Clostridium difficile-associated diarrhea (CDAD) can present variably as a mild diarrheal illness to severe diarrhea, colitis, and, in the most serious cases, death. Patients may experience 20 or more diarrheal episodes daily with resulting dehydration. CDAD affects more than 700,000 people in the United States annually, but the incidence may be higher because cases are often underreported, undiagnosed, or left untreated. Estimates for medical treatment and hospital stays associated with CDAD have been reportedly as high as $3.8 billion annually.
Risk Factors & Recurrence of CDAD
Patients typically develop CDAD from the use of broad-spectrum antibiotics that disrupt the normal gastrointestinal (GI) flora. This can allow C difficile to sporulate and proliferate. Older patients are at particularly high risk for CDAD, possibly because of a weakened immune system or the presence of underlying disease. About two-thirds of CDAD patients are 65 or older. Other risk factors associated with CDAD include (but are not limited to) prolonged hospital stays, renal impairment, recent abdominal surgery, and sharing hospital rooms with CDAD-infected patients. About 20% to 30% of patients experience CDAD recurrence following treatment. Risk factors for recurrence of CDAD include older age, concomitant antibiotics, low albumin, poor performance status, poor immune response to toxins, and fecal incontinence. In patients who have experienced up to two episodes of CDAD, risk of recurrence increases to 50% to 65%.
A Welcome Treatment Addition for CDAD
Metronidazole (Flagyl, Pfizer) and vancomycin (Vancocin, ViroPharma) have long been used as therapies for patients with CDAD. Vancomycin is FDA approved for this use. Metronidazole does not carry an FDA indication for treatment of CDAD but became popular after 1994 when guidelines cautioned against using vancomycin for fear of resistance to gastrointestinal Enterococcus. Outcomes with these antibiotics vary in terms of initial clinical response and frequency of recurrence. In May 2011, the FDA approved fidaxomicin (Dificid, Optimer Pharmaceuticals) as the first new antibiotic indicated for CDAD in more than 25 years. Fidaxomicin, an orally administered macrolide, is minimally absorbed from the GI tract. It is dosed as a 200 mg tablet orally BID for 10 days with or without food.
Approval of fidaxomicin followed the completion of two large randomized, double blinded, placebo controlled clinical trials comparing the drug to vancomycin in the treatment of CDAD. Fidaxomicin was non-inferior to vancomycin in initial cure of CDAD with a similar safety profile. However, significantly more patients on vancomycin experienced CDAD relapse when compared with the fidaxomicin group. Patients on fidaxomicin had a sustained clinical response (resolution of CDAD without recurrence at 4 weeks) that was statistically significantly superior to vancomycin. Adverse effects reported in the studies included nausea, vomiting, abdominal pain, GI hemorrhage, anemia, and neutropenia.
Studies suggest that fidaxomicin has less impact on fecal flora. This is postulated as one reason that recurrence rates are lower. Considering the high relapse rates seen in CDAD, in addition to the increasing disease burden, fidaxomicin may well represent a true treatment advance in the CDAD armamentarium. Future studies evaluating efficacy in younger/special patient populations, severe CDAD, and in multiply relapsing CDAD will likely reveal more information on safety and efficacy. Pharmacoeconomic studies will hopefully evaluate the drug’s comparative cost-effectiveness of treatment, allowing for clinicians to optimize the use of this therapy.
Readings & Resources (click to view)
Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis. 2011;53:440-447. Available at: http://cid.oxfordjournals.org/content/53/5/440.long.
Mullane KM, Gorbach S. Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti Infect Ther. 2011;9:767-777.
Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422-431.
Kelly CP, LaMont JT. Clostridium difficile — more difficult than ever. N Engl J Med. 2008;359:1932-1940.