Clostridium difficile infection occurs as a complication CASE REPORT
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1 GASTROENTEROLOGY 2005;128: CASE REPORT Clostridium difficile Toxoid Vaccine in Recurrent C. difficile Associated Diarrhea STAVROS SOUGIOULTZIS,* LORRAINE KYNE, DENISE DRUDY,* SARAH KEATES,* SEEMA MAROO,* CHARALABOS POTHOULAKIS,* PAUL J. GIANNASCA, CYNTHIA K. LEE, MICHEL WARNY, THOMAS P. MONATH, and CIARÁN P. KELLY* *Gastroenterology Division and Gerontology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and Acambis, Inc., Cambridge, Massachusetts 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- g 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. Clostridium difficile infection occurs as a complication of antibiotic use and is now the most commonly identified cause of nosocomial infectious diarrhea in the developed world. 1 3 C difficile associated diarrhea (CDAD) and pseudomembranous colitis are believed to result from the actions of 2 bacterial exotoxins, toxin A and toxin B, that are produced by pathogenic strains of the bacterium. 4 6 Both toxins have cytotoxic and proinflammatory properties Toxin A causes intestinal injury and secretion in both animals and humans. 9,11,12 Toxin B has little effect on the intact intestine in animal models but appears to be a potent toxin for human colon Management of CDAD involves discontinuation of the inciting antimicrobial agent if possible, as well as supportive care. 1 3,18 If symptoms are prolonged or severe, therapy with oral metrondiazole or vancomycin is indicated. Although these agents are usually effective in treating initial episodes of CDAD, approximately 20% of patients treated with metronidazole or vancomycin will have recurrent diarrhea after treatment is discontinued, and some will have multiple recurrences. 19 Patients who suffer 2 or more episodes of CDAD have a greater than 50% risk for further relapses, and this recurrent form of CDAD continues to be a substantial management problem Factors associated with an increased risk for recurrence include advanced age ( 65 years), severity of the patient s comorbid medical problems, and prolonged antibiotic use. 23 Furthermore, several studies indicate that the host s immune response to C difficile toxins influences the clinical course of the infection as well as the risk of recurrence We reported recently that asymptomatic carriers of C difficile have serum IgG antitoxin A antibody levels that are approximately 3-fold higher than patients with CDAD. 27 In another study, we found that patients with high serum IgG antitoxin A antibody levels during a first episode of CDAD were 48-fold less likely to develop recurrent diarrhea compared with patients with lower serum antitoxin antibody levels. 23 These and other Abbreviations used in this paper: CDAD, C difficile-associated diarrhea by the American Gastroenterological Association /05/$30.00 doi: /j.gastro
2 March 2005 CLOSTRIDIUM DIFFICILE VACCINE 765 studies indicate that a host immune response to C difficile toxins may be protective and reduce the risk for recurrent CDAD. An anti-c difficile toxoid vaccine has been developed containing formalin-inactivated partially purified toxins A and B. The parenterally administered vaccine also protected hamsters from diarrhea and death following oral challenge with toxigenic C difficile. 28,29 Kotloff et al have reported their experience using the C difficile toxoid vaccine administered to healthy adult volunteers. 30 The candidate vaccine was well tolerated and induced robust immune responses to both toxin A and toxin B. In a subsequent study, we also found that the serum antitoxin A antibody concentrations that were achieved during vaccination far exceeded the concentrations that were associated with protection in our clinical studies of CDAD. 31 The aims of this study were to examine whether the C difficile vaccine would be safe and immunogenic in patients with multiple episodes of recurrent CDAD. Materials and Methods 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 criteria required that subjects be 18 to 85 years of age and in stable health and that clinical laboratory tests (complete blood count, blood chemistries, urinalysis) did not show any unexpected clinically significant abnormalities. Serologic testing for HIV, HBsAg, and HCV were negative. Patients did not have any history of anaphylaxis, wheezing, urticaria, or angioedema or of previous severe allergic reactions to a drug or vaccine. They were not immunosuppressed and did not have a history of chronic or recurrent immune-mediated or inflammatory disease, including collagen vascular diseases or rheumatoid arthritis. The study protocol was approved by the Institutional Review Board at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, and written informed consent was obtained from all study subjects. C difficile Toxoid Vaccine The C difficile toxoid vaccine was produced as previously described. 