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.

Major findings

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.

Purpose

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).

Table 1

Grading of clinical evidence in the therapy of travelers’ diarrhea 101

Category Grade Definition 
Strength of evidence Good evidence to support a recommendation for use 
 Moderate evidence to support a recommendation for use 
 Poor evidence to support a recommendation 
 Moderate evidence to support a recommendation against use 
 Good evidence to support a recommendation against use 
Quality of evidence Evidence from ≥1 properly randomized, controlled trial 
 II Evidence from ≥1 well‐designed clinical trial without randomization, from case‐controlled analysis of cohort study 
 III Consensus evidence, evidence from one authority or reports of expert committees 
Category Grade Definition 
Strength of evidence Good evidence to support a recommendation for use 
 Moderate evidence to support a recommendation for use 
 Poor evidence to support a recommendation 
 Moderate evidence to support a recommendation against use 
 Good evidence to support a recommendation against use 
Quality of evidence Evidence from ≥1 properly randomized, controlled trial 
 II Evidence from ≥1 well‐designed clinical trial without randomization, from case‐controlled analysis of cohort study 
 III Consensus evidence, evidence from one authority or reports of expert committees 

Target population

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.

Desired Outcome and Methods

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.”

Etiologic agents of TD and Their antimicrobial susceptibility as a background

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

Chemotherapy, drugs to consider, clinical trials, and concerns

Management of diarrhea includes receipt of electrolytes and calories, symptomatic treatment, and antimicrobial therapy. The panel considered each of the management modalities.

Fluid and Electrolyte Therapy and Diet During TD

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

Drugs used to relieve symptoms

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.

Antibacterial drugs

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).

Table 2

Double‐blind, placebo‐controlled antibacterial treatment trials in adults with travelers’ diarrhea (including p values)

 Duration post‐treatment diarrhea (TLUS) Hrs Treatment failures (%)* 
Year (location), study drug, and duration, reference Placebo Study drug Placebo Study drug 
1981 (Mexico) TMP/SMX for 5 d 31 93 29 (p< 0.001) 47 5 (p< 0.001) 
1984 (Mexico) TMP/SMX and Ciprofloxacin (cipro) for 5 d 102 81 20 (TMP) and 29 (cipro) (p< 0.001 for both) 32 5 (TMP) and 7 (cipro) (p< 0.0001 for both) 
1986–1988 (Mexico) Ofloxacin 5 (of 5 d) and 3 (of 3 d) 103 56 39 (of 5) (p= NS) and 28 (of 3) (p< 0.05) 29 11 (of 5) and 5 (of 3) (p= 0.0001 groups combined) 
1993 (Belize) Ciprofloxacin, single dose 33 54 25 (p< 0.0001) Not reported Not reported 
1987–1989 (Mexico) TMP/SMX, single dose (SD)and 3 d 80 59 28 (SD) (p≤ 0.005) and 34 (3d) (p= NS) 56 10 (SD) and 9 (3d) (p< 0.05 for both) 
1986–1988 (Africa, Asia, Latin America), norfloxacin 104 Not reported Not reported 62 26 (p= 0.0001) 
1989 (Morocco) norfloxacin, 3 d 105 79 29 (p< 0.001) 53 16 (p< 0.001) 
1999–2000 (Guatemala, Mexico, and Kenya), rifaximin for 3 d 93 60 600 mg/d 33 and 1,200 mg/d 33 (p= 0.0001 for both) 35 600 mg/d 16 and 1,200 mg/d 17 (p= 0.001 for both) 
2002–2003 (Mexico, Guatemala and India), rifaximin (rif) versus ciprofloxacin 4 66 rif 32 (p= 0.0014) and cipro 29 (p= 0.0003) 26 rif 11 (p= 0.0039) and cipro 17 (p= 0.05) 
 Duration post‐treatment diarrhea (TLUS) Hrs Treatment failures (%)* 
Year (location), study drug, and duration, reference Placebo Study drug Placebo Study drug 
1981 (Mexico) TMP/SMX for 5 d 31 93 29 (p< 0.001) 47 5 (p< 0.001) 
1984 (Mexico) TMP/SMX and Ciprofloxacin (cipro) for 5 d 102 81 20 (TMP) and 29 (cipro) (p< 0.001 for both) 32 5 (TMP) and 7 (cipro) (p< 0.0001 for both) 
1986–1988 (Mexico) Ofloxacin 5 (of 5 d) and 3 (of 3 d) 103 56 39 (of 5) (p= NS) and 28 (of 3) (p< 0.05) 29 11 (of 5) and 5 (of 3) (p= 0.0001 groups combined) 
1993 (Belize) Ciprofloxacin, single dose 33 54 25 (p< 0.0001) Not reported Not reported 
1987–1989 (Mexico) TMP/SMX, single dose (SD)and 3 d 80 59 28 (SD) (p≤ 0.005) and 34 (3d) (p= NS) 56 10 (SD) and 9 (3d) (p< 0.05 for both) 
1986–1988 (Africa, Asia, Latin America), norfloxacin 104 Not reported Not reported 62 26 (p= 0.0001) 
1989 (Morocco) norfloxacin, 3 d 105 79 29 (p< 0.001) 53 16 (p< 0.001) 
1999–2000 (Guatemala, Mexico, and Kenya), rifaximin for 3 d 93 60 600 mg/d 33 and 1,200 mg/d 33 (p= 0.0001 for both) 35 600 mg/d 16 and 1,200 mg/d 17 (p= 0.001 for both) 
2002–2003 (Mexico, Guatemala and India), rifaximin (rif) versus ciprofloxacin 4 66 rif 32 (p= 0.0014) and cipro 29 (p= 0.0003) 26 rif 11 (p= 0.0039) and cipro 17 (p= 0.05) 

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 subsequent development of HUS. 42 STEC are not common causes of TD, minimizing this concern in travel medicine. Enhancement of HUS by antibacterial treatment of S dysenteriae1 diarrhea seems to be a rare event. 43

