Diarrhea: a Placebo-Controlled Study

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1992, p. 87-91 Vol. 36, No. 1 0066-4804/92/010087-05$02.00/0 Copyright 1992, American Society for Microbiology Five versus Three Days of Ofloxacin Therapy for Traveler's Diarrhea: a Placebo-Controlled Study HERBERT L. DuPONT,l* CHARLES D. ERICSSON,' JOHN J. MATHEWSON,' AND MARGARET W. DuPONT2 Center for Infectious Diseases, University of Texas Health Science Center at Houston, the Medical School, and School of Public Health, Houston, Texas 77030,1 and Pharmaco Testing, Inc., New Braunfels, Texas 781302 Received 20 June 1991/Accepted 4 October 1991 In this double-blind study with 232 patients, 300 mg of ofloxacin given orally twice daily for 5 or 3 days was compared with placebo for the treatment of acute diarrhea in U.S. students visiting Guadalajara, Mexico. The 3-day regimen of ofloxacin was found to be as effective as the 5-day regimen in producing a clinical and microbiologic cure. Clinical cures for patients who received ofloxacin for 5 days occurred in 59 of 66 (89%) subjects, whereas clinical cure occurred in 77 of 81 (95%) of those who received ofloxacin for 3 days and in 56 of 79 (71%) of those who took placebo (P = 0.0001). When the duration of diarrhea after therapy was begun was compared in subgroups, a significant (P < 0.05) shortening of posttreatment illness occurred in comparison with that in the placebo group for the following groups: for 5 days of ofloxacin, cases of shigellosis (32 versus 98 h); for 3 days of ofloxacin, all cases (28 versus 56 h), cases of enterotoxigenic Escherichia coil diarrhea (26 versus 66 h), cases of shigellosis (24 versus 98 h), all cases of illnesses associated with a bacterial enteropathogen (28 versus 69 h), and cases of illnesses in which numerous leukocytes were found in stool by microscopy (22 versus 49 h). Microbiologic eradication rates were 75 of 78 (96%) for patients who received ofloxacin and 37 of 46 (80%) for patients who received placebo (P 0.009). There was no significant difference in the number of adverse events reported by patients in either of the treatment groups. Minor self-limiting adverse events caused by the drug were experienced by 7 of 152 (5%) patients on ofloxacin and by none of the patients on placebo. The results of this study indicate that ofloxacin is effective in shortening the ilness and in eradicating the pathogen from patients with diarrhea caused by bacterial enteropathogens. Ofloxacin is safe and effective in the treatment of patients with both culture-positive and culture-negative traveler's diarrhea. The recommended duration of therapy is 3 days. Bacteria are responsible for up to 50% of the cases of acute diarrhea seen in clinical practice. When patients with traveler's diarrhea and severe noninfantile diarrhea and dysentery are examined, bacterial enteropathogens are responsible for well over half of the cases (1, 3). Antimicrobial agents have been shown to be effective in the treatment of diarrhea as a result of enterotoxigenic Escherichia coli (ETEC) infection, shigellosis, and traveler's diarrhea (2, 3, 6, 9, 14). An important consideration in the treatment of diarrhea is the development of resistance to the commonly used antimicrobial agents with repeated exposure. Traveler's diarrhea, which is defined as the development of at least three stools per day in travelers who go outside their own country, is increasing as nearly 300 million people cross the borders of their own countries annually. Between 30 and 50% of travelers from developed countries who spend at least 3 weeks in developing tropical countries develop diarrhea. Bacterial pathogens have typically been recovered from approximately 60% of the cases; however, the results of studies on the prevention and treatment of traveler's diarrhea with antibiotics suggest that bacteria play a central role in the pathogenesis of the disease in a greater proportion of cases. The most common pathogen encountered is ETEC, which is also responsible for a high percentage of acute bacterial diarrhea in children from developing countries. Ofloxacin is a fluorinated carboxyquinolone agent with a broad spectrum of activity against gastrointestinal pathogens, including E. coli and species of Salmonella, Shigella, Campylobacter, Yersinia, Plesiomonas, Aeromonas, and * Corresponding author. 