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Comparison between Isavuconazole and other azoles against characterised clinical isolates and yeast model systems

Abstract number: P2176

Sanglard D., Ischer F., Coste A., Ferrari S.

Objectives: Isavuconazole (ISA) is a novel azole with a broad activity range and is evaluated in clinical trials. In order to compare ISA against other azoles utilised in the therapy of fungal diseases (Fluco-, FLC; Vori-, VRC, Itra-, ITR; Posaconazole, POS), Saccharomyces cerevisiae (Sc) was used as a host for the expression of Candida albicans (Ca) genes involved in azole resistance (ABC transporters CDR1, CDR2 and Major Facilitator (MF) MDR1; ERG11 alleles with mutations) and 16 pairs of Ca matched clinical isolates with known azole resistance mechanisms were investigated. Testing of azole susceptibility among these different yeast isolates allows quantitative comparisons between the above-mentioned azoles.

Methods: Sc isolates expressing CDR1, CDR2, MDR1 and ERG11 alleles were described elsewhere (AAC 39: 1995). Sequential Ca clinical isolates with increasing MICs to several azoles were obtained from the University Hospital Centre and their azole resistance mechanisms described elsewhere (EC 3: 1994; EC 6:2007). The collection of clinical Ca isolates (38) is representative for most of the existing azole resistance mechanisms and their combinations. Susceptibility testing was performed according to CLSI standards using RPMI for clinical isolates and YNB for Sc.

Results: When transporters were expressed in Sc, results showed that FLC, VRC, ITR, POS and ISA were substrates of CDR1 and CDR2, since their expression resulted in relative MIC increase to all azoles tested as compared to control. On the opposite, the expression of MDR1 did not increase POS, ITR and ISA MIC, suggesting that these azoles were poor substrates for MDR1. When mutated ERG11 alleles were expressed, relative increases of azole MIC (from 4- to 32-fold) were observed for FLC, VOR and ISA when at least 2 mutations were present in the same ERG11 allele, whereas no MIC increase were measured when ITR and POS were tested. These results suggest that ERG11 mutations have limited effect on ITR and POS activity. Upon MIC testing of clinical Ca isolates with azoles, the MIC90 for FLC, VRC, ITR, POS and ISA were 128, 2, 1, 0.5 and 2 mg/ml, respectively, and showed that ISA had comparable activities than ITR, POS and VOR.

Conclusions: Resistance mechanisms of clinical isolates have differentiated impact on azole MIC depending on the azole structure. The main resistance mechanisms in yeasts involving ABC transporters and ERG11 decrease the activity of ISA, while MDR1 has limited effect.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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