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

Loperamide for the Treatment of Travelers Diarrhea: Broad or Narrow Usefulness?

Thomas Butler
Department of Microbiology and Immunology, Ross University School of Medicine, North Brunswick, New Jersey

(See the article by Riddle et al. on pages 100714)

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The meta-analysis by Riddle et al. in this issue of Clinical Infectious Diseases [1] focuses on the antidiarrheal drug loperamide hydrochloride and its efcacy when combined with antimicrobials to shorten illness in adults with travelers diarrhea. Loperamide is a piperadine derivative that slows intestinal motility because of its activation of m-opiate receptors. By decreasing peristalsis and increasing anal sphincter tone, it increases intestinal transit time, thus retaining luminal contents and giving more time for reabsorption of secreted uid. The drug has a less prominent effect through inhibition of intestinal secretion by its action on G1-linked receptors to counter increases in cyclic adenosine monophosphate caused by bacterial enterotoxins. It is available over the counter as a diarrheal remedy and has been recommended for travelers diarrhea for 125 years [2]. A newer form of the drug, loperamide oxide, was tested in Germany and was shown to be more effective than placebo against diarrhea [3]. Its advantage, as a prodrug that is changed to loperamide
Received 2 July 2008; accepted 2 July 2008; electronically published 9 September 2008. Reprints or correspondence: Dr. Thomas Butler, Ross University, 630 US Hwy. 1, North Brunswick, NJ 08902 (tomxanadu@gmail.com). Clinical Infectious Diseases 2008; 47:10156 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4708-0005$15.00 DOI: 10.1086/591704

by anaerobic bacteria in the intestine, is to give more-prolonged and higher drug concentrations in the intestinal lumen, with less absorption into the blood, potentially causing fewer systemic adverse effects, such as CNS depression, than when loperamide hydrochloride is administered. Clinical studies in the meta-analysis enrolled young US students or military personnel in prospective randomized trials in Mexico, Thailand, and Egypt. The most common microbial cause of diarrhea identied in study participants were enterotoxigenic Escherichia coli, followed by Shigella species, Campylobacter species, Salmonella species, enteroaggregative E. coli, Giardia lamblia, Entamoeba histolytica, and Cryptosporidium species. Pathogenesis of travelers diarrhea occurs at the epithelial cell surface of the intestine, where enterotoxins cause uid production or invasive pathogens elicit inammation. Neural signals are transmitted from this surface to smooth muscle to increase peristalsis, giving rise to symptoms of cramps and frequent bowel movements. Travelers diarrhea is unique for a high attack rate because of a low level of immunity in travelers against prevalent pathogens in the food and water from the visited countries. Travelers are also a selected population of usually young, healthy adults who develop mild or moderately severe nondehydrating illnesses that do not require hospitalization. They do not die as young children

and malnourished inhabitants of developing countries sometimes do when infected with the same pathogens, and the travelers usually recover in a few days, even when treated with placebo [4]. Although initially not immune against local pathogens, travelers mount effective immune responses that are instrumental in their recoveries from self-limited illness. Absence of signicant dehydration in most cases was demonstrated in a randomized trial of oral rehydration solutions in addition to loperamide, which showed no benet of oral rehydration solutions to hasten recovery from symptomatic illness [5]. Trials in the analysis pertinently compared treatments of loperamide hydrochloride plus an antimicrobial drug with the same antimicrobial drug alone. Most of the analyzed studies reported that loperamide conferred a substantial benet by reducing frequency of loose stools by approximately one-half and by shortening the average duration of diarrhea from 1.5 days to !1 day, with a range of mean reductions of duration of 223 h. How broadly applicable are these results to all diarrheal illness in travelers and other persons? Two studies in the analysis were partly discordant with regard to benecial action: patients with Campylobacter infection in Thailand, where these infections showed uoroquinolone resistance [6], and patients with Shigella infections in

