Infectious diarrhea is a common problem

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1 THE EMERGING ROLE OF NONABSORBABLE ORAL ANTIBIOTIC THERAPY IN THE MANAGEMENT OF TRAVELERS DIARRHEA * Robert Steffen, MD ABSTRACT The short- and long-term consequences associated with diarrhea in travelers highlight the importance of the effective management of this illness. The use of nonabsorbed, orally administered antibiotics has been proposed as an important strategy for overcoming limitations of currently available treatments for infectious diarrhea in travelers. Several nonabsorbed or poorly absorbed antibiotics have been shown to be effective for infectious diarrhea. Rifaximin, the nonabsorbed (<0.5%) antibiotic that has been most extensively studied for infectious diarrhea, demonstrates all of the advantages posited by proponents of the strategy of using nonabsorbed antimicrobial therapy for enteric infections: rifaximin achieves high luminal concentrations to eradicate causative pathogens; shows no systemic toxicity; has tolerability and safety profiles comparable to those of placebo; and has gutspecific activity that limits its use to enteric infections. In more than 15 years of clinical use for enteric infections, rifaximin has not been associated with bacterial resistance. (Adv Stud Med. 2003;3(10A):S951-S958) *Based on a presentation given by Dr Steffen at a roundtable discussion held in February 2003, Dallas, Texas. Professor of Travel Medicine; Head, Division of Epidemiology and Prevention of Communicable Diseases, University of Zurich, Switzerland. Address correspondence to: Robert Steffen, MD. roste@ifspm.unizh.ch. Infectious diarrhea is a common problem among travelers from developed to developing countries a group that includes tourists, business travelers, students, foreign-aid volunteers, workers of government and nongovernment organizations, and military personnel. For example, in a study of 140 western Canadian employees who traveled on international business, 45% reported infectious diarrhea as a travel-related health problem. 1 The only more common health problem associated with travel was jet lag. Similarly, infectious diarrhea was one of the primary illnesses experienced by US, Canadian, and British troops deployed to the Arabian desert during the Gulf War in August Across studies, the incidence rate of infectious diarrhea among those traveling from developed to developing countries ranges from 20% to 90%, 3 with the degree of risk dependent on factors such as the traveler s country of origin, destination country, age, duration of stay, season of travel, and standard of accommodations. 3-9 This incidence has recently been confirmed among more than travelers, mainly vacationers, at 4 frequent destinations. 5 On average, untreated travelers diarrhea lasts 4 days, but may extend to 1 week or more in approximately 15% of cases. 8,10-12 Travelers diarrhea can necessitate bed rest and cause sufferers to alter their itineraries and cancel planned activities. 5 These consequences are often costly for the vacationer and can be particularly disruptive for those who are required to work abroad. Apart from causing acute distress, infectious diarrhea in unusual cases can lead to complications such as arthritis, Guillain-Barré syndrome, and, rarely, death It occasionally has been linked to the development of chronic enteric conditions, such as irritable bowel syndrome. 17,18 Advanced Studies in Medicine S951

2 The short- and long-term consequences associated with infectious diarrhea in travelers highlight the importance of its effective management. Approaches to managing infectious diarrhea in travelers include information about risk factors (mainly education about careful behavior, such as avoiding potentially contaminated food and beverage items), chemoprophylaxis with antibiotics or bismuth subsalicylate, and treatment. 