E D I T O R I A L C O M M E N TA R Y

Azithromycin for the Self-Treatment of Traveler’s Diarrhea Herbert L. DuPont The University of Texas–Houston School of Public Health and Medical School, St. Luke’s Episcopal Hospital and Baylor College of Medicine, Houston, Texas

(See the article by Tribble et al. on pages 338–46)

In this issue of Clinical Infectious Diseases, Tribble et al. [1] present data on the occurrence of traveler’s diarrhea among US military personnel stationed in Thailand, where the principal pathogen was fluoroquinolone-resistant Campylobacter species, and they provide evidence of the utility of single-dose azithromycin as therapy for the illness. After 156 adult military personnel were randomized to receive a single (1-g) dose of azithromycin or a 3-day regimen of either azithromycin or levofloxacin (both given in a 500 mg dose once daily), the mean duration of diarrhea after treatment initiation (i.e., the time to passage of the last unformed stool [TLUS]) was 39 h for subjects receiving single-dose azithromycin, compared with 43 h for subjects receiving a 3-day regimen of azithromycin and 56 h for those receiving a 3-day regimen of levofloxacin. The rate of microbiological eradication was significantly higher with the use of azithromycin-based regimens, although, as has been previously shown, microbiological cure did not correlate with the clinical response to therapy [2]. The highest rate of nausea during the 30 min after treatment initiation occurred in the group receiving Received 17 October 2006; accepted 19 October 2006; electronically published 28 December 2006. Reprints or correspondence: Dr. Herbert L. DuPont, 6720 Bertner Ave., MC 1-164, Houston, TX 77030 (hdupont @sleh.com). Clinical Infectious Diseases 2007; 44:347–9  2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4403-0006$15.00

single-dose azithromycin. The authors’ conclusion was that single-dose azithromycin is recommended as empirical therapy for traveler’s diarrhea in Thailand, in view of the importance of resistant Campylobacter species, and they suggested that azithromycin is a reasonable first-line option for empirical management for visitors to other areas where the risk for diarrhea is high. This is the second study of US military personnel in Thailand in the past decade showing the importance of ciprofloxacinresistant Campylobacter species and the potential value of azithromycin for treatment [3]. We lack studies of the epidemiology of travelers’ diarrhea in nonmilitary populations in Thailand. The present incidence of diarrhea among international visitors to Thailand is unknown. One recent preliminary study suggested that the rate of traveler’s diarrhea among persons from Europe and the United States visiting Phuket and Chiang Mai, Thailand, was in the range of 5%– 6%, making the risk in this region low to moderate [4]. On the basis of the 2 published studies of US military personnel in Thailand, the influence of daily doxycycline used routinely for malaria chemoprophylaxis in this population while in Thailand has not been determined with regard to the rates of occurrence or microbiological profile of traveler’s diarrhea. Doxycycline could promote enteric infection with more-resistant enteric bacteria and/or could prevent enteric infection

with the more susceptible diarrheogenic Escherichia coli, by inhibiting the organisms [5] or by altering their virulence properties [6]. Rates of traveler’s diarrhea remain high during travel to high-risk tropical and semitropical regions, despite pretravel advice. Self-treatment of illness remains the mainstay of disease management [7]. In one study of travelers with diarrhea acquired during international travel, 82% reported experiencing improvement in their illness as a result of self-treatment [8]. This study underscored both the importance of self-treatment of illness and the impossibility of identifying one drug that is active against all agents that might cause diarrhea during international travel. A potential key to the recommendation of a specific drug for self-treatment of traveler’s diarrhea is knowledge of the expected occurrence of pathogens in the geographic area to be visited. In most parts of Latin America and Africa, diarrheogenic E. coli, including enterotoxigenic E. coli and enteroaggregative E. coli, are the major pathogens encountered [9–11]. In Asia, invasive pathogens (Shigella, Salmonella, and Campylobacter species) appear to be more common as causes of traveler’s diarrhea than is the case for travel to other regions of the world [1, 3, 10, 12, 13]. Throughout the world, Campylobacter isolates are showing an increased rate of resistance to ciprofloxacin [14–16], with very high rates noted in Thailand. In Thailand, the rate of ciprofloxacin resistance

