Treatment of Travelers' Diarrhea: Ciprofloxacin plus Loperamide Compared with Ciprofloxacin Alone A Placebo-Controlled, Randomized Trial David N. Taylor, MD; Jose L. Sanchez, MD; William Candler, DO; Scott Thornton, MSc; Charles McQueen, MD; and Peter Echeverria, MD
Objective: To compare the safety and efficacy of loperamide used in combination with ciprofloxacin or ciprofloxacin alone for the treatment of travelers' diarrhea. Design: Double-blind, placebo-controlled, randomized clinical trial. Setting: United States Army hospital in Egypt. Participants: United States military personnel with travelers' diarrhea (n = 104) during a military exercise in November 1989. Persons who were noncompliant, had bloody diarrhea, or had received antidiarrheal medications before entry into the study were excluded. Interventions: All participants with travelers' diarrhea were treated with ciprofloxacin, 500 mg twice daily for 3 days. Fifty of these patients were randomly assigned to receive loperamide, a 4-mgfirstdose and 2 mg for every loose stool (as much as 16 mg/d), and 54 were randomly assigned to receive placebo. Measurements: Enterotoxigenic Escherichia coli was isolated from 57% of patients; Shigella and Salmonella, seen in 4% and 2% of patients, respectively, were not common. Main Results: After 24 hours, the symptoms of 82% of patients in the ciprofloxacin and loperamide group compared with 67% in the ciprofloxacin and placebo group had improved or fully recovered (odds ratio, 2.3; 95% CI, 0.8 to 6.3; P = 0.08). After 48 hours, the symptoms of 90% of both groups had improved or fully recovered. The mean number of stools for those receiving loperamide was not much lower than those who did not receive loperamide after 24 hours (1.9 ± 0.2 [SE] compared with 2.6 ± 0.2) or 48 hours (3.1 ± 0.3 compared with 4.0 ± 0.3) of treatment (P = 0.19). Conclusions: In a region where enterotoxigenic E. coli was the predominant cause of travelers' diarrhea, loperamide combined with ciprofloxacin was not better than treatment with ciprofloxacin alone. Loperamide appeared to have some benefit in the first 24 hours of treatment in patients infected with enterotoxigenic E. coli. Both regimens were safe.
Uiarrheal disease is an important medical problem for U.S. military personnel on duty in the developing world. During previous peacetime exercises in Egypt, more than one third of soldiers had diarrhea during 4- to 6-week maneuvers. The risk for diarrheal illness in soldiers, as in travelers in general, was associated with the consumption of local foods and drinks. Ciprofloxacin, 500 mg twice daily for 5 days, has consistently decreased the duration of travel-related or domestically acquired diarrhea from 3 or 4 days to 1 or 2 days (1-4). The response to treatment for susceptible organisms was comparable to that to treatment with trimethoprim-sulfamethoxazole. In recent studies, however, an increased number of enteropathogens that were resistant to trimethoprim-sulfamethoxazole decreased this drug's efficacy (3, 4). Antimotility drugs may also have a role in treatment. The diarrheal symptoms of Swiss travelers and U.S. students in Mexico responded more rapidly to loperamide (Imodium, McNeil Consumer Products, Fort Washington, Pennsylvania) when compared with bismuth subsalicylate and various antimicrobial agents (5, 6). The main concern about loperamide is that a related antimotility compound, diphenoxylate plus atropine (Lomotil, Searle Pharmaceuticals, Inc., Chicago, Illinois), caused illness to worsen in volunteers who had been experimentally infected with Shigella (7). However, in two recent field studies, none of 17 patients with nondysenteric shigellosis was adversely affected by loperamide therapy (3, 6). Among U.S. students in Mexico, the combination of trimethoprim-sulfamethoxazole plus loperamide was shown to be superior to either alone for travelers' diarrhea (3). The average duration of diarrhea was 1 hour for the combination compared with 34 hours for the same agents alone. Because most studies have indicated that ciprofloxacin is superior to trimethoprim-sulfamethoxazole, we sought to determine whether a similar benefit could be obtained by using loperamide in combination with ciprofloxacin for 3 days. Patients and Methods
Annals of Internal Medicine. 1991;114:731-734.
Efficacy Study
From the Walter Reed Army Institute of Research, Washington, DC; the U.S. Naval Medical Research Unit #3, Cairo, Egypt; and the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. For current author addresses, see end of text.
