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SPECIAL REPORT

Treating Travellers’ Diarrhoea

Travellers’ Diarrhoea The Epidemiology of Travellers’ Diarrhoea The Aetiology of E-Coli – The Good Commensal Gone Bad The Pre-Travel Risk Assessment: to Prescribe or not to Prescribe The Returned Traveller with Diarrhoea

Published by Global Business Media


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

SPECIAL REPORT

Treating Travellers’ Diarrhoea

Contents Foreword

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Dr Robert Sykes, Editor Travellers’ Diarrhoea The Epidemiology of Travellers’ Diarrhoea The Aetiology of E-Coli – The Good Commensal Gone Bad The Pre-Travel Risk Assessment: to Prescribe or not to Prescribe The Returned Traveller with Diarrhoea

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor Dr Robert Sykes Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.

Travellers’ Diarrhoea

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Dr Mike Townend, MB, ChB (Hons), Dip Trav Med, FFTM RCPS (Glasg), Hon Fellow BGTHA

Causes of Travellers’ Diarrhoea Sources of Infection for Travellers Reducing the Risk of TD Treatment of TD Key Points

The Epidemiology of Traveller’s Diarrhoea

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Susan Thomas, Medical Correspondent

Risk of Acquiring Travellers’ Diarrhoea Destination Host Factors

The Aetiology of E-Coli – The Good Commensal Gone Bad

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John Bushnell, Staff Writer

Escherichia Coli (E. coli) Species ETEC – A Major Problem for the Traveller STEC – Less Common but a Cause of Bloody Diarrhoea and HUS Conclusions

The Pre-Travel Risk Assessment: to Prescribe or not to Prescribe

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Dr Robert Sykes, Editor

Boil it, Cook it, Peel it, or Forget it! Medical Prophylactic Measures Antibiotic Prophylaxis Summary

The Returned Traveller with Diarrhoea

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Dr Robert Sykes, Editor

Clinical Presentation: History and Assessment Management Treatment Summary

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

Foreword T

ravellers’ diarrhoea (TD) is among the most frequently reported problems for travellers. It is responsible for a significant socioeconomic burden, and both its prevention and management remain a challenge. This Special Report aims to provide an overview of the general approach to the management of TD according to best practice guidelines. We begin with an excellent article written by Dr Mike Townend, providing an overview of TD, sponsored by Norgine Pharmaceuticals Ltd who were involved in the outline development and medico-legal approval of the article. Founded in 1906, Norgine is a speciality pharmaceutical company with an extensive pan-European presence and a focus on gastroenterology, hepatology and incontinence. The remainder of the Report can be split into two sections. In the first part, we have two articles that expand upon key themes concerning the epidemiology and aetiology of diarrhoea in the returned traveller. Following this, we have two articles focusing on the clinical consultation surrounding TD: the pre-travel consultation, and the returned traveller. Although we cannot provide in depth details on the minutiae of these consultations, it is hoped that the reader will leave feeling confident in how to manage them. Guidelines in this article largely focus on information from expert consensus, the Centers for Disease Control and Prevention (CDC), the World Health Organisation (WHO), the Clinical Knowledge Summary (CKS) database, and the Health Protection Agency (HPA). Although not extensively used, NICE guideline CG84 “Diarrhoea and vomiting in children under 5” is also utilised. Excellent UK orientated

resources are also available on both Travellers’ diarrhoea, as well as food and water hygiene, from the National Travel Health Network and Centre (NaTHNaC; www.nathnac.org). In general the NaTHNaC website is an excellent resource for the UK based clinician looking for up to date information on travel risk. Furthermore, when reading the articles themselves, it is important to bear in mind some of the key concerns raised in the 2010 HPA document “Foreign travelassociated illness – a focus on Travellers’ diarrhoea.” It points out several key limitations to the UK data: in spite of being the main pathogen, data on E. coli is not available through routine reporting; laboratoryconfirmed GI illness under-represents the total disease burden in the general population by a factor of between 88 and 136; this under-representation is even more pronounced for infections associated with travel, since travel history reporting is incomplete; laboratory data cannot distinguish between UK residents travelling abroad and overseas residents who arrive in the UK as visitors; information on dates of travel and onset of illness is incomplete through laboratory reporting, making absolute attribution of illness to travel problematic. The result is that, although we have a broad idea of the scale of the problem, we do not know its true magnitude. Efforts need to be made by health care professionals at all tiers, to ensure that better reporting occurs, in order that better strategic planning and management can be put in place.

Robert Sykes Editor

Dr Robert Sykes qualified with a degree in medicine (MBChB Honours) in 2004 from the University of Liverpool where he was awarded the George Holt Medal for high academic achievement, along with commendations for a number of his clinical reviews. As a postgraduate he entered into a GP vocational training scheme before opting to work in a portfolio career, and in 2008, he set up Northern Editing (www.docrob.co.uk/nothernediting) for medical writing and editing. Currently, he is also the Executive Editor for the UK’s only peer support organisation for doctors with mental illness, the Doctors’ Support Network (registered charity 1103741; www.dsn.org.uk).

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

Travellers’ Diarrhoea Dr Mike Townend, MB, ChB (Hons), Dip Trav Med, FFTM RCPS (Glasg), Hon Fellow BGTHA

Primary Care Reports

IN REALITY, TRAVELLERS SELDOM FOLLOW ADVICE ON FOOD AND WATER HYGIENE

T

RAVELLERS’ DIARRHOEA (TD) is usually defined as the passage of three or more unformed stools over a 24 hour period, occurring during or soon after travel. It is the commonest travel related health problem1,2, affecting around 1 million people annually and up to 50% of travellers to developing countries 3,4. It may last for as little as 24 hours or as much as several days, with a mean duration of about 4 days, and in a minority of cases chronic diarrhoea may result. Its severity is also very variable, ranging from a minor inconvenience to a severe illness that completely disrupts travel plans. In 90% of travellers, symptoms appear within the first two weeks of travel, though the onset may be at any time during travel or within a few days of returning home. Travellers are 6.5 times more likely to develop diarrhoea than they would have at home3. The highest incidence of TD5, from 20% to 50% of travellers, occurs in developing countries such as those in South and Southeast Asia. Africa and parts of South America

Causes of Travellers’ Diarrhoea In around 75-80% of cases, bacterial infection is responsible for causing TD6. Enterotoxigenic

E coli (ETEC) is the most frequent bacterial cause, accounting for half to two thirds of all bacterial infections, with Shigella spp, Salmonella spp, Campylobacter and other strains of E coli accounting for most of the remainder. Around 10-15% of cases are caused by protozoa such as Giardia, Entamoeba and Cylcospora. Viruses such as Rotavirus and Norovirus account for only a small proportion of cases, in contrast to diarrhoea occurring in the UK in which viruses are the commonest causative agent. Some pathogens including some strains of E coli (ETEC and EPEC) and Vibrio cholerae cause secretory diarrhoea characterised by gut hypersecretion of fluid. This type of infection usually has a short incubation period and produces profuse watery stools. Invasive pathogens such as Shigella, Salmonella, Campylobacter and some strains of E coli (EIEC and EHEC) invade the gut wall causing inflammation and mucosal damage which may lead to ulceration and bleeding. This type of infection is characterised by frequent small volume stools which may contain blood, mucus or pus, and are accompanied by abdominal cramps and tenesmus. This syndrome is referred to as dysentery. Other organisms such as Entamoeba histolyitica may also cause dysentery.

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

In 90% of travellers, symptoms appear within the first two weeks of travel, though the onset may be at any time during travel or within a few days of returning home.

A mixed secretory and invasive pattern may be produced by some organisms such as Salmonella, Campylobacter and some strains of E coli (EIEC and EHEC).

Sources of Infection for Travellers Organisms responsible for causing TD are transmitted by faecal-oral transmission, i.e. by ingestion of food and/or water contaminated by organisms of faecal origin. There are many reasons why this is more likely to occur in a less developed country than it is in a developed country: • Water used for cooking, washing produce or drinking may come from a source that has suffered faecal contamination due to poor infrastructure • Sewage disposal may be of poor quality or non-existent, leading to contamination of water sources • The food supply chain is unlikely to be well controlled, and food handling and food hygiene standards are unlikely to be high • Food may be left exposed to contamination, e.g. by flies, or at temperatures likely to encourage bacterial growth in buffets • D airy production is unlikely to be well controlled or pasteurisation used, leading to possible contamination of products such as milk, butter, cheese and ice cream • Shellfish, especially filter-feeding molluscs, may have been harvested from water contaminated by sewage • Ice in drinks may have been made from contaminated water • Facilities for personal hygiene e.g. hand washing, for both travellers and food handlers, may be inadequate or completely absent

Reducing the Risk of TD However careful the traveller, it is not possible to eliminate completely the risk of developing diarrhoea as there are many factors beyond the Travellers’ control. Attention to the following factors is, however, likely to reduce the risk. Water7 In countries outside Western Europe, Scandinavia, North America and Australasia water from any sources, including taps, may be contaminated. It may be rendered suitable for drinking or cleaning teeth by the following methods. • Boiling. At sea level it is necessary to bring water to a boil for no more than a minute, but at higher altitude longer periods of boiling are needed as water boils at lower temperatures as altitude increases

