• 1

    Brewster SJ, Taylor DN, 2004. Epidemiology of travelers’ diarrhea. Keystone JS, Kozarsky PE, Freedman DO, Nothdurft HD, Connor BA, eds. Travel Medicine. First Edition. New York, NY: Mosby, Elsevier, 175–184.

  • 2

    Steffen R, Tornieporth N, Clemens SA, Chatterjee S, Cavalcanti AM, Collard F, De Clercq N, DuPont HL, von Sonnenburg F, 2004. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med 11 :231–238.

    • Search Google Scholar
    • Export Citation
  • 3

    Steffen R, 1986. Epidemiologic studies of travelers’ diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 8 :S122–S130.

    • Search Google Scholar
    • Export Citation
  • 4

    Merson MH, Morris GK, Sack DA, Wells JG, Feeley JC, Sack RB, Creech WB, Kapikian AZ, Gangarosa EJ, 1976. Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress. N Engl J Med 294 :1299–1305.

    • Search Google Scholar
    • Export Citation
  • 5

    Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P, 1988. Etiology of diarrhea among travelers and foreign residents in Nepal. JAMA 260 :1245–1248.

    • Search Google Scholar
    • Export Citation
  • 6

    Adachi JA, Jiang ZD, Mathewson JJ, Verenkar MP, Thompson S, Martinez-Sandoval F, Steffen R, Ericsson CD, DuPont HL, 2001. Enteroaggregative Escherichia coli as a major etiologic agent in traveler’s diarrhea in 3 regions of the world. Clin Infect Dis 32 :1706–1709.

    • Search Google Scholar
    • Export Citation
  • 7

    DuPont HL, Ericsson CD, 1993. Prevention and treatment of traveler’s diarrhea. N Engl J Med 328 :1821–1827.

  • 8

    Taylor DN, Echeverria P, Blaser MJ, Pitarangsi C, Blacklow NR, Cross JH, Weniger B, 1985. Polymicrobial aetiology of travellers’ diarrhoea. Lancet 1 :381–383.

    • Search Google Scholar
    • Export Citation
  • 9

    Ryan ET, Wilson ME, Kain KC, 2002. Illness after international travel. N Engl J Med 347 :505–516.

  • 10

    Ericsson CD, DuPont HL, 1993. Travelers’ diarrhea: approaches to prevention and treatment. Clin Infect Dis 16 :616–624.

  • 11

    Hyams KC, Bourgeois AL, Merrell BR, Rozmajzl P, Escamilla J, Thornton SA, Wasserman GM, Burke A, Echeverria P, Green KY, 1991. Diarrheal disease during Operation Desert Shield. N Engl J Med 325 :1423–1428.

    • Search Google Scholar
    • Export Citation
  • 12

    Taylor DN, Connor BA, Shlim DR, 1999. Chronic diarrhea in the returned traveler. Med Clin North Am 83 :1033–1052.

  • 13

    Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL, 2004. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol 99 :1774–1778.

    • Search Google Scholar
    • Export Citation
  • 14

    Rees JH, Soudain SE, Gregson NA, Hughes RA, 1995. Campylobacter jejuni infection and Guillain-Barré syndrome. N Engl J Med 33 :1374–1379.

    • Search Google Scholar
    • Export Citation
  • 15

    Rees JR, Pannier MA, McNees A, Shallow S, Angulo FJ, Vugia DJ, 2004. Persistent diarrhea, arthritis, and other complications of enteric infections: a pilot survey based on California FoodNet surveillance, 1998–1999. Clin Infect Dis 38 :S311–S317.

    • Search Google Scholar
    • Export Citation
  • 16

    Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, Hennessy T, Griffin PM, DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, Reller LB, Osterholm MT, Bennish ML, Pickering LK, Infectious Diseases Society of America, 2001. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 32 :331–350.

    • Search Google Scholar
    • Export Citation
  • 17

    Steffen R, 2003. The emerging role of nonabsorbable oral antibiotic therapy in the management of travelers’ diarrhea. Adv Stud Med 3 :S951–S958.

    • Search Google Scholar
    • Export Citation
  • 18

    Hoge CW, Gambel JM, Srijan A, Pitarangsi C, Echeverria P, 1998. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 26 :341–345.

    • Search Google Scholar
    • Export Citation
  • 19

    Gomi H, Jiang ZD, Adachi JA, Ashley D, Lowe B, Verenkar MP, Steffen R, DuPont HL, 2001. In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing traveler’s diarrhea in four geographic regions. Antimicrob Agents Chemother 45 :212–216.

    • Search Google Scholar
    • Export Citation
  • 20

    Ericsson CD, 2001. Rifaximin: A new approach to the treatment of travelers’ diarrhea. J Travel Med 8 :S25.

  • 21

    Vila J, Vargas M, Ruiz J, Corachan M, Jimenez De Anta MT, Gascon J, 2000. Quinolone resistance in enterotoxigenic Escherichia coli-causing diarrhea in travelers to India in comparison with other geographical areas. Antimicrob Agents Chemother 44 :1731–1733.

    • Search Google Scholar
    • Export Citation
  • 22

    Smith KE, Besser JM, Hedberg CW, Leano FT, Bender JB, Wicklund JH, Johnson BP, Moore KA, Osterholm MT, 1999. Quinolone–resistant Campylobacter jejuni infections in Minnesota, 1992–1998. N Engl J Med 340 :1525–1532.

    • Search Google Scholar
    • Export Citation
  • 23

    Kuschner RA, Trofa AF, Thomas RJ, Hoge CW, Pitarangsi C, Amato S, Olafson RP, Echeverria P, Sadoff JC, Taylor DN, 1995. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 21 :536–541.

    • Search Google Scholar
    • Export Citation
  • 24

    Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Martinez-Sandoval F, Knirsch C, DuPont HL, 2003. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis 37 :1165–1171.

    • Search Google Scholar
    • Export Citation
  • 25

    DuPont HL, Ericsson CD, Mathewson JJ, Palazzini E, DuPont MW, Jiang ZD, Mosavi A, de la Cabada FJ, 1998. Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers’ diarrhea. Digestion 59 :708–714.

    • Search Google Scholar
    • Export Citation
  • 26

    DuPont HL, Jiang Z-D, Ericsson CD, Adachi JA, Mathewson JJ, DuPont MW, Palazzini E, Riopel LM, Ashley D, Martinez-Sandoval F, 2001. Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 33 :1807–1815.