28,30,31 Briefly, toxins A and B were partially purified from the culture filtrate of C difficile strain ATCC by ammonium sulfate precipitation. Toxins were further purified by an S300 Sephacryl size exclusion column and were then inactivated with formaldehyde. The total protein concentration of the vaccine was 0.52 mg/ml of which toxins A and B composed approximately 44% at a 1.5:1 toxin A to toxin B ratio. Finally, the vaccine was diluted to contain 50 g protein per 0.4 ml, which was the dose delivered in each inoculation. Vaccination Regimen and Safety Assessments C difficile toxoid vaccine was injected intramuscularly at the deltoid region on 4 occasions, on days 0, 7, 28, and 56. Patients were monitored at the study site for 30 minutes after vaccination to detect immediate adverse reactions. The 33- year-old female subject was advised to practice contraception throughout the course of the study, and a urine pregnancy test was obtained at the screening visit and before each inoculation. Participants also completed a daily symptom diary throughout the treatment period to record all adverse events, including pain, redness, and itching at the injection site as well as general symptoms such as abdominal pain, headache, allergic reactions, and change in bowel habit. Participants were also contacted by telephone 2 consecutive days after each inoculation to monitor for any change in their symptoms. Blood and urine samples were obtained at study entry, prior to each vaccination and 2 weeks after the last vaccination (day 70) to monitor the complete blood count and differential white blood cell count, prothrombin and partial thromboplastin time, serum electrolytes, glucose, liver and renal function tests, amylase, and urinalysis. Serum samples were also collected at baseline, before each of the 4 vaccinations, and 2 weeks after the last vaccination and stored at 80 C for subsequent antitoxin antibody measurements and cytotoxin neutralization assays. All patients continued on vancomycin therapy at doses ranging from 125 mg twice daily to 250 mg 4 times daily until their fourth inoculation on day 56. Antitoxin ELISAs and Cytotoxin Neutralization Assays Serum IgA, IgG, and IgM antitoxin A and antitoxin B antibody levels were measured by ELISA as previously described. 23,25 27,32,33 Toxin A and toxin B were purified from culture supernatant of C difficile VPI strain (ATCC 43255). Microplates (PolySorp, Nunc, Fisher Scientific, Pittsburgh, PA) were coated overnight with toxin A or toxin B (0.05 g in100 L carbonate-bicarbonate buffer, ph 9.6) at 4 C. After washing with PBS supplemented with 0.05% Tween 20 (PBST), plates were saturated with 1% BSA/PBST (200 L/well) for 1 hour at room temperature. After washing, serum samples diluted 100-fold in 0.1% BSA/PBST (100 L/well) were incubated for 1 hour in duplicate. Bound antibodies were detected using horseradish peroxidase-conjugated anti-immunoglobulin G, A, or M (Dako Corporation, Carpinteria, CA) diluted 1000-fold in PBST/0.1%BSA (100 L/ well). After washing with PBST, TMB peroxidase substrate and peroxidase solution (Kirkegaard and Perrry Laboratories, Gaithersburg, MD) was added (100 L/well). The reaction was stopped after 3 minutes by the addition of 1 mol/l phosphoric
