Expert Review of the Evidence Base for Self‐Therapy of Travelers’ Diarrhea

The most frequent illness among people traveling from industrialized regions to developing countries is travelers’ diarrhea (TD). For all people entering areas known to pose a high risk for TD, medication should be included in the travel kit on trips, which can be taken for self‐therapy of resultant diarrheal illness. Drugs aimed at relief of symptoms, particularly loperamide, are the preferred standard treatment of TD by some professionals in Europe. Travel medicine experts in the United States and many in Europe feel that an antimicrobial agent that cures while shortening the duration of illness represents the mainstay of therapy. Loperamide combined with an appropriate antimicrobial agent will provide the most rapid relief of TD. In the following document, the authors used an evidence base when available to determine the strength and quality of evidence and when data were lacking, the panel of experts provided consensus opinion. Drugs used for symptomatic relief, including bismuth subsalicylate (BSS) and loperamide, decrease the number of unformed stools passed during a bout of TD but may not speed up illness recovery. The majority of authors of this document recommended that for all people traveling from low‐risk to high‐risk regions, one of the three antibacterial drugs should be transported with them for self‐treatment of diarrhea that occurs, given in respective order of development for TD therapy: a fluoroquinolone (ciprofloxacin or levofloxacin), rifaximin, or azithromycin. Azithromycin is preferred for treatment when diarrhea is complicated by dysentery (passage of grossly bloody stools) or by high fever and for use in children with TD. A number of experts would recommend additionally including loperamide in the travel kit for adults with TD as this may accelerate relief of the illness when used with an antimicrobial agent. An uncertain proportion of Europeans feel that it is sufficient to include loperamide alone in the travel kit for routine self‐treatment of TD. The purpose of this review is to provide available evidence for effectiveness of self‐therapy of TD during international travel. This area is controversial with differing support among specialists for the various known effective drugs and use of drugs in various regions of the world. In the review, these differences of opinion are identified. The risks and benefits of the available approaches are discussed. Recommendations are graded by the strength and quality of evidence (Table 1). When evidence is lacking, the quality of evidence is graded as category III, representing a consensus of expert authors (Table 1). Grading of clinical evidence in the therapy of travelers’ diarrhea 101 Grading of clinical evidence in the therapy of travelers’ diarrhea 101 These recommendations are made for travel populations originating from an industrialized country and visiting destinations with suboptimal hygienic conditions in the tropics or subtropics. The travel populations include healthy adult travelers, children, pregnant women, people with underlying illness and immunosuppression, and the elderly. The concepts apply less to infants because unlike other groups, they receive food and drinks safely prepared by caregivers. The target audience for receipt of the material includes nurse‐ and physician‐travel medicine practitioners, primary care physicians, medical students and residents in training, and infectious diseases and tropical medicine specialists. The authors were asked to consider the current status of the effectiveness of self‐treatment of TD according to the region into which people travel and the different enteric pathogens likely encountered. PubMed was reviewed for papers on TD treatment, which was augmented by the extensive files maintained on the topic by the authors. The authors provide a perspective on current recommendations for self‐therapy of TD. Outcome measures and future studies needed are presented. A separate Expert Review of the Evidence Base for Prevention of TD has been developed by the authors of this report. Chemoprophylaxis as a means of dealing with TD is discussed in that review. Details of the review process including selection of literature considered by the panel and plans for periodic updating of the evidence base can be found athttp://www.istm.org; click on “ISTM Committees,” and then “Publications.” The most important causes of TD are bacterial in origin with two types of diarrhea‐producing Escherichia coli[enterotoxigenic E coli(ETEC) and enteroaggregative E coli(EAEC)] associated with approximately half of the illness in Latin America and Africa. 