A second therapeutic concern is that antibacterial drugs may lead to prolongation or worsening of enteric infection caused by strains of nontyphoid Salmonella(NTS). Antibacterial drugs can influence the duration of carriage of an infecting strain of NTS. An often quoted study of treatment of NTS indicated that carriage of the organism was prolonged by at least 3 weeks secondary to ciprofloxacin therapy. 44 A second clinical study failed to see such prolongation of carriage of NTS when patients were treated with either ciprofloxacin or TMP/SMX. 45 NTS strains usually are not spread from person to person due to inoculum size required. Also the short‐term carriage is of little clinical significance to the affected people. 46 A Cochrane analysis of results of therapy of people with gastroenteritis due to Salmonella showed that therapy may result in increased rate of relapse, increase in risk for a positive culture after 3 weeks, and increase risk for adverse drug reaction with no decrease in length of illness. 47

The third treatment concern is that antibacterial therapy with drugs that deplete colonic flora, seen characteristically with fluoroquinolone administration, 48 may predispose to development of Clostridium difficile colitis after therapy of TD. 49, 50 A recent publication reported four patients with TD who developed C difficile colitis following treatment with ciprofloxacin. 51

The fourth area of concern relates to widespread use of antibacterial drugs in both human and animal populations leading to antibacterial resistance among enteric pathogens 34, 52–56 and for the absorbed antibiotics, extraintestinal bacteria. 57 While fluoroquinolone resistance of ETEC strains causing TD has occurred, 56 the major public health concern is fluoroquinolone resistance among strains of Clostridium jejuni or Shigella. 5, 53, 55, 58–60 Fluoroquinolone resistance by Streptococcus pneumonia is of clinical importance. 57

The consensus of authors of this review is that concerns about antibiotic treatment of Shiga toxin‐producing organisms or nontyphoid Salmonella, possible predisposition to C difficile diarrhea, or contribution to antibiotic resistance development are not sufficient reasons to withhold antimicrobial therapy as treatment for TD.

There are a number of potentially important issues related to selection of antibiotics for travel to high‐risk regions. In a randomized, double‐blind treatment study of TD, rifaximin (400 mg twice a day for 3 days) was of equivalent value in shortening TD compared with ciprofloxacin (500 mg twice a day for 3 days) in adults in Mexico, where diarrheagenic E coli are known to be the most common cause of illness. 35 A second study failed to demonstrate an advantage overall when ciprofloxacin was compared with rifaximin therapy in TD in Mexico, Guatemala, and India, yet a subgroup with invasive illness showed reduced benefit following treatment with rifaximin. 4

Three clinical trials demonstrated that azithromycin was as effective as a fluoroquinolone in the treatment of TD occurring in Thailand or Mexico. 5, 60, 61 Azithromycin has also been shown to be active in the treatment of diarrhea caused by invasive strains of Campylobacter, including fluoroquinolone‐resistant strains 5,34 and Shigella spp., 62 and the drug is active against the noninvasive diarrheagenic E coli.34

For diarrheagenic E coli, the principal causes of TD worldwide, all three antimicrobial drugs used currently to treat TD are effective.Campylobacter strains occurring in most parts of the world show a high degree of resistance to fluoroquinolones including ciprofloxacin. 5,53,63,64 Rates of resistance to Campylobacter strains were found to be high for rifaximin in one study. 65 Erythromycin resistance of Campylobacter spp. in economically developed countries generally is stable at less than 5%, 66, 67 whereas higher resistance has been reported from some countries including Thailand, 59,68 Nigeria, 69 Spain, 55 Taiwan, 70 and Canada. 71 Strains of Campylobacter spp. that show high‐level resistance to erythromycin also appear to be resistant to azithromycin, 72,73 although azithromycin concentrates in tissues and may be effective treatment even when infecting strains show a moderately high minimal inhibitory concentration to the drug.

For fluoroquinolone‐susceptible Campylobacter and the other invasive bacterial pathogens, fluoroquinolones and azithromycin represent the preferred treatments. Invasive bacterial enteropathogens occur more commonly in South Asia, 3–5 when compared with other high‐risk regions, which has led some travel medicine experts to select azithromycin preferentially for travelers to that region, expressing concern that rifaximin would be less effective against invasive pathogens and ciprofloxacin‐like drugs would be less active against resistant strains of Campylobacter.

One difference between the various anti‐TD antibiotics is the expected rate of adverse events. In all clinical trials, nonabsorbed rifaximin has shown the tolerability profile of the placebo control, suggesting that this preparation would have fewer systemic adverse events than absorbed drugs. The adverse events for absorbed drugs are of low but predictable frequency: fluoroquinolones—insomnia, irritability, and Candida vaginitis and azithromycin—gastrointestinal symptoms. In the United States, a black box warning against tendon rupture has been added for the fluoroquinolone agents.

An unproven benefit of antibacterial chemotherapy of TD is prevention of persistent enteric symptoms and chronic diarrhea. Two studies demonstrated that 10% to 12% of adults with TD will progress to postinfectious irritable bowel syndrome (PI‐IBS). 74, 75 One study indicated that PI‐IBS most commonly developed following enteric infection by inflammatory bacterial pathogens. 76 The same research team provided evidence that PI‐IBS persisted in most cases for at least 6 years after disease onset. 77 A separate study also confirmed common persistence of new onset PI‐IBS for at least 5 years after illness began. 78 When treatment is begun only after developing classic TD (passing ≥3 unformed stools plus one or more signs or symptoms of enteric infection such as abdominal pain or cramps), PI‐IBS was not prevented. 74 It is not known if persistent complications can be prevented by starting antimicrobial therapy earlier in the course of enteric infection, after passage of the first unformed stool or at the first presence of signs or symptoms of enteric infection.

Combination therapy

Loperamide can be administered with antibiotics, where the objective of therapy is to combine rapid improvement in symptoms with the symptomatic treatment with slower onset curative effects of the antibacterial drug 79–81 (Table 3). Not all trials have reported benefit of adding loperamide to antibacterial therapy, 82, 83 but all trials have concluded the combination was safe. The rare occurrence of worsening of the disease when antimotility drugs are used alone to treat invasive disease 84 has not been encountered in any of these studies when effective antibacterial therapy also is used.

