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DR BERNARD HUDSON MBBS (Hons) DTPH FACTM FAFPHM FRACP FRCPA

Dr Bernard Hudson is a Senior Staff Specialist with the Department of Microbiology & Infectious Diseases at Royal North Shore Hospital in Sydney and the Medical Director of Travel Health Advisor formerly known in Australia and New Zealand as MASTA. He is also a Senior Lecturer in Infectious Diseases at Sydney University and a Clinical Associate Professor at James Cook University in North Queensland.

This article discusses the latest evidence on the incidence and prevalence of Traveller’s Diarrhoea, and how it is best prevented, assessed and treated.

Traveller’s Diarrhoea

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Dietary indiscretions are common

‘Traveller’s Diarrhoea’ is a term often applied to any type of diarrhoea in travellers, irrespective of cause. Traveller’s Diarrhoea is seen in visitors to virtually any country with only Australia, New Zealand,

northern Europe, Canada and the U.S.A. being regarded as low risk destinations (incidence less than 7%).

Some destinations such as cruises on the Nile and Mexican tourist locations are notorious for high rates of Traveller’s Diarrhoea. Incidence of Traveller’s Diarrhoea in travellers making trips from developed to developing countries is estimated at 20-60% for trip duration of one month. More than 90% of all Traveller’s Diarrhoea cases occur within the first two weeks of travel to the risk destination.1

Classically Traveller’s Diarrhoea is an illness with non-bloody diarrhoea, without fever, that starts within two weeks of arrival in a developing country and lasts for 3-5 days. Traveller’s Diarrhoea can vary from just a few extra, loose bowel movements per day to an illness with profuse bloody diarrhoea and fever (dysentery). Dysentery occurs in up to 10% of persons.

EXPERT MONOGRAPH ISSUE 32

Take Home Messages

` Up to half of those people travelling from a developed

country to a developing country for a month will develop

Traveller’s Diarrhoea.

` Enterogenic Escherichia coli is the commonest cause of

Traveller’s Diarrhoea in most countries.

` ‘Boil it, cook it, peel it or forget it’ is sound advice that

may help prevent Traveller’s Diarrhoea.

` Other options for possible prevention include the oral

cholera vaccine, Dukoral, probiotics and Travelan.

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Hormonal Contraception Trouble-shooting Part One: The Overweight Woman

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Traveller’s Diarrhoea

Of those affected, it is estimated that 30% will be confined to bed, and 40% will have to curtail their activities. Dehydration is always a concern, especially in warm climates when it can be severe, even fatal, particularly in children.

The microbes that cause Traveller’s Diarrhoea are usually spread by contaminated water or food. Incubation period (time from exposure to first symptoms) ranges from 10 hours to three days.

Colourful descriptions for Traveller’s Diarrhoea common to particular destinations (‘Bali Belly’, ‘Inca Quick-step’, ‘Montezuma’s Curse/Revenge’ etc.) usually apply to diarrhoea caused by these ‘local’ strains of E.coli in the particular country or destination.

Enterotoxigenic E.coli (ETEC) is the commonest cause of Traveller’s Diarrhoea in most studies (20-75% of cases), but this varies depending on the area. For example, some studies have shown ETEC as a cause of Traveller’s Diarrhoea to be more common in Latin American and African countries than in Asia.1,2

A variety of other E.coli species have been implicated in Traveller’s Diarrhoea (see Table 1).

One study found the highest incidence regions for Traveller’s

Diarrhoea, irrespective of cause (viral, parasitic, bacterial) to be

South America, sub-Saharan Africa and South Asia (Bangladesh,

India, Nepal, Pakistan), with South Asia having the highest rates

of diarrhoea (approximately fourfold greater than sub-Saharan

Africa and South America and 800-fold greater than for travel to

western and northern Europe).2 Diarrhoea in travellers can also

have a variety of non-infective causes, including septicaemia

and malaria, where diarrhoea may be prominent and lead the

physician away from the correct diagnosis with sometimes fatal

consequences. Toxin-mediated illnesses such as ciguatera should

also be considered. Infectious causes of Traveller’s Diarrhoea are

listed in Table 1.

An expert group from the International Society of Travel Medicine

has produced guidelines for prevention and treatment of Traveller’s

Diarrhoea, first published in 2009 and updated in 2017.3

In order to develop evidence-based guidelines for prevention and

management of Traveller’s Diarrhoea, one needs to have working

definitions for grades of severity of the condition. Definitions of

severity are listed in Table 2.

Table 2: Grading of Severity of Traveller’s Diarrhoea

(adapted from Riddle MS et al.)

