Environmental Advising travellers

Karin Leder about management of travellers’ diarrhoea

Background Travellers’diarrhoea (TD) continues to affect 20–50% of Travellers’ diarrhoea (TD) affects a large proportion of international travellers. This prevalence has not changed over international travellers. These people will often present to many decades.1,2 High-risk areas include developing tropical general practice for advice before they travel. and semi-tropical regions of South-East Asia, Sub-Saharan Objective Africa and Latin America, whereas moderate-risk areas This article will review the current concepts and practical include South-East Asia, the Middle East, Oceania and the issues for advising people planning to travel about their risks Caribbean.3 Travellers at high risk of developing TD or at high of TD and how to manage symptoms if they develop during risk of complications include those with insulin-dependent the trip. diabetes mellitus, congestive heart failure, advanced cancer, Discussion human immunodeficiency virus (HIV) infection, inflammatory Avoidance, immunisation, non-antibiotic interventions bowel disease or other bowel abnormalities, reactive arthritis, and antibiotic prophylaxis are all methods for preventing reduced gastric acidity, or those who are HLA-B27-positive.4 TD. However, advice regarding self-management through rehydration, antibiotic treatment and appropriate seeking of medical advice are most important. How is TD defined? Keywords Classic, severe TD is usually defined as at least three unformed bowel travel; diarrhea; antidiarrheals; prophylaxis; vaccination movements occurring within a 24-hour period, often accompanied by cramps, nausea, vomiting, fever and/or blood in the stools.5–7 Moderate TD is defined as one or two unformed bowel movements and other symptoms occurring every 24 hours or as three or more unformed bowel movements without additional symptoms. Mild TD is defined as one or two unformed bowel movements without any additional symptoms and without interference with daily activities.8,9 TD generally resolves spontaneously, usually after 3–4 days,8 but, in the interim, frequently leads to disruption of planned activities. What are the causes of TD? Approximately 50–80% of TD is caused by bacterial infections; enterotoxigenic (ETEC) is the most common cause overall. Other bacterial causes include enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), , Campylobacter and Salmonella species. The exact breakdown of organisms varies according to destination, season and other factors. Noroviruses cause 10–20% of TD cases. Protozoal parasites should be considered particularly in those with persistent diarrhoea (illness lasting ≥14 days) or when antibacterial therapy fails to shorten illness.10

34 REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 44, NO. 1–2, JANUARY–FEBRUARY 2015 How can TD be prevented? data regarding overall efficacy of reducing all-cause TD are currently Methods for preventing TD include avoidance, immunisation, lacking. non‑antibiotic interventions or antibiotic prophylaxis.11 Should antibiotic prophylaxis against TD be What avoidance measures are generally given? recommended and do they work? Quinolone antibiotics are highly effective (80–95%) in preventing TD, Avoidance of TD has traditionally relied on recommendations regarding but antibiotic prophylaxis is rarely indicated.4 It may result in a false careful food and drink choices (avoiding untreated/unboiled tap water, sense of security and hence less caution in dietary choices, it poses including ice and water used for brushing teeth, and raw foods such risks of side effects, diarrhoea associated with Clostridium difficile, as salads, uncooked vegetables or fruits that cannot be peeled). and, more importantly, would lead to a vast amount of antibiotic use, This underpins the saying ‘Boil it, cook it, peel it or forget it…. easy thus predisposing to more rapid development of antibiotic resistance to remember, impossible to do’. Additional standard advice is that globally.11 Therefore non-antibiotic options for prevention and a focus undercooked or raw meat, fish and shellfish are high-risk foods. However, instead on empirical self-treatment if needed according to symptoms are whether deliberately or inadvertently, most people find it very difficult the mainstay of management, aligning with the antimicrobial stewardship to adhere to dietary restrictions12 and over 95% of people disobey the perspective of minimisation of antimicrobial overuse and reducing rules of ‘safe’ eating and drinking within a few days of leaving home. promotion of antimicrobial resistance. Additionally, there is minimal evidence for a correlation between In rare circumstances, it may be reasonable to consider short courses adherence to dietary precautions and a reduced risk of TD,13 