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

  1. Herbert L. DuPont1,2,
  2. Zhi-Dong Jiang1,
  3. Charles D. Ericsson1,
  4. Javier A. Adachi1,
  5. John J. Mathewson1,a,
  6. Margaret W. DuPont1,
  7. Ernesto Palazzini4,
  8. Lise M. Riopel3,
  9. David Ashley5, and
  10. Francisco Martinez Sandoval6
  1. 1Center for Infectious Diseases, The University of Texas—Houston School of Public Health and Medical School, Houston
  2. 2St. Luke's Episcopal Hospital and Baylor College of Medicine, Houston
  3. 3Salix Pharmaceuticals, Palo Alto, California
  4. 4Alfa Wassermann, SpA, Bologna, Italy
  5. 5Ministry of Health of Jamaica, Montego Bay
  6. 6Universidad Autonoma de Guadalajara, Guadalajara, Mexico
  1. Reprints or correspondence: Dr. Herbert L. DuPont, St. Luke's Episcopal Hospital, 6720 Bertner Ave., MC 1-164, Houston, TX 77030 (hdupont{at}sleh.com).

  1. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 1999 (abstract 2227).

  • ↵a Present affiliation: Assistant Laboratory Chief, Bureau of Laboratory Services, Houston Department of Health and Human Services, Houston, Texas.

 
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Abstract

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 traveler's diarrhea.

Diarrhea affects ∼40% of persons who travel to tropical and semitropical areas of the developing world. In up to 85% of patients with traveler's diarrhea, bacteria appear to be responsible for the illness [1, 2]. The principal bacterial causes of diarrhea are enterotoxigenic Escherichia coli, enteroaggregative E. coli, Shigella species, Campylobacter jejuni, Salmonella species, Aeromonas species, Plesiomonas species, and non-cholerae Vibrio species. Administration of antibacterial drugs has become the recommended therapy for this illness. Because of their activity against each of these bacteria, fluoroquinolones have become the accepted therapeutic agents for traveler's diarrhea in adults [3].

Rifaximin is a rifamycin derivative with antibacterial activity caused by inhibition of bacterial synthesis of RNA [4]. The drug is active against gram-positive and gram-negative bacteria, including both aerobes and anaerobes. Less than 0.1% of the oral dose of rifaximin is absorbed [5, 6]. Rifaximin is available in Italy for the treatment of acute bacterial diarrhea [6], portosystemic encephalopathy [7], and small-bowel bacterial overgrowth syndrome [8]. Rifaximin is also licensed in Mexico, as well as in other countries in Europe, Asia, and Africa.

Previous studies by our group have shown that nonabsorbable antibacterial drugs were highly effective in treating traveler's diarrhea. Both bicozamycin [9] and aztreonam [10] given orally were shown to reduce diarrhea and lead to bacteriologic cures in groups who travel from the United States to Mexico. Unfortunately, neither of these drugs was developed for oral use against enteric infection. The present study was developed to examine the safety and tolerability as well as the clinical and microbiological efficacy of rifaximin in the treatment of traveler's diarrhea. The comparative drug, ciprofloxacin, was the current standard for treatment of the disease [3, 11].

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Methods

This was a double-blind, double-dummy, randomized clinical trial conducted from June 1997 through September 1998 (1) in Guadalajara, Mexico, among students from the United States who were attending classes in the Guadalajara summer programs of the University of Arizona and the University of San Diego [2], and (2) in Ocho Rios, Jamaica, among international tourists staying in resort hotels [12]. For enrollment, subjects needed to be at least 18 years of age and have diarrhea. Subjects were excluded if they were pregnant, were breast-feeding, had an unstable medical condition, or had taken >2 doses of an antidiarrheal medication in the 24 h before enrollment, any number of doses of symptomatic therapy within 2 h of enrollment, or any antimicrobial drug with expected activity against enteric bacterial pathogens within the week before enrollment.

