Secondary Logo

Journal Logo

Traveler’s Diarrhea Recommendations for Solid Organ Transplant Recipients and Donors

Beeching, Nicholas J. MD, PhD1,2; Carratalà, Jordi MD, PhD3; Razonable, Raymund R. MD4; Oriol, Isabel MD3; Vilela, Eduardo Garcia MD, PhD5

doi: 10.1097/TP.0000000000002015
Reviews
Free

1 Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

2 NIHR Health Protection Research Unit (HPRU) in Gastrointestinal Infections, The Farr Institute, University of Liverpool, United Kingdom.

3 Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, Spain.

4 Division of Infectious Diseases, Department of Medicine, the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.

5 Alfa Institute of Gastroenterology, Clinic Hospital of Federal University of Minas Gerais, Belo Horizonte, Brazil.

Received 2 July 2017. Revision received 31 October 2017.

Accepted 15 November 2017.

N.J.B. is partially supported by the National Institute of Health Research Health Protection Research Unit in Gastrointestinal Infections, a collaboration between the University of Liverpool, the University of East Anglia, the University of Oxford and Public Health England.

The authors declare no conflicts of interest.

N.J.B. is part of the European Study Group for Infections in Travellers and Migrants (ESGITM).

J.D. is part of the European Study Group for Infections in Compromised Hosts (ESGICH).

Funded by a technical cooperation agreement between the Pan American Health organization (PAHO) and the Ministry of Health of Brazil.

This review is a chapter of Recommendations for Management of Endemic Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors: Latin America supplement.

Correspondence: Nicholas J. Beeching, Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, United Kingdom. (nicholas.beeching@lstmed.ac.uk).

Diarrhea is the most common illness in people traveling from resource-rich to resource-limited regions of the world.1 Most episodes of traveler’s diarrhea (TD) are benign and self-limited, but may require extra care in immunosuppressed patients.2,3 The major associated problem is dehydration, which can be exacerbated by immunosuppressive agents.

TD refers to diarrhea that develops during or within 10 days of returning from travel to resource-limited countries or regions. For epidemiological purposes, it is traditionally categorized into 3 forms: severe, moderate, and mild.4 Severe TD refers to the passage of 6 or more unformed stools in a 24-hour period irrespective of the presence of at least 1 of these other symptoms: nausea, vomiting, abdominal pain or cramps, fever, or blood in stools. Moderate TD is defined as the passage of 1 or 2 unformed stools in 24 hours, plus at least 1 of the above symptoms or 3 to 5 unformed stools in 24 hours without other symptoms. Passage of 1 or 2 unformed stools in 24 hours without other symptoms is considered mild. Recently, a more functional classification has been proposed, taking into account the tolerability of the diarrheal illness and functional impairment of the patient that it causes.5,6

Back to Top | Article Outline

EPIDEMIOLOGY

The incidence of TD is approximately 10% to 40%, depending on the travel destination. There have been few systematic studies in transplant recipients, so much of the discussion below is extrapolated from studies in all travelers. In immunosuppressed travelers, rates of infection are not necessarily higher, but the severity of illness can be increased.3,7 The viral, bacterial, and parasitic organisms that cause TD are usually transmitted by food and water, and the risk of TD is the highest in regions where sanitation and hygienic practices are poor. South and Southeast Asia, Africa (except South Africa), South and Central America, and Mexico are considered high risk (incidence greater than 20%). Regions that are moderate risk (10-20%) include Caribbean Islands, South Africa, Central and East Asia, Eastern Europe, and the Middle East, including Israel. Northern and Western Europe, Australia and New Zealand, the United States, Canada, Singapore, and Japan are classified as low-risk areas (less than 10%).4 Two decades ago, the incidence of TD was about 60%8,9 but it has decreased in countries with increasing economies and in some previously high-risk destinations with improved tourism infrastructure. South Asia, India, Nepal, and West/Central Africa remain the destinations with the highest risk.

The largest experience in travelers returning with disease acquired during travel to developing countries comes from GeoSentinel, the global surveillance network of the International Society of Travel Medicine and the United States Centers for Disease Control and Prevention10,11 Since GeoSentinel’s inception in 1995, it has grown to include more than 50 reporting sites in 24 countries on 6 continents, with over 200 000 patient records collected. Retrospective observational studies from the GeoSentinel network showed that rates of gastrointestinal infection reported in travelers returning to high-income settings, such as Western and Northern Europe, were inversely related to the income level of the country they had visited.3,12,13 These studies are particularly valuable for providing insight into the etiology and risk factors for the development of prolonged diarrhea in returned travelers. These differ from the bacterial and viral causes of the more common short-lived diarrhea typically experienced by travelers earlier during their travel.