87 Vibrio (18). There are several potentially significant differences between ofloxacin and the other quinolones and the other classes of antimicrobial agents traditionally used to treat diarrhea. The quinolones are active against the enteric pathogen Campylobacterjejuni and resistance, which rarely develops, does not appear to be plasmid mediated, therefore decreasing the likelihood of the spread of resistance. This study was carried out to evaluate the efficacy and safety of ofloxacin compared with those of placebo in the treatment of bacterial diarrhea occurring in U.S. residents traveling in an area where bacterial diarrhea is common. The novel part of the study is the comparison of 3 days versus the accepted 5 days of antimicrobial therapy for the illness. (This work was presented at the International Congress for Infectious Diseases, Montreal, Quebec, Canada, 17 July 1990.) MATERIALS AND METHODS Two hundred thirty-two adults who developed diarrhea while they were temporarily studying in Guadalajara, Mexico, were enrolled in this double-blind, randomized, placebocontrolled, parallel treatment study from June 1986 to December 1988. Patients were eligible for enrollment in the study if they were between 18 and 65 years of age; were U.S. residents staying in Mexico; and had a presunmptive diagnosis of acute (duration of less than 60 h) diarrhea, defined as four or more unformed stools in the previous 24 h, or three or more in the previous 8 h, and fever, abdominal discomfort, urgency, or other gastrointestinal complaints. Females of childbearing potential had to have a negative pregnancy test and menstrual period within the previous 30 days and to

88 DUPONT ET AL. be using an established method of contraception. Patients were excluded from the study if they had moderate dehydration, toxicity, or severe infection requiring parenteral therapy; other gastrointestinal disease or severe vomiting; allergy to nalidixic acid, cinoxacin, or any members of the quinolone class of antimicrobial agents; significant underlying medical problems; a requirement for a second antimicrobial agent; used an antidiarrheal medication in the previous 12 h; or had previously been treated with ofloxacin. Patients were randomized to one of four treatment arms: ofloxacin, 300 mg orally twice daily for 3 or 5 days, or placebo for 3 or 5 days. Two patients were assigned to receive ofloxacin for every one patient assigned to receive the placebo. Patients and investigators were blinded to the identity of the study drug throughout the course of the study. Pre- and posttherapy physical examinations were performed on each patient. Stool cultures and microscopic parasitology examinations were done at the time of admission into the study and after 5 days into the study. The microbiologic procedures used have been described previously (12). ETEC included strains which produced heatlabile or heat-stable enterotoxin. An ophthalmologic evaluation, including an assessment of color discrimination and visual acuity, was also performed pre- and posttherapy. The laboratory studies that were performed included complete blood count with differential and platelet count; serum chemistry, including electrolytes, blood urea nitrogen, creatinine, bilirubin, and transaminase levels; and urinalysis before and after therapy. Patients were seen daily and were questioned by investigators regarding symptoms and adverse events. Diary cards filled out by all study participants were used to document the time and consistency of each stool. The primary efficacy variables in the study were clinical response and microbiologic eradication. Samples from patients with documented pathogens at the time of admission were recultured after the completion of therapy. Depending on the culture results, admission pathogens were classified as either eradicated or persistent. Clinical response was determined by the investigator on the basis of response of the signs and symptoms of the gastrointestinal tract infection to treatment. Patients were evaluated daily. Infections were categorized as cure (complete resolution of illness) or failure (deterioration of clinical status during therapy or diarrhea persisting 5 days or longer after therapy was begun). Patients who were declared to be clinical failures were given symptomatic and/or antimicrobial therapy as indicated by the field physician. Microbiologic efficacy analysis was performed by analyzing the microbiologic outcome for all patients with an initial pathogen and by determining its absence or presence in posttherapy culture. Clinical efficacy analysis was performed on patients who had an initial pathogen and on the entire population of patients who completed the therapy. All patients who took any study medication and had any follow-up assessment were included in the safety analysis. Adverse experiences were assessed by questioning patients at each daily visit. Investigators graded the severity of each adverse event and determined the relationship of the event to the study drug as none, possible, probable, definite, or unknown. Safety analysis consisted of a comparison of the rate of adverse events, changes in physical examination, and changes in laboratory parameters between the groups