The participation of subjects was completely voluntary. Details of the study were explained to the subjects. Written consent was obtained from each subject prior to enrollment in this protocol. Subjects were allowed to withdraw from the study at any time.

The study was reviewed and approved by The University of Texas—Houston Health Science Center Committee for the Protection of Human Subjects and local regulatory authorities where the study was conducted. In addition, the Ministry of Health of Jamaica and the Secretaria de Salud of Jalisco, Mexico, reviewed the protocol and approved the conduct of the study in their respective territories.

Consenting subjects underwent screening procedures, which included the recording of medical history, a brief medical examination, and clinical blood studies. Eligible subjects were then randomized to receive one of the following treatment regimens in a double-blind fashion: 2 tablets of rifaximin (200 mg each) plus 1 tablet of ciprofloxacin placebo twice per day for 3 days or 2 tablets of rifaximin placebo plus 1 tablet of ciprofloxacin (500 mg) twice per day for 3 days. Both placebos looked identical to the corresponding active compounds. The ciprofloxacin and ciprofloxacin placebo tablets were manufactured by Madaus (Barcelona). Medications were randomized in blocks of 10 patients per group. Blocks of 10 medications were distributed to the various sites.

Subjects were seen daily in our clinics at the schools in Guadalajara or at resort hotels in Ocho Rios for 5 days. Subjects completed daily diaries of clinical symptoms and signs, including the time and form of all stools passed during the 5-day study period. Safety was assessed by means of physical examination, assessment of vital signs, and routine blood studies relevant to hematologic, liver, and kidney function. Use of antidiarrheal compounds, including aspirin, ibuprofen, and antiperistaltic agents, was prohibited during the study.

A stool sample was obtained before administration of the medication and again on day 4 or 5 after initiation of antimicrobial therapy, for identification of enteropathogens. Bacterial pathogens sought in our local laboratories included Shigella, Salmonella, Aeromonas, Vibrio, and Plesiomonas species, Campylobacter jejuni, and Yersinia enterocolitica. Protozoal pathogens, including Entamoeba histolytica and Cryptosporidium and Giardia species, were identified by use of ELISA (Alexon). Five E. coli–like colonies were isolated from each stool sample and transported to Houston on peptone stabs. In Houston, enterotoxigenic E. coli was sought by looking for production of heat-labile and heat-stable enterotoxin by a DNA hybridization/probe technique [13], and enteroaggregative E. coli was sought by HEp-2 cell assay for adherence [14].

In vitro susceptibility testing to determine the MIC of the isolated enteric bacterial pathogens was performed with agar dilution methods, following the recommendations of the National Committee of Clinical Laboratory Standards [15].

Definitions. Stool form was defined according to 3 categories: “formed” (stool retained its shape), “soft” (stool took the shape of a container), and “watery” (stool could be poured). Both soft and watery stools were considered to be unformed. To be eligible, subjects had to pass ≥3 unformed stools in 24 h and to have been ill for ≤72 h. One or more additional signs or symptoms of enteric infection had to have been present, including nausea, vomiting, abdominal cramps or pain, tenesmus, dysentery (passage of grossly bloody stools), and fecal urgency. Collection of a pretreatment stool that was confirmed by clinic personnel to be unformed was required prior to enrollment. Wellness (cure) was defined as: (1) passage of no unformed stools in a 48-h interval and no fever, with or without other clinical symptoms, or (2) passage of no watery stools and no more than 2 soft stools in a 24-h interval and no fever or other clinical symptoms of enteric infection (see above for list of symptoms). The time to last unformed stool (TLUS) was defined as the interval from initiation of therapy until passage of the last unformed stool, after which subjects were declared healthy. In determinations of the TLUS, a mild excess of gas or mild flatulence was not considered to be a symptom of continuing illness.