Back to Top | Article Outline

Risk Groups

Environmental Factors

The risk of having diarrhea is highest during the first 7 days of travel and then progressively decreases. As well as destination, style of travel and available budget are important as they often determine where a traveler purchases meals. Backpackers often favor street vendors, which are known to have a high-risk of contaminated food.14 Buffet-style foods exposed to warm environmental conditions, even those served in a 5-star hotel, are also associated with a high incidence of TD.15 The risk of TD varies depending on the season, with a higher risk during warmer and wetter seasons.16

Back to Top | Article Outline

Host Factors

Genetic factors associated with an increased risk of TD are being increasingly recognized and are also being linked with susceptibility to postdiarrheal irritable bowel syndrome.17 For example, polymorphisms in genes controlling production of the proinflamatory cytokine interleukin 8 and lactoferrin correlate with greater intestinal inflammation and symptoms in US travelers to Mexico.18,19 Osteoprotegerin, an immunoregulatory member of the tumor necrosis factor receptor superfamily, may function as an antiinflammatory modulator that increases susceptibility to TD and CD14, a receptor for bacterial lipopolysaccharide binding, is associated with the innate immune response to enteric infection and inflammation. Single-nucleotide polymorphisms of these may increase susceptibility to TD.20,21 Possession of different blood group ABO(H) histocompatibility antigens has long been associated with susceptibility to bacterial enteropathogens, such as Vibrio cholerae, and more recently absence mutations in the related FUT2 gene, which provides ligands for virus binding, have been shown to reduce susceptibility to Norovirus infection.22,23

Younger travelers tend to have a greater risk of acquiring TD, probably because they eat more food, resulting in the ingestion of a larger quantity of pathogens.24 Also, younger travelers are more adventurous.24 Anything that reduces the gastric acid barrier to pathogens increases the risk of a wide variety of gastrointestinal infections from cholera to Clostridium difficile. This includes gastric sugery for peptic ulcer disease, antacids, H2 receptor antagonists and protein pump inhibitors. Many transplant recipients will be taking these medications.25,26

Back to Top | Article Outline

ETIOLOGY

Because there are few studies of travel-related diarrhea in transplant patients, the following discussion extrapolates from more general studies in travelers, highlighting areas of known or potential differences in the immunosuppressed. Although causes of diarrhea in solid-organ transplant recipients are similar to those in the general population, there are some differences, such as a higher incidence of drug-induced diarrhea and opportunistic infections in transplant patients.25 In a study of 52 diarrheal episodes among 43 solid-organ transplant recipients, the cause was determined in 43 (83%) recipients. Infectious etiologies accounted for 77% of cases, whereas drug-related diarrhea occurred in 23%.26

The relative importance of different pathogens in traveler's diarrhea greatly varies per the region visited and the season of travel.1 As in the general population, bacterial agents are the most frequent cause of TD in transplant patients.27 The most common causes are enterotoxigenic Escherichia coli (ETEC) and enteroaggregative E. coli, followed by Shigella, Salmonella, Campylobacter, Aeromonas, noncholeric vibrios, and Plesiomonas spp.1 In Asia, Campylobacter jejuni is a particularly frequent cause of traveler's diarrhea.28

Although viruses are rarely identified as the cause of traveler's diarrhea, their true importance is probably underappreciated because specific diagnostic tests (such as polymerase chain reaction) are not often performed in routine clinical practice.29 Noroviruses are recognized to be a leading cause of acute viral gastroenteritis worldwide and have been implicated in TD in visitors to Mexico, especially during the winter.30 Although noroviruses are increasingly being recognized as a significant cause of both acute and chronic diarrhea in solid-organ transplant recipients, their role as a cause of TD has not been specifically analyzed.31,32 Rotaviruses are known not only as a cause of TD but also of severe gastroenteritis in immunocompromised hosts, including transplant patients.33

Certain parasitic infections (Cryptosporidium spp, Cystoisospora belli, Cyclospora spp, Microsporidia, Giardia intestinalis) are highly prevalent in developing regions, and may be a significant cause of gastroenteritis in solid-organ recipients.34 However, most of the available information on diarrhea due to intestinal protozoa in transplant patients is derived from case reports or small series from single institutions.35,36

Cryptosporidium and Giardia the most common parasites infecting transplant recipients, especially in travelers to endemic regions.34 Cryptosporidial infection is a common cause of infective diarrhea in transplant recipients in endemic areas, such as India, the Middle East, and South America. In India, its prevalence was estimated to be over 20% in a study conducted by Udgiri et al.36 The microsporidia most often linked to gastrointestinal illnesses are Enterocytozoon bieneusi and Encephalitozoon intestinalis. However, Entameba histolytica is rarely identified in transplant recipients.34

Strongyloides stercoralis is a gut nematode that causes chronic gastrointestinal and skin manifestations due to its autoinfective lifecycle. Transplant recipients are at risk for developing Strongyloides hyperinfection syndrome secondary to chronic intestinal infection, acquisition of primary Strongyloides infection in tropical and subtropical areas, or allograft transmission.37