Table 3

Clinical treatment studies where antibacterial drugs were combined with loperamide in the treatment of adults with travelers’ diarrhea

Region studied Antibacterial drug employed Comment on additive effects References 
Mexico Ofloxacin Major* 79, 106 
Egypt Ciprofloxacin Minimal 83 
Thailand Ciprofloxacin Minimal 82 
Mexico Azithromycin Major* 107 
Mexico Rifaximin Major* 108 
Region studied Antibacterial drug employed Comment on additive effects References 
Mexico Ofloxacin Major* 79, 106 
Egypt Ciprofloxacin Minimal 83 
Thailand Ciprofloxacin Minimal 82 
Mexico Azithromycin Major* 107 
Mexico Rifaximin Major* 108 
*

Rapid improvement (shortened time from initiation of treatment until time that the last unformed stool during illness was passed, reduction in diarrhea stool number)

Antimicrobial susceptibility and fecal levels of drug

In vitro susceptibility of bacterial strains is an important predictor of clinical response to antibiotic therapy in bacterial diarrhea. 85 The current antimicrobial breakpoints used to determine susceptibility are based on minimal inhibitory concentration (MIC) of the drug for the organism and expected serum concentration of drug. 86, 87 The available breakpoints are likely to be insensitive for predicting the outcome of treatment of intestinal and urinary tract infections when curative drugs concentrate at very high concentrations in the site of infection. For bacterial diarrhea, gut levels of fluoroquinolones exceed 500 μg/g 88–90 and rifaximin reach levels of 8,000 μg/g 91 after 3 days therapy. Azithromycin therapy leads to high tissue levels of the drug during therapy. 92 Studies are needed to develop new breakpoints for enteric pathogens and drugs used to treat intestinal tract infections based on organism MICs and intestinal and mucosal levels of biologically active drug achieved.

While rifaximin improves clinical illness of uncomplicated TD with similar efficiency as therapy with absorbed antibacterial drugs such as flouroquinolones, studies have shown a lower rate of pathogen eradication from stool with rifaximin. 4, 35, 93 The importance of this observation is called into question by results of a previous study showing a lack of correlation between pathogen eradication and clinical improvement of antibacterial therapy of TD. 94 There are at least two possible explanations for variable rates of pathogen eradication in the face of clinical response as occurs with rifaximin. First, bile‐soluble rifaximin may primarily exert its beneficial effect in the bile‐rich small bowel as opposed to the aqueous environment in the colon. Second, the drug may alter pathogen virulence even in subinhibitory concentrations. 95

Specific recommendations for self‐treatment of TD are provided. The strength of each recommendation and the quality of the evidence backing the recommendation are indicated by a rating scale provided inTable 1.

Treatment of TD in children

For children, the mainstay of treatment of TD while in developing regions is fluid and electrolyte therapy and dietary management. TD therapy should center on oral fluid and electrolyte treatment using only bottled or previously boiled water. Breast‐fed infants should continue nursing on demand before, during, and after diarrhea to minimize exposure to contaminated food and beverages and to provide protective factors. 8, 96 Unless it occurs under the direction of a physician, antibacterial and symptomatic therapy should not be used for infants (≤12 months of age).

Therapy with BSS is not recommended for young children because of the concern of excessive salicylate absorption. 97 Loperamide is not recommended due to lack of known efficacy and concern for side effects. Fluoroquinolone treatment currently is not recommended for therapy of TD in children due to potential drug toxicity. 98 Fluoroquinolones while not approved for use in children may be safe for TD therapy since the drugs are given for only 1 to 3 days. 99 Azithromycin is an approved drug in pediatrics and can be given to children with more severe cases of TD in a dose of 10 mg/kg/d for 3 days for children 6 months to 12 years of age. 100 Rifaximin, while not approved for use in children in most countries, should be safe to administer based on weight of the child. Rifaximin is available in a small number of countries as a pediatric suspension.

Current Recommendations and Summary Views on Self‐Treatment of TD

The following statements provide the authors’ perspective on the self‐treatment of TD based on the previous studies outlined above. The recommendations help identify medication to add to the travel kit before leaving home, which may be influenced by the trip destination. The strength and quality of evidence of various treatment options are presented inTable 4.

Table 4

Clinical evidence for efficacy of the various therapeutic approaches in the management of adults with TD

Therapeutic agent Strength of evidence Quality of evidence Comments 
Bismuth subsalicylate Inexpensive; will turn stools and tongues black (harmless bismuth sulfide); leads to important salicylate absorption, 97 must take multiple doses; not to be used in persons with advanced acquired immunodeficiency syndrome or with chronic enteric disease where bismuth absorption may occur across the damaged mucosa 109 
Kaolin, pectin, or attipulgite Clinical trials have shown that these agents make stools more formed without providing other advantages 110 
Loperamide Loperamide is the most effective symptomatically acting antidiarrheal compound 18 
Diphenoxylate hydrochloride with atropine (Lomotil) Effective but contains atropine which causes anticholinergic side effects without antidiarrheal effects 111 and with overdose liability for children due to central opiate effects 112 
TMP/SMX III Expected worldwide resistance limits value of this drug 34 
Fluoroquinolones* Effective, side effects and concern about stimulation of resistance among extraintestinal bacteria 57 
Rifaximin Safest available drug for noninvasive forms of TD due to diarrheagenic E coli strains; not effective for febrile and dysenteric TD 
Azithromycin Effective against all bacterial forms of TD with its major use being for febrile and dysenteric TD 5 
Therapeutic agent Strength of evidence Quality of evidence Comments 
Bismuth subsalicylate Inexpensive; will turn stools and tongues black (harmless bismuth sulfide); leads to important salicylate absorption, 97 must take multiple doses; not to be used in persons with advanced acquired immunodeficiency syndrome or with chronic enteric disease where bismuth absorption may occur across the damaged mucosa 109 
Kaolin, pectin, or attipulgite Clinical trials have shown that these agents make stools more formed without providing other advantages 110 
Loperamide Loperamide is the most effective symptomatically acting antidiarrheal compound 18 
Diphenoxylate hydrochloride with atropine (Lomotil) Effective but contains atropine which causes anticholinergic side effects without antidiarrheal effects 111 and with overdose liability for children due to central opiate effects 112 
TMP/SMX III Expected worldwide resistance limits value of this drug 34 
Fluoroquinolones* Effective, side effects and concern about stimulation of resistance among extraintestinal bacteria 57 
Rifaximin Safest available drug for noninvasive forms of TD due to diarrheagenic E coli strains; not effective for febrile and dysenteric TD 
Azithromycin Effective against all bacterial forms of TD with its major use being for febrile and dysenteric TD 5 

TMP = trimethoprim; SMX = sulfamethoxazole; TD = travelers’ diarrhea.

*

ciprofloxacin, norfloxacin, levofloxacin, ofloxacin.

