Fidaxomicin Comparable to Vancomycin and Provides More Durable Disease Resolution

Results of a prospective, multicenter, randomized clinical trial [N Engl J Med. 2011;364 (5):422-431] show that fidaxomicin confers similar rates of clinical cure compared with vancomycin in patients with Clostridium difficile infection, along with superior sustained or durable resolution of disease. Currently, metronidazole and vancomycin are the standard treatments for C difficile infection. However, rates of recurrence are high and carry similar rates of severe illness and death seen with the primary infection. Retreatment with metronidazole or vancomycin may resolve the relapse in many patients, but many patients will have additional relapses. Fidaxomicin is a macrocyclic antibiotic that is more active in vitro than vancomycin against clinical isolates of C difficile and is poorly absorbed from the intestinal tract with a low incidence of systemic side effects, which makes it a promising candidate to treat C difficile infection. To compare the efficacy of fidaxomicin to vancomycin to treat C difficile infection, investigators randomized 629 patients from 52 sites in the United States and 15 sites in Canada with C difficile infection to treatment with fidaxomicin (n=302) or vancomycin (n=327). Patients included in the study were at least 16 years of age with a diagnosis of C difficile infection (defined as the presence of diarrhea and C difficile toxin in stool specimen). Patients were excluded from the study if they had a life-threatening or fulminant C difficile infection, toxic megacolon, previous exposure to fidaxomicin, history of ulcerative colitis or Crohn’s disease, or >1 occurrence of C difficile infection within 3 months prior to the study. The primary end point of the study was the rate of clinical cure (defined as the resolution of diarrhea and no need for further treatment for C difficile infection as of the second day after the end of treatment). The secondary end point was recurrence of C difficile infection during the 4 weeks after the end of treatment and global cure. These end points were evaluated in 2 populations: a modified intention-to-treat population (patients who received at least 1 dose of the study medication) that included 596 patients randomized to fidaxomicin (n=287) or vancomycin (n=309) and a perprotocol population (patients in the modified intention-to-treat group who received treatment for at least 3 days for patients with treatment failure or 8 days for patients with clinical cure) that included 548 patients randomized to fidaxomicin (n=265) or vancomycin (n=283). The study found that rates of clinical cure with fidaxomicin were noninferior to vancomycin in both the modified intention-to-treat analysis (88.2% vs 85.8%, respectively) and per-protocol population (92.1% vs 89.8%). The study also found that fidaxomicin was associated with significantly fewer infection recurrences than vancomycin in both the modified intention-to-treat group (15.4% vs 25.3%; a reduction with fidaxomicin of 9.9 percentage points; 95% confidence interval [CI], −16.6 to −2.9; P=.005) and the per-protocol analysis (13.3% vs 24.9%; a reduction with fidaxomicin of 10.7 percentage points; 95% CI, −17.9 to −3.3; P=.004). When examined by type of C difficile infection, this lower rate of recurrence in the fidaxomicin-treated group was seen in patients with non−North American Pulsed Field type 1 strains of C difficile (7.8% vs 25.5%; a reduction with fidaxomicin of 17.7 percentage points; 95% CI, −27.5 to −7.9; P<.001). The recurrence rates between fidaxomicin and vancomycin were for the more hypervirulent strain of C difficile infection (NAP1/B1/027). These numbers represent a 69% relative reduction in recurrences with fidaxomicin compared with vancomycin in the subgroup of patients with non-NAP1/B1/027 strains. Patients receiving vancomycin had a 3.3 times as high (95% CI, 1.6-6.9) relative risk of recurrence with a non-NAP1/B1/027 strain than those receiving fidaxomicin. Based on these results, the study concludes that the effectiveness of fidaxomicin and vancomycin are similar in terms of clinical resolution of acute diarrheal disease due to C difficile infection, with a more sustained or durable resolution of disease achieved with fidaxomicin that may be “attributable to lesser impairment of the intestinal microbiome during treatment of the infection.”