptoms, with 2–5 loose stools per day. The incubation period between exposure and clinical presentation can be a clue to the etiology:
- Bacterial toxins generally cause symptoms within a few hours.
- Bacterial and viral pathogens have an incubation period of 6–72 hours.
- Protozoal pathogens generally have an incubation period of 1–2 weeks and rarely present in the first few days of travel. An exception can be Cyclospora cayetanensis, which can present quickly in areas of high risk.
Untreated bacterial diarrhea usually lasts 3–7 days. Viral diarrhea generally lasts 2–3 days. Protozoal diarrhea can persist for weeks to months without treatment. An acute bout of gastroenteritis can lead to persistent gastrointestinal symptoms, even in the absence of continued infection (see Chapter 11, Persistent Diarrhea in Returned Travelers). This presentation is commonly referred to as postinfectious irritable bowel syndrome. Other postinfectious sequelae may include reactive arthritis and Guillain-Barré syndrome.
For travelers to high-risk areas, several approaches may be recommended that can reduce, but never completely eliminate, the risk for TD. These include following instructions regarding food and beverage selection, using agents other than antimicrobial drugs for prophylaxis, using prophylactic antibiotics, and carefully washing hands with soap where available. Carrying small containers of alcohol-based hand sanitizers (containing ≥60% alcohol) may make it easier for travelers to clean their hands before eating when handwashing is not possible. No vaccines are available for most pathogens that cause TD, but travelers should refer to the Cholera, Hepatitis A, and Typhoid & Paratyphoid Fever sections in Chapter 4 regarding vaccines that can prevent other foodborne or waterborne infections to which travelers are susceptible.
Food and Beverage Selection
Care in selecting food and beverages can minimize the risk for acquiring TD. See the Food & Water Precautions section in this chapter for CDC’s detailed food and beverage recommendations. Although food and water precautions continue to be recommended, travelers may not always be able to adhere to the advice. Furthermore, many of the factors that ensure food safety, such as restaurant hygiene, are out of the traveler’s control.
Nonantimicrobial Drugs for Prophylaxis
The primary agent studied for prevention of TD, other than antimicrobial drugs, is bismuth subsalicylate (BSS), which is the active ingredient in adult formulations of Pepto-Bismol and Kaopectate. Studies from Mexico have shown that this agent (taken daily as either 2 oz. of liquid or 2 chewable tablets 4 times per day) reduces the incidence of TD by approximately 50%. BSS commonly causes blackening of the tongue and stool and may cause nausea, constipation, and rarely tinnitus.
Travelers with aspirin allergy, renal insufficiency, and gout, and those taking anticoagulants, probenecid, or methotrexate should not take BSS. In travelers taking aspirin or salicylates for other reasons, the use of BSS may result in salicylate toxicity. BSS is not generally recommended for children aged <12 years; however, some clinicians use it off-label with caution to avoid administering BSS to children aged ≤18 years with viral infections, such as varicella or influenza, because of the risk for Reye syndrome. BSS is not recommended for children aged <3 years or pregnant women. Studies have not established the safety of BSS use for periods >3 weeks. Because of the number of tablets required and the inconvenient dosing, BSS is not commonly used as prophylaxis for TD.
The use of probiotics, such as Lactobacillus GG and Saccharomyces boulardii, has been studied in the prevention of TD in small numbers of people. Results are inconclusive, partially because standardized preparations of these bacteria are not reliably available. Studies are ongoing with prebiotics to prevent TD, but data are insufficient to recommend their use. There have been anecdotal reports of beneficial outcomes after using bovine colostrum as a daily prophylaxis agent for TD. However, commercially sold preparations of bovine colostrum are marketed as dietary supplements that are not Food and Drug Administration (FDA) approved for medical indications. Because no data from rigorous clinical trials demonstrate efficacy, there is insufficient information to recommend the use of bovine colostrum to prevent TD.
Although prophylactic antibiotics can prevent some TD, the emergence of antimicrobial resistance has made the decision of how and when to use antibiotic prophylaxis for TD difficult. Controlled studies have shown that use of antibiotics reduces diarrhea attack rates by 90% or more. The prophylactic antibiotic of choice has changed over the past few decades as resistance patterns have evolved. Fluoroquinolones have been the most effective antibiotics for the prophylaxis and treatment of bacterial TD pathogens, but increasing resistance to these agents among Campylobacter and Shigella species globally limits their potential use. In addition fluoroquinolones are associated with tendinitis and an increased risk of Clostridioides difficile infection, and current guidelines discourage their use for prophylaxis. Alternative considerations include azithromycin, rifaximin, and rifamycin SV.
