Skip to main content Accessibility help

Recurrent Clostridium Difficile Disease: Epidemiology and Clinical Characteristics

  • Lynne V. McFarland (a1) (a2), Christina M. Surawicz (a3), Moshe Rubin (a4), Robert Fekety (a5), Gary W. Elmer (a1) and Richard N. Greenberg (a6) (a7)...



To describe the epidemiology, diagnosis, risk factors, patient impact, and treatment strategies for recurrent Clostridium difficile-associated disease (CDAD).


Data were collected as part of a blinded, placebo-controlled clinical trial testing a new combination treatment for recurrent CDAD. Retrospective data regarding prior CDAD episodes were collected from interviews and medical-chart review. Prospective data on the current CDAD episode, risk factors, and recurrence rates were collected during a 2-month follow-up.


National referral study.


Patients with recurrent CDAD.


Treatment with a 10-day course of low-dose (500 mg/d) or high-dose (2 g/d) vancomycin or metronidazole (1 g/d).


Recurrent CDAD was found to have a lengthy course involving multiple episodes of diarrhea, abdominal cramping, nausea, and fever. CDAD may recur over several years despite frequent treatment with antibiotics. Recurrence rates were similar regardless of the choice or dose of antibiotic. Recurrent CDAD is not a trivial disease: patients may have multiple episodes (as many as 14), may require hospitalization, and the mean lifetime cost of direct medical care was $10,970 per patient. Fortunately, the disease does not become progressively more severe as the number of episodes increase. Two risk factors predictive for recurrent CDAD were found: increasing age and a decreased quality-of-life score at enrollment.


Recurrent CDAD is a persistent disease that may result in prolonged hospital stays, additional medical costs, and rare serious complications.


