Loperamide, a synthetic antidiarrheal agent, has not been studied in large numbers of patients with dysentery. Although it does not contain atropine (as does Lomotil), its primary action is to slow intestinal motility. In studies designed to look at nondysenteric diarrhea, loperamide has recently been used, either alone or in combination with antibiotics (cotrimazole or ciprofloxacin), to treat more than 25 adults with Shigella infections [3-7]. Although loperamide did not deliver a definable therapeutic advantage, the drug appeared to be safe in treating patients infected with Shigella. Because loperamide is frequently used in the treatment of diarrhea, which is often due to Shigella, a double-blind, placebo-controlled, randomized clinical trial of loperamide in the treatment of bacillary dysentery (primarily due to Shigella) was done.

Methods

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Study Design

Between 28 November 1990 and 29 February 1992, we studied patients with dysentery at Bamrasnaradura Hospital, Nonthaburi, Thailand. Dysentery was defined as three or more loose stools containing blood or mucus associated with at least one of the following symptoms: abdominal cramps, nausea, vomiting, or temperature greater than 38 °C. Patients entered in the study had symptoms for fewer than 60 hours. Patients were excluded if they had received antimotility drugs or antibiotics in the previous 7 days, were pregnant, were immunosuppressed, or could not be followed for the next 10 days.

Adults admitted to the Bamrasnaradura Hospital who met the study criteria and gave consent were treated with 500 mg of ciprofloxacin (Cipro, Miles Pharmaceuticals, West Haven, Connecticut) twice daily for 3 days. Patients were sequentially assigned a study number and an associated vial containing 16 caplets of loperamide (Imodium, McNeil Consumer Products Company, Fort Washington, Pennsylvania) or identical placebo. Numbered vials were randomized before the beginning of the study using a computer-generated random number table. Nurses, physicians, investigators, and patients were blinded to treatment regimen throughout the study. Patients received 4 mg (two caplets) of loperamide as an initial dose under the observation of a nurse. Patients were instructed to take one caplet after every loose stool (as many as eight caplets per day).

Age, duration of diarrhea in hours, number of previous unformed stools, previous medication, and history of symptoms were recorded. Patients were examined by a physician, and stool specimens were collected at study entry. Patients were interviewed daily for 3 days (or until diarrheal symptoms had resolved) and again 10 days later.

Symptoms, the time of the last unformed stool, and the number of unformed stools occurring during the previous 24 hours were recorded. Stools (or rectal swabs) were collected at the time of each interview.

Laboratory Studies

Stools were examined microscopically for fecal leukocytes and erythrocytes after staining with methylene blue [8] and were cultured promptly on MacConkey and Hektoen agar before and after inoculation in Selenite F broth (Difco, Detroit, Michigan).

Bacterial, viral, and intestinal protozoa were identified as previously described [9, 10]. Up to 10 lactose-fermenting and up to 10 nonlactose-fermenting Escherichia coli, as identified on a MacConkey plate, were saved on Dorset egg yolk media slants. Escherichia coli isolates were tested within 1 month of isolation for heat-labile and heat-stable toxin production in the Y-1 adrenal cell [11] and suckling mouse [12] assays. Escherichia coli isolates were also fixed on Whatman 541 filters (Millipore Corporation, Bedford, Massachusetts) as described by Maas [13] and were tested for genes coding for Shiga-like toxin I and II as well as those with the 17-kilobase EcoRI fragment of pWR100 [14]. Isolates that hybridized with the 17-kilobase EcoRI probe were speciated and tested using the Sereny test [15].

Shigella, enteroinvasive E. coli, and enterotoxigenic E. coli as well as Aeromonas, Plesiomonas, and Vibrio species were tested for susceptibility to ampicillin, chloramphenicol, ciprofloxacin, nalidixic acid, trimethoprim-sulfamethoxazole, and tetracycline by disc diffusion [16] using CM471 agar (Oxoid Ltd., Basingstoke, United Kingdom). Enteroinvasive and enterotoxigenic E. coli were serotyped as described by Orskov and Orskov [17].

Intestinal parasites were identified by direct microscopy of saline suspension of stools after formalin-ether concentration, polyvinyl alcohol fixation of stools, and trichrome staining [18]. Cryptosporidium was identified microscopically with a modified dimethyl-sulfoxide method [19]. Rotavirus was identified using a monoclonal enzyme-linked immunosorbent assay (Pathfinder, Kallsted Laboratories, Austin, Texas) [20].

Data Analysis

All investigators, nurses, and laboratory personnel were blinded to treatment group until all end points were determined at the end of the study. Data were entered from data collection forms and laboratory records into a computer database. Patients not followed until the resolution of diarrhea and those found not to have met the enrollment criteria were excluded from the analysis before unblinding. Infections with enteroinvasive E. coli or Shigella were evaluated together because of the similar pathogenicity of these organisms [21]. Statistical comparisons were made using Epi Info software [22]. A P value of less than 0.05 was considered statistically significant. The sample size necessary to show a difference of 24 hours in duration of diarrhea (80% power, P < 0.05) was 66 patients with Shigella or enteroinvasive E. coli. We planned to conduct this study over a 1-year period or until 66 patients with Shigella or enteroinvasive E. coli infections were entered. Data analysis included a chi-square with Yates correction (or two-tailed Fisher exact test if an expected cell was less than five) for the detection of proportional differences between the two treatment groups; the Student t-test for the comparison of mean ages and weights; and the Mann-Whitney-Wilcoxon test for the evaluation of non-normally distributed outcome variables (duration of diarrhea and number of diarrheal stools). Confidence intervals (CIs) of 95% are given where appropriate.

