CDAD is caused by an overgrowth of C. difficile, a resident anaerobic spore forming bacterium of the lower gastrointestinal tract. This overgrowth is caused by the use of antibiotics for the treatment of common community and hospital acquired infections. Although they treat the underlying infection, many antibiotics disrupt the natural gut flora and allow C. difficile to proliferate. C. difficile produces toxins that lead to severe diarrhea, pseudomembraneous colitis, and toxic megacolon.
CDAD treatment options are limited. Vancocin® (oral vancomycin pulvules, ViroPharma) is the only FDA approved agent for the treatment of CDAD. Despite this indication, Vancocin is generally relegated to second line treatment for severe and relapse cases due to concerns about vancomycin-resistant enterococci (VRE) generation and the drug's high cost. Despite lacking an approved label for CDAD, oral metronidazole (Flagyl, generic) is the de facto first line standard of care in virtually all CDAD cases — mainly because metronidazole is cheap and generally efficacious in most mild to moderate CDAD cases. Both Vancocin and metronidazole are typically dosed three or four times daily for treatment courses of 10 to 14 days and historical response rates for both agents have been reported to be as high as 90 percent. However, the utility of these antibiotics is limited due to relapse (either re-infection with same pathogen or new infection) rates in the 20- to 30-percent range. Relapse occurs because Vancocin and metronidazole, due to their broad spectrum of anaerobic activity, hinder the re-establishment of the natural GI flora.
From 2000 to 2005, the number of U.S. inpatient CDAD courses of therapy has grown to greater than 500,000, a compound annual growth rate of over 8 percent. During this same time period, sales volume (kilograms) of Vancocin grew by 50 percent while metronidazole grew by 35 percent. This rapid growth followed years of relatively stable incidence rates. A variety of factors are believed to have contributed to this explosion in CDAD incidence:
The most critical factor in the increase in incidence and severity of CDAD is the emergence of a newly identified hyper-virulent C. difficile strain, noted as the toxinotype III, NAP1, or BI strain. This strain produces up to 20 times the amount of toxins A and B compared to historical strains and an additional binary toxin (CDT) whose role in CDAD pathogenesis is currently unknown. Numerous reports in the literature refer to the increasing incidence and outbreak nature of the NAP1 strain, and it is clearly implicated with increased disease severity, lower response rates, increased relapses, and higher mortality rates. The NAP1 strain is currently recognized as one of the top emerging pathogens in the ID community as evidenced by the number of symposia, second only to MRSA, on the subject at recent ICAAC and IDSA meetings and an increased number of media reports on the topic.