1–3 In Asia, ETEC and EAEC cause approximately one third of the illness, with infection by the invasive pathogens,Shigella,Salmonella, and Campylobacter seen in up to 20% of the cases. 3–5 There has been a progressive increase in antimicrobial resistance among major bacterial enteric pathogens associated with TD worldwide. Noroviruses cause between 10% to 20% of TD cases, 6 often resulting in vomiting as well as diarrhea. Protozoal parasites are unusual causes of TD but should be considered in anyone with persistent diarrhea (illness lasting ≥14 days) or when antibacterial therapy fails to shorten illness. 7 Management of diarrhea includes receipt of electrolytes and calories, symptomatic treatment, and antimicrobial therapy. The panel considered each of the management modalities. Oral rehydration treatment (ORT) has been lifesaving in infants with dehydrating forms of acute diarrhea 8–10 in developing regions and in all age groups with cholera‐like illnesses. 11 TD in older children and otherwise healthy adults is not a life‐threatening condition. Adults with TD or parents of older children are for the most part educated people who know the importance of maintaining fluid intake during episodes of diarrhea. One randomized study of ORT plus loperamide versus loperamide alone was carried out in young adults with TD. 12 The study failed to show clinical improvement or improvement in urine specific gravity in the group receiving ORT treatment when the two groups were compared providing evidence that adults can easily maintain fluid balance by consuming available foods and beverages. During a bout of acute TD, consumption of small quantities of easily digestible foods are recommended to aid in mucosal recovery from enteric infection 13 as has been established in pediatric studies. One study demonstrated that for adults with TD, dietary restrictions afforded no clinical benefit compared with an unrestricted diet. 14 Breast‐fed infants should continue their feedings during and after rehydration, and formula‐fed infants should continue their usual formula immediately upon rehydration in amounts sufficient to satisfy energy and nutrient requirements. Lactose‐free or lactose‐reduced formulas usually are not necessary. A meta‐analysis of clinical trials indicated no advantages of lactose‐free formulas over lactose‐containing formulas for the majority of infants, although some infants with malnutrition or severe dehydration recovered more quickly when given lactose‐free formula. 15 Children receiving semisolid foods or solid foods should continue to receive their usual diet during episodes of diarrhea. 8 Nonspecific drugs control symptoms more rapidly than antibacterial drugs but may not cure illness. 16–18 These drugs have value in controlling symptoms of milder forms of TD. For more severe or intense TD, symptomatic drugs, if used, should be combined with antibacterial therapy. The agent that has been evaluated most commonly for symptom relief of TD has been loperamide. Other symptomatic antidiarrheal drugs have been evaluated including antisecretory agents, which may work through a physiologic mechanism. The first antisecretory drug used was BSS, with antidiarrheal effects working through its salicylate moiety. 19 Acetyl salicylic acid (aspirin) appears to have similar antisecretory effects and has been found to reduce pediatric diarrhea, 20 but acetyl salicylate is toxic to the stomach causing gastric erosions and bleeding 21 not seen with BSS that has gastroprotective effects. 22 Loperamide has antisecretory effects as well as antimotility effects. 23 One antisecretory agent evaluated in TD is zaldaride maleate, an inhibitor of intestinal calmodulin that alters intracellular calcium and transport processes. 24 A second antisecretory drug, crofelemer, blocks intestinal chloride channels and has been used with success in the treatment of TD. 25 A third antisecretory drug, racecadotril, an enkephalinase inhibitor of endogenous opiates, has been used successfully in children 26 and adults 27 with diarrhea but has not been evaluated in TD. Efficacy of the antisecretory drugs with widely varying mechanisms of action shows the complexity of the secretory processes in acute diarrhea. The new antisecretory drugs are in development and not available in most regions of the world. Shortly after ETEC was implicated as an important causative agent of TD, 28–30 a study demonstrated the value of antibacterial therapy in shortening the illness. 