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THE INCIDENCE OF TD IS STRONGLY ASSOCIATED WITH THE HYGIENE CONDITIONS OF THE DESTINATIONS

SOURCES OF DRINKABLE WATER ARE OFTEN DIFFICULT TO FIND, ESPECIALLY IN REMOTE REGIONS

• Filtration. A fabric bag filter can remove particulate matter that may interfere with other methods of purification. Ceramic filters are effective in removing pathogens but they need regular cleaning and are relatively fragile, becoming ineffective if cracked or broken. Small filters, usually combined with a drinking bottle, are an effective means of producing a personal supply of drinking water but are less useful for larger quantities. Recently introduced types of filter bottle are able to remove over 99% of all pathogens. • Chemical purification. The most popular method of chemical purification is the use of tablets that release chlorine or iodine into the water, though 2.5% tincture of iodine 4-6 drops per litre of water, left for 20-30 minutes before drinking is also widely used. Visible impurities should be filtered out before using a chemical method. The taste of chlorine or iodine may be removed after the purification period by adding a small amount of ascorbic acid or juice from a citrus fruit. The use of iodine has been banned by the EEC for purely technical reasons not concerned with its safety. • Ultraviolet light (UVL) interferes with the reproduction of micro-organisms and may be used to purify water. The use of natural UVL is unreliable as the amount of exposure is difficult


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

to quantify. The Steripen is a portable batteryoperated device producing UVL that can be used for this purpose. • Bottled water is widely available, but may not always be free from contamination. It also has adverse environmental effects when large numbers of plastic bottles are discarded. Food Relatively low standards of food handling and hygiene may lead to contamination of food, and even in expensive restaurants or hotels this may occur if standards lapse. • Freshly and adequately cooked food which is brought hot to the table is likely to be safe to eat in most situations, as is street food that is well cooked and immediately eaten • Raw or undercooked foods should be avoided • Street food left open to flies should be avoided • Buffets are best avoided, as they allow micro-organisms to multiply at a congenial temperature, though often they are the only available source of food • Salads may have been washed in contaminated water and are best avoided • Fruit may have been washed in contaminated water and is best avoided unless personally washed and peeled • Seafood, especially filter-feeding molluscs such as mussels and oysters, should be avoided, particularly if raw • Personal hygiene. Hand washing after using toilet facilities and before preparing or eating food is essential. If suitable facilities are inadequate or unavailable, antiseptic hand wipes or alcohol gel are a good alternative.

Treatment of TD Many cases of TD will resolve spontaneously and require little treatment other than maintaining an adequate fluid intake. The very young and the very old demand special attention, as they are less able to regulate their fluid balance and may become more easily dehydrated. Oral rehydration Rehydration is the cornerstone of treatment for TD and is frequently the only treatment likely to be needed. The addition of easily absorbable carbohydrate to the fluids enhances absorption of water from the gut. Glucose and electrolyte powders in convenient sachet form are available to make up oral rehydration solution (ORS), but a simple “do it yourself” method is to add a three finger pinch of salt and a palmful of sugar to 500ml water. Double-ended spoons are also available for measuring out sugar and salt in appropriate

amounts. The use of ORS is of most importance in the very young and the very old, as they are less likely to be able to regulate their fluid and electrolyte balance, and also for those with severe diarrhoea. Drinking water is likely to be adequate for most healthy adults with TD. Clear soups containing a little salt, and sugar-containing soft drinks are also very useful.

Primary Care Reports

Diet Unless diarrhoea is accompanied by nausea or vomiting it is not necessary to avoid food completely. Easily absorbable carbohydrate such as boiled rice, white bread, boiled or mashed potatoes or plain pasta may all be eaten and may enhance absorption of water from the gut. Antidiarrhoeal drugs Drugs such as loperamide10,11 reduce stool frequency by reducing gut motility. They also relieve symptoms such as abdominal pain, cramps and distension and may reduce the overall length of the illness. Placebo controlled trials have shown such drugs to be fast acting, safe and effective as a treatment for mild to moderate non-invasive diarrhoea in adults and children12. Their use is not appropriate in children under the age of 4 years or in the treatment of dysenteric diarrhoea. Antimicrobial agents Treatment with antimicrobial drugs is not required in all cases of TD. The most commonly used antimicrobial used for treatment of TD is ciprofloxacin, either in a course of 3 to 5 days or as a single dose13. It has been shown to decrease both the duration of diarrhoea and stool frequency, but at risk of adverse effects from the drugs, though most adverse effects are minor14. Unfortunately, no doubt due at least in part to its widespread use in self-treatment by travellers, resistance to ciprofloxacin is emerging15,16, particularly in Campylobacter and some Salmonella species in South Asia. For resistant infections, a suitable alternative drug is azithromycin. Rifaximin-α17 is a virtually non-absorbable antimicrobial drug that is effective against noninvasive gut pathogens. It has been found to be effective and well tolerated in the treatment of diarrhoea, with a wide spectrum of action, but is ineffective against inflammatory or invasive organisms. Systemic absorption has been shown to be less than 0.04%. Unlike systemically absorbable antimicrobial agents such as

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

Unfortunately, no doubt due at least in part

ciprofloxacin or azithromycin, the emergence of resistance to rifaximin is unlikely to be a major public health concern, as it has no use in the treatment of systemic infections.

Key Points

to its widespread use in self-treatment by travellers, resistance to ciprofloxacin is emerging.

• Travellers’ diarrhoea is common in travellers to developing countries • The risk of developing it can be reduced, but not eliminated, by careful attention to food and drink consumption and personal hygiene • C hemoprophylaxis with antimicrobial drugs is unlikely to be appropriate for the majority of travellers, though prebiotics may offer some protection • Rehydration is the mainstay of treatment for all travellers • Both antimotility and antimicrobial drugs, either alone or in combination, are safe and effective treatments for Travellers’ diarrhoea

in most travellers, though antimicrobial drugs carry a small risk of adverse effects • R esistance to systemically absorbed antimicrobial drugs is emerging in some parts of the world. The use of non-absorbable antimicrobial drugs goes some way towards solving this problem, though rifaximin is not effective against organisms that invade the gut wall

Norgine Pharmaceuticals Ltd was involved in the outline development and medicolegal approval of this article and provided financial support for its publication. The article is peer reviewed and the author and publisher retained final editorial control of the content. The opinions expressed in the article are not necessarily those of the publisher or Norgine Pharmaceuticals Ltd.

References: 1

 Kamat D, Mathur A. Prevention and management of Travellers’ diarrhoea. Disease-a-Month 52(7): 289-302, 2006

Health Protection Agency. Illness in England, Wales and Northern Ireland associated with foreign

2

travel. Comm Dis Surv Centre 2004. Health Protection Agency, London Peltola H. Travellers’ diarrhoea: epidemiology and clinical aspects. In Textbook of Travel Medicine

3

and Health. Ed Becker. Hamilton Canada Dupont HL, Capsuto EG. Persistent diarrhea in travellers. Clin Inf Dis 22(1): 124-8, 1996

4

Steffen R, de Bernardis C, Banos A. Travel epidemiology – a global perspective. Int J Antimicrob.

5

Agents. 2(1): 89-95, 2003 Lloyd R. Bennett C. Travellers’ diarrhoea: causes, prevention and treatment. Nursing Standard.

6

26(40):51-6; 2012 http://www.cdc.gov/healthywater/ accessed 05/10/2012

7

Prevention of traveler’s diarrhea with rifaximin in US travellers to Mexico. Martinez.Sandoval

8

F,Ericsson CD, Jiang ZD, et al. J Trav Med 17(2): 111.117, 2010 Prevention, prebiotics and travel-related diarrhoea. Blackwood TI, McIntosh PA. J Brit Global Trav

9

H Assoc, 19:7-11, 2012 Gorbach SL. Treating diarrhoea. BMJ 314: 1776-7, 1997

10

DuPont HL. Guidelines on acute infectious diarrhea in adults. Am J Gastroent.

11

92: 1962-1974, 1997 Farthing M. Travellers’ diarrhoea. Gut 35: 1-4, 1994

12

Salam I, Katelaris P. Leigh-Smith S. Farthing MJ.. Randomised trial of single-dose ciprofloxacin for

13 

travellers’ diarrhoea. Lancet 344(8936):1537-9, 1994 Cochrane Collaboration. Antibiotic treatment for travellers’ diarrhoea.

14

John Wiley & Sons Ltd, 2009 Traveler’s diarrhea in Nepal: an update on the pathogens and antibiotic resistance.