    • Search Google Scholar
    • Export Citation
  • 27

    Jiang ZD, Lowe B, Verenkar MP, Ashley D, Steffen R, Tornieporth N, von Sonnenburg F, Waiyaki P, DuPont HL, 2002. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay). J Infect Dis. 185 :497–502.

    • Search Google Scholar
    • Export Citation
  • 28

    Steffen R, Sack DA, Riopel L, Jiang ZD, Sturchler M, Ericsson CD, Lowe B, Waiyaki P, White M, DuPont HL, 2003. Therapy for travelers’ diarrhea with rifaximin on various continents. Am J Gastroenterol 98 :1073–1078.

    • Search Google Scholar
    • Export Citation
  • 29

    DuPont HL, Cooperstock M, Corrado ML, Fekety R, Murray DM, 1992. Evaluation of new anti-infective drugs for the treatment of acute infectious diarrhea. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 15 :S228–S235.

    • Search Google Scholar
    • Export Citation
  • 30

    Jiang ZD, Ke S, Palazzini E, Riopel L, DuPont H, 2000. In vitro activity and fecal concentration of rifaximin after oral administration. Antimicrob Agents Chemother 44 :2205–2206.

    • Search Google Scholar
    • Export Citation
  • 31

    Ericsson CD, DuPont HL, Mathewson JJ, Johnson PC, de la Cabada FJ, Bitsura JA, 1988. Test-of-cure stool cultures for traveler’s diarrhea. J Clin Microbiol 26 :1047–1049.

    • Search Google Scholar
    • Export Citation
  • 32

    DuPont HL, Jiang Z-D, Okhuysen P, Ericsson CD, de la Cabada FJ, Ke S, DuPont MW, Martinez-Sandoval F, 2005. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Int Med 142 :805–812.

    • Search Google Scholar
    • Export Citation
  • 33

    Taylor DN, McKenzie R, Durbin A, Carpenter C, Atzinger CB, Haake R, Bourgeois AL, 2006. Rifaximin, a nonabsorbed oral antibiotic, prevents shigellosis after experimental challenge. Clin Infect Dis 42 :1283–1288.

    • Search Google Scholar
    • Export Citation

 

 

 

 

A RANDOMIZED, DOUBLE-BLIND, MULTICENTER STUDY OF RIFAXIMIN COMPARED WITH PLACEBO AND WITH CIPROFLOXACIN IN THE TREATMENT OF TRAVELERS’ DIARRHEA

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  • 1 Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Center for Infectious Diseases, The University of Texas, Houston School of Public Health and Medical School, Houston, Texas; Division of Communicable Diseases, Institute of Social and Preventive Medicine of the University of Zurich, Zurich, Switzerland; Enteric Infectious Disease Research Center, The University of Texas, Houston, Texas; Salix Pharmaceuticals, Inc., Morrisville, North Carolina; School of Public Health, University of Texas, Houston, Texas, and St. Luke’s Episcopal Hospital, Baylor College of Medicine, Houston, Texas

Rifaximin was compared with placebo and ciprofloxacin for treatment of travelers’ diarrhea in a randomized, double-blind clinical trial. Adult travelers (N = 399) consulting travel clinics in Mexico, Guatemala, and India were randomized to receive rifaximin 200 mg three times a day, ciprofloxacin (500 mg two times a day and placebo once a day), or placebo three times a day for 3 days. Patients recorded in daily diaries the time and consistency of each stool and documented symptoms for 5 days after treatment. Stool samples were collected for microbiologic evaluations before and after treatment. The median time to last unformed stool (TLUS) in the rifaximin group (32.0 hours) was less than one half that in the placebo group (65.5 hours; P = 0.001; risk ratio 1.6; 95% confidence interval 1.2, 2.2; primary efficacy endpoint). The median TLUS in the ciprofloxacin group was 28.8 hours (P = 0.0003 versus placebo; P = 0.35 versus rifaximin). Rifaximin was less effective than ciprofloxacin for invasive intestinal bacterial pathogens. Oral rifaximin is a safe and effective treatment of travelers’ diarrhea caused by noninvasive pathogens.

INTRODUCTION

Travelers’ diarrhea, usually contracted from contaminated food or water, affects 20–50% of individuals traveling from developed to developing countries.13 Bacteria, most commonly enterotoxigenic Escherichia coli (ETEC) and enteroaggregative E. coli (EAEC), are responsible for up to 80% of acute cases; other bacteria such as Shigella, Salmonella, and Campylobacter, as well as viruses and protozoa, make up the remainder of known causes.46 In most microbiologic studies of travelers’ diarrhea, up to one third of the cases remain undiagnosed. Because many of these cases seem to respond to antibiotics and manifest indirect evidence of ETEC infection, such as seroconversion to the heat-labile enterotoxins, it has been assumed that ETEC or other undiagnosed bacteria were the cause.7,8 Travelers’ diarrhea can cause serious illness and be economically costly for travelers. One in three individuals with travelers’ diarrhea requires bed rest, and one in five is confined to bed for 1–2 days.9,10 Affected individuals may incur costs of medication, medical services, and canceled or rescheduled activities. In some cases, the impact of travelers’ diarrhea extends beyond the individual sufferer. For example, among American soldiers in Saudi Arabia during Operation Desert Shield, mission preparedness was undoubtedly affected by the frequent occurrence of travelers’ diarrhea, at least one episode of which was reported by 57% of 2,022 soldiers surveyed in one study.11 Although travelers’ diarrhea usually lasts less than 1 week, diarrhea can persist for more than 2 weeks in 2–10%, and as many as 10% can develop post-infectious irritable bowel syndrome.12,13 Other sequelae of acute bacterial diarrhea include reactive arthritis with shigellosis and Guillain-Barré syndrome with Campylobacter infection.14,15 The acute personal and economic impacts of travelers’ diarrhea underscore the importance of effective treatment.

