Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection

Abstract

Fidaxomicin causes less disruption of anaerobic microbiota during treatment of Clostridium difficile infection (CDI) than vancomycin and has activity against many vancomycin-resistant enterococci (VRE). In conjunction with a multicenter randomized trial of fidaxomicin versus vancomycin for CDI treatment, we tested the hypothesis that fidaxomicin promotes VRE and Candida species colonization less than vancomycin. Stool was cultured for VRE and Candida species before and after therapy. For patients with negative pretreatment cultures, the incidence of VRE and Candida species acquisition was compared. For those with preexisting VRE, the change in concentration during treatment was compared. The susceptibility of VRE isolates to fidaxomicin was assessed. Of 301 patients, 247 (82%) had negative VRE cultures and 252 (84%) had negative Candida species cultures before treatment. In comparison with vancomycin-treated patients, fidaxomicin-treated patients had reduced acquisition of VRE (7% vs 31%, respectively; P < .001) and Candida species (19% vs 29%, respectively; P = .03). For patients with preexisting VRE, the mean concentration decreased significantly in the fidaxomicin group (5.9 vs 3.8 log(10) VRE/g stool; P = .01) but not the vancomycin group (5.3 vs 4.2 log(10) VRE/g stool; P = .20). Most VRE isolates recovered after fidaxomicin treatment had elevated fidaxomicin minimum inhibitory concentrations (MICs; MIC(90), 256 µg/mL), and subpopulations of VRE with elevated fidaxomicin MICs were common before therapy. Fidaxomicin was less likely than vancomycin to promote acquisition of VRE and Candida species during CDI treatment. However, selection of preexisting subpopulations of VRE with elevated fidaxomicin MICs was common during fidaxomicin therapy.

Trial registration: ClinicalTrials.gov NCT00314951.

Figure 1.

Flow diagram of subjects enrolled in the randomized trial of fidaxomicin versus vancomycin for treatment of Clostridium difficile infection and of the subset evaluated for acquisition and overgrowth of vancomycin-resistant enterococci and Candida species. Abbreviations: CDI, Clostridium difficile infection; VRE, vancomycin-resistant enterococci.

Figure 2.

Percentages of patients with negative pretreatment cultures for vancomycin-resistant enterococci and Candida species who acquired VRE or Candida species in stool during treatment of Clostridium difficile infection with vancomycin or fidaxomicin. The lower limit of detection was approximately 1 log₁₀ colony-forming units per gram of stool. P values and 95% confidence intervals are included for the differences between treatment groups in the primary end point. Abbreviation: CI, confidence interval.

Figure 3.

Change in concentration of vancomycin-resistant enterococci in stool of colonized patients during treatment of Clostridium difficile infection with vancomycin (n = 27) and fidaxomicin (n = 27). The thin lines connect pre- and posttreatment values for the subset of 12 fidaxomicin- and 10 vancomycin-treated patients with posttreatment concentrations less than the limit of detection (approximately 1 log₁₀ colony-forming unit [CFU] per gram of stool). The thick horizontal lines show the mean concentration of VRE (log₁₀ CFU/g of stool) for each group. Abbreviations: CFU, colony-forming unit; VRE, vancomycin-resistant enterococci.