Coinfection is a common feature of parasitic infection in the setting of transplantation, and invasive disease may be associated with disseminated viral or bacterial infections.34

Back to Top | Article Outline

CLINICAL MANIFESTATIONS

TD is characterized by an increase in frequency of bowel movements and a change in consistency of the stool (soft to liquid) that usually begins within 2 to 3 days of arrival. More than 90% of illnesses start within the first 2 weeks.1,6,28

Three overlapping syndromes may be discerned. The first is short-lived watery diarrhea with little or no fever. This may be triggered by invasive pathogens, and be associated with secretory diarrhea. The second syndrome is a more prolonged disease, which may be accompanied by bloody diarrhea (dysentery) and fever. The third is chronic diarrhea lasting for more than 1 month, which affects 1% to 3% of patients with diarrhea. This syndrome is often associated with parasitic infections, but also can be due to invasive bacterial pathogens, such as Shigella, Salmonella, and Campylobacter.11,12 Giardiasis and amebiasis can be linked with chronic diarrhea in solid-organ transplant recipients. Giardia usually causes enteritis with watery diarrhea, malabsorption, bloating and flatulence, whereas amebiasis produces more often colitis with bloody stools.25 Intestinal microsporidiosis is also a well-known cause of chronic diarrhea and wasting in immunocompromised hosts.38

Diarrhea in organ transplant recipients is a potentially debilitating condition that can lead to severe dehydration, which compromises renal function, a marked increase in toxicity of immunosuppressants, and organ rejection, producing a negative impact on the recipient’s quality of life.26,39 Long-term complications of TD can occur, such as postinfectious irritable bowel syndrome, reactive arthritis often associated with HLA-B27, and Guillain-Barré syndrome.3 It is not clear whether long-term sequelae such as irritable bowel syndrome are more common or severe in solid-organ transplant recipients compared with other travelers.

Back to Top | Article Outline

DIAGNOSIS APPROACH

Most self-limited episodes of diarrhea while traveling will not require investigation, but a different approach is needed for diarrhea that persists. This approach is sometimes limited to investigation of those that continue to have diarrhea after empiric treatment for common pathogens, such as Giardia.40 Discriminating between immunosuppression-related and infection-related gastrointestinal complications after transplantation can be difficult and is often based on the patient’s net state immunosuppression, the presence of anatomic abnormalities and the patient’s epidemiologic exposures.41 For this reason, we advocate a low threshold for laboratory workup of transplant patients with travel-related diarrhea, to include both travel and other causes. Diagnosis and management of posttransplant diarrhea should include stool culture, stool C. difficile assessment, and blood Cytomegalovirus (CMV) quantitative viral load. A stepwise approach to the general diagnosis of diarrhea in solid organ recipients has been described elsewhere.41

Importantly, transplant recipients suffering from diarrhea refractory to standard treatment, especially those at risk for additional waterborne diseases, should undergo a full evaluation for intestinal parasitic infection.42 This includes fecal testing for leukocytes, ova, and parasites; appropriate stains for Cryptosporidium spp, Cystoisospora belli and Cyclospora cayetanensis; Giardia and Cryptosporidium antigen screen or enzyme immunoassay; and Norovirus detection by polymerase chain reaction. Although new multipathogen molecular tests are very promising, they need further validation and standardization before becoming widely implemented.1,6,42

Back to Top | Article Outline

TREATMENT

The majority of food-borne illnesses, including TD, are self-limited, and require mainly supportive management and fluid replacement. Fluids and electrolytes should be replaced aggressively because diarrhea-induced dehydration can result in renal insufficiency and enhance the potential toxicities of antirejection medications. Antimotility agents, such as loperamide, are also recommended with good evidence for added efficacy when used in combination with antibacterial therapy.43 Bismuth subsalicylate has been used to treat TD, but should be used with caution in solid-organ transplant patients because it is converted to salicylic acid and bismuth salts, and these can result in toxicity among transplant patients with diminished renal function.

Solid-organ transplant recipients may be at increased risk of complications, including bloodstream infection (with potential seeding at distant sites). Dehydration can potentiate the nephrotoxic effects of calcineurin inhibitors. More aggressive treatment of TD is therefore recommended for solid-organ transplant recipients.44 Although randomized controlled clinical trials have not been performed specifically in transplant recipients, the clinical benefit of treating TD has been demonstrated in numerous studies performed in the nontransplant population.45,46 In a meta-analysis of controlled trials, antibiotic treatment was significantly associated with shorter duration of diarrhea, although it also led to higher incidence of side effects.46 Data from these studies in nontransplant population serve as evidence to support these recommendations for the management of transplant patients with TD.