The Infectious Diseases Society of America (IDSA) guidelines recommend empirical antibiotic therapy for travelers’ diarrhea.16 However, current treatment options have significant shortcomings.7,17 The usefulness of trimethoprim-sulfamethoxazole, one of the mainstays of antidiarrheal antibiotic therapy in the United States, is limited by the emergence of widespread bacterial resistance.1820 Ciprofloxacin, a fluoroquinolone antibiotic, is well tolerated and largely effective against E. coli and Shigella, but case reports of ciprofloxacin-resistant ETEC have been reported from travelers returning from India.21 More significantly, the emergence of ciprofloxacin-resistant Campylobacter species has decreased the effectiveness of ciprofloxacin for empirical treatment of travelers’ diarrhea, particularly in Asia.22 In areas where Campylobacter is prevalent or quinolone treatment has failed, azithromycin is now used as an alternative.23,24 Azithromycin is also a systemic antibiotic that is used primarily for the treatment of respiratory infections. Although enteric pathogens are susceptible to azithromycin, the resolution of symptoms is not as rapid as with the fluoroquinolones.24

A non-absorbed antibiotic theoretically confers several advantages that have been identified as characteristics of the ideal antibiotic for infectious diarrhea7,16,17,25: targeted activity at the source of infection, low potential for systemic side effects and drug interactions, and—because its value and use are limited to gastrointestinal infections—the potential for limited or delayed development of clinically relevant bacterial resistance. This randomized, double-blind, parallel-group study was conducted to compare the efficacy and tolerability of the non-absorbed oral antibiotic rifaximin (Xifaxan, Salix Pharmaceuticals, Inc., Morrisville, NC) with those of ciprofloxacin and placebo for the treatment of travelers’ diarrhea. Rifaximin was first marketed in 1987 in Italy and is now approved in 17 countries, including most recently the United States, for treatment of gastrointestinal bacterial infections. Rifaximin has broad spectrum in vitro antibacterial activity, the tolerability profile of placebo, no known drug interactions, and has not been associated with bacterial resistance in 18 years of clinical use.17 Previous studies in patients with travelers’ diarrhea showed rifaximin to be more effective than placebo and as effective as trimethoprim-sulfamethoxazole and ciprofloxacin in shortening the duration of diarrheal illness2527; however, the sample sizes of these studies were inadequate to support definitive conclusions about efficacy of rifaximin for illness caused by specific pathogens. The study reported herein is the first large, placebo-controlled study to assess comprehensively the bacteriologic and clinical efficacy of rifaximin versus that of ciprofloxacin, the current standard of care.

MATERIALS AND METHODS

Patients.

Male or female patients at least 18 years of age and consulting one of seven travel health clinics in Mexico, Guatemala, India, or Peru were eligible if they had acute diarrhea, defined as three or more unformed stools during the 24 hours preceding enrollment, accompanied by at least one of the following signs and symptoms: abdominal pain or cramps, excessive gas/flatulence, nausea, vomiting, fever (≥ 100°F or ≥ 37.8°C), fecal urgency, blood and/or mucus in the stool, or tenesmus. Exclusion criteria included duration of diarrhea more than 72 hours, moderate or severe dehydration, clinically significant disease other than diarrheal illness, and, in women, being pregnant or breast feeding. In addition, patients were excluded if they had taken theophylline or any antimicrobial active against diarrheal pathogens within the 7 days before randomization; more than two doses of a symptomatic antidiarrheal compound including antimotility, absorbent, or antisecretory agents within 8 hours before randomization; and any nonsteroidal anti-inflammatory drug or fever-reducing agent within 2 hours before randomization. All patients provided written, informed consent.

Procedures.

The protocol for this randomized, multicenter, double-blind, parallel-group study was approved by The University of Texas Houston Health Science Center Committee for the Protection of Human Subjects, the Johns Hopkins Committee on Human Research, and the Secretaria de Salud of Jalisco, Mexico. Definitions, measurements, and endpoints in this study were modeled on the US Food and Drug Administration (FDA)/IDSA guidelines for testing antibiotics in bacterial diarrhea.28 Patients were enrolled from July 10, 2002, to May 14, 2003. Eligible patients were randomized 2:1:1 to receive rifaximin 200 mg three times a day, ciprofloxacin (500 mg two times a day and placebo once a day), or placebo three times a day. Treatment was to begin no more than 72 hours after the onset of diarrhea and was to continue for 3 days (days 1–3). For 5 days after randomization, patients recorded in daily diaries the date, time, and consistency of each stool and documented diarrheal symptoms (abdominal pain or cramps, excessive gas/flatulence, nausea, vomiting, fever [≥ 100°F or ≥ 37.8°C], fecal urgency, blood and/or mucus in the stool, tenesmus). Stool samples were collected before treatment, on day 2, and after treatment between days 3 and 5.

Measures and Statistics.

Efficacy.

The primary efficacy endpoint was the time to last unformed stool (TLUS), defined as the interval beginning with the first dose of study medication and ending with the last unformed stool passed, in the rifaximin group versus the placebo group. Both soft stools (defined as taking the shape of a container) and watery stools (defined as those that could be poured) were considered to be unformed. Cox proportional hazards models (Wald statistic) with a two-sided test and a significance level of 0.05 were used to compare TLUS between rifaximin and placebo, ciprofloxacin and placebo, and rifaximin and ciprofloxacin. For TLUS analyses, data from patients for whom TLUS could not be calculated because of premature withdrawal caused by treatment failure or completion of the study without becoming well were censored as having a TLUS of 120 hours. Data from patients who terminated early for reasons other than treatment failure were censored at the time of the last available information on unformed stools. Power calculations revealed that 400 patients (~200 in the rifaximin group and 100 in each of the other two groups) would provide at least 90% power to show a difference between rifaximin and placebo in the primary endpoint at the 0.05 level of significance with a two-sided test.

Because the efficacy of rifaximin could differ as a function of etiology, TLUS was analyzed for the subgroups of patients with diarrheagenic E. coli (ETEC and/or EAEC; non-invasive group); the subgroup defined by the presence of Shigella, Campylobacter jejuni, and Salmonella (invasive group); and the subgroup of patients with pathogen-negative illness. Efficacy was also analyzed among the subgroup of patients with non-invasive diarrhea as defined by the absence of both fever (as defined above) and occult blood in the stool.