31 Since then a number of studies have been conducted to establish the value of antibacterial drugs in TD in essentially all areas of the developing world where high rates of diarrhea exist among international travelers (Table 2). Double‐blind, placebo‐controlled antibacterial treatment trials in adults with travelers’ diarrhea (including p values) TLUS = time to last unformed stool, calculated from time of initiation of therapy until passage of the last unformed stool after wellness is declared; TMP = trimethoprim; SMX = sulfamethoxazole. Diarrhea continuing when the study was completed at 5 days (>120 hours). †Drugs developed for use in travelers’ diarrhea. Double‐blind, placebo‐controlled antibacterial treatment trials in adults with travelers’ diarrhea (including p values) TLUS = time to last unformed stool, calculated from time of initiation of therapy until passage of the last unformed stool after wellness is declared; TMP = trimethoprim; SMX = sulfamethoxazole. Diarrhea continuing when the study was completed at 5 days (>120 hours). †Drugs developed for use in travelers’ diarrhea. The principal measurements of response to antibacterial therapy in the various placebo‐controlled clinical trials have been duration of post‐treatment diarrhea, called time to last unformed stool (TLUS); failure to respond to treatment; 32 and number of unformed stools passed during illness. 33 TLUS is calculated as the time from taking the first dose of study medication until passage of the last unformed stool after which subjects are declared well (duration of post‐initiation of therapy diarrhea). Published studies have shown that antibacterial drugs shorten the mean or median TLUS compared with the corresponding placebo response (Table 2). Treatment failure, defined as clinical worsening during therapy or failure to achieve wellness by 5 days, 32 is reduced similarly in adults with TD randomized to receive an antibacterial drug compared with a placebo (Table 2). In one placebo‐controlled treatment trial, subjects receiving a placebo passed an average of 11.4 liquid stools during their illness compared with 5.0 liquid stools in a ciprofloxacin‐treated group (p< 0.0001). 33 The drugs with the most extensive evaluation in treatment of TD are trimethoprim/sulfamethoxazole (TMP/SMX) and the fluoroquinolones (ofloxacin, norfloxacin, and ciprofloxacin). TMP/SMX resistance has become widespread, limiting the value of this combination antibiotic. 34 The fluoroquinolones remain active against a high percentage of the etiologic agents of TD. 34 The poorly absorbed (<0.4%) rifaximin and systemically absorbed azithromycin have been shown to be effective treatments of TD. 5,35 The absorbed antibacterial drugs including the fluoroquinolones and azithromycin have been administered for 3 days or for a single dose with no apparent clinically important difference in efficacy between 3‐day and one‐dose treatment in shortening the duration of TD. In various trials, nonabsorbed rifaximin has been given routinely for 3 days. Available evidence suggests that bacterial species within a genus (Shigella sonnei vs Shigella flexneri) or presence of different virulence factors among diarrhea‐producing species (ETEC strains varying by toxin type produced or EAEC strains differing by virulence factors present) do not translate into differences in required therapy. Enteric infection by Shigella dysenteriae1 (Shiga bacillus) appears to be an exception that may need 5 days of therapy rather than a single‐dose or 3‐day treatment course, 36, 37 but this organism is a rare cause of TD. There are four microbe‐specific concerns possibly relevant to empiric antibacterial therapy of TD. First is the concern that certain antibacterial drugs can complicate enteric disease caused by Shiga toxin‐producing E coli(STEC) by increasing the risk of hemolytic uremic syndrome (HUS). Some antibiotics promote the release of Shiga‐toxin, 38 while others do not seem to do so. 39–42 A meta‐analysis did not show an association between antimicrobial therapy use in patients with hemorrhagic colitis due to E coli O157:H7 and development of are not causes of TD, this concern in travel of by antibacterial treatment of dysenteriae1 diarrhea to be a rare A second concern is that antibacterial drugs may to or worsening of enteric infection caused by strains of drugs can the duration of of an of An often study of treatment of indicated that of the organism was by at 3 to therapy. A second clinical study failed to of of when patients were with or strains usually are not from to due to the is of clinical to the A of of therapy of people with due to that therapy may in of increase in risk for a after 3 and increase risk for drug with no decrease in of illness. The third treatment concern is that antibacterial therapy with drugs that seen with fluoroquinolone may to development of colitis after therapy of TD. A four patients with TD who developed colitis following treatment with The area of concern to use of antibacterial drugs in and populations to antibacterial resistance among enteric pathogens and for the absorbed fluoroquinolone resistance of ETEC