Abstract
This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a quarterly publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to
Background
The diagnosis of Clostridium difficile infection (CDI) is typically defined by a combination of laboratory and clinical findings, including (a) diarrhea (at least 3 unformed stools in less than 24 hours), and (b) a positive stool test for C. difficile or colonoscopic/histopathologic results suggesting pseudomembranous colitis. Known risk factors associated with the risk of developing CDI are advanced age (> 64 years), increased length of hospitalization, and prior antimicrobial or antineoplastic therapy. Clinical presentation ranges from no symptoms, mild to moderate diarrhea, to fulminant, potentially lethal pseudomembranous colitis. Additional symptoms may include fever, cramping, abdominal discomfort, and leukocytosis. Mild to moderate disease is defined as leukocytosis with white blood cell count (WBC) less than 15,000 cells/μL and serum creatinine (SCr) level less than 1.5 times the premorbid level. Severe disease is defined as leukocytosis with WBC of at least 15,000 cells/μL or a SCr at least 1.5 times higher than premorbid level. Severe, complicated disease is defined as the additional presence of hypotension or shock, ileus, or megacolon. 1
Prevention has primarily focused on the minimization of transmission via cleaning and disinfection measures in patient care settings and the restriction of antimicrobial therapy and duration. Recommendations for treatment include the discontinuation of the offending antimicrobial agent, if present, and initiation of empiric treatment as soon as the diagnosis is suspected while waiting for the results of the stool toxin assay. Metronidazole and oral vancomycin have been the primary antimicrobial treatment for CDI. 1 Rifaximin, like vancomycin, is not absorbed after oral administration and thus reaches high concentrations in the feces.
Patient Population
Adult patients with multiple episodes of refractory CDI.
Dosage and Duration
In reviewed data, rifaximin was started immediately after vancomycin therapy was completed, and dosing ranged from 400 mg 3 times daily to 200 mg twice to 3 times daily for 2- to 3-week periods. Most regimens were tapered.
Results
Rifaximin for the management of recurrent, refractory CDI has been primarily studied in less than 50 patients in noncontrolled settings. Though mentioned in national guidelines as an alternative regimen, specific recommendations for therapy are not given. 1
Guidelines
The current Society for Healthcare Epidemiology of America and Infectious Diseases Society of America (SHEA/IDSA) clinical practice guidelines for CDI in adults recommend the discontinuation of the offending antimicrobial agent, if a factor, and initiation of empiric treatment as soon as the diagnosis is suspected while waiting for the results of the stool toxin assay. Antiperistaltic agents should be avoided as they may mask symptoms and may precipitate toxic megacolon.
For an initial mild to moderate CDI episode, oral metronidazole (500 mg 3 times daily for 10 to 14 days) is recommended as first-line therapy (level A-I evidence: good evidence from at least 1 randomized, controlled trial [RCT]).
For an initial severe CDI episode, oral vancomycin (125 mg 4 times daily for 10 to 14 days) is considered the drug of choice (level B-I evidence: moderate evidence from at least 1 RCT).
For an initial severe and complicated CDI episode, the therapy of choice is a combination of oral or nasogastric tube administration of vancomycin (500 mg 4 times daily) with intravenous metronidazole (500 mg every 8 hours) for 10 to 14 days. If complete ileus is present, the rectal administration of vancomycin is added to this regimen as 500 mg in approximately 100 mL of normal saline every 6 hours as a retention enema (level C-III evidence: poor evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees).
Recommended treatment for the first recurrence of CDI is the same as the initial episode and depends on the severity of presentation. Vancomycin is recommended for the first recurrence in patients with WBC at least 15,000 cells/μL or higher (or a rising SCr) as these patients are at a higher risk of developing complications (level A-II evidence: good evidence from at least 1 well-designed clinical trial without randomization, from cohort or case controlled analytical studies, from multiple time series, or from dramatic results from uncontrolled experiments).
