Cross-Resistance between Fluconazole and Ravuconazole and the Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Ravuconazole among 12,796 Clinical Isolates of Candida spp

Abstract

Cross-resistance within a class of antimicrobial agents is a problem that is often encountered with antibacterial agents, and it is also an issue with antifungal agents. A current example is ravuconazole, a new triazole antifungal with an expanded spectrum and potency against Candida spp., Aspergillus spp., and other opportunistic fungal pathogens. The present study addresses the issue of cross-resistance between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict the susceptibility of Candida spp. to ravuconazole. Reference broth microdilution MIC results for 12,796 strains of Candida spp. isolated from more than 200 medical centers worldwide were used. Ravuconazole MICs and tentative interpretive categories (susceptible, ≤1 μg/ml; resistant, ≥2 μg/ml) were compared with those of fluconazole by using regression statistics and error rate bounding analyses. For all 12,796 isolates, the absolute categorical agreement rate was 92.5% (rate of false-susceptible results, or very major errors [VME], 0.1%). Ravuconazole was active (MIC, ≤1 μg/ml) against 99.9% of the fluconazole-susceptible isolates, 96% of the fluconazole-susceptible dose-dependent isolates, and 49% of the fluconazole-resistant isolates, including 99% of the Candida krusei isolates. Since ravuconazole is 16- to 32-fold more potent than fluconazole, the performance of fluconazole as a surrogate marker for ravuconazole susceptibility was improved by designating those isolates with fluconazole MICs of ≤32 μg/ml susceptible to ravuconazole, resulting in a categorical agreement rate of 98.3%, with a VME rate of 0.3% (99 and 0.4%, respectively, when C. krusei was omitted). Cross-resistance between fluconazole and ravuconazole applies most directly to fluconazole-resistant Candida glabrata and is variable among other species of Candida. Fluconazole may serve as a surrogate marker to predict the susceptibility of Candida spp. to ravuconazole.