strains causing TD has the major concern is fluoroquinolone resistance among strains of or resistance by is of clinical The consensus of authors of this review is that concerns treatment of Shiga toxin‐producing or to diarrhea, or to resistance development are not sufficient to antimicrobial therapy as treatment for TD. There are a number of important to selection of antibiotics for travel to high‐risk In a treatment study of TD, rifaximin a for 3 days) was of value in shortening TD compared with a for 3 days) in adults in where E coli are known to be the most cause of illness. A second study failed to an when was compared with rifaximin therapy in TD in and a with invasive illness reduced benefit following treatment with clinical trials demonstrated that azithromycin was as effective as a fluoroquinolone in the treatment of TD in or Azithromycin has been shown to be active in the treatment of diarrhea caused by invasive strains of including strains and Shigella and the drug is active against the E For E the principal causes of TD all three antimicrobial drugs used to TD are strains in most of the world show a high of resistance to fluoroquinolones including of resistance to Campylobacter strains were found to be high for rifaximin in one resistance of Campylobacter in developed countries is at less than resistance has been from some countries including and of Campylobacter that show resistance to to be to although azithromycin in and may be effective treatment when strains show a high to the For Campylobacter and the other invasive bacterial fluoroquinolones and azithromycin the preferred bacterial more commonly in Asia, 3–5 when compared with other high‐risk regions, which has some travel medicine experts to azithromycin for travelers to that concern that rifaximin would be less effective against invasive pathogens and drugs would be less active against strains of One difference between the various antibiotics is the of In all clinical trials, nonabsorbed rifaximin has shown the of the placebo that this would have than absorbed The for absorbed drugs are of but and and In the United a against has been for the fluoroquinolone An benefit of antibacterial of TD is of persistent enteric symptoms and diarrhea. studies demonstrated that 10% to of adults with TD will to syndrome One study indicated that most commonly developed following enteric infection by bacterial The provided evidence that in most for at 6 after disease A separate study of new for at 5 after illness When treatment is after developing TD unformed stools plus one or more or symptoms of enteric infection as or was not is not known if persistent can be by antimicrobial therapy in the of enteric after passage of the first unformed stool or at the first presence of or symptoms of enteric Loperamide can be administered with where the of therapy is to rapid improvement in symptoms with the symptomatic treatment with effects of the antibacterial drug (Table all trials have benefit of loperamide to antibacterial but all trials have the combination was The rare of worsening of the disease when antimotility drugs are used alone to invasive disease has not been in of these studies when effective antibacterial therapy is treatment studies where antibacterial drugs were combined with loperamide in the treatment of adults with travelers’ diarrhea improvement time from initiation of treatment until time that the last unformed stool during illness was in diarrhea stool treatment studies where antibacterial drugs were combined with loperamide in the treatment of adults with travelers’ diarrhea improvement time from initiation of treatment until time that the last unformed stool during illness was in diarrhea stool In of bacterial strains is an important of clinical response to therapy in bacterial diarrhea. The current antimicrobial used to determine are on of the drug for the organism and of The available are likely to be for the of treatment of intestinal and when drugs at high in the of For bacterial diarrhea, of fluoroquinolones and rifaximin of after 3 days therapy. Azithromycin therapy to high of the drug during therapy. are needed to new for enteric pathogens and drugs used to intestinal on organism and intestinal and mucosal of active drug rifaximin clinical illness of TD with similar as therapy with absorbed antibacterial drugs as studies have shown a of from stool with The importance of this is called into by of a study a of between and clinical improvement of antibacterial therapy of TD. There are at two for rates of in the of clinical response as with rifaximin may its in the small as to the in the the drug may virulence in recommendations for self‐treatment of TD are The strength of each and the quality of the evidence the are indicated by