that received ofloxacin and placebo. Antimicrobial susceptibility testing to ofloxacin was performed on all bacterial isolates by either the Kirby-Bauer ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Clinical responses of U.S. adults with diarrhea acquired in Mexico following initiation of 5 days of ofloxacin, 3 days of ofloxacin, or a placebo No. (%) No. of Treatment group subjects Cured within: Treatment treated failurea 24 h 48 h 5 days fiue Ofloxacin, 5 days 66 27 (41) 48 (72) 59 (89) 7 (11) Ofloxacin, 3 days 81 48 (59) 65 (80) 77 (95) 4 (5) Placebo 79 30 (38) 43 (54) 56 (71) 23 (29) P valueb 0.015 0.0015 0.0001 0.0001 a Clinical deterioration during therapy or continuing illness after 5 days. b Differences among any of the three treatment groups. disk diffusion test or by MIC tests performed in accordance with the protocol of the National Committee for Clinical Laboratory Standards (12a). The statistical analyses performed by Salma Marani used the Wilcoxon rank sum test, the chi-square test, or Fisher's exact test, as appropriate. Differences in the durations of posttreatment illness were determined by the Kruskall- Wallis analysis of variance. Significance was defined as P < 0.05. This study was approved by the Committee for the Protection of Human Subjects at The University of Texas Health Science Center at Houston. RESULTS Two hundred thirty-two patients enrolled in the study were evaluable for drug reactions and safety. Nine subjects were excluded from clinical evaluation because they left the country after enrollment (one subject treated with placebo, one subject treated with ofloxacin for 5 days); were noncompliant with diaries and medication administration for or did not return for follow-up (one subject treated with placebo, two subjects treated with ofloxacin for 5 days); developed concomitant illness and were removed from the trial (three subjects treated with ofloxacin for 3 days, one subject treated with ofloxacin for 5 days). Microbiologic efficacy analysis was performed on 103 patients with a positive preenrollment stool culture for bacterial pathogen. Clinical efficacy analysis was performed on a total of 223 patients, including 120 patients from whom no pathogen was initially isolated but whose symptoms were evaluated during therapy. The treatment groups were similar with respect to age, sex, and race. The mean age of subjects in all three groups was 28 years. The mean duration of pretreatment diarrhea was similar in the three groups, varying from 27 to 29 h. The follow-up stool sample was collected from 1 to 5 days after the completion of therapy. Clinical efficacy was determined by examining changes in the clinical responses of the subjects (Table 1). Clinical cure occurred during therapy in over 90% of ofloxacin-treated subjects, whereas it occurred in 71% of those in the placebo group (P = 0.0001). Perhaps the greatest clinical relevance was the clinical failure rate of 11 of 147 (7%) of the ofloxacin-treated subjects versus 23 of 79 (29%) of the placebo-treated subjects (P = 0.0001). The data in Fig. 1 demonstrate the response to therapy over the 5 days of observation after the initiation of the study drug. By a "survival curve" presentation, the number of subjects who were well by day of study can be seen in the three groups. The duration of illness after the initiation of therapy

VOL. 36, 1992 OFLOXACIN THERAPY FOR TRAVELER'S DIARRHEA 89 40 E 60 10 0 20 40 60 80 te of subjects mon pathogens isolated were ETEC, Plesiomonas shigelloi- Number of Hours Post Ininiato of Therapy o ofoacnfoxsdayor3dy5oprdwt hs i FIG. 1. Comparative effectiveness of treatment of p iatients with a bacterial pathogen in pretreatment stools. Percentag who were well by hour posttreatment in subjects who received ofioxacin for 5 days or 3 days compared with those giiven a placebo for 5 or 3 days. Patient category Mean duration of posttreatment (h) in subjects treated with: Ofloxacin, 5 days Ofloxacin, 3 days All cases 39 ± 36a (66) 28 ± 30b (81) ETEC 36 ± 31a (18) 26 ± 33b (22) Shigella spp. 32 ± 25b (11) 24 ± 16C (5) All bacteria' 41 ± 35a (29) 28 ± 28b (36) Negative for 37 ± 37a (37) 27 ± 33a (45) bacteria Fecal leukocyte 45 ± 35 (11) 22 ± 31b (16) positive a P was not significant in comparison with the placebo-trea b p < 0.05 in comparison with the placebo-treated group. c P = 0.05 in comparison with the placebo-treated group. dall bacteria include ETEC, Shigella spp., P. shigelloides, C. jejuni, Salmonella spp., and enteropathogenic E. coli. TABLE 3. Microbiologic responses by pathogen in U.S. adults with diarrhea acquired in Mexico for ofloxacin-treated groups combined Enteropathogen No. of patients/no. of pathogens (%)a Total no. of patho- Ofloxacin, Placebo gens 3 or 5 days ETEC (P = 0.29)b 38/39 (97) 21/24 (88) 63 Shigella