although of antibiotic prophylaxis in individuals at very high risk of infection (eg common sense nevertheless supports care with food selection.4 severely immunocompromised).11 Globally, one of the most commonly Where people eat may be more important than what people eat. Risks used agents in this regard is rifaximin, a non-absorbed semisynthetic are associated, in descending order, with street vendors, restaurants rifamycin derivative, which has been shown to be effective and is and private homes. Use of antibacterial handwash before eating is also approved for use for TD prevention in some countries, but it is not recommended.14 approved for this indication in Australia. Other options include the antibiotics discussed below for TD self-treatment. Which vaccines can be considered? Immunisation has little practical role in the prevention of TD and the only How should self-treatment of TD be potentially relevant vaccines are those against rotavirus (infants only) and managed? the oral cholera vaccine. Because of the limitations of TD prevention measures, the pre-travel The cholera vaccine has >90% efficacy for prevention of Vibrio consultation should be viewed as an opportunity to ‘arm’ travellers with cholera but travellers are rarely at risk of infection with this pathogen.1 the knowledge and medication needed to appropriately self-treat, should The vaccine contains a recombinant B subunit of the cholera toxin that TD occur during their trip. is antigenically similar to the heat-labile toxin of ETEC; therefore, the The first goal of therapy is the prevention and treatment of cholera vaccine may also reduce ETEC TD. However, it is not licensed dehydration, which is of particular concern for young children, pregnant for TD prevention in Australia and, although initially thought to offer a women and the elderly. Commercial packets of oral rehydration salts are 15–20% short-term (3 months) reduction in TD, a recent Cochrane review readily available in pharmacies and should be purchased before travel. showed no statistically significant effects on ETEC diarrhoea or all-cause The other element of TD self-treatment is to recommend travellers diarrhoea.15 Overall, there is, therefore, insufficient evidence to support bring an antimotility agent plus an antibiotic with them. is general use of the cholera vaccine for TD protection, but it may still be preferred over the /atropine combination, as the latter agent considered for individuals with increased risk of severe or complicated TD is generally less effective and associated with a greater potential for (eg immunosuppressed or underlying inflammatory bowel disease). adverse effects. Other vaccines directed against organisms spread by the faecal–oral route are the vaccines for typhoid, hepatitis A and polio, but infection When should loperamide alone versus with these organisms rarely causes TD.15 loperamide plus an antibiotic be taken? For mild symptoms of watery diarrhoea, self-treatment with oral Do non-antibiotic interventions work? rehydration plus loperamide is recommended. Loperamide therapy alone Several probiotic agents have been studied for treatment and prevention has no untoward effects in mild TD18 but if symptoms worsen, or do not of TD, including Lactobacillus and Saccharomyces preparations. However, improve after 24 hours, antibiotics should be added. If TD is moderate their effectiveness for TD prevention has been limited,11,16,17 and a or severe at onset, then combination therapy with loperamide plus consensus group has recommended against their use.4 Other over-the- antibiotics should be started immediately, as this optimises the clinical counter agents are also available (eg travelan, which contains bovine benefit of self-treatment by providing more rapid relief and shortening the colostrum harvested from cows immunised with an ETEC vaccine) but symptom duration.10,19

REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 44, NO. 1–2, JANUARY–FEBRUARY 2015 35 FOCUS Advising travellers about management of travellers’ diarrhoea

The recommended dose of loperamide is two tablets (4 mg) stat, then effects, especially paralytic ileus, toxic megacolon and drowsiness one tablet after each bowel motion to a maximum of eight per 24-hour (narcotic effect) with loperamide.1 The lower age limit recommended period until the TD has resolved. Despite warnings regarding the safety for avoiding loperamide varies by location; US guidelines state that of antidiarrhoeal agents with bloody diarrhoea or diarrhoea accompanied loperamide should not be given to infants <2 years of age, the UK <4 years by fever, the combination with antibiotics is likely to be safe in the setting and Australian guidelines state <12 years.14 However, most Australian of mild febrile dysentery,18 and a number of studies have shown the practitioners are