Isavuconazole Susceptibility in Triazole Resistant Aspergillus fumigatus

Ref ID: 19279


L. Gregson, J. Goodwin, A. Johnson, L. McEntee, C. B. Moore, M. Richardson, W. W. Hope, S. J. Howard

Author address:

Univ. of Liverpool, Liverpool, UNITED KINGDOM; Univ. Hosp. of South Manchester, Manchester, UNITED KINGDOM.

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014


ackground: Triazoles are first-line agents for treatment of aspergillosis. The prevalence of triazole resistance in Aspergillus fumigatus is increasing. The extent of cross-resistance between triazole agents is poorly defined. Isavuconazole is a triazole currently being studied in phase III clinical trials. The in vitro susceptibility of isavuconazole against non-wild-type strains of A. fumigatus is not well characterized. Methods: Forty clinical A. fumigatus isolates, the majority of which had elevated MICs to at least one triazole, and had a putative molecular mechanism of resistance defined, were tested for susceptibility using CLSI methodology. The following compounds were tested: amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole. Results: Thirty-one strains had triazole MICs above the wild-type range. All had high (>8 mg/L) itraconazole MICs, of which 77% (24/31) and 68% (21/31) had raised posaconazole and voriconazole MICs respectively. Isolates with raised triazole MICs had higher isavuconazole MICs. Specifically, isavuconazole MICs mirrored changes in voriconazole susceptibility (Spearman’s correlation coefficient 0.885, P<0.001). Isolates with cyp51A alterations at codons 98, 138, 431, 434 and 448 revealed a pan-azole resistant phenotype, including raised isavuconazole MICs. Isavuconazole MICs tended to be lower in isolates with substitutions at position 54. In contrast, isavuconazole MICs were more variable, and were more likely to be raised, in isolates with M220 alterations. Conclusions: Isavuconazole MICs were more likely to be raised in strains with reduced susceptibility to other triazoles, and tended to mirror changes in voriconazole susceptibility. The extent to which this reduced in vitro susceptibility has an impact on clinical care remains to be established.

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Conference Year: 2013

Link to conference website: NULL

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