Empiric antibiotic therapy is recommended for those with moderate to severe frequency of TD (3 or more stools per day), and for all those with invasive symptoms (eg, bloody stools) and systemic illness (eg, fever).1,6,47 However, short lived mild diarrhea (1-2 stools per day) without systemic symptoms, that is tolerated by the patient, rarely requires antimicrobial therapy. Antibiotic regimens are chosen to target the most common bacterial pathogens, including ETEC and enteroaggregative E. coli, followed by Salmonella, Shigella and Campylobacter jejuni. These usually cover the less commonly encountered causes, such as Aeromonas spp, Plesiomonas spp, and Vibrio spp.27,48,49

The first-line empiric drug regimens against these bacterial pathogens are ciprofloxacin, levofloxacin, and azithromycin (Table 1). In general, ciprofloxacin is the standard empiric drug for self-treatment of TD except for travelers to South and Southeast Asia, where azithromycin is the preferred drug.1,6 In separate studies, single doses of ciprofloxacin (500 mg orally), levofloxacin (500 mg orally), and azithromycin (1000 mg orally) were effective in reducing the severity and duration of diarrhea in most travelers.50-52 Multiple doses taken over a course of 3 to 7 days have also been recommended44 (Table 1). In some studies, however, single-dose azithromycin had better efficacy than a 3-day regimen and had less side effects.53

TABLE 1

TABLE 1

The choice of empiric regimen should take into consideration the resistance patterns in a specific geographic location.54 For example, the widespread use of fluoroquinolones for empiric treatment of TD and other bacterial infections has led to the selection and emergence of ciprofloxacin resistance, especially among Campylobacter isolates.55,56 There is increasing resistance to fluoroquinolones among Campylobacter isolates in Thailand, and azithromycin is now recommended as first-line empiric treatment of diarrhea among travelers in Thailand and Southeast Asia.53 In a randomized study, azithromycin treatment resulted in a better outcome than levofloxacin treatment of TD in Thailand, where the predominant pathogen was Campylobacter species.53 There have also been increasing reports of quinolone-resistant Shigella57 and Salmonella58 isolates among travelers returning from India. The potential for drug-drug interactions should be considered in the treatment of TD among transplant recipients. Although rifaximin has been approved for the treatment of traveler's diarrhea caused by noninvasive bacterial pathogens, some caution against its use among solid-organ transplant recipients due to its potential for interaction with cyclosporine.59 However, rifaximin is a nonabsorbable rifamycin that is not expected to inhibit the cytochrome p450 isoenzymes. The role of rifaximin as self-administered empiric therapy is debated because patients are often unable to distinguish noninvasive from the invasive forms of diarrhea, so a second (systemically active) antimicrobial would need to be given concurrently. Azithromycin, a macrolide antibiotic, may inhibit cytochrome p450 and reduce tacrolimus metabolism, leading to higher systemic tacrolimus levels that can manifest as nephrotoxicity and neurotoxicity. Nephrotoxicity may be further enhanced by diarrhea-induced dehydration. These interactions do not contraindicate the use of azithromycin, but do highlight the role of hydration, and monitoring and adjustment of immunosuppressive drug levels in solid-organ transplant patients with TD.

If TD does not improve after empiric antibacterial therapy, solid-organ transplant patients should seek medical consultation and have their stools examined for resistant bacterial pathogens and/or other potential nonbacterial causes (see diagnosis).60 Antimicrobial susceptibility testing should be performed for bacterial enteropathogens to guide antibiotic therapy (Table 1).

Parasitic infections account for 1% to 20% of all cases of TD, including G. intestinalis, Cryptosporidium spp, Cyclospora cayetanensis, Cystoisospora belli and Entameba histolytica.61,62 In contrast to the sudden onset symptoms for bacterial and viral diarrhea, the onset is more gradual for parasitic infections. First-line treatments for G. intestinalis, the most common parasitic cause of TD, include metronidazole, tinidazole or nitazoxanide (Table 1).63 Drug-resistant parasites have been reported with increasing frequency in certain parts of the world, particularly nitroimidazole resistance in G. intestinalis infections acquired in India.64 These may require treatment with second-line agents such as albendazole, paromomycin or mepacrine (quinacrine).63 Entameba infections are also treated with metronidazole or tinidazole, usually combined with a lumicidal agent such as paromomycin (Table 1). Cryptosporidium infections are often self-limited, but nitazoxanide may be considered for severe cases. Cyclospora and Cystoisospora infections are generally treated with trimethoprim-sulfamethoxazole (Table 1).