At this time, prophylactic antibiotics should not be recommended for most travelers. Prophylactic antibiotics afford no protection against nonbacterial pathogens and can remove normally protective microflora from the bowel, increasing the risk of infection with resistant bacterial pathogens. Travelers may become colonized with extended-spectrum β-lactamase (ESBL)–producing bacteria, and this risk is increased by exposure to antibiotics while abroad. Additionally, the use of antibiotics may be associated with allergic or adverse reactions, and prophylactic antibiotics limit the therapeutic options if TD occurs; a traveler relying on prophylactic antibiotics will need to carry an alternative antibiotic to use if severe diarrhea develops despite prophylaxis.
The risks associated with the use of prophylactic antibiotics should be weighed against the benefit of using prompt, early self-treatment with antibiotics when moderate to severe TD occurs, shortening the duration of illness to 6–24 hours in most cases. Prophylactic antibiotics may be considered for short-term travelers who are high-risk hosts (such as those who are immunosuppressed or with significant medical comorbidities) or those who are taking critical trips (such as engaging in a sporting event) without the opportunity for time off in the event of sickness.
Oral Rehydration Therapy
Fluids and electrolytes are lost during TD, and replenishment is important, especially in young children or adults with chronic medical illness. In adult travelers who are otherwise healthy, severe dehydration resulting from TD is unusual unless vomiting is prolonged. Nonetheless, replacement of fluid losses remains an adjunct to other therapy and helps the traveler feel better more quickly. Travelers should remember to use only beverages that are sealed, treated with chlorine, boiled, or are otherwise known to be purified.
For severe fluid loss, replacement is best accomplished with oral rehydration solution (ORS) prepared from packaged oral rehydration salts, such as those provided by the World Health Organization. ORS is widely available at stores and pharmacies in most developing countries. ORS is prepared by adding 1 packet to the indicated volume of boiled or treated water—generally 1 liter. Travelers may find most ORS formulations to be relatively unpalatable due to their saltiness. In mild cases, rehydration can be maintained with any palatable liquid (including sports drinks), although overly sweet drinks, such as sodas, can cause osmotic diarrhea if consumed in quantity.
Antimotility agents provide symptomatic relief and are useful therapy in TD. Synthetic opiates, such as loperamide and diphenoxylate, can reduce frequency of bowel movements and therefore enable travelers to ride on an airplane or bus. Loperamide appears to have antisecretory properties as well. The safety of loperamide when used along with an antibiotic has been well established, even in cases of invasive pathogens; however, acquisition of ESBL-producing pathogens may be more common when loperamide and antibiotics are coadministered. Antimotility agents alone are not recommended for patients with bloody diarrhea or those who have diarrhea and fever. Loperamide can be used in children, and liquid formulations are available. In practice, however, these drugs are rarely given to small children (aged <6 years).
Antibiotics are effective in reducing the duration of diarrhea by about a day in cases caused by bacterial pathogens that are susceptible to the particular antibiotic prescribed. However, there are concerns about adverse consequences of using antibiotics to treat TD. Travelers who take antibiotics may acquire resistant organisms such as ESBL-producing organisms, resulting in potential harm to travelers—particularly those who are immunosuppressed or women who may be prone to urinary tract infections—and the possibility of introducing these resistant bacteria into the community. In addition, there is concern about the effects of antibiotic use on travelers’ microbiota and the potential for adverse consequences such as Clostridioides difficile infection as a result. These concerns have to be weighed against the consequences of TD and the role of antibiotics in shortening the acute illness and possibly preventing postinfectious sequelae (see Chapter 11, Persistent Diarrhea in Returned Travelers).
Primarily because of these concerns, an expert advisory panel was convened in 2016 to prepare consensus guidelines on the prevention and treatment of TD. A classification of TD using functional impact for defining severity (Box 2-03) was suggested rather than the frequency-based algorithm that has traditionally been used. The guidelines suggest an approach that matches therapeutic intervention with severity of illness, in terms of both safety and effectiveness (Table 2-10).
The effectiveness of a particular antimicrobial drug depends on the etiologic agent and its antibiotic sensitivity (Table 2-11). As empiric therapy or to treat a specific bacterial pathogen, first-line antibiotics have traditionally been the fluoroquinolones, such as ciprofloxacin or levofloxacin. Increasing microbial resistance to the fluoroquinolones, especially among Campylobacter isolates, may limit their usefulness in many destinations, particularly South and Southeast Asia, where both Campylobacter infection and fluoroquinolone resistance is prevalent. Increasing fluoroquinolone resistance has been reported from other destinations and in other bacterial pathogens, including in Shigella and Salmonella. In addition, the use of fluoroquinolones has been associated with tendinopathies and the development of C. difficile infection. FDA warns that the potentially serious side effects of fluoroquinolones may outweigh their benefit in treating uncomplicated respiratory and urinary tract infections; however, because of the short duration of therapy for TD, these side effects are not believed to be a significant risk.
