Whole-genome sequencing demonstrates that fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with Clostridium difficile.

David W Eyre,Carlos Del Ojo Elias,David Griffiths,Derrick W Crook,Tim E A Peto,Sherwood L Gorbach,Farah Babakhani,Jaime Seddon,A Sarah Walker

doi:10.1093/infdis/jit598

Abstract

Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3–10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25–.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11–1.01]; P = .05).

Highlights

Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes
In the ITT analysis, 68 of 494 (14%) randomly assigned to receive fidaxomicin, compared with 131 of 496 (26%) randomly assigned to receive vancomycin, experienced CDI recurrence
Isolates were obtained at the times of randomization and recurrence from 93 of 199 participants (47%) and stored; these isolates were from 28 of 68 fidaxomicin recipients (41%) with CDI recurrence compared with 65 of 131 vancomycin recipients (50%) with CDI recurrence (P = .29)

Summary

Introduction

Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Compared with the previous standard-of-care, vancomycin, Several methods can be used to distinguish same-strain relapse from new-strain reinfection. Traditional genotyping methods such as ribotyping or multilocus sequencing typing may not detect diversity present at a whole-genome level [6] and may underestimate reinfection rates, where strains are common (eg, NAP1/ribotype-027/ST1) or diverse (eg, ribotype-015). Our objective was to use data from the original phase 3 trials and whole-genome sequencing to estimate the impact of fidaxomicin versus vancomycin on C. difficile samestrain relapse versus new-strain reinfection

Objectives

Methods

Results

Conclusion