This double-blind, randomized clinical trial was designed to determine whether the addition of loperamide to ciprofloxacin, compared with treatment with ciprofloxacin alone, shortened the duration of travelers' diarrhea. The study was conducted at a military camp 30 km west of Cairo. Soldiers seeking medical care for diarrhea at the treatment facility were considered for
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study enrollment. We enrolled patients with three or more liquid stools in 24 hours or one or two liquid stools accompanied by abdominal cramps or vomiting. Persons with high fever (> 38.3 °C), grossly bloody diarrhea, or diarrhea for longer than 60 hours were excluded from the study. Persons who had previously received oral antibiotics or antimotility agents or who were noncompliant were excluded from the final data analysis. Adequate compliance was defined as the ingestion of at least 80% of the study medications, as indicated. Exclusions were made by the investigators before breaking the code. Case histories were obtained from and physical examinations were done on all participants. Each patient kept a daily record of symptoms, the time and form of each stool, and the frequency of medication use. Abdominal pain, nausea, vomiting, and fever were graded daily as mild, moderate, moderately severe, or severe. After 24 and 48 hours of therapy, all patients were interviewed. Patients with symptoms could return for additional follow-up visits. Improvement, determined every 24 hours, was defined as a 50% decrease in the daily number of stools compared with the previous 24 hours. Recovery was defined as total relief from (the disappearance of) all symptoms. The length of time lost from duty was also determined. Persons who met the case definition, gave written informed consent, and provided a stool specimen were randomly assigned to one of two groups. The ciprofloxacin and loperamide group received ciprofloxacin (Cipro, Miles Pharmaceuticals, West Haven, Connecticut), 500 mg twice daily for 3 days, plus loperamide (Imodium, McNeil Consumer Products Company, Fort Washington, Pennsylvania), a 4-mg initial dose followed by a 2-mg caplet after each unformed stool (no more than eight caplets per day). The ciprofloxacin and placebo group received ciprofloxacin, 500 mg twice daily for 3 days, plus placebo, taken in the same fashion as loperamide. Patients received the first dose of ciprofloxacin and the antimotility study drug while under observation and self-administered subsequent doses, recording the dosing information (time and quantity) in their diaries. Laboratory Studies Stool specimens obtained at entry were assessed for color, graded on a scale of 1 (liquid) to 5 (formed) for consistency, tested for occult blood, and examined microscopically for leukocytes and red blood cells. Stools were processed for enteric bacterial, viral, and protozoal pathogens, as previously described (8). Approximately 2 g of stool were placed into CaryBlair and buffered-glycerol saline bacterial transport media and 10% formalin and merthiolate-iodine-formalin for parasite preservation. A separate 1-g fecal specimen was frozen in liquid nitrogen and later tested for rotavirus using an enzyme-linked immunosorbent assay technique (Rotazyme II, Abbott Laboratories, Chicago, Illinois). Stools were inoculated onto MacConkey, Hektoen, and Shigella-Salmonella agars. Stools were processed for Campylobacter species using the membrane filter technique, with a nonselective medium incubated at 37 °C under microaerobic conditions (9). Salmonella, Shigella, and Aeromonas species were detected using standard methods (8). To detect enterotoxigenic Escherichia coli, five lactose-positive Table 1. Improvement Placebo
or Recovery
Patient Variables
after Treatment
colonies and any lactose-negative colonies were probed with an alkaline phosphatase-labeled oligonucleotide probe for heatlabile and heat-stable toxins (New England Nuclear, Boston, Massachusetts). All E. coli were shipped on slants to Bangkok and tested in the Y-l adrenal cell and suckling mouse assays for enterotoxin production (8). Nonenterotoxigenic colonies were probed for localized enteroadherence and enteroinvasiveness (10, 11). Colonies that hybridized with the probe were examined with the HeLa cell adherence assay (12). Susceptibility to antimicrobial agents was determined by the disk diffusion method (13). Data Analysis Data were entered directly from patient diaries and were statistically analyzed using the Statistical Analysis Systems (SAS Institute, Cary, North Carolina) (14). The evaluation included the use of the Mantel-Haenszel contingency table (r x n) chi-square for the detection of differences in response between the two treatment groups; the Student /-test for the comparison of means; the Mann-Whitney (/-test for the comparison of rank sums; life-table survival analysis (log-rank test) for the comparison of response to therapy by group; and the Wilcoxon rank test for the evaluation of possible confounding variables. Confidence intervals (CIs) of 95% are given where appropriate. Results Diarrhea Rates The highest incidence of diarrhea (4.7% of all soldiers on the base per week) was reported during the first week of the study when regular field dining facilities were not yet operational and soldiers were living off the base and eating at local restaurants. After the base and field dining facilities were established, diarrhea rates initially decreased and then increased to approximately 2%/wk during successive weeks when more soldiers were permitted to leave the base. Efficacy Study From 26 October to 19 November 1989, 162 U.S. soldiers participating in field training maneuvers in Egypt were examined for symptoms of diarrhea. Thirtynine persons did not meet the study entry criteria, because they could not return for follow-up or because their illness was too mild. Of the 123 patients who were initially enrolled and from whom cultures were obtained, 13 were excluded because they had used other antidiarrheal medications and 6 (3 in each treatment
with Ciprofloxacin plus Loperamide
732
plus
Ciprofloxacin and Placebo Group (ri = 54) 48 h 24 h
Ciprofloxacin and Loperamide Group (n = 50) 24 h 48 h - n (%) -
2 Enterotoxigenic Escherichia coli Shigella or Salmonella species
or Ciprofloxacin
41 (82)
45 (92)
36 (67)
48 (89)
12 (67) 9(82) 20 (95) 21 (78) 2(67)
15 (83) 9(82) 21 (100) 24 (89) 3 (100)
19 (56) 7(78) 10(91) 22 (69) 2(67)
29 9 10 30 3
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(85) (100) (91) (94) (100)
Table 2. Antimicrobial
Susceptibility
of Enteropathogens
Isolated among U.S. Soldiers in Egypt*
TrimethoprimSulfamethoxazole
Ciprofloxacin
< 39 25 12 76 4 2
— 0 0 0 0 0 0
Tetracycline
Ampicillin
>
%— 28 36 33 32 25 0
49 56 33 49 75 50
46 60 67 54 50 50
* LTST = E. coli that produce heat-labile and heat-stable toxins; ST = E. coli that produce heat-stable toxin alone; LT = E. coli that produce heat-labile toxin alone. t Including Shigella flexneri (two isolates), S. boydii (one isolate), and S. sonnei (one isolate).
