Prevention and Management of Traveler’s Diarrhea in Children: Suggestions for Change in Management

John C. Christenson, MD

The Problem

Much of what we know about travelers' diarrhea (TD) and its epidemiology comes from studies performed in adults. Data regarding TD in children is somewhat limited. Pediatric caregivers have realized for years that children are not just "small" adults. Younger children appear to be at a high risk for severe disease. In addition, current published recommendations for the empiric management of TD in children suggest that trimethoprim-sulfamethoxazole (TMP-SMZ) be used.^1,2,4 However, because of the rising rates of resistance to TMP-SMZ among bacterial enteric pathogens, fluoroquinolones (FQ) have become the recommended agents for adult travelers.^1,3,5 The recommendations for children have in part been based on the concern over side effects. But why should children be treated as "second-class" travelers and receive a potentially inferior therapy? Also, can antidiarrheal medications such as BSS be used in children?

In the following paragraphs a change in the management of TD in children is suggested.

TD is a common problem encountered by international travelers. Up to 50 percent of individuals visiting developing countries will be affected by the condition. Persons become infected through the consumption of contaminated water, food and beverages.¹ A majority of episodes of TD are caused by enterotoxigenic Escherichia coli (ETEC). Other common pathogens are Campylobacter jejuni, Salmonella sp., Shigella sp., rotavirus, Norwalk virus, and Giardia lamblia.^2,3

Epidemiology

A retrospective study performed by investigators at the University of Zurich has given us a better understanding of the epidemiology of TD in children.⁶ They evaluated 363 pediatric travelers. Over 75 percent of travelers had a duration of travel of 4 weeks or less. Three-fourths of the children traveled to Latin America and Africa. The attack rate of TD varied according to age groups. Within 14 days of travel, 40 percent of traveling children under 2 years of age developed TD. The incidence of TD according to other age groups was, 8.5 percent for the 3-6 year age group; 21.7 percent for the 7-14 year group; and 36 percent for the 15 to 20 years group. Two-thirds of travelers to North Africa and India developed diarrhea. The severity of TD in the younger group was significant. While the average duration of TD was 11.5 days (median, 3), the mean duration of TD in the 0- 2 years group was 29.5 days (median, 17.5). Approximately 20 percent of patients required confinement to bed and close to 15 percent required care by a doctor. Overall, 40 percent of travelers observed recommended dietary preventive measures. Only 60 percent of children under 2 years of age "observed" recommended precautions. In this study, young children appear to be susceptible to severe TD. Few patients received oral rehydration fluids.

Prevention

Much has been written about the prevention of TD. Just like with adults, an emphasis on basic preventive measures such as the proper preparation and consumption of food and beverages, avoidance of contaminated water, and proper hygiene are critical.^4,5 This needs to be discussed with all traveling families. The prophylactic use of antidiarrheal agents such as bismuth subsalicylate (BSS) has been shown to reduce the incidence of TD among college students.⁷ While this approach, and the prophylactic use of antibiotics, may be appealing to some travelers, there are many arguments against its routine use. There are legitimate concerns, especially for the pediatric traveler, over side effects of various medications. These concerns include allergies, antibiotic-associated diarrhea, Reye syndrome, unnecessary costs, selection of resistant organisms, and a false sense of security resulting from a lesser than optimal adherence to dietary precautions (thinking they are covered by "prophylactic agents"). Proper hygiene is also key. Handwashing before and after using restrooms and before and after food preparation cannot be overemphasized. Young children should not crawl on the bare floor. Young infants tend to put "contaminated" hands and toys in their mouths.^4,8 All family members should wash their hands before touching or playing with young infants.

Treatment

The "currently recommended" management of TD in children may need some revisions. The most important aspect of the management of TD at any age is proper hydration. Proper oral or intravenous hydration fluids are key to the prevention and treatment of dehydration. Various commercially-made or homemade preparations can be used. Parents need to be told to carry these when traveling with young children, and they need to be taught how to use them appropriately.

Antidiarrheal medications such as loperamide, BSS, and diphenoxylate hydrochloride are frequently used by adult travelers. These are usually not recommended for children due to the concern over side effects. Diphenoxylate-HCl is not used in children because it has been shown to cause respiratory depression. While loperamide can reduce the frequency and severity of diarrhea in children, in various studies, children experienced adverse effects such as drowsiness, irritability, personality changes, paralytic ileus, abdominal distension and vomiting.^9-11 Probiotics like Lactobacillus casei sp. strain GG have been used to treat acute diarrhea. They also appear to shorten the duration of illness.¹² Kaolin-pectin has been found to be ineffective for the treatment of acute diarrhea.