Viral causes of TD are often self-limited, but if severe and persistent, one should consider reducing the dose of pharmacologic immunosuppression. CMV may also reactivate to cause gastrointestinal disease that most often presents as diarrhea, coincident with travel. CMV is treated with intravenous ganciclovir (5 mg/kg every 12 hours) or oral valganciclovir (900 mg PO BID)65 for at least 14 days. Other pathogens that may present with diarrhea during travel include C. difficile,66 especially among solid-organ transplant recipients who are at risk due to use of antibiotic prophylaxis. Treatment of C. difficile consists of oral vancomycin (125-250 mg PO QID), metronidazole (500 mg PO or IV TID) or fidaxomicin (200 mg BID) depending on local licencing and availability. Noninfectious causes of diarrhea may be observed among solid-organ transplant recipients, sometimes as an adverse effect of mycophenolate mofetil. Treatment of drug-associated diarrhea entails reduction in the dose, or substitution of the culprit drug with another alternative immunosuppressive therapy.

Back to Top | Article Outline

PREVENTION

Individualized risk assessments should be made about potential hazards for all travelers, particularly those with immunosuppression. Transplant patients who already have gastrointestinal problems and/or whose hydration status is in fine balance, may need special counseling about the wisdom of travel to high-risk settings.67,68

Advice should be provided about personal hygiene and dietary precautions. There is good evidence that hand washing before handling food reduces the risk of diarrheal disease and travelers should consider carrying antiseptic wipes or alcohol hand rubs for situations where water may not be available for hand washing.69 Protection of the water supply or sterilizing water at the point of delivery reduces the incidence of diarrheal disease in resource-poor settings, and travelers to areas with poor sanitation may need to carry sterilization tablets, water filters, or both (a wide variety are available).70 Travelers should be reminded to examine drinks purchased in bottles and cans to ensure that the original seal is present (to ensure they are tamper free), and to use a drinking straw if drinking directly from the container, to avoid imbibing pathogens present on the surface of the bottle or can. Ice in cooled drinks may be of uncertain origin and sterility and should be avoided, and bottled water should be used to clean teeth. Alcoholic drinks may potentiate diarrhea and dehydration.

The conventional advice is to avoid all foodstuff that have not been freshly prepared or properly cooked. High-risk foods are salads, foods that have been reheated, food left uncovered and therefore visited by flies, and any food cooked in unhygienic circumstances. Food that is freshly cooked by a street vendor and served immediately on sterile plates may be safer than food left out in a hotel buffet. The old adage “cook it, boil it, peel it or forget it” emphasizes the need to avoid contamination of fruit and other uncooked foods by fingers of uncertain cleanliness. However, much food is not cooked to a high enough temperature to kill all enteropathogens. Repeated anecdotal experience and many surveys have shown poor compliance by travelers with advice about safe food and water and little impact of such advice on the incidence of TD.1,6,28,71

Other preventive measures should be considered for this high-risk group. The evidence base for effectiveness of prebiotics and probiotics is poor and they are not widely recommended. Loperamide or similar antimotility agents have been recommended by some in the past, but there is no evidence to support their use in prevention (as opposed to treatment).72 Bismuth salicylate has moderate efficacy in preventing travelers diarrhea but has to be taken frequently, has associated problems such as staining the tongue and teeth, and should be avoided by people with salicylate allergy. Toxicity has been reported in patients with renal insufficiency; as this is common in solid-organ transplant recipients, bismuth salicylate is a less attractive option for this group of travelers.

Short-term chemoprophylaxis with systemically absorbed antibiotics is highly effective in preventing traveler’s diarrhea, provided that enteropathogens at the destination are susceptible. Current opinion favours avoiding the use of such agents for trips lasting more than 14 days, after which most but not all risk of TD has reduced, and limiting such use to essential trips for business or leisure reasons.6 As solid-organ transplant patients are at increased risk of complications of TD, there may be more reason to prescribe prophylaxis, but this still has to be balanced against the risk of side-effects of medication and drug-drug interactions. The acquisition of multidrug resistant enteropathogens is an increasingly important hazard of travel. There is increasing evidence that even short-term travel to the Indian subcontinent carries a high risk of acquiring MDR pathogens and that this risk is increased in those that use prophylactic antibiotics.73,74 Although this is not harmful for the individual per se, it could pose problems for solid-organ transplant patients who become carriers and may become sources of MDR pathogens in their local and hospital environments.

The systemic agents usually recommended are quinolones such as ciprofloxacin taken in standard doses for short periods. In Asian countries, such as Thailand and India, where quinolone resistance is common, azithromycin might be preferred for prophylaxis but drug-drug interactions (eg with tacrolimus) must be considered. The nonabsorbed antimicrobial rifaximin is increasingly recommended for prophylaxis, but its potential for use in treatment is very limited in solid-organ transplant patients as invasive pathogens would not be covered.

Finally, what about a role for immunization? Cholera vaccine is only indicated for the small number of travelers who will be working in settings where cholera is a risk, for example, in humanitarian outbreak relief. It does not provide adequate protection against other causes of TD and should not be recommended for that purpose.75,76 Despite intense interest and research on vaccines against other bacteria causing TD, results have been disappointing to date even when vaccines induce good immunity.77 As effective vaccines against Norovirus infection become available, travelers will be a very good group in which to test efficacy, particularly in known high-risk settings such as cruise ships. However, these are not yet available.