group) were excluded because they were noncompliant. The characteristics, such as sex, age, branch of service, ethnic group, and rank, of the 104 study participants were similar in both treatment groups and comparable to those of the overall camp population. For fully compliant patients, the conditions of 82% of those who received ciprofloxacin and loperamide had improved or fully recovered after 24 hours compared with 67% of those who received ciprofloxacin and placebo (odds ratio, 2.3; 95% CI, 0.8 to 6.3; P = 0.08) (Table 1). After 48 hours, the conditions of nearly 90% of both groups had improved or fully recovered (P > 0.2). The mean number of loperamide (2-mg) caplets taken in the ciprofloxacin and loperamide group was less than the number of placebo caplets taken in the ciprofloxacin and placebo group (4.3 ± 0.2 compared with 5.1 ± 0.3; P = 0.2). The mean number of liquid stools was less for the ciprofloxacin and loperamide group after 24 hours (1.9 ± 0.2 compared with 2.6 ± 0.2; P = 0.19) and 48 hours (3.1 ± 0.3 compared with 4.0 ± 0.3; P = 0.19). The medications were well tolerated, and no adverse effect was noted in either study group. The mean duration of diarrhea before treatment was longer in the ciprofloxacin and loperamide group than in the ciprofloxacin and placebo group (43 compared with 27 h; P = 0.06). When the data were stratified to control for the duration of illness before treatment, response still did not differ substantially between the two treatment groups (odds ratio, 1.4; CI, 0.3 to 6.4; P > 0.05) (Table 1). When diarrhea before treatment lasted for 1 day or less, the symptoms of more patients receiving loperamide than of patients receiving placebo had improved or fully recovered after 24 hours of treatment (67% compared with 56%; P > 0.2). The conditions of patients with diarrhea for more than 1 day were probably already improving so that less of a difference between treatment groups was seen (Table 1). When the data were stratified by pathogens isolated, only persons infected with enterotoxigenic E. coli benefited from the use of loperamide (78% compared with 69%; P > 0.2). No difference between the treatment groups was apparent for those persons infected with Salmonella or Shigella, although the number of cases was small (Table 1). Life-table analysis of response data based on the probability of remaining ill over time for 104 patients revealed no differences between the groups overall (P > 0.2). Nor
was an association noted when the data of the 123 patients who had been initially enrolled were analyzed (P > 0.2). The following possibly confounding variables were evaluated in the model: the presence of fecal leukocytes, the degree of compliance with each of the two study medications, and the concomitant use of antidiarrheal medications. None of these variables was a confounder according to the model (P > 0.2). Etiology Enterotoxigenic E. coli, identified in 57% of 104 study patients, was the predominant enteric pathogen. Fiftyone percent of the enterotoxigenic E. coli produced both heat-labile and heat-stable toxins, 15% produced heat-labile toxin alone, and 34% produced heat-stable toxin alone. Shigella species were isolated from 4 patients, and Salmonella species were isolated from 2 patients. All enterotoxigenic E. coli, Salmonella, and Shigella were susceptible to ciprofloxacin. Approximately one third of the enteropathogens were resistant to trimethoprim-sulfamethoxazole, and approximately half were resistant to tetracycline or ampicillin (Table 2). Rotavirus, Campylobacter species, and E. coli that hybridized with the enterotoxigenic E. coli adherence factor or enteroinvasive probes were not detected. Discussion Our objective in conducting this trial was to determine whether the combination of ciprofloxacin and loperamide was both safe and effective for travelers' diarrhea. Because ciprofloxacin has already been shown to be effective, we compared the combination of ciprofloxacin and loperamide with that of ciprofloxacin alone rather than with placebo alone (2, 4). Further, the use of a placebo alone was not acceptable because of concern about the performance of the soldiers during military maneuvers. Loperamide alone was not tested because the 13% failure rate of loperamide alone found in a study of travelers to Mexico was thought to be unacceptably high (3). We found that loperamide was safe, but that it provided only a small additional benefit when given with ciprofloxacin compared with treatment with ciprofloxacin alone. Because the differences between treatment
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groups were smaller than we had anticipated, our study did not have sufficient statistical power (0.42) to show a statistically significant effect on recovery time with the use of loperamide in addition to ciprofloxacin. Clearly, however, the trend favored the use of loperamide. With the differences that we noted between the treatment groups at 24 hours, we would have needed about 180 subjects per group to detect a statistically significant difference. The benefit of loperamide was seen only in the first 24 hours of illness and only in patients infected with enterotoxigenic E. coli. Although the number of cases was small, the conditions of persons infected with Salmonella or Shigella did not improve faster with the administration of loperamide; however, their illness did not become worse. An antisecretory effect of loperamide has been shown in vitro (15). This effect may be more important than the antimotility effect; we did not see constipation or poor outcome, effects that have been found after treatment with antimotility agents, in patients with Shigella infection (7). After having symptoms for 1 day, most patients were already recovering so that an additional effect of loperamide was not seen. Using