A potential alternative to fluoroquinolones is azithromycin, although enteropathogens with decreased azithromycin susceptibility have been documented in several countries. Rifaximin has been approved to treat TD caused by noninvasive strains of E. coli. However, since it is often difficult for travelers to distinguish between invasive and noninvasive diarrhea, and since they would have to carry a backup drug in the event of invasive diarrhea, the overall usefulness of rifaximin as empiric self-treatment remains to be determined.
Single-dose regimens are equivalent to multidose regimens and may be more convenient for the traveler. Single-dose therapy with a fluoroquinolone is well established, both by clinical trials and clinical experience. The best regimen for azithromycin treatment may also be a single dose of 1,000 mg, but side effects (mainly nausea) may limit the acceptability of this large dose. Giving azithromycin as 2 divided doses on the same day may limit this adverse event.
Treatment of TD Caused by Protozoa
The most common parasitic cause of TD is Giardia intestinalis, and treatment options include metronidazole, tinidazole, and nitazoxanide (see Chapter 4, Giardiasis). Although cryptosporidiosis is usually a self-limited illness in immunocompetent people, nitazoxanide can be considered as a treatment option. Cyclosporiasis is treated with trimethoprim-sulfamethoxazole. Treatment of amebiasis is with metronidazole or tinidazole, followed by treatment with a luminal agent such as iodoquinol or paromomycin.
A new therapeutic option is rifamycin SV, which was approved by FDA in November 2018 to treat TD caused by noninvasive strains of E. coli in adults. Rifamycin SV is a nonabsorbable antibiotic in the ansamycin class of antibacterial drugs formulated with an enteric coating that targets delivery of the drug to the distal small bowel and colon. Two randomized clinical trials showed that rifamycin SV was superior to placebo and noninferior to ciprofloxacin in the treatment of TD.
Treatment for Children
Children who accompany their parents on trips to high-risk destinations can contract TD as well, with elevated risk if they are visiting friends and family. Causative organisms include bacteria responsible for TD in adults, as well as viruses including norovirus and rotavirus. The main treatment for TD in children is ORS. Infants and younger children with TD are at higher risk for dehydration, which is best prevented by the early initiation of oral rehydration. Empiric antibiotic therapy should be considered if there is bloody or severe watery diarrhea or evidence of systemic infection. In older children and teenagers, treatment recommendations for TD follow those for adults, with possible adjustments in the dose of medication. Among younger children, macrolides such as azithromycin are considered first-line antibiotic therapy, although some experts now use short-course fluoroquinolone therapy (despite its not being FDA-approved for this indication in children) for travelers aged <18 years. Rifaximin is approved for use in children aged ≥12 years. Rifamycin SV is approved for use only in adults.
Breastfed infants should continue to nurse on demand, and bottle-fed infants can continue to drink formula. Older infants and children should be encouraged to eat and may consume a regular diet. Children in diapers are at risk for developing diaper rash on their buttocks in response to the liquid stool. Barrier creams, such as zinc oxide or petrolatum, could be applied at the onset of diarrhea to help prevent and treat rash. Hydrocortisone cream is the best treatment for an established rash. More information about diarrhea and dehydration is discussed in Chapter 7, Traveling Safely with Infants & Children.
Box 2-03. Travelers’ diarrhea definitions
Mild (acute): diarrhea that is tolerable, is not distressing, and does not interfere with planned activities.
Moderate (acute): diarrhea that is distressing or interferes with planned activities.
Severe (acute): diarrhea that is incapacitating or completely prevents planned activities; all dysentery is considered severe.
Table 2-10. Travelers’ diarrhea treatment recommendations
Therapy of mild travelers’ diarrhea
Therapy of moderate travelers’ diarrhea
Therapy of severe travelers’ diarrhea
1These treatment recommendations were developed prior to the approval of rifamycin SV in the United States. Because it is in the same category of antimicrobial drug as rifaximin and because they have the same mechanism of action, rifamycin SV can be considered as an alternative to rifaximin.
Table 2-11. Acute diarrhea antibiotic treatment recommendations
|Azithromycin2,3||1,000 mg||Single or divided dose4|
|500 mg daily||3 days|
|Levofloxacin||500 mg daily||1–3 days4|
|Ciprofloxacin||750 mg||Single dose4|
|500 mg bid||3 days|
|Ofloxacin||400 mg bid||1–3 days4|
|Rifamycin SV5||388 mg bid||3 days|
|Rifaximin5||200 mg tid||3 days|
1 Antibiotic regimens may be combined with loperamide 4 mg initially followed by 2 mg after each loose stool, not to exceed 16 mg in a 24-hour period.
2 Use empirically as first-line in Southeast Asia or other areas if fluoroquinolone-resistant bacteria are suspected.
3 Preferred regimen for dysentery or febrile diarrhea.
4 If symptoms are not resolved after 24 hours, continue daily dosing for up to 3 days.
5 Do not use if clinical suspicion for Campylobacter, Salmonella, Shigella, or other causes of invasive diarrhea. Use may be reserved for patients unable to receive fluoroquinolones or azithromycin.
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