Rifaximin (Xifaxan®)

Special Feature

By Esther Wee, Duyen Nguyen, Paul Hsiao, and Jessica C. Song, Esther Wee and Duyen Nguyen are PharmD Candidates at the University of the Pacific, Paul Hsiao is PharmD, Pharmacist Specialist, Santa Clara Valley Medical Center, and Jessica C. Song, MA, is PharmD, Pharmacy Residency Coordinator, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.

Esther Wee, Duyen Nguyen, Paul Hsiao, and Jessica C. Song report no financial relationships relevant to this field of study.

Travelers' diarrhea is the most common clincal ailment affecting tourism among travelers who move from industrialized to developing countries.1 Travelers' diarrhea is usually self limiting, and is defined as the passage of 3 or more loose stools per day in addition to one of the following gastrointestinal symptoms: fever, nausea, abdominal cramps, or fecal urgency.2 Travelers' diarrhea is expected to occur in 11 million travelers each year and, although rarely life threatening, it is associated with at least 1% of sufferers being hospitalized, 20% being confined to bed, and up to 40% changing their itinerary.3

The majority of travelers' diarrhea cases are caused by infectious enteropathogenic microorganisms that colonize the traveler's bowel through the ingestion of contaminated food or water. Although specific causative organisms vary around the world, bacteria account for at least 85% of cases of travelers' diarrhea.1-3 Enterotoxigenic Escherichia coli (ETEC) is the pathogen most frequently isolated in individuals with travelers' diarrhea from most geographic areas. These organisms produce a heat stable or heat labile enterotoxin that induces secretory diarrhea. Other E. coli, including enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC) and enteroaggregative E. coli (EAEC), are increasingly being recognized as common causes of travelers' diarrhea.1-3 In addition, invasive pathogens such as Campylobacter, Shigella, non-typhoid Salmonella, Vibrio parahaemolyticus as well as Aeromonas hydrophila, Plesiomonas shigelloides, and Yersinia enterocolitica have been frequently isolated in specific geographic locations.4–5

Although travelers are often advised to "boil it, cook it, peel it or forget it," counseling travelers about food precautions and adherence to dietary recommendations does not eliminate the risk of travelers' diarrhea.5 Moreover, antibiotic prophylaxis is not recommended by the Centers for Disease Control and Prevention because overuse of such agents can promote the emergence of antibiotic resistance.6 Agents for the prevention and treatment of travelers' diarrhea include bismuth subsalicylate (Pepto-Bismol), taken as 1 oz of liquid or two chewable tablets every 30 minutes for eight doses, as it has been shown to decrease stool frequency and shorten the duration of illness in several placebo-controlled studies. However, its insufficient efficacy precludes its use for the treatment of travelers' diarrhea. The use of probiotics, such as Lactobacillus GG and Saccharomyces boulardii, has been studied in the prevention of travelers' diarrhea with inconclusive efficacy outcomes.6 Therefore, despite the availability of numerous non-antibacterial preparations, antibacterial drugs play the central role in the therapy of travelers' diarrhea.

The Infectious Diseases Society of America guidelines recommend empirical antibiotic therapy for travelers' diarrhea.7 The selection of specific antibiotics is driven by the goal of therapy and by the known susceptibility of pathogens to available antibiotics. The most widely used antibiotics in the past for the treatment of travelers' diarrhea were ampicillin, tetracyclines and co-trimoxazole (trimethoprim-sulfamethoxazole). More recently, quinolones such as ciprofloxacin or levofloxacin, have emerged as the drugs of choice for empirically treating adults with travelers' diarrhea because of their efficacy against most enteropathogens.5 However, these agents have significant shortcomings as the activity of co-trimoxazole is steadily decreasing due to increasing resistance worldwide. In addition, the proportion of quinolone-resistant strains among Campylobacter isolates may limit their usefulness in some destinations such as Thailand and Nepal.5,6

Rifaximin (Xifaxan®) is an oral rifamycin antibiotic structurally related to rifampin. It is a semisynthetic antibiotic and the addition of a pyridoimidazole ring to its chemical structure makes rifaximin nonabsorbable.8,9

FDA approval was granted in 2004 for the treatment of travelers' diarrhea in adults and in children 12 years of age or older caused by noninvasive strains of E. coli.4 This article will provide a review of rifaximin's 1) spectrum of activity, pharmacological and pharmacokinetic properties, 2) safety and efficacy profile, 3) dosage, interaction, and resistance patterns, 4) clinical efficacy and 5) comparative efficacy relative to other available antibiotics.

Spectrum of Activity

Recent in vitro studies have examined the susceptibility patterns of various enteropathogens to rifaximin, ciprofloxacin, levofloxacin, azithromycin and trimethoprim-sulfamethoxazole.10–12 The minimum inhibitory concentrations (MICs) of rifaximin (RIF) and other antibacterials against bacterial enteropathogens known to cause travelers' diarrhea are shown in Table 1.

