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DIPHENOXYLATE, LOPERAMIDE AND BISMUTH SUBSALICYLATE ARE FIRST LINE DRUG TREATMENT FOR MILD TRAVELERS' DIARRHEA, NIH CONFERENCE FINDS; FLUIDS FIRST

Executive Summary

First line drug treatment for Travelers' Diarrhea is diphenoxylate or loperamide, according to an NIH Consensus Conference statement from a Jan. 28-30 meeting in Bethesda, Md. "If rapid relief of symptoms is desired after one or three unformed stools accompanied by cramps, nausea or malaise, diphenoxylate or loperamide may be taken," the consensus statement says under its recommendations for treatment. Bismuth subsalicylate (1 oz. every 30 minutes for eight doses) is a first line "alternative" treatment, according to the NIH conference. "Although this regimen decreases the number of stools and increases their consistency, it does not improve symptoms during the first 4 hours of treatment." Prior to drug treatment, the conference panel recommended, consumption of fluids should be tried as a treatment. The panel determined that Travelers' Diarrhea (TD) "is usually a mild, self-limited disorder, with complete recovery in the absence of therapy; hence, therapy should be considered optional." For moderate to severe cases of TD, the panel suggested that the antimicrobial agents trimethoprim/sufamethoxazole (TMP/SMX), doxycycline or TMP alon may be used after "three or more loose stools with symptoms." TMP/SMX (160 mg TMP and 800 mg SMX), doxycycline (100 mg) or TMP (200 mg) should be taken twice daily with a 3-5 day treatment period recommended. The panel noted that antimicrobial treatment can potentially shorten a 3-5 day illness to one or 1-1/2 days. The panel, headed by Dr. Sherwood L. Gorbach, Tufts University School of Medicine, recommended that travelers who suffer persisting diarrhea with fever and blood or mucus in their stool should seek medical attention. Consensus Panel Does Not Recommend Drug Use For Prevention Of Travelers' Diarrhea Several agents proposed to control TD symptoms -- diarrhea and abdominal cramps -- have not been proven effective by rigorous clinical trials, the statement indicated. These include adsorbants such as activated charcoal and starches kaolin and pectin. Kaolin and pectin appear to give the stools "more consistency but have not been shown to decrease cramps and frequency of stools nor to shorten the course of infectious diarrhea." "Travelers to areas of high risk," the NIH panel suggested, "should obtain an antimotility drug or bismuth subsalicylate for milder forms of TD, and an antimicrobial agent (TAMP/SMX, doxycycline, or TMP alone) for more severe TD." The panel noted: "By obtaining the proper drugs in advance, the beleaguered traveler might avoid buying over-the-counter drugs abroad with potentially dangerous ingredients." While recommended for therapeutic uses, bismuth subsalicylate, antimotility agents, and antimicrobial agents were not recommended for prophylactic or preventive use by the panel. Bismuth subsalicylate taken in liquid form (2 oz. four times daily) or in tablet form (0.6 g four times daily) has been shown to decrease the incidence of diarrhea by 60-77% in two studies, the group acknowledged. Nevertheless, it was felt that neurological side effects might result from the large doses of bismuth and that tinnitus could result from the salicylate. "Carefully controlled studies have indicated that two agents, doxycycline and TMP/SMX, when taken prophylactically, are consistently effective in reducing the incidence of TD by 50% to 86% in various areas of the developing world," the panel noted. Side effects that are known to occur with antimicrobial therapy, weighed against a relatively nonthreatening disease that has not produced a known fatality, led the panel to conclude that prophylactic use of the antimicrobial agents should not be recommended. The panel also found "no sound basis for recommending use of antimicrobial agents prophylactically for special groups of travelers," such as diplomats or businessmen. Skin rashes, skin photosensitivity, blood disorders, and Stevens-Johnson Syndrome were identified by the panel as risks associated with antimicrobial usage. The case for prophylactic use of bismuth subsalicylate was presented by Robert Steffen, MD, of the University of Zurich, who stated that "within the scope of nonantibiotic prophylaxis of TD, only one agent, bismuth subsalicylate, appears effective, lacking serious adverse reactions and documented enough to be considered by the panel." Lactobacillus prophylaxis was tested on three occasions between 1978-81 as a possible modifier of intestinal flora, however, no preventive effect was demonstrated, Dr. Steffens explained in a pre-conference abstract. The panel found that "the active agents and mode of action of bismuth subsalicylate remain to be elucidated, and the tablet form of the drug requires further evaluation." Data presented by Robert DuPont, MD, of the University of Texas, showed that TMP/SMX and TMP by itself were effective in reducing the incidence of TD by up to 86% in two studies of U.S. students traveling to Mexico. Approximately 5% of those taking TMP/SMX developed skin rash. DuPont indicated that two groups of travelers should take prophylactic drugs during brief periods of time: persons on "critical," short-term business trips and individuals who are "more susceptible to diarrhea and its potential complications." Entero-Vioform and related halogenated hydroxyquinoline derivatives, the panel concluded, are not helpful in preventing TD any may have serious neurological side effects. These antimicrobial drugs "should never be used for prophylaxis of TD." The report defines travelers' diarrhea as a mild, self-limited infectious disease caused by the ingestion of fecally contaminated food or water. Escherichia coli, a common species of enteric bacteria are the leading pathogen, although "a host of other bacteria, viruses and protoxoa have been implicated in some cases." the disease affects approximately one-third of travelers from industrialized nations to developing countries, which this year is expected to total about 16 mil. While the panel agreed that dietary and hygenic precautions are the only safe and simple preventive measures for TD, the disease still occurs in many travelers despite their close attention to such practices. "Available data support only the instruction of travelers in regard to sensible dietary practices as a prophylactic measure," the report states. "They will prevent some, but not all, diarrhea." In addressing immunization as a potential prophylactic measure, the panel concluded that "no available vaccines and none that are expected to be available in the next five years are effective against TD." It did, however, recommend that newer approaches to vaccine development be applied to the microorganisms that are known to cause the disease. Regarding further research, the panel suggested work to develop "a better understanding of the neurohumoral control of intestinal secretion and its potential interaction with microbial exterotoxin" as an aid in designing "more rational therapeutic strategies for TD." The panel added: "Further study of antisecretory and absorption-enhancing agents may improve pharmacologic therapy and enhance the efficacy and acceptability of oral replacement solutions. Improved understanding of the components of motility that will enhance but not impede absorption may help in the design of rational antimotility therapy."

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