Grade Features

Mild (acute)

(a) tolerable (b) not distressing (c) does not interfere with

planned activities

Moderate (acute)(a) distressing; or (b) interferes with planned activities

Severe (acute)*(a) incapacitating; or (b) completely prevents

planned activities

Persistent Diarrhoea lasting two or more weeks

*All dysentery (grossly bloody stools) is considered severe

If one needs to find a causative pathogen, Traveller’s Diarrhoea

is best diagnosed by laboratory tests to detect the offending

microbe(s) in the faeces of an infected person. In practice, tests

are only done in cases with severe or persistent illness. Because

most travellers have recovered after return home, most data on the

causative pathogens are provided from research studies. Improved

diagnostic methods, especially molecular methods, are being

increasingly utilised in such studies.

TABLE 1: INFECTIOUS CAUSES OF TRAVELLER’S DIARRHOEA*

Most Common

` E.coli (ETEC)

` E.coli (EAEC)

` E.coli (EIEC)

` Shigella

` Salmonella (non-typhoid)

` Campylobacter jejuni

` Viruses – astro, noro, rotaviruses, likely more

Less common

` Giardia

` Cryptosporidium

` Amoebic (E.histolytica)

` Vibrio species

` Aeromonas species

ETEC – Enterotoxigenic E.coli; EAEC – Enteroaggregative

E.coli; EIEC – Enteroinvasive E.coli

*Frequency of causative pathogen varies by region

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Traveller’s Diarrhoea

Figure 1: Management of Traveller’s Diarrhoea

Sudden Onset of Nausea/Vomiting/Diarrhoea

↓

Maintain Hydration*

↓ ↓ ↓

Mild Moderate Severe

↓ ↓ ↓ ↓ ↓

Symptoms Tolerable Tolerable Distressing Incapacitated

↓ ↓ ↓ ↓ Fever

↓ ↓ ↓ ↓ Bloody diarrhoea

↓ ↓ ↓ ↓ ↓

No Treatment Loperamide Loperamide Loperamide Antibiotics

↓ ↓ ↓ & +/-

↓ ↓ Persists Antibiotics Loperamide**

↓ ↓ ↓ ↓ ↓

↓ ↓ Add antibiotics ↓ ↓

↓ ↓ ↓ ↓ ↓

Diarrhoea persists especially if severe, worse, bloody

↓

Stool Specimen & Medical Assessment

*Oral rehydration solution if available. **Avoid loperamide if fever or bloody stools. Notes: For definitions of severity, see Table 1. For antibiotic choices and dosing, see Table 3.

Table 3: Antibiotic Treatment Options for Traveller’s Diarrhoea (adapted from Riddle MS et al.5)

Antibiotic* Daily Dose (oral) Schedule Duration (days)

Azithromycin*** 1000mg Single dose or 500mg twice daily 1**

Azithromycin 500mg 500mg daily 3

Ciprofloxacin 750mg Single dose 1**

Ciprofloxacin 1000mg 500mg twice daily 3

Rifaximin# 600mg 200mg three times daily 3

*Loperamide is given with all antibiotic treatments (maximum 16mg in any 24-hour period). **If symptoms are still present and significant at 24 hours, continue treatment for another 2 days (3 days total therapy, as per the schedule for the 3-day course set out in the row below the single dose therapy). ***Azithromycin is preferred: it covers Campylobacter (which is often resistant to fluoroquinolones); and it is the preferred choice for dysentery or diarrhoea with fever. #Rifaximin should not be used if invasive diarrhoea is suspected (usually caused by Campylobacter, Salmonella or Shigella).

Treatment of Traveller’s Diarrhoea focuses on fluid replacement with oral rehydration which is adequate in most cases, but intravenous fluids can be required in severe cases. Antibiotics can also be given but fluid replacement is still most important for the majority of cases. Sachets of oral rehydration solution are preferred for oral fluid replacement and should be carried when travelling overseas. Antibiotic treatment is generally reserved for more severe cases. See treatment algorithm in Figure 1 and doses in Table 3.

Under some circumstances antibiotics may be advised for certain travellers to prevent Traveller’s Diarrhoea (see Table 4). This should only be done after seeking medical advice. It is less commonly advised now because of the prevalence of antibiotic resistance in bacteria that cause diarrhoea in travellers, limiting the protective efficacy of the prophylaxis.

An additional important consideration is concern with increased risk of faecal carriage of multiresistant gut bacteria that is associated with antibiotic use in travellers to developing countries.

Prevention of Traveller’s Diarrhoea is by simple food and water precautions. An easily remembered aphorism is ‘boil it, cook it, peel it, or forget it’. Unfortunately, compliance with this advice is often poor. ‘Dietary indiscretions’ are common, even within the first day of arrival at the risk destination. Other preventive measures are also available and include the oral cholera vaccine, Dukoral, some probiotics and Travelan. Protection provided by each does vary, so these options should be discussed with the individual traveller.

