Antimicrobials have been the agents of choice for treatment of Clostridium difficile infection (CDI) for >30 years, primarily metronidazole and vancomycin. Antimicrobials have been highly successful and are likely to continue to play a major role in the treatment of patients who already have CDI. However, there remain several areas of CDI treatment that are suboptimal—namely, the management of fulminant or complicated severe CDI and management of recurrent CDI.
Patients with fulminant disease frequently experience failure to respond to medical management with antimicrobials and either die or require subtotal colectomy as a life‐saving measure. Antimicrobial treatment is thought to be, at least in part, responsible for frequent CDI recurrences, presumably as a result of the unintended effects on the normal gastrointestinal microbiota that leave patients vulnerable to relapse or reinfection. As a result, a number of non‐antimicrobial management approaches have been proposed and under development, some of which have entered clinical trials. In addition, new antimicrobial treatments designed to improve response and to avoid damage to the microbiota are also under clinical development.
The prevention and treatment of CDI may include infection control measures, antimicrobial stewardship, restoration of the protective microbiota, and increased immunity to C. difficile toxins, in addition to antimicrobial treatment agents. It is our purpose to review the progress in antimicrobial treatment, the “inside the box” approach to CDI management, as well as to review non‐antimicrobial “outside the box” strategies for CDI management that are in trials involving humans or that are currently available for treatment.
Antimicrobial “Inside the Box” CDI Management
Shortly after the infectious cause of pseudomembranous colitis was recognized, oral vancomycin and metronidazole were demonstrated as effective treatments, although vancomycin is the only agent that has received US Food and Drug Administration (FDA) approval for this indication. Early prospective, randomized trials concluded that metronidazole was not inferior to vancomycin, with initial cure rates >90%. Recurrent infections, however, occurred at substantial rates for both agents, and avoiding this complication remains a major unmet need in CDI management. Decreased response rates and slower responses for metronidazole have been noted since 2004. A microbiological and clinical observational study showed that patients treated with metronidazole were less likely to have resolution of diarrhea and were more likely to have C. difficile detected in feces at day 5, compared with those treated with vancomycin. In 2007, Zar et al, in a randomized, prospective clinical study, showed that vancomycin was superior to metronidazole for treatment of severe CDI. Other, older agents that have been evaluated as treatment for CDI include bacitracin, teicoplanin, and fusidic acid. These drugs, however, either offer no advantage over metronidazole and vancomycin or have been unavailable to clinicians in the United States.