Julia Chiappe, Pharm.D., Clinical Pharmacy Specialist, Integris Baptist Medical Center
Due to the expense and limited supply of intravenous immune globulin (IVIG), it is important to be aware of the literature supporting each individual indication. A brief overview of the literature available on the use of IVIG for Clostridium difficile-associated disease (CDAD) follows.
The response rate for the treatment of CDAD with oral metronidazole or oral vancomycin is greater than 90%. The recurrence rate is estimated at 15-25%.1 The pathogenesis of C. difficile is thought to result from the exotoxins A and B whose enterotoxic, cytotoxic, and proinflammatory properties lead to a wide spectrum of responses ranging from asymptomatic carriage to fulminant colitis with toxic megacolon. Recurrent and severe episodes may occur in patients with low C. difficile antitoxin antibody responses.2 Patients who develop serum antitoxin A immunoglobulin G (IgG) titers in response to exposure tend to be 48 times less likely to develop diarrhea than are those who do not mount a response.3 Similarly, after colonization with C. difficile, an association between increased serum levels of IgG antibody against toxin A and asymptomatic carriage of C. difficile was found.4 IVIG contains C. difficile antitoxin and has been used in some patients with relapsing or severe C. difficile colitis as a form of passive immunization.2 Salcedo et al investigated the anti-C. difficile toxin antibody levels in nine immunoglobulin preparations. All immunoglobulin preparations tested contained IgG against C difficile toxins A and B at IgG concentrations of 0.4-1.6 mg/mL. Control serum from a healthy volunteer who lacked specific antibodies against C. difficile toxin A or toxin B failed to neutralise the cytotoxicity of C. difficile culture filtrate in this assay.5
Reports of fourteen patients who received IVIG for treatment of CDAD were found in English-language journals as of June 20, 2008.5-10 Most reports involved patients with ages ranging from 53 – 77 years. One report included treatment of 5 children with 400 mg/kg of IVIG every 3 weeks. Regimens used in adult patients varied in dose (200 – 400 mg/kg) and frequency (from one time to recurring doses). Results were all similarly positive with resolution of diarrhea occurring most commonly within one week. Some patients, however, did not respond for up to 26 days after start of IVIG therapy. Of three retrospective reviews2,11,12 on this subject, one12 found no difference in clinical outcomes among IVIG-treated patients compared with 18 matched control cases. No randomized clinical studies have been published to date.
The limited literature available to support the use of IVIG for CDAD is similar to the amount of supporting literature available for many off-label IVIG indications. Other common findings for IVIG therapy include the variability of anti-C. difficile toxin antibody concentrations in commercially available IVIG preparations as well as the difficulty in determining whether a patient is deficient in anti-C. difficile IgG antibodies. Due to the increasing demand for IVIG for multiple indications, hospitals cannot support the routine use of IVIG for even complicated C. difficile infections. Its use should be reserved for life-threatening cases that have failed conventional treatments.
References
1. Kyne L, Kelly CP. Recurrent C. difficile diarrhoea. Gut 2001 Jul;49(1):152-3.
2. McPherson S, Rees CJ, Ellis R, Soo S, Panter SJ. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum 2006 May;49(5):640-5.
3. Owens RC. Clostridium difficile-associated disease: an emerging threat to patient safety. Pharmacotherapy 2006;26;299-311.
4. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000 Feb 10;342(6):390-7.
5. Salcedo J, Keates S, Pothoulakis C, et al. Intravenous immunoglobulin therapy for severe C. difficile colitis. Gut 1997; 41:366.
6. Warny M, Denie C, Delmee M, Lefebvre C. Gamma globulin administration in relapsing Clostridium difficile-induced pseudomembranous colitis with a defective antibody response to toxin A. Acta Clin Belg 1995; 50:36.
7. Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991; 118:633.
8. Hassoun A, Ibrahim F. Use of intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis. Am J Geriatric Pharmacotherapy 2007 Mar;5(1):48-51.
9. Murphy C, Vernon M, Cullen M. Intravenous immunoglobulin for resistant Clostridium difficile infection. Age Ageing 2006 Jan;35(1):85-6.
10. Beals IL. Intravenous immunoglobulin for recurrent Clostridium difficile diarrhoea. Gut 2002 Sep;51(3):456.
11. Wilco MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrobic Chemotherapy 2004 May;53(5):882-4.
12. Juang P, Sledder SJ, Scheibe NK, et al. Clinical outcomes of intravenous immune globulin in severe clostridium difficile-associated diarrhea. Am J Infect Control 2007; 35:131.