Dukoral® is a killed bacterial vaccine that contains many artificial B-subunits of cholera toxin which stimulates production of antibodies to a heat labile toxin that is produced by most ETEC strains. This toxin is also closely related to the B-subunit of cholera toxin that binds to small bowel epithelial cells to cause toxin-mediated diarrhoea.

Dukoral, therefore, by stimulating gut mucosal production of such antibodies, provides protection against illness due to both Vibrio cholerae and most ETEC strains. Dukoral is only licensed in Australia for protection against cholera, but is licensed for protection against both cholera and ETEC Traveller’s Diarrhoea in a number of developed countries.

A two-dose schedule is required, with boosters every five years for ongoing ETEC Traveller’s Diarrhoea protection.

A Cochrane Review published in 2013 queried the benefit of Dukoral in preventing Traveller’s Diarrhoea due to ETEC or all causes.4 Only one suitable trial for analysis, providing low quality evidence, was identified (502 USA travellers to Mexico) and no statistically significant benefit was identified.

Sachets of oral rehydration solution are preferred for oral

fluid replacement and should be carried when travelling overseas

Two studies conducted on over 50,000 travellers to Bangladesh and Morocco with the precursor to this vaccine (containing cholera toxin B subunit, rather than recombinant B subunit) did show significant protective efficacy for three months against ETEC Traveller’s Diarrhoea. Anecdotal benefit reported by travellers would suggest that, like with all vaccines, some persons produce a more effective and protective immune response than others.

Travelan® is a hyperimmune bovine colostrum powder (BCP) that contains antibodies against 14 different ETEC strains. The antibodies bind to ETEC in the gut and prevent them from attaching

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Table 4: Antibiotic Prophylaxis Options for Traveller’s Diarrhoea (adapted from Diemert DJ.1)

Antibiotic Daily Dose (oral) Schedule Comment

Bismuth subsalicylate (Pepto-bismol)

8 tabs (262mg tab) or 120mls

2 tabs with meals and at night before bed or

30mls with meals and at night before bed

Not available in Australia. Commonly used and recommended in USA. Bismuth based so dark tongue, dark stools and tinnitus main side effects

Norfloxacin 400mg Single dose Photosensitivity and gastrointestinal upset problematic

Ciprofloxacin 500mg Single dose Photosensitivity and gastrointestinal upset problematic

Rifaximin# 6400mg 200mg three times dailyAvailable in Australia for TD treatment. Prophylaxis doses vary. Gastrointestinal upset, headache main side effects

to the gut epithelium and therefore prevent the toxigenic diarrhoea caused by ETEC.

One Travelan caplet is taken before every meal for the duration of the trip. One small study of 30 volunteers showed 77-91% protective efficacy against diarrhoea caused by 14 different ETEC strains.5 For trips of short duration, Travelan definitely has a role although downsides may include lack of protection against all ETEC strains and travellers may find it inconvenient to carry the required quantities for long trips. More widespread protection against pathogens other than ETEC may be possible, but further data are required.6

Probiotics are widely used in the community but studies showing proven medical benefit are variable in number and quality. There is some evidence for protective efficacy in prevention of Traveller’s Diarrhoea, but studies have conflicting results.This may reflect the likely fact that some probiotics are more effective than others.

A meta-analysis of 12 studies showed a beneficial prophylactic effect.7

Proposed mechanisms for the beneficial effects of probiotics include: suppression of the growth of ‘harmful’ or pathogenic bacteria; blocking their attachment to gut epithelium and supporting or improving gut mucosal function and immunity. Despite the likely benefit, there is currently not enough evidence to recommend probiotics as a major prophylaxis option against Traveller’s Diarrhoea.8

One of the probiotics included in the above mentioned meta-analysis found to provide some benefit was Saccharomyces boulardii.9 This probiotic has been widely available and extensively studied.

In 2009, the International Society of Travel Medicine expert group acknowledged the issue of antibiotic resistance in pathogens causing TD, but in 2017, it was identified as a major concern.3

There are two issues.10,11,12

Firstly, there is the global problem of increasing antibiotic resistance in causative pathogens, negatively impacting use of antibiotics for treatment and prevention. Secondly, taking antibiotics, for any reason, not just Traveller’s Diarrhoea, increases the individual’s risk of faecal carriage with multiresistant gut organisms including Escherichia coli and Klebsiella pneumoniae.