In summary, most evidence about prevention and treatment of TD in solid-organ transplant patients is extrapolated from other groups of nonimmunosuppressed travelers. The higher risk of illness in transplant patients justifies more aggressive preventive and therapeutic approaches than in other travelers but this should be tempered by careful consideration of drug-drug interactions. Each patient should have an individualized risk assessment for each trip, and on occasions it may be necessary to recommend changes to the itinerary.

Back to Top | Article Outline

ORGAN DONORS WITH DIARRHEA

Living donors originating from resource-poor countries have potential risk for transmission of enteropathogenic strains of Salmonella, Shigella, ETEC (or any, bacterial enteric pathogens), but the actual risk of transmission from such donors remains undetermined. Therefore, they should be screened out for intestinal parasites and enteropathogenic bacteria before donation.

Donors with unexplained persistent diarrhea should be investigated and deferred until the diagnosis and appropriate treatment.

Back to Top | Article Outline

REFERENCES

1. Steffen R, Hill DR, DuPont HL. Traveler's diarrhea: a clinical review. JAMA. 2015;313:71–80.
2. Rosen J. Travel medicine and the solid-organ transplant recipient. Infect Dis Clin North Am. 2013;27:429–457.
3. Greenwood Z, Black J, Weld L, et al. Gastrointestinal infection among international travelers globally. J Travel Med. 2008;15:221–228.
4. von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhoea at various tourist destinations. Lancet. 2000;356:133–134.
5. Riddle MS, DuPont HL, Connor BA. ACG clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol. 2016;111:602–622.
6. Riddle MS, Connor BA, Beeching NJ, et al. Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report. J Travel Med. 2017;24(Suppl 1):S2–S19.
7. Baaten GG, Geskus RR, Kint JA, et al. Symptoms of infectious diseases in immunocompromised travelers: a prospective study with matched controls. J Travel Med. 2011;18:318–326.
8. Steffen R, Tornieporth N, Clemens SA, et al. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med. 2004;11:231–237.
9. Chongsuvivatwong V, Chariyalertsak S, McNeil E, et al. Epidemiology of travelers' diarrhea in Thailand. J Travel Med. 2009;16:179–185.
10. Centers for Disease Control and Prevention. CDC Yellow Book 2018: Health Information for International Travel. Oxford, UK: Oxford University Press; 2017.
12. Swaminathan A, Torresi J, Schlagenhauf P, et al. A global study of pathogens and host risk factors associated with infectious gastrointestinal disease in returned international travellers. J Infect. 2009;59:19–27.
13. Ross AG, Cripps AW. Enteropathogens and chronic illness in returning travelers. N Engl J Med. 2013;369:784.
14. Piyaphanee W, Kusolsuk T, Kittitrakul C, et al. Incidence and impact of travelers' diarrhea among foreign backpackers in Southeast Asia: a result from Khao San Road, Bangkok. J Travel Med. 2011;18:109–114.
15. Fletcher SM, Maharaj SR, James K. Description of the food safety system in hotels and how it compares with HACCP standards. J Travel Med. 2009;16:35–41.
16. Mattila L, Siitonen A, Kyrönseppä H, et al. Seasonal variation in etiology of travelers' diarrhea. Finnish-Moroccan Study Group. J Infect Dis. 1992;165:385–388.
17. Connor P, Porter CK, Swierczewski B, et al. Diarrhoea during military deployment: current concepts and future directions. Curr Opin Infect Dis. 2012;25:546–554.
18. Jiang ZD, Okhuysen PC, Guo DC, et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis. 2003;188:506–511.
19. Mohamed JA, DuPont HL, Jiang ZD, et al. A novel single-nucleotide polymorphism in the lactoferrin gene is associated with susceptibility to diarrhea in North American travelers to Mexico. Clin Infect Dis. 2007;44:945–952.
20. Mohamed JA, DuPont HL, Jiang ZD, et al. A single-nucleotide polymorphism in the gene encoding osteoprotegerin, an anti-inflammatory protein produced in response to infection with diarrheagenic Escherichia coli, is associated with an increased risk of nonsecretory bacterial diarrhea in North American travelers to Mexico. J Infect Dis. 2009;199:477–485.
21. Mohamed JA, DuPont HL, Flores J, et al. Single nucleotide polymorphisms in the promoter of the gene encoding the lipopolysaccharide receptor CD14 are associated with bacterial diarrhea in US and Canadian travelers to Mexico. Clin Infect Dis. 2011;52:1332–1341.
