Clostridium difficile--beyond antibiotics.

In this decade, the prevention and control of Clostridium difficile infection in health care settings has become a global public health challenge. Infection rates have increased dramatically, and several large outbreaks associated with toxinotype III BI/NAP1/027 strains have been described.1 One of the major incongruities in the management of C. difficile infection is that antibiotics are the mainstay of treatment for this antibioticassociated condition. Standard therapy with oral metronidazole or vancomycin has not changed since the 1970s. Although antibiotics are effective at inhibiting C. difficile and treating symptoms, the use of such drugs does not allow for the reestablishment of normal bowel flora. As a result, 15 to 30% of patients will have recurrent C. difficile infection after the cessation of treatment.1 Many patients will have multiple recurrences. For older, frailer patients, such recurrences may lead to additional complications, as well as perpetuating the spread of C. difficile in health care settings. In the community, there are many sufferers of recurrent C. difficile infection who have frequent episodes of diarrhea, which has a significant effect on social and occupational functioning. Various approaches to the management of recurrent C. difficile infection have been tried with variable success. Such measures include repeated courses of metronidazole or vancomycin, tapered and pulsed courses of vancomycin, combinations of antibiotics, toxin binders, probiotics, and immunotherapy. Probiotic therapy ranges from the aesthetically very acceptable but probably ineffective use of probiotic drinks and supplements to the less aesthetically acceptable but probably effective fecal transplantation.2 Intravenous pooled human immunoglobulin products have been used off-label and on an ad hoc basis for passive immunotherapy. However, pharmacokinetic and efficacy data for these products are not available.1 Active immunization with a C. difficile toxoid vaccine is currently being tested in a phase 2, randomized, secondary prevention trial (ClinicalTrials.gov number, NCT00772343). In this issue of the Journal, Lowy et al.3 present the results of a multicenter, randomized, double-blind, placebo-controlled trial of two novel neutralizing fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1) for the secondary prevention of C. difficile infection. Among 484 eligible patients who were screened at 30 centers in the United States and Canada, 200 were enrolled in the study. These patients were given standard therapy for C. difficile infection and were randomly assigned to receive a single intravenous infusion of either CDA1+CDB1 or saline placebo. Patients were followed for 84 days. The primary outcome measure was recurrent C. difficile infection. The trial results are impressive. In the intention-to-treat analysis, recurrent infection developed in 7 of 101 patients (7%) in the antibody group, as compared with 25 of 99 patients (25%) in the placebo group, a relative reduction of 72%. Patients with multiple recurrences were particularly likely to benefit, with a relative reduction of 82% in the recurrence rate, as compared with the placebo group. CDA1+CDB1 had no effect on the duration or severity of initial episodes of infection. The monoclonal antibodies were not immunogenic and had an adverse-event profile similar to that of placebo. The trial results are consistent with previous studies showing that inadequate circulating antibody levels against C. difficile toxins predispose patients to symptomatic and recurrent infection