ArticlesFidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial
Introduction
Clostridium difficile infection generally occurs after exposure to broad-spectrum antibiotics, but any antibiotic that disrupts the normal flora of the gut can increase susceptibility.1, 2 The illness can be mild and self-limiting, but might progress to severe disease, with ileus, toxic megacolon, and sometimes death.3 Incidence, severity, and acquisition in people formerly classed as low risk seem to be increasing.4, 5
A hypervirulent, fluoroquinolone-resistant C difficile strain, NAP1/BI/027, is associated with severe symptoms, high recurrence rates, and substantial mortality.6 Although ribotype 027 is decreasing in incidence in Europe,4 it is a threat in Canada and the USA, and other strains are responsible for outbreaks in Europe. Ribotype 078 causes infection with severity similar to that of 027, but is more often community-acquired, infects more young individuals, and also causes disease in animals.4, 7 Ribotype 017, which emerged as an outbreak in Canada in 2000, has been identified in Europe and is associated with high mortality.8
Fidaxomicin is roughly eight-times more potent in vitro than is vancomycin against clinical isolates of C difficile, including NAP1/BI/027.9 Fidaxomicin has minimum systemic absorption, high faecal concentrations, long post-antibiotic effect, and restricted activity against normal gut flora, providing active and selective therapy for infection with C difficile.10, 11 Fidaxomicin was recently approved for treatment of this infection in the USA in May, 2011, and in Europe in December, 2011.
In a phase 3 trial12 in Canada and the USA, fidaxomicin was non-inferior to vancomycin for clinical cure, and superior for recurrence and sustained response 4 weeks after completion of treatment. The aim of our trial, identical in design and procedures, was to compare the efficacy of fidaxomicin and vancomycin in Europe, as well as in Canada and the USA.
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Patients
In this prospective, multicentre, double-blind, randomised, non-inferiority trial, patients were recruited from 45 sites in Europe and 41 sites in Canada and the USA between April 19, 2007, and Dec 11, 2009. Eligible patients had C difficile infection, defined by more than three unformed bowel movements (UBM) in the 24 h before randomisation and either toxin A or B of C difficile in stools within 48 h of randomisation, and were aged 16 years or older. Patients could have received as many as
Results
535 patients were enrolled and randomly allocated to receive treatment with fidaxomicin (n=270) or vancomycin (n=265; figure 1). The database was locked on Jan 27, 2010. The patients from European centres were slightly older than were those from Canada and the USA, but fewer were women (table 1). A greater proportion of patients were inpatients at the time of enrolment in Europe than in Canada and the USA (table 1). Fewer patients in Europe than in Canada and the USA had a previous episode of C
Discussion
Fidaxomicin was non-inferior to vancomycin for clinical cure rate. These findings match those from a study done in just Canada and the USA,12 in which cure rates in a modified intention-to-treat population were 88·2% with fidaxomicin versus 85·8% with vancomycin (panel). Treatment with fidaxomicin was associated with a lower rate of recurrence in the 4 weeks after completion of treatment than was vancomycin. This difference was larger than that in the previous study,12 in which 15·4% of
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