3 766 SOUGIOULTZIS ET AL GASTROENTEROLOGY Vol. 128, No. 3 acid (50 L) and optical density (OD) was measured at 450 nm with a reference OD at 630 nm. Human pooled plasma containing high anti-c difficile toxin A and toxin B antibody activity was used in all assays as the standard; the undiluted standard was assigned an arbitrary level of 10,000 ELISA units (EU). Cytotoxicity was determined by rounding of IMR-90 fibroblasts in tissue culture after exposure to purified C difficile toxin A or B. 30,33 38 Neutralization of cytotoxicity by subjects sera was quantified by adding an equal volume of serial 2-fold dilutions of the serum sample (diluted in EMEM culture medium) to 8 times the minimum 50% cytotoxic dose of the toxin preparation (in EMEM) to achieve a final toxin concentration of 4 times the minimum 50% cytotoxic dose. The minimum 50% cytotoxic dose for each toxin preparation was defined as the minimum dose resulting in 50% cell rounding at 24 hours (in these studies, 10 ng/ml for toxin A, and 0.04 ng/ml for toxin B). After incubation at room temperature for 60 minutes, the serum/toxin mixture was added to the IMR-90 monolayers (100 L/well). The neutralizing activity of the serum sample was reported as the highest dilution of serum that prevented rounding of 50% of the IMR-90 cells after overnight culture at 37 C. Results 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 mg. Five days later, he developed diarrhea, and a stool sample was positive for C difficile toxin A. Metronidazole, 250 mg 4 times daily, was prescribed. After 3 days of therapy, there was no improvement in his diarrhea. Metronidazole was discontinued and replaced by oral vancomycin, 125 mg 3 times daily. His diarrhea resolved, and vancomycin therapy was discontinued after 21 days of treatment. Ten days later, he developed recurrent diarrhea, and stool testing was again positive for C difficile toxin. Vancomycin was restarted, and the diarrhea resolved but recurred again when the vancomycin was discontinued. He again resumed treatment with oral vancomycin, and, in June 2001, he underwent a radical prostatectomy for early stage prostatic carcinoma. After surgery, the dosage of vancomycin was gradually tapered followed by pulse dosing. 22 In August, he discontinued treatment with vancomycin completely but, within 1 week, developed another episode of CDAD. He enrolled in the vaccine trial in September 2001 having been on treatment with oral vancomycin almost continuously for 7 months. Case 2 In August 2000, a 71-year-old woman developed diarrhea after taking cefuroxime 250 mg twice daily for 7 days to treat a urinary tract infection. A stool test was positive for C difficile toxin A. The diarrhea responded well to treatment with metronidazole, 500 mg twice daily for 10 days. However, the diarrhea recurred 10 days after stopping metronidazole treatment. Stool testing was again positive for C difficile toxin, and vancomycin 125 mg was administered 4 times daily. The diarrhea resolved but recurred when vancomycin was discontinued. During the following months, the patient attempted to discontinue treatment with oral vancomycin on at least 10 occasions, but, at each attempt, diarrhea recurred within 3 to 10 days of stopping the antibiotic therapy. On most occasions, the vancomycin dose was gradually tapered. During this 18-month period, she also received courses of therapy with cholestyramine, Pepto- Bismol, VSL3 (a cocktail of probiotics containing strains of Lactobacillus, Bifidobacterium, and Streptococcus salivarius) or pooled normal intravenous immunoglobulin, but none of these different approaches was effective in preventing subsequent recurrence of CDAD. 3,19 She enrolled in the vaccine trial in June 2002 having been on treatment with oral vancomycin almost continuously for 22 months. Case 3 In September 2001, a 33-year-old woman developed diarrhea while taking cefuroxime 250 mg twice daily for 4 days to treat a urinary tract infection. A stool test was positive for C difficile toxin. She took metronidazole 250 mg 4 times daily for 2 weeks with resolution of the diarrhea. Three days after stopping metronidazole, the diarrhea recurred, and she was again treated with oral metronidazole for 2 additional weeks. When the metronidazole therapy was stopped, she suffered a recurrence of diarrhea, and a stool test was again positive for C difficile toxin. She was subsequently treated with a variety of regimens, including a gradually tapering dose of vancomycin, bacitracin, rifampicin, Saccharomyces boulardii, and Lactobacillus GG. On each occasion, diarrhea recurred within 2 to 9 days of stopping antibiotic therapy. She enrolled in the vaccine trial in June 2002 having been on treatment with metronidazole or vancomycin almost continuously for 9 months.