the same end point (complete recovery), we did not see the marked decrease in diarrhea with combination therapy that was found in travelers to Mexico (3). In the groups receiving single-agent therapy, the response to ciprofloxacin alone in Egypt was greater than the response to trimethoprim-sulfamethoxazole alone in Mexico after 48 hours (86% compared with 65%); the symptoms of all of 54 patients in Egypt (compared with the conditions of 29 of 32 patients in Mexico) responded to treatment. In the groups receiving combination therapy, 74% of the patients who received trimethoprim-sulfamethoxazole plus loperamide in Mexico compared with 50% of patients who received combination therapy in Egypt had recovered after 24 hours. After 48 hours, however, 88% of the patients in Mexico and 83% of patients in Egypt had recovered. Ciprofloxacin alone thus was more effective than trimethoprimsulfamethoxazole alone, and the addition of loperamide did not appear to make ciprofloxacin much more effective. In the travelers to Mexico, the mean duration of diarrhea was reported to be 1 hour for combination therapy compared with 34 hours for loperamide alone (3). Although loperamide, with antisecretory and antimotility effects, clearly decreases diarrhea more rapidly than do antibiotics, which have no effect on preformed toxin, the reason trimethoprim-sulfamethoxazole (or ciprofloxacin) so markedly potentiates the effect of loperamide is not pharmacologically apparent (16). Further, another study found that more than half of 94 Swiss travelers still had diarrhea after 8 hours of selftreatment with loperamide (5). Although the results of our study showed only a minimal reduction in the length of illness with the use of the antimotility agent, loperamide, in addition to ciprofloxacin, this treatment regimen appears to be safe for
734
the treatment of travelers' diarrhea in an area where enterotoxigenic E. coli is the predominant pathogen. The views of the authors do not purport to reflect the positions of the U.S. Department of the Army, the U.S. Department of the Navy, or the U.S. Department of Defense. Acknowledgments: The authors thank CDR Louis Bourgeois, of the U.S. Navy, and Dr. Noshy Mansour for their assistance at the U.S. Naval Medical Research Unit # 3 in Cairo; the staff of the 47th Field Support Hospital, Fort Sill, Oklahoma; and LTC Michael Roeder, of the 332nd Medical Brigade, Nashville, Tennessee, and Jeff Garwin, MD, and John Travers, MD, of McNeil Consumer Products, for providing loperamide and placebo. Requests for Reprints: David N. Taylor, MD, Enteric Infections Branch, Walter Reed Army Institute of Research, Washington, DC 20307-5100. Current Author Addresses: Dr. Taylor: Enteric Infections Branch, Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100. Dr. Sanchez: Department of Field Studies, Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, DC 203075100. Dr. Candler: Preventive Medicine Service, U.S. Army Medical Department Activity, Panama, APO Miami, FL 34004-5000. LT. Thornton: Department of Bacteriology, U.S. Naval Medical Research Unit # 3 , FPO NY 09527. Dr. McQueen: Department of Gastroenterology, Division of Medicine, Walter Reed Army Institute of Research, Washington, DC 20307-5100. Dr. Echeverria: Department of Bacteriology, Armed Forces Research Institute of Medicine Sciences, APO San Francisco, CA 96346-5000. References 1. Pichler HE, Diridl G, Stickler K, Wolf D. Clinical efficacy of ciprofloxacin compared with placebo in bacterial diarrhea. Am J Med. 1987;82(Suppl 4A):329-32. 2. Ericsson CD, Johnson PC, DuPont HL, Morgan DR, Bitsura JA, de la Cabada PJ. Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea: a placebo-controlled trial. Ann Intern Med. 1987;106:216-20. 3. Ericsson CD, DuPont HL, Mathewson JJ, West MS, Johnson PC, Bitsura JM. Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA. 1990;263:257-61. 4. Goodman LJ, Trenholme GM, Kaplan RL, et al. Empiric antimicrobial therapy of domestically acquired acute diarrhea in urban adults. Arch Intern Med. 1990;150:541-6. 5. Steffen R, Heusser R, Tschopp A, DuPont HL. Efficacy and side effects of six agents in the self-treatment of traveler's diarrhoea. Travel Medicine International. 1988;6:153-7. 6. Johnson PC, Ericsson CD, DuPont HL, Morgan DR, Bitsura JA, Wood LV. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA. 1986;255:757-60. 7. DuPont HL, Hornick RB. Adverse effect of Lomotil therapy in shigellosis. JAMA. 1973;226:1525-8. 8. Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P. Etiology of diarrheal disease among travelers and foreign residents in Nepal. JAMA. 1988;260:1245-8. 9. Steele TW, McDermott SN. The use of membrane filters applied directly to the surface of agar plates for the isolation of Campylobacter jejuni from feces. Pathology. 1984;16:263-5. 10. Nataro JP, Baldini MM, Kaper JB, Black RE, Bravo N, Levine MM. Detection of an adherence factor of enteropathogenic Escherichia coli with a DNA probe. J Infect Dis. 1985;152:560-5. 11. Taylor DN, Echeverria P, Pal T, et al. The role of Shigella species, enteroinvasive Escherichia coli, and other enteropathogens as causes of childhood dysentery in Thailand. J Infect Dis. 1986; 153: 1132-8. 12. Scaletsky IC, Silva ML, Trabulsi LR. Distinctive patterns of adherence of enteropathogenic Escherichia coli to HeLa cells. Infect Immun. 1984;45:534-6. 13. Bauer AW, Kirby WW, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966;45:493-6. 14. SAS Users Guide: Statistics, Version 5 Edition. Cary, North Carolina: SAS Institute Inc.; 529-57. 15. Black RE. Epidemiology of travelers' diarrhea and relative importance of various pathogens. Rev Infect Dis. 1990;12(Suppl l):S73-9. 16. Guandalini S, Fasano A, Rao MC, et al. Effects of loperamide on intestinal ion transport. J Pediatr Gastroenterol Nutr. 1984;3:593601.
