Medications for the prevention and treatment of travellers’ diarrhea

Journal of Travel Medicine, 2017, Vol 24, Suppl 1, S17–S22 doi: 10.1093/jtm/taw097 Review Review Medications for the prevention and treatment of travellers’ diarrhea 1 Vaccine Development Global Program, PATH, Seattle, WA, USA, 2Section of Infectious Diseases, Department of Global Health and Center for Global Health and Development, Boston University School of Public Health, Boston, MA, USA, 3 Section of Infectious Diseases Department of Medicine, Boston University School of Medicine, Boston, MA, USA and 4 Jackson Hole Travel and Tropical Medicine, Jackson Hole, WY, USA *To whom correspondence should be addressed. Email: Presented at ISTM Foundation TD Summit, April 15, 2016, Atlanta, Georgia, USA Submitted 18 July 2016; editorial decision 18 July 2016; accepted 13 December 2016 Abstract Background. Travellers’ diarrhea (TD) remains one of the most common illnesses encountered by travellers to less developed areas of the world. Because bacterial pathogens such as enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli, Campylobacter spp. and Shigella spp. are the most frequent causes, antibiotics have been useful in both prevention and treatment of TD. Methods. Results of trials that assessed the use of medications for the prevention and treatment of TD were identified through PubMed and MEDLINE searches using search terms ‘travellers’ diarrhea’, ‘prevention’ and ‘treatment’. References of articles were also screened for additional relevant studies. Results. Prevention of TD with antibiotics has been recommended only under special circumstances. Doxycycline, trimethoprim–sulfamethoxazole, fluoroquinolones and rifaximin have been used for prevention, but at present the first three antibiotics may have limited use secondary to increasing resistance, leaving rifaximin as the only current option. Bismuth subsalicylate (BSS) (Pepto-Bismol tablets) is also an option for prophylaxis. Treatment with antibiotics has been recommended for moderate to severe TD. Azithromycin is the drug of choice, especially in Asia where Campylobacter is common. Fluoroquinolone antibiotics continue to be effectively used in Latin America and Africa where ETEC is predominant. BSS and loperamide (LOP) also are effective as standalone treatments. LOP may be used alone for treatment of mild TD or in conjunction with antibiotics for treatment of TD. Conclusions. Historically, antibiotic prophylaxis has not been routinely recommended and has been reserved for special circumstances such as when a traveller with an underlying illness cannot tolerate TD. Antibiotics with or without LOP have been useful in shortening the duration and severity of TD. Emerging antibiotic resistance, limited new antibiotic alternatives and faecal carriage of antibiotic-resistant bacteria by travellers may prompt a reevaluation of classic recommendations for treatment and prevention of TD with antibiotics. Key words: Traveller’s diarrhea, prevention, treatment, fluoroquinolone, azithromycin, bismuth subsalicylate, loperamide Introduction Preventing and treating travellers’ diarrhea (TD) during and after a journey continue to be important clinical challenges. Bacterial pathogens such as enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli, Campylobacter species and Shigella spp. still predominate as causes; however the list of etiologic agents causing diarrheal disease includes a broad spectrum of bacteria, viruses and parasites.1–3 As diagnostic methods improve, multiple pathogens are detected in a higher proportion of TD illnesses.4,5 Antimicrobial resistance of enteric bacterial pathogens continues to increase and requires surveillance to monitor current trends.6 Emerging research has further highlighted the acute and chronic health consequences of TD.7 There is now increasing awareness of alterations to gut C International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: V David N. Taylor, MD1, Davidson H. Hamer, MD2,3, and David R. Shlim, MD4 S18 microflora caused by even a short course of antibiotics.8 Some of these changes to the gut microflora appear to be associated with chronic gastrointestinal symptoms and enteropathy, and there is growing recognition of colonization with multi-drug resistant bacteria in returning travellers.9 This review outlines the classical recommendations for use of antimicrobial and other agents in the treatment and prevention of TD and sets the stage for the consensus statements that follow on how recommendations might need to change in view of emerging concerns for the use of antimicrobial agents. Methods Historical Definitions of Diarrhea Diarrhea is one of the most common illnesses acquired during travel. TD caused by ETEC, the most common aetiology, is usually a watery diarrhea associated with nausea, vomiting, and abdominal cramping or pain. Shigella and Campylobacter may also be associated with bloody diarrhea instead of watery diarrhea and a longer and more severe course of illness, associated with invasion of the gut mucosa. ETEC is confined to the lumen of the gut and disease is mediated by toxin. Invasion of the gut mucosa or spread to blood or other tissues does not occur. The spectrum of illness has been categorized as mild, moderate or severe. Severe diarrhea is characterized by more than 10 loose, watery stools in a single day, moderate diarrhea is more than a few diarrhea stools but less than 10 diarrhea stools in a day, and mild diarrhea is a few diarrhea stools in a day. In clinical and epidemiologic studies, TD has been defined as three or more unformed stools or two unformed stools with at least one accompanying symptom (nausea, vomiting, abdominal pain, fever, blood in stool) within 24 h.10 History of Antibiotic Use for TD When Dr Benjamin Kean first started investigating diarrhea in travellers in Mexico in the 1950s, the aetiology was elusive. The known bacterial pathogens of the time were not present in these patients.11 An exhaustive search for protozoan pathogens proved fruitless.12 An interesting observation, at the time, was that non-absorbable antibiotics (phthalylsulfathiazole and neomycin) prevented diarrhea in travellers.13,14 Eventually, the discovery of ETEC confirmed the predominantly bacterial aetiology of TD in Mexico.15,16 Studies in the mid-East, Asia and South America provided additional proof that bacteria were the main cause of TD.2,17,18 By 1970s, the threat of TD was such a concern that studies were done to see if prophylactic antibiotics would prevent TD. Doxycycline was proven to prevent TD in two studies in the late 1970s.19,20 At the same time, clinicians were convinced that travellers who were able to make good decisions about what to avoid eating and drinking could also avoid TD. This feeling continues to persist, despite the absence of any reliable studies demonstrating that travellers can avoid TD by watching what they eat.21 (...truncated)