“Improvement” was defined as a ≥50% reduction in the number of unformed stools passed during a 24-h period, in comparison with the number of unformed stools passed during the 24 h immediately before enrollment in the study. “Treatment failure” was defined as (1) clinical deterioration or worsening of clinical symptoms after at least 24 h of therapy, in comparison with pretreatment symptoms and number of stools passed; (2) failure of clinical symptoms to abate after at least 24 h of therapy; or (3) illness continuing after 120 h. “Bacteriologic cure” was defined by a negative posttreatment stool examination for the etiologic organism identified before treatment. “Bacteriologic failure” of treatment was defined as the continued presence in the posttreatment stool sample of the infecting organism found in the corresponding pretreatment sample. “Adverse experience” was a clinical finding or patient complaint in the daily diary that was not present in the 24 h immediately before enrollment in the trial.

The primary clinical efficacy end point was rapidity of resolution of diarrhea and modification of stools, as measured by the TLUS. Secondary end points included the number of unformed stools passed per time interval of study; the number of subjects whose condition improved 0–24 h and >24–48 h after enrollment in the trial; the number of subjects with clinical symptoms (nausea, vomiting, abdominal pain and cramps, excess gas or flatulence, urgency, tenesmus, and/or fever) for the 0–24-h, >24–48-h, >48–72-h, >72–96-h, and >96–120-h intervals after enrollment; the number of subjects whose treatment failed (who did not become healthy); the number of subjects who had bacteriological cure; and occurrence of adverse experiences.

Statistical analyses. The sample size was based on comparison of the treatment groups with respect to the proportion of subjects who passed the last unformed stool by the end of the first 24 h of study. Historical data indicated that the probability of passing the last unformed stool by the end of the first 24 h was 0.62 for ciprofloxacin. The calculation was based on a 0.05 level of significance (α = 0.05), a power of 0.80, an alternative probability of 0.41 for the rifaximin group, and an equal number of subjects in each group. This is equivalent to assuming a median TLUS of 17 h for the ciprofloxacin group and a median TLUS of 31 h for the rifaximin group (hazard ratio, 0.55). The final sample size of 188 patients provided >80% power for the specific alternative.

All statistical analyses were based on the intent-to-treat principle, defined as all subjects included in the treatment groups to which they were randomized. TLUS was summarized with use of Kaplan-Meier estimates. Subjects for whom TLUS could not be calculated because of early withdrawal because of treatment failure were noted as having a censored TLUS as of 120 h. Data for subjects for whom TLUS could not be calculated because of early termination for reasons other than treatment failure (e.g., adverse event or being lost to follow-up) were censored at the time for which the last information on unformed stools was available. The objective of the analysis of TLUS was to demonstrate that the TLUS for rifaximin was not inferior to that for ciprofloxacin. A procedure described by Com-Nouque et al. [16] that established equivalence (noninferiority) with survival-type data was used for the analysis. For improvement, continuing clinical signs and symptoms of enteric illness, wellness, treatment failure, bacteriologic cure, and incidence of adverse events, the χ2 test was used (the alternative was Fisher's exact test). For number of unformed stools passed per interval, the treatment groups were compared with use of a repeated-measures analysis of variance model for time intervals 0–24 h, >24–48 h, >48–72 h, >72–96 h, and >96–120 h as the repeated effect.

All comparisons of treatment groups were performed with use of 2-sided tests at a 0.05 level of significance. Data analyses were performed by STATPROBE (Seattle).

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Results

Of the 187 subjects enrolled in the study, 93 were randomized to receive rifaximin and 94 were randomized to receive ciprofloxacin. Twenty-four patients were enrolled in Jamaica and 163 in Mexico. Ninety-two of 93 subjects in the rifaximin group completed the trial. One subject randomized to receive rifaximin was lost to follow-up. Ninety of 94 subjects in the ciprofloxacin group completed the trial. One patient randomized to receive ciprofloxacin was lost to follow-up, 2 were noncompliant with medication or with provision of the daily diaries, and 1 patient had Cryptosporidium species recovered from pretreatment stool samples and requested to be withdrawn from the study after 2 days in the trial. Demographics and baseline disease characteristics are shown in tables 1 and 2. The 2 groups were comparable in terms of sex, race, age, and weight. Other baseline or pretreatment symptoms in the 2 groups (rifaximin vs. ciprofloxacin) were nausea (57% vs. 67%), vomiting (19% vs. 17%), abdominal pain or cramps (91% vs. 89%), and fever (9% vs. 9%). Table 2 shows pretreatment stool microbiological results for the treatment groups, including the enteropathogen detected and whether fecal leukocytes were found. Microbiologically, the groups were comparable.