  1. TD is a nonfatal, self‐limiting illness. Treatment is designed to reduce symptoms and shorten illness limiting the duration of inconvenience, particularly when travelers need to follow a schedule.

  2. Oral fluid and electrolyte requirements in TD can be met in nearly all cases by increasing fluids and salt‐containing foods in the diet. While restriction of diet during diarrhea treatment appears to have no overt clinical benefit, it should be useful for people with acute diarrhea to consume easily digestible foods, which have been demonstrated in children with acute enteric infection to help repair and regenerate enterocytes after intestinal injury.

  3. For most adults with moderate to severe TD without fever or dysentery (passage of bloody stools), one of the three oral treatments listed in alphabetical order may be given and expected to be of equivalent value in shortening illness: (1) azithromycin in a single 1,000 mg dose; (2) fluoroquinolone (ciprofloxacin 750 mg, levofloxacin 500 mg, or norfloxacin 400 mg) given once; with an incomplete response to single dose, the same drug and same dosage can be repeated the next two mornings (3 days therapy); or (3) rifaximin 200 mg three times a day for 3 days.

Some panel members recommend either ciprofloxacin or rifaximin as the standard self‐treatment for travel to Latin America, Africa, and large parts of Asia, reserving azithromycin for all future travelers to South East Asia (mainly Thailand). Others recommend a fluoroquinolone or rifaximin as standard treatment of all nonfebrile, nondysenteric TD regardless of region, including South Asia, reserving azithromycin for treatment failures. Rifaximin is not available in many countries, limiting this choice for many.

  1. When high fever is present (39.4°C) or travelers are passing grossly bloody stools (dysentery), 1,000 mg of azithromycin in a single dose is the recommended therapy for adults. The pediatric dose is 5 mg/kg/d for 3 days. If azithromycin is not selected for standard therapy, travelers may be advised to take two medications with them, either a fluoroquinolone or a rifaximin for uncomplicated illness and azithromycin for febrile or dysenteric illness or when TD fails to respond to primary treatment. Transporting two TD therapies may be confusing for some travelers.

  2. If available, loperamide can be given with one of the antibacterial drugs described above to accelerate recovery and control diarrhea. It is given to adults with diarrhea in a dose of 4 mg initially followed by 2 mg (one capsule) after each unformed stool passed, not to exceed 8 mg (4 capsules) in 24 hours with the total treatment duration ≤48 hours.

  3. An unknown percentage of European travel medicine experts recommend loperamide alone as standard self‐treatment of TD. The dose of loperamide for adults is given above.

Performance, outcome measures, and future research

The following outcome measures will be important to examine as studies of TD therapy are evaluated, and future studies are designed:

  1. The frequency of possession and use of symptomatic and antibacterial therapy in travelers to high‐risk tropical and semitropical regions.

  2. The clinical response to treatment among people with TD by therapeutic agent and geographic area visited.

  3. The frequency of treatment failures and causes of illness in refractory cases.

  4. The antibacterial susceptibility of bacterial enteropathogens recovered from subjects with TD by year of study and geographic location of the illness.

  5. The effectiveness of early initiation of therapy in preventing chronic functional disease of the intestine including PI‐IBS.

  6. The safety and effectiveness of antibacterial drugs for treatment and prevention of TD in children and other special groups including the elderly, the chronically ill or immunosuppressed and the pregnant.

  7. The safety and effectiveness of the newer antisecretory drugs for treatment of TD.

  8. The value of rifaximin treatment of TD in areas where prevalent invasive pathogens are encountered including many areas of Asia.

  9. The occurrence of resistance of each of the important drugs in TD therapy: fluoroquinolones, rifaximin, and azithromycin.

  10. The additive or synergistic value of combining antisecretory drugs with antimicrobial drugs in the treatment of TD.

Conclusions

TD will continue to be a problem of international travel. People traveling to high‐risk regions of the developing world will need to be encouraged to take with them medication for self‐therapy that is known to be effective in controlling symptoms and duration of most cases of TD. Novel antisecretory drugs should be developed for use in therapy of TD with or without concomitant antibacterial treatment in view of the more physiologic approach of these classes of drugs.

Declaration of interests

H.L.D.P has consulted with, received honoraria for speaking and has received research grants administered through his university from Salix Pharmaceutical Company; has received a consulting fee from Romark Institute for Medical Research; has received research grants administered through his university from Optimer Pharmaceuticals and IOMAI Corporation; and has received an honorarium for consulting and/or speaking with McNeil Consumer Healthcare and Merck Vaccine Division.

C.D.E has received speaking honoraria from and is on an advisory board for Salix.

S.G. is a part‐time employee of a pharmaceutical company (Optimer Pharmaceuticals, Inc., San Diego, CA, USA) that is currently in a phase 3 trial to test a drug to treat TD.

L.R. gave lectures and participated in advisory boards and phases II‐II studies SBL vaccine, Sanofi Pasteur MSD, and Glaxo Smith Kline.

R.S. has accepted fee for speaking, organizing and chairing education, consulting and/or serving on advisory boards, also reimbursement for attending meetings and funds for research from Astral, Baxter, Berna Biotech/Crucell, GlaxoSmithKline, Novartis Vaccine, Optimer, Roche, Salix, Sanofi Pasteur MSD, and/or SBL Vaccine.

T.W. receives fee for speaking from Sanofi Pasteur, GSK, UCB, and Novartis Vaccines.

M.J.G.F. and L.K.P. state that they have no conflicts of interest.