Results

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From November 1990 to February 1992, patients with dysentery were screened by a nurse each morning, Monday through Friday. Ninety-two adults met the enrollment criteria. Two patients refused to submit additional specimens, one vomited his initial medication, and one could not be located after discharge from the hospital. Our final sample included 88 analyzable patients with dysentery.

Forty-two patients received loperamide and 46 received placebo. Characteristics of the evaluable patients are shown in Table 1. Patients in the loperamide and placebo groups did not differ significantly in age, weight, sex, fecal leukocytes or erythrocytes, proportion who had fever at enrollment, duration of diarrhea before enrollment, or number of diarrheal stools during the 24 hours immediately preceding enrollment. Shigella species were isolated from 44 (50%) and enteroinvasive E. coli from 3 (3%) study participants (Table 2). The patients in whom Shigella or enteroinvasive E. coli were isolated had a lower mean weight (53 compared with 58 kg) and had a longer duration of diarrhea before enrollment (26 compared with 8 hours) than did the patients in whom these organisms were not cultured. Severity of illness was greater in the Shigella-enteroinvasive E. coli group, which had a higher proportion of volunteers with fecal leukocytes (87% compared with 46%), fecal erythrocytes (94% compared with 34%), and fever at enrollment (47% compared with 22%) than did other patients. The median number of stools passed in the 24 hours before enrollment was similar in the two groups (10 and 8 stools, respectively).

After treatment, the number of diarrheal stools was fewer for patients with dysentery who received loperamide (median, 4.5 and 7.0 stools, respectively; P = 0.030). This difference was caused by patients infected with Shigella or enteroinvasive E. coli (P = 0.016) (Table 3). In addition, the duration of diarrhea was less in patients infected with Shigella or enteroinvasive E. coli who received loperamide (P = 0.028) (Table 3). During the observation period after the start of treatment, the percentage of patients infected with Shigella or enteroinvasive E. coli receiving loperamide compared with placebo did not differ statistically in the following parameters: abdominal cramps (21% compared with 27%, P = 0.282), nausea (16% compared with 18%, P = 0.903), vomiting (16% compared with 19%, P = 0.770), or constipation (5% compared with 0%, P = 0.447). An oral temperature greater than 38 °C was not found in any participant for more than 1 day after enrollment. Shigella or enteroinvasive E. coli were isolated 1 day after beginning treatment from 6 of 42 (14%) patients receiving loperamide and from 3 of 46 (7%) receiving placebo. None of the patients was infected with the same enteric pathogen more than 1 day after starting treatment. All Shigella and enteroinvasive E. coli isolates were susceptible to ciprofloxacin and nalidixic acid; 93% and 80% were resistant to tetracycline; 67% and 40% to both ampicillin and chloramphenicol; and 81% and 60% to trimethoprim-sulfamethoxazole.

Discussion

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This double-blind, placebo-controlled, randomized trial is the first published study to determine the efficacy of an antimotility drug in the treatment of naturally occurring, invasive diarrhea. Loperamide used with ciprofloxacin decreased the number of diarrheal stools and shortened the duration of illness in Shigella-infected patients with dysentery. Loperamide did not shorten the duration of illness in patients with dysentery caused by other enteric pathogens. Contrary to previous concerns [2], treatment with an anti-peristaltic agent did not lead to prolonged fever or extended excretion of bacterial enteric pathogens. Due to low enrollment, the study was discontinued after 15 months (3 months longer than we had initially planned) before achieving 66 analyzable patients with Shigella or enteroinvasive E. coli infections. Many patients with dysentery at Bamrasnaradura Hospital had taken an antimotility drug (diphenoxylate-atropine or loperamide) before coming to the hospital and therefore did not meet the enrollment criteria.

Adverse side effects from loperamide were not detected; however, the number of patients studied was small. In children with watery diarrhea, shock and enterocolitis have been reported after treatment with loperamide [23, 24]. The World Health Organization does not recommend either diphenoxylate hydrochloride or loperamide to diarrhea in children [25]. No children with dysentery were included in this study, and it would be prudent not to assume that the present results seen among adults are applicable to children.

Most of the patients in this study had fecal leukocytes and erythrocytes, and many had fever at the time of enrollment; however, no patients were critically ill. It would be wise not to extrapolate the results of this study to critically ill patients. Based on the results of this and other studies [3-7], loperamide used together with an antibiotic did not lead to complications in patients infected with Shigella. Loperamide would be beneficial in the treatment of travelers and in certain other groups who are at risk for developing bacillary dysentery in areas where Shigella is a prominent cause of dysentery, in travelers to Nepal [26], or in military personnel deployed to developing countries with unhygienic conditions [27]. However, the cost of loperamide, in addition to that of an antibiotic to which Shigella and enteroinvasive E. coli are sensitive, may preclude the use of the combination for most indigenous persons in developing countries. Oral fluids and electrolytes remain the mainstay of treatment whenever dehydration is present.

Today, most Shigella remain susceptible to ciprofloxacin, but the approach used in this study would not be applicable if ciprofloxacin-resistant Shigella emerge. Treatment with an antibiotic to which Shigella are sensitive is important for the resolution of symptoms [28, 29]. Fluoroquinolones are one of the few groups of oral antibiotics to which Shigella have been shown to be sensitive in a number of countries [27, 30, 31].

This study shows that loperamide offers additional benefit to patients receiving ciprofloxacin in the treatment of dysentery caused by Shigella or enteroinvasive E. coli. The combination of loperamide and ciprofloxacin can be used to treat diarrhea in adults, even in areas where Shigella is a common etiologic agent.

The views of the authors do not purport to reflect the positions of the U.S. Departments of the Navy, Army, or Defense, or the governments of Thailand or Japan.