Figure 1
Figure 1

Comparative effectiveness of treatment of patients with traveler's diarrhea. The percentages of subjects who remained ill by hour after treatment, among those who received rifaximin or ciprofloxacin for 3 days, are compared. When the patients became healthy (i.e., the time from initiation of therapy to passage of last unformed stool was determined), they were removed from the comparison.

Figure 2
Figure 2

Mean number of unformed stools passed per day of study by subjects with traveler's diarrhea taking rifaximin or ciprofloxacin. The mean values for the 2 treatment groups were comparable for each day of the study.

Table 1
Table 1

Demographic characteristics of the 2 treatment groups (patients who received rifaximin versus patients who received ciprofloxacin).

Table 2
Table 2

Baseline disease characteristics of the 2 treatment groups (patients who received rifaximin versus patients who received ciprofloxacin).

Compliance with both medications was good. More than 95% of patients in both groups took the prescribed number of tablets for days 1 and 2, and >90% took them for day 3, as determined by daily diaries and returned medication cards.

In figure 1, a comparison of the cumulative percentages of subjects remaining ill during the study is illustrated. The curves exclude those for which the TLUS was determined or who became healthy. TLUS for the 2 groups can be determined from the figure. The 2 curves are similar. The median TLUS was 25.7 h (95% CI, 20.9–38.0) for rifaximin-treated subjects, compared with 25.0 h (95% CI, 18.5–35.2) for ciprofloxacin-treated patients. A total of 12 (13%) of the 93 rifaximin recipients and 11 (12%) of the 94 ciprofloxacin subjects had a censored TLUS. A TLUS of 0 h, which indicated that the criteria for wellness were met immediately after enrollment in the study, was noted for 7 (8%) of 93 subjects in the rifaximin group and 19 (20%) of 94 subjects in the ciprofloxacin group. In the groups of pathogen-negative patients (47 rifaximin recipients and 46 ciprofloxacin recipients), the median TLUS was 25.5 h for rifaximin recipients and 30 h for ciprofloxacin recipients (P = .340). In the group of patients with pathogen-specific illness (43 rifaximin recipients and 47 ciprofloxacin recipients), the median TLUS was 25.7 h for rifaximin recipients and 25.0 h for ciprofloxacin recipients (P = .614). The analysis of the data provides sufficient evidence that the treatment groups were equivalent with respect to TLUS (P = .006), rejecting the hypothesis that rifaximin is inferior with the technique described by Com-Nougue et al. [16].

The numbers of unformed stools passed during the 3 days of therapy and 5 days of observation are shown in figure 2. The bar graph reveals a similar mean number of stools passed per interval in the 2 treatment groups. No significant difference was seen between the treatment groups in terms of number of unformed stools passed (P = .267).

Improvement within 0–24 h after enrollment in the trial occurred in 54 (58%) of the subjects randomized to receive rifaximin and in 60 (64%) of those randomized to receive ciprofloxacin (P = .419). Improvement was noted by 0–48 h after enrollment for 77 subjects (83%) and 80 subjects (85%) in the respective groups (P = .667).

Clinical symptoms after initiation of therapy were similar in the 2 groups, with the exception of 2 symptoms. Nausea was less common among the rifaximin-treated subjects than it was among the ciprofloxacin-treated subjects at 24–48 h (18% vs. 34%, respectively; P = .012) and 48–72 h (10% vs. 23%, respectively; P = .009). The incidence of tenesmus was significantly greater among the rifaximin-treated subjects during the 0–24-h interval (P = .016), but there were no significant differences in the incidence of tenesmus during the 24–48-h and 48–72-h intervals (P = .348). At baseline, tenesmus was noted in a larger percentage of subjects in the rifaximin group than in the ciprofloxacin group.