a provided For children, the mainstay of treatment of TD while in developing regions is fluid and therapy and dietary TD therapy should on fluid and treatment or Breast‐fed infants should continue on and after diarrhea to to food and and to provide it the of a antibacterial and symptomatic therapy should not be used for infants of with BSS is not recommended for young children because of the concern of salicylate Loperamide is not recommended due to of known efficacy and concern for effects. treatment is not recommended for therapy of TD in children due to drug while not for use in children may be for TD therapy the drugs are given for to 3 days. Azithromycin is an drug in and can be given to children with more severe of TD in a dose of for 3 days for children 6 to 12 of while not for use in children in most should be to on of the is available in a small number of countries as a pediatric The following provide the perspective on the self‐treatment of TD on the studies The recommendations medication to to the travel kit which may be by the The strength and quality of evidence of various treatment are evidence for efficacy of the various approaches in the management of adults with TD TMP = trimethoprim; SMX = TD = travelers’ diarrhea. norfloxacin, evidence for efficacy of the various approaches in the management of adults with TD TMP = trimethoprim; SMX = TD = travelers’ diarrhea. norfloxacin, TD is a illness. Treatment is to reduce symptoms and shorten illness limiting the duration of particularly when travelers need to a Oral fluid and in TD can be in all by increasing and foods in the diet. of diet during diarrhea treatment appears to have no clinical it should be for people with acute diarrhea to easily digestible which have been demonstrated in children with acute enteric infection to and after intestinal For most adults with to severe TD fever or dysentery (passage of bloody one of the three treatments in order may be given and to be of value in shortening azithromycin in a single fluoroquinolone (ciprofloxacin or given with an response to single the drug and can be the two days or rifaximin three a for 3 days. Some panel recommend or rifaximin as the standard self‐treatment for travel to Latin and of Asia, azithromycin for all future travelers to recommend a fluoroquinolone or rifaximin as standard treatment of all TD of including Asia, azithromycin for treatment is not available in many limiting this for When high fever is or travelers are grossly bloody stools of azithromycin in a single dose is the recommended therapy for The pediatric dose is 5 for 3 days. azithromycin is not for standard travelers may be to two with a fluoroquinolone or a rifaximin for illness and azithromycin for or illness or when TD fails to respond to primary two TD may be for some loperamide can be given with one of the antibacterial drugs to accelerate recovery and control diarrhea. is given to adults with diarrhea in a dose of by after each unformed stool not to 8 in 24 with the treatment duration An percentage of travel medicine experts recommend loperamide alone as standard self‐treatment of TD. The dose of loperamide for adults is given The following measures will be important to as studies of TD therapy are and future studies are The of and use of symptomatic and antibacterial therapy in travelers to high‐risk tropical and The clinical response to treatment among people with TD by agent and area The of treatment and causes of illness in cases. The antibacterial of bacterial recovered from subjects with TD by of study and of the illness. The effectiveness of initiation of therapy in disease of the including The and effectiveness of antibacterial drugs for treatment and of TD in children and other groups including the the or and the The and effectiveness of the antisecretory drugs for treatment of TD. The value of rifaximin treatment of TD in areas where invasive pathogens are including many areas of The of resistance of each of the important drugs in TD therapy: rifaximin, and azithromycin. The or value of antisecretory drugs with antimicrobial drugs in the treatment of TD. TD will continue to be a of international travel. traveling to high‐risk regions of the developing world will need to be to with them medication for self‐therapy that is known to be effective in controlling symptoms and duration of most of TD. antisecretory drugs should be developed for use in therapy of TD with or antibacterial treatment in of the more physiologic of these of has for and has administered through from has a from for has administered through from and and has an for with and has from and is on an for is a of a that is in a 3 to a drug to TD. and in and studies and has for and on for and for from for from and and that they have no of