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REF: http://www2.ncid.cdc.gov/travel/yb/utils/ybGet.asp?section=dis&obj=travelers_diarrhea.htm&cssNav=browseoyb

Travelers' Diarrhea                                       See  Infectious Colitis  

Treatment overview:                                              (REF: Dynamed 2009)

• mild cases usually self-limited to 3-5 days
• fluid and electrolyte replacement (e.g., oral rehydration salt packets) usually unnecessary, but might be important in young children

Symptom relief

• bismuth subsalicylate 30 mL orally every 30 minutes (up to 8 doses/day) shown to decrease number of stools by 50% in mild cases in patients > 2 years old (Grade B-I)
• loperamide (Imodium) 4 mg orally, then 2 mg after each loose stool up to 16 mg/day (Grade A-I) unless blood in stools or temperature > 38.5° C (101.3° F)
• loperamide-simethicone combination appears to provide faster and more complete symptom relief of acute nonspecific traveler's diarrhea than either component alone or placebo (level 2 [mid-level] evidence)

Antibiotics may reduce duration by 1-2 days

• provide patients with 3 days of antibiotics in anticipation of travel (Grade B-I)
• treatment of choice is fluoroquinolone (Grade A-I)  
  • ciprofloxacin (Cipro) 500 mg orally twice daily
  • levofloxacin (Levaquin) 500 mg orally daily
  • norfloxacin (Noroxin) 400 mg orally twice daily
  • ofloxacin (Floxin) 200 mg orally twice daily
• azithromycin 1,000 mg orally once is alternative treatment in all destinations especially in areas of fluoroquinolone resistance (Grade B-I)
• rifaximin (Xifaxan) 200 mg orally 3 times daily is another alternative in patients without blood in stools or fever
• continue antibiotics until symptoms resolved, but seek medical attention if symptoms worsen or persist > 3 days (Grade B-I)

Loperamide plus antibiotics shortens duration of symptoms in older children or adults (Grade B-III); do not use if blood in stools or temperature > 38.5° C (101.3° F)

Description

Travelers' diarrhea (TD) is a clinical syndrome resulting from microbial contamination of ingested food and water; it occurs during or shortly after travel, most commonly affecting persons traveling from an area of more highly developed hygiene and sanitation infrastructure to a less developed one. Thus, TD is defined more by circumstances of acquisition than by a specific microbial agent. In fact, there is considerable diversity in etiologic agents, which include bacteria, parasites, or viruses. A similar but less common syndrome is toxic gastroenteritis, caused by ingestion of pre-formed toxins. In this syndrome, vomiting may predominate, and symptoms usually resolve within 12-18 hours.

Pathogen isolation rates among TD studies vary from 30% to 60%. Most cases in which no pathogen is identified respond to antibiotics, suggesting that most of these are bacterial in origin.

Bacterial Enteric Pathogens

Bacteria are the most common cause of TD. In studies of etiologic agents at various destinations, bacteria are responsible for approximately 85% of TD cases, parasites about 10%, and viruses 5%.

• Enterotoxigenic Escherichia coli (ETEC)
  The most common cause of TD worldwide is ETEC. Ingestion of a large inoculum of this organism is necessary to produce disease. These high inoculums occur when there is a breakdown in sanitation, which is often the case in developing countries where ETEC infections are common. ETEC typically produces a watery diarrhea associated with cramps. Fever may be low or absent.
• Enteroaggregative E. coli (EAEC)
  EAEC are increasingly recognized as a cause of TD and may be responsible for up to 25% of cases. EAEC resemble ETEC in clinical presentation and response to antibiotics.
• Campylobacter jejuni
  Campylobacter jejuni is a common cause of diarrhea in developed countries but is many times more prevalent in developing countries. The risk of acquiring infection with Campylobacter appears to vary by destination, with travel to Asia posing a higher risk in most studies. Campylobacter infections may be associated with bloody diarrhea as well as fever.
• Salmonella spp.
  Although nontyphoidal Salmonella infections are frequently associated with foodborne outbreaks in industrialized countries, they are an infrequent cause of TD worldwide.
• Shigella spp.
  The low infectious dose of this organism makes it one of the more commonly reported bacteria associated with TD. Shigella may cause a bloody diarrhea with constitutional symptoms and fever.
• Vibrio spp.
  Diarrhea caused by Vibrio parahaemolyticus and non-O-group 1 Vibrio cholerae may be associated with eating raw or partially cooked seafood. Vibrio cholerae O-group 1 has in general been a rare cause of TD, but recent reports suggest this organism may be associated with the typical TD clinical picture in Western travelers to developing countries.
• Other Bacteria
  Other organisms that have been isolated from patients with TD include Aeromonas hydrophila, Plesiomonas shigelloides, and Yersinia enterocolitica.
• Parasitic Enteric Pathogens
  Parasitic protozoan pathogens account for about 10% of cases of TD and usually present with a more insidious onset. Travelers often complain of persistent symptoms, and the likelihood of recovery of a parasite rather than bacteria from stool specimens increases proportionately with duration of symptoms. The most common organisms in this category include Giardia intestinalis, Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica, and Dientamoeba fragilis.
• Viral Enteric Pathogens
  The contribution of viruses to the burden of TD appears to be quite small, although they can cause substantial morbidity from gastroenteritis, with primarily nausea and vomiting. Sporadic viral infections account for 5%-10% of cases of TD. Enteric viruses such as rotavirus and norovirus, which infect children in developing countries, may also infect travelers to developing countries. Outbreaks of norovirus have been reported on cruise ships. In such outbreaks, a high percentage of susceptible people are likely to become ill.