Secondary efficacy endpoints included the proportion of patients with improvement in diarrheal syndrome (defined as reduction of at least 50% in the number of unformed stools during 24-hour post-enrollment intervals compared with the 24 hours immediately preceding enrollment), the number of unformed stools passed per unit of time, the proportion of patients with wellness (defined as no watery stools and no more than two soft stools in a 24-hour interval with no other clinical symptoms except for mild excess gas/flatulence or no unformed stools in a 48-hour interval with no fever [≥ 100°F or 37.8°C], with or without other clinical symptoms), and the proportion of patients who failed treatment (defined as clinical deterioration or worsening of symptoms after at least 24 hours of therapy or illness continuing after 120 hours of treatment with the study medication or after at least 24 hours of therapy). The secondary efficacy endpoints were compared among groups using repeated measures analysis of variance (ANOVA; for number of unformed stools passed per unit time) or the Cochran-Mantel-Haenszel test stratified by center (all other secondary endpoints).

All efficacy analyses were performed on data from the intent-to-treat population, defined as all randomized patients, as well as on data from the efficacy-evaluable population, defined as patients who met the inclusion/exclusion criteria, took at least 2 days of study medications as prescribed, completed the daily diaries for at least 2 days, and did not take any prohibited medications that could have impacted clinical outcome. Overall, differences in baseline characteristics between the intent-to-treat population and the efficacy-evaluable population were unremarkable. However, the percentage of intent-to-treat patients from Goa that did not qualify for the efficacy-evaluable population (13.7%) was more than three times higher than the percentage of intent-to-treat patients that did not qualify for the efficacy-evaluable population (4.3%). Results of the two analyses were similar, and only the data from the intent-to-treat population are reported herein.

Microbiology.

Pre- and post-treatment stool samples were assessed to identify bacterial pathogens. Local laboratories identified at the genus level the presence or absence of pathogens including Shigella, Salmonella, Aeromonas, Vibrio, and Plesiomonas species; Campylobacter jejuni; and Yersinia enterocolitica. Protozoal pathogens and Campylobacter were identified by use of enzyme-linked immunosorbent assays (ELISA). Bacterial colonies from each stool sample were transferred to peptone stabs and shipped to the Enteric Infectious Disease Research Laboratory (Houston, Texas), which performed pathogen verification, speciation, and minimum inhibitory concentration (MIC) analyses.19 A DNA hybridization/probe technique was used to assess for the production of heat-labile and heat-stable enterotoxins, showing the presence of ETEC; EAEC was identified with the HEp-2 cell assay for adherence.6,2730

Data from these assessments were used to determine rates of microbiologic eradication (defined as a negative post-treatment culture result for an etiologic pathogen that had been positive before treatment) for the microbiology population, defined as patients having both a positive pre-treatment stool sample and a positive or negative post-treatment sample.

Safety.

The primary safety measure was the incidence of adverse events, defined as any untoward medical occurrences (regardless of their suspected cause) reported by a patient or noted by clinical staff during the study. Adverse events were summarized for the safety population, which consisted of randomized patients who received at least one dose of study medication and had at least one post-baseline safety assessment.

RESULTS

Patients.

A total of 399 patients were randomized to treatment (197 rifaximin, 101 placebo, 101 ciprofloxacin). Demographics did not differ among treatment groups. Study participants had a mean age of 33 years (range, 18–80 years), were nearly equally divided between men (51.9%) and women (48.1%), and were predominantly white (82.5%). Most of the subjects traveling to Mexico and Guatemala were US college students studying Spanish. The mean age of travelers to Mexico was 25 years, to Guatemala was 29 years, to Calcutta was 28 years, and to Goa was 47 years.

The percentages of patients completing the study were similar among groups (rifaximin, 90%; placebo, 83%; ciprofloxacin, 93%; P < 0.05 ciprofloxacin versus placebo). Baseline illness characteristics were similar among groups (Table 1). The presence of at least one enteric pathogen was identified in the pre-treatment stool sample for the majority (64.4%) of the intent-to-treat population. The most common pathogens identified in each treatment group were ETEC (34%); EAEC (19%); and invasive pathogens, consisting of Shigella, Campylobacter, and Salmonella, which were isolated from 18% (range, 12–28%). No pathogen could be isolated from 36% of subjects (Table 2).

Efficacy.

Rifaximin was significantly more effective than placebo at reducing the duration of diarrheal illness as reflected in the primary endpoint of TLUS. The median TLUS in the rifaximin group (32.0 hours) was less than one half that in the placebo group (65.5 hours; P = 0.0014; risk ratio 1.63; 95% confidence interval [CI] of the risk ratio, 1.21, 2.19; Table 3). Ciprofloxacin was also more effective than placebo with respect to this endpoint (28.8 versus 65.5 hours; P = 0.0003; risk ratio 1.89; 95% CI of the risk ratio, 1.34–2.65). There was no significant difference between rifaximin and ciprofloxacin with respect to the primary endpoint (TLUS), P = 0.35 (relative risk 0.88; 95% CI, 0.66–1.15).

Median TLUS was shorter in the rifaximin group compared with the placebo group among patients with diarrheagenic E. coli but without evidence of invasive pathogens (P = 0.045) and among patients with pathogen-negative illness (P = 0.0024). Follow-up of patients was notably difficult at the Goa field site. For subjects from all sites with invasive pathogens, median TLUS in the rifaximin group could not be calculated because more than one half of patients failed to achieve wellness, and median TLUS in the placebo group and the ciprofloxacin group was ≥65 hours. If the patients from Goa are excluded, median TLUS for invasive pathogens was 44 hours for rifaximin, 24 hours for ciprofloxacin, and 58 hours for placebo (rifaximin versus placebo, P = 0.50; Table 3). Exclusion of the subjects from the Goa field site in the diarrheagenic E. coli and nonpathogen groups did not significantly alter the outcome presented in Table 3.

TLUS was also analyzed excluding subjects with fever and/or blood in the stool at the time of presentation. The median TLUS in the rifaximin group (23.3 hours) was less than one half that in the placebo group (48.1 hours; P = 0.0002; risk ratio 2.1; 95% CI of the risk ratio, 1.4, 3.1; Table 4). Ciprofloxacin was also more effective than placebo with respect to this endpoint (27.4 versus 48.1 hours; P = 0.005; risk ratio 1.8; 95% CI of the risk ratio, 1.2, 2.8). In subjects without fever and/or blood in the stool, the clinical responses to rifaximin and ciprofloxacin were nearly identical.