Recommended treatment for the second or later CDI recurrence is vancomycin via a tapered and/or pulse regimen. The immediate initiation of oral rifaximin after vancomycin therapy in patients with multiple episodes of CDI has been noted in national guidelines. Caution is recommended with the use of this agent, because of the potential for isolates to develop an increased minimum inhibitory concentration (MIC) during therapy. 1
Noncontrolled Trials
In a retrospective chart review, 8 women (43 to 88 years of age; mean age, 72 years) who were asymptomatic for recurrent CDI-associated diarrhea were treated with varying doses of rifaximin therapy for 2 weeks. All patients had been treated with vancomycin immediately prior to the initiation of rifaximin. Additionally, all patients had undergone previous treatment attempts with metronidazole (n=8), vancomycin (n=8), vancomycin and rifampin (n=3), pulsatile or tapered vancomycin (n=6), or Saccharomyces boulardii (n=3). Patients received oral rifaximin 400 mg twice daily (n=6), 200 mg 3 times daily (n=1), or 200 mg twice daily (n=1). Follow-up specimens were obtained 2 to 4 weeks after rifaximin therapy. After treatment with rifaximin, 7 of 8 patients reported no further CDI-associated diarrhea symptoms. Negative stool cultures were obtained 7 to 40 days after in 5 of 8 patients. One patient was reportedly culture negative at day 50. After treatment with rifaximin, patients were symptom-free for at least 1.5 months, compared with a mean of 11 days with previous treatment regimens. Rifaximin use immediately following treatment with vancomycin may be an effective way to break the cycle of recurrences. 2
The same investigative group 3 evaluated a similar regimen of rifaximin as post vancomycin treatment in an additional 6 patients with recurrent, refractory CDI. After vancomycin therapy was stopped, patients were started on oral rifaximin (400 mg twice daily) for 2 weeks. Four patients (67%) had no further diarrhea episodes. Two patients who experienced recurrence had MIC concentrations greater than 256 μg/mL to rifampin. The authors suggested that serial therapy with vancomycin followed by rifaximin may be an alternative for some patients with multiple episodes of recurrent CDI. However, they also noted that prior exposure to rifamycins may be a risk factor for resistant isolates. 3
Case Reports
In a case series, 6 patients (mean age, 67 years) were administered rifaximin for unresponsive, recurrent CDI-associated diarrhea (1 to 4 recurrences). Prior treatment regimens included metronidazole alone or with vancomycin, or nitanoxanide alone or in combination with vancomycin and metronidazole. The majority of patients (n=5) were administered oral rifaximin in a tapered fashion: 400 mg 3 times daily for 2 weeks, followed by 200 mg 3 times daily for 2 weeks. Within 4 to 17 days (mean, 8 days), 5 of the 6 patients experienced complete resolution of diarrhea without subsequent recurrences over a follow-up period up to 398 days. One patient died due to unrelated causes. In this case series, tapered regimens of oral rifaximin appeared to be efficacious in the majority of patients with recurrent, refractory CDI. 4
In a case report, a male patient (56 years old) with a third recurrence of CDI-associated diarrhea received oral rifaximin (400 mg 3 times daily for 2 weeks) in combination with vancomycin and a probiotic (Culturelle). Prior failed regimens included intravenous and oral metronidazole, oral vancomycin, and a probiotic (Lactinex). A second course of rifaximin was required in combination with vancomycin, which resulted in resolution of symptoms. The dose of rifaximin was increased to 400 mg 4 times daily for 3 weeks in combination with vancomycin (125 mg twice daily). At the end of this regimen, the patient was treated for an additional 2 weeks with oral rifaximin (400 mg 3 times daily) and once-daily probiotic (Flora-Q). After the completion of this regimen, the patient reported only occasional cramping. Follow-up at days 30 and 180 revealed complete resolution of CDI-associated diarrhea. 5
Safety
This is a limited safety profile. Refer to package labeling for complete prescribing information (eg, warnings and precautions, adverse reactions, drug interactions).
Although rifaximin was well tolerated, with no specific adverse effects reported in the cited literature, caution is recommended with the use of this agent because of the potential for isolates to develop an increased MIC during therapy. 1 Prior exposure to rifamycins may be a risk factor for resistant isolates.3,6
Therapy Considerations
Rifaximin for the management of recurrent, refractory CDI has been primarily studied in noncontrolled settings. Though mentioned in national guidelines as an alternative, specific recommendations for therapy are not provided. Caution is recommended with the use of this agent because of the potential for isolates to develop an increased MIC during therapy. Prior exposure to rifamycins may be a risk factor for resistant isolates.