Pharmacology Update

Fidaxomicin Tablets (Dificid™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A new orally administered macrocylic antibiotic has been approved by the FDA for the treatment of Clostridium difficile infection. Fidaxomicin is a fermentation product of Dactylosporangium aurantiacum and is marketed by Optimer Pharmaceuticals, Inc., as Dificid.

Indications

Fidaxomicin is indicated for the treatment of C. difficile-associated diarrhea (CDAD) in adults (18 years of age and older).1

Dosage

The recommended dose is 200 mg taken orally twice daily for 10 days.1 The tablets may be taken with or without food.

Fidaxomicin is available as 200 mg tablets.

Potential Advantages

Fidaxomicin showed similar efficacy in treating C. difficile infection compared to vancomycin but with a significantly lower rate of recurrence.2 Fidaxomicin also is more likely to preserve normal fecal flora than vancomyin.3,4 It has minimal systemic absorption.

Potential Disadvantages

Fidaxomicin has greater systemic exposure (2-4 fold) in elderly patients (65 years and older).1 Fidaxomicin does not provide any advantage in recurrence with the hypervirulent BI/NAP1/027 strains of C. difficle.2 A single course of fidaxomicin is expected to cost approximately $2800.

Comments

Fidaxomicin is a minimally absorbed, macrocyclic antibacterial agent with demonstrated in vitro bactericidal and post-antibiotic activity against C. difficle. It generally lacks activity against gram-negative anaerobes and facultative aerobes and is less likely to affect the composition of the intestinal flora.3,5 The approval of fidaxomicin was based on two randomized, double-blinded, non-inferiority studies compared to vancomycin.1,2 Adult subjects with CDAD were randomized to fidaxomicin (200 mg twice daily for 10 days) or vancomycin (125 mg four times a day for 10 days). CDAD was defined by > 3 unformed bowel movements or > 200 mL of unformed stool in the 24 hours before randomization and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled subjects were required to have had only one prior CDAD episode in the past 3 months. Those with life-threatening disease or other complicated signs (e.g., significant dehydration, megacolon) were excluded. The primary efficacy endpoint was clinical response rate at the end of therapy (i.e., resolution of symptoms and no need for further therapy for C. difficile). Secondary endpoints included sustained response/recurrence of CDAD within 25 days/4 weeks post-therapy. Trial 1 included 596 subjects and Trial 2 had 509. Clinical responses were identical, 88% for fidaxomicin and 86% and 87% for vancomycin, respectively. However, sustained response was significantly better for fidaxomicin, 70% and 72% compared to 57% for vancomycin due to lower rates of proven or suspected CDAD during the follow-up period. The median time to resolution of diarrhea was shorter with fidaxomicin, 58 hours compared to 78 hours. The advantage of fidaxomicin over vancomycin in recurrence was mainly with non-B1/NAP1/027 strains.2 There were no major differences in adverse events with gastrointestinal symptoms being most frequently reported including nausea, vomiting, and abdominal pain.

Clinical Implications

CDAD is a serious condition that is the most common antibiotic-associated diarrhea. It is becoming more common and more difficult to treat with a high recurrence rate. Oral vancomycin currently is the only FDA-approved therapy. Fidaxomicin provides an important alternative to vancomycin for the treatment of CDAD, particularly with non BI/NAP1/07 strains.

References

1. Dificid Prescribing Information. San Diego, CA: Opti-mer Pharmaceuticals, Inc.; May 2011.

2. Louie TJ, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364:422-431.

3. Tannock GW, et al. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology 2010;156:3354-3359.

4. Miller M. Fidaxomicin (OPT-80) for the treatment of Clostridium difficile infection. Expert Opin Pharmacother 2010;11:1569-1578.

5. Finegold SM, et al. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrob Agents Chemother 2004;48:4898-4902.