Cholestyramine And Its Role In C. Difficile Infections

David F. McAuley, Pharm.D.
GlobalRPh Inc.
Introduction:
Closridium difficile is the primary cause of nosocomial gastrointestinal illness in adult patients.^1,2,3 Also, the most common site of infection with this organism is the colon.¹ The universal recommendation in adult patients diagnosed with C.difficile colitis is to discontinue, whenever possible, the antibiotic that is initiating the disease.^2,4 However, it should be stressed that most pediatric C. difficile disease is not associated with antibiotics.² A potential therapy for antibiotic-associated pseudomembranous colitis is to bind the luminal Clostridium difficile toxins A and B using a nonabsorbable binding agent such as cholestyramine.^5,6,7,8

Evidence:
C. Kelly and J. LaMont reported that cholestyramine has been given as adjunctive therapy in patients with relapsing C. difficile pseudomembranous colitis. The usual regimen for cholestyramine is 4 grams three or four times daily. Therapy is continued for one to two weeks, usually with vancomycin. The authors also mentioned an uncontrolled study (n=11) with relapsing C. difficile pseudomembranous colitis that received tapering doses of vancomycin plus colestipol (similar anion-binding resin). The combined regimen led to resolution of symptoms in all patients and was sustained for at least six weeks.⁷

Relevant comments were uncovered using DRUGDEX®: 1) “Cholestyramine has been effective in reducing diarrhea caused by pseudomembranous colitis (PMC) in several case reports (Burbige & Milligan, 1975; Sinatra et al, 1976; Kreutzer & Milligan 1978); however, other case reports have found only a 36 to 50% success rate (Bartlett, 1984; Tedesco, 1982).” 2) “Cholestyramine or colestipol for one to three weeks after stopping vancomycin is recommended for treating patients with PMC who relapse during vancomycin treatment (Tedesco, 1982; Bartlett, 1984).” The authors stated that this approach was successful in 15 patients. The usual adult dosage is 4 grams three or four times daily administered for three days to two weeks.⁶

C. Kurtz and associates confirmed the use of cholestyramine in the treatment for C. difficile colitis in some patients, however, stated that the resin has shown only modest activity and is not recommended for use in patients with severe cases of C. difficile colitis.^8,9 An important therapy recommendation was mentioned: “Cholestyramine also binds to vancomycin and must be dosed separately if it is used in combination with this antibiotic.”⁸

D. Fields reported in the 2002 issue of Hospital Pharmacy that the usual initial therapy of C. difficile colitis is metronidazole or vancomycin. The author stated the following key points: 1) The first line of therapy should be metronidazole (IV or po). 2) Metronidazole has similar efficacy and relapse rates when compared to vancomycin, but is significantly less expensive. 3) Using metronidazole as a first line agent limits exposure of vancomycin to other fecal organisms such as enterococci in an attempt to prevent vancomycin-resistant enterococcus (VRE). 4) Vancomycin use should be restricted to patients that fail metronidazole therapy and patients who cannot tolerate metronidazole. It may also be used for patients with severe life-threatening cases of C. difficile infectious colitis.⁴

J. Stroehlein reported in 2004 that although mild cases may resolve by discontinuing antibiotics (return of colonic microflora), oral metronidazole or vancomycin is indicated if the process is more severe. Metronidazole may be given in moderate cases but in severe cases vancomycin is the preferred treatment. Cholestyramine is mentioned as a useful adjunct.³

Conclusion:
Kelly CP and LaMont JT reported that the response rate to cholestyramine in patients with C. difficile colitis is associated with a better overall response rate of 68 percent compared to colestipol (36 versus 22 percent with placebo). However, this still compares poorly to response rates of over 96 percent with vancomycin or metronidazole.⁷ These findings along with results from other studies relegate the anion-binding resins as adjunct agents only. It follows that cholestyramine should not be used alone as primary therapy for C. difficile colitis.

In refractory cases of C. difficile colitis, cholestyramine can be a useful adjunct.³ Dosing should be 4 grams orally tid or qid x 3 to 14 days, but may continue for several weeks.^6,7,10,11 Cholestyramine should be given two to three hours apart from vancomycin to prevent it from binding with vancomycin.^2,8,12 Pediatric use: cholestyramine has been tried in a few children but the studies are limited and have not been placebo controlled trials.²

References:

1) Jacobs A, Barnard K, Fishel R, Gradon J D. Extracolonic manifestations of clostridium difficile infections: presentation of 2 cases and review of the literature. MEDICINE. 2001;80(2): p 88-101.

2) Mcfarland L V; Brandmarker S A; Guandalini S. Pediatric clostridium difficile: A phantom menace or clinical reality? J PED GASTROENTEROL NUTR. 2000;31(3): p 220-231.

3) Stroehlein JR. Treatment of Clostridium difficile Infection. Curr Treat Options Gastroenterol. 2004 Jun;7(3):235-239.

4) Fields D. C. Difficile Prevention and Treatment. HOSP PHARM. 2002;37(7):p 781-783.

5) Palace GP, Lazari P, Norton K. Analysis of the physicochemical interactions between Clostridium difficile toxins and cholestyramine using liquid chromatography with post-column derivatization. Biochim Biophys Acta. 2001 Mar 9;1546(1):171-84.

6) Klasco RK (Ed): DRUGDEX® System. Thomson Micromedex, Greenwood Village, Colorado (Edition expires [ 11/2005]).

7) Kelly CP, LaMont JT. Treatment of recurrent Clostridium difficile infection. UpToDate®. 2005;13(2). https://www.uptodate.com/ . Accessed: 7/5/2005.

8) Kurtz CB, Cannon EP, Brezzani A, Pitruzzello M, Dinardo C, Rinard E, Acheson DW, Fitzpatrick R, Kelly P, Shackett K, Papoulis AT, Goddard PJ, Barker RH Jr, Palace GP, Klinger JD. GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis. Antimicrob Agents Chemother. 2001 Aug;45(8):2340-7.

9) Burbige, E. J., and F. D. Milligan. 1975. Pseudomembranous colitis. Association with antibiotics and therapy with cholestyramine. JAMA 231:1157– 1158.

10) Joyce AM, Burns DL. Recurrent Clostridium difficile colitis: Tackling a tenacious nosocomial infection. Postgraduate Med. 2002 Nov;112(5).

11) Moncino MD, Falletta JM. Multiple relapses of Clostridium difficile-associated diarrhea in a cancer patient. Successful control with long-term cholestyramine therapy. Am J Pediatr Hematol Oncol. 1992 Nov;14(4):361-4.

12) Chico GF. Clostridium difficile Colitis. Emerg Med 37(1):27-32, 2005.