15

Pandey P. Bodhidatta L. Lewis M. Murphy H et al. J Trav Med 18(2):102-8, 2011 Mendez Arancibia E. Pitart C. Ruiz J. Marco F. Gascon J. Vila J. Evolution of antimicrobial

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resistance in enteroaggregative Escherichia coli and enterotoxigenic Escherichia coli causing Travellers’ diarrhoea. J Antimicrob Chemoth. 64(2):343-7, 2009 Robins GW, Wellington K. Rifaximin: a review of its use in the management of travellers’

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diarrhoea. Drugs 65(12): 1697-1713, 2005 Authorship sponsored by a grant from Norgine Pharmaceuticals Ltd 6 | WWW.PRIMARYCAREREPORTS.CO.UK


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

The Epidemiology of Travellers’ Diarrhoea

Primary Care Reports

Susan Thomas, Medical Correspondent

T

R AV E L L E R S ’ D I A R R H O E A ( T D) represents a significant burden at both the socioeconomic and the personal level. On average, 30–50% of travellers to high-risk areas are estimated to develop TD . Symptoms are generally minor, but up to 40% change their travel plans, whilst up to 20–30% are confined to bed, and approximately 1% require hospital admission2. Around 80% of TD is confirmed to be due to infective enteropathogens . Over the past 20 years, foreign travel has been increasing steadily in the UK with around 65% travelling for holidays and 18% to visit friends and relatives1,4. In 2008, a significant 61,994,105 UK residents reported travelling abroad, with the vast majority going to continental Europe and less than 20% travelling to medium and high risk destinations (figure 1a). Large outbreaks of travel-associated gastrointestinal (GI) illness are rarely identified in the UK, although at least three notable ones have been reported in recent years. In 2003, there was an outbreak of cryptosporidium associated with travel to Majorca5, in 2007 there was an outbreak of mixed aetiology in travellers returning from the Dominican Republic6, whilst in 2009, an outbreak involving Cryptosporidium and Salmonella Enteritis, was reported in travellers returning from Turkey7.

Overall, there is no doubt that TD poses a significant public health problem, and this article seeks to clarify the epidemiological risks associated with its development.

Risk of Acquiring Travellers’ Diarrhoea Although there is generally good data on what areas pose a high risk for the development of TD, this data is patchy, making a true estimation of the burden of TD difficult1,2. Outbreaks of TD can occur in any travelling population such as tourists, business travellers and military populations8,9. Risk is not however universally the same, and a variety of host and destination related factors have roles to play.

Destination What is the risk of TD according to destination? The risk of travellers acquiring TD when travelling from a high-income country to a low-income country is very much dependent on destination, but has been reported to be as high as 60% in some studies2,10. According to the Health Protection Agency (HPA)1, the world can be divided into three zones of risk: low risk zones (Incidence <7%) include western Europe, USA, Canada, Japan, Australia

Figure 1a.  Visits  abroad  by  area  of  the  world,  UK  residents:  2008  (N  =  61,  994,105)*     Rest  of  the  world/  South  and  Central   America/  A-­‐  ustralia   and  New  Zealand     Caribbean  –  1%  each   Sub-­‐Saharan  and  southern  Africa   %       South  East  Asia  and  Far  East   2  2   %       Indian  subcontinent   2  %       North  Africa  and  the  Middle  East   4  %       North  America    

73 %      

7 %      

Europe non  EU        

Europe EU    

6 %      

*Health Protection  Agency.  Foreign  travel-­‐associated  illness  –  a  focus  on  travellers’  diarrhoea.  2010  report.  London:  Health   Protection  Agency;  2010  

Figure 1b.  Map  showing  the  risk  zones  for  traveller’s  diarrhoea  *  

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SPECIAL REPORT: TREATING TRAVELLERSâ&#x20AC;&#x2122; DIARRHOEA

In 2008, a significant 61,994,105 UK residents reported travelling abroad, with the vast majority going to continental Europe and less than 20% travelling to medium and high risk destinations.

and New Zealand; Intermediate risk zones (Incidence <20%) include southern Europe, Israel, South Africa, some Caribbean islands, and the Pacific; and high risk zones (incidence >20%) include Africa, Latin America, the Middle East and most parts of Asia (See figure 1b). A UK study identified that cases that had travelled outside northern Europe had a nine-fold increased risk of TD when they travelled to countries around the Mediterranean and the Middle East, and a 31-fold increased risk if they had travelled elsewhere11. Comparing rates over time, it is apparent that there has been a significant reduction in the incidence and prevalence of TD in southern Europe12, as well as in Tunisia and Jamaica over recent decades13,14. In contrast, little risk reduction has been observed at other non-EU destinations1,2. The most popular region of travel for UK residents however, remains continental Europe [Figure 1a]. What factors in the destination affect the incidence of TD? Even at a single destination, there are highly significant differences in TD incidence rates. We know that the greatest risk of TD is during the first few weeks of travel, with the risk diminishing somewhat over time15. The most important factors appear to be the choice of hotel and the choice of restaurant. In Jamaica, the selection of a hotel was found to be crucial, where the incidence rate of TD for 18 hotels

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visited for 1 week varied significantly between 0% and 33%16. Some studies have added to this, suggesting that staying in a luxury hotel may actually increase the risk of TD due to the fact that food is more frequently prepared by hand and that all-inclusive holidays are associated with a higher risk due to an increased consumption of local food and alcohol2,17. The type of travel also plays a role: beach resort vacations are associated with lower attack rates (28%), whilst tours (31% - 32%), and more specifically adventure tours (34%), are associated with higher attack rates18, and all inclusive tours tending to have the highest attack rates of all19. There is also some evidence that the season of travel has some relevance, with the peak percentage of affected travellers occurring in the June to October period20. The choice of eating establishment is also an important factor. Certainly, eating meals purchased in cafeterias or from street vendors can be very risky21,22, as can the consumption of unpasteurized milk and beer23. Although wine drinking may have some protective effect24, it is not recommended to rely upon this25. As a rule, most studies generally agree that poor hygiene within a chosen eating establishment or hotel is a major factor associated with an increased risk of TD.

Host Factors Age, Sex and the Travellersâ&#x20AC;&#x2122; origin Various studies have demonstrated that


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

Primary Care Reports

The choice of eating establishment is also an important factor. Certainly, eating meals purchased in cafeterias or from street vendors can be very risky. younger age is a risk factor for TD. Infants, toddlers, and young adults (15–30 years old) in particular, are prone to developing TD26,27. This is a rational observation given that infants tend to indiscriminately touch objects with their hands and mouths, whilst young adults are thought to have less food discipline. In most studies, no significant difference in TD incidence rates has been observed according to sex28.

Travellers from developed countries, visiting developing countries, have the highest risk of acquiring TD of any group1,2. People from developing countries tend to have a very low incidence of TD (2%–8%) when visiting other developing countries29. Equally, studies have demonstrated that travellers who have recently visited the tropics also have a lower rate of TD30. In both cases, this is probably as a result of some developed immunity. Genetics and Other host factors There is also evidence of a genetic susceptibility to TD. For example, diarrhoea due to infection with enteroaggregative Escherichia coli occurs significantly more often in individuals with the AA genotype than in individuals with other genotypes31. In addition, a lack of gastric acidity, either as a result of surgery or in association with the use of such medications as omeprazole or magnesium and aluminium hydroxide, has been identified as a risk factor for TD32.

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

References: 1

 Health Protection Agency. Foreign travel-associated illness – a focus on travellers’ diarrhoea. 2010 report. London: Health Protection Agency; 2010

2

Steffen R. Epidemiology of Travellers’ diarrhea. Clin Infect Dis 2005;41:S536-S540.

3

D. Patel. Occupational travel. Occupational Medicine 2011;61:6–18. From http://occmed.oxfordjournals.org/content/61/1/6.long

4

H  PA. Foreign travel-associated illness, England, Wales and Northern Ireland: 2007 report. London; Health Protection Agency: 2007

5

Galmes A, et al. Cryptosporidiosis outbreak in British tourists who stayed at a hotel in Majorca, Spain. Eurosurveillance 2003; 7 (33). Available online at www.eurosurveillance.org/ViewArticle.aspx?ArticleId=2275.

6

HPA. Outbreak of gastrointestinal illness in tourists visiting the Dominican Republic. Health Protection Report 2007; 1 (33): news. Available online at: http://www.hpa.org.uk/hpr/archives/2007/news2007/news3307.htm#dr

7

 HPA. Gastroenteritis associated with travel to Turkey. Health Protection Report 2009; 3 (42): news. Available online at: www.hpa.org.uk/hpr/archives/2009/news4209.htm#turkey

8

Hyams KC, et al. Diarrheal disease during Operation Desert Shield. N Engl J Med 1991;325:1423–8.

9

Sanchez JL, et al. Diarrheal disease incidence and morbidity among United States military personnel during short-term missions overseas. Am J Trop Med Hyg 1998; 58:299–304.)]

10

Centers for Disease Control and Prevention. CDC Health Information for International Travel 2010. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 2009.

11

A Report of the Study of Infectious Intestinal Disease in England. London: The Stationery Office, 2000.

12

Cartwright RY. Food and waterborne infections associated with package holidays. J Appl Microbiol 2003;94:12S–24S.

13

Ashley et al. Interventions to prevent and control food-borne diseases associated with a reduction in traveler’s diarrhea in tourists to Jamaica. J Travel Med 2004;11:364–9.

