Empirical Antimicrobials for Traveler's Diarrhea
- Charles D. Ericsson, Section Editor and
- Robert Steffen, Section Editor
- 1 Division of Infectious Diseases, Department of Internal Medicine, University of Texas-Houston Medical School, Houston, Texas
- 2 St. Luke's Episcopal Hospital and Baylor College of Medicine, Houston, Texas
- Reprints or correspondence: Dr. Charles D. Ericsson, Clinical Infectious Diseases, University of Texas-Houston Medical School, 6431 Fannin St., 1.722 JFB, Houston, TX 77030 (Charles.D.Ericsson{at}uth.tmc.edu).
Abstract
Over 7 million cases of traveler's diarrhea, defined as the passage of ⩾3 unformed stools in a 24-h period, occur each year among visitors to developing countries. Bacterial enteric pathogens are the most common etiologic agents isolated. Preliminary clinical results for patients with diarrhea predominately caused by Campylobacter species have shown that azithromycin may be an effective alternative to fluoroquinolones for the treatment of traveler's diarrhea.
Traveler's diarrhea is the most common travel-related medical problem in terms of prevalence and economic impact. Traveler's diarrhea affects 20%-50% of the 35 million travelers from industrialized to developing countries every year, resulting in >7 million cases among travelers [1–3]. Point of origin, destination, host factors, and exposure to contaminated food and water are the main risk factors [1, 2]. It usually develops during the first week after arrival into a high-risk region, but it may also appear at any time during and even after short-term trips. It may occur more than once during the same trip.
For study purposes, the most commonly accepted definition of traveler's diarrhea is the passage of ⩾3 unformed stools in a 24-hour period. In addition, a criterion included in many definitions is the presence of ⩾1 symptom of enteric disease, such as nausea, vomiting, abdominal cramps, fever, fecal urgency, tenesmus, or the passage of bloody, mucoid stools [1–3]. How to counsel patients about when to begin antimicrobial therapy on the basis of study definitions is problematic.
Historical Perspective
The relationship between traveler's diarrhea and nonconventional enteric pathogens was first studied in the 1950s and 1960s by B. H. Kean [4]. Gorbach, Kean, and colleagues were the first to identify enterotoxigenic Escherichia coli as the most important bacterial etiologic agent of traveler's diarrhea in Mexico [5]. Since then, more studies have identified several other infectious pathogens, including bacteria, parasites, and viruses [2, 6, 7].
As soon as there was evidence of an infectious etiology for traveler's diarrhea, several antimicrobial agents were studied. After Kean's sentinel studies, drugs evaluated included ampicillin [8], furazolidone [8], tetracycline [9], and sulfa drugs [10], especially for the treatment of dysentery [11]. Key studies demonstrated their efficacy for the treatment of the syndrome, and they were rapidly popularized, but temporal success was limited because of increasing resistance. Other antibiotics (trimethoprim alone, bicozamycin, and aztreonam) showed good results in clinical trials but never achieved wide use because of marketing decisions and the development of other antimicrobial options [10, 12, 13].
Another significant improvement in the treatment of traveler's diarrhea has been the reduction in the number of days that antimicrobial therapy is used, decreasing from as many as 10 days in initial studies to a single dose [2, 8, 10, 11, 14]. The use of currently recommended antimicrobial agents is supported by findings in controlled clinical trials and knowledge of epidemiology/resistance patterns and safety profiles.
Rationale for Empirical Antimicrobial Therapy
Infectious agents are the primary cause of traveler's diarrhea, and among them, bacterial enteric pathogens are the most common etiologic agents isolated (∼80% of those cases with an identified pathogen). Etiologic agents are remarkably similar in different areas of the world, although their frequency varies somewhat by region. The main reason for using an antimicrobial agent for treatment of traveler's diarrhea is that antimicrobial agents active against these bacterial enteropathogens have shown to be effective in the earlier relief of traveler's diarrhea [1, 2, 14]. Such therapy minimizes the severity and duration of passage of unformed stools and the concomitant symptoms of enteric infection [1, 2, 14]. Even in cases in which no pathogen is identified (20%–40%), the average length of illness is shortened with antimicrobial therapy. This observation suggests that a proportion of this subset of illness is caused by bacterial pathogens [2, 6, 15].
General Therapeutic Approach
Travelers might decide to treat illness even though it does not meet the standard definition of diarrhea. Advice about how to begin self-therapy must be practical and should not be driven by study criteria. Travelers should be reminded that changes in diet, stress, menstruation, and excessive alcohol consumption might cause relatively benign changes in stool consistency or frequency. Although these episodes are occasionally bothersome, most patients and experts would not count these episodes as traveler's diarrhea and certainly would not consider antimicrobial treatment.
