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 diarrhea (at least 3 unformed stools in less than 24 hours) and a positive stool test for C. difficile or colonoscopic/histopathologic results suggesting pseudomembranous colitis. Known risk factors associated with the development of CDI are advanced age (>64 years), increased length of hospitalization, and prior antimicrobial or antineoplastic therapy. Clinical presentation ranges from no symptoms, to 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 that 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 the 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 has been the primary antimicrobial treatment for CDI. Oral vancomycin, the only drug in the United States with the US Food and Drug Administration (FDA)–approved indication for CDI, has poor absorption and thus reaches high fecal concentrations and reduces the risk of systemic toxicity. Passive immunotherapy with intravenous immunoglobulins (IVIG) has been suggested for patients with severe CDI who do not respond to other therapies. 1
Patient Population
Adult patients with episode of refractory, severe, complicated CDI.
Dosage and Duration
Passive immunotherapy with IVIG, dosed as 150 to 400 mg/kg, has been suggested for patients who do not respond to other therapies. 1 In retrospective reviews and case reports, the majority of patients have received single doses within the dose range cited previously, with a few patients receiving 2 or 3 doses (on consecutive days to 2 to 21 days apart) and 1 patient receiving 6 doses.2–6
Results
Immunoglobulins for the management of severe, complicated, refractory CDI have not been evaluated in controlled clinical trials. The majority of published information has been documented in retrospective reviews and case reports, enrolling less than 75 patients. 2 Although mentioned in national guidelines as therapy for severe refractory disease, specific recommendations are not provided.
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 the initiation of empiric treatment as soon as the diagnosis is suspected while waiting for the results of the stool toxin assay. 1 Antiperistaltic agents should be avoided as they may mask symptoms and may precipitate toxic megacolon.
For an initial CDI episode of mild to moderate nature, 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.)
For an initial CDI episode of severe nature, 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 randomized, controlled trial.)
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 IV metronidazole (500 mg every 8 hours) for 10 to 14 days. If complete ileus is present, the 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.) The guidelines note that passive immunotherapy IVIG has been suggested for patients who do not respond to other therapies, but no specific recommendations are provided.
Recommended treatment for the first recurrence of CDI is the same as the initial episode and is dependent upon the severity of presentation. Vancomycin is recommended for the first recurrence in patients with a 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. Although various regimens have been used, the recommended dosage included in the guidelines is 125 mg 4 times daily for 10 to 14 days followed by 125 mg twice daily for a week, 125 mg once daily for 1 week, and then 125 mg every 2 or 3 days for 2 to 8 weeks to accommodate the restoration of normal gut flora. There is no evidence that the addition of cholestyramine, colestipol, and other anion-exchange resins decreases the risk of a further recurrence. In addition, these agents are contraindicated because they bind vancomycin. 1
Noncontrolled Trials
In a retrospective analysis, 79 patients with severe, laboratory-confirmed CDI and diarrhea received standard therapy with IV metronidazole and oral vancomycin and vancomycin enemas when needed. Of these, 18 also received a single dose of IVIG (200 to 300 mg/kg). Eighteen patients who did not receive IVIG were matched to serve as a control group. The mean age was similar in both the IVIG and standard therapy groups (67 vs 72.5 years). Primary clinical outcomes did not differ between the 2 groups, including the number of colectomies (3 in each group), all-cause mortality (3 in each group), negative outcome (6 vs 5), and increased length of hospitalization (25.1 vs 32.9 days). The authors concluded that the use of IVIG had no benefit as adjuvant treatment for CDI. 7
In a retrospective review, 14 patients with severe, refractory, recurrent CDI diarrhea were treated with IVIG (150 to 400 mg/kg) while being maintained on vancomycin and metronidazole. The majority of patients received a single dose, with 2 patients receiving 2 doses (separated by 21 days). The median age was 79 years (range, 54 to 91 years), and the median length of symptoms prior to treatment with IVIG was 29 days (range, 3 to 90 days). All patients had received prior therapy with metronidazole or vancomycin. A total of 64% (n=9) of the patients responded, with bowels normalizing within a median of 10 days (range, 2 to 26 days). One patient had partial response but later died from a recurrence, and the remaining 4 patients died of other causes within 3 weeks of infusion. 6
In a retrospective analysis of 580 laboratory-confirmed CDI patients, 5 received IVIG (300 to 500 mg/kg) as 1 dose (n=2), 2 doses (n=2), or 6 doses (n=1). All patients had received prior therapy with metronidazole and vancomycin. Four patients had partial to full response with resolution occurring within 11 days: 2 were without further recurrence, 1 experienced recurrence after 6 weeks, and 1 died due to unrelated causes. One patient did not experience therapeutic benefit. 5
Safety
This is a limited safety profile. Refer to package labeling for complete prescribing information (eg, warnings and precautions, adverse reactions, drug interactions).
Immune Globulin Intravenous (Human) (Gammagard) products have a boxed warning regarding reports of renal dysfunction, acute renal failure, osmotic nephrosis, and death associated with use. 8
Therapy Considerations
Current evidence regarding the use of IVIG in the management of severe refractory CDI is limited by data from small, noncontrolled settings with varied results. Although mentioned as an option for severe, refractory disease in national guidelines for CDI, no specific recommendations for use are made. Larger controlled trials are needed.