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Objective: To compare the safety and efficacy of loperamide used in combination with ciprofloxacin or ciprofloxacin alone for the treatment of travelers' diarrhea. Design: Double-blind, placebo-controlled, randomized clinical trial. Setting: United States Army hospital in Egypt. Participants: United States military personnel with travelers' diarrhea (n = 104) during a military exercise in November 1989. Persons who were noncompliant, had bloody diarrhea, or had received antidiarrheal medications before entry into the study were excluded. Interventions: All participants with travelers' diarrhea were treated with ciprofloxacin, 500 mg twice daily for 3 days. Fifty of these patients were randomly assigned to receive loperamide, a 4-mgfirstdose and 2 mg for every loose stool (as much as 16 mg/d), and 54 were randomly assigned to receive placebo. Measurements: Enterotoxigenic Escherichia coli was isolated from 57% of patients; Shigella and Salmonella, seen in 4% and 2% of patients, respectively, were not common. Main Results: After 24 hours, the symptoms of 82% of patients in the ciprofloxacin and loperamide group compared with 67% in the ciprofloxacin and placebo group had improved or fully recovered (odds ratio, 2.3; 95% CI, 0.8 to 6.3; P = 0.08). After 48 hours, the symptoms of 90% of both groups had improved or fully recovered. The mean number of stools for those receiving loperamide was not much lower than those who did not receive loperamide after 24 hours (1.9 ± 0.2 [SE] compared with 2.6 ± 0.2) or 48 hours (3.1 ± 0.3 compared with 4.0 ± 0.3) of treatment (P = 0.19). Conclusions: In a region where enterotoxigenic E. coli was the predominant cause of travelers' diarrhea, loperamide combined with ciprofloxacin was not better than treatment with ciprofloxacin alone. Loperamide appeared to have some benefit in the first 24 hours of treatment in patients infected with enterotoxigenic E. coli. Both regimens were safe.
Uiarrheal disease is an important medical problem for U.S. military personnel on duty in the developing world. During previous peacetime exercises in Egypt, more than one third of soldiers had diarrhea during 4- to 6-week maneuvers. The risk for diarrheal illness in soldiers, as in travelers in general, was associated with the consumption of local foods and drinks. Ciprofloxacin, 500 mg twice daily for 5 days, has consistently decreased the duration of travel-related or domestically acquired diarrhea from 3 or 4 days to 1 or 2 days (1-4). The response to treatment for susceptible organisms was comparable to that to treatment with trimethoprim-sulfamethoxazole. In recent studies, however, an increased number of enteropathogens that were resistant to trimethoprim-sulfamethoxazole decreased this drug's efficacy (3, 4). Antimotility drugs may also have a role in treatment. The diarrheal symptoms of Swiss travelers and U.S. students in Mexico responded more rapidly to loperamide (Imodium, McNeil Consumer Products, Fort Washington, Pennsylvania) when compared with bismuth subsalicylate and various antimicrobial agents (5, 6). The main concern about loperamide is that a related antimotility compound, diphenoxylate plus atropine (Lomotil, Searle Pharmaceuticals, Inc., Chicago, Illinois), caused illness to worsen in volunteers who had been experimentally infected with Shigella (7). However, in two recent field studies, none of 17 patients with nondysenteric shigellosis was adversely affected by loperamide therapy (3, 6). Among U.S. students in Mexico, the combination of trimethoprim-sulfamethoxazole plus loperamide was shown to be superior to either alone for travelers' diarrhea (3). The average duration of diarrhea was 1 hour for the combination compared with 34 hours for the same agents alone. Because most studies have indicated that ciprofloxacin is superior to trimethoprim-sulfamethoxazole, we sought to determine whether a similar benefit could be obtained by using loperamide in combination with ciprofloxacin for 3 days. Patients and Methods
Annals of Internal Medicine. 1991;114:731-734.
Efficacy Study
From the Walter Reed Army Institute of Research, Washington, DC; the U.S. Naval Medical Research Unit #3, Cairo, Egypt; and the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. For current author addresses, see end of text.
