title: Evaluation of the in vitro activity of isavuconazole and comparator voriconazole against 2635 contemporary clinical Candida and Aspergillus isolates.
abstract: OBJECTIVE
  The in vitro activity of isavuconazole was determined for 1677 Candida and 958 Aspergillus isolates from 2012 to 2014 with voriconazole as comparator.
  
  
  METHODS
  Aspergillus isolates were screened for resistance using azole-agar. Aspergillus isolates that screened positive and all Candida isolates underwent EUCAST broth microdilution testing. Isolates were categorized as wild-type (wt) or non-wt, adopting EUCAST epidemiological cut-off values (ECOFFs) (where available) or wt upper limits (wtULs; two two-fold dilutions above the MIC50). The CYP51A gene was sequenced for non-wt Aspergillus fumigatus isolates. Itraconazole and posaconazole MICs were determined for selected Aspergillus isolates with isavuconazole MIC ≥2 mg/L.
  
  
  RESULTS
  Isavuconazole MIC50(range) (mg/L) against Candida species were: Candida albicans: ≤0.03 (≤0.03 to >4), Candida dubliniensis: ≤0.03 (≤0.03), Candida glabrata: ≤0.03 (≤0.03-4), Candida krusei: 0.06 (≤0.03-0.5), Candida parapsilosis: ≤0.03 (≤0.03-0.06), Candida tropicalis: ≤0.03 (≤0.03 to >4), Saccharomyces cerevisiae (anamorph: Candida robusta): ≤0.03 (≤0.03-0.5). Non-wt isavuconazole/voriconazole MICs were found for C. albicans: 0.8/1.0%, C. dubliniensis: 0/1.8%, C. glabrata: 14.9/9.5%, C. krusei: 2.7/1.4%, C. parapsilosis: 1.7/1.8%, C. tropicalis: 14.3/19.1% and S. cerevisiae: 10.0/0%. Isavuconazole MIC50(range) (mg/L) against Aspergillus species were: A. fumigatus: 1 (≤0.125 to >16), Aspergillus niger: 2 (1-8), Aspergillus terreus: 1 (0.25-8), Aspergillus flavus: 1 (0.5-2), Aspergillus nidulans: ≤0.125 (≤0.125-0.25). Non-wt isavuconazole/voriconazole MICs were found for 13.7/15.2% A. fumigatus, 4.9/0% A. niger and 48.2/22.2% A. terreus.
  
  
  CONCLUSIONS
  Isavuconazole displayed broad in vitro activity, similar to that of voriconazole. Up to 15% of C. glabrata, C. tropicalis and A. fumigatus isolates were non-wt, reflecting increased resistance at a reference centre and technical issues. Significant CYP51A alterations were reliably detected applying the isavuconazole breakpoint.
authors.affiliation: Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: K M T
authors.initials: KMT
authors.lastname: Astvad
authors.affiliation: Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: R K
authors.initials: RK
authors.lastname: Hare
authors.affiliation: Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark; Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: maca@ssi.dk.
authors.forename: M C
authors.initials: MC
authors.lastname: Arendrup
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000382:microbiology; D001230:Aspergillus / Q000187:drug effects* / Q000235:genetics; D002175:Candida / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000382:microbiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009570:Nitriles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole
keywords: Aspergillus; Azole-screening agar; CYP51A; Candida; ECOFFs; EUCAST; Isavuconazole; TR(34)/L98H; TR(46)/Y121F/T289A; Voriconazole