Wellness during the study was declared for a total of 81 (87%) of 93 subjects in the rifaximin group and 83 (88%) of 94 subjects in the ciprofloxacin group (P = .803). There were a total of 9 treatment failures (10%) in the rifaximin group and 5 (6%) in the ciprofloxacin group (P = .258). All of the failures were after 72 h and were a result of nondeclaration of wellness by the end of the observation period.

In table 3 the etiologic organisms found in pretreatment stools and the bacteriologic response to therapy are presented. In this analysis, only subjects with an identified pretreatment pathogen who provided a posttreatment sample are included. Stool microbiological studies were negative for an enteropathogen for 48 (52%) of 92 subjects in the rifaximin group furnishing pretreatment stools and for 47 (50%) of 94 subjects in the ciprofloxacin group. In 44 (48%) of 92 subjects in the rifaximin group, an enteropathogen was identified; the pathogen-detection rate was 50% (47 of 94) for the ciprofloxacin group. The principal pathogen identified was enterotoxigenic E. coli, occurring in 36 (39%) of 92 rifaximin-treated and 36 (38%) of 94 ciprofloxacin-treated subjects who provided pretreatment stool samples. Among patients who had a pretreatment bacterial pathogen identified, 3 subjects in the rifaximin group and 6 in the ciprofloxacin group did not provide a posttreatment stool sample. For those with a pathogen in the pretreatment sample who provided a posttreatment sample, 29 (74%) of 39 pathogens in the rifaximin group and 38 (88%) of 43 in the ciprofloxacin group were eradicated (P = .152). Enterotoxigenic E. coli was not eradicated in 10 (30%) of 33 rifaximin-treated subjects or 4 (12%) of 32 ciprofloxacin-treated subjects in whom this was the sole pathogen (RR, 2.42; 95% CI, 0.85–6.5). The mean TLUS for the 10 rifaximin-treated, enterotoxigenic E. coli–associated microbiological failures was 35.6 h, compared with an mean TLUS of 10.9 h for the 4 ciprofloxacin-treated, enterotoxigenic E. coli—associated microbiologic failures (P = .09).

Table 3
Table 3

Microbiological outcome (cure or failure) after 3 days of treatment with rifaximin or ciprofloxacin in patients who provided pretreatment and posttreatment stool samples for microbiological assessment.

In vitro antimicrobial susceptibility testing was performed on the bacterial enteropathogens isolated before treatment (table 4). Forty-four bacterial pathogens in the rifaximin treatment group and 48 in the ciprofloxacin treatment group were tested for susceptibility to both drugs used in the trial (one enterotoxigenic E. coli strain in each treatment group was not available for testing because it was not viable on subculture). The MIC90 (MIC for ≥90% of strains tested) was 0.25–32 μg/mL for rifaximin and <0.016–0.125 μg/mL for ciprofloxacin. In vitro susceptibilities to rifaximin and ciprofloxacin of the pretreatment and posttreatment enterotoxigenic E. coli isolates in all cases of microbiological treatment failures are listed in table 5. In only 1 of the 10 rifaximin-treated subjects, the rifaximin MIC of the posttreatment isolate of enterotoxigenic E. coli was three 2-fold dilutions higher than for the corresponding pretreatment strain (pretreatment MIC of rifaximin was 0.5 μg/mL and the posttreatment MIC was 4 μg/mL). For 3 other rifaximin-treated subjects, the MIC of rifaximin was 1 dilution lower for the posttreatment versus pretreatment sample. The pretreatment enterotoxigenic E. coli isolate from 1 rifaximin-treated subject did not grow on subculture, and, therefore, it was not available for susceptibility testing, but the corresponding posttreatment isolate's MIC of rifaximin was low. None of the strains recovered from the 4 ciprofloxacin-treated subjects with pretreatment and posttreatment enterotoxigenic E. coli isolates showed increased resistance in the second sample when compared with the first. For 1 subject the initial MIC of ciprofloxacin decreased (from 0.5 μg/mL) to <0.016 μg/mL against the posttreatment isolate.