14

Cartwright RY, Chahed M. Foodborne diseases in travellers. World Health Stat Q 1997;50:102–10.)]

15

Shlim DR, et al. Persistent high risk of diarrhoea among foreigners in Nepal during the first 2 years of residence. Clin Infect Dis 1999;29:613-616.

16

Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of traveler’s diarrhea in Jamaica. JAMA 1999;281:811–7.

17

Steffen R, et al. Epidemiology, Etiology, and Impact of Travelers’ Diarrhea in Jamaica. JAMA 1999; 281 (9); 811-7.

18

Steffen R, et al. Epidemiology of diarrhea in travelers. JAMA 1983;249:1176–80.

19

Huang DB, et al. United States male students who heavily consume alcohol in Mexico are at greater risk of travelers’ diarrhea than their female counterparts. J Travel Med 2004;11:143–7.

20

Peltola H and Gorbach SL. Chapter 12.1: Travelers’ Diarrhea – Epidemiology and Clinical Aspects. In: DuPont HL and Steffen R. Textbook of Travel Medicine and Health. Hamilton; BC Decker: 1997.

21

Hoge CW, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. JAMA 1996;275:533–8.

22

Hill DR, Beeching NJ. Travelers’ diarrhea. Curr Op Inf Dis 2010; 23: 481-7)]

23

Steffen R, et al. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med 2004;11:231–8.]

24

Weisse, et al. Wine as a digestive aid: comparative antimicrobial effects of bismuth salicylate and red and white wine. BMJ 1995;311:1657–60.

25

Cook KA, et al. Don’t rely on drinking wine to prevent Travellers’ diarrhoea. BMJ 1996;312:642.

26

Cobelens FGJ, et al. Incidence and risk factors of diarrhoea in Dutch travellers: consequences for priorities in pre-travel health advice. Trop Med Int Health 1998;3:896–903.)

27

Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler’s diarrhea in infants and children. Pediatr Infect Dis J 1991; 10:719–23.

28

Cavalcanti A, et al. Traveler’s diarrhea: epidemiology and impact on visitors to Fortaleza, Brasil. Rev Panam Salud Publica 2002;11:245–52.

29

DuPont HL, et al. Diarrhea of travelers to Mexico: relative susceptibility of United States and Latin American students attending a Mexican University. Am J Epidemiol 1977;105:37–41.

30

Steffen R, Tornieporth N, Clemens SA, et al. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med 2004;11:231–8.

31

Jiang ZD, et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis 2003;188:506–11.

32

Neal KR, et al. Omeprazole as a risk factor for campylobacter gastroenteritis: case-control study. BMJ 1996;312:414–5

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The Aetiology of E-Coli – The Good Commensal Gone Bad John Bushnell, Staff Writer

T

RAVELLERS’ DIARRHOEA (TD) may be caused by a variety of different organisms. In the majority of cases, bacteria such as Escherichia coli1, Salmonella spp.2, Shigella spp. 3 and Campylobacter spp.4 are responsible for most acute infectious diarrhoea, but the parasites Giardia lamblia5 and Cryptosporidium6 are also implicated, as are viruses such as Norovirus7,8. More recently, bacteria such as enterotoxigenic bacteroides fragilis and Arcobacter spp. are increasingly found to be causative9, although the diagnostic capabilities of most laboratories tend to limit the organisms actually identified10. In many cases of TD a causative pathogen is never found7,11. It is also worth noting that the likely pathogen also varies due to the seasonal popularity of the destination12. However, to look at all the potential pathogens in detail would be beyond the remit of this Report. Since the significant number of identified cases tend to be due to E-coli, this common gut commensal will be our focus.

Escherichia Coli (E. coli) Species E. coli are a diverse group of bacteria, and although most strains are harmless commensals, some species can cause disease and are referred to as enterovirulent E. coli (EVEC). Several EVEC strains secrete toxins that act on the intestinal lining causing diarrheal illness, and can be broken down into several categories based on the mechanism of virulence. The World Health Organisation (WHO) recognises enteropathogenic (EPEC), enterohaemorragic (EHEC), enteroinvasive (EIEC), enterotoxigenic (ETEC), Shiga toxinsecreting (STEC), diarrhoea-associated haemolytic (DHEC), entero-aggregative (EAAggEC or EAEC), and cytolethal distending toxin-secreting (CDTEC) E. coli strains13. Of these, STEC and ETEC tend to have received the most attention in the literature. A systematic review of the global aetiology of TD from 51 studies identified ETEC as the most common pathogen, followed by EAEC14.

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In the future, the application of polymerase chain reaction techniques for virulence genes may increase the detection of other strains in stools negative for the common enteropathogens15. STEC is a species that also receives particular attention due to its association with bloody diarrhoea, and the haemolytic uraemic syndrome (HUS).

ETEC – A Major Problem for the Traveller ETEC strains are the most common cause of TD affecting individuals travelling from industrialized countries to developing regions of the world16,17. Each year, there are an estimated 10 million cases of ETEC diarrhoea worldwide18. The incidence of ETEC in travellers from industrialized regions to developing countries is in the 30 to 45% range19, and it has been suggested to account for as many as 80% of all cases of TD20. ETEC function by attaching to specific receptors on the surface of enterocytes courtesy of their hair-like fimbriae, which define strain-specific antigenicity (of which more than 20 have been identified). Once attached to the intestinal epithelium, ETEC produce both heat-labile (LT) and heat-stable (ST) toxins. Destruction of the intestinal microvilli results from the intimate adherence or the toxic effect exerted over the epithelia, resulting in water secretion and watery diarrhoea21. Other signs and symptoms typically reported in ETEC infection include headache, fever, and nausea and vomiting, with some patients developing a prolonged diarrhoea lasting a week or more22. Additionally, a genetic predisposition to produce high levels of interleukin-10 (IL-10) makes some travellers more likely to experience symptomatic ETEC diarrhoea23. ETEC continues to show high levels of resistance to traditional antibiotics such as ampicillin, trimethoprimsulfamethoxazole, and doxycycline, with the first-line antibiotic options currently being the fluoroquinolones and azithromycin24,25. Although they will probably be of more benefit

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

ETEC strains are the most common cause of TD affecting individuals travelling from industrialized countries to developing regions of the world.

to children in developing countries, research is currently underway toward developing an effective vaccine for use against ETEC strains26.

STEC – Less Common but a Cause of Bloody Diarrhoea and HUS Some enterohaemorragic E. coli strains have been lysogenized with phages from Shigella dysenteriae, to become shiga toxin-secreting E. coli (STEC)27. The O157:H7 serotype, is the most common strain and causes a watery diarrhoea that rapidly progresses to frank haemorrhagic colitis1. STEC may, in around 20% of case, lead to serious sequelae, including HUS, which is characterized by thrombocytopenia, haemolytic anaemia and renal failure. This occurs when shiga toxins are translocated to the circulatory system and transported by leukocytes to capillary endothelial cells in renal glomeruli and other organs where it inhibits protein synthesis. The natural reservoir of the O157:H7 pathogen is cattle, which harbours the bacterium in its intestines: outbreaks in humans are linked to ingestion of meat or other foods contaminated by bovine faeces (WHO). Variants of the STEC subgroup are verocytotoxic E. coli (VTEC) or enterohaemorrhagic E. coli (EHEC); a specific strain of STEC that caused a large outbreak in Europe in 2011 was labelled O104:H4 (EHEC)28. Other E. coli serogroups, including E. coli O145, O26, O111, and O103, are sometimes called “non-O157 STECs.” Currently, there is limited public health surveillance data on the occurrence of non-O157 STECs,

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and many infections may go undiagnosed or unreported1. It is important to note that antibiotics are not recommended for patients with suspected STEC infections since some studies have shown that their use in patients with STEC infections might increase the risk of HUS29.

Conclusions E. coli is of course not the only pathogen with a causative role in the development of TD. Indeed, campylobacter is a significant pathogen too, and is the most frequently identified cause of TD in South Asia where it predominates over ETEC and EAEC30,31. Most people who become ill with campylobacteriosis will develop diarrhoea (can be bloody), cramping, abdominal pain, nausea, vomiting and fever within five days after exposure. Although treatment is not normally required, erythromycin or azithromycin can be beneficial as with ETEC. Together, these 2 pathogens constitute the most like causes of TD in the returning traveller, and are most commonly screened for when stool samples are sent for analysis. Although some clinicians may consider initiating systemic therapy with empirical antibiotics, it is important to bear in mind that the risk of HUS may be increased in bloody diarrhoea associated with STEC. Additionally, the increasing prevalence of antibiotic resistance should always be in the back of one’s mind as the common pathogens are gaining increasing resistance to our most effective antimicrobial agents, with even the quinolones showing evidence of this over the last couple of decades23.