Many of these resistant organisms have acronyms that denote the type of antibiotic resistance exhibited by these organisms such as CRE (carbapenem resistant Enterobacteriaceae), ESBL (extended spectrum beta-lactamase), KPC (K.pneumoniae carbapenemases) etc. Carriage may be prolonged or permanent.

While travellers carrying these multiresistant gut organisms may never have any clinical illness caused by gut colonisation by these organisms, some do. Examples of infections caused by these multiresistant gut organisms include, inter alia, both lower and upper urinary tract infections (UTIs) and post-surgical infections, especially septicaemia following trans-rectal prostate biopsy.

A history of travel to a developing country should be sought in patients with such infections. For prostate biopsy, such a history should be specifically sought, as pre-biopsy screening (rectal swab) for multiresistant gut organisms can guide both antibiotic prophylaxis for the procedure as well as consideration of an alternative route of biopsy.

Finally, some travellers complain of gastrointestinal upset following return from developing country travel. Symptoms include dyspepsia, bloating, food intolerances and loose stools.13,14

In most travellers, symptoms resolve over the weeks following return but some travellers have persistent symptoms. If an infective cause is found, it is commonly giardiasis. Some causes are listed in Table 5.

Traveller’s Diarrhoea

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Video Resources

Children & Travel, Tuberculosis, travel and Maternal immunisations – Interview by Dr Nigel Crawford

Travel Medicine for Children – Interview by Dr Nigel Crawford

Watch the full lectures on the Healthed website. Visit www.healthed.com.au/video

Table 5: Rate of Pathogen Detection per 1000 Unwell Returned Travellers (Adapted from Swaminathan A et al.13)

PathogenRate/1000 travellers

Giardia species 31.3

Campylobacter species 14.8

Entamoeba histolytica 14.0

Shigella species 7.0

Strongyloides species 6.8

Salmonella (non-typhoidal) species 5.2

Dientamoeba fragilis 4.5

Ascaris 4.3

Salmonella typhi 3.8

Hookworm 2.7

Tapeworm 2.7

Others* Less than 2.7

*Included in decreasing order of frequency; hepatitis A, Trichuris, S.paratyphi, C.difficile, Enterobius, Cryptosporidium, Cyclospora, hepatitis E, Yersinia, Clonorchis, Fasciola, Trichomonas, Isospora, V.cholerae.

Faecal testing in the laboratory should be requested in those with persistent symptoms following return home. Standard tests are now supplemented by molecular tests wherein multiple pathogens can be detected on a single sample.

Positive results for agents like Blastocystis hominis and Dientamoeba fragilis may be difficult to interpret as to their role in the patient’s illness. It is also important to determine whether the symptoms are due to a first episode of inflammatory bowel disease, coeliac disease or other medical conditions.

Some returned travellers require referral to a gastroenterologist for assessment and upper and lower gastrointestinal endoscopy to exclude such conditions, as well as diagnose conditions such as amoebiasis, generally rare other parasite and helminth infections, Clostridium difficile (pseudomembranous) colitis, and conditions usually diagnosed on small bowel biopsy such as tropical sprue and Whipples disease.

Declaration

Dr Bernard Hudson was commissioned by Healthed for this article. The ideas, opinions and information presented are solely those of the author. The advertiser does not necessarily endorse or support the views expressed in this article.

The author’s competing interests statement can be viewed at www.healthed.com.au/monographs.

References

Parts of this article have been adapted with permission from www.travelhealthadvisor.com.au.

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3. Riddle MS, Connor BA, Beeching NJ, DuPont HL, Hamer DH, Kozarsky P et al. Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report. J Travel Med. 2017 Apr 1; 24(Suppl 1): S57-S74.

4. Ahmed T, Bhuiyan TR, Zaman K, Sinclair D, Qadri F. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev. 2013 Jul 5; (7); CD009029.

5. Otto W, Najnigier B, Stelmasiak T, Robins-Browne RM. Randomized control trial using a tablet formulation of hyperimmune bovine colostrum to prevent diarrhea caused by enterotoxigenic Escherichia coli in volunteers. Scand J Gastroenterol. 2011 Jul; 46(7-8): 862-68.

6. Sears KT, Tennant SM, Reymann MK, Simon R, Konstantopoulos N, Blackwelder WC, et al. Bioactive immune components of anti-diarrheagenic enterotoxigenic Escherichia coli hyperimmune bovine colostrum products. Clin Vaccine Immunol. 2017 Aug 4; 24(8): e00186-16. Available from: https://cvi.asm.org/content/24/8/e00186-16.long DOI: 10.1128/CVI.00186-16

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Editorial TeamMedical Editors: Dr Linda Calabresi, Dr Vivienne Miller Managing Editor: Karina Lozada Editorial Assistant: Neil Harris Commissioning Editor: Dr Ramesh Manocha