3 Although education is undoubtedly beneficial for the individual traveler who modifies behavior to reduce risks, it Treatment is not widely practiced and, thus, has not proved to reduce the overall incidence of travelers diarrhea. Chemoprophylaxis is currently not widely accepted. Therefore, treatment remains the primary mode of management of travelers diarrhea. This paper discusses current approaches to the acute treatment of travelers diarrhea, unmet therapeutic needs, and the emerging role of nonabsorbable oral antibiotic therapy in the management of infectious diarrhea in travelers. CURRENT APPROACHES TO TREATING INFECTIOUS DIARRHEA Nonspecific strategies for treating infectious diarrhea in travelers include awaiting spontaneous remission with fluid and electrolyte replacement, oral rehydration, antimotility agents (eg, loperamide), and bismuth subsalicylate (Table 1). 3,19,20 These treatments can be useful for symptomatic relief, and oral rehydration is paramount in preventing complications in children and senior travelers. However, nonspecific approaches do not always effect a rapid clinical cure. Bismuth subsalicylate, which has weak antibacterial properties, is a possible exception to this generalization. Food-borne or water-borne bacteria most often enterotoxigenic Escherichia coli, enteroaggregative E coli, Campylobacter species, Salmonella species, and Shigella species account for approximately 80% of cases of infectious diarrhea in travelers. 8 Viruses and protozoa account for the minority of cases, but protozoa, such as Cryptosporidium, are becoming increasingly important causes of travelers diarrhea. 3 In keeping with the predominantly bacterial etiology of infectious diarrhea in travelers, antibiotic therapy is a mainstay of treatment for at least moderate or severe illness (Table 1). 3,19,20 Antibiotics are prescribed for infectious diarrhea to reduce symptoms and duration Table 1.Acute Treatments for Infectious Diarrhea in Travelers Oral rehydration salts Antimotility agents (eg, loperamide) Bismuth subsalicylate Quinolones Macrolides Trimethoprimsulfamethoxazole Doxycycline and other tetracyclines Description NONSPECIFIC TREATMENTS Essential for the elderly, young children, or patients with serious illness for addressing adverse effects of electrolyte loss Do not reduce the amount or duration of diarrhea or eradicate causative pathogens Provide rapid relief of symptoms May cause constipation Do not eradicate causative pathogens; recurrence possible Should not be given alone in the presence of signs of invasive illness (ie, fever, bloody stools) Should not be used by infants or toddlers, or during pregnancy Rarely cause serious or fatal complications, including paralytic bowel obstruction and perforation Has antibacterial, anti-inflammatory, antisecretory, and adsorbent properties Despite antibacterial activity, is less effective than antibiotics Is inexpensive and has few side effects ANTIBIOTICS Data from Steffen et al 3 ; DuPont 19 ; Murphy et al. 20 Effective in short courses against most causative organisms Often ineffective against Campylobacter Should not be used in pregnant women Resistance is increasingly observed Use for infectious diarrhea is a public health concern because resistance engendered during treatment of such typically self-limiting infections limits the utility of quinolones for serious or life-threatening infections Adverse events possible (eg, neuropsychological) Erythromycin useful for susceptible Campylobacter, but insufficient coverage of gram-negative bacteria limits usefulness as empiric therapy Azithromycin has broader coverage than erythromycin Resistance is increasing No longer useful because of bacterial resistance No longer useful because of bacterial resistance S952 Vol. 3 (10A) November 2003

3 of disease and to eradicate fecal shedding, thereby preventing transmission of enteric pathogens. Antibiotics also possibly prevent sequelae, including dissemination of infection outside of the intestinal tract. Given the high likelihood of a bacterial cause of infectious diarrhea in travelers and the unfeasibility, particularly when abroad, of obtaining rapid microbiologic results, the Infectious Diseases Society of America guidelines recommend that empiric antibiotic therapy be initiated without obtaining a fecal specimen. 13 For travelers with frequent watery bowel movements that interfere with activities, an antibiotic-loperamide combination, which provides the rapid symptom relief of the antimotility agent and the curative efficacy of the antibiotic, is advocated. 