This double-blind, randomized clinical trial was designed to determine whether the addition of loperamide to ciprofloxacin, compared with treatment with ciprofloxacin alone, shortened the duration of travelers' diarrhea. The study was conducted at a military camp 30 km west of Cairo. Soldiers seeking medical care for diarrhea at the treatment facility were considered for
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study enrollment. We enrolled patients with three or more liquid stools in 24 hours or one or two liquid stools accompanied by abdominal cramps or vomiting. Persons with high fever (> 38.3 °C), grossly bloody diarrhea, or diarrhea for longer than 60 hours were excluded from the study. Persons who had previously received oral antibiotics or antimotility agents or who were noncompliant were excluded from the final data analysis. Adequate compliance was defined as the ingestion of at least 80% of the study medications, as indicated. Exclusions were made by the investigators before breaking the code. Case histories were obtained from and physical examinations were done on all participants. Each patient kept a daily record of symptoms, the time and form of each stool, and the frequency of medication use. Abdominal pain, nausea, vomiting, and fever were graded daily as mild, moderate, moderately severe, or severe. After 24 and 48 hours of therapy, all patients were interviewed. Patients with symptoms could return for additional follow-up visits. Improvement, determined every 24 hours, was defined as a 50% decrease in the daily number of stools compared with the previous 24 hours. Recovery was defined as total relief from (the disappearance of) all symptoms. The length of time lost from duty was also determined. Persons who met the case definition, gave written informed consent, and provided a stool specimen were randomly assigned to one of two groups. The ciprofloxacin and loperamide group received ciprofloxacin (Cipro, Miles Pharmaceuticals, West Haven, Connecticut), 500 mg twice daily for 3 days, plus loperamide (Imodium, McNeil Consumer Products Company, Fort Washington, Pennsylvania), a 4-mg initial dose followed by a 2-mg caplet after each unformed stool (no more than eight caplets per day). The ciprofloxacin and placebo group received ciprofloxacin, 500 mg twice daily for 3 days, plus placebo, taken in the same fashion as loperamide. Patients received the first dose of ciprofloxacin and the antimotility study drug while under observation and self-administered subsequent doses, recording the dosing information (time and quantity) in their diaries. Laboratory Studies Stool specimens obtained at entry were assessed for color, graded on a scale of 1 (liquid) to 5 (formed) for consistency, tested for occult blood, and examined microscopically for leukocytes and red blood cells. Stools were processed for enteric bacterial, viral, and protozoal pathogens, as previously described (8). Approximately 2 g of stool were placed into CaryBlair and buffered-glycerol saline bacterial transport media and 10% formalin and merthiolate-iodine-formalin for parasite preservation. A separate 1-g fecal specimen was frozen in liquid nitrogen and later tested for rotavirus using an enzyme-linked immunosorbent assay technique (Rotazyme II, Abbott Laboratories, Chicago, Illinois). Stools were inoculated onto MacConkey, Hektoen, and Shigella-Salmonella agars. Stools were processed for Campylobacter species using the membrane filter technique, with a nonselective medium incubated at 37 °C under microaerobic conditions (9). Salmonella, Shigella, and Aeromonas species were detected using standard methods (8). To detect enterotoxigenic Escherichia coli, five lactose-positive Table 1. Improvement Placebo
or Recovery
Patient Variables
after Treatment
colonies and any lactose-negative colonies were probed with an alkaline phosphatase-labeled oligonucleotide probe for heatlabile and heat-stable toxins (New England Nuclear, Boston, Massachusetts). All E. coli were shipped on slants to Bangkok and tested in the Y-l adrenal cell and suckling mouse assays for enterotoxin production (8). Nonenterotoxigenic colonies were probed for localized enteroadherence and enteroinvasiveness (10, 11). Colonies that hybridized with the probe were examined with the HeLa cell adherence assay (12). Susceptibility to antimicrobial agents was determined by the disk diffusion method (13). Data Analysis Data were entered directly from patient diaries and were statistically analyzed using the Statistical Analysis Systems (SAS Institute, Cary, North Carolina) (14). The evaluation included the use of the Mantel-Haenszel contingency table (r x n) chi-square for the detection of differences in response between the two treatment groups; the Student /-test for the comparison of means; the Mann-Whitney (/-test for the comparison of rank sums; life-table survival analysis (log-rank test) for the comparison of response to therapy by group; and the Wilcoxon rank test for the evaluation of possible confounding variables. Confidence intervals (CIs) of 95% are given where appropriate. Results Diarrhea Rates The highest incidence of diarrhea (4.7% of all soldiers on the base per week) was reported during the first week of the study when regular field dining facilities were not yet operational and soldiers were living off the base and eating at local restaurants. After the base and field dining facilities were established, diarrhea rates initially decreased and then increased to approximately 2%/wk during successive weeks when more soldiers were permitted to leave the base. Efficacy Study From 26 October to 19 November 1989, 162 U.S. soldiers participating in field training maneuvers in Egypt were examined for symptoms of diarrhea. Thirtynine persons did not meet the study entry criteria, because they could not return for follow-up or because their illness was too mild. Of the 123 patients who were initially enrolled and from whom cultures were obtained, 13 were excluded because they had used other antidiarrheal medications and 6 (3 in each treatment
with Ciprofloxacin plus Loperamide
732
plus
Ciprofloxacin and Placebo Group (ri = 54) 48 h 24 h
Ciprofloxacin and Loperamide Group (n = 50) 24 h 48 h - n (%) -
2 Enterotoxigenic Escherichia coli Shigella or Salmonella species
or Ciprofloxacin
41 (82)
45 (92)
36 (67)
48 (89)
12 (67) 9(82) 20 (95) 21 (78) 2(67)
15 (83) 9(82) 21 (100) 24 (89) 3 (100)
19 (56) 7(78) 10(91) 22 (69) 2(67)
29 9 10 30 3
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(85) (100) (91) (94) (100)
Table 2. Antimicrobial
Susceptibility
of Enteropathogens
Isolated among U.S. Soldiers in Egypt*
TrimethoprimSulfamethoxazole
Ciprofloxacin
< 39 25 12 76 4 2
— 0 0 0 0 0 0
Tetracycline
Ampicillin
>
%— 28 36 33 32 25 0
49 56 33 49 75 50
46 60 67 54 50 50
* LTST = E. coli that produce heat-labile and heat-stable toxins; ST = E. coli that produce heat-stable toxin alone; LT = E. coli that produce heat-labile toxin alone. t Including Shigella flexneri (two isolates), S. boydii (one isolate), and S. sonnei (one isolate).
