Azithromycin for Travelers' Diarrhea in Thailand

Abstract & Commentary

By Barbara E. U. Burkhardt, MD, and Philip R. Fischer, MD, DTM&H

Dr. Burkhardt is a resident in the Department of Pediatric and Adolescent Medicine at the Mayo Clinic in Rochester, MN. Dr. Fischer is a Professor of Pediatrics, Division of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Dr. Fischer and Dr. Burkhardt report no financial relationship relevant to this field of study.

Synopsis: In Thailand, where Campylobacter is frequently a cause of traveler's diarrhea, a single dose of 1000 mg of azithromycin is more effective than 3 daily 500 mg doses or 3 days of levofloxacin both in resolving symptoms of travelers' diarrhea and in clearing infection.

Source: Tribble DR, et al.: Travelers' Diarrhea in Thailand: Randomized, Double-Blind Trial Comparing Single-Dose and 3-Day Azithromycin-Based Regimens with a 3-Day Levofloxacin Regimen. Clinical Infectious Diseases. 2007;44:338-346.

Travelers' Diarrhea in Thailand is increasingly associated with fluoroquinolone-resistant Campylobacter jejuni. This led Tribble and colleagues to study azithromycin as an alternative first-line antibiotic for acute diarrhea.

In a double-blind, placebo-controlled trial conducted in 2000 and 2001, 156 adult military personnel were randomized to receive either single-dose oral azithromycin (1 gram), a 3-day course of azithromycin (500 milligrams daily), or 3 days of levofloxacin (500 milligrams daily). Patients were followed with symptom report cards and repeated clinic visits at 24 hours and 72 hours after initiation of treatment.

Resolution of symptoms at 72 hours occurred in 96% of subjects receiving a single-dose azithromycin regimen as compared to 85% of patients in the 3-day azithromycin group and 70% of those on 3 days of levofloxacin (P = 0.002). The mean times to the last unformed stool were 39 vs 43 vs 56 hours, respectively. While not correlated with clinical cure at 72 hours, microbiological eradication of an isolated organism was observed more frequently with azithromycin (100%) than with levofloxacin (21%; P < 0.001).

Commentary

Travelers' diarrhea affects an estimated 15 million or more travelers to developing countries every year. Stand-by medications are frequently prescribed for travelers who will not have immediate access to medical care at their destination. Due to increasing microbial resistance against antibiotics worldwide, and especially in some specific parts of the world, it has become difficult to choose an appropriate oral antibiotic for visitors to areas such as Thailand.

The patients studied by Tribble and colleagues were all generally healthy adult military personnel. Therefore, the application of these findings beyond this defined population (eg, to persons with preexisting health problems, elderly travelers, or children) is difficult. Moreover, the majority of the study subjects were using doxycycline for antimalarial prophylaxis. This practice could contribute to the development of resistance among intestinal organisms and might also have caused a relative predominance of Campylobacter (as compared to toxigenic Escherichia coli) in study subjects. Most pathogenic isolates identified in subjects with diarrhea were Campylobacter (all susceptible to azithromycin), and less frequently Salmonella, but with a higher rate of resistance to azithromycin than against fluoroquinolones. However, most cases of travelers' diarrhea worldwide are caused by E. coli, and susceptibilities of E. coli strains should be the primary basis for choosing an antibiotic for presumptive treatment. For all of these reasons, the findings of the study should not be overly generalized.

The American Academy of Pediatrics issued a policy statement in September of 2006 addressing safety and possible uses of fluoroquinolones in children. Due to the potential for musculoskeletal side effects, fluoroquinolones should be avoided unless multidrug resistant bacteria need to be treated orally. Gastrointestinal infections caused by multidrug resistant Shigella species, Salmonella species, Vibrio cholerae, or Campylobacter jejuni may fall under this category.1 As an empirical treatment for travelers' diarrhea in children, however, the use of fluoroquinolones would not be recommended. The same considerations apply during pregnancy. Azithromycin, on the other hand, is considered safe for infants and children of any age and is listed as a class B drug during pregnancy.

The worldwide prevalence of fluoroquinolone resistant human pathogenic bacteria is increasing. Campylobacter and Salmonella species resistant to fluoroquinolones were isolated in the UK as early as the 1990s,2,3 and resistance to quinolones among Salmonella enterica isolates in Spain steadily increased between 1991 and 2003.4,5 In Europe, Latin America, and North America, fluoroquinolone resistant Campylobacter species were rarely found in a 2003 study.6,7 Fluoroquinolone resistance affects a significant proportion of E. coli among hospital patients in Indonesia.8 Fluoroquinolone resistant, as well as multidrug resistant, Shigella strains were highly and increasingly prevalent between 2001 and 2003 in India9 and have also been spreading in Japan since 2000.10 Thailand has an especially high prevalence of reduced fluoroquinolone susceptibility in Salmonella strains.5 Likewise, Campylobacter in Thailand is mostly resistant to fluoroquinolones.11 While up to 15% of enterotoxigenic E. coli in Thailand may be resistant to azithromycin, azithromycin-resistance is less prevalent than is resistance to other antibiotics.12

On a large scale, this resistance of enteric pathogens has been attributed to the use of fluoroquinolones in animal food as well as inappropriate prescribing practices for human disease,3,11 but antimicrobial resistance of enteric pathogens may also be acquired during the acute illness, as shown by Tribble. Interestingly, the presence of antimicrobial resistance is not limited to individuals with prior use of antibiotics.13

Acute bacterial or viral gastroenteritis is usually self-limited, requiring only fluid and electrolyte replacement therapy.11 Travelers are often, however, provided with a prescription for an antibiotic for use in the event of bothersome travelers' diarrhea. The choice of a particular agent to offer to travelers to take along depends on several factors, including local prevalence of pathogens and their resistance patterns, and the person's age and health status. A growing body of evidence suggests that azithromycin is a reasonable first line choice when presumptive treatment of travelers' diarrhea is deemed appropriate14 - for travelers to Thailand, for children and pregnant women and, likely, for all travelers. A single large dose seems more effective than standard daily doses for 3 days.

Prevention of travelers' diarrhea remains most important, and although not a guarantee for successful avoidance of an enteric infection, water and food hygiene measures should be taught at each pre-travel clinic visit. Immunizations such as rotavirus vaccine for young infants or typhoid vaccine should be used where applicable.

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