John J. Mathewson

Risk and aetiology of diarrhoea at various tourist destinations.

Almost two of three tourists developed travellers diarrhoea during 2-week stays at high-risk destinations. Large differences in infection rates between hotels were seen. Patients with milder forms of diarrhoea show a similar chronology to those more severely affected. Although enterotoxigenic Escherichia coil was the most frequent cause, viral pathogens were detected more often than in other studies.

Rifaximin versus Ciprofloxacin for the Treatment of Traveler's Diarrhea: A Randomized, Double-Blind Clinical Trial

Rifaximin is a poorly absorbed rifamycin derivative under investigation for treatment of infectious diarrhea. Adult students from the United States in Mexico and international tourists in Jamaica were randomized to receive either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for 3 days, following a double-blinded model, from June 1997 to September 1998. A total of 187 subjects with diarrhea were studied. Time from initiation of therapy to passage of last unformed stool was comparable for those receiving rifaximin or ciprofloxacin (median, 25.7 hours versus 25.0 hours, respectively). There was no significant difference in the proportion of subjects in the 2 groups with respect to clinical improvement during the first 24 hours (P=.199), failure to respond to treatment (P=.411), or microbiological cure (P=.222). The incidence of adverse events was low and similar in each group. Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of travelers diarrhea.

Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers' diarrhea.

Background/Aims: Bacterial enteropathogens, the major cause of travelers’ diarrhea, are customarily treated with antibacterial drugs. Rifaximin, a nonabsorbed antimicrobial was examined as treatment for travelers’ diarrhea. Methods: A randomized, prospective, double-blind clinical trial was carried out in 72 US adults in Mexico. Patients with acute diarrhea received one of three doses of rifaximin (200, 400 and 600 mg t.i.d.) or trimethoprim/sulfamethoxazole (TMP/SMX, 160 mg/800 mg b.i.d.) for 5 days. Results were compared with data from 2 placebo-treated historical control populations. Results: The shortest duration of treated diarrhea was seen in the group receiving 200 mg rifaximin t.i.d (NS). Clinical failure to respond to treatment occurred in 6 of 55 (11%) rifaximin-treated subjects versus 5 of 17 (29%) of TMP/SMX-treated subjects (NS). Sixteen of twenty (80%) of the enteropathogens isolated from the rifaximin-treated subjects and 7 of 7 (100%) from the TMP/SMX group were eradicated by treatment (NS). Sixteen of twenty-four (67%) enteropathogens identified were susceptible to TMP and all 24 were inhibited by ≤50 µg/ml of rifaximin. Rifaximin reduced the number of unformed stools passed during the first 24 h of treatment when compared with 2 control placebo groups (3.3 versus 5.1; p = 0.008 and 0.0001) and led to a reduced duration of post-enrollment diarrhea (mean values of 43.1 versus 68.1 and 81.9 h; p = 0.001). Conclusions: Rifaximin shortened the duration of travelers’ diarrhea compared with TMP/SMX and 2 earlier studied placebo-treated groups. A poorly absorbed drug if effective in treating bacterial diarrhea has pharmacologic and safety advantages over the existing drugs.

Emergence of resistant fecal Escherichia coli in travelers not taking prophylactic antimicrobial agents.

Fecal specimens from individuals traveling to Mexico were examined before, during, and after travel for the presence of Escherichia coli resistant to ampicillin, chloramphenicol, gentamicin, kanamycin, streptomycin, sulfonamides, trimethoprim (TMP), and TMP-sulfamethoxazole (TMP-SMX). None of these individuals took prophylactic antibiotics, although 4 of 13 took short courses of an antimicrobial agent for therapy of travelers diarrhea. With an average of 9.3 E. coli per sample, resistance to all agents tested except gentamicin was shown to increase during the time in Mexico (P less than 0.001 to P less than 0.05). For example, no TMP-resistant (Tmpr) E. coli isolates were found by this method before travel, whereas 57% of the individuals had Tmpr and Tmpr-Smxr E. coli by the final week in Mexico. This increase in resistance occurred regardless of whether an individual took a short course of antimicrobial therapy. This study shows that travel itself, even without the use of prophylactic or therapeutic antimicrobial agents, is associated with the acquisition of resistant E. coli. Travel to developing nations may rival other sources of resistant organisms.

Five versus three days of ofloxacin therapy for traveler's diarrhea: a placebo-controlled study.

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 less than 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 coli 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative in vitro activities of ten antimicrobial agents against bacterial enteropathogens.

The in vitro susceptibilities of 50 strains of Salmonella spp., 80 strains of Shigella spp., and 50 enterotoxigenic Escherichia coli, 14 Yersinia enterocolitica, 6 Aeromonas hydrophila, 4 Plesiomonas shigelloides, 9 Vibrio parahaemolyticus, and 30 Campylobacter jejuni strains that were recently isolated from worldwide sources were determined for 10 antimicrobial agents. The antimicrobial agents tested included ampicillin, bicozamycin, doxycycline, enoxacin (CI-919), erythromycin, furazolidone, amdinocillin, norfloxacin, trimethoprim, and trimethoprim-sulfamethoxazole. Ampicillin resistance occurred frequently in strains of Salmonella and Shigella spp. and enterotoxigenic E. coli strains. The most active agents against all of the bacteria tested were enoxacin and norfloxacin. Furazolidone and amdinocillin were also highly active against the majority of strains. Trimethoprim and trimethoprim-sulfamethoxazole were inhibitory at low concentrations against all test except C. jejuni isolates. The in vitro results of this study confirm the high prevalence of bacterial resistance to ampicillin. However, this work also identifies four antimicrobial agents, enoxacin, furazolidone, norfloxacin, and amdinocillin, that would be appropriate for further testing in clinical trials.

