Articles
Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial

https://doi.org/10.1016/S1473-3099(11)70374-7Get rights and content

Summary

Background

Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA.

Methods

In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728.

Findings

Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI −4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI −4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died.

Interpretation

Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin.

Funding

Optimer Pharmaceuticals.

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.

Section snippets

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

References (25)

  • M Arvand et al.

    Clostridium difficile ribotypes 001, 017, and 027 are associated with lethal C difficile infection in Hesse, Germany

    Euro Surveill

    (2009)
  • KM Mullane 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)
  • Cited by (0)

    View full text