Fidaxomicin is a narrow-spectrum macrocyclic antibacterial. It inhibits bacterial RNA synthesis, interfering with RNA polymerase at a different site to the rifampicin class of antibiotics.1
Inhibition of the clostridial RNA polymerase occurs at a concentration 20-fold lower than that of the E. coli enzyme; this partially explains the specificity of fidaxomicin activity. In addition, fidaxomicin is not significantly systemically absorbed and is considered to be a topically acting drug. It is associated with minimal disruption of normal gut flora.1
Two double-blind phase III studies of identical design were conducted to demonstrate the non-inferiority of fidaxomicin to vancomycin in the treatment of C. difficile infection.2,3
Patients 16 years of age and older with acute symptoms of C. difficile infection and a positive stool toxin test were randomised to receive 10 days’ treatment with either oral fidaxomicin (200mg twice daily) or oral vancomycin (125mg four times daily). Patients were assessed daily during the treatment period and then at least weekly until day 28.2,3
Clinical cure, defined as resolution of diarrhoea and no further need for treatment, was the primary endpoint. Participants were also assessed for recurrence of C. difficile infection, using the same criteria as for recruitment, and for global cure (ie, cure with no recurrence) as secondary endpoints.2,3
Results from first study
The first study enrolled 629 patients, of whom 596 qualified for the modified intention-to-treat analysis and 548 were included in the per-protocol analysis. Rates of clinical cure for fidaxomicin were non-inferior to vancomycin in both analyses: 88.2% with fidaxomicin (253 of 287 patients) and 85.8% with vancomycin (265 of 309 patients) in the modified intention-to-treat analysis; and 92.1% (244 of 265) and 89.8% (254 of 283), respectively, in the per-protocol analysis.2
Significantly fewer patients experienced recurrence of infection in the fidaxomicin group than in the vancomycin group: 15.4% vs 25.3% in the modified intention-to-treat analysis (p=0.005), and 13.3% vs 24% in the per-protocol analysis (p=0.004). Rates of global cure were correspondingly higher with fidaxomicin than vancomycin (p=0.006 in both analyses).2
Results from second study
In the second study, rates of clinical cure were similar for both drugs and were within the predetermined non-inferiority margin. In the modified intention-to-treat analysis, 87.7% of patients who received fidaxomicin (221 of 252) achieved clinical cure, compared with 86.8% of patients (223 of 257) who received vancomycin. Clinical cure rates in the per-protocol analysis were 91.7% (198 of 216 patients) in the fidaxomicin group and 90.6% (213 of 235 patients) in the vancomycin group.3
Consistent with the first study, fidaxomicin-treated patients had lower recurrence rates and higher global cure rates than vancomycin-treated patients (p=0.0002 and p=0.001, respectively, in the modified intention-to-treat analysis).3
There were no significant differences in the incidence of treatment-emergent adverse events between fidaxomicin and vancomycin in either study. Adverse events likely to be related to study drug were mostly gastrointestinal, including nausea, vomiting, diarrhoea and abdominal pain.2,3
- Dificlir Summary of Product Characteristics, December 2011.
- Louie TJ et al. N Engl J Med 2011; 364: 422–3
- Cornely OA et al. Lancet Infect Dis 2012; 12: 281–9.