21 UNMET NEEDS IN ACUTE TREATMENT OF TRAVELERS DIARRHEA Antimicrobial resistance has rendered ineffective the tetracyclines and trimethoprim-sulfamethoxazole, which were standards of antidiarrheal care in past decades. 22,23 Although fluoroquinolones and some macrolides retain efficacy against most causative organisms, resistance of common enteric pathogens to both of these antibiotic classes is increasing. For example, the incidence of quinolone resistance among Campylobacter jejuni isolates from humans increased from 1% to 10% from 1992 to 1998 in Minnesota, a finding the authors attributed to foreign travel and, secondarily, to previous quinolone use and the acquisition of resistant strains from poultry. 24 In a 1998 study of diarrheal illness among 169 US military personnel deployed to Thailand, in vitro resistance was observed in 96% of 23 Campylobacter isolates. 25 Suboptimal clinical response to ciprofloxacin occurred more often in Campylobacter infections (17% of cases with suboptimal response) than in infections arising from other causes, including nontyphoidal Salmonella and enterotoxigenic E coli (6% of cases with suboptimal response). Quinolone resistance among S typhi and S paratyphi has also rendered these agents less effective for enteric fever in India in recent years. 26 Increasing quinolone resistance is of concern, and alternative antibiotics are urgently needed. Secondary to resistance, other limitations of treatments for infectious diarrhea in travelers include suboptimal tolerability and safety. 19 Although not serious in the majority of cases, side effects (eg, constipation with antimotility therapy, nausea and diarrhea with macrolides, central nervous system effects with quinolones) can be as distressing to the patient as the symptoms of infectious diarrhea itself. NONABSORBABLE ANTIBIOTICS IN TRAVELERS DIARRHEA The use of nonabsorbable orally administered antibiotics has been proposed as a means of overcoming some of the limitations of currently available antidiarrheal therapies. 7,19 Potential advantages of a nonabsorbable oral antibiotic include: (1) ability to achieve high luminal concentrations to eradicate causative pathogens; (2) little or no potential for systemic toxicity; (3) benign tolerability and safety profiles; and (4) gut-specific activity, which would restrict the use of the nonabsorbed antibiotic to enteric infections and thereby potentially limit the development of bacterial resistance relative to that observed with antibiotics used for extraintestinal as well as enteric infections (Table 2). 7,19 Several poorly absorbed antibiotics, including bicozamycin, aztreonam, and rifaximin, have been studied in travelers diarrhea. Data are most plentiful with rifaximin, which has been studied for introduction in the United States and elsewhere for empiric treatment of infectious diarrhea in travelers. AZTREONAM AND BICOZAMYCIN Aztreonam, which is less than 1% absorbed after oral administration, and bicozamycin, which is less than 3% absorbed after oral administration, have each been studied in 1 well-controlled trial in patients with travelers diarrhea. 27,28 The efficacy of aztreonam (100 mg 3 times daily; n = 98) compared with placebo (n = 93) for 5 days Table 2. Potential Advantages of Nonabsorbed Antibiotics for Travelers Diarrhea Ability to achieve high luminal concentrations to eradicate causative pathogens Little or no potential for systemic toxicity Benign tolerability and safety profiles Gut-specific activity leading to limited use and, theoretically, limited bacterial resistance Data from DuPont et al. 7,19 Advanced Studies in Medicine S953