22. Lindesmith L, Moe C, Marionneau S, et al. Human susceptibility and resistance to Norwalk virus infection. Nat Med. 2003;9:548–553.
23. Rydell GE, Kindberg E, Larson G, et al. Susceptibility to winter vomiting disease: a sweet matter. Rev Med Virol. 2011;21:370–382.
24. Pitzurra R, Steffen R, Tschopp A, et al. Diarrhoea in a large prospective cohort of European travellers to resource-limited destinations. BMC Infect Dis. 2010;10:231.
25. Angarone M, Ison MG. Diarrhea in solid organ transplant recipients. Curr Opin Infect Dis. 2015;28:308–316.
26. Arslan H, Inci EK, Azap OK, et al. Etiologic agents of diarrhea in solid organ recipients. Transpl Infect Dis. 2007;9:270–275.
27. Subramanian A. Diarrhea in organ transplant recipients. http://www.antimicrobe.org/new/t12_dw.html. Updated 2011.
28. Al-Abri SS, Beeching NJ, Nye FJ. Traveller's diarrhoea. Lancet Infect Dis. 2005;5:349–360.
29. Lee LY, Ison MG. Diarrhea caused by viruses in transplant recipients. Transpl Infect Dis. 2014;16:347–358.
30. Koo HL, Ajami NJ, Jiang ZD, et al. Noroviruses as a cause of diarrhea in travelers to Guatemala, India, and Mexico. J Clin Microbiol. 2010;48:1673–1676.
31. Echenique IA, Stosor V, Gallon L, et al. Prolonged norovirus infection after pancreas transplantation: a case report and review of chronic norovirus. Transpl Infect Dis. 2016;18:98–104.
32. Echenique IA, Penugonda S, Stosor V, et al. Diagnostic yields in solid organ transplant recipients admitted with diarrhea. Clin Infect Dis. 2015;60:729–737.
33. Stelzmueller I, Wiesmayr S, Swenson BR, et al. Rotavirus enteritis in solid organ transplant recipients: an underestimated problem? Transpl Infect Dis. 2007;9:281–285.
34. Kotton CN, Lattes R. AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S234–S251.
35. Bonatti H, Barroso LF, Sawyer RG, et al. Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations. Transpl Infect Dis. 2012;14:635–648.
36. Udgiri N, Minz M, Kashyap R, et al. Intestinal cryptosporidiasis in living related renal transplant recipients. Transplant Proc. 2004;36:2128–2129.
37. Roxby AC, Gottlieb GS, Limaye AP. Strongyloidiasis in transplant patients. Clin Infect Dis. 2009;49:1411–1423.
38. Lanternier F, Boutboul D, Menotti J, et al. Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review. Transpl Infect Dis. 2009;11:83–88.
39. Kotton CN, Ryan ET, Fishman JA. Prevention of infection in adult travelers after solid organ transplantation. Am J Transplant. 2005;5:8–14.
40. de Saussure PP. Management of the returning traveler with diarrhea. Therap Adv Gastroenterol. 2009;2:367–375.
41. Maes B, Hadaya K, de Moor B, et al. Severe diarrhea in renal transplant patients: results of the DIDACT study. Am J Transplant. 2006;6:1466–1472.
42. Polage CR. Editorial commentary: microbiologic testing in post-solid organ transplant diarrhea. Clin Infect Dis. 2015;60:738–740.
43. Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combination with antibiotics on treatment outcomes in traveler's diarrhea: a systematic review and meta-analysis. Clin Infect Dis. 2008;47:1007–1014.
44. Kotton CN, Hibberd PL. AST Infectious Diseases Community of Practice. Travel medicine and transplant tourism in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):337–347.
45. DuPont HL, Ericsson CD. Prevention and treatment of traveler's diarrhea. N Engl J Med. 1993;328:1821–1827.
46. De Bruyn G, Hahn S, Borwick A. Antibiotic treatment for travellers' diarrhoea. Cochrane Database Syst Rev. 2000:CD002242.
47. Kendall ME, Crim S, Fullerton K, et al. Travel-associated enteric infections diagnosed after return to the United States, Foodborne Diseases Active Surveillance Network (FoodNet), 2004-2009. Clin Infect Dis. 2012;54(Suppl 5):S480–S487.
48. DuPont HL. Travellers' diarrhoea: contemporary approaches to therapy and prevention. Drugs. 2006;66:303–314.
49. Shah N, DuPont HL, Ramsey DJ. Global etiology of travelers’ diarrhea: systematic review from 1973 to the present. Am J Trop Med Hyg. 2009;80:609–614.
50. Salam I, Katelaris P, Leigh-Smith S, et al. Randomised trial of single-dose ciprofloxacin for travellers' diarrhoea. Lancet. 1994;344:1537–1539.
51. Sanders JW, Frenck RW, Putnam SD, et al. Azithromycin and loperamide are comparable to levofloxacin and loperamide for the treatment of traveler's diarrhea in United States military personnel in Turkey. Clin Infect Dis. 2007;45:294–301.