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Mexico [7] showed no benet from loperamide. Antimicrobial drugs without loperamide reduced diarrheal duration by approximately one-half when compared with placebo, as was demonstrated for trimethoprim-sulfamethoxazole in Mexico [4]. When used alone, loperamide reduces the duration of diarrhea and the frequency of bowel movements, compared with placebo [4, 8] but has less effect than in combination with an antimicrobial drug [4, 9]. In countries visited by travelers, children who have not yet acquired immunity to enterotoxigenic E. coli are susceptible to disease, but children !6 years of age are not advised to receive loperamide because of potential overdoses that could cause CNS depression. Patients with bloody diarrhea or high temperatures were excluded from the analyzed studies. It is not known whether loperamide therapy will be effective against diarrhea caused by norovirus, the most common cause of outbreaks of nonbacterial gastroenteritis worldwide [10]. The analyzed studies, nevertheless, were soundly designed as prospective and randomized studies, with most using loperamide placebos in a double-blind manner. An unavoidable fault of the study methods was quantitative imprecision, because the studies used patients self-reported frequency of stools and time since their last unformed stools. These data were subjective, according to different perceptions of what constitutes an unformed stool. Another problem, perhaps related to subjective reporting of symptoms, is heterogeneity of enrolled patients responses to loperamide. In 4 separate studies of students in Mexico, the mean and median

durations of diarrhea after the start of loperamide therapy had a range of 027 h. A conclusion from the analyzed trials is that loperamide should be combined narrowly with an antimicrobial drug for travelers to areas where enterotoxigenic E. coli is anticipated to be the major diarrheal pathogen. Loperamide should not be regarded as a broad empirical x, because it does not benet patients with excessive diarrhea, such as those with cholera, and should not be used to treat bloody dysentery; patients with Shigella or Campylobacter infection may not derive any benet from the drug, but they seem not to be harmed by it. What explains the drugs success? It works especially well in lowvolume secretory diarrhea, probably because a decrease in peristalsis and an increase in anal sphincter tone causes retention of secreted uid, giving more time for intestinal mucosa distal to secretion sites to reabsorb excess luminal uid. Reduced peristalsis also diminishes fecal urgency and frequency of bowel movements. It makes mild or moderately severe diarrhea even milder. A healthy distal colon absorbs water and salt avidly and should be the major site of absorption of additional uid presented to it during secretory diarrhea. Shigella and Campylobacter species cause primarily distal colitis, whereas enterotoxigenic E. coli affects the small intestine; therefore, impaired absorption in the colon may explain refractoriness of infection due to Shigella and Campylobacter when treated with loperamide [11]. Although loperamide should continue to be used by travelers, priority should be placed on selecting an appropriate antimicrobial to be combined with it. This selection will burden practitioners

of travel medicine to be familiar with prevalent microbes in different countries and their antimicrobial susceptibilities.
Acknowledgments
Potential conicts of interest. T.B.: no conicts.

References
1. Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combination with antibiotics on treatment outcomes in travelers diarrhea: a systematic review and meta-analysis. Clin Infect Dis 2008; 47:100714 (in this issue). 2. Gorbach SL. Travelers diarrhea. N Engl J Med 1982; 307:8813. 3. Dettmer A. Loperamide oxide in the treatment of acute diarrhea in adults. Clin Ther 1994; 16:97280. 4. Ericsson CD, DuPont HL, Mathewson JJ, et al. Treatment of travelers diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA 1990; 263:25761. 5. Caeiro JP, DuPont HL, Albrecht H, et al. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of travelers diarrhea. Clin Infect Dis 1999; 28:12869. 6. Petruccelli BP, Murphy GS, Sanchez JL, et al. Treatment of travelers diarrhea with ciprooxacin and loperamide. J Infect Dis 1992; 165:55760. 7. Ericsson CD, DuPont HL, Mathewson JJ. Single dose ooxacin plus loperamide compared with single dose or three days of ooxacin in the treatment of travelers diarrhea. J Travel Med 1997; 4:37. 8. Van Loon FPL, Bennish ML, Speelman, P, et al. Double blind trial of loperamide for treating acute watery diarrhoea in expatriates in Bangladesh. Gut 1989; 30:4925. 9. DuPont HL, Jiang Z-D, Belkind-Gerson J, et al. Treatment of travelers diarrhea: randomized trial comparing rifaximin, rifaximin plus loperamide, and loperamide alone. Clin Gastroenterol Hepatol 2007; 5:4516. 10. Dolin R. Noroviruses: challenges to control. N Engl J Med 2007; 357:10723. 11. Butler T, Speelman P, Kabir I, et al. Colonic dysfunction during shigellosis. J Infect Dis 1986; 154:81724.

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