Rifaximin is a semisynthetic rifamycin derivate that was approved as Xifaxan (Salix Pharmaceuticals, Morrisville, NC) by the US Food and Drug Administration (FDA) in 2004 for the treatment of traveler's diarrhea caused by noninvasive strains of Escherichia coli in children 12 years and older (1). It has been approved in Italy since 1987 for the treatment of acute and chronic gastrointestinal infections, bacterial diarrhea, hepatic encephalopathy, and pre- and postsurgical prophylaxis.
Rifaximin acts by blocking bacterial RNA polymerase (2). In vitro rifaximin has activity against a variety of organisms including aerobic and anaerobic Gram-positive as well as Gram-negative bacteria (1). The added pyrido-imidazole ring makes this drug virtually nonabsorbable, resulting in high concentrations in the gastrointestinal tract (1,2). Approximately 97% of radiolabeled rifaximin is excreted in the feces as unchanged drug, with 0.32% of the dose detected in urine, and undetectable levels in bile or breast milk. Absorption remains minimal even in the face of chronic mucosal inflammation, such as in UC (3). Minimal systemic absorption gives rifaximin an excellent safety profile with minimal adverse effects. In a large placebo-controlled trial, rifaximin had a placebo-like tolerability profile (4).
The etiology of inflammatory bowel disease (IBD) remains largely unknown, so current treatment is aimed at modifying the pathogenic mechanisms involved, mostly using anti-inflammatory drugs or immunosuppressants. There is clinical and experimental data that suggest that IBD is a result of an abnormal genetically determined response of the immune system to intestinal flora. This hypothesis supports a therapeutic role for antibiotics (5). Antibiotics that have been used with some success include metronidazole, ciprofloxacin, and clarithromycin (6–8).
In pediatric IBD patients, metronidazole and ciprofloxacin have been commonly used to treat flares of disease. Adverse effects of metronidazole and ciprofloxacin, however, remain of concern and neither of these medications is FDA approved for use in children with IBD. Adverse effects such as nausea, metallic taste, gastrointestinal disturbances, and polyneuropathy limit long-term use of metronidazole. Ciprofloxacin is better tolerated in the short term, but can induce nausea, diarrhea, and skin rashes. With concomitant long-term steroid use, ciprofloxacin can be associated with tendonitis and achilles tendon rupture (9). An adult study showed that the adverse effects of metronidazole and ciprofloxacin in patients with active Crohn disease (CD) caused treatment interruptions in more than 20% of cases and reduced compliance in more than 30% of patients (10,11).
We reviewed our experience with rifaximin as a treatment option for IBD. Because of its broad spectrum, low adverse effect profile and case reports of its benefits in IBD, it is being increasingly used for IBD flares in our practice.
This retrospective study was conducted on patients ages 8 to 21 years with known diagnosis of IBD who were treated with rifaximin for flare of symptoms. The study was reviewed and approved by the Cleveland Clinic institutional review board.
Data collected included the patient's age, sex, ethnicity, diagnosis, and disease distribution, duration of disease, all previous therapy, concurrent medications and the symptoms, which led to a trial of rifaximin (Table 1). The dosage of rifaximin prescribed was recorded and changes in treatment regimens were noted in the 15 days preceding and following the prescription of rifaximin to evaluate for possible confounding therapeutic agents. Symptom improvement intervals were recorded in days, weeks, and months. The efficacy of treatment was evaluated based on subjective improvement claimed by patients as none, mild, moderate, and optimum relief and recorded separately for each individual symptom. Adverse effects were recorded for a 1-month period after initiating medications. Gene testing for IBD at the time was not done for any of these children.
The exact Mantel-Haenzel test for correlation of ordinal variables was used to assess whether there was an association between total daily dose, amount of symptom relief, and time to symptom relief for the presenting complaints of abdominal pain, diarrhea, and bleeding in the stools. An exact 95% confidence interval was computed for the percentage of patients who experienced relief of symptoms. All tests were 2-tailed and were performed at a significance level of 0.05. SAS 9.1 software (SAS Institute, Cary, NC) was used for analyses.
Twenty-three pediatric patients were found to have worsening symptoms of their IBD and were prescribed rifaximin for presumed flare. Of these patients 12 had CD and 11 had UC with a median age of 15.08 years. The most common complaints were diarrhea (87%), abdominal pain (74%), and bloody stools (65%).
Patients were given rifaximin at varying doses from 400 to 1200 mg/day at the physician's discretion. The doses ranged between 10 and 30 mg/kg with a median prescribed dose of 20 mg/kg. Analysis revealed that of the 20 patients who presented with diarrhea, 12 had relief of diarrhea within 4 weeks of treatment and 5 in the first week of starting rifaximin. In 17 patients who presented with abdominal pain, 12 patients had relief within 4 weeks and 3 of these patients had relief within 1 week. Visible bleeding resolved in 10 of 15 patients within 4 weeks of therapy and 3 of the 10 had improvement within 1 week (Table 2).