References

1
Adachi
JA
Jiang
ZD
Mathewson
JJ
,et al.
Enteroaggregative Escherichia coli as a major etiologic agent in traveler’s diarrhea in 3 regions of the world
.
Clin Infect Dis
 
2001
;
32
:
1706
1709
.
2
Black
RE
.
Epidemiology of travelers’ diarrhea and relative importance of various pathogens
.
Rev Infect Dis
 
1990
;
12
(
Suppl 1
):
S73
S79
.
3
Jiang
ZD
Lowe
B
Verenkar
MP
,et al.
Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay)
.
J Infect Dis
 
2002
;
185
:
497
502
.
4
Taylor
DN
Bourgeois
AL
Ericsson
CD
,et al.
A randomized, double‐blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers’ diarrhea
.
Am J Trop Med Hyg
 
2006
;
74
:
1060
1066
.
5
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
.
6
Ko
G
Garcia
C
Jiang
ZD
,et al.
Noroviruses as a cause of traveler’s diarrhea among students from the United States visiting Mexico
.
J Clin Microbiol
 
2005
;
43
:
6126
6129
.
7
DuPont
HL
Capsuto
EG
.
Persistent diarrhea in travelers
.
Clin Infect Dis
 
1996
;
22
:
124
128
.
8
King
CK
Glass
R
Bresee
JS
Duggan
C
.
Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy
.
MMWR Recomm Rep
 
2003
;
52
(
RR‐16
):
1
16
.
9
Kielmann
AA
Mobarak
AB
Hammamy
MT
,et al.
Control of deaths from diarrheal disease in rural communities. I. Design of an intervention study and effects on child mortality
.
Trop Med Parasitol
 
1985
;
36
:
191
198
.
10
Victora
CG
Bryce
J
Fontaine
O
Monasch
R
.
Reducing deaths from diarrhoea through oral rehydration therapy
.
Bull World Health Organ
 
2000
;
78
:
1246
1255
.
11
Pierce
NF
Banwell
JG
Mitra
RC
,et al.
Oral replacement of water and electrolyte losses in cholera
.
Indian J Med Res
 
1969
;
57
:
848
855
.
12
Caeiro
JP
DuPont
HL
Albrecht
H
Ericsson
CD
.
Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler’s diarrhea
.
Clin Infect Dis
 
1999
;
28
:
1286
1289
.
13
Duggan
C
Santosham
M
Glass
RI
.
The management of acute diarrhea in children: oral rehydration, maintenance, and nutritional therapy. Centers for Disease Control and Prevention
.
MMWR Recomm Rep
 
1992
;
41
(
RR‐16
):
1
20
.
14
Huang
DB
Awasthi
M
Le
BM
,et al.
The role of diet in the treatment of travelers’ diarrhea: a pilot study
.
Clin Infect Dis
 
2004
;
39
:
468
471
.
15
Brown
KH
Peerson
JM
Fontaine
O
.
Use of nonhuman milks in the dietary management of young children with acute diarrhea: a meta‐analysis of clinical trials
.
Pediatrics
 
1994
;
93
:
17
27
.
16
DuPont
HL
Flores Sanchez
J
Ericsson
CD
,et al.
Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea
.
Am J Med
 
1990
;
88
(
6A
):
15S
19S
.
17
DuPont
HL
Sullivan
P
Pickering
LK
Haynes
G
,et al.
Symptomatic treatment of diarrhea with bismuth subsalicylate among students attending a Mexican university
.
Gastroenterology
 
1977
;
73
(
4 Pt 1
):
715
718
.
18
Johnson
PC
Ericsson
CD
DuPont
HL
Morgan
DR
,et al.
Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers’ diarrhea
.
JAMA
 
1986
;
255
:
757
760
.
19
Powell
DW
Tapper
EJ
Morris
SM
.
Aspirin‐stimulated intestinal electrolyte transport in rabbit ileum in vitro
.
Gastroenterology
 
1979
;
76
:
1429
1437
.
20
Burke
V
Gracey
M
Suharyono
Sunoto
.
Reduction by aspirin of intestinal fluid‐loss in acute childhood gastroenteritis
.
Lancet
 
1980
;
1
(
8182
):
1329
30
.
21
Venerito
M
Treiber
G
Wex
T
,et al.
Effects of low‐dose aspirin on gastric erosions, cyclooxygenase expression and mucosal prostaglandin‐E2 do not depend on Helicobacter pylori infection
.
Aliment Pharmacol Ther
 
2006
;
23
:
1225
1233
.
22
Gilster
J
Bacon
K
Marlink
K
,et al.
Bismuth subsalicylate increases intracellular Ca2+, MAP‐kinase activity, and cell proliferation in normal human gastric mucous epithelial cells
.
Dig Dis Sci
 
2004
;
49
:
370
378
.
23
Epple
HJ
Fromm
M
Riecken
EO
Schulzke
JD
.
Antisecretory effect of loperamide in colon epithelial cells by inhibition of basolateral K+ conductance
.
Scand J Gastroenterol
 
2001
;
36
:
731
737
.
24
DuPont
HL
Ericsson
CD
Mathewson
JJ
,et al.
Zaldaride maleate, an intestinal calmodulin inhibitor, in the therapy of travelers’ diarrhea
.
Gastroenterology
 
1993
;
104
:
709
715
.
25
DiCesare
D
DuPont
HL
Mathewson
JJ
,et al.
A double blind, randomized, placebo‐controlled study of SP‐303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico
.
Am J Gastroenterol
 
2002
;
97
:
2585
2588
.
26
Salazar‐Lindo
E
Santisteban‐Ponce
J
Chea‐Woo
E
Gutierrez
M
.
Racecadotril in the treatment of acute watery diarrhea in children
.
N Engl J Med
 
2000
;
343
:
463
467
.
27
Wang
HH
Shieh
MJ
Liao
KF
.
A blind, randomized comparison of racecadotril and loperamide for stopping acute diarrhea in adults
.
World J Gastroenterol
 
2005
;
11
:
1540
1543
.
28
DuPont
HL
Olarte
J
Evans
DG
,et al.
Comparative susceptibility of latin american and united states students to enteric pathogens
.
N Engl J Med
 
1976
;
295
:
1520
1521
.
29
Gorbach
SL
Kean
BH
Evans
DG
Evans
DJ
Jr
,et al.
Travelers’ diarrhea and toxigenic Escherichia coli
.
N Engl J Med
 
1975
;
292
:
933
936
.
30
Merson
MH
Morris
GK
Sack
DA
,et al.
Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress
.
N Engl J Med
 
1976
;
294
:
1299
1305
.
31
DuPont
HL
Reves
RR
Galindo
E
Sullivan
PS
,et al.
Treatment of travelers’ diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone
.
N Engl J Med
 
1982
;
307
:
841
844
.
32
DuPont
HL
Cooperstock
M
Corrado
ML
Fekety
R
,et al.
Evaluation of new anti‐infective drugs for the treatment of acute infectious diarrhea. Infectious Diseases Society of America and the Food and Drug Administration
.
Clin Infect Dis
 