BSS has been shown to be safe and effective for the treatment of TD in adults.¹³ The most commonly reported side effects in adults have been constipation, black tongue, and darkened stools. Mild insignificant tinnitus has also been reported. BSS is also effective in children. Treated children demonstrated a decrease in stool frequency and water content, with stools becoming significantly more firm and a shorter duration of illness.^14,15 BSS was well tolerated. Much of the recommendations against the use of BSS in children is based on a potential for adverse events, salicylate poisoning and Reye syndrome. However, short courses of BSS (less than 7 days) have been shown to be safe in children.

As initial management, adult travelers are commonly prescribed an antidiarrheal agent such as loperamide or BSS. If symptoms persist or illness is severe, an antibiotic such as a fluoroquinolone (ciprofloxacin, norfloxacin, ofloxacin, or levofloxacin) is recommended.¹ As stated above, many authors are recommending TMP-SMZ for children. Antimicrobial resistance around the developing world has significantly influenced the recommendations for adults. A study in Thailand by Hoge and associates¹⁶ demonstrated that more than 90 percent of Shigella strains were resistant to sulfisoxazole and TMP-SMZ. Approximately 40 percent of ETEC and Salmonella isolates were also resistant. None of the isolates of Shigella sp. were resistant to ciprofloxacin or azithromycin. Only 1-2 percent of Shigella and ETEC isolates were resistant to nalidixic acid. In addition, they demonstrated that 84 percent of Campylobacter isolates were resistant to ciprofloxacin. Only 15 percent of these were resistant to azithromycin. In many parts of the world many of the bacterial enteric pathogens that may affect travelers are now resistant to TMP-SMZ. In my opinion, this agent should not be used for the empiric treatment of TD in children.

What is the recommended agent for the treatment of TD in children? Can we use fluoroquinolones in children? Many studies have demonstrated the efficacy of fluoroquinolones (FQ) in the treatment of TD. Since their introduction, individuals have been cautioned about the use of FQ in children because of the risk for arthropathy and cartilage damage. While this has been demonstrated in animals, studies in children, mainly cystic fibrosis patients, have not demonstrated an increase in cartilage toxicity.^17,18 FQ are frequently used by clinicians to treat infections by Pseudomonas aeruginosa such as chronic suppurative otitis media and urinary tract infections. No increase in reports of cartilage toxicity have been documented. Use of nalidixic acid in children also has failed to demonstrate an increase in cartilage damage.^19,20 It appears that ciprofloxacin could be used as treatment of TD in children when no other alternative is available. However, the potential side effects of FQ should be discussed with the parents.

Driven by an increase in ciprofloxacin-resistance among Campylobacter isolates, many clinicians have demonstrated interest in the use of azithromycin as treatment of TD. Azithromycin is highly active in vitro against common enteric pathogens such as ETEC, Campylobacter and Shigella.²¹ Researchers at the Dhaka Diarrhoeal Treatment Centre have demonstrated that azithromycin is comparable to ciprofloxacin in the treatment of shigellosis.²² Clinical and bacteriologic successes were observed in over 80 percent and 90 percent of cases, respectively. Other clinicians have considered cefixime as a potential therapeutic agent for the treatment of TD in children. In one study the agent was found to be superior to TMP-SMZ in the treatment of shigellosis.²³ However, in another study cefixime was found to be ineffective in adults.²⁴

For years it has been suspected that antibiotic therapy may increase the risk of developing hemolytic uremic syndrome (HUS) in children with hemorrhagic colitis caused by E. coli O157:H7. A recent study confirmed this clinical observation.²⁵ The obvious question would be, how does this affect the pediatric traveler when visiting developing countries? Should we avoid the use of antibiotics? In reality, infections caused by shiga-toxin-like producing strains of E. coli (STEC) are rare outside of industrialized countries. In developing countries, a greater risk of HUS is probably observed when treating shigellosis with ineffective antibiotics.

Summary

Whenever possible, young infants should not travel to developing countries. When traveling, parents need to be prepared to provide proper and safe rehydration fluids to children with diarrhea. Following prevention, this is the most important aspect of therapy. Breast feeding should be encouraged when possible. Avoid tap water and follow dietary protective measures. Prophylactic antibiotics or antidiarrheal agents are not recommended for children.

Do all children with TD need antibiotic therapy? Probably not, many children can be managed with supportive care with oral fluids and an appropriate diet. However, a major reason for treating a child with TD is to shorten the duration of illness and to avoid complications. While BSS appears to be safe in children, the risk of Reye syndrome is real and caution is merited. Of available antibiotics azithromycin (10 mg/kg/day as single daily dose for up to 5 days) appears to be the preferred agent for the treatment of TD in children. For the macrolide-allergic individual, ciprofloxacin (20 mg/kg/day, divided in 2 equal daily doses for up to 5 days) can be used as an alternative. Nalidixic acid can also be used. However, its availability in many regions of the United States is limited. If diarrhea has resolved after 1-2 doses, antimicrobial therapy could be discontinued. Diphenoxylate and loperamide should not be used in young children. The risks and benefits of antidiarrheal and antimicrobial therapy need to be discussed with parents during pretravel clinic visits.