4 March 2005 CLOSTRIDIUM DIFFICILE VACCINE 767 Figure 1. Serum IgG antitoxin A antibody values in 3 subjects with recurrent C difficile associated diarrhea. The subjects received intramuscular inoculations of a C difficile toxin vaccine on days 0, 7, 28, and 56 (arrows). Serum IgG antitoxin A antibody was measured by ELISA. The highest dilutions of serum that neutralized the cytotoxicity of purified C difficile toxin A are shown in parentheses for all serum samples that had detectable toxin neutralizing activity. Clinical Outcome and Safety Data All 3 subjects discontinued treatment with oral vancomycin after their fourth and final inoculation with the C difficile toxoid vaccine. Follow-up was available for all subjects for at least 6 months after they completed vaccination and discontinued vancomycin treatment, and none developed recurrent CDAD. The vaccine was well tolerated, and there were no adverse events that were definitely or probably related to vaccination. Adverse events that were possibly related to vaccination based on temporal association included a mild headache in subject 1 and mild abdominal pain and a change in bowel habit in subject 2. Subject 2 also reported transient polyarthralgia after the fourth inoculation. She later developed atypical polyarthritis with a normal erythrocyte sedimentation rate, a negative rheumatoid factor test, and slightly elevated C-reactive protein. Approximately 2 months after completion of the study, a clinical diagnosis of polymyalgia rheumatica was made by a rheumatologist. She was treated with a course of oral corticosteroids with good effect. Immune Response to C difficile Toxins Two of the 3 subjects showed an increase in both antitoxin A and antitoxin B serum IgG antibody levels compared with their baseline values (Figures 1 and 2). Subject 2 showed 3-fold (1.9 to 5.7 EU) and 52-fold (1.2 to 63.0 EU) increases in serum IgG antibodies against toxin A and toxin B, respectively. Subject 3 showed a 4-fold (8.2 to 34.6 EU) increase in serum IgG antitoxin A and a 20-fold (4.6 to 93.9 EU) increase in serum IgG antitoxin B antibody values. Antibody increases were seen after the fourth vaccination for toxin A and after the third for toxin B (Figures 1 and 2). Subject 1 did not demonstrate any substantial increase in antibody levels against either toxin (1.3-fold for both toxin A and toxin B) (Figures 1 and 2). There was no significant increase in serum IgA or IgM antitoxin A or B antibodies in any subject. The ability of serum to neutralize the cytotoxic activity of C difficile toxin A and toxin B generally coincided with increases in antitoxin antibody levels as measured by ELISA (Figures 1 and 2). Subject 1 did not develop serum toxin neutralizing activity at any time point. Subject 2 developed neutralizing activity against toxin A after the fourth vaccination and against toxin B after the third. Subject 3 developed neutralizing activity against toxin A after the third vaccination and against toxin B after the fourth. 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 also previously used a variety of treatment regimens in an attempt to prevent further recurrences. Figure 2. Serum IgG antitoxin B antibody values in 3 subjects with recurrent C difficile associated diarrhea. The subjects received intramuscular inoculations of a C difficile toxin vaccine on days 0, 7, 28, and 56 (arrows). Serum IgG antitoxin B antibody was measured by ELISA. The highest dilutions of serum that neutralized the cytotoxicity of purified C difficile toxin B are shown in parentheses for all serum samples that had detectable toxin neutralizing activity.