Corresponding author

1910 Fairview Ave E, #208, Seattle, WA 98102


Hide All
1. Burdon, DW. Clostridium difficile: the epidemiology and prevention of hospital-acquired infection. Infection 1982;10:203204.
2. Wüst, J, Sullivan, NM, Hardegger, U, Wilkins, TD. Investigation of an outbreak of antibiotic-associated colitis by various typing methods. J Clin Microbiol 1982;16:10961101.
3. Tabaqchali, S, O'Farrell, S, Holland, D, Silman, R. Typing scheme for Clostridium difficile: its application in clinical and epidemiological studies. Lancet 1984;i:935938.
4. Johnson, S, Gerding, DN, Olson, MM, Weiler, MD, Hughes, RA, Clabots, CR, et al. Prospective, controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial transmission. Am J Med 1990:80:137140.
5. McFarland, LV, Mulligan, ME, Kwok, RYY, Stamm, WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320:204210.
6. Bowen, KE, McFarland, LV, Greenberg, RN, Ramsey, MM, Record, KE, Svenson, J. Isolation of Clostridium difficile at a university hospital: a two-year study. Clin Infect Dis 1995;20(suppl 2) :S261S262.
7. Gerding, DN, Johnson, S, Peterson, LR, Mulligan, ME, Silva, J Jr. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol 1995;16:459477.
8. Fekety, R. Guidelines for the diagnosis and management of Clostridium difficile-associateA diarrhea and colitis. Am J Gastroenterol 1997;92:739750.
9. Feldman, RJ, Kallich, M, Weinstein, MP Bacteremia due to Clostridium difficile: case report and review of extraintestinal C difficile infections. Clin Infect Dis 1995;20:15601562.
10. Pron, B, Merckx, J, Touzet, P, Ferroni, A, Poyart, C, Berche, P, et al. Chronic septic arthritis and osteomyelitis in a prosthetic knee joint due to Clostridium difficile . Eur J Clin Microbiol Infect Dis 1995;14:599601.
11. Lowenkron, SE, Waxner, J, Khullar, P, Ilowite, JS, Niederman, MS, Fein, AM. Clostridium difficile infection as a cause of severe sepsis. Intensive Care Med 1996;22:990994.
12. Fekety, R, McFarland, LV, Surawicz, CM, Greenberg, RN, Elmer, GW, Mulligan, ME. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Clin Infect Dis 1997;24:324333.
13. Qualman, SJ, Petric, M, Karmali, MA, Smith, CR, Hamilton, SR. Clostridium difficile invasion and toxin circulation in fatal pediatric pseudomembranous colitis. Am J Clin Pathol 1990;94:410416.
14. Walley, T, Milson, D. Loperamide related toxic megacolon in Clostridium difficile colitis. Postgrad Med J 1990;66:582.
15. Riley, TV, Bowman, RA, Carroll, SM. Diarrhea associated with Clostridium difficile in a hospital population. Med J Aust 1983;1:166169.
16. Yablon, SA, Krotenberg, R, Fruhmann, K. Clostridium difficile-reiated disease: evaluation and prevalence among inpatients with diarrhea in two freestanding rehabilitation hospitals. Arch Phys Med Rehabil 1993;74:913.
17. Pear, SM, Williamson, TH, Bettin, KM, Gerding, DN, Galgiani, JN. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med 1994;120:272277.
18. Samore, MH, DeGirolami, PC, Tlucko, A, Lichtenberg, DA, Melvin, ZA, Karchmer, AW. Clostridium difficile colonization and diarrhea at a tertiary care hospital. Clin Infect Dis 1994;18:181187.
19. Barbut, F, Corthier, G, Charpak, Y, Cerf, M, Monteil, H, Fosse, T, et al. Prevalence and pathogenicity of Clostridium difficile in hospitalized patients. A French multicenter study. Arch Intern Med 1996;156:14491454.
20. Hirschhorn, LR, Trnka, Y, Onderdonk, A, Lee, M-LT, Platt, R. Epidemiology of community-acquired Clostridium difficile-associated diarrhea. J Infect Dis 1994;169:127133.
21. McFarland, LV, Surawicz, CM, Greenberg, RN, Fekety, R, Elmer, GW, Moyer, KA, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271:19131918.
22. Liacouras, CA, Piccoli, DA. Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis. J Clin Gastroenterol 1996;22:186189.
23. Tvede, M, Rask-Madsen, J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1:11561160.
24. Tedesco, FJ, Gordon, D, Fortson, WC. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis. Am J Gastroenterol 1985;80:867868.
25. Biller, JA, Katz, AJ, Flores, AF, Buie, TM, Gorbach, SL. Treatment of recurrent Clostridium difficile colitis with Lactobacillus GG. J Pediatr Gastroenterol Nutr 1995;21:224226.
26. Walters, BAJ, Roberts, R, Stafford, R, Seneviratne, E. Recurrence of antibiotic associated colitis: endogenous persistence of C difficile during vancomycin therapy. Gut 1983;24:206212.
27. Bartlett, JG. Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis 1994;18(suppl 4):S265S272.
28. George, WL, Volpicelli, NA, Stiner, DB, Richman, DD, Liechty, EJ, Mok, HYI, et al. Relapse of pseudomembranous colitis after vancomycin therapy. N Engl J Med 1979;301:414415.
29. Tarlov, AR, Ware, JE Jr, Greenfield, S, Nelson, EC, Perrin, E, Zubkoff, M. The medical outcomes study. An application of methods for monitoring the results of medical care. JAMA 1989;262:925930.
30. Johnson, LL, McFarland, LV, Dearing, P, Raisys, V, Schoenknect, FD. Identification of Clostridium difficile in stool specimens by culture-enhanced gas-liquid chromatography. J Clin Microbiol 1989;27:22182221.