group) were excluded because they were noncompliant. The characteristics, such as sex, age, branch of service, ethnic group, and rank, of the 104 study participants were similar in both treatment groups and comparable to those of the overall camp population. For fully compliant patients, the conditions of 82% of those who received ciprofloxacin and loperamide had improved or fully recovered after 24 hours compared with 67% of those who received ciprofloxacin and placebo (odds ratio, 2.3; 95% CI, 0.8 to 6.3; P = 0.08) (Table 1). After 48 hours, the conditions of nearly 90% of both groups had improved or fully recovered (P > 0.2). The mean number of loperamide (2-mg) caplets taken in the ciprofloxacin and loperamide group was less than the number of placebo caplets taken in the ciprofloxacin and placebo group (4.3 ± 0.2 compared with 5.1 ± 0.3; P = 0.2). The mean number of liquid stools was less for the ciprofloxacin and loperamide group after 24 hours (1.9 ± 0.2 compared with 2.6 ± 0.2; P = 0.19) and 48 hours (3.1 ± 0.3 compared with 4.0 ± 0.3; P = 0.19). The medications were well tolerated, and no adverse effect was noted in either study group. The mean duration of diarrhea before treatment was longer in the ciprofloxacin and loperamide group than in the ciprofloxacin and placebo group (43 compared with 27 h; P = 0.06). When the data were stratified to control for the duration of illness before treatment, response still did not differ substantially between the two treatment groups (odds ratio, 1.4; CI, 0.3 to 6.4; P > 0.05) (Table 1). When diarrhea before treatment lasted for 1 day or less, the symptoms of more patients receiving loperamide than of patients receiving placebo had improved or fully recovered after 24 hours of treatment (67% compared with 56%; P > 0.2). The conditions of patients with diarrhea for more than 1 day were probably already improving so that less of a difference between treatment groups was seen (Table 1). When the data were stratified by pathogens isolated, only persons infected with enterotoxigenic E. coli benefited from the use of loperamide (78% compared with 69%; P > 0.2). No difference between the treatment groups was apparent for those persons infected with Salmonella or Shigella, although the number of cases was small (Table 1). Life-table analysis of response data based on the probability of remaining ill over time for 104 patients revealed no differences between the groups overall (P > 0.2). Nor
was an association noted when the data of the 123 patients who had been initially enrolled were analyzed (P > 0.2). The following possibly confounding variables were evaluated in the model: the presence of fecal leukocytes, the degree of compliance with each of the two study medications, and the concomitant use of antidiarrheal medications. None of these variables was a confounder according to the model (P > 0.2). Etiology Enterotoxigenic E. coli, identified in 57% of 104 study patients, was the predominant enteric pathogen. Fiftyone percent of the enterotoxigenic E. coli produced both heat-labile and heat-stable toxins, 15% produced heat-labile toxin alone, and 34% produced heat-stable toxin alone. Shigella species were isolated from 4 patients, and Salmonella species were isolated from 2 patients. All enterotoxigenic E. coli, Salmonella, and Shigella were susceptible to ciprofloxacin. Approximately one third of the enteropathogens were resistant to trimethoprim-sulfamethoxazole, and approximately half were resistant to tetracycline or ampicillin (Table 2). Rotavirus, Campylobacter species, and E. coli that hybridized with the enterotoxigenic E. coli adherence factor or enteroinvasive probes were not detected. Discussion Our objective in conducting this trial was to determine whether the combination of ciprofloxacin and loperamide was both safe and effective for travelers' diarrhea. Because ciprofloxacin has already been shown to be effective, we compared the combination of ciprofloxacin and loperamide with that of ciprofloxacin alone rather than with placebo alone (2, 4). Further, the use of a placebo alone was not acceptable because of concern about the performance of the soldiers during military maneuvers. Loperamide alone was not tested because the 13% failure rate of loperamide alone found in a study of travelers to Mexico was thought to be unacceptably high (3). We found that loperamide was safe, but that it provided only a small additional benefit when given with ciprofloxacin compared with treatment with ciprofloxacin alone. Because the differences between treatment
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groups were smaller than we had anticipated, our study did not have sufficient statistical power (0.42) to show a statistically significant effect on recovery time with the use of loperamide in addition to ciprofloxacin. Clearly, however, the trend favored the use of loperamide. With the differences that we noted between the treatment groups at 24 hours, we would have needed about 180 subjects per group to detect a statistically significant difference. The benefit of loperamide was seen only in the first 24 hours of illness and only in patients infected with enterotoxigenic E. coli. Although the number of cases was small, the conditions of persons infected with Salmonella or Shigella did not improve faster with the administration of loperamide; however, their illness did not become worse. An antisecretory effect of loperamide has been shown in vitro (15). This effect may be more important than the antimotility effect; we did not see constipation or poor outcome, effects that have been found after treatment with antimotility agents, in patients with Shigella infection (7). After having symptoms for 1 day, most patients were already recovering so that an additional effect of loperamide was not seen. Using the same end point (complete recovery), we did