Rifaximin has broad spectrum in vitro bactericidal activity against gram positive, gram-negative, aerobic, and anaerobic bacteria.4 Although a MIC90 range of 16–32 mg/L for rifaximin against ETEC and EAEC is relatively high and normally considered to represent drug resistance, a MIC90 of 32 mg/L is approximately 250-fold lower than the concentration of rifaximin in stools following 3 days of rifaximin administration.9

Pharmacologic Properties

A summary of the pharmacologic, pharmacokinetic, and clinical properties of rifaximin can be found in Table 2.8,13–18 Although in vitro studies demonstrated the potential of rifaximin to interact with cytochrome P450 3A4 (CYP 3A4), clinical interactions with drugs metabolized by human cytochrome P450 isoenzymes have not been documented. In addition, rifaximin has not been shown to alter pre-systemic metabolism of oral contraceptives containing ethinyl estradiol and norgestimate.8

Rifaximin is not inactivated by gastric fluids and undergoes minimal systemic absorption (< 0.4% after oral administration) in both the fasting state and when administered within 30 minutes of a high-fat breakfast.9 Rifaximin's low solubility in water and high solubility in bile may translate into greater antimicrobial effects in the small bowel.9

In 4 healthy male volunteers given radio labeled rifaximin as a single dose, fecal and urinary excretion rates approached 97% and 0.3%, respectively. The systemic absorption of rifaximin (200 mg 3 times daily) was also evaluated in 13 subjects with shigellosis on day 1 and 3 of a 3-day therapeutic regimen, with no evidence of rifaximin accumulation following repeated administration for 3 days.8

Hepatically impaired patients (including hepatic encephalopathy) do not require dose reduction, as rifaximin undergoes minimal systemic absorption.8

Clinical Efficacy of Rifaximin for Treatment of TD

Three pivotal multicenter, randomized, double-blind clinical trials have assessed the utility of rifaximin in patients with travelers' diarrhea (Table 3).12,19,20

Studies comparing the effectiveness of rifaximin and ciprofloxacin in patients with travelers' diarrhea,12,20 secondary to non-invasive pathogens, suggest the equivalence of rifaximin and ciprofloxacin. The primary endpoint highlighted in the Phase III studies was based on the time passed from the initiation of therapy until the passage of the last unformed stool (TLUS).12,19,20

Steffen et al compared rifaximin to placebo in the treatment of 349 evaluable patients with travelers' diarrhea.19 Only adult patients with acute travelers' diarrhea who did not receive concurrent administration of anti-diarrheal compounds that could influence the outcomes of the study were randomized to receive rifaximin 200 mg tid or 400 mg tid, or placebo. Both doses of rifaximin significantly reduced the duration of diarrhea (TLUS) when compared to placebo (P = 0.0001). A larger number of rifaximin-treated patients achieved wellness (see Table 3 for definition) and a lower proportion of rifaximin recipients experienced treatment failures, compared with placebo-treated patients.

Of note, the study conducted by Taylor et al demonstrated the relative lack of efficacy of rifaximin compared to that of ciprofloxacin in treating patients with travelers' diarrhea caused by invasive pathogens (including Campylobacter jejuni, Shigella spp., and Salmonella spp.). Interestingly, the proportion of patients with baseline invasive enteropathogens was nearly 2-fold higher in the rifaximin group compared to that reported in the ciprofloxacin group, suggesting that rifaximin recipients had more serious illness at baseline. Treatment failure occurred in more than 50% of the 46 rifaximin-treated patients with invasive pathogens in pre-treatment stool samples, and less than 25% of rifaximin recipients with C. jejuni isolated as the sole baseline pathogen achieved wellness.9,20

Non-FDA Approved Indications

DuPont and colleagues recently evaluated the efficacy of rifaximin as prophylaxis against travelers' diarrhea.13 This randomized, double-blind, placebo-controlled trial enrolled 210 adult students from the United States who had been in Mexico for less than 72 hours. Subjects received rifaximin 200 mg once (n = 50), twice (n = 52), or three (n = 54) times daily or placebo (n = 54) for 14 days. The primary efficacy outcome was the occurrence of diarrhea3 (3 unformed stools/24 hours), along with one additional sign and symptom of enteric infection. Travelers' diarrhea developed in 15% of the combined rifaximin group and in 54% of placebo-treated patients (rate ratio, 0.27, 95% CI, 0.17-0.43). The investigators concluded that future studies should determine whether rifaximin is effective in preventing the development of post-infectious irritable bowel syndrome.