Rifaximin was significantly more effective than placebo for secondary endpoints including improvement in diarrheal syndrome (P < 0.05 for the 48- to 72- and 72- to 96-hour intervals after enrollment in the study), number of unformed stools passed after the first dose of study medication (P = 0.0002), proportion of patients achieving wellness (P = 0.0039), and the incidence of treatment failure (P = 0.0115). Ciprofloxacin was also statistically superior to placebo on these measures (P < 0.05). There was no statistical difference between rifaximin and ciprofloxacin for improvement of diarrhea (P > 0.05) and achievement of wellness (P = 0.74). Ciprofloxacin was statistically superior to rifaximin for number of unformed stools passed (6.2 versus 8.8, respectively; P < 0.0004) and incidence of treatment failure (P = 0.05; Table 3).

Microbiology.

Eradication rates.

Across all pathogens, microbiologic eradication was observed in 61.6% of the rifaximin group, 51.7% of the placebo group, and 80.7% of the ciprofloxacin group (P = 0.20 rifaximin versus placebo, P = 0.001 ciprofloxacin versus placebo, P = 0.001 rifaximin versus ciprofloxacin). Among patients with diarrheagenic E. coli (without evidence of invasive pathogens), microbiological eradication in the rifaximin group was higher than with placebo (77% versus 63%) but not as high as with ciprofloxacin (93%). Among patients with invasive pathogens the microbiological eradication rate was 73% in the rifaximin group and 77% with ciprofloxacin compared with 44% in the placebo group (Table 3).

Rifaximin MICs.

The rifaximin MIC was determined for all bacterial pathogens. Table 5 compares the bacterial eradication rates and MICs in rifaximin-treated patients. Microbial eradication rates were highest for EAEC and Shigella. ETEC was isolated from 19 (27%) of 71 patients where ETEC was isolated in the pre-treatment stool specimen. The ETEC isolates from 10 of 19 patients with a post-treatment ETEC isolate showed a ≥ 4-fold increase in MIC compared with the pre-treatment isolate. ETEC with low initial MICs was less likely to persist. If the pre-treatment ETEC MIC to rifaximin was < 4 μg/mL, the eradication rate was 92%. If the pretreatment MIC was ≥ 4 μg/mL, the eradication rate was 63% (P = 0.011). The change in MIC did not affect clinical outcome. Among the 19 subjects with ETEC isolated after treatment, clinical cure was observed in 15 (83%) of 18 (1, no determination made). A change in MIC was observed in 60% of those cured and 33% (one of three) who failed. Among persons receiving ciprofloxacin, initial MICs to ciprofloxacin were elevated (≥ 0.25 μg/mL) in 5 (42%) of 12 Campylobacter and 12 (9%) of 136 ETEC.

Adverse events.

The incidence of adverse events was similar among the treatment groups (Table 6). The most common adverse event was headache. Two patients in the ciprofloxacin group withdrew prematurely from the study because of adverse events (constipation and vomiting) that were considered by the investigator to be drug related. No patient in the rifaximin group or the placebo group withdrew prematurely because of drug-related adverse events.

DISCUSSION

In this large, multi-center study, rifaximin 200 mg three times a day for 3 days was efficacious and well tolerated for the treatment of diarrhea in travelers to Latin America and India. These findings support data from previous studies showing rifaximin to be superior to placebo, non-inferior to ciprofloxacin, and comparable with trimethoprim-sulfamethoxazole in a trial carried out when pathogens were susceptible to this drug in reducing the duration of diarrheal illness while having placebo-like tolerability.25,26,28,29 The efficacy and tolerability results are consistent with the non-absorbed, gut-selective nature of the drug.

This study extends previous research by showing that rifaximin is effective clinically and bacteriologically for non-invasive pathogens that cause more than 80% of travelers’ diarrhea. Diarrheagenic E. coli, which produces its effect by attaching to the lumen wall and secreting toxins, is exposed to an antibiotic within the lumen of the gastrointestinal tract. In corroboration of previous findings, pathogens could not be isolated from the stool in more than one third of patients in this study. Diarrheal illness in this subgroup of patients is important as it often responds to anti-infective therapy—a finding that suggests undetected bacterial pathogens as the cause of illness. Rifaximin was effective for patients with no pathogen in the pre-treatment stool culture.

Patients infected with invasive pathogens or who have signs of invasive pathogens (fever and/or blood in the stool) respond less well to rifaximin—probably because the organisms have invaded the tissues and are no longer in contact with a luminal agent. Although Shigella was eradicated in 10 of 11 cases, the clinical response was not significantly different from that observed with placebo. The highest rate of isolation of invasive pathogens was from the Goa site. Unfortunately the follow-up was poor at Goa. The travelers at Goa were in their late 40s compared with the late 20s at the other sites, but we don’t know why older subjects would provide less follow-up. Invasive pathogens were common enough at other sites so that subjects from Goa could be excluded and still provide a picture of the relative efficacy for invasive pathogens.

In this study, ETEC was isolated after rifaximin treatment in a quarter of specimens and frequently showed higher MICs than the pre-treatment isolate. In contrast, EAEC was usually eradicated from the stool, and anti-microbial resistance was not observed. Anti-microbial resistance was also not observed in the few Shigella, Campylobacter, or Salmonella spp. that were isolated after therapy. ETEC with a MIC ≥ 4 μg/mL was more likely to be cultured after treatment in both the rifaximin and placebo groups. This change in MIC did not affect the clinical response. Luminal concentrations of rifaximin have been measured in the range of 1,000 μg/mL, a value far exceeding the MIC of most of the bacterial isolates.30 Together the findings suggest that MIC and eradication rates may not be good predictors of clinical efficacy for a non-absorbed antibiotic. A similar result was observed in a previous study in which the presence or absence of organism eradication did not predict clinical response to an antibiotic (TLUS was 32 hours when organism was eradicated and 33 hours when it was not).31

Diarrhea continues to be the most common health problem facing travelers to Africa, Asia, and Latin America. While antibiotics are the single most effective treatment of travelers’ diarrhea, the choice of antibiotic is limited by increasing bacterial resistance to anti-diarrheal antibiotics and the lack of an antibiotic that is tolerated by and safe for the spectrum of patient groups vulnerable to diarrheal illness. Because rifaximin is non-absorbed, the risk of systemic side effects and drug interactions is minimal and has little or no impact on nonenteric bacteria, a property that may delay or prevent the development of clinically relevant bacterial resistance to the drug.