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

References: 1

 CDC (2008c) Escherichia coli. Centers for Disease Control and Prevention. www.cdc.gov CDC (2008e) Salmonellosis. Centers for Disease Control and Prevention. www.cdc.gov

2 3

CDC (2008f) Shigellosis. Centers for Disease Control and Prevention. www.cdc.gov

4

CDC (2008a) Campylobacter. Centers for Disease Control and Prevention. www.cdc.gov

5

CDC (2008d) Giardiasis. Centers for Disease Control and Prevention. www.cdc.gov

6

CDC (2008b) “Crypto” - Cryptosporidiosis. Centers for Disease Control and Prevention. www.cdc.gov

7

Peltola H, Gorbach SL. Travelers’ diarrhoea – epidemiology and clinical aspects. In: DuPont HL, Steffen R, editors. Textbook of travel medicine and health. Hamilton, ON, Canada: Blackwell Science; 1997.

8

Health Protection Agency. Foreign travel-associated illness – a focus on travellers’ diarrhoea. 2010 report.London: Health Protection Agency; 2010.

9

Jiang ZD, Dupont HL, Brown EL, et al. Microbial etiology of travelers’ diarrhoea in Mexico, Guatemala, and India: importance of enterotoxigenic Bacteroides fragilis and Arcobacter species. J Clin Microbiol 2010;48:1417–9.

10

Alastair C. McGregor, et al. Geographic, symptomatic and laboratory predictors of parasitic and bacterial causes of diarrhoea in travellers. Transactions of the Royal Society of Tropical Medicine and Hygiene 106 (2012) 549– 553. Available http://dx.doi.org/10.1016/j.trstmh.2012.04.008

11

Al-Abri S, Beeching NJ, Nye FJ. Travellers’ diarrhoea [review]. Lancet Infectious Diseases 2005; 5: 349-60.

12

Louis VR, Gillespie IA, O’Brien SJ, Russek-Cohen E, Pearson AD, Colwell RR. Temperature-Driven Campylobacter Seasonality in England and Wales. Appl Env Microbiol 2005; 71 (1): 85-92.

13

WHO (World Health Organisation), Initiative for Vaccine Research (IVR). Diarrhoeal Diseases (Updated February 2009). Available at http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index4.html

14

Shah N, DuPont HL, Ramsay DJ. Global Etiology of Travelers’ Diarrhea: Systematic Review from 1973 to the Present. Am J Trop Hyg 2009; 80 (4): 609-14.

15

Meraz IM, et al. Enterotoxigenic Escherichia coli and Diffusely Adherent E. coli as Likely Causes of a Proportion of Pathogen-Negative Travelers’ Diarrhea – A PCR-Based Study. J Trav Med 2008; 15: 412-8.

16

Black RE. Epidemiology of travelers’ diarrhoea and relative importance of various pathogens. Rev Infect Dis. 1990 Jan-Feb;12 Suppl 1:S73-9.

17

Gemma Northey, et al. Sentinel surveillance for travellers’ diarrhoea in primary care. BMC Infect Dis. 2007; 7: 12 Published online 2007 November 6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2186334/

18

Steffen R, et al. Vaccination against enterotoxigenic Escherichia coli, a cause of travelers’ diarrhoea. J Travel Med. 2005 Mar-Apr;12(2):102-7.

19

Subekti DS et al. “Prevalence of enterotoxigenic Escherichia coli (ETEC) in hospitalized acute diarrhoea patients in Denpasar, Bali, Indonesia.” Diagnostic Microbiology and Infectious Disease 2003. 47: 399-405.

20

Penny M. Diarrhoeal diseases. In: Eddleston M, et al, editors. Oxford: Handbook of tropical medicine. 2nd edn. Oxford: Oxford University Press, 2005;117–68.

21

Arenas-Hernández MM, Martínez-Laguna Y, Torres AG. Clinical implications of enteroadherent Escherichia coli. Curr Gastroenterol Rep. 2012 Oct;14(5):386-94. doi: 10.1007/s11894-012-0277-1.

22

J. Daniel Dubreuil. The Whole Shebang: The Gastrointestinal Tract, Escherichia coli Enterotoxins and Secretion. Curr. Issues Mol. Biol. 14: 71-82.

23

Flores J,et al. Influence of host interleukin-10 polymorphisms on development of traveler’s diarrhea due to heat-labile enterotoxin-producing Escherichia coli in travelers from the United States who are visiting Mexico. Clin Vaccine Immunol. 2008 Aug;15(8):1194-8. doi: 10.1128/CVI.0007008. Epub 2008 Jun 25.

24

Rendi-Wagner P, Kollaritsch H. Drug prophylaxis for travelers’ diarrhea. Clin Infect Dis. 2002 Mar 1;34(5):628-33. Epub 2002 Jan 16.

25

Ouyang-Latimer J et al. In vitro antimicrobial susceptibility of bacterial enteropathogens isolated from international travelers to Mexico, Guatemala, and India from 2006 to 2008. Antimicrob Agents Chemother. 2011 Feb;55(2):874-8. Epub 2010 Nov 29.

26

Zhang W, Sack DA.Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans. Expert Rev Vaccines. 2012 Jun;11(6):677-94. doi: 10.1586/erv.12.37.

27

Karmali MA. Infection by Shiga toxin-producing Escherichia coli: an overview. Mol Biotechnol. 2004 Feb;26(2):117-22.

28

WHO (World Health Organisation) International Health Regulations: Outbreaks of E. coli O104:H4 infection. Available at: http://www.euro.who.int/en/what-we-do/health-topics/emergencies/international-health-regulations/outbreaks-of-e.-coli-o104h4-infection

29

CDC E. coli (Escherichia coli) resources for Clinicians and Laboratories. Guidance to Healthcare Providers and Clinical Laboratories. www.cdc.gov

30

Pandey P, et al. Travelers’ diarrhea in Nepal: an update on the pathogens and antibiotic resistance. J Travel Med. 2011 Mar-Apr;18(2):102-8. doi: 10.1111/j.1708-8305.2010.00475.x. Epub 2010 Nov 30.

31

DuPont HL. Systematic review: the epidemiology and clinical features of travellers’ diarrhoea. Aliment Pharmacol Ther 2009; 30: 187-96.

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The Pre-Travel Risk Assessment: to Prescribe or not to Prescribe Dr Robert Sykes, Editor

Although food and water related precautions can be difficult to adhere to, they continue to be recommended. ‘Boil it, cook it, peel it, or forget it!’ remains the mainstay of prophylactic advice.

R

ISK ASSESSMENT is key to the pre travel assessment, and should ideally guide all aspects of it. The above article covering the epidemiology of travellers’ diarrhoea (TD) details the many additional factors that should also be weighed. However, the most important risk factor is undoubtedly the country to be visited, and the relative risk of travellers’ diarrhoea (TD) can be obtained from the map shown in Figure 1b. If there is a need to assess the risk for individual countries where travellers should practice strict food, water, and personal hygiene precautions, the National Travel Health Network and Centre (NaTHNaC) website (www.nathnac.org) is an excellent resource providing current information on risk. The other major risk is the individual’s susceptibility to TD and their risk of complications. Those at higher risk would include: young children and babies; the elderly and frail; the immunocompromised (such as those with HIV infection or AIDS); those with medical conditions such as severe cardiac or renal disease, or inflammatory

bowel disease; and people with reduced acidity in the stomach. In addition, the availability of local medical services is important. In this article we look at the broad range of advice that we offer to the foreign traveller, with a particular focus on the use of antibiotic prophylaxis.

Boil it, Cook it, Peel it, or Forget it! Although food and water related precautions can be difficult to adhere to, they continue to be recommended. ‘Boil it, cook it, peel it, or forget it!’1 remains the mainstay of prophylactic advice. The WHO Five Keys to Safer Food have been specifically adapted to travellers2, and although the advice given in this guide is important for every traveller, it is of particular importance for the high-risk groups mentioned. The five areas are briefly summarized in the table 3a. Certainly, the selection of food that is served piping hot is safer than foods from a buffet or that have been sat around for a while. Equally, care should be taken to avoid products that may have been diluted or

Table 3a. The WHO Five Keys To Safer Food* 1. Keep Clean: Wash your hands often and always before handling and consuming food. 2. R  aw and cooked food should be kept separate: When frequenting street food vendors or buffets in hotels and restaurants, make sure that cooked food is not in contact with raw food that could contaminate it. Avoid any uncooked food, apart from fruits and vegetables that can be peeled or shelled. 3. F  ood should be cooked thoroughly: In general, make sure your food has been thoroughly cooked and remains steaming hot. It is critical that all parts of the food be thoroughly cooked, i.e. reaching 70° C in all parts. Avoid raw seafood, poultry meat that is still red or where the juices are pink, and minced meat/burgers that are still rare because they contain harmful bacteria throughout. 4. F  ood should be kept at safe temperatures: Cooked food held at room temperature for several hours constitutes another major risk for food- borne illness. Avoid these foods at buffets, markets, restaurants and street vendors if they are not kept hot or refrigerated/on ice. By holding food refrigerated or on ice (at temperatures below 5°C) or piping hot (above 60°C) the growth of micro- organisms is slowed down or stopped. 5. C  hoose safe water and food: Ice cream, drinking water, ice cubes and raw milk can easily be contaminated with dangerous microorganisms or chemicals if they are made from contaminated ingredients. If in doubt avoid them. Peel all fruits and vegetables if eaten raw. When the safety of drinking water is doubtful, bring it to a vigorous boil. If boiling is not possible, micropore filtering and use of disinfectant agents such as iodine tablets should be considered. Beverages which are either bottled or otherwise packaged are usually safe to drink. * WHO. Food Safety: Guide on safe food for travellers. Published by the Department of Food Safety, Zoonoses and Foodborne Diseases. Available: http://www.who.int/foodsafety/publications/consumer/travellers/en/index.html