Higher total daily doses of rifaximin were significantly associated with better relief of abdominal pain (P = 0.046); 1 of the 6 patients taking 400 mg/day versus 4 of 5 of the patients taking 1200 mg/day experienced moderate or optimum relief. The associations between total daily dose and amount of symptom relief for the presenting complaints of diarrhea and bloody stools, and between total daily dose and time to symptom relief, for the presenting complaints abdominal pain, diarrhea, and bleeding in stools, were not statistically significant (Table 3).
Analyzing the usage of concurrent medication with rifaximin revealed that 14 of the 23 patients (61%) experienced relief of symptoms during a period in which addition of rifaximin was the only meaningful treatment change. In this subset of patients, 80% had resolution of all of their symptoms and 20% had relief of 2 out of 3 or 1 out of 2 symptoms.
Only 1 patient had an adverse effect of a temporary increase in diarrhea symptoms on starting rifaximin. The diarrhea resolved in 4 to 5 days and did not require discontinuation of the drug.
Since the introduction of rifaximin in the United States in 2004, it has become an increasingly valuable medication for use in gastroenterology. It has an FDA labeled indication for traveler's diarrhea; however, off-label it has potential efficacy on the basis of retrospective studies for IBS, bacterial overgrowth, hepatic encephalopathy, and Helicobacter pylori gastritis. There are several studies in adults that show that rifaximin is efficacious in patients with IBD. A small, randomized, double-blinded, placebo-controlled study of 26 patients with UC refractory to steroids, demonstrated a significant improvement of the condition in 64% of subjects in the rifaximin group compared with 42% of subjects who received placebo (12). Also, for patients with active CD, an open-label study of rifaximin administered for 16 weeks demonstrated clinical remission in 62% of patients (13).
To date there are limited data evaluating the use of rifaximin in pediatric patients with IBD. Our results involving children affected by IBD indicate that the administration of rifaximin significantly improved clinical symptoms. There was a statistically significant association between total daily dose of rifaximin and level of relief of abdominal pain. Only 17% of patients treated with 400 mg/day had any improvement, whereas in those treated with 1200 mg/day, 80% had improvement in their abdominal pain. Taking into account the use of concurrent medications, 61% of patients experienced optimum relief of overall symptoms during a period in which rifaximin was the only meaningful treatment change. This compares favorably to the results of a clinical trial in adult patients with active CD in which 45% of the patients treated with metronidazole and ciprofloxacin versus 63% of patients treated with steroids achieved clinical remission in a 12-week study period (14).
Rifaximin maintains a topical action without systemic adverse effects and the lack of resistant bacterial strains may allow prolonged and repeated treatments. The drug has a bactericidal rather than bacteriostatic property and has a broad spectrum of activity, covering Gram-positive and Gram-negative, aerobic and anaerobic species associated with gastrointestinal infection (1,15). Resistance to rifaximin has been demonstrated both in vitro and in vivo in intestinal flora. It decreased rapidly after the end of treatment, and disappeared completely after 1 to 16 weeks for various gastrointestinal strains. Therefore, it appears that rifaximin-resistant strains are unable to permanently colonize the gastrointestinal tract (16).
The systemic absorption of rifaximin by both normal mucosa and inflamed mucosa is minimal. In 1 study that observed the systemic absorption of rifaximin after single oral administration of 400 mg, in patients with mild to moderate UC, urinary excretion was found to be negligible, and plasma concentration was undetectable in almost all of these patients (3).
Currently, there is no standard dosage of rifaximin that is being used to treat pediatric patients. Our data support the use of higher dosages in the range of 1200 mg/day, which gave significant improvement in abdominal pain. Larger doses would give higher luminal concentrations for better bactericidal effects. Because rifaximin is minimally absorbed, larger doses should not be associated with increased systemic adverse effects, as was demonstrated in our patient population. There were no significant adverse effects in any of our dosage ranges used. However, prospective trials with standardized treatment dosages would prove beneficial.
It is important to realize that most of these patients had been taking 1 or more therapeutic agent(s) for treatment of their disease and had been prescribed rifaximin amidst many ongoing maintenance treatment regimens for breakthrough “flare ups.” A few occasions were because of the failure of metronidazole and/or ciprofloxacin to resolve symptoms; few were in an attempt to spare steroids. These certainly were the confounding factors in our study, which we tried to clarify by assessing any new treatments that had been used preceding or following the initiation of rifaximin. We analyzed the clinical response with the knowledge of the typical time frame of clinical response to different therapeutic agents. Despite this limitation, 61% of our patients seemed to experience relief of their symptoms as a direct result of treatment with rifaximin.
A significant proportion of our patients (65%) did not have pretreatment stool cultures to identify possible infectious causes of “flares.” It would have been useful to know whether the response to rifaximin was because of the presence or absence of pathogenic bacteria. Our study was limited also by the lack of uniformity in obtaining objective markers of response to treatment. This was because of both physician and patient factors. Clinical and laboratory parameters as incorporated in tools such as the Pediatric Crohn Disease Activity Index may be useful in prospective studies to increase the validity of response to rifaximin in pediatric IBD.
Despite these limitations, we feel that rifaximin is a promising new antibiotic for use in children with IBD. Its precise benefit in children with IBD, however, needs to be evaluated in a prospective, controlled manner with more objective data.
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