prepared to use loperamide in children aged 6 years or combination to be more efficacious than use of either agent alone.7,18–20 older, if needed to control symptoms. Rapid institution of effective treatment shortens symptoms to 30 hours A paediatric (powder) formulation of azithromycin is available and or less in most people.12 For example, the duration of diarrhoea was is the most commonly recommended agent for children. The usual dose significantly (P = 0.0002) shorter following treatment with azithromycin is 10–25 mg/kg for up to 3 days. A practical tip is to ensure that the plus loperamide (11 h) than with azithromycin alone (34 h).19 pharmacy does not reconstitute the powder into a solution, as once dissolved, the solution lasts only for 10 days. Instead, sterile water should Which antibiotic should be be provided along with instructions on how to reconstitute the powder recommended for empirical if needed. Fluoroquinolones (ciprofloxacin or norfloxacin 10mg/kg bd) self-treatment of TD? are an alternative option if there are reasons for avoiding azithromycin, The most commonly used antibiotics for empirical TD therapy are with previous concerns regarding potential effects on cartilage not fluoroquinolones (either norfloxacin or ciprofloxacin) or azithromycin substantiated in recent studies.14,22 (Table 1). Cotrimoxazole has been used but is no longer recommended because of widespread resistance. For TD caused by ETEC, the Does starting antibiotics early prevent fluoroquinolones and azithromycin have similar efficacy; however, in Asia the chances of developing prolonged (particularly South and South-East Asia), Campylobacter is a common symptoms? cause of TD and strains occurring in this part of the world show a high Although TD symptoms are short-lived in most cases, 8–15% of affected degree of resistance to fluoroquinolones.10,21 Therefore, azithromycin travellers are symptomatic for more than a week and 2% develop chronic is preferred for travellers to this region. Azithromycin remains generally diarrhoea lasting a month or more.11 Episodes of TD have been shown to efficacious despite emerging resistance, and is also the preferred be associated with a quintuple risk of developing irritable bowel syndrome treatment for diarrhoea with complications of dysentery or high fever, and (IBS), and post-travel IBS occurs in 3–10% of travellers. However, it is for use in pregnant women or children under the age of 8 years, in whom unknown whether IBS can be prevented by starting antimicrobial therapy avoidance of quinolones is preferred. Moreover, the 24-hour dosing of earlier in the course of enteric infection.4,18,23 azithromycin may be preferable to the 12-hourly dosing schedule required with fluoroquinolones. Should tinidazole also be prescribed and, if so, for whom? What is the optimal dosing schedule? Tinidazole can be prescribed as a second antibiotic for empirical The fluoroquinolones and azithromycin have been administered as a self‑treatment as it is effective against the protozoan parasitic enteric single dose or for 3 days (Table 1). Usually a single dose is adequate and there is no apparent clinically important difference in efficacy with either dosing schedule for TD.10 However, for bacteria such as Campylobacter Table 1. Antibiotics used for self-treatment of and Shigella dysenteriae, single-dose therapy may be inadequate.11 It is TD1,10,19,24 reasonable, therefore, to give travellers a 3-day supply of antibiotics and • Single dose therapy: tell them to continue taking the therapy (either 12- or 24-hourly, depending –– Single dose of ciprofloxacin 500 mg or norfloxacin on which antibiotic is prescribed) only if their TD symptoms persist. If the 400 mg TD has resolved, no further antibiotics need to be taken and any remaining –– Azithromycin 500 mg or 1000 mg stat* antibiotic doses can be kept in case of a second bout of TD. It is prudent • 3-day treatment: to specifically highlight that this advice differs from the usual instructions –– Ciprofloxacin 500 mg or norfloxacin 400 mg 12 to take all tablets even if symptoms have resolved. hourly x 6 tabs –– Azithromycin 500 mg daily x 3 tablets What is the optimal empirical TD *Azithromycin 1000 mg has equal efficacy but management in children? is associated with poorer tolerability and more gastrointestinal side effects, especially nausea There are few data on empirical treatment of TD in children and Note: in Australia azithromycin packs contain three limited options for therapy. The mainstay of therapy is oral rehydration tablets. In New Zealand, there are two tablets per pack, solution, particularly for children <6 years of age. Antimotility agents thereby more easily lending itself to a 1000 mg stat dose are contraindicated for children because of the increased risk of adverse than a 500 mg daily dose for up to 3 days.