1992
;
15
Suppl. 1
:
S228
S235
.
33
Salam
I
Katelaris
P
Leigh‐Smith
S
Farthing
MJ
.
Randomised trial of single‐dose ciprofloxacin for travellers’ diarrhoea
.
Lancet
 
1994
;
344
:
1537
1539
.
34
Gomi
H
Jiang
ZD
Adachi
JA
,et al.
In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing traveler’s diarrhea in four geographic regions
.
Antimicrob Agents Chemother
 
2001
;
45
:
212
216
.
35
DuPont
HL
Jiang
ZD
Ericsson
CD
,et al.
Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double‐blind clinical trial
.
Clin Infect Dis
 
2001
;
33
:
1807
1815
.
36
Bennish
ML
Salam
MA
Khan
WA
Khan
AM
.
Treatment of shigellosis: III. Comparison of one‐ or two‐dose ciprofloxacin with standard 5‐day therapy. A randomized, blinded trial
.
Ann Intern Med
 
1992
;
117
:
727
734
.
37
Kabir
I
Butler
T
Khanam
A
.
Comparative efficacies of single intravenous doses of ceftriaxone and ampicillin for shigellosis in a placebo‐controlled trial
.
Antimicrob Agents Chemother
 
1986
;
29
:
645
648
.
38
Zhang
X
McDaniel
AD
Wolf
LE
,et al.
Quinolone antibiotics induce Shiga toxin‐encoding bacteriophages, toxin production, and death in mice
.
J Infect Dis
 
2000
;
181
:
664
670
.
39
Ohara
T
Kojio
S
Taneike
I
,et al.
Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response
.
Antimicrob Agents Chemother
 
2002
;
46
:
3478
3483
.
40
Kimmitt
PT
Harwood
CR
Barer
MR
.
Toxin gene expression by shiga toxin‐producing Escherichia coli: the role of antibiotics and the bacterial SOS response
.
Emerg Infect Dis
 
2000
;
6
:
458
465
.
41
Ochoa
TJ
Chen
J
Walker
CM
Gonzales
E
,et al.
Rifaximin does not induce toxin production or phage‐mediated lysis of Shiga toxin‐producing Escherichia coli
.
Antimicrob Agents Chemother
 
2007
;
51
:
2837
2841
.
42
Safdar
N
Said
A
Gangnon
RE
Maki
DG
.
Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta‐analysis
.
JAMA
 
2002
;
288
:
996
1001
.
43
Bennish
ML
Khan
WA
Begum
M
,et al.
Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella dysenteriae type 1 infection in Bangladesh
.
Clin Infect Dis
 
2006
;
42
:
356
362
.
44
Neill
MA
Opal
SM
Heelan
J
,et al.
Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: experience during an outbreak in health care workers
.
Ann Intern Med
 
1991
;
114
:
195
199
.
45
Sanchez
C
Garcia‐Restoy
E
Garau
J
,et al.
Ciprofloxacin and trimethoprim‐sulfamethoxazole versus placebo in acute uncomplicated Salmonella enteritis: a double‐blind trial
.
J Infect Dis
 
1993
;
168
:
1304
1307
.
46
Musher
DM
Rubenstein
AD
.
Permanent carriers of nontyphosa salmonellae
.
Arch Intern Med
 
1973
;
132
:
869
872
.
47
Sirinavin
S
Garner
P
.
Antibiotics for treating salmonella gut infections
.
Cochrane Database Syst Rev
 
2000
:CD001167.
48
Johnson
PC
Ericsson
CD
Morgan
DR
,et al.
Lack of emergence of resistant fecal flora during successful prophylaxis of traveler’s diarrhea with norfloxacin
.
Antimicrob Agents Chemother
 
1986
;
30
:
671
674
.
49
McDonald
LC
Killgore
GE
Thompson
A
,et al.
An epidemic, toxin gene‐variant strain of Clostridium difficile
.
N Engl J Med
 
2005
;
353
:
2433
2441
.
50
Pepin
J
Saheb
N
Coulombe
MA
,et al.
Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile‐associated diarrhea: a cohort study during an epidemic in Quebec
.
Clin Infect Dis
 
2005
;
41
:
1254
1260
.
51
Norman
F
Perez‐Molina
J
De Ayala
P
,et al.
Clostridium difficile‐associated diarrhea after antibiotic treatment for traveler’s diarrhea
.
Clin Infect Dis
 
2008
;
46
:
1060
1063
.
52
Bennish
ML
Salam
MA
Hossain
MA
,et al.
Antimicrobial resistance of Shigella isolates in Bangladesh, 1983‐1990: increasing frequency of strains multiply resistant to ampicillin, trimethoprim‐sulfamethoxazole, and nalidixic acid
.
Clin Infect Dis
 
1992
;
14
:
1055
1060
.
53
Nachamkin
I
Ung
H
Li
M
.
Increasing fluoroquinolone resistance in Campylobacter jejuni, Pennsylvania, USA, 1982‐2001
.
Emerg Infect Dis
 
2002
;
8
:
1501
1503
.
54
Prats
G
Mirelis
B
Llovet
T
,et al.
Antibiotic resistance trends in enteropathogenic bacteria isolated in 1985‐1987 and 1995‐1998 in Barcelona
.
Antimicrob Agents Chemother
 
2000
;
44
:
1140
1145
.
55
Saenz
Y
Zarazaga
M
Lantero
M
,et al.
Antibiotic resistance in Campylobacter strains isolated from animals, foods, and humans in Spain in 1997‐1998
.
Antimicrob Agents Chemother
 
2000
;
44
:
267
271
.
56
Vila
J
Vargas
M
Ruiz
J
,et al.
Quinolone resistance in enterotoxigenic Escherichia coli causing diarrhea in travelers to India in comparison with other geographical areas
.
Antimicrob Agents Chemother
 
2000
;
44
:
1731
1733
.
57
Fuller
JD
Low
DE
.
A review of Streptococcus pneumoniae infection treatment failures associated with fluoroquinolone resistance
.
Clin Infect Dis
 
2005
;
41
:
118
121
.
58
Haukka
K
Siitonen
A
.
Emerging resistance to newer antimicrobial agents among Shigella isolated from Finnish foreign travellers
.
Epidemiol Infect
 
2007
;
136
:
1
7
.
59
Hoge
CW
Gambel
JM
Srijan
A
,et al.
Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years
.
Clin Infect Dis
 
