Gastroenterology

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 764-770
Gastroenterology

Case report
Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea

https://doi.org/10.1053/j.gastro.2004.11.004Get rights and content

Background & aims: Recurrent C difficile-associated diarrhea (CDAD) is associated with a lack of protective immunity to C difficile toxins. A parenteral C difficile vaccine containing toxoid A and toxoid B was reported previously to be safe and immunogenic in healthy volunteers. Our aim was to examine whether the vaccine is also well tolerated and immunogenic in patients with recurrent CDAD. Methods: Subjects received 4, 50-μg intramuscular inoculations of the C difficile vaccine over an 8-week period. Serum antitoxin antibodies were measured by ELISA, and toxin neutralizing activity was evaluated using the tissue culture cytotoxin assay. Results: Three patients with multiple episodes of recurrent CDAD were vaccinated. Two of the 3 showed an increase in serum IgG antitoxin A antibodies (3-fold and 4-fold increases, respectively) and in serum IgG antitoxin B antibodies (52-fold and 20-fold, respectively). Both also developed cytotoxin neutralizing activity against toxin A and toxin B. Prior to vaccination, the subjects had required nearly continuous treatment with oral vancomycin for 7, 9, and 22 months, respectively, to treat recurrent episodes of CDAD. After vaccination, all 3 subjects discontinued treatment with oral vancomycin without any further recurrence. Conclusions: A C difficile toxoid vaccine induced immune responses to toxins A and B in patients with CDAD and was associated with resolution of recurrent diarrhea. The results of this study support the feasibility of active vaccination against C difficile and its toxins in high-risk individuals but must be validated in larger, randomized, controlled trials.

Section snippets

Entry criteria

An open-label study was performed in subjects with recurrent CDAD defined as a history of a change in bowel habit with 3 or more unformed bowel movements per day for at least 2 days, associated with a positive stool toxin test for C difficile (either tissue culture cytotoxin assay or toxin A or B enzyme immunoassay) that occurred within 30 days of discontinuation of therapy with metronidazole or oral vancomycin that had been administered for treatment of a prior episode of CDAD. Study inclusion

Case 1

A 51-year-old man presented to his primary care physician because of increased frequency of micturation and nocturia. He was found to have an elevated level of serum prostate-specific antigen and was treated with ciprofloxacin 500 mg, twice daily for 21 days for suspected chronic prostatitis. Further studies revealed a localized prostate lesion, and, in February 2001, he underwent transrectal prostate biopsy after enema preparation and an additional single prophylactic dose of ciprofloxacin 500

Discussion

Recurrent C difficile–associated diarrhea is a common clinical problem and affects as many as 35% of all patients treated for CDAD in our institution.23, 39 The management of patients with multiple recurrences is especially challenging.19 The subjects in this study are typical of such patients in that they had good control of symptoms for prolonged periods while taking vancomycin but repeatedly suffered recurrent diarrhea within a few days of attempting to discontinue this antibiotic. They had

References (49)

  • C.P. Kelly et al.

    Clostridium difficile colitis

    N Engl J Med

    (1994)
  • J.G. Bartlett et al.

    Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia

    N Engl J Med

    (1978)
  • S.P. Borriello

    12th C.L. Oakley lecture. Pathogenesis of Clostridium difficile infection of the gut

    J Med Microbiol

    (1990)
  • C. Pothoulakis

    Pathogenesis of Clostridium difficile-associated diarrhoea

    Eur J Gastroenterol Hepatol

    (1996)
  • J.K. Linevsky et al.

    IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes

    Am J Physiol

    (1997)
  • N.M. Sullivan et al.

    Purification and characterization of toxins A and B of Clostridium difficile

    Infect Immun

    (1982)
  • M. Warny et al.

    p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis

    J Clin Invest

    (2000)
  • D.M. Lyerly et al.

    Effects of Clostridium difficile toxins given intragastrically to animals

    Infect Immun

    (1985)
  • T.J. Mitchell et al.

    Effect of toxin A and B of Clostridium difficile on rabbit ileum and colon

    Gut

    (1986)
  • S. Johnson et al.

    Fatal pseudomembranous colitis associated with a variant Clostridium difficile strain not detected by toxin A immunoassay

    Ann Intern Med

    (2001)
  • A.P. Limaye et al.

    Pseudomembranous colitis caused by a toxin A(−) B(+) strain of Clostridium difficile

    J Clin Microbiol

    (2000)
  • D.M. Lyerly et al.

    Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile

    Infect Immun

    (1992)
  • M. Riegler et al.

    Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro

    J Clin Invest

    (1995)
  • S.P. Sambol et al.

    Toxin gene analysis of a variant strain of Clostridium difficile that causes human clinical disease

    Infect Immun

    (2000)
  • Cited by (216)

    • Exploring ways to improve CDI outcomes

      2018, Medecine et Maladies Infectieuses
    View all citing articles on Scopus

    Drs. Kellly and Pothoulakis have acted as consultants or scientific advisors to companies, Bicodex Inc., GelTex Pharmaceuticals Inc., SynSorb Biotech Inc., and ActivBiotics Inc., interested in developing therapeutic intervention for C difficile diarrhea. Dr. Kyne acted as a consultant for GelTex Pharmaceuticals Inc. Drs. Giannasca, Warny, Lee, and Monath are employees and shareholders of Acamis Inc.

    During this study, L. Kyne held a Paul Beeson Faculty Scholars in Aging Research career development award.

    Supported by grants AG00971 (to L.K.), AI053069 (to C.P.K.), and RR01032 (to Beth Israel Deaconess Medical Center, General Clinical Research Center) from the National Institutes of Health and by Acambis, Inc.

    View full text