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Table 3b. Common sense rules about food and water for the traveller*: • All food, but especially meat, fish and poultry must be thoroughly cooked and served hot – most bugs are killed by temperatures above 60°C. • Avoid drinking too much alcohol. • Check seals on all drinks – do not drink from bottles or cans with broken seals. • Food that is not properly cooked or has been left standing at room temperature increases risk. • Take care with drinking water. Only drink water purified by boiling or filtering combined with chemical disinfection, or safely bottled water. • Try small amounts of new foods until you are used to different tastes and flavours. * NaTHNaC. Travel health information sheets: Travellers Diarrhoea. November 2011. Accessed at: http://www.nathnac.org/travel/factsheets/travellersdiarrhoea.htm

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Table 3c. Potentially unsafe foods that the traveller should take care with: • Salads. • Raw fruit and vegetables, unless you wash and peel them yourself. • Food left exposed to flies. • Food shared with lots of people, such as buffets. • Any unpasteurised products, including dairy products and fruit juices. • Undercooked or raw fish, meat or shellfish. • Reheated food – especially fish, meat or rice. • Takeaways and street food – unless thoroughly cooked in front of you. • Unpasteurised milk, cheese, ice cream and other dairy products. • Fresh or cooked food that has been allowed to stand at room temperature in warm environments. * NaTHNaC. Travel health information sheets: Food and water Hygeine. January 2011. Accessed at: http://www.nathnac.org/travel/misc/travellers_food.htm

washed with local water, as well as raw or undercooked meat, and unpeeled 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 may also be safely drunk. Common sense rules can be followed, as in table 3b3, in order to achieve risk reduction, as can avoiding the foods recognized as being potentially unsafe in table 3c4.

Medical Prophylactic Measures Beyond this common advice, several other areas have received significant attention over the years. A good overview of the options available is summarised5 as in table 3d. The use of bismuth subsalicylate is no longer recommended and the use of probiotics is unproven to date, with further research needed before they can be recommended5,6. Equally, antidiarrheal drugs (such as loperamide) should not be taken prophylactically, due to the lack of data on either their safety or efficacy7. There has been some hope over the last decade that vaccines might offer some benefit, but due to the wide range of causative agents, this is likely to be an impossible task. Having said this, travellers to risky areas must still receive appropriate vaccination against other intestinal infections such as cholera, hepatitis A, and typhoid5. In addition, an oral cholera vaccine may produce cross-protective immunity against some

enterotoxigenic strains of Escherichia coli (which expresses a heat labile enterotoxin similar to cholera toxin), although prevention is estimated to occur in only 1-7% of cases, making its use impractical for this purpose specifically8,9.

Antibiotic Prophylaxis Whilst travellers at low to intermediate risk require only reassurance and the general advice on hygiene measures 3, antibiotic prescribing may be appropriate for certain high-risk travellers. This can take the form of either empirical antibiotic treatment (to use if affected) or a prophylactic course for the duration of their trip10. Prophylactic antibiotics are certainly effective in the prevention of TD but they are not recommended for the healthy traveller who would just prefer not to experience TD, due to the potential for drug-associated adverse reactions and resistance5,11,12. Indeed, the prophylactic antibiotic of choice has changed over the past few decades as resistance patterns have evolved. For example, in the 1980s doxycyclineresistant strains evolved in many targeted tourist destinations13, followed rapidly by other systemic antimicrobials, such as trimethoprimsulfamethoxazole14.

The Fluoroquinolones and Azithromycin Since the late 1980’s the fluoroquinolones have been broadly recognized as the most effective antibiotics for the prophylaxis and treatment of bacterial TD pathogens15,16. Of this class,

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

In a 2010 study of

Table 3d. Summary of the CKS Guidance for Traveller’s Diarrhoea* • Assess the risk of traveller’s diarrhoea.

rifaximin prophylaxis in travellers to Mexico, 76%

o The risk is highest for people travelling to the Middle East, Africa, Central and South America, and most of Asia.

• For people at low or intermediate risk of traveller’s diarrhoea:

o Provide information on food hygiene and safe drinking water if the person is travelling to locations with low standards of hygiene and sanitation.

o Offer advice regarding self-management and when to seek medical advice if they develop diarrhoea during their travels.

• For people at high risk of traveller’s diarrhoea:

in the rifaximin group completed treatment without developing TD compared to 51% in the placebo group, with rifaximin providing a 58% protection rate overall

oE  mphasize the importance of personal hygiene, as well as food hygiene and safe drinking water, to reduce the risk of traveller’s diarrhoea.

oW  arn the person about the risk of waterborne infection and to avoid contaminated recreational water.

o Do not routinely offer prophylactic antibiotics for prevention of traveller’s diarrhoea.

o Antibiotic prophylaxis may be appropriate for certain high-risk travellers.

o Consider whether a prescription for empirical antibiotic treatment to use if affected is a more suitable alternative if prophylaxis is not indicated, and the person is travelling to particularly high-risk locations where medical assistance is poor or not available.

o Inform the person that there are no universal vaccines for traveller’s diarrhoea.

o Offer advice regarding self-management and when to seek medical advice if the person develops diarrhoea during their trip.

(*available: http://www.cks.nhs.uk/diarrhoea_prevention_and_advice_for_travellers)

ciprofloxacin is the recommended first line due to both its cost and proven efficacy5,17. Azithromycin is recommended if resistance to the fluoroquinolones is suspected or known, and in children and pregnant women6,9,18. Unfortunately, increasing resistance to these agents is developing and may limit their benefit in the future19,20, particularly amongst campylobacter species21.

Rifaximin

against TD, with fewer adverse events.

The non-absorbable antibiotic rifaximin may offer a real alternative to traditional antibiotics, with effectiveness demonstrated against noninvasive strains of E. coli22. In a 2010 study of rifaximin prophylaxis in travellers to Mexico, 76% in the rifaximin group completed treatment without developing TD compared to 51% in the placebo group, with rifaximin providing a 58% protection rate overall against TD, with fewer adverse events23. Recently an algorithm has been developed to identify travellers for which chemoprophylaxis is appropriate recommending rifaximin as the preferred drug, followed by a fluoroquinolone24.

Duration of antibiotic prophylaxis Based on expert opinion, the usual recommendation is to offer short-term antibiotic prophylaxis for no longer than 3 weeks8,18,25,26. Most experts discourage prophylaxis for longer than 3 weeks as there is a possibility

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that this might inhibit the development of natural immunity seen with medium- to longterm stays in the country26,27.

Summary Prevention is effectively achieved through appropriate food and beverage selection, hygiene and antimicrobial prophylaxis where appropriate. Carrying small containers of alcohol-based hand cleaners (containing at least 60% alcohol) may make it easier for travellers to clean their hands before eating25. The evidence is also that prophylactic antibiotics should not be recommended for the vast majority of travellers: they offer no protection against nonbacterial pathogens, can be associated with allergic or adverse reactions and their use contributes to drug resistance. On the other hand, there is a much stronger argument for their use in short-term travellers who are high-risk hosts (such as those who are immunosuppressed) or who are taking critical trips during which even a short bout of diarrhoea could affect the trip. The use of prophylactic antibiotics should also be weighed against the possibility of using prompt, early self-treatment with antibiotics when TD occurs. Additionally, the non-absorbable agent rifaximin offers a very real alternative that appears to mitigate many of the problems associated with prophylactic antibiotic use.


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

References: 1

 Kozicki M, Steffen R, Schär M. ‘Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea? Int J Epidemiol. 1985 Mar;14(1):169-72.

2

WHO. Food Safety: Guide on safe food for travellers. Published by the Department of Food Safety, Zoonoses and Foodborne Diseases. Available: http://www.who.int/foodsafety/publications/consumer/travellers/en/index.html

3

4

5

6

NaTHNaC. Travel health information sheets: Travellers Diarrhoea. November 2011. Accessed at: http://www.nathnac.org/travel/factsheets/travellersdiarrhoea.htm NaTHNaC. Travel health information sheets: Food and water Hygeine. January 2011. Accessed at: http://www.nathnac.org/travel/misc/travellers_food.htm NHS Clinical Knowledge Summaries. Scenario: Diarrhoea – prevention and advice for travellers. Version 1.1. Accessed at: http://www.cks.nhs.uk/diarrhoea_prevention_and_advice_for_travellers National institute for clinical excellence. NICE clinical guideline 84: Diarrhoea and vomiting caused by gastroenteritis: diagnosis, assessment and management in children younger than 5 years

7

WHO (2009) International travel and health: situation as on 1 January 2009. World Health Organization. www.who.int

8

Hill, D.R., et al. (2006) The practice of travel medicine: guidelines by the Infectious Diseases Society of America.