52. Adachi JA, Ericsson CD, Jiang ZD, et al. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis. 2003;37:1165–1171.
53. Tribble DR, Sanders JW, Pang LW, et al. Traveler's diarrhea in Thailand: randomized, double-blind trial comparing single-dose and 3-day azithromycin-based regimens with a 3-day levofloxacin regimen. Clin Infect Dis. 2007;44:338–346.
54. Pons MJ, Gomes C, Martinez-Puchol S, et al. Antimicrobial resistance in Shigella spp. causing traveler's diarrhea (1995–2010): a retrospective analysis. Travel Med Infect Dis. 2013;11:315–319.
55. Pollett S, Rocha C, Zerpa R, et al. Campylobacter antimicrobial resistance in Peru: a ten-year observational study. BMC Infect Dis. 2012;12:193.
56. Bottieau E, Clerinx J, Vlieghe E, et al. Epidemiology and outcome of Shigella, Salmonella and Campylobacter infections in travellers returning from the tropics with fever and diarrhoea. Acta Clin Belg. 2011;66:191–195.
57. Mensa L, Marco F, Vila J, et al. Quinolone resistance among Shigella spp. isolated from travellers returning from India. Clin Microbiol Infect. 2008;14:279–281.
58. Al-Mashhadani M, Hewson R, Vivancos R, et al. Foreign travel and decreased ciprofloxacin susceptibility in Salmonella enterica infections. Emerg Infect Dis. 2011;17:123–125.
59. Zanger P, Nurjadi D, Gabor J, et al. Effectiveness of rifaximin in prevention of diarrhoea in individuals travelling to south and southeast Asia: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2013;13:946–954.
60. Wyss MN, Steffen R, Dhupdale NY, et al. Management of travelers’ diarrhea by local physicians in tropical and subtropical countries—a questionnaire survey. J Travel Med. 2009;16:186–190.
61. Bednarska M, Bajer A, Welc-Faleciak R, et al. Cyclospora cayetanensis infection in transplant traveller: a case report of outbreak. Parasit Vectors. 2015;8:411.
62. Slack A. Parasitic causes of prolonged diarrhoea in travellers—diagnosis and management. Aust Fam Physician. 2012;41:782–786.
63. Minetti C, Chalmers RM, Beeching NJ, et al. Giardiasis. BMJ. 2016;355:i5369.
64. Nabarro LE, Lever RA, Armstrong M, et al. Increased incidence of nitroimidazole-refractory giardiasis at the Hospital for Tropical Diseases, London: 2008–2013. Clin Microbiol Infect. 2015;21:791–796.
65. Razonable RR, Humar A. AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):93–106.
66. Michal Stevens A, Esposito DH, Stoney RJ, et al. Clostridium difficile infection in returning travellers. J Travel Med. 2017;24: taw099.
67. Askling HH, Dalm VA. The medically immunocompromised adult traveler and pre-travel counseling: status quo 2014. Travel Med Infect Dis. 2014;12:219–228.
68. Aung AK, Trubiano JA, Spelman DW. Travel risk assessment, advice and vaccinations in immunocompromised travellers (HIV, solid organ transplant and haematopoeitic stem cell transplant recipients): a review. Travel Med Infect Dis. 2015;13:31–47.
69. Ejemot-Nwadiaro RI, Ehiri JE, Arikpo D, et al. Hand washing promotion for preventing diarrhoea. Cochrane Database Syst Rev. 2015;9:CD004265.
70. Clasen TF, Alexander KT, Sinclair D, et al. Interventions to improve water quality for preventing diarrhoea. Cochrane Database Syst Rev. 2015:CD004794.
71. Schlagenhauf P, Weld L, Goorhuis A, et al. Travel-associated infection presenting in Europe (2008-12): an analysis of EuroTravNet longitudinal, surveillance data, and evaluation of the effect of the pre-travel consultation. Lancet Infect Dis. 2015;15:55–64.
72. Letizia A, Riddle MS, Tribble D, et al. Effects of pre-deployment loperamide provision on use and travelers’ diarrhea outcomes among U.S. military personnel deployed to Turkey. Travel Med Infect Dis. 2014;12:360–363.
73. Hassing RJ, Alsma J, Arcilla MS, et al. International travel and acquisition of multidrug-resistant Enterobacteriaceae: a systematic review. Euro Surveill. 2015;20.
74. Barreto Miranda I, Ignatius R, Pfüller R, et al. High carriage rate of ESBL-producing Enterobacteriaceae at presentation and follow-up among travellers with gastrointestinal complaints returning from India and Southeast Asia. J Travel Med. 2016;23:tav024.
75. Hill DR, Ford L, Lallloo DG. Oral cholera vaccines: use in clinical practice. Lancet Infect Dis. 2006;6:361–373.
76. Ahmed T, Bhuiyan TR, Zaman K, et al. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev. 2013;7:CD009029.
77. Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis. 2014;14:197–204.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.