What preventive measures are effective for travelers' diarrhea?

Travelers can minimize their risk for TD by practicing the following effective preventive measures:

• Avoid eating foods or drinking beverages purchased from street vendors or other establishments where unhygienic conditions are present
• Avoid eating raw or undercooked meat and seafood
• Avoid eating raw fruits (e.g., oranges, bananas, avocados) and vegetables unless the traveler peels them.

If handled properly well-cooked and packaged foods usually are safe. Tap water, ice, unpasteurized milk, and dairy products are associated with increased risk for TD. Safe beverages include bottled carbonated beverages, hot tea or coffee, beer, wine, and water boiled or appropriately treated with iodine or chlorine.

Clinical Presentation

Definitions of TD that rely on rigid criteria for frequency of loose stools in a 24-hour period are commonly used in clinical research studies but are not relevant to the clinical syndrome as it affects travelers. Travelers' diarrhea is characterized by the fairly abrupt onset of loose, watery or semi-formed stools associated with abdominal cramps and rectal urgency. Symptoms may be preceded by a prodrome of gaseousness and abdominal cramping and additional symptoms may be associated, such as nausea, bloating, and fever. Vomiting may occur in up to 15% of those affected. Travelers' diarrhea is generally self-limited and lasts 3-4 days even without treatment, but persistent symptoms may occur in a small percentage of travelers. Postinfectious sequelae have been described, including reactive arthritis, Guillain-Barré syndrome, and postinfectious irritable bowel syndrome (PI-IBS). PI-IBS may occur in up to 3% of persons who contracted travelers' diarrhea.

Is prophylaxis of travelers' diarrhea recommended?

CDC does not recommend antimicrobial drugs to prevent TD. Studies show a decrease in the incidence of TD with use of bismuth subsalicylate and with use of antimicrobial chemoprophylaxis. Several studies show that bismuth subsalicylate taken as either 2 tablets 4 times daily or 2 fluid ounces 4 times daily reduces the incidence of travelers' diarrhea. The mechanism of action appears to be both antibacterial and antisecretory. Use of bismuth subsalicylate should be avoided by persons who are allergic to aspirin, during pregnancy, and by persons taking certain other medications (e.g., anticoagulants, probenecid, or methotrexate). In addition, persons should be informed about potential side effects, in particular about temporary blackening of the tongue and stool, and rarely ringing in the ears. Because of potential adverse side effects, prophylactic bismuth subsalicylate should not be used for more than 3 weeks.

Some antibiotics administered in a once-a-day dose are 90% effective at preventing travelers' diarrhea; however, antibiotics are not recommended as prophylaxis. Routine antimicrobial prophylaxis increases the traveler's risk for adverse reactions and for infections with resistant organisms. Because antimicrobials can increase a traveler 's susceptibility to resistant bacterial pathogens and provide no protection against either viral or parasitic pathogens, they can give travelers a false sense of security. As a result, strict adherence to preventive measures is encouraged, and bismuth subsalicylate should be used as an adjunct if prophylaxis is needed.

Prevention

For travelers to high-risk areas, several approaches may be recommended, which can minimize but never completely eliminate the risk of TD. These include 1) instruction regarding food and beverage selection, 2) use of agents other than antimicrobial drugs for prophylaxis, and 3) use of prophylactic antibiotics.