5 768 SOUGIOULTZIS ET AL GASTROENTEROLOGY Vol. 128, No. 3 These included tapering and pulsed doses of oral vancomycin, combination therapy with other antibiotics (rifampicin, bacitracin), cholestyramine, probiotic therapy (Saccharomyces boulardii, Lactobacillus GG, and VSL 3), and passive immunotherapy using intravenous immunoglobulin. The reason why some patients are predisposed to prolonged and recurrent CDAD is not entirely clear. The failure to cure CDAD is seldom associated with microbial resistance to metronidazole or vancomycin. It may result from persistence of C difficile or its spores in the intestine, despite antibiotic therapy. 22 Alternatively, recurrent diarrhea and colitis may follow reinfection of susceptible individuals with the same or a different strain of C difficile from their environment. 40 There is now substantial evidence that an inadequate humoral immune response to C difficile toxins is associated with an increased risk for recurrent CDAD. The earliest published report was that high titers of serum IgG antitoxin B antibodies were associated with recovery from CDAD without subsequent relapse. 24 Warny et al reported that serum IgG and fecal IgA antitoxin antibodies were significantly higher in patients with a single, brief episode of CDAD compared to those with recurrent CDAD. 26 In another study, children with relapsing CDAD had significantly lower serum IgG antitoxin A antibodies compared with controls. 25 Furthermore, intravenous infusion of pooled normal immunoglobulin containing IgG antitoxin A increased serum IgG antitoxin A levels and appeared to be effective in preventing further relapses. In a recent study, patients with symptomless C difficile infection had a high serum IgG antitoxin A antibody, but there was no evident association between protection and either serum or secretory IgA antitoxin. 27 In another prospective cohort study of 63 patients, those who had only a single episode of diarrhea showed a significant increase in their serum IgG antitoxin A antibodies during their first episode of CDAD, whereas those who later had recurrent CDAD did not. 23 Taken together, these studies indicate that recurrent CDAD is associated with a failure to develop a protective immune response to C difficile toxins. 41 Vaccination using inactivated C difficile toxins protects animals against C difficile-associated enterocolitis and death. In a previous study, a C difficile toxoid vaccine similar to that used in this study was administered to 30 healthy volunteers. 30 Over 90% of the subjects showed substantial increases in their serum antitoxin A and antitoxin B antibodies and developed serum toxin neutralizing activity. However, as discussed above, the ability of patients with recurrent CDAD to mount an immune response to C difficile toxins seems to be impaired. In a previous study of healthy volunteers, the C difficile toxoid vaccine induced substantially greater immune responses, in the form of elevations in serum IgG antitoxin A, than those observed in patients with C difficile infection. 31 The presentation of C difficile toxin antigens in the context of multiple intramuscular inoculations of purified toxoids is very different from that occurring during colonic luminal infection. These differences in antigen type and in the route and nature of antigen presentation may account for the ability of the vaccine to induce immune responses that are different from those observed during natural infection. However, it may be especially difficult to induce protective immunity through vaccination in those individuals who fail to develop immunity during natural challenge with C difficile. 42 This issue was a major factor in our decision to perform this pilot study in patients with recurrent CDAD. If active vaccination is ineffective in this population, alternative approaches such as passive immunotherapy using hyperimmune globulin may be required. 23,25,33,42 This study examines vaccination against C difficile in at-risk subjects. Two of our 3 subjects with recurrent CDAD showed an increase in serum IgG antitoxin antibodies. However, perhaps predictably, the fold increases in antitoxin antibodies were relatively modest when compared with those observed previously in healthy volunteers. 30,31 This was especially the case for serum IgG antitoxin A of which 3-fold and 4-fold increases above baseline were observed, whereas, for serum IgG antitoxin B, there were 52-fold and 20-fold increases, respectively, in the same 2 subjects. This finding agrees with our previous studies, demonstrating a specific decrease in humoral immune responses to toxin A in symptomatic and recurrent CDAD. 23,25 27 Both subjects who had increases in antitoxin antibodies by ELISA showed concomitant toxin neutralizing activity in their sera. This is arguably an important indicator of protective immunity reflecting the inhibition of a key biologic function of the toxins, ie, monoglucosylation of rho proteins leading to disaggregation of filamentous actin and cell rounding. 43,44 However, a correlation between serum toxin neutralizing activity as determined using the tissue culture cytotoxin assay and inhibition of enterotoxicity or protection against C difficile associated diarrhea and colitis has not been demonstrated in humans. After vaccination, all 3 subjects, including one who showed no substantial increase in serum antitoxin antibodies or serum toxin neutralizing activity, were able to discontinue vancomycin without further recurrence of CDAD. There are a number of possible explanations for our finding that 1 of the 3 subjects did not mount an evident antitoxin antibody response during vaccination yet remained disease free. One possibility is that his