1998
;
26
:
341
345
.
60
Kuschner
RA
Trofa
AF
Thomas
RJ
,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
541
.
61
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
.
62
Khan
WA
Seas
C
Dhar
U
,et al.
Treatment of shigellosis: V. Comparison of azithromycin and ciprofloxacin. A double‐blind, randomized, controlled trial
.
Ann Intern Med
 
1997
;
126
:
697
703
.
63
Kassenborg
HD
Smith
KE
Vugia
DJ
,et al.
Fluoroquinolone‐resistant Campylobacter infections: eating poultry outside of the home and foreign travel are risk factors
.
Clin Infect Dis
 
2004
;
38
Suppl. 3
:
S279
S284
.
64
Wardak
S
Szych
J
Zasada
AA
Gierczynski
R
.
Antibiotic resistance of Campylobacter jejuni and Campylobacter coli clinical isolates from Poland
.
Antimicrob Agents Chemother
 
2007
;
51
:
1123
1125
.
65
Sierra
JM
Ruiz
J
Navia
MM
,et al.
In vitro activity of rifaximin against enteropathogens producing traveler’s diarrhea
.
Antimicrob Agents Chemother
 
2001
;
45
:
643
644
.
66
Engberg
J
Aarestrup
FM
Taylor
DE
,et al.
Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates
.
Emerg Infect Dis
 
2001
;
7
:
24
34
.
67
Gupta
A
Nelson
JM
Barrett
TJ
,et al.
Antimicrobial resistance among Campylobacter strains, United States, 1997‐2001
.
Emerg Infect Dis
 
2004
;
10
:
1102
1109
.
68
Sanders
JW
Isenbarger
DW
Walz
SE
,et al.
An observational clinic‐based study of diarrheal illness in deployed United States military personnel in Thailand: presentation and outcome of Campylobacter infection
.
Am J Trop Med Hyg
 
2002
;
67
:
533
538
.
69
Coker
AO
Adefeso
AO
.
The changing patterns of Campylobacter jejuni/coli in Lagos, Nigeria after ten years
.
East Afr Med J
 
1994
;
71
:
437
440
.
70
Li
CC
Chiu
CH
Wu
JL
Huang
YC
,et al.
Antimicrobial susceptibilities of Campylobacter jejuni and coli by using E‐test in Taiwan
.
Scand J Infect Dis
 
1998
;
30
:
39
42
.
71
Gaudreau
C
Gilbert
H
.
Antimicrobial resistance of Campylobacter jejuni subsp. jejuni strains isolated from humans in 1998 to 2001 in Montreal, Canada
.
Antimicrob Agents Chemother
 
2003
;
47
:
2027
2029
.
72
Gaudreau
C
Michaud
S
.
Cluster of erythromycin‐ and ciprofloxacin‐resistant Campylobacter jejuni subsp. jejuni from 1999 to 2001 in men who have sex with men
, Quebec,
Canada. Clin Infect Dis
 
2003
;
37
:
131
136
.
73
Taylor
DE
Chang
N
.
In vitro susceptibilities of Campylobacter jejuni and Campylobacter coli to azithromycin and erythromycin
.
Antimicrob Agents Chemother
 
1991
;
35
:
1917
1918
.
74
Okhuysen
PC
Jiang
ZD
Carlin
L
Forbes
C
,et al.
Post‐diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico
.
Am J Gastroenterol
 
2004
;
99
:
1774
1778
.
75
Stermer
E
Lubezky
A
Potasman
I
,et al.
Is traveler’s diarrhea a significant risk factor for the development of irritable bowel syndrome? A prospective study
.
Clin Infect Dis
 
2006
;
43
:
898
901
.
76
Thornley
JP
Jenkins
D
Neal
K
,et al.
Relationship of Campylobacter toxigenicity in vitro to the development of postinfectious irritable bowel syndrome
.
J Infect Dis
 
2001
;
184
:
606
609
.
77
Neal
KR
Barker
L
Spiller
RC
.
Prognosis in post‐infective irritable bowel syndrome: a six year follow up study
.
Gut
 
2002
;
51
:
410
413
.
78
Tornblom
H
Holmvall
P
Svenungsson
B
Lindberg
G
.
Gastrointestinal symptoms after infectious diarrhea: a five‐year follow‐up in a Swedish cohort of adults
.
Clin Gastroenterol Hepatol
 
2007
;
5
:
461
464
.
79
Ericsson
CD
DuPont
HL
Mathewson
JJ
.
Single dose ofloxacin plus loperamide compared with single dose or three days of ofloxacin in the treatment of traveler’s diarrhea
.
J Travel Med
 
1997
;
4
:
3
7
.
80
Ericsson
CD
DuPont
HL
Mathewson
JJ
,et al.
Treatment of traveler’s diarrhea with sulfamethoxazole and trimethoprim and loperamide
.
JAMA
 
1990
;
263
:
257
261
.
81
Ericsson
CD
Nicholls‐Vasquez
I
DuPont
HL
Mathewson
JJ
.
Optimal dosing of trimethoprim‐sulfamethoxazole when used with loperamide to treat traveler’s diarrhea
.
Antimicrob Agents Chemother
 
1992
;
36
:
2821
2824
.
82
Petruccelli
BP
Murphy
GS
Sanchez
JL
,et al.
Treatment of traveler’s diarrhea with ciprofloxacin and loperamide
.
J Infect Dis
 
1992
;
165
:
557
560
.
83
Taylor
DN
Sanchez
JL
Candler
W
,et al.
Treatment of travelers’ diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. A placebo‐controlled, randomized trial
.
Ann Intern Med
 
1991
;
114
:
731
734
.
84
DuPont
HL
Hornick
RB
.
Adverse effect of lomotil therapy in shigellosis
.
JAMA
 
1973
;
226
:
1525
1528
.
85
Bennish
ML
Salam
MA
Haider
R
Barza
M
.
Therapy for shigellosis. II. Randomized, double‐blind comparison of ciprofloxacin and ampicillin
.
J Infect Dis
 
1990
;
162
:
711
716
.
86
Ambrose
PG
.
Antimicrobial susceptibility breakpoints: PK‐PD and susceptibility breakpoints
.
Treat Respir Med
 
2005
;
4
(
Suppl 1
):
5
11
.
87
Olofsson
SK
Cars
O
.
Optimizing drug exposure to minimize selection of antibiotic resistance
.
Clin Infect Dis
 