Table 4
Table 4

MICs of bacterial isolates obtained before treatment in a trial comparing rifaximin and ciprofloxacin in therapy for traveler's diarrhea.

Table 5
Table 5

MICs of pretreatment and posttreatment isolates of enterotoxigenic Escherichia coli in a trial comparing rifaximin and ciprofloxacin in therapy for traveler's diarrhea in cases of microbiological treatment failure.

Thirty-one (33%) of the subjects randomized to receive rifaximin had at least 1 adverse event, compared with 34 (36%) of the ciprofloxacin recipients. The complaints were nonspecific, mild, and similar in the 2 treatment groups; weakness, dizziness, headache, fatigue, constipation, cough, insomnia, and respiratory symptoms were commonly noted. Transient skin rash was reported by 1 subject receiving rifaximin and 2 subjects receiving ciprofloxacin. The drugs were both well tolerated.

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Discussion

Elsewhere, we have shown that orally administered, poorly absorbed antimicrobials with in vitro activity against bacterial enteropathogens were effective in the treatment of traveler's diarrhea [10, 11]. In these studies, bicozamycin [10] and aztreonam [11] were effective against enterotoxigenic E. coli diarrhea and diarrhea caused by other enteropathogens, including invasive bacteria. In 1968, a study was published that showed that absorbable ampicillin was superior to poorly absorbed neomycin in the treatment of shigellosis [17]. This study led to the concept that absorption of an antimicrobial was necessary to treat invasive bacterial diarrhea. Studies that used rhesus monkeys with experimentally induced shigellosis provided evidence that one nonabsorbed antimicrobial, bicozamycin, was more effective than another nonabsorbed antimicrobial, kanamycin, despite similar in vitro activity [18]. These findings suggested that factors other than absorption may have explained the overall difference in response in the earlier study. We believe that the concept that an absorbed drug is needed for bacterial infection, invasive or noninvasive, should be reexamined.

Certainly, on the basis of our current and previous studies [9, 10, 19], nonabsorbed antimicrobial agents can be effective in therapy for traveler's diarrhea. Poorly absorbed drugs have theoretical advantages over absorbed drugs in terms of safety. Systemic side effects should be fewer, systemic drug interactions should be minimized, and the agents may be safe in pediatric populations and, perhaps, in pregnant women. In contrast to other poorly absorbed drugs we have evaluated, rifaximin is being developed commercially for use against diarrheal diseases. The drug has been available for use in European countries for some time. Given that rifaximin is largely nonabsorbed, thrice-daily dosing may be more beneficial than is twice-daily dosing. A multicenter, placebo-controlled study of rifaximin administered 3 times per day at 2 different dose levels is under way in Mexico, Guatemala, and Kenya.

Elsewhere, we have demonstrated the superiority of rifaximin over trimethoprim-sulfamethoxazole in the treatment of traveler's diarrhea in Mexico [19]. The present study shows the equivalence of rifaximin and ciprofloxacin in the treatment of acute traveler's diarrhea. More ciprofloxacin than rifaximin recipients in the present study had a TLUS of 0 h (8% vs. 20%), suggesting a more rapid clinical response for a subgroup of subjects treated with the fluoroquinolone. Both drugs shortened the duration of diarrhea to ∼1 day after therapy was begun. This contrasts with durations of 59–93 h for diarrhea untreated with antibacterial drugs [3]. The fluoroquinolones given for 1–3 days are currently considered the drugs of choice for this illness [3, 11, 20].