9

Clinical Infectious Diseases 43, 1499-1539. Hill, D.R. and Ryan, E.T. (2008) Management of travellers’ diarrhoea. British Medical Journal 337(Oct 6), a1746.

10

Ryan ET, Kain KC. Health advice and immunization for travelers. N Engl J Med 2000;342:1716-25.

11

Ericsson, Steffen et al. Drug Prophylaxis for Travelers’ Diarrhea. Clin Infect Dis. (2002) 34 (5): 628-633.

12

Gorbach SL, Edelman R. Travelers’ diarrhea: National Institutes of Health Consensus Development Conference.

13

Rev Infect Dis 1986;8((Suppl 2)):109-233. Sack RB, et al. Doxycycline prophylaxis of travelers’ diarrhea in Honduras, an area where resistance to doxycycline is common among enterotoxigenic Escherichia coli. Am J Trop Med Hyg 1984;33:460-6.

14

Heck JE, et al. Prevention of travelers’ diarrhea: ciprofloxacin versus trimethoprim/sulfamethoxazole in adult volunteers working in Latin America and the Caribbean. J Travel Med 1994;1:36-42.

15

Johnson PC, Ericsson CD, Morgan DR, et al. Lack of emergence of resistant fecal flora during successful prophylaxis of traveler’s diarrhea norfloxacin. Antimicrob Agents Chemother 1986;30:671-4.

16

Parry H, et al. The prophylaxis of travelers’ diarrhea: a double-blind placebo controlled trial of ciprofloxacin during a Himalayan expedition. J Infect 1994;28:337-8.

17

ABPI Medicines Compendium (2008c) Summary of product characteristics for Ciproxin tablets 500mg. Electronic Medicines Compendium. Datapharm Communications Ltd. www.emc.medicines.org.uk

18

19

Al-Abri, S.S., Beeching, N.J. and Nye, F.J. (2005) Travellers’ diarrhoea. Lancet Infectious Diseases 5(6), 349-360. Cheong H-J, et al. Bacteremia due to quinolone-resistant Escherichia coli in a teaching hospital in South Korea. Clin Infect Dis 2001;33:48-53.

20

Hoge CW, et al. Trends in antibiotics resistance among diarrhea pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341-5.

21

Kuschner R, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536-41.

22

Layer P, Andresen V. Review article: rifaximin, a minimally absorbed oral antibacterial, for the treatment of travellers’ diarrhoea. Aliment Pharmacol Ther. 2010 Jun;31(11):1155-64. doi: 10.1111/j.1365-2036.2010.04296.x. Epub 2010 Mar 11.

23

Martinez-Sandoval F, Ericsson CD, et al.Prevention of travelers’ diarrhea with rifaximin in US travelers to Mexico. J Travel Med. 2010 MarApr;17(2):111-7.

24

DuPont HL. Systematic review: prevention of travellers’ diarrhoea. Aliment Pharmacol Ther. 2008 May;27(9):741-51. Epub 2008 Feb 14.

25

CDC (2009) Chapter 2. The pre-travel consultation. Self-treatable diseases: travelers’ diarrhea. The Yellow Book: CDC health information for international travel 2010. www.cdc.gov

26

DuPont, H.L., Ericsson, C.D., Farthing, M.J. et al. (2009b) Expert review of the evidence base for prevention of travelers’ diarrhea. Journal of Travel Medicine 16(3), 149-160.

27

Wiström J, et al. Ecological effects of short-term ciprofloxacin treatment of travelers’ diarrhea. J Antimicrob Chemother 1992;30:693-706. WWW.PRIMARYCAREREPORTS.CO.UK | 17


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

The Returned Traveller with Diarrhoea Dr Robert Sykes, Editor

The newer rifampicin-like agent, rifaximin offers an alternative, safe option to the management of TD, demonstrating only minimal potential for developing bacterial resistance and for drugdrug interactions.

T

RAVELLERS’ DIARRHOEA (TD) poses a significant risk as the most common illness reported in international travellers, particularly in those travelling from highincome countries to low-income regions where hygiene and sanitation may be less robust1,2,3. Somewhere in the region of 12% will present with classical TD on their return home4. These symptoms typically present during or shortly after a period of foreign travel5 with the passing of three or more unformed stools in a 24 hour period, often accompanied by at least one of the following: fever, nausea, vomiting, cramps, tenesmus, or bloody stools (dysentery). In about half of the cases, it is mild and self-limiting, lasting no more than 3-5 days1-4. However, illness severity can vary significantly depending on both the individual and the aetiological cause. It can cause serious illness, be extremely unpleasant, disrupt travel, and can become prolonged. Therefore, we need to be in a position to know who needs treatment, and who needs reassurance and supportive advice.

Clinical Presentation: History and Assessment A careful history must of course be taken. In particular, the presence of any associated symptoms (especially abdominal pain, nausea, fever) or blood in the faeces as

well as the nature and severity of the diarrhoea (mild: <4 stools per day or moderate-severe: 5+ stools per day), needs to be determined 5. Some useful pointers as to the underlying aetiology can also be determined in the history 6. Bacterial and viral diarrhoea tend to present with classical symptoms within 6-48 hours and lasts 3-5 days (Norovirus usually has more prominent vomiting). Protozoal diarrhoea on the other hand usually has an incubation period of 1-2 weeks (e.g. Giardia intestinalis or E. histolytica) with a more gradual onset of low-grade symptoms, and can persist for months. A useful summary of clinical features can be found in table 4a. Additional post infective sequelae have been reported including prolonged diarrhoea and even Guillain-Barré syndrome.

Management Treatment and laboratory investigations are usually both unhelpful and unnecessary. Clinically mild cases with minimal symptoms, should be managed with reassurance and advice to return if symptoms deteriorate. Moderate to severe diarrhoea can be determined clinically as more frequent (>45 loose motions per day) diarrhoea, but where the patient is not passing blood and is afebrile. Such patients may benefit from both

Table 4a. A clinical approach to the possible aetiology of diarrhoea*. Clinical presentation

Potential pathogen

Few, high volume stools; may be watery and severe in cholera; pale, fatty and smelly in giardiasis

Vibrio cholerae, ETEC, early shigellosis, Giardia, V. parahaemolyticus

Frequent small volume stools Shigella, Salmonella, Campylobacter, diarrhoeagenic pathotypes of E. coli, Yersinia enterocolitica, Entamoeba histolytica Tenesmus, faecal urgency, dysentery Shigella, Salmonella, EIEC, EHEC, Campylobacter, E. histolytica, V. parahaemolyticus (rarely) Predominance of vomiting

Viral (eg. rotavirus, calicivirus, norovirus) or intoxication (eg. S. aureus food poisoning)

Predominance of fever Shigella, Salmonella (especially enteric fever group), Campylobacter, viral agents, EIEC Prolonged diarrhoea (>2 weeks)

Giardia, E. histolytica, Cryptosporidium

* Modified from: Kass, R. Traveller’s diarrhoea. Aust Fam Physician 2005;34:243–5.

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

investigation and anti-diarrhoeal medication. Where a patient presents with severe, persistent diarrhoea and/or they are febrile and/or passing blood in their faeces, then attempts need to be made to identify the cause of the illness in order that specific treatment can be prescribed. Specifically, malaria may need to be excluded; any patient returning from a tropical area who presents with diarrhoea AND fever should have a blood smear examined. It is important that clinicians are aware of local protocols for the investigation of stool samples in cases of severe diarrhoea7. An excellent, up to date overview of the management of TD in the ill returned traveller can be found on the NHS’s national travel health network and centre (NaTHNaC) website8, and section 4.2 includes an excellent flow chart that can be followed9.

Treatment Fluid replacement is universally essential in the treatment of diarrhoea3. Fluids and electrolytes are lost in TD, and replenishment is important, especially in young children or adults with chronic medical illness. Dietary recommendations might also be helpful in these patients; the ‘BRAT’ diet (bananas, rice, apple sauce and toast) is sometimes suggested with avoidance of milk products often recommended due to possible transient lactose deficiency10. For more severe fluid loss, replacement is best accomplished with oral rehydration salts (ORS – see table 4b). However, any liquid should allow for adequate hydration. Antimotility Agents Antimotility agents provide symptomatic relief in uncomplicated diarrhoea and may also serve as useful adjuncts to antibiotic therapy11. Loperamide, for example, can reduce bowel movement frequency and enable travellers to ride on an airplane or bus while awaiting the effects of antibiotics12. Antisecretory agents should be avoided when treating bloody diarrhoea, or where the patient is febrile13,14 although there

is no such restriction in uncomplicated cases15.