References

1. Adachi JA, Ostrosky-Zeichner L, DuPont HL, Ericsson CD. Empirical antimicrobial therapy for traveler's diarrhea. Clin Infect Dis 2000;31:1079-1083
2. Hostetter MK. Epidemiology of travel-related morbidity and mortality in children. Pediatr Rev 1999;20:228-233
3. Blair DC. A week in the life of a travel clinic. Clin Microbiol Rev 1997;10:650-673
4. Fischer PR. Travel with infants and children. Infect Dis Clin North Am 1998;12:355-368
5. Ryan ET, Kain KC. Health advice and immunizations for travelers. N Engl J Med 2000;342:1716-1725
6. Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler's diarrhea in infants and children. Pediatr Infect Dis J 1991;10:719-723
7. DuPont HL, Ericsson CD, Johnson PC, de la Cabada FJ. Use of bismuth subsalicylate for the prevention of travelers' diarrhea. Rev Infect Dis 1990;12(supplement 1):S64-S67
8. Leggat PA, Speare R, Kedjarune U. Traveling with children. J Travel Med 1998;5:142-146
9. Motala C, Hill ID, Mann MD, Bowie MD. Effect of loperamide on stool output and duration of acute infectious diarrhea in infants. J Pediatr 1990;117:467-471
10. Diarrhoeal Diseases Study Group (UK). Loperamide in acute diarrhoea in childhood: results of a double blind, placebo controlled multicentre clinical trial. BMJ 1984;289:1263-1267
11. Karrar ZA, Abdulla MA, Moody JB, MacFarlane SBJ, Bwardy MA, Hendrickse RG. Loperamide in acute diarrhea in childhood: results of a double blind, placebo controlled clinical trial. Ann Trop Pediatr 1987;7:122-127
12. Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T. A human Lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children. Pediatrics 1991;88:90-97
13. DuPont HL, Sullivan P, Pickering LK, Haynes G, Ackerman PB. Symptomatic treatment of diarrhea with bismuth subsalicylate among students attending a Mexican university. Gastroenterology 1977;73:715-718
14. Figueroa-Quintanilla D, Salazar-Lindo E, Sack RB, Leon-Barua R. Sarabia-Arce S, Campos-Sanchez M, Eyzaguirre-Maccan E. A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. N Engl J Med 1993;328:1653-1658
15. Soriano-Brucher H, Avendano P, O'Ryan M, Braun SD, Manhart MD, Balm TK, Soriano HA. Bismuth subsalicylate in treatment of acute diarrhea in children: A clinical study. Pediatrics 1991;87:18-27
16. Hoge CW, Gambel JM, Srijan A, Pitarangsi C, Echevarria P. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341-345
17. Schaad UB, Salam MB, Aujard Y, Dagan R, Green SDR, Peltola H, Rubio TT, Smith AL, Adam D. Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission. Pediatr Infect Dis J 1995;14:1-9
18. Warren RW. Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones. Pediatr Infect Dis J 1997;16:118-122
19. Nuutinen M, Turtinen J, Uhari M. Growth and joint symptoms in children treated with nalidixic acid. Pediatr Infect Dis J 1994;13:798-800
20. Schaad UB, Wedgwood-Krucko J. Nalidixic acid in children: retrospective matched controlled study for cartilage toxicity. Infection 1987;15:165-168
21. Gordillo ME, Singh KV, Murray BE. In vitro activity of azithromycin against bacterial enteric pathogens. Antimicrob Agents Chemother 1993;37:1203-1205
22. Khan WA, Seas C, Dhar U, Salam MA, Bennish ML. Treatment of shigellosis: V. Comparison of azithromycin and ciprofloxacin. A double-blind, randomized, controlled trial. Ann Intern Med 1997;126:697-703
23. Ashkenazi S, Amir J, Waisman Y, Rachmel A, Garty BZ, Samra Z, Varsano I, Nitzan M. A randomized, double-blind study comparing cefixime and trimethoprim-sulfamethoxazole in the treatment of childhood shigellosis. J Pediatr 1993;123:817-821
24. Salam MA, Seas C, Khan WA, Bennish ML. Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults. Ann Intern Med 1995;123:505-508
25. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930-1936

John is Professor of Pediatrics and in the Division of Infectious Diseases and Geographic Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.