The results of this study indicate that rifaximin is an important alternative to systemic antibiotics for most cases of travelers’ diarrhea, including cases in patients for whom quinolones are not recommended. Rifaximin is appropriate for patients suspected of being infected with non-invasive pathogens, particularly diarrheagenic E. coli, which is the primary cause of travelers’ diarrhea. Considering side effect profile, absence of alteration of flora, and public health importance of avoiding broad use of fluoroquinolones, rifaximin is the treatment of choice for afebrile, non-dysenteric travelers’ diarrhea. Recently, rifaximin was found to prevent travelers’ diarrhea among US students in Mexico.32 Prophylactic use of rifaximin may also prevent Shigella before it becomes invasive.33 Thus, rifaximin is an important new, non-absorbed antibiotic useful in both the treatment and prevention of travelers’ diarrhea.

Table 1

Baseline illness characteristics in the intent-to-treat population (ITT)

RifaximinPlaceboCiprofloxacin
Baseline characteristics(n = 197)(n = 101)(n = 101)
    Unformed stools in the 24-hour period before randomization
        Mean ± SD7.3 ± 4.616.9 ± 4.586.9 ± 3.88
        Median6.06.06.0
        Range3–303–303–29
Pretreatment clinical symptomsn (%)n (%)n (%)
    Abdominal pain or cramps186 (94.4)92 (91.1)96 (95.0)
    Excessive gas/flatulence100 (50.8)50 (49.5)49 (48.5)
    Nausea119 (60.4)59 (58.4)59 (58.4)
    Vomiting38 (19.3)19 (18.8)17 (16.8)
    Fever (≥ 100°F or ≥ 37.8°C)39 (19.8)16 (15.8)20 (19.8)
    Fecal urgency136 (69.0)71 (70.3)67 (66.3)
    Blood and/or mucus in stool33 (16.8)15 (14.9)11 (10.9)
    Tenesmus53 (26.9)25 (24.8)27 (26.7)
    Occult blood64 (32.5)34 (33.7)25 (24.8)
Table 2

Isolation rate of enteric pathogens among the study centers

PathogenCalcutta (n = 89) No. (%)Goa (n = 117) No. (%)Guatemala* (n = 106) No. (%)Mexico† (n = 87) No. (%)Total (n = 399) No. (%)
* Including Peru (n = 3).
† Guadalajara (n = 65), Cuernavaca (n = 19), and Puerto Vallarta (n = 3).
‡ ETECs were categorized as producing heat-labile (LT), heat-stable (ST), or both enterotoxins (ST/LT).
ETEC42 (47)34 (29)34 (32)27 (31)137 (34)
    ETEC-LT‡25 (28)16 (14)14 (13)8 (9)63 (16)
    ETEC-ST4 (4)4 (3)8 (8)8 (9)24 (6)
    ETEC-ST/LT13 (15)14 (12)12 (11)11 (13)50 (13)
EAEC16 (18)17 (15)26 (25)15 (17)74 (19)
Campylobacter jejuni5 (6)25 (21)6 (6)8 (9)44 (11)
Shigella species5 (6)5 (4)5 (5)5 (6)20 (5)
Salmonella species04 (3)3 (3)07 (2)
Vibrio cholerae2 (2)0002 (1)
Aeromonas hydrophila1 (1)4 (3)005 (1)
Plesiomonas species07 (6)1 (1)08 (2)
Giardia lamblia13 (15)12 (10)2 (2)2 (2)29 (7)
Cryptosporidium parvum2 (2)6 (5)2 (2)6 (7)16 (4)
Entamoeba histolytica4 (4)0004 (1)
At least one pathogen63 (71)80 (68)62 (58)52 (60)257 (64)
No pathogen isolated26 (29)37 (32)44 (42)35 (40)142 (36)
More than one pathogen isolated20 (22)26 (22)15 (14)10 (11)71 (18)
Table 3

Summary of efficacy results among all persons enrolled, those fully evaluable, and pathogen subgroups

Rifaximin 200 mg three times a day × 3 daysPlaceboCipro 500 mg two times a day × 3 days
For the subgroup analyses, median TLUS and clinical wellness were calculated for the intent-to-intent population, and microbiological eradication was calculated for the modified intent-to-treat population, defined as all patients in the intent-to-treat population with positive pretreatment stool samples and a posttreatment sample.
* This subgroup excludes subjects with concurrent invasive pathogens defined as Campylobacter jejuni, Shigella species, and Salmonella species.
† The analysis of invasive pathogens was performed excluding data from the Goa site so that TLUS could be calculated. TLUS could not be calculated for the Goa site because over half the subjects were lost to follow-up.
Intention-to-treat populationn = 197n = 101n = 101
    Median TLUS (hours)32.065.528.8
    Clinical wellness76.6%61.4%78.2%
    Treatment failure14.7%26.7%6.9%
Efficacy evaluable populationn = 186n = 91n = 94
    Median TLUS (hours)30.648.328.4
    Clinical wellness78.5%65.9%81.9%
    Treatment failure13.4%26.4%7.4%
Subroups
    Patients with diarrheagenic E. coli*n = 73n = 38n = 40
        Median TLUS (hours)24.038.023.4
        Clinical wellness65/73 (89.0%)28/38 (73.7%)33/40 (82.5%)
        Microbiological eradication56/73 (76.7%)24/38 (63.2%)37/40 (92.5%)
    Patients with invasive pathogens†n = 22n = 9n = 7
        Median TLUS (hours)43.758.324.4
        Clinical wellness15/22 (68.2%)5/9 (55.6%)6/7 (85.7%)
        Microbiological eradication16/22 (72.7%)4/9 (44.4%)5/7 (71.4%)
    Patients with no detectable pathogenn = 67n = 38n = 37
        Median TLUS (hours)23.571.629.7
        Clinical wellness56/67 (83.6%)22/38 (57.9%)30/37 (81.1%)
Table 4

Efficacy results excluding patients with fever and/or blood in the stool at presentation

RifaximinPlaceboCiprofloxacin
* Any pathogen is defined as any of the pathogens listed in Table 2.
Restricted populationn = 116n = 60n = 65
    Median TLUS (hours)23.348.127.4
    Clinical wellness87.1%61.7%80.0%
    Treatment failure8.6%28.3%7.7%
Any pathogen*n = 77n = 32n = 34
    Median TLUS (hours)24.342.827.4
    Clinical wellness66/77 (85.7%)21/32 (65.6%)25/34 (73.5%)
    Microbiological eradication47/77 (61.0%)16/32 (50.0%)28/34 (82.4%)
Table 5