2007
;
45
(
Suppl 2
):
S129
S136
.
88
Cofsky
RD
DuBouchet
L
Landesman
SH
.
Recovery of norfloxacin in feces after administration of a single oral dose to human volunteers
.
Antimicrob Agents Chemother
 
1984
;
26
:
110
111
.
89
DuPont
HL
Ericsson
CD
Robinson
A
Johnson
PC
.
Current problems in antimicrobial therapy for bacterial enteric infection
.
Am J Med
 
1987
;
82
(
4A
):
324
328
.
90
Heimdahl
A
Kager
L
Nord
CE
.
Changes in the oropharyngeal and colon microflora in relation to antimicrobial concentrations in saliva and faeces
.
Scand J Infect Dis Suppl
 
1985
;
44
:
52
58
.
91
Jiang
ZD
Ke
S
Palazzini
E
Riopel
L
,et al.
In vitro activity and fecal concentration of rifaximin after oral administration
.
Antimicrob Agents Chemother
 
2000
;
44
:
2205
2206
.
92
Rakita
RM
Jacques‐Palaz
K
Murray
BE
.
Intracellular activity of azithromycin against bacterial enteric pathogens
.
Antimicrob Agents Chemother
 
1994
;
38
:
1915
1921
.
93
Steffen
R
Sack
DA
Riopel
L
,et al.
Therapy of travelers’ diarrhea with rifaximin on various continents
.
Am J Gastroenterol
 
2003
;
98
:
1073
1078
.
94
Ericsson
CD
DuPont
HL
Mathewson
JJ
Johnson
PC
,et al.
Test‐of‐cure stool cultures for traveler’s diarrhea
.
J Clin Microbiol
 
1988
;
26
:
1047
1049
.
95
Jiang
ZD
Ke
S
Shao
R
DuPont
H
.
Rifaximin alteration of microbial virulence of enterotoxigenic
Escherichia coli
 . 9th Conference International Soc Travel Med, Lisbon, Portugal (Abstract P0031.14).
2005
May 2.
96
Morrow
AL
Pickering
LK
.
Human milk and infectious diseases. In: Long S
, Pickering, LK, Prober, CG, eds.
Principles and practice of pediatric infectious diseases
.
2nd Ed
.
Philadelphia: Churchill‐Livingstone
,
2002
:
80
87
.
97
Pickering
LK
Feldman
S
Ericsson
CD
Cleary
TG
.
Absorption of salicylate and bismuth from a bismuth subsalicylate—containing compound (Pepto‐Bismol)
.
J Pediatr
 
1981
;
99
:
654
656
.
98
Gough
A
Barsoum
NJ
Mitchell
L
McGuire
EJ
,et al.
Juvenile canine drug‐induced arthropathy: clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids
.
Toxicol Appl Pharmacol
 
1979
;
51
:
177
187
.
99
Forsythe
CT
Ernst
ME
.
Do fluoroquinolones commonly cause arthropathy in children?
CJEM
 
2007
;
9
:
459
462
.
100
Ruuskanen
O
.
Safety and tolerability of azithromycin in pediatric infectious diseases: 2003 update
.
Pediatr Infect Dis J
 
2004
;
23
(
2 Suppl
):
S135
S139
.
101
Gross
PA
Barrett
TL
Dellinger
EP
,et al.
Purpose of quality standards for infectious diseases. Infectious Diseases Society of America
.
Clin Infect Dis
 
1994
;
18
:
421
.
102
Ericsson
CD
Johnson
PC
DuPont
HL
,et al.
Ciprofloxacin or trimethoprim‐sulfamethoxazole as initial therapy for travelers’ diarrhea. A placebo‐controlled, randomized trial
.
Ann Intern Med
 
1987
;
106
:
216
220
.
103
DuPont
HL
Ericsson
CD
Mathewson
JJ
DuPont
MW
.
Five versus three days of ofloxacin therapy for traveler’s diarrhea: a placebo‐controlled study
.
Antimicrob Agents Chemother
 
1992
;
36
:
87
91
.
104
Wistrom
J
Jertborn
M
Hedstrom
SA
,et al.
Short‐term self‐treatment of travellers’ diarrhoea with norfloxacin: a placebo‐controlled study
.
J Antimicrob Chemother
 
1989
;
23
:
905
913
.
105
Mattila
L
Peltola
H
Siitonen
A
Kyronseppa
H
,et al.
Short‐term treatment of traveler’s diarrhea with norfloxacin: a double‐blind, placebo‐controlled study during two seasons
.
Clin Infect Dis
 
1993
;
17
:
779
782
.
106
Ericsson
CD
DuPont
HL
Mathewson
JJ
.
Optimal dosing of ofloxacin with loperamide in the treatment of non‐dysenteric travelers’ diarrhea
.
J Travel Med
 
2001
;
8
:
207
209
.
107
Ericsson
CD
DuPont
HL
Okhuysen
PC
Jiang
ZD
,et al.
Loperamide plus azithromycin more effectively treats travelers’ diarrhea in Mexico than azithromycin alone
.
J Travel Med
 
2007
;
14
:
312
319
.
108
DuPont
HL
Jiang
ZD
Belkind‐Gerson
J
,et al.
Treatment of travelers’ diarrhea: randomized trial comparing rifaximin, rifaximin plus loperamide, and loperamide alone
.
Clin Gastroenterol Hepatol
 
2007
;
5
:
451
456
.
109
Mendelowitz
PC
Hoffman
RS
Weber
S
.
Bismuth absorption and myoclonic encephalopathy during bismuth subsalicylate therapy
.
Ann Intern Med
 
1990
;
112
:
140
141
.
110
Portnoy
BL
DuPont
HL
Pruitt
D
Abdo
JA
,et al.
Antidiarrheal agents in the treatment of acute diarrhea in children
.
JAMA
 
1976
;
236
:
844
846
.
111
Reves
R
Bass
P
DuPont
HL
Sullivan
P
,et al.
Failure to demonstrate effectiveness of an anticholinergic drug in the symptomatic treatment of acute travelers’ diarrhea
.
J Clin Gastroenterol
 
1983
;
5
:
223
227
.
112
Ahmad
SR
.
Lomotil overdose
.
Pediatrics
 
1992
;
89
(
5 Pt 1
):
980
981
.

Author notes

Guest Editor:Heikki Peltola