Classically, the primary objective of therapy for diarrhea has been prevention and treatment of dehydration. Fortunately, most patients can prevent dehydration by replacing their losses with readily available fluids. Contrary to dogma, fluid and electrolyte replacement is not a high priority for most adults with traveler's diarrhea, especially if they are treated with the antisecretory/antimotility agent loperamide [16].
We believe that, in addition to preventing dehydration, important objectives of successful antimicrobial treatment of traveler's diarrhea include reducing the symptoms and duration of diarrheal illness (and the inconveniences they present) and preventing the cancellation of planned activities. Such goals are best accomplished by empirical self-therapy with a combination of an antimicrobial and loperamide [2, 17]. Figure 1 outlines our approach for the treatment of traveler's diarrhea. Empirical self-therapy, regardless of the cause of diarrhea, has emerged as a valid approach to treatment of traveler's diarrhea.
Figure 1
General approach to therapy for traveler's diarrhea (a, travelers on critical trips might consider earlier addition of a single dose of a fluoroquinolone; b, reassess symptoms after 24 h and discontinue use of antimicrobials if diarrhea has stopped; c, avoid intentional use of antimotility agents, unless a critical trip or activity is planned, and administer a fluoroquinolone for 1–3 days).
Choice of a specific antimicrobial agent has been determined, in part, by a growing understanding of the many causes of traveler's diarrhea and regional antimicrobial resistance of some of the enteropathogens [1, 2]. Since 40% of travelers developing diarrhea will have mild, self-limiting disease that ceases within 1 or 2 days, we suggest withholding antibiotics unless ⩾2 loose stools are passed or the associated symptoms are severe (abdominal cramps and pain as well as systemic toxicity) [1, 2, 14]. Some disease begins so explosively that therapy should logically be begun before passage of a third loose stool. In addition, some travelers on short, critical trips may elect to treat themselves at the first symptom of disease.
The conditions of a small number of travelers with diarrhea secondary to viruses (10%–12% of traveler's diarrhea cases with an identified etiologic agent) or parasites (2%–4%) [1, 2] will not improve with recommended empirical antimicrobial therapy. They might also develop persistent diarrhea that lasts for >14 days, which is reported to occur in ∼3% of travelers with acute diarrhea [18]. We recommend that travelers seek competent medical assistance for the diagnosis and treatment of diarrheal illness that lasts longer than a few days despite treatment.
Antimicrobial Agents
Although multiple antimicrobial agents have been used to treat traveler's diarrhea, only a couple of well-studied antimicrobials retain enough activity against common enteric pathogens to be predictably useful. Fluoroquinolones and, to a lesser extent, trimethoprim-sulfamethoxazole (TMP-SMZ), among well-studied and marketed antimicrobial drugs, can still be recommended for treatment of traveler's diarrhea. Their recommended dosages are shown in table 1.
Table 1
Antimicrobial agents for self-treatment of traveler's diarrhea.
TMP-SMZ. For years, the treatment agent of choice for traveler's diarrhea was TMP-SMZ [11, 19, 20]. TMP-SMZ is much less expensive than fluoroquinolones, and its use is not contraindicated for children, who should take it in combination with erythromycin for coverage of possible Campylobacter infection. Use of TMP-SMZ has been limited in recent years because of increasing resistance worldwide [21–22–23].
Fluoroquinolones. Since the first clinical study that showed that ciprofloxacin was effective for the treatment of traveler's diarrhea [24], fluoroquinolones have become the drugs of choice in empirical therapy for moderate to severe traveler's diarrhea in adults [1, 2, 14]. Multiple studies have demonstrated that fluoroquinolones decrease the duration of diarrhea from 3–4 days to a little more than 1 day, with associated diminishment of clinical symptoms [17, 24–28]. These studies have also helped to define the commonly recommended duration of 3 days of treatment with fluoroquinolones; however, we have now shown that the use of a single large dose of an antibiotic results in an equivalent outcome [17, 19, 20]. Our team has considered all fluoroquinolones as equivalently active in the treatment of traveler's diarrhea.
All fluoroquinolones (norfloxacin, ciprofloxacin, fleroxacin, pefloxacin, ofloxacin, and levofloxacin) have excellent oral absorption. Drug interactions are uncommon and side effects are minimal. Occasional rashes, photosensitivity, and gastrointestinal complaints are the most important concerns for travelers [29]. To date, fluoroquinolones maintain excellent in vitro activity against most bacterial pathogens associated with traveler's diarrhea, although the rising incidence of resistance and in vivo emergence of resistance of Campylobacter jejuni to fluoroquinolones are disquieting [23, 30].