spp. (P = 0.028) 16/16 (100) 5/8 (63) 24 P. shigelloides (P = 0.11) 9/9 (100) 3/5 (60) 14 Others (P = 0.50)c 12/14 (86) 8/9 (89) 23 Total (P = 0.009) 75/78 (96) 37/46 (80) 124 a Some patients had more than 1 pathogen and each is included here. b No response was recorded for three subjects. C. jejuni (nine strains), Salmonella spp. (five strains), enteropathogenic E. 100 120 coli (one strain), A. hydrophila (eight strains). des, Shigella spp., and Aeromonas hydrophila. There were no significant differences in the etiologic agents identified in the various treatment groups. Microbiologic eradication rates for bacterial pathogens were 36 of 38 (95%) for the group treated with ofloxacin for 5 days, 39 of 40 (98%) for the differed in the various groups according to thie length of group treated with ofloxacin for 3 days, and 37 of 46 (80%) ofloxacin therapy and the presence of a bacte-rial entero- for the group that received placebo. In Table 3, eradication pathogen or microscopic leukocytes in pretreattment stools data are summarized after combining the data for the two (Table 2). When compared with the correspond] ing placebo- ofloxacin treatment groups. The overall eradication rate was treated cases, illness was shortened in those who received 5 75 of 78 (96%) for the ofloxacin-treated group and 37 of 46 days of ofloxacin therapy and who had cul[ture-proven (80%) for the placebo-treated group (P = 0.009). The most shigellosis (32 versus 98 h). In the patients raridomized to common isolate, ETEC, was eradicated from 38 of 39 (97%) receive ofloxacin for 3 days, even more imprerssive reduc- of the patients who received ofloxacin and from 21 of 24 tions in posttreatment diarrhea were seen. Signifficantreduc- (88%) of the patients who received placebo (P was not tions in posttreatment illness in this group wass seen in all significant). Shigella strains were eradicated from posttreatdiarrhea (26 ment stools of 16 of 16 (100%) ofloxacin-treated subjects cases (28 versus 56 h), subjects with ETEC ( versus 66 h), subjects with shigellosis (24 versus 98 h) versus 5 of 8 (63%) placebo-treated subjects (P = 0.028). P. subjects with diarrhea associated with all bactcerial entero- shigelloides was eradicated from nine of nine of the ofloxa- in whom cin-treated subjects and three of five of the placebo-treated pathogens combined (28 versus 69 h), and subjects leukocytes were found microscopically in piretreatment subjects (P was not significant). The three organisms identi- duration fied in posttreatment stools of those randomized to receive stools (22 versus 49 h). Although a reduction in Ithe of illness was seen in ofloxacin-treated groups with stools ofloxacin, a heat-labile toxin-positive and heat-stable toxin- were positive ETEC isolate and two C. jejuni isolates, were each negative for bacterial enteropathogens, the differences not significant. susceptible to ofloxacin before and after therapy. A total of 124 pathogens were isolated friom the 103 The incidence of adverse events that was probably or patients with culture-positive stool samples. Thie most com- definitely thought to be related to the study drug was 3 of 68 (4%) in the group treated with ofloxacin for 5 days and 4 of 84 (5%) in the group treated with ofloxacin for 3 days. These events included two reports each of TABLE insomnia, dizziness, and 2. Duration of posttreatment diarrhea in U.' diarrhea acquired in Mexico according to eti( S- adults with dysgeusia and one report each of sleep disorder, nausea, and )logy vaginitis. There were no definite or probable drug-related ± SE (n) adverse events in the group treated with placebo. Two patients, both of whom were on ofloxacin, discontinued the Placebo study medication because of adverse experiences. One of these patients experienced nausea and vaginitis and the 56 ± 48 (79) other one experienced headache and rash. All reactions were 66 ± 48 (26) considered to be clinically nonserious, and all were self- 698 ±349 (36) limiting. 46 46 (43) No significant ophthalmologic changes were observed after treatment with the study drugs. No hematologic, blood 49 ± 46 (25) chemistry, or urinary findings could be related to ofloxacin treatment. ited group. DISCUSSION A. hydrophila, This randomized double-blind study was conducted to compare ofloxacin with placebo in the treatment of acute