Quinolone-resistant C. jejuni is growing in importance worldwide. In Thailand, quinolone-resistant C. jejuni is the major cause of traveler's diarrhea [21]. Agents with activity against these organisms are needed. There are 2 potential reasons for the emergence of quinolone resistance among enteric pathogens. First, in some parts of the world, quinolones are used in veterinary populations, which appears to be important in the emergence of resistance of nontyphoid Salmonella species [22] and C. jejuni [23]. Second, the fluoroquinolones are a major class of drugs used widely in human medicine for the treatment of urinary tract infections and respiratory infections, in addition to diarrheal disease.

The present study provides evidence that rifaximin is effective in therapy for traveler's diarrhea as well as enterotoxigenic E. coli diarrhea, as studied in Guadalajara, Mexico, and Ocho Rios, Jamaica. We had insufficient numbers of patients who had isolates of Shigella, Salmonella, and Campylobacter species recovered to be certain of the value of rifaximin for diarrhea caused by these invasive pathogens. Rifaximin has been used in the therapy for bacterial diarrhea in children, against which it appears to be effective [24–26].

Rifaximin shows in vitro activity against a broad range of enteric pathogens. The MIC90 is 16–50 μg/mL for these various bacterial enteropathogens [27]. Ordinarily, isolates at this level of susceptibility would be considered “resistant” or, at best, “intermediate”. However, the drug is active against bacterial enteropathogens in vivo, which is explained by the extremely high luminal levels of the drug when it is administered orally. The fecal levels obtained in our groups in the present study after 3 days of oral therapy were in the range of 4000–8000 μg/g [27], which is 80–500 times higher than the MIC90 found in this study for bacterial enteropathogens.

Rifaximin is a rifamycin derivative. It is known that rifampicin frequently induces resistance by infecting organisms when it is the sole drug used. We believe that rifaximin differs from its cousin in this regard. Growing Mycobacterium tuberculosis in the presence of varying doses of rifaximin did not induce the occurrence of rifampicin-resistant strains [28]. In addition, we have not seen clinically relevant resistance develop in either of 2 studies (the present study and a study published elsewhere [19]) when stool samples were cultured before and after treatment and bacterial enteropathogens were examined for in vitro susceptibility.

We believe that the findings in the present study, coupled with those of previous studies, strongly suggest that rifaximin is active against bacterial enteric infection and traveler's diarrhea. Further studies are needed to evaluate the efficacy of the drug against dysenteric shigellosis and bacterial diarrhea in children.

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Acknowledgments

The following people participated in the clinical trial, providing study materials and patients: Dr. Deanna Ashley, Dr. Sylvia Botros, Dr. Sheila Campbell-Forrester, Dr. Catherine Devine, Dr. Daniel DiCesare, Dr. Andrew DuPont, Dr. Jennifer Finch, Dr. Lauren Gass, Dr. Mariela Glandt, Dr. Matthew Holland, Dr. Steven Maislos, Dr. David Martin, Dr. David McMillan, Ms. Carmen Pulido, Mrs. Dorothy Ruelas, Mrs. Sharon Thompson, Mrs. Jackie Vaca, Dr. Chad Wagner, and Dr. Sara Woods.

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Footnotes

  • Participation in this study was completely voluntary. Details of the study were explained to the subjects. Written consent was obtained from each subject prior to enrollment in this protocol. Subjects were allowed to withdraw from the study at any time. The study was reviewed and approved by The University of Texas—Houston Health Science Center Committee for the Protection of Human Subjects and the local regulatory authorities where the study was conducted. In addition, the Ministry of Health of Jamaica and the Secretaria de Salud of Jalisco, Mexico, reviewed the protocol and approved the conduct of the study in their respective territories.

  • Financial support: Alfa Wasserman SpA, Bologna, Italy, and Salix Pharmaceuticals, Palo Alto, California.

  • Received November 30, 2000.
  • Revision received May 25, 2001.
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  1. Clin Infect Dis. (2001) 33 (11): 1807-1815. doi: 10.1086/323814
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