The current recommendations against their use in therapy for pregnant women and children and their relative expense are limitations of fluoroquinolones, but only pregnancy is a strong contraindication. Usually cost is not a relevant issue for most affluent travelers. Even young adult travelers on a tight budget should be able to afford a single dose of fluoroquinolone. Although fluoroquinolones are still not approved for use in therapy for children, a recent review of their prolonged use in children with cystic fibrosis and of their use in randomized controlled trials in cases of shigellosis supports the safety of their use in short courses, especially for the treatment of children with severe traveler's diarrhea [31].
Another obstacle to consider with regard to children is the current lack of commercial liquid preparations of fluoroquinolones. Currently, antimicrobial drugs for treatment of traveler's diarrhea in children include TMP-SMZ (with erythromycin if Campylobacter infection is a possibility) and furazolidone. Another consideration could be nalidixic acid, which has been used widely to treat children with diarrhea in developing countries, but according to the US Federal Drug Administration, it can be recommended for use only when the benefits outweigh the risks.
Combination with Symptomatic Agents
Although mild forms of traveler's diarrhea can be treated satisfactorily with a symptomatic agent alone, more severe disease is better treated with an antibiotic, and a combination of loperamide with an antimicrobial agent produces even faster and more complete results. Only loperamide has been fully studied and shown to be effective in combination with different antimicrobial drugs.
The combination of an antibiotic and loperamide has been studied, with each agent being administered at the usual dosage. In one study, more than half of the subjects passed no further unformed stools once combination therapy was begun [19]. The average duration of diarrhea was only a few hours, even when subjects had blood in stools at enrollment. This result was superior to treatment with either agent alone and was confirmed in subsequent studies [17, 20], including one that showed that ciprofloxacin plus loperamide treats shigella dysentery more effectively than ciprofloxacin alone [26]. Recently, a single dose of a fluoroquinolone in combination with loperamide has also been shown to be highly effective [17].
Some researchers have not verified such remarkable results with the combination of an antimicrobial and loperamide, either when the untreated control group had relatively mild disease or when Campylobacter species was the prevalent isolate [28, 32]. Most of the evidence supports the use of this combination therapy [17, 19, 20, 33]. Despite the apparent safety of loperamide for treatment of shigellosis, we prefer to avoid the intentional use of this drug in that small proportion of cases of traveler's diarrhea that present with severe diarrhea or evidence of dysentery. For these patients, we generally recommend an antimicrobial alone, although if the patient has poor access to toilets or has critical planned activities [1, 2, 14], the addition of loperamide to an antibiotic is a reasonably safe approach.
Another drug with some antimicrobial properties is bismuth subsalicylate. Bismuth subsalicylate is less efficacious than TMP-SMZ and fluoroquinolones. Furthermore, the concurrent administration of bismuth subsalicylate and a fluoroquinolone should be avoided, because of the known chelation of fluoroquinolones by bivalent cations [34].
Newer Antimicrobial Agents and Future Directions
The driving force behind the development of new antimicrobial agents is the emergence of resistance among bacterial enteric pathogens against the various antimicrobials used to treat traveler's diarrhea. During the past few years, resistance to fluoroquinolones has been reported from Thailand and Southeast Asia [23, 30]. The same pattern of resistance has begun to be seen in other areas of the world (H. L. DuPont, unpublished data).
Rifaximin and azithromycin are 2 newer antimicrobials that have shown promising results. Rifaximin is a poorly absorbed rifamycin derivative that we have demonstrated to be safe and effective in comparison with TMP-SMZ [35] or ciprofloxacin (H. L. DuPont, personal communication) in the treatment of traveler's diarrhea. No strains resistant to rifaximin have been reported to date (H. L. DuPont, unpublished data).
Although azithromycin, an azalide, needs to be studied further, its in vitro activity and preliminary clinical results in therapy for patients with diarrhea predominantly caused by Campylobacter species have shown that azithromycin might be an effective alternative to fluoroquinolones in the treatment of traveler's diarrhea [30]. A possible advantage of azithromycin would be its potential for safe use in therapy for children and pregnant woman.
Future research into the management of traveler's diarrhea should include studies of active and passive immunization, symptomatic medications, combination therapy with agents other than loperamide, single-dose antimicrobial therapy, and alternative medications based on natural substances. Since development of resistance is a likely consequence of the frequent use of an antimicrobial agent for the treatment of traveler's diarrhea, the search for novel agents active against enteric pathogens should continue.
- Received June 19, 2000.
- © 2000 by the Infectious Diseases Society of America
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