Care in selecting food and beverages for consumption may minimize the risk for acquiring TD. Travelers should be advised to eat foods that are freshly cooked and served piping hot and to avoid water and beverages diluted with water (reconstituted fruit juices, ice, milk) and foods washed in water, such as salads. Other risky foods include raw or undercooked meat and seafood and raw fruits and vegetables. Safe beverages include those that are bottled and sealed or carbonated. Boiled beverages and those appropriately treated with iodine or chlorine might also be safely consumed. Studies of TD risk at high-risk destinations show that consumption of food or beverages from street vendors poses a particularly high risk, and some studies suggest certain food items such as reheated prepared foods or buffet items are also high risk.

Although food and water precautions continue to be recommended, travelers may have difficulty following this advice. Furthermore, many of the factors that ensure food safety are out of the traveler's control.

The primary agent other than antimicrobial drugs studied for prevention of TD is bismuth subsalicylate (BSS), which is the active ingredient in Pepto-Bismol. Studies from Mexico have shown this agent (taken as either 2 oz of liquid or two chewable tablets four times per day) to reduce the incidence of TD from 40% to 14%. BSS commonly causes blackening of the tongue and stool and may cause nausea, constipation, and rarely tinnitus. BSS should be avoided by travelers with aspirin allergy, renal insufficiency, and gout and by those taking anticoagulants, probenecid, or methotrexate. In travelers taking aspirin or salicylates for other reasons, the use of BSS may result in salicylate toxicity. Caution should be used in administering BSS to children with viral infections, such as chickenpox or influenza, because of the risk of Reye syndrome. BSS is not recommended for children <3 years of age. Studies have not established the safety of BSS use for periods of greater than 3 weeks.

The use of probiotics, such as Lactobacillus GG and Saccharomyces boulardii, has been studied in the prevention of TD in limited numbers of subjects. Results are inconclusive.

Travelers should be cautioned that other nonantimicrobial agents, such as enterovioform and related halogenated hydroxyquinoline derivatives, are sometimes available to travelers at their destination. These substances are not useful in preventing TD, may cause serious neurologic adverse events, and should never be used for prophylaxis.

Prophylactic antibiotics have been demonstrated to be quite effective in the prevention of TD. Controlled studies have shown that diarrhea attack rates are reduced from 40% to 4% by the use of antibiotics. The ideal antibiotic is one to which the pathogenic bacteria are sensitive, which has changed over the past few decades as resistance patterns have evolved. Agents such as TMP-SMX and doxycycline are no longer considered effective antimicrobials against enteric bacterial pathogens. The fluoroquinolones (as Cipro)  have been the most popular and effective antibiotics for the prophylaxis and treatment of bacterial TD pathogens, but increasing resistance to these agents, initially among Campylobacter species and now among other TD pathogens, may limit their benefit in the future. A newly approved nonabsorbable antibiotic, rifaximin, is being investigated for its potential use in TD prophylaxis. Prophylactic antibiotics should not be recommended for most travelers. In addition to affording no protection against nonbacterial pathogens, they may also give the traveler a false sense of security, leading to neglect of the food and water precautions that might protect against other enteric diseases. In addition, the use of antibiotics may be associated with allergic or adverse reactions in a certain percentage of travelers, an unnecessary occurrence, as early self-treatment with antibiotics for established TD is quite effective.

Prophylactic antibiotics may be considered for short-term travelers who are high-risk hosts (such as those who are immunosuppressed) or are taking critical trips during which even a short bout of diarrhea could impact the purpose of their trip.

What treatment measures are effective for travelers' diarrhea?

TD usually is a self-limited disorder and often resolves without specific treatment; however, oral rehydration is often beneficial to replace lost fluids and electrolytes. Clear liquids are routinely recommended for adults. Travelers who develop three or more loose stools in an 8-hour period---especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in stools---may benefit from antimicrobial therapy. Antibiotics usually are given for 3-5 days. Currently, fluoroquinolones are the drugs of choice. Commonly prescribed regimens are 500 mg of ciprofloxacin twice a day or 400 mg of norfloxacin twice a day for 3-5 days. Trimethoprim-sulfamethoxazole and doxycycline are no longer recommended because of the high level of resistance to these agents. Bismuth subsalicylate also may be used as treatment: 1 fluid ounce or 2 262 mg tablets every 30 minutes for up to eight doses in a 24-hour period, which can be repeated on a second day. If diarrhea persists despite therapy, travelers should be evaluated by a doctor and treated for possible parasitic infection.

When should antimotility agents not be used to treat travelers' diarrhea?

Antimotility agents (loperamide, diphenoxylate, and paregoric) primarily reduce diarrhea by slowing transit time in the gut, and, thus, allows more time for absorption. Some persons believe diarrhea is the body's defense mechanism to minimize contact time between gut pathogens and intestinal mucosa. In several studies, antimotility agents have been useful in treating travelers' diarrhea by decreasing the duration of diarrhea. However, these agents should never be used by persons with fever or bloody diarrhea, because they can increase the severity of disease by delaying clearance of causative organisms. Because antimotility agents are now available over the counter, their injudicious use is of concern. Adverse complications (toxic megacolon, sepsis, and disseminated intravascular coagulation) have been reported as a result of using these medications to treat diarrhea.