4 was assessed in a randomized double-blind study of patients with travelers diarrhea acquired during travel from the United States to Mexico. 27 Compared with placebo, aztreonam shortened the duration of illness of any cause by 40 hours and shortened the duration of illness attributed to enterotoxigenic E coli by 50 hours. The overall incidence of adverse events did not differ between the aztreonam group and the placebo group. The efficacy of oral bicozamycin (500 mg 4 times daily; n = 74) compared with placebo (n = 74) for 3 days was assessed in a randomized double-blind study of 138 adults with travelers diarrhea acquired while visiting Guadalajara, Mexico. 28 Compared with placebo, bicozamycin significantly reduced the duration of diarrhea of all causes (29.2 ± 27.3 vs 63.7 ± 46.1 hours), diarrhea attributed to Shigella infection (36.5 hours vs 89.5 hours), and diarrhea attributed to infection with toxigenic E coli (31.1 hours vs 69.0 hours). 7 Side effects, assessed by questionnaire, were equally uncommon in the bicozamycin and placebo groups. These data on aztreonam and bicozamycin demonstrate the potential of poorly absorbed antibiotics in the treatment of infectious diarrhea in travelers. These antibiotics significantly reduced the duration of diarrhea, including illness caused by mucosally invasive pathogens, such as Shigella. Furthermore, as expected on the basis of their minimal systemic availability, these poorly absorbed antibiotics were well tolerated when administered as 3-day or 5-day courses. Despite the promising results of these 2 studies, neither aztreonam nor bicozamycin was assessed further for the treatment of infectious diarrhea possibly because, when these studies were conducted more than 20 years ago, the need for new antimicrobial options was not as salient as it is now. Bicozamycin is not currently available for human use, and aztreonam is marketed for parenteral administration only. 21 RIFAXIMIN Rifaximin, a broad-spectrum antibiotic that is less than 0.5% absorbed after oral administration, has been extensively evaluated for treating bacterial diarrheal diseases. Rifaximin was first marketed 15 years ago in Italy and is now available in 13 countries for a variety of enteric applications, including treatment of infectious diarrhea. Rifaximin is projected to soon be introduced in the United States for the empiric treatment of infectious diarrhea in travelers. PHARMACOKINETICS The very low absorption of rifaximin after oral administration has been confirmed in several studies, one of which employed a radiolabeled drug ( 14 C-rifaximin). In the latter study, 14 C-rifaximin was administered as a single oral dose (400 mg) to 4 healthy males aged 30 to 41 years. 29 No radioactivity was measurable in blood, and rifaximin concentrations were undetectable in most plasma samples. Almost all (97%) of the rifaximin dose was excreted in the feces as unchanged drug; only 0.32% of the dose was recovered from the urine. These results, which have been corroborated in other studies using nonradiolabeled rifaximin, 30,31 show that less than 0.5% of an oral dose of rifaximin is absorbed. These studies show that rifaximin is virtually unabsorbed from the gastrointestinal tract in healthy volunteers. Comparable results were obtained in studies of patients with gastrointestinal illness. In one study in which 12 patients with mild or moderate ulcerative colitis received a single oral dose of rifaximin (400 mg), rifaximin concentrations were below the limit of detection of the analytic method (ie, 2 ng/ml) for nearly all plasma samples obtained at the predetermined sampling times of 1, 4, 8, and 24 hours postdose. 29 Likewise, in a study in which 13 patients with active Crohn s disease received a single oral dose of rifaximin (400 mg), rifaximin concentrations through 24 hours postdose were extremely low (range of mean peak plasma levels, ng/ml). 29 These data are important in showing that rifaximin is virtually unabsorbed in conditions characterized by inflamed intestinal tissue, which has been speculated to allow increased drug absorption compared with noninflamed tissue. MICROBIOLOGY In vitro, rifaximin has a broad spectrum of bactericidal activity against both gram-positive and gramnegative bacteria and both aerobic isolates and anaerobic isolates, including Bacteroides, Bifidobacterium, Campylobacter jejuni, Clostridium difficile, enteroaggregative E coli, enteroadherent E coli, Enterobacter cloacae, Fusobacterium, Klebsiella pneumoniae, Plesiomonas shigelloides, Peptostreptococcus, Prevotella, Proteus species, Pseudomonas aeruginosa, Salmonella species, Shigella species, Serratia species, Streptococcus species, and Yersinia enterocolitica. 29 Rifaximin also shows some activity against Cryptosporidia and Giardia, protozoa that are increasingly important causes of infectious diarrhea. S954 Vol. 3 (10A) November 2003