31. Willey, SH, Bartlett, JG. Cultures for Clostridium difficile in stools containing a cytotoxin neutralized by Clostridium sordellii antitoxin. J Clin Microbiol 1979;10:880884.
32. De Girolami, PC, Hanff, PA, Eichelberger, K, Longhi, L, Teresa, H, Pratt, J, et al. Multicenter evaluation of a new enzyme immunoassay for detection of Clostridium difficile enterotoxin A. J Clin Microbiol 1992;30:10851088.
33. Borriello, SP, Vale, T, Brazier, JS, Hyde, S, Chippeck, E. Evaluation of a commercial enzyme immunoassay kit for the detection of Clostridium difficile toxin A. Eur J Clin Microbiol Infect Dis 1992;11:360363.
34. Doern, GV, Coughlin, RT, Wu, L. Laboratory diagnosis of Clostridium difficile-associated gastrointestinal disease: comparison of a monoclonal antibody enzyme immunoassay for toxins A and B with a monoclonal antibody enzyme immunoassay for toxin A only and two cytotoxicity assays. J Clin Microbiol 1992;30:20422046.
35. Yannelli, B, Gurevich, I, Schoch, P, Cunha, BA. Yield of stool cultures, ova and parasite tests, and Clostridium difficile determinations in nosocomial diarrheas. Am J Infect Control 1988;16:246249.
36. Siegel, DL, Edelstein, PH, Nachamkin, I. Inappropriate testing for diarrheal diseases in the hospital. JAMA 1990;263:979982.
37. Thompson, JS, Hodge, DS, Borczyk, AA. Rapid biochemical test to identify verocytotoxin-positive strains of E coli serotype 0157. J Clin Microbiol 1990;28:21652168.
38. Nath, SK, Thornley, JH, Kelly, M, Kucera, B, On, SLW, Holmes, B, et al. A sustained outbreak of Clostridium difficile in a general hospital: persistence of a toxigenic clone in four units. Infect Control Hosp Epidemiol 1994;15:382389.
39. Olson, MM, Shanholtzer, CJ, Lee, JT Jr, Gerding, DN. Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol 1994;15:371381.
40. Kofsky, P, Rosen, L, Reed, J, Tolmie, M, Ufberg, D. Clostridium difficile-a common and costly colitis. Dis Colon Rectum 1991;34:244248.
41. McFarland, LV, Surawicz, CM, Stamm, WE. Risk factors for Clostridium difficile carriage and C difficile-associated diarrhea in a cohort of hospitalized patients. J Infect Dis 1990;162:678684.
42. Eriksson, S, Aronsson, B. Medical implications of nosocomial infection with Clostridium difficile . Scand J Infect Dis 1989;21:733734.
43. Wenisch, C, Parschalk, B, Hasenhündl, M, Hirschl, AM, Graninger, W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996;22:813818.
44. Teasley, DG, Gerding, DN, Olson, MM, Peterson, LR, Gebhard, RL, Schwartz, MJ, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983;2:10431046.
45. Nelson, DE, Auerbach, SB, Baltch, AL, Desjardin, E, Beck-Sague, C, Rheal, C, et al. Epidemie Clostridium difficile-associated diarrhea: role of second- and third-generation cephalosporins. Infect Control Hosp Epidemiol 1994;15:8894.
46. Lai, KK, Melvin, ZS, Menard, MJ, Kotilainen, HR, Baker, S. Clostridium difficile-associated diarrhea: epidemiology, risk factors, and infection control. Infect Control Hosp Epidemiol 1997;18:628632.
47. Brown, EB, Talbot, GH, Axelrod, P, Provencher, M, Hoegg, C. Risk factors for Clostridium difficile toxin-associated diarrhea. Infect Control Hosp Epidemiol 1990;11:283290.
48. Zimmerman, RK. Risk factors for Clostridium difficile cytotoxin-positive diarrhea after control for horizontal transmission. Infect Control Hosp Epidemiol 1991;12:96100.
49. Impallomeni, M, Galletly, NP, Wort, SJ, Starr, JM, Rogers, TR. Increased risk of diarrhoea caused by Clostridium difficile in elderly patients receiving cefotaxime. BMJ 1995;311:13451346.
50. Ehrenpreis, ED, Lievens, MW, Craig, RM. Clostridium difficile-associated diarrhea after norfloxacin. J Clin Gastroenterol 1990;12:188189.
51. McFarland, LV, Bauwens, JE, Melcher, SA Surawicz, CM, Greenberg, RN, Elmer, GW. Ciprofloxacin-associated Clostridium difficile disease. Lancet 1995;346:977.
52. Surawicz, CM, McFarland, LV, Elmer, G, Chinn, J. Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii . Am J Gastroenterol 1989;84:12851287.
53. Ariano, RE, Zhanel, GG, Harding, GKM. The role of anion-exchange resins in the treatment of antibiotic-associated pseudomembranous colitis. Can Med Assoc J 1990;142:10491051.
54. Fekety, R, Silva, J, Kauffman, C, Buggy, B, Deery, HG. Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med 1989;86:1519.
55. Larson, HE, Borriello, SP. Quantitative study of antibiotic-induced susceptibility to Clostridium difficile enterocecitis in hamsters. Antimicrob Agents Chemother 1990;34:13481353.
56. Gonzoles, R, Steiner, JF, Sande, MA. Antibiotic prescribing for adults with colds, upper respiratory tract infection, and bronchitis in ambulatory care physicians. JAMA 1997;278:901904.
57. Schwartz, B, Bell, DM, Hughes, JM. Preventing the emergence of antimicrobial resistance. A call for action by clinicians, public health officials and patients. JAMA 1997;278:944945.
58. Hueston, WJ. Antibiotics: neither cost effective nor ‘cough’ effective. J Fam Pract 1997;44:261265.


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed