Isavuconazole is a novel, broad-spectrum, antifungal azole. In order to evaluate its interactions with known azole resistance mechanisms, isavuconazole susceptibility among different yeast models and clinical isolates expressing characterized azole resistance mechanisms was tested and compared to those of fluconazole, itraconazole, posaconazole, and voriconazole. Saccharomyces cerevisiae expressing the Candida albicans and C. glabrata ATP binding cassette (ABC) transporters (CDR1, CDR2, and CgCDR1), major facilitator (MDR1), and lanosterol 14-␣-sterol-demethylase (ERG11) alleles with mutations were used. In addition, pairs of C. albicans and C. glabrata strains from matched clinical isolates with known azole resistance mechanisms were investigated. The expression of ABC transporters increased all azole MICs, suggesting that all azoles tested were substrates of ABC transporters. The expression of MDR1 did not increase posaconazole, itraconazole, and isavuconazole MICs. Relative increases of azole MICs (from 4-to 32-fold) were observed for fluconazole, voriconazole, and isavuconazole when at least two mutations were present in the same ERG11 allele. Upon MIC testing of azoles with clinical C. albicans and C. glabrata isolates with known resistance mechanisms, the MIC 90 s of C. albicans for fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole were 128, 2, 1, 0.5, and 2 g/ml, respectively, while in C. glabrata they were 128, 2, 4, 4, and 16 g/ml, respectively. In conclusion, the effects of azole resistance mechanisms on isavuconazole did not differ significantly from those of other azoles. Resistance mechanisms in yeasts involving ABC transporters and ERG11 decreased the activity of isavuconazole, while MDR1 had limited effect.
Invasive fungal infections (IFIs) caused by yeasts are an important cause of morbidity and mortality. Candida spp. are opportunistic fungal pathogens and a particular cause for concern in immunocompromised individuals (1). Candida infections may account for more than 70% of all IFIs (2). Candidemia is a significant problem in the intensive care unit, as it is associated with a crude mortality rate of 42.6% and high resource use (3).Azoles constitute a class of drug commonly used for treating infections caused by Candida spp., and the Infectious Diseases Society of America recommends them as a primary treatment for candidemia in nonneutropenic patients (1). They are fungistatic in most cases and work by binding and inhibiting the enzyme lanosterol 14-␣-sterol-demethylase (encoded by ERG11), which is involved in converting lanosterol into ergosterol (4, 5). As ergosterol is an essential component of the fungal cell membrane, disruption of its biosynthesis inhibits fungal growth.Repeated exposure to azoles and drug pressure in Candida spp. can lead to the emergence of azole-resistant strains, thereby increasing the risk of treatment failure and breakthrough infections (6, 7). Fluconazole resistance is common in many isolates of Candida spp., but they can remain susceptible t...