not see the marked decrease in diarrhea with combination therapy that was found in travelers to Mexico (3). In the groups receiving single-agent therapy, the response to ciprofloxacin alone in Egypt was greater than the response to trimethoprim-sulfamethoxazole alone in Mexico after 48 hours (86% compared with 65%); the symptoms of all of 54 patients in Egypt (compared with the conditions of 29 of 32 patients in Mexico) responded to treatment. In the groups receiving combination therapy, 74% of the patients who received trimethoprim-sulfamethoxazole plus loperamide in Mexico compared with 50% of patients who received combination therapy in Egypt had recovered after 24 hours. After 48 hours, however, 88% of the patients in Mexico and 83% of patients in Egypt had recovered. Ciprofloxacin alone thus was more effective than trimethoprimsulfamethoxazole alone, and the addition of loperamide did not appear to make ciprofloxacin much more effective. In the travelers to Mexico, the mean duration of diarrhea was reported to be 1 hour for combination therapy compared with 34 hours for loperamide alone (3). Although loperamide, with antisecretory and antimotility effects, clearly decreases diarrhea more rapidly than do antibiotics, which have no effect on preformed toxin, the reason trimethoprim-sulfamethoxazole (or ciprofloxacin) so markedly potentiates the effect of loperamide is not pharmacologically apparent (16). Further, another study found that more than half of 94 Swiss travelers still had diarrhea after 8 hours of selftreatment with loperamide (5). Although the results of our study showed only a minimal reduction in the length of illness with the use of the antimotility agent, loperamide, in addition to ciprofloxacin, this treatment regimen appears to be safe for
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the treatment of travelers' diarrhea in an area where enterotoxigenic E. coli is the predominant pathogen. The views of the authors do not purport to reflect the positions of the U.S. Department of the Army, the U.S. Department of the Navy, or the U.S. Department of Defense. Acknowledgments: The authors thank CDR Louis Bourgeois, of the U.S. Navy, and Dr. Noshy Mansour for their assistance at the U.S. Naval Medical Research Unit # 3 in Cairo; the staff of the 47th Field Support Hospital, Fort Sill, Oklahoma; and LTC Michael Roeder, of the 332nd Medical Brigade, Nashville, Tennessee, and Jeff Garwin, MD, and John Travers, MD, of McNeil Consumer Products, for providing loperamide and placebo. Requests for Reprints: David N. Taylor, MD, Enteric Infections Branch, Walter Reed Army Institute of Research, Washington, DC 20307-5100. Current Author Addresses: Dr. Taylor: Enteric Infections Branch, Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100. Dr. Sanchez: Department of Field Studies, Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, DC 203075100. Dr. Candler: Preventive Medicine Service, U.S. Army Medical Department Activity, Panama, APO Miami, FL 34004-5000. LT. Thornton: Department of Bacteriology, U.S. Naval Medical Research Unit # 3 , FPO NY 09527. Dr. McQueen: Department of Gastroenterology, Division of Medicine, Walter Reed Army Institute of Research, Washington, DC 20307-5100. Dr. Echeverria: Department of Bacteriology, Armed Forces Research Institute of Medicine Sciences, APO San Francisco, CA 96346-5000. References 1. Pichler HE, Diridl G, Stickler K, Wolf D. Clinical efficacy of ciprofloxacin compared with placebo in bacterial diarrhea. Am J Med. 1987;82(Suppl 4A):329-32. 2. Ericsson CD, Johnson PC, DuPont HL, Morgan DR, Bitsura JA, de la Cabada PJ. Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea: a placebo-controlled trial. Ann Intern Med. 1987;106:216-20. 3. Ericsson CD, DuPont HL, Mathewson JJ, West MS, Johnson PC, Bitsura JM. Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA. 1990;263:257-61. 4. Goodman LJ, Trenholme GM, Kaplan RL, et al. Empiric antimicrobial therapy of domestically acquired acute diarrhea in urban adults. Arch Intern Med. 1990;150:541-6. 5. Steffen R, Heusser R, Tschopp A, DuPont HL. Efficacy and side effects of six agents in the self-treatment of traveler's diarrhoea. Travel Medicine International. 1988;6:153-7. 6. Johnson PC, Ericsson CD, DuPont HL, Morgan DR, Bitsura JA, Wood LV. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA. 1986;255:757-60. 7. DuPont HL, Hornick RB. Adverse effect of Lomotil therapy in shigellosis. JAMA. 1973;226:1525-8. 8. Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P. Etiology of diarrheal disease among travelers and foreign residents in Nepal. JAMA. 1988;260:1245-8. 9. Steele TW, McDermott SN. The use of membrane filters applied directly to the surface of agar plates for the isolation of Campylobacter jejuni from feces. Pathology. 1984;16:263-5. 10. Nataro JP, Baldini MM, Kaper JB, Black RE, Bravo N, Levine MM. Detection of an adherence factor of enteropathogenic Escherichia coli with a DNA probe. J Infect Dis. 1985;152:560-5. 11. Taylor DN, Echeverria P, Pal T, et al. The role of Shigella species, enteroinvasive Escherichia coli, and other enteropathogens as causes of childhood dysentery in Thailand. J Infect Dis. 1986; 153: 1132-8. 12. Scaletsky IC, Silva ML, Trabulsi LR. Distinctive patterns of adherence of enteropathogenic Escherichia coli to HeLa cells. Infect Immun. 1984;45:534-6. 13. Bauer AW, Kirby WW, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966;45:493-6. 14. SAS Users Guide: Statistics, Version 5 Edition. Cary, North Carolina: SAS Institute Inc.; 529-57. 15. Black RE. Epidemiology of travelers' diarrhea and relative importance of various pathogens. Rev Infect Dis. 1990;12(Suppl l):S73-9. 16. Guandalini S, Fasano A, Rao MC, et al. Effects of loperamide on intestinal ion transport. J Pediatr Gastroenterol Nutr. 1984;3:593601.
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