Treatment

Antibiotics are the principal element in the treatment of TD. Adjunctive agents used for symptomatic control may also be recommended.

Antibiotics

As bacterial causes of TD far outnumber other microbial etiologies, empiric treatment with an antibiotic directed at enteric bacterial pathogens remains the best therapy for TD. The benefit of treatment of TD with antibiotics has been proven in a number of studies. The effectiveness of a particular antimicrobial depends on the etiologic agent and its antibiotic sensitivity. Both as empiric therapy or for treatment of a specific bacterial pathogen, first-line antibiotics include those of the fluoroquinolone class, such as ciprofloxacin or levofloxacin. Increasing microbial resistance to the fluoroquinolones, especially among Campylobacter isolates, may limit their usefulness in some destinations such as Thailand and Nepal. An alternative to the fluoroquinolones in this situation is azithromycin. Rifaximin 200 mg (2-3x/day x 2 weeks) has been approved for the treatment of TD caused by noninvasive strains of E. coli.

The standard treatment regimens consist of 3 days of antibiotic, although when treatment is initiated promptly shorter courses, including single-dose therapy, may reduce the duration of the illness to a few hours.

Nonspecific Agents

Bismuth subsalicylate (Pepto-Bismol), taken as 1 oz of liquid or two chewable tablets every 30 minutes for eight doses, has been shown to decrease stool frequency and shorten the duration of illness in several placebo-controlled studies. This agent has both antisecretory and antimicrobial properties. BSS should be used with caution in travelers on aspirin therapy or anticoagulants or those who have renal insufficiency. In addition, BSS should be avoided in children with viral infections, such as varicella or influenza, because of the risk of Reye syndrome.

Other nonspecific agents, such as kaolin pectin, activated charcoal, and probiotics, have had a limited role in the treatment of TD.

Antimotility Agents

Antimotility agents provide symptomatic relief and serve as useful adjuncts to antibiotic therapy in TD. Synthetic opiates, such as loperamide and diphenoxylate, can reduce bowel movement frequency and enable travelers to resume their activities while awaiting the effects of antibiotics. Loperamide appears to have antisecretory properties as well. Although earlier studies suggest these agents should not be used in diarrheal illness associated with high fever or blood in the stool, more recent studies suggest these medications may be used in such instances as long as antibiotics are administered concurrently. Loperamide and diphenoxylate are not recommended for children <2 years of age.

Oral Rehydration Therapy

Fluid and electrolytes are lost in cases of 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 present. Nonetheless, replacement of fluid losses remains an important adjunct to other therapy. Travelers should remember to use only beverages that are sealed or carbonated. For more severe fluid loss, replacement is best accomplished with oral rehydration solutions (ORS), such as World Health Organization ORS solutions, which are widely available at stores and pharmacies in most developing countries. (See Table 4-19 for details.) ORS is prepared by adding one packet to the appropriate volume of boiled or treated water. Once prepared, solutions should be consumed or discarded within 12 hours (24 hours if refrigerated).

Treatment of Protozoan Etiologies

The most common parasitic cause of TD is Giardia intestinalis, and treatment options include metronidazole, tinidazole, and nitazoxanide. Although cryptosporidiosis is usually a self-limited illness in immunocompetent persons, nitazoxanide can be considered as a treatment option. Cyclosporiasis is treated with TMP-SMX. Treatment of amebiasis is with metronidazole or tinidazole, followed by treatment with a luminal agent such as iodoquinol or paromomycin.

Treatment for Children

Children who accompany their parents on trips to high-risk destinations may be expected to have TD as well. There is no reason to withhold antibiotics from children who contract TD. In older children and teenagers, treatment recommendations for TD follow those for adults, with possible adjustments in dose of medication. Macrolides such as azithromycin are considered first-line antibiotic therapy in children, although some experts are using short-course fluoroquinolone therapy with caution for travelers <18 years of age. Rifaximin is approved for use starting at age 12.

Infants and younger children are at higher risk for developing dehydration from TD, which is best prevented by the early use of ORS solutions. Breastfed infants should continue to nurse on demand, and bottle-fed infants should be offered full strength lactose-free or -reduced formula. Older infants and children should continue their regular diets during the illness.

Other information that may be of interest to travelers can be found at the CDC Travelers' Health homepage at http://www.cdc.gov/travel.

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