C. difficile toxins may be the ultimate protection strategy against CDI. Both passive immunity with monoclonal antibodies and active vaccines are currently undergoing clinical trials involving humans. The use of 2 intravenously administered monoclonal antibodies directed against toxins A and B when added to standard CDI treatment with vancomycin or metronidazole in a phase 2 clinical trial involving 200 patients decreased the CDI recurrence rate in patients who received the monoclonal antibodies to 7%, compared with 25% in the placebo group (P<.001). In treated patients with 11 prior CDI episode, recurrence rates were decreased to 7%, compared with 38% for the placebo group (P = .006), and in treated patients with the BI/NAP1/027 strain, recurrence was 8%, compared with 32% for the placebo group (P = .06). Hamster studies had confirmed the superiority of 2 monoclonal antibodies directed against both toxin A and toxin B, compared with 1 monoclonal antibody alone, and this was further confirmed in a small trial involving humans that used only the CDA-1 anti-toxin A antibody that resulted in no significant difference in recurrence with the single monoclonal antibody (5 [17%] of 29), compared with placebo (3 [18%] of 17). The only currently available antibody treatment for CDI is pooled intravenous immunoglobulin (IVIG), for which only retrospective clinical evaluation for treatment of severe and recurrent CDI has been published. IVIG was initially reported as effective for immunoglobulin-deficient children with chronic recurrent CDI. IVIG preparations contain neutralizing levels of IgG antibody to toxin A and toxin B. No conclusive evidence of benefit for IVIG has been demonstrated in retrospective analyses of its use for treatment of recurrent CDI, nor has an effective dose been established (range, 125–400 mg/kg in single or repeated doses). For severe or fulminant CDI, one retrospective study compared 18 patients who received IVIG (dose range, 200–300 mg/kg) with a group of patients with similarly severe CDI who did not receive IVIG and found no difference in mortality, colectomy rate, or length of stay; the conclusion was that the use of IVIG for severe CDI is unsubstantiated. A larger and more recent uncontrolled, retrospective series of 21 patients with severe CDI treated with widely varying doses of IVIG demonstrated survival in only 43% of patients. Thus, to date, there are insufficient data to support use of IVIG for either recurrent or severe CDI.
Active rather than passive immunization is an attractive goal for effective and durable protection against CDI. Vaccines have been focused on developing immunity to the C. difficile toxins, on the basis of animal studies and human natural antibody levels that indicate protection against clinical illness correlates with serum IgG antibody to toxins A and B, while having no apparent effect on gastrointestinal colonization. This observation is consistent with the high rates of stool colonization with toxigenic C. difficile among patients in the hospital environment who remain asymptomatic. In humans, preliminary trials of a parenteral vaccine containing toxoids A and B have shown that the product is safe and induces vigorous serum antibody responses in healthy adults. Among 3 patients given the vaccine who required continuous vancomycin to manage recurrent CDI, all 3 were able to discontinue vancomycin, and large increases in levels of serum IgG antibodies to toxin A (3–4-fold) and toxin B (20–52-fold) were found in 2 of the patients. A phase 2 trial is currently ongoing to evaluate injectable C. difficile toxoid vaccine for prevention of CDI recurrence. Major questions regarding the immune response to vaccine in elderly populations, the magnitude and duration of vaccine protection, and the selection of an appropriate at-risk population for vaccination remain to be answered.