Enteroaggregative Escherichia coli as a Cause of Traveler's Diarrhea: Clinical Response to Ciprofloxacin

The purpose of this study was to determine the role of enteroaggregative Escherichia coli (EAEC) in the development of travelers diarrhea and the clinical response of patients with EAEC diarrhea following treatment with ciprofloxacin. Sixty-four travelers with diarrhea and no other recognized enteropathogen were enrolled in treatment studies in Jamaica and Mexico from July 1997 to July 1998. EAEC was isolated from 29 travelers (45.3%). There was a significant reduction in the duration of posttreatment diarrhea in the 16 patients treated with ciprofloxacin, as compared with that in the 13 patients who received placebo (mean of 35.3 versus 55.5 hours; P = .049). There was a nonsignificant reduction in the mean number of unformed stools passed during the 72 hours after enrollment in the ciprofloxacin-treated group (5.6), as compared with that in the placebo group (7.5) (P = .128). This study provides additional evidence that EAEC should be considered as a cause of antibiotic-responsive travelers diarrhea.

A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico.

OBJECTIVE:The study was designed to evaluate the effectiveness of SP-303 (Provir), a plant-derived product with novel antisecretory properties, in the treatment of travelers’ diarrhea.METHODS:A total of 184 persons from the United States who acquired diarrhea in Jamaica or Mexico were enrolled in a double-blind, placebo-controlled study examining the effectiveness of three doses of SP-303 in reducing illness. Subjects were treated with 125 mg, 250 mg, or 500 mg SP-303 or a matching placebo four times a day for 2 days. Subjects kept daily diaries of symptoms and were seen each day for 3 days. Of the subjects, 169 (92%) were included in the efficacy analysis.RESULTS:The most common etiological agent identified was enterotoxigenic Escherichia coli, found in 19% of subjects. The mean time interval from taking the first dose of medication until passage of the last unformed stool during 48 h therapy (TLUS48) was 38.7 h for the placebo group. TLUS48 was shortened by SP-303: 30.6 h for the 125-mg dose group (p = 0.005); 30.3 h for the 250-mg group; and 32.6 h for the 500-mg group (p = 0.01). Treatment failures were seen in 29.3% in the placebo group compared with 7.3% (p = 0.01), 4.3 (p = 0.002), and 9.8 (p = 0.026) in the three treatment groups. SP-303 was well tolerated at all doses.CONCLUSIONS:SP-303 was effective in shortening the duration of travelers’ diarrhea by 21%. This antisecretory approach works directly against the pathophysiology of travelers’ diarrhea and is not likely to potentiate invasive forms of diarrhea or to produce posttreatment constipation.

Comparative efficacy of loperamide hydrocholoride and bismuth subsalicylate in the management of acute diarrhea

An open-label, parallel comparison of loperamide hydrochloride (Imodium A-D) and bismuth subsalicylate (Pepto-Bismol) was conducted using nonprescription dosages in adult students with acute diarrhea (three or more unformed stools in the preceding 24 hours plus at least one additional symptom of enteric infection). For the two-day study period, the daily dosage was limited to 8 mg (40 ml) for loperamide-treated subjects and to 4.9 g for bismuth subsalicylate-treated subjects. At these dosages, loperamide significantly reduced the average number of unformed bowel movements relative to bismuth subsalicylate. Following the initial dose of treatment, control of diarrhea was maintained significantly longer with loperamide than with bismuth subsalicylate. Time to last unformed stool was significantly shorter with loperamide than with bismuth subsalicylate. In providing overall subjective relief, subjects rated loperamide significantly better than bismuth subsalicylate at the end of the 24 hours. Both treatments were well tolerated, and none of the minor adverse effects reported resulted in discontinuation of therapy. It was concluded that loperamide is effective at a daily dosage limit of 8 mg (40 ml) for the treatment of acute nonspecific diarrhea and provides faster, more effective relief than bismuth subsalicylate.

Etiology of outpatient pediatric nondysenteric diarrhea: A multicenter study in the United States

BACKGROUND Few data have been published recently on the etiology of outpatient pediatric diarrhea in the US. METHODS We determined the etiology of acute, nondysenteric diarrhea among 147 children between 2 and 11 years old presenting to 9 outpatient clinics in various regions of the US between August, 1991, and August, 1993. Enteropathogens were sought by conventional laboratory methods. The various diarrheagenic Escherichia coli were sought. RESULTS A recognized etiologic agent was detected in the stools of 89 (60.5%) children and 15 (10) patients had multiple agents detected. Rotavirus was found in 43 (29.3%) of the children, with a spring and winter peak in occurrence. Giardia lamblia was identified in 22 (15%) cases with a spring peak. HEp-2 cell-adherent E. coli were found in 15 (10.2%). Other agents found included: enteric adenovirus in 7 (4.8%); Salmonella in 5 (3.4%); enterohemorrhagic E. coli in 5 (3.4%); enteropathogenic E. coli in 2 (1.4%); enterotoxigenic E. coli in 2 (1.4%); Entamoeba histolytica in 1 (0.70%); and Campylobacter jejuni in 1 (0.7%). CONCLUSIONS In addition to the presence of conventional enteropathogens, diarrheagenic E. coli (HEp-2 cell-adherent E. coli, enterohemorrhagic E. coli, enteropathogenic E. coli and enterotoxigenic E. coli) were associated with endemic pediatric diarrhea in the US.