In Vitro Activities of Isavuconazole and Other Antifungal Agents against Candida Bloodstream Isolates

Abstract

Isavuconazole is the active component of the new azole antifungal agent BAL8557, which is entering phase III clinical development. This study was conducted to compare the in vitro activities of isavuconazole and five other antifungal agents against 296 Candida isolates that were recovered consecutively from blood cultures between 1995 and 2004 at a tertiary care university hospital. Microdilution testing was done in accordance with CLSI (formerly NCCLS) guideline M27-A2 in RPMI-1640 MOPS (morpholinepropanesulfonic acid) broth. The antifungal agents tested were amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, and isavuconazole. C. albicans was the most common species, representing 57.1% of all isolates. There was no trend found in favor of non-Candida albicans species over time. In terms of MIC 50 s, isavuconazole was more active (0.004 mg/liter) than amphotericin B (0.5 mg/liter), itraconazole (0.008 mg/liter), voriconazole (0.03 mg/liter), flucytosine (0.125 mg/liter), and fluconazole (8 mg/liter). For isavuconazole, MIC 50 s/MIC 90 s ranged from 000.2/0.004 mg/liter for C. albicans to 0.25/0.5 mg/liter for C. glabrata. Two percent of isolates (C. glabrata and C. krusei) were resistant to fluconazole; C. albicans strains resistant to fluconazole were not detected. There were only two isolates with MICs for isavuconazole that were >0.5 mg/liter: both were C. glabrata isolates, and the MICs were 2 and 4 mg/liter, respectively. In conclusion, isavuconazole is highly active against Candida bloodstream isolates, including fluconazole-resistant strains. It was more active than itraconazole and voriconazole against C. albicans and C. glabrata and appears to be a promising agent against systemic Candida infections.Over the past two decades, the incidence of Candida bloodstream infections has increased dramatically (3, 15), primarily due to the increase in the number of at-risk patients. Mortality rates associated with systemic Candida infections remain high (1, 4). Several Candida spp., such as C. glabrata and C. krusei, exert reduced susceptibility to fluconazole, the first available triazole antifungal agent (8). Recently, a new generation of triazoles, including posaconazole, voriconazole, ravuconazole, and isavuconazole, has been developed. As a prodrug, BAL8557 is the water-soluble triazole precursor suitable for oral and intravenous administration (11). In vitro, the active moiety isavuconazole shows broad-spectrum activity against all major opportunistic fungi (e.g., Candida, Cryptococcus, Aspergillus, Absidia, Rhizopus, and Rhizomucor species) and the dimorphic fungi (13,16). In rat models, the active drug is highly effective against systemic candidiasis and disseminated Aspergillus flavus infection (14).In this study, we compared the in vitro activity of isavuconazole with those of fluconazole, itraconazole, voriconazole, amphotericin B, and flucytosine against 296 clinical isolates of Candida spp. from bloodstream infections. (Table 1). All isolates were identified to the species level b...

In Vitro Antifungal Activities of Isavuconazole (BAL4815), Voriconazole, and Fluconazole against 1,007 Isolates of Zygomycete, Candida , Aspergillus , Fusarium , and Scedosporium Species

“…(13,17). In an experimental neutropenic murine model of disseminated Aspergillus flavus infection, it showed high survival rates (19).…”

In Vitro Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds

“…This compound can be administered either orally or intravenously as a prodrug, which then is converted by plasma esterases into the active component (3)(4)(5)(6). Previous in vitro studies have demonstrated potent antifungal activity against both common and uncommon fungal pathogens, including Candida, Aspergillus, non-Candida yeasts, and non-Aspergillus molds (7)(8)(9)(10)(11)(12)(13)(14)(15). Furthermore, isavuconazole significantly reduced the organism burden in kidneys of mice infected with Candida tropicalis and the organism burden in both kidneys and brains of neutropenic mice infected with Candida krusei (16).…”

“…The in vitro MIC profile of isavuconazole against yeasts and molds has been determined in various studies using the broth microdilution (BMD) method of either the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (7)(8)(9)(10)(11)(12)(13)15); however, only one study provided a "head-to-head" comparison of these two methods for testing isavuconazole and the comparison was limited to testing isavuconazole against Aspergillus flavus (10). To date, there are no studies comparing the activity of isavuconazole against Candida as determined by both CLSI and EUCAST BMD methods.…”

Determination of Isavuconazole Susceptibility of Aspergillus and Candida Species by the EUCAST Method

“…Isavuconazole action includes in vitro activity against Aspergillus and Candida species, although the susceptibility of few clinical isolates has been studied (7)(8)(9)(10)(11)(12)(13). Epidemiological cutoff (ECOFF) values can assist in identifying isolates with raised MICs and/or a greater risk of the presence of a mechanism of resistance.…”