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among Campylobacter isolates increased from 0% before 1991 to 84% in 1995 [14]. Although the scenario is not common, we are seeing travelers with diarrhea acquired in Mexico and South America who fail to respond to ciprofloxacin but who have a resistant Campylobacter isolate recovered from stool, suggesting that this problem is not confined to Asia. Considering the drugs available and the occurrence of bacterial enteropathogens showing differences in susceptibility, we have a dilemma in making general recommendations for all travelers as we arm them with antibacterial drugs for selftreatment of diarrhea during travel to high-risk areas. Rifaximin is as effective as the absorbed drugs for treatment of the most common form of watery diarrhea due to noninvasive pathogens [17, 18]. Absorbed fluoroquinolones and azithromycin are preferred for the less commonly occurring cases of inflammatory diarrhea due to invasive bacterial pathogens. One study suggested that, for treatment of diarrhea due to susceptible noninvasive pathogens, a fluoroquinolone may be more rapidly effective (TLUS, 0 h) than azithromycin [19]. Of potential importance, fluoroquinolones show different activity against Campylobacter strains. In 2 studies, levofloxacin was 1–2-fold more active against C. jejuni strains than was ciprofloxacin [20, 21], and in one of the studies, moxifloxacin was the most active of the available fluoroquinolones [21]. Azithromycin shows a high degree of activity against diarrhea due to enterotoxigenic E. coli, enteroaggregative E. coli [19], multiresistant Shigella [22] species, and ciprofloxacin-resistant Campylobacter species [1, 3]. Certainly, azithromycin is the drug with the broadest activity against the bacterial pathogens causing traveler’s diarrhea. Also, this azalide drug has favorable pharmacokinetics for single-dose therapy, showing an 11–14-h half-life, with nearly 50% of active drug excreted in feces and resulting in high levels in the gut lumenal [23]. Azithromycin concentrates in tissues, including human neutro-

phils and other cells, and is biologically active in the presence of neutrophils [24]. Azithromycin appears to be the drug of choice for treatment of febrile dysentery in the international traveler, for whom the expected cause of illness is Campylobacter or Shigella species. It is difficult to justify the routine inclusion of azithromycin in the travel medicine kit for each of the 50 million annual travelers to tropical and semitropical regions where the risk for diarrhea is high and where most cases of traveler’s diarrhea consist of nonfebrile watery diarrhea. Also, there is concern about the potential for stimulating resistance among extraintestinal endogenous flora, including Streptococcus pneumoniae, during drug administration, limiting future value of the drug for treatment of systemic infection. An important issue for many international travelers is the relative cost of the various self-treatment options. For this editorial, the drug costs of the various treatment options for potential travelers were reviewed at 2 busy retail pharmacies in Houston, Texas. The first pharmacy was an independent, hospital-based outpatient pharmacy, and the second was a national chain. The cost of the recommended regimens for treatment of traveler’s diarrhea at the 2 pharmacies, respectively, were as follows: for azithromycin (1-g single dose), $34.25 and $42.69; for ciprofloxacin (500 mg twice daily for 3 days), $16.25 and $43.49; for levofloxacin (500 mg once daily for 3 days), $44.69 and $40.55; and for rifaximin (200 mg given 3 times daily for 3 days), $47.95 and $43.79. The costs of the various regimens were remarkably similar, with important variation in the price of ciprofloxacin noted. The agents to routinely employ as we arm travelers with a single drug for selftreatment of resultant traveler’s diarrhea include well-tolerated and nonabsorbed (!0.4%) rifaximin, although it should be realized that the less commonly encountered invasive bacterial pathogens will not be covered, or one of the absorbed drugs with potential for inducing resis-

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tance in extraintestinal flora. The absorbed drugs include levofloxacin or ciprofloxacin, which will not be effective against antimicrobial-resistant strains (including fluoroquinolone-resistant Campylobacter species), and azithromycin, which appears to provide the maximum coverage. Another potential use of azithromycin in international travelers to regions where the risk for diarrhea is high is to preferentially employ it with breakthroughs during rifaximin chemoprophylaxis. For a subgroup of persons on a tight schedule; for those in whom illness has occurred in the past, thereby suggesting an increased susceptibility to the illness [25]; for those with underlying illness that makes them more susceptible to diarrhea or to complications of illness (e.g., insulin-dependent diabetes, cancer, and AIDS); and for those who request it, rifaximin chemoprophylaxis may be given to prevent illness during travel to areas where the risk for diarrhea is high [26, 27]. Rifaximin is effective in preventing diarrhea due to diarrheogenic E. coli [26] and, probably, invasive diarrhea due to Shigella species [28]. For many persons who elect to take rifaximin chemoprophylaxis, azithromycin could be added to their travel medicine kit as standby therapy for diarrhea for patients with breakthrough illness. For these persons, if illness does not develop during a trip, the azithromycin can be saved for future trips occurring within the shelf life of the drug. It is not known whether self-treatment with azithromycin for traveler’s diarrhea will be effective in preventing chronic postinfectious irritable bowel syndrome, which occurs in up to 10% of persons with bacterial diarrhea, including persons with traveler’s diarrhea [29, 30]. Although our studies evaluating travelers to Mexico suggest that a variety of treatments for fully established traveler’s diarrhea (defined as passage of ⭓3 unformed stools plus an enteric symptom) do not prevent the complication, we do not know whether early treatment or initiation of antimicrobial therapy with passage of the first un-

formed stool could possibly reduce the occurrence of this chronic complication. Future study should look for this potential with the available antibacterial drugs, including azithromycin. Acknowledgment Potential conflicts of interest. H.L.D. has received speakers’ honoraria and recent research grants, through his university, from Salix Pharmaceutical, as well as past research funding from Pfizer.

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