6 March 2005 CLOSTRIDIUM DIFFICILE VACCINE 769 recovery from recurrent CDAD was independent of the vaccination regime and occurred despite his continued lack of a protective immune response. A second possibility is that vaccination was protective but that the parameters used to monitor the immune response (ie, serum antitoxin antibody concentrations by ELISA and cytotoxicity neutralizing activity) do not accurately measure the true effectors of protective immunity to CDAD. It is not clear whether the positive outcome in all 3 subjects indicates that the C difficile vaccine is clinically effective because the study was small and uncontrolled. However, our findings do support the feasibility of active vaccination against C difficile and its toxins in high-risk individuals. Suitable study population may include those with chronic diseases that are likely to require frequent antibiotic therapy and admission to health care facilities at which CDAD is endemic. 41,42,45 These populations are similar to those in whom immunization against influenza and pneumococcus are currently performed. This factor could facilitate the administration of a C difficile vaccine if it can be combined with other recommended immunizations. In institutions such as hospitals or nursing homes, herd immunity can be very important in limiting the spread of infectious diseases. 46 It is not clear that a toxoid-based vaccine can prevent intestinal colonization by C difficile. 29 Nonetheless, vaccination may indirectly reduce cross infection if infected individuals are protected against CDAD because patients with diarrhea are a major source for person-to-person spread and for environmental contamination by C difficile and its spores Based on the encouraging results obtained in this pilot study, we believe that the efficacy of vaccination against C difficile should be tested by randomized controlled trials in populations at risk for C difficile toxin-induced diarrhea and pseudomembranous colitis. References 1. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002;346: Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330: Kyne L, Farrell RJ, Kelly CP. 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Antimicrob Agents Chemother 1997;41: Kim K, Pickering LK, DuPont HL, Sullivan N, Wilkins T. In vitro and in vivo neutralizing activity of human colostrum and milk against purified toxins A and B of Clostridium difficile. J Infect Dis 1984; 150: Wada N, Nishida N, Iwaki S, Ohi H, Miyawaki T, Taniguchi N, Migita S. Neutralizing activity against Clostridium difficile toxin in the supernatants of cultured colostral cells. Infect Immun 1980; 29: Warny M, Fatimi A, Bostwick EF, Laine DC, Lebel F, LaMont JT, Pothoulakis C, Kelly CP. Bovine immunoglobulin concentrateclostridium difficile retains C difficile toxin neutralising activity after passage through the human stomach and small intestine. Gut 1999;44: 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: Wilcox MH, Fawley WN, Settle CD, Davidson A. Recurrence of symptoms in Clostridium difficile infection relapse or reinfection? J Hosp Infect 1998;38: Kelly CP. Immune response to Clostridium difficile infection. Eur J Gastroenterol Hepatol 1996;8: Wilcox M, Minton J. Role of antibody response in outcome of antibiotic-associated diarrhoea. Lancet 2001;357: Just I, Wilm M, Selzer J, Rex G, Eichel-Streiber C, Mann M, Aktories K. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J Biol Chem 1995;270: Just I, Selzer J, Wilm M, Eichel-Streiber C, Mann M, Aktories K. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995;375: Kyne L, Kelly CP. Prospects for a vaccine for Clostridium difficile. BioDrugs 1998;10: Starr JM, Rogers TR, Impallomeni M. Hospital-acquired Clostridium difficile diarrhoea and herd immunity. Lancet 1997;349: Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva J Jr. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol 1995;16: Nolan NP, Kelly CP, Humphreys JF, Cooney C, O Connor R, Walsh TN, Weir DG, O Briain DS. An epidemic of pseudomembranous colitis: importance of person to person spread. Gut 1987;28: Samore MH. Epidemiology of nosocomial clostridium difficile diarrhoea. J Hosp Infect 1999;43(Suppl): Received June 27, Accepted October 27, Address requests for reprints to: Ciarán P. Kelly, M.D., Dana 601, Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts ckelly2@bidmc.harvard.edu; fax: (617) 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. 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