Pre-treatment and post-treatment rifaximin MICs for bacterial isolates among patients who were treated with rifaximin 200 mg three times a day for 3 days

Pre-treatmentPost-treatment
PathogenIsolates (n)Rifaximin MIC rangeIsolates (n)Percent totalRifaximin MIC rangeAt least 4-fold increase in rifaximin MIC
ETEC710.5 to > 1,02419274 to > 1,02410
EAEC290.5–322740
Shigella110.25–256190.50
Campylobacter60.06–0.54670.06–0.1250
Salmonella41–412520
Table 6

Number (%) of patients with adverse effects (reported in at least 2% of patients in a group (safety population)

Rifaximin (n = 199)Placebo (n = 100)Ciprofloxacin (n = 100)
Any event53 (26.6)25 (25.0)24 (24.0)
Headache16 (8.0)9 (9.0)5 (5.0)
Constipation8 (4.0)5 (5.0)8 (8.0)
Flatulence4 (2.0)3 (3.0)2 (2.0)
Rectal tenesmus4 (2.0)1 (1.0)1 (1.0)
Dizziness2 (1.0)2 (2.0)2 (2.0)
Vomiting2 (1.0)1 (1.0)2 (2.0)
Nausea1 (0.5)1 (1.0)2 (2.0)

*

Address correspondence to David N. Taylor, 1700 Perimeter Park Dr., Morrisville, NC 27560. E-mail: david.taylor@salix.com

Authors’ addresses: David N. Taylor, 1700 Perimeter Park Dr., Morrisville, NC 27560, E-mail: david.taylor@salix.com. A. Louis Bourgeois, Department of International Health, Johns Hopkins University, Bloomberg School of Public Health, 624 N. Broadway, Room 20, Baltimore, MD 21205, E-mail: abourgeo@jhsph.edu. Charles D. Ericsson, The University of Texas Medical School at Houston, Department of Internal Medicine, Division of Infectious Diseases, 6431 Fannin, Suite JFB 1.728, Houston, TX 77030, E-mail: Charles.D.Ericsson@uth.tmc.edu. Robert Steffen, Division of Communicable Diseases, Institute of Social and Preventive Medicine of the University of Zurich, Zurich, Switzerland, E-mail: roste@ifspm.unizh.ch. Zhi-Dong Jiang, Enteric Infectious Disease Research Center, The University of Texas, Houston, TX 77030, E-mail: Zjiang@sph.uth.tmc.edu. Jane Halpern, Johns Hopkins University, 624 N. Broadway, Room 20, Baltimore, MD 21205, E-mail: jhalpern@towson.edu. Robert Haake, 1700 Perimeter Park Dr., Morrisville, NC 27560, E-mail: robert.haake@salix.com. Herbert L. Du-Pont, Internal Medicine, St. Luke’s Episcopal Hospital, 6720 Bertner Ave., Room P-153, Mail Code: 1-164, Houston, TX 77030, E-mail: hdupont@sleh.com. Rifaximin Study Group: Santanu Chatterjee (Calcutta, India), Dilip Motghare (Goa, India), Edwin Asturias (Antigua, Guatemala), Francisco Martinez Sandoval (Guadalajara, Mexico), Jaime Belkind-Gerson (Cuernavaca, Mexico), Alejandro Rios Ramirez (Puerto Vallarta, Mexico), and Eduardo Gotuzzo (Lima, Peru).

Disclosure: Authors Haake and Taylor are currently employed by Salix Pharmaceuticals, US marketer of rifaximin. Authors DuPont, Ericsson, and Steffen serve as consultants to Salix Pharmaceuticals. Dr. Jiang has received grants from Salix Pharmaceuticals. The research described in this manuscript was funded by Salix Pharmaceuticals, Inc.

REFERENCES

  • 1

    Brewster SJ, Taylor DN, 2004. Epidemiology of travelers’ diarrhea. Keystone JS, Kozarsky PE, Freedman DO, Nothdurft HD, Connor BA, eds. Travel Medicine. First Edition. New York, NY: Mosby, Elsevier, 175–184.

  • 2

    Steffen R, Tornieporth N, Clemens SA, Chatterjee S, Cavalcanti AM, Collard F, De Clercq N, DuPont HL, von Sonnenburg F, 2004. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med 11 :231–238.

    • Search Google Scholar
    • Export Citation
  • 3

    Steffen R, 1986. Epidemiologic studies of travelers’ diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 8 :S122–S130.

    • Search Google Scholar
    • Export Citation
  • 4

    Merson MH, Morris GK, Sack DA, Wells JG, Feeley JC, Sack RB, Creech WB, Kapikian AZ, Gangarosa EJ, 1976. Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress. N Engl J Med 294 :1299–1305.

    • Search Google Scholar
    • Export Citation
  • 5

    Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P, 1988. Etiology of diarrhea among travelers and foreign residents in Nepal. JAMA 260 :1245–1248.

    • Search Google Scholar
    • Export Citation
  • 6

    Adachi JA, Jiang ZD, Mathewson JJ, Verenkar MP, Thompson S, Martinez-Sandoval F, Steffen R, Ericsson CD, DuPont HL, 2001. Enteroaggregative Escherichia coli as a major etiologic agent in traveler’s diarrhea in 3 regions of the world. Clin Infect Dis 32 :1706–1709.

    • Search Google Scholar
    • Export Citation
  • 7

    DuPont HL, Ericsson CD, 1993. Prevention and treatment of traveler’s diarrhea. N Engl J Med 328 :1821–1827.

  • 8

    Taylor DN, Echeverria P, Blaser MJ, Pitarangsi C, Blacklow NR, Cross JH, Weniger B, 1985. Polymicrobial aetiology of travellers’ diarrhoea. Lancet 1 :381–383.

    • Search Google Scholar
    • Export Citation
  • 9

    Ryan ET, Wilson ME, Kain KC, 2002. Illness after international travel. N Engl J Med 347 :505–516.