5 Rifaximin was active against 427 enteropathogens (298 from a pretreatment stool sample and 129 from a posttreatment stool sample) isolated from patients with travelers diarrhea contracted during travel to Mexico, Guatemala, Kenya, and Jamaica from 1996 through For all organisms, the minimum inhibitory concentration for at least 50% of tested strains (MIC 50 ) and MIC for at least 90% of tested strains (MIC 90 ) values were substantially lower than the fecal rifaximin concentrations of 8000 µg per gram rifaximin achieved during clinical use (Table 3). 32 That rifaximin MIC 50 and MIC 90 values were a small fraction of fecal rifaximin concentrations reflects a high degree of susceptibility of enteric pathogens to the drug. Importantly, the clinically relevant concentration of rifaximin for determining bacterial susceptibility is that in the feces (8000 µg/g) 32 rather than in the plasma. Plasma levels are used to determine bacterial susceptibility to systemically available antibiotics but cannot be used for rifaximin, which is not systemically available. CLINICAL EFFICACY IN INFECTIOUS DIARRHEA IN TRAVELERS The clinical efficacy of rifaximin in travelers diarrhea was assessed in 3 clinical trials All studies enrolled adult travelers with acute diarrhea defined as at least 3 unformed stools within the 24 hours preceding randomization and at least 1 sign or symptom of enteric infection (ie, abdominal pain or cramps, nausea, vomiting, fever of 100ºF or 37.8ºC or above, dysentery, fecal urgency, excessive gas/flatulence, or tenesmus). One study compared the efficacy and tolerability of rifaximin 600 mg and 1200 mg daily for 3 days with those of placebo. 33 Rifaximin was significantly superior to placebo in the treatment of travelers diarrhea for the primary efficacy endpoint of the median time to last unformed stool (TLUS; 33 hours for rifaximin 600 mg or 1200 mg vs 60 hours for placebo; P =.0001 each rifaximin group versus placebo; Figure) 33 as well as for all secondary endpoints, including improvement in diarrheal syndrome (88% to 91% of patients improved within 72 hours with rifaximin compared with 73% with placebo) and mean number of unformed stools (4.7 over the first 48 hours postdose in each rifaximin group compared with 6.4 with placebo). Significantly more patients taking each dose of rifaximin compared with placebo experienced clinical cure (79% rifaximin 600 mg and 81% rifaximin 1200 mg versus 61% placebo), defined as no unformed stools within a 48-hour period with no fever or no watery stools and no more than 2 soft stools within a 24-hour period with no fever and no other clinical symptoms except for mild excess gas/flatulence. Table 3. Rifaximin MIC Values for Isolates from Clinical Trials MIC 50 MIC 90 MIC Range Organism Isolates (n) (µg/ml) (µg/ml) (ug/ml) Aeromonas Campylobacter Enterotoxigenic E coli Plesiomonas shigelloides Salmonella Shigella Vibrio Total MIC = minimum inhibitory concentration. Data from Jiang et al. 32 Figure. Median TLUS in a Placebo-Controlled Trial of Rifaximin for Travelers Diarrhea P =.0001 for rifaximin vs placebo. TLUS = time to last unformed stool. Data from DuPont et al. 33 Advanced Studies in Medicine S955

6 Investigators were asked to report any untoward medical occurrence as an adverse event, regardless of whether they considered it to be caused by study medication. The adverse-event profile of rifaximin was comparable to that of placebo (Table 4). 33 The most common adverse events, including flatulence, abdominal pain, tenesmus, and fecal incontinence, probably constituted symptoms of infectious diarrhea itself rather than side effects of study medication. The second study, which compared the efficacy and tolerability of rifaximin 800 mg daily for 3 days with those of ciprofloxacin 500 mg twice daily for 3 days, was statistically powered to show noninferiority of rifaximin. 34 Rifaximin was equivalent to ciprofloxacin in the treatment of travelers diarrhea for the primary efficacy endpoint of median TLUS (26 hours vs 25 hours) as well as for secondary endpoints, including improvement in diarrheal syndrome (83% of patients by 48 hours postdose in the rifaximin group and 85% in the ciprofloxacin group), mean number of unformed stools (5.1 during the first 48 hours postdose with rifaximin and 4.5 with ciprofloxacin), and clinical cure (87% vs 88%). These data demonstrate that rifaximin is as effective at effecting clinical improvement as a quinolone, the current antimicrobial standard of care for infectious diarrhea. A similar pattern of results was observed in a third study in which rifaximin (600, 1200, or 1800 mg daily) was compared with trimethoprim-sulfamethoxazole (320 mg/1600 mg daily) for 5 days. 35 The numbers of patients receiving rifaximin 600, 1200, and 1800 mg daily were 18, 18, and 19, respectively; 17 patients received trimethoprim-sulfamethoxazole. Unlike the study of rifaximin and ciprofloxacin, the study with trimethoprim-sulfamethoxazole was an exploratory analysis that was not statistically powered to show noninferiority of rifaximin. The pattern of results was the same as that observed in the ciprofloxacin study: rifaximin was at least as effective as the comparator agent in improving clinical status. The median TLUS values were 26.3, 40.5, and 35.0 in the rifaximin 600-, 1200-, and 1800-mg dosing groups, respectively, compared with 47.0 hours with trimethoprim-sulfamethoxazole. The percentages of patients with clinical cure were 89%, 100%, and 90% in the rifaximin 600-, 1200-, and 1800-mg dosing groups, respectively, compared with 82% for trimethoprim-sulfamethoxazole. Although rifaximin was numerically better then trimethoprim-sulfamethoxazole on these efficacy measures, no statistical differences were observed because of the small sample size and resulting low statistical power. Notably, this study was conducted during the year 1996, before bacterial resistance rendered trimethoprim-sulfamethoxazole less effective for travelers diarrhea. Nineteen additional controlled and open-label studies have evaluated the efficacy and tolerability of rifaximin for infectious diarrhea These additional studies are generally smaller and less well controlled than the 3 studies described above. These limitations notwithstanding, the additional studies provide important information about rifaximin efficacy and tolerability in patient subgroups, such as children and the elderly, that were not included in the 3 large, well-controlled clinical trials. The results of the 19 additional studies are consistent with those of the 3 studies described above in showing that rifaximin was effective and well tolerated in the treatment of infectious diarrhea. Table 4. Patients Reporting Adverse Events in a Placebo- Controlled Study of Rifaximin Rifaximin, n (%) Adverse Event 600 mg/day 1200 mg/day Placebo, n (%) (n = 124) (n = 126) (n = 129) Flatulence 32 (26) 36 (29) 42 (33) Abdominal pain 21 (17) 28 (22) 23 (18) Tenesmus 19 (15) 14 (11) 19 (15) Fecal incontinence 16 (13) 21 (17) 20 (16) Nausea 16 (13) 20 (16) 18 (14) Headache 15 (12) 22 (18) 12 (9) Pyrexia 8 (7) 7 (6) 9 (7) Vomiting 5 (4) 3 (2) 3 (2) Constipation 4 (3) 3 (2) 3 (2) Dizziness 1 (1) 5 (4) 5 (4) AST increased 4 (3) 0 4 (3) Fatigue 0 4 (3) 0 Diarrhea 2 (2) 2 (2) 8 (6) Adverse events occurring in >2% of patients in an active treatment group are listed. AST = aspartate aminotransferase. Data from DuPont et al. 33 S956 Vol. 3 (10A) November 2003

7 DOSING On the basis of these clinical studies, the optimum dosage regimen for rifaximin appears to be one 200- mg tablet taken 3 times daily for 3 days. Whether less frequent or prolonged dosing is equally effective has not yet been established. RESISTANCE It has been suggested that one advantage of a nonabsorbable antibiotic over an absorbable antibiotic for enteric infections is circumscribed use (Table 1), which limits the potential for development of widespread bacterial resistance that can occur when an antibiotic is used extensively for infections affecting various body systems. Postmarketing data with rifaximin support the hypothesis that circumscribed use of an antibiotic limits the development of bacterial resistance. Clinically relevant resistance to rifaximin has not been reported during postmarketing surveillance or in the medical literature during more than 15 years of use of the drug. The ability of bacteria to develop resistance to rifaximin has also been assessed in microbiologic and clinical studies. 