90 DUPONT ET AL. traveler's diarrhea and to determine the drug's effect on the eradication of bacterial pathogens. While we have previously shown that an antimicrobial agent together with loperamide is perhaps the optimal therapy for afebrile, nondysenteric traveler's diarrhea (5), a placebo can successfully be used in trials in patients with this milder form of illness if rescue medication is made available for those who fail to respond. Two hundred thirty-two patients who were U.S. citizens on short-term visits to Guadalajara, Mexico, and who had signs and symptoms of traveler's diarrhea were enrolled in the study. Clinical and microbiologic cure rates were indistinguishable for the 3- and 5-day regimens of ofloxacin, although the 3-day regimen appeared to be associated with a more favorable clinical response. The differences between the 5- and the 3-day regimens were not significant. In the present study, ofloxacin significantly shortened the duration of diarrhea compared with a placebo for all cases combined, regardless of etiology, which represents additional support for the findings of other studies (2, 3, 6, 7, 12). This indicates that most cases of traveler's diarrhea represent enteric bacterial infections. The subgroups of patients who clinically responded to ofloxacin included those with ETEC diarrhea, shigellosis, diarrhea associated with any bacterial enteropathogen, and those with microscopic fecal leukocytes found in pretreatment stool specimens. When numerous leukocytes are found in diarrheal stools, the patient has a diffuse colitis usually caused by an invasive bacterial enteropathogen (10). We have previously produced evidence that the fecal leukocyte test is a valuable means of determining which patients, both children (15, 16) and adults (1), benefit the most from antimicrobial therapy. While a significant reduction in stool culture positivity resulted in those with proven bacterial diarrhea randomized to receive a course of ofloxacin compared with those who received placebo, a single posttherapy stool was collected only shortly after completing treatment (1 to 5 days after treatment). A residual intestinal antimicrobial effect may have influenced this result. Also, we did not follow stools for 1 month or longer to look at the duration of excretion (13). As reported previously (4), we do not believe that follow-up stool cultures are an important feature of antimicrobial clinical trials in subjects with traveler's diarrhea in whom fecal excretion of bacteria is short-lived and reinfection is common and in whom the focus should be on clinical efficacy (4) Ȧ significant potential advantage of the fluoroquinolones over the other chemotherapeutic agents used to treat bacterial diarrhea is their activity against Shigella spp., C. jejuni, and trimethoprim-resistant enteric bacteria (18). Results of this study indicate that ofloxacin was effective in the treatment of diarrhea caused by Shigella spp. in our patient population. In the present study, the number of patients infected with C. jejuni was insufficient to make an evaluation of the relative efficacy of ofloxacin against this pathogen. Similarly, an insufficient number of Salmonella strains was encountered to evaluate the efficacy of ofloxacin against this pathogen. In a single case report of nontyphoid Salmonella carriage, ofloxacin was effective in eliminating intestinal infection (11). In addition to the unique antimicrobial spectra of the quinolones, these agents are known to concentrate in the intestine. In a study of intestinal flora changes following a lower dose of ofloxacin (200 mg twice daily), fecal concentrations were 327 + 274,ug/g after 4 days of therapy (17). We have evaluated the available quinolones in the treatment of acute diarrhea (1, 7). While side-by-side comparisons have ANTIMICROB. AGENTS CHEMOTHER. not been carried out, we believe that for most cases of acute bacterial diarrhea, including traveler's diarrhea, norfloxacin (400 mg), ciprofloxacin (500 mg), or ofloxacin (300 mg) given twice daily for 3 days would show equivalent clinical efficacies. Ofloxacin may be uniquely suited to single-dose therapy in view of its better absorption and longer terminal elimination half-life (8, 19). A half-life of approximately 6 h is seen following oral administration of any dose of ofloxacin, with residual drug found in plasma for up to 5 days after a single dose (8). We are carrying out a clinical trial in which we are comparing 3 days of ofloxacin therapy (200 mg twice daily) with single-dose ofloxacin (400 mg) therapy with or without loperamide in subjects with traveler's diarrhea. The results of this study indicate that ofloxacin is more effective than placebo in producing a clinical cure and eradicating gastrointestinal pathogens from patients with bacterial diarrhea. Ofloxacin was well tolerated and, with the exception of mild insomnia, produced no more adverse reactions than did the placebo. A 3-day regimen of ofloxacin is recommended over the accepted 5-day regimen for antimicrobial therapy of traveler's diarrhea. ACKNOWLEDGMENTS The present study was supported by the National Institutes of Health (ROl AI-23049) and by a grant from Ortho Pharmaceuticals. 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