Antimicrobial Therapy Antimicrobial treatment should be considered where the patient has bloody diarrhoea (dysentery), is suffering from cholera with severe dehydration, where the diarrhoea has a proven parasitic aetiology, and where there is proven enteropathogenic E. coli infection5,12. The specific treatment depends on the organism itself, as well as known drug sensitivities. In general, the antimicrobial choice is determined by local policies, but has been well documented in the literature10. While patients with mild diarrhoea do not usually require treatment, the duration of TD in adults can be shortened by the use of ciprofloxacin16. It has a clear indication and cost benefit in TD over other agents17, even though increasing resistance and the risk of quinoloneassociated arthropathy18 limit its wider use. Although it is not licensed for the treatment of TD specifically, azithromycin is recommended by the World Health Organization (WHO)19 and experts17 for the treatment of TD if resistance to fluoroquinolones is suspected/known, as well as for children and pregnant women. Unfortunately, resistance is growing even in ciprofloxacin and azithromycin, as occurred with the traditional antibiotics ampicillin, trimethoprim and doxycycline20,21. However, most guidelines recommend their use as the first line option5,12,22,23. The newer rifampicin-like agent, rifaximin offers an alternative, safe option to the management of TD, demonstrating only minimal potential for developing bacterial resistance and for drugdrug interactions 24. A 2010 review of 10 publications found that, when administered three times daily for 3 days, rifaximin was superior to placebo or loperamide, and that it was at least as effective as ciprofloxacin in reducing the duration of illness and restoring wellbeing in patients with TD, regardless of whether the pathogen had been identified25. In the UK it is licenced

Table 4b. Composition of the World Health Organization oral rehydration salts for diarrheal illness* INGREDIENT AMOUNT Sodium chloride

2.6 g/L

Potassium chloride

1.5 g/L

Glucose, anhydrous

13.5 g/L

Trisodium citrate, dehydrate

2.9 g/L (or 2.5 g/L)

Water 1 L * World Health Organization. Oral rehydration salts (ORS): production of the new ORS. Geneva: WHO; 2006.

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SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

The over-riding message must be that prevention is better than cure. So, tackling the issues in the pre-travel consultation is essential; stressing the importance that patients “boil it, cook it, peel it, or forget it!”

for TD that is not associated with fever, bloody diarrhoea, blood or leucocytes in the stool, or 8 or more unformed stools in the previous 24 hours26. It is also not recommended for diarrhoea associated with invasive organisms such as Campylobacter and Shigella27. The recommended duration for any antimicrobial therapy is 3-days, in line with WHO recommendations23 and expert opinion28. Experts argue that patients should be free to re-evaluate their symptoms after 24 hours of starting antibiotic treatment and to complete the 3-day course if they are still unwell, or to stop sooner if they are improved29,30. Once therapy is commenced with any agent, the clinician should bear in mind the possibility of antibiotic associated diarrhoea due to C. difficile and consider the withdrawal of treatment11, although Rifaximin has recognised benefits here too31. 20 | WWW.PRIMARYCAREREPORTS.CO.UK

Summary Most cases of TD are mild, of short duration and require neither investigation nor antibiotic treatment; where the diarrhoea is severe, bloody and/or prolonged, then the opposite is true, and if the patient is systemically ill, blood culture is mandatory. With regard to treatment, fluid replacement is the single most important aspect, and when clinically indicated, the most useful group of routinely available antibiotics are the fluoroquinolones and azithromycin, although the newer agent rifaximin may be a superior option where available. The addition of antimotility agents may offer symptomatic relief in troublesome, uncomplicated TD, but can be associated with problems. The over-riding message must be that prevention is better than cure. So, tackling the issues in the pre-travel consultation is essential; stressing the importance that patients “boil it, cook it, peel it, or forget it!32”


SPECIAL REPORT: TREATING TRAVELLERS’ DIARRHOEA

References: 1

 K Jong EC, Kleger MM, McMullen R. Approach to infectious diarrhoea in the returned traveller. In: The tropical and travel medicine manual. 2nd edn. Philadelphia: Saunders, 1995;295–312. Keystone JS, Kozarsky PE. Health advice for international travel. In: Guerrant RL, et al, editors. Essentials of tropical infectious diseases.

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Philadelphia: Churchill-Livingstone, 2001;128–40. 3

Leggat PA, Goldsmid JM. Travellers’ diarrhoea: health advice for travellers. Travel Med Inf Dis 2004;2:17–22.

4

Kass, R. Travellers’ diarrhoea. Aust Fam Physician 2005;34:243–5.

5

Al-Abri S, Beeching NJ, Nye FJ. Travellers’ diarrhoea [review]. Lancet Infectious Diseases 2005; 5: 349-60.

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Keddy K, Goldsmid JM, Frean J. Tropical gastrointestinal infections. In: Goldsmid, JM, Leggat PA, editors. Primer of tropical medicine. 1st edn. Brisbane: ACTM, 2005. Inglis TJJ. Clinical microbiology. Edinburgh: Churchill-Livingstone, 1997.

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http://www.nathnac.org/yellow_book/YBmainpage.htm

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http://www.nathnac.org/yellow_book/PostTravel-DiarrhoeaAlgorithm.pdf.pdf

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Thielman NM, Guerrant RL. Acute infectious diarrhoea. New Engl J Med 2004;350:38–47.

11

Goldsmid, JM. Travelers Diarrhoeal. Australian Family Physician Vol. 36, No. 5, May 2007

12

CDC 2012. The Yellow Book: Chapter 2 – the pre travel consultation. Accessed at: http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-2-the-pretravel-consultation/travelers-diarrhea.htm

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Fuller D, Hasnat M, Marks MK, Curtis N. Fever in a returned traveller. J Paediatr Child Health 2004;40:315–6.

14

Kass, R. Travellers’ diarrhoea. Aust Fam Physician 2005;34:243–5.

15

Ericsson CD. Travelers’ diarrhea. Int J Antimicrob Agents 2003;21:116–24.

16

Penny M. Diarrhoeal diseases. In: Eddleston M, et al, editors. Oxford: Handbook of tropical medicine. 2nd edn. Oxford: Oxford University Press, 2005;117–68

17

Hill, D.R., et al. (2006) The practice of travel medicine: guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43, 1499-1539.

18

ABPI Medicines Compendium (2008c) Summary of product characteristics for Ciproxin tablets 500mg. Electronic Medicines Compendium. Datapharm Communications Ltd. www.emc.medicines.org.uk [Free Full-text]

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WHO (2009) International travel and health: situation as on 1 January 2009. World Health Organization. www.who.int [Free Full-text]

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Rendi-Wagner P, Kollaritsch H. Drug prophylaxis for travelers’ diarrhea. Clin Infect Dis. 2002 Mar 1;34(5):628-33. Epub 2002 Jan 16.

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Ouyang-Latimer J et al. In vitro antimicrobial susceptibility of bacterial enteropathogens isolated from international travelers to Mexico, Guatemala, and India from 2006 to 2008. Antimicrob Agents Chemother. 2011

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NHS Clinical Knowledge Summaries. Scenario: Diarrhoea – prevention and advice for travellers. Version 1.1. Accessed at: http://www.cks.nhs.uk/diarrhoea_prevention_and_advice_for_travellers

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WHO (2007) A guide on safe food for travellers. World Health Organization. www.who.int [Free Full-text]

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Ericsson CD. Safety and tolerability of the antibacterial rifaximin in the treatment of travellers’ diarrhoea. Drug Saf. 2006;29(3):201-7.

25

Layer P, Andresen V. Review article: rifaximin, a minimally absorbed oral antibacterial, for the treatment of travellers’ diarrhoea. Aliment Pharmacol Ther. 2010 Jun;31(11):1155-64. Epub 2010 Mar 11.

26

Accessed from BNF January 2013 online: http://www.medicinescomplete.com/mc/bnf/current/PHP3568-xifaxanta.htm#PHP3568-xifaxanta

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Accessed from BNF January 2013 online: http://www.medicinescomplete.com/mc/bnf/current/PHP3566-rifaximin.htm

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DuPont, H.L., Ericsson, C.D., Farthing, M.J. et al. (2009a) Expert review of the evidence base for self-therapy of travelers’ diarrhea. Journal of Travel Medicine 16(3), 161-171.

29 30 31

Al-Abri, S.S., Beeching, N.J. and Nye, F.J. (2005) Travellers’ diarrhoea. Lancet Infectious Diseases 5(6), 349-360. Hill, D.R. and Ryan, E.T. (2008) Management of travellers’ diarrhoea. British Medical Journal 337(Oct 6), a1746. Shah D, DuPont HL, et al. Clostridium difficile infection: update on emerging antibiotic treatment options and antibiotic resistance. Expert Rev Anti Infect Ther. 2010 May;8(5):555-64. doi: 10.1586/eri.10.28.

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Kozicki M, Steffen R, Schär M. ‘Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea? Int J Epidemiol. 1985 Mar;14(1):169-72.

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Primary Care Reports – Treating Traveller's Diarrhoea – Norgine  

Primary Care – Special Report on Treating Travellers’ Diarrhoea

Primary Care Reports – Treating Traveller's Diarrhoea – Norgine  

Primary Care – Special Report on Treating Travellers’ Diarrhoea