48 After the standard 3-day course of rifaximin therapy, posttreatment MICs of rifaximin did not increase relative to pretreatment MICs. 33 Although resistance of commensal organisms to rifaximin was observed after a longer, 5-day course of oral therapy, resistance was transient such that all bacterial strains regained susceptibility to rifaximin within 1 to 12 weeks after treatment was discontinued. 48 The transitory nature of resistance to rifaximin may be attributed to poorer viability of rifaximin-resistant organisms relative to wild-type (nonresistant) ones. These data suggest that rifaximin is not associated with clinically meaningful resistance, a property that differentiates it from other antibiotics used to treat enteric infections. CONCLUSIONS The use of nonabsorbed orally administered antibiotics has been proposed as an important strategy for overcoming limitations of currently available antimicrobial treatments for infectious diarrhea in travelers. Several nonabsorbed or poorly absorbed antibiotics have been demonstrated effective for infectious diarrhea, including that caused by pathogens associated with invasive disease. Rifaximin, the nonabsorbed (<0.5%) antibiotic that has been most extensively studied for infectious diarrhea, demonstrates all of the advantages posited by proponents of the strategy of using nonabsorbed antimicrobial therapy for enteric infections: it achieves high luminal concentrations to eradicate causative pathogens, shows no systemic toxicity, has tolerability and safety profiles comparable to those of placebo, and has gut-specific activity that limits its use to enteric infections. (The efficacy of rifaximin for invasive forms of travelers diarrhea is currently being investigated.) In more than 15 years of clinical use and clinical study for enteric applications, including hepatic encephalopathy, preoperative and postoperative prophylaxis in gastrointestinal surgery, diverticular disease, Clostridium difficile associated colitis, small-bowel bacterial overgrowth, Crohn s disease, and pouchitis, rifaximin has not been associated with clinically relevant bacterial resistance. REFERENCES 1. Rogers HL, Reilly SM. A survey of the health experiences of international business travelers. AAOHN J. 2002;50: Hyams KC, Riddle J, Trump DH, et al. Endemic infectious diseases and biological warfare during the Gulf War: a decade of analysis and final concerns. Am J Trop Med Hyg. 2001;65: Steffen R, Kollaritsch H, Fleischer K. Travelers diarrhea in the new millennium: consensus among experts from Germanspeaking countries. J Travel Med. 2003;10: Hamer DH, Gorbach SL. Infectious diarrhea and bacterial food poisoning. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger & Fordtran s Gastrointestinal and Liver Disease. Vol 2. 6th ed. Philadelphia, Pa: WB Saunders Company; 1998: von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhoea at various tourist destinations. Lancet. 2000;356: Steffen R. Epidemiologic studies of travelers diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis. 1986;8(suppl 2):S122-S DuPont HL, Ericsson CD. Prevention and treatment of traveler s diarrhea. N Engl J Med. 1993;328: Peltola H, Gorbach SL. Travelers diarrhea: epidemiology and clinical aspects. In: DuPont HL, Steffen R, eds. Textbook of Travel Medicine and Health. 2nd ed. Hamilton, Ontario: BC Decker, Inc; 2001: Castelli F, Pezzoli C, Tomasoni L. Epidemiology of travelers diarrhea. J Travel Med. 2001;8(suppl 2):S26-S Steffen R, van der Linde F, Gyr K, et al. Epidemiology of diarrhea in travelers. JAMA. 1983;249: Peltola H, Kyrönseppä H, Hölsä P. Trips to the south a health hazard: morbidity of Finnish travellers. Scand J Infect Dis. 1983;15: Advanced Studies in Medicine S957

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