Several small studies have shown that in patients with hepatic encephalopathy, rifaximin displays equivalent effcacy to that of lactulose and neomycin in regards to clinical improvement and decrease in blood ammonia concentration.14 A recently published prospective, randomized, double-blind, double-dummy, controlled study compared the efficacy and safety of rifaximin to that of lactilol.14 Mas and associates enrolled 103 patients with grade I–III hepatic encephalopathy and randomized them to receive 5 to 10 days of rifaximin 1200 mg/day (divided in 3 doses) or lactilol 60 g/day. Global efficacy rates were 81.6% and 80.4%, respectively, in the rifaximin and lactilol groups (P-value not reported). However, rifaximin lowered plasma ammonia levels to a greater extent compared to lactilol (↓ from baseline of 51.0 g/dL vs 15.1 g/dL, P = 0.008).

Prantera et al conducted a multicenter, double-blind, randomized, placebo-controlled study that enrolled 83 patients with mild to moderate Crohn's disease.15 Patients either received once daily or twice daily rifaximin 800 mg, or placebo for 12 weeks. Clinical remission (as defined by a Crohn's Disease Activity Index of less than 150) represented the primary efficacy endpoint. At the end of the study, 52% of the high-dose (twice daily) rifaximin-treated patients were in remission, compared with 32% of low-dose rifaximin-treated patients and 33% of placebo-treated patients (non-significant difference). However, patients treated with twice daily rifaximin exhibited significantly lower treatment failure rates compared to that of placebo-treated patients (4% vs 33%, P = 0.01).

One small, but controlled investigation assessed the efficacy of rifaximin in patients with moderate to severe active, corticosteroid-refractory ulcerative colitis.16 Twenty-eight patients were randomized to receive twice daily rifaximin 400 mg or placebo for 10 days as an adjunct medication to standard corticosteroid treatment. Although clinical efficacy did not differ significantly between rifaximin and placebo recipients, rifaximin-treated patients experienced significant improvements in stool frequency (↓ from baseline of 2.1 vs 1.1, P < 0.02), rectal bleeding (P < 0.05), and sigmoidoscopic score (↓ from baseline of 0.75 vs 0.57, P = 0.06).

Sharara and colleagues studied the efficacy of rifaximin, in alleviating chronic symptoms of bloating and flatulence in 124 patients.17 This randomized, doubleblind, placebo-controlled trial randomly assigned patients to receive twice daily rifaximin 400 mg or placebo for 10 days. Of the 124 patients, approximately half of the patients met the Rome II criteria for diagnosing irritable bowel syndrome. Subjective global symptom relief at the end of the 10-day treatment period was the primary efficacy end point (response to the question, "Do you consider that your symptoms have improved since starting the study drug?"). A significantly higher proportion of rifaximin-treated patients reported global symptom relief compared with placebo recipients (41.3% vs 22.9%, P = 0.03).

Conclusion

Ideal properties of antibacterial drugs for travelers' diarrhea include minimally absorbed drug with little value outside enteric infections, activity against a broad range of bacterial enteropathogens, and safe use in young children and pregnant women. Rifaximin is an ideal candidate for the treatment of non-invasive travelers' diarrhea, because this non-absorbed antibiotic theoretically offers targeted activity at the source of infection, low potential for side effects and drug interactions, and the potential for delayed bacterial resistance, as its use is limited to gastrointestinal infections.1

Trimethoprim plus sulfamethoxazole (TMP/SMX) has been shown to be safe and effective for travelers' diarrhea although its resistance is increasing worldwide. Quinolones have been considered to represent the best treatment option for travelers' diarrhea, but resistance to this drug class has become problematic in Southern Asia, where up to 30% of travelers' diarrhea cases have been attributed to Campylobacter jejuni.5 In Thailand and adjacent areas, azithromycin may be the preferred agent for the treatment of travelers' diarrhea, as it has excellent activity against most enteropathogens responsible for causing this condition, including quinolone-resistant Campylobacter spp. However, the onset of action of azithromycin may be slower compared with other agents, and reports of macrolide resistance among Campylobacter spp. have surfaced in Thailand.

In addition to the indication of gastrointestinal bacterial infections, rifaximin has also been studied to treat or prevent several other conditions involving the gastrointestinal flora. Such conditions include prophylaxis against travelers' diarrhea, hepatic encephalopathy, inflammatory bowel disease (Crohn's disease, corticosteroid-refractory ulcerative colitis), and functional bowel disorders with flatulence.

In conclusion, quinolones and rifaximin are the first-line agents for the treatment of travelers' diarrhea in most geographic regions, except for Thailand, where azithromycin should be used instead. Rifaximin shows promise as a chemoprophylactic agent against travelers' diarrhea and as treatment options for hepatic encephalopathy, Crohn's disease, corticosteroid-refractory ulcerative colitis, and for irritable bowel syndrome.

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