36 REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 44, NO. 1–2, JANUARY–FEBRUARY 2015 Advising travellers about management of travellers’ diarrhoea FOCUS pathogen Giardia intestinalis. A dose of 2 g (4 x 500 mg tablets) stat is team. She received grants from Sanofi to develop a mobile phone app for recommended. However, for most short-term travellers, tinidazole may splenectomised patients and from GSK to research the use of the HBV be unnecessary and the complexity of the additional instructions required vaccine. GSK also paid her to lecture on travel risks at the Asia Pacific Travel Health Conference. She has received support from both GSK and may be unwarranted. It is optimally recommended, therefore, for travellers Sanofi to attend travel medicine conferences. departing on trips of significant duration (>2–3 weeks). If prescribed, the Provenance and peer review: Commissioned, externally peer reviewed instructions should be to take tinidazole if the TD persists following the 3-day course of antibiotic therapy (fluoroquinolone or azithromycin). This References will mean that the TD has lasted for at least 72 hours, thus increasing the 1. Diemert DJ. Prevention and self-treatment of travelers’ diarrhea. Prim Care 2002;29:843–55. likelihood of a parasitic cause. 2. Department of Health and Human Services. Centers for Disease Control and Prevention. Travelers’ Diarrhea. Available at www.cdc.gov/ncidod/dbmd/disea- When should medical care for acute seinfo/travelersdiarrhea_g.htm [Accessed 25 November 2014]. symptoms be recommended? 3. Paredes-Paredes M, Flores-Figueroa J, Dupont HL. Advances in the treatment of travelers’ diarrhea. Curr Gastroenterol Rep 2011;13:402–07. While most episodes of TD are amenable to self-treatment, if there is 4. DuPont HL, Ericsson CD, Farthing MJ, et al. Expert review of the evidence base a risk of dehydration due to intolerance of oral fluids or comorbidities, for prevention of travelers’ diarrhea. J Travel Med 2009;16:149–60. 5. Nair D. Travelers’ diarrhea: prevention, treatment, and post-trip evaluation. J as well as in the setting of frank blood in the stool or unremitting fevers Fam Pract 2013;62:356–61. (>38.5°C for 48 hours), medical therapy should be sought.18 6. De Bruyn G, Hahn S, Borwick A. Antibiotic treatment for travellers’ diarrhoea. The Cochrane Database Syst Rev 2000:CD002242. 7. Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combina- How should TD be managed after return? tion with antibiotics on treatment outcomes in traveler’s diarrhea: a systematic While a full description of TD management is beyond the scope of this review and meta-analysis. Clin Infect Dis 2008;47:1007–14. 8. Steffen R. Epidemiology of traveler’s diarrhea. Clin Infect Dis 2005;41(Suppl article, for returning travellers with diarrhoea, at least one (preferably 8):S536–40. three) stool sample(s) should be taken, including specific requests for 9. Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of evaluation of parasites. For patients who are unwell, particularly those traveler’s diarrhea in Jamaica. JAMA 1999;281:811–17. 10. DuPont HL, Ericsson CD, Farthing MJ, et al. Expert review of the evidence base with fevers or dysentery, initiation of empirical antibiotic treatment with for self-therapy of travelers’ diarrhea. J Travel Med 2009;16:161–71. azithromycin or a quinolone may be needed while awaiting results. For 11. Diemert DJ. Prevention and self-treatment of traveler’s diarrhea. Clin Microbiol Rev 2006;19:583–94. those with prolonged symptoms, tinidazole as empirical therapy for 12. Travelers’ diarrhea. NIH Consensus Development Conference. JAMA protozoan parasites may be considered. Endoscopic evaluation may also 1985;253:2700–04. be advisable if no infectious cause is found and symptoms do not resolve. 