  • 10

    Ericsson CD, DuPont HL, 1993. Travelers’ diarrhea: approaches to prevention and treatment. Clin Infect Dis 16 :616–624.

  • 11

    Hyams KC, Bourgeois AL, Merrell BR, Rozmajzl P, Escamilla J, Thornton SA, Wasserman GM, Burke A, Echeverria P, Green KY, 1991. Diarrheal disease during Operation Desert Shield. N Engl J Med 325 :1423–1428.

    • Search Google Scholar
    • Export Citation
  • 12

    Taylor DN, Connor BA, Shlim DR, 1999. Chronic diarrhea in the returned traveler. Med Clin North Am 83 :1033–1052.

  • 13

    Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL, 2004. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol 99 :1774–1778.

    • Search Google Scholar
    • Export Citation
  • 14

    Rees JH, Soudain SE, Gregson NA, Hughes RA, 1995. Campylobacter jejuni infection and Guillain-Barré syndrome. N Engl J Med 33 :1374–1379.

    • Search Google Scholar
    • Export Citation
  • 15

    Rees JR, Pannier MA, McNees A, Shallow S, Angulo FJ, Vugia DJ, 2004. Persistent diarrhea, arthritis, and other complications of enteric infections: a pilot survey based on California FoodNet surveillance, 1998–1999. Clin Infect Dis 38 :S311–S317.

    • Search Google Scholar
    • Export Citation
  • 16

    Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, Hennessy T, Griffin PM, DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, Reller LB, Osterholm MT, Bennish ML, Pickering LK, Infectious Diseases Society of America, 2001. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 32 :331–350.

    • Search Google Scholar
    • Export Citation
  • 17

    Steffen R, 2003. The emerging role of nonabsorbable oral antibiotic therapy in the management of travelers’ diarrhea. Adv Stud Med 3 :S951–S958.

    • Search Google Scholar
    • Export Citation
  • 18

    Hoge CW, Gambel JM, Srijan A, Pitarangsi C, Echeverria P, 1998. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 26 :341–345.

    • Search Google Scholar
    • Export Citation
  • 19

    Gomi H, Jiang ZD, Adachi JA, Ashley D, Lowe B, Verenkar MP, Steffen R, DuPont HL, 2001. In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing traveler’s diarrhea in four geographic regions. Antimicrob Agents Chemother 45 :212–216.

    • Search Google Scholar
    • Export Citation
  • 20

    Ericsson CD, 2001. Rifaximin: A new approach to the treatment of travelers’ diarrhea. J Travel Med 8 :S25.

  • 21

    Vila J, Vargas M, Ruiz J, Corachan M, Jimenez De Anta MT, Gascon J, 2000. Quinolone resistance in enterotoxigenic Escherichia coli-causing diarrhea in travelers to India in comparison with other geographical areas. Antimicrob Agents Chemother 44 :1731–1733.

    • Search Google Scholar
    • Export Citation
  • 22

    Smith KE, Besser JM, Hedberg CW, Leano FT, Bender JB, Wicklund JH, Johnson BP, Moore KA, Osterholm MT, 1999. Quinolone–resistant Campylobacter jejuni infections in Minnesota, 1992–1998. N Engl J Med 340 :1525–1532.

    • Search Google Scholar
    • Export Citation
  • 23

    Kuschner RA, Trofa AF, Thomas RJ, Hoge CW, Pitarangsi C, Amato S, Olafson RP, Echeverria P, Sadoff JC, Taylor DN, 1995. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 21 :536–541.

    • Search Google Scholar
    • Export Citation
  • 24

    Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Martinez-Sandoval F, Knirsch C, DuPont HL, 2003. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis 37 :1165–1171.

    • Search Google Scholar
    • Export Citation
  • 25

    DuPont HL, Ericsson CD, Mathewson JJ, Palazzini E, DuPont MW, Jiang ZD, Mosavi A, de la Cabada FJ, 1998. Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers’ diarrhea. Digestion 59 :708–714.

    • Search Google Scholar
    • Export Citation
  • 26

    DuPont HL, Jiang Z-D, Ericsson CD, Adachi JA, Mathewson JJ, DuPont MW, Palazzini E, Riopel LM, Ashley D, Martinez-Sandoval F, 2001. Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 33 :1807–1815.

    • Search Google Scholar
    • Export Citation
  • 27

    Jiang ZD, Lowe B, Verenkar MP, Ashley D, Steffen R, Tornieporth N, von Sonnenburg F, Waiyaki P, DuPont HL, 2002. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay). J Infect Dis. 185 :497–502.

    • Search Google Scholar
    • Export Citation
  • 28

    Steffen R, Sack DA, Riopel L, Jiang ZD, Sturchler M, Ericsson CD, Lowe B, Waiyaki P, White M, DuPont HL, 2003. Therapy for travelers’ diarrhea with rifaximin on various continents. Am J Gastroenterol 98 :1073–1078.

    • Search Google Scholar
    • Export Citation
  • 29

    DuPont HL, Cooperstock M, Corrado ML, Fekety R, Murray DM, 1992. Evaluation of new anti-infective drugs for the treatment of acute infectious diarrhea. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 15 :S228–S235.

    • Search Google Scholar
    • Export Citation
  • 30

    Jiang ZD, Ke S, Palazzini E, Riopel L, DuPont H, 2000. In vitro activity and fecal concentration of rifaximin after oral administration. Antimicrob Agents Chemother 44 :2205–2206.

    • Search Google Scholar
    • Export Citation
  • 31

    Ericsson CD, DuPont HL, Mathewson JJ, Johnson PC, de la Cabada FJ, Bitsura JA, 1988. Test-of-cure stool cultures for traveler’s diarrhea. J Clin Microbiol 26 :1047–1049.

    • Search Google Scholar
    • Export Citation
  • 32

    DuPont HL, Jiang Z-D, Okhuysen P, Ericsson CD, de la Cabada FJ, Ke S, DuPont MW, Martinez-Sandoval F, 2005. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Int Med 142 :805–812.

    • Search Google Scholar
    • Export Citation
  • 33

    Taylor DN, McKenzie R, Durbin A, Carpenter C, Atzinger CB, Haake R, Bourgeois AL, 2006. Rifaximin, a nonabsorbed oral antibiotic, prevents shigellosis after experimental challenge. Clin Infect Dis 42 :1283–1288.

    • Search Google Scholar
    • Export Citation
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