13. Shlim DR. Looking for evidence that personal hygiene precautions prevent traveler’s diarrhea. Clin Infect Dis 2005;41(Suppl 8):S531–35. 14. Plourde PJ. Travellers’ diarrhea in children. Paediatr Child Health 2003;8:99– Key points 103. 15. Ahmed T, Bhuiyan TR, Zaman K, Sinclair D, Qadri F. Vaccines for preventing • Travellers’ diarrhoea continues to affect 20–50% of people undertaking enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev trips to areas with under-developed sanitation and there is minimal 2013;7:CD009029. evidence for beneficial effects of dietary precautions. 16. Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointes- tinal diseases. PloS One 2012;7:e34938. • Evidence for the benefit of cholera vaccine in reducing TD is limited, 17. Centers for Disease Control Prevention. Yellow Book. Chapter 2. Travelers’ but it can be considered in people at high risk of infection. Diarrhea. Available at wwwnc.cdc.gov/travel/yellowbook/2014/chapter-2-the- • In 50–80% of TD cases, TD is caused by bacterial infection. Mild pre-travel-consultation/travelers-diarrhea [Accessed 25 November 2014]. 18. Wingate D, Phillips SF, Lewis SJ, et al. Guidelines for adults on self-medication diarrhoea can be managed with an antimotility agent (loperamide) for the treatment of acute diarrhoea. Aliment Pharmacol Ther 2001;15:773–82. alone, but for moderate or severe diarrhoea, early self-treatment with 19. Ericsson CD, DuPont HL, Okhuysen PC, Jiang ZD, DuPont MW. Loperamide plus azithromycin more effectively treats travelers’ diarrhea in Mexico than azithro- loperamide in conjunction with antibiotics is advised. mycin alone. J Travel Med 2007;14:312–19. • Recommended empirical antibiotics are fluoroquinolones (norfloxacin / 20. Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in ciprofloxacin) or azithromycin for up to 3 days, although in the setting of the treatment of bacillary dysentery. Ann Intern Med 1993;118:582–86. 21. Tribble DR, Sanders JW, Pang LW, et al. Traveler’s diarrhea in Thailand: rand- increasing resistance, the latter is preferred for travellers to South and omized, double-blind trial comparing single-dose and 3-day azithromycin-based South-East Asia. regimens with a 3-day levofloxacin regimen. Clin Infect Dis 2007;44:338–46. 22. Yung A, Leder K, Torresi J, et al. Manual of Travel Medicine. 3rd edn. Author Melbourne: IP Communciations, 2011. Karin Leder MBBS, FRACP, PhD, MPH, DTMH, Head of Infectious Disease 23. Stermer E, Lubezky A, Potasman I, Paster E, Lavy A. Is traveler’s diarrhea a significant risk factor for the development of irritable bowel syndrome? A pro- Epidemiology Unit, School of Public Health and Preventive Medicine, spective study. Clin Infect Dis 2006;43:898–901. Monash University, and Director of Travel and Immigrant Health Services, 24. Expert Group for Antibiotic. Antiobiotic: gastrointestinal tract infections: acute Victorian Infectious Disease Service, Melbourne Health, Parkville, VIC. : acute diarrhoea in special groups: travellers’ diarrhoea. In: eTG [email protected] Complete [Internet] Melbourne. Therapeutic Guidelines Ltd, 2014. Competing interests: Karin Leader received a consultancy fee from Imuron in relation to the C. difficile vaccine. She is also an ISTM board member and received a consultancy from ISTM to join the GeoSentinel leadership

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