title: Azole, polyene and echinocandin MIC distributions for wild-type, TR34/L98H and TR46/Y121F/T289A Aspergillus fumigatus isolates in the Netherlands.
abstract: OBJECTIVE
  To determine the MIC distributions of itraconazole, voriconazole and posaconazole and non-azole drugs for wild-type cyp51A, as well as TR(34)/L98H and TR(46)/Y121F/T289A cyp51A mutants of Aspergillus fumigatus.
  
  
  METHODS
  We retrieved MIC and cyp51A sequence data for 952 clinical A. fumigatus strains isolated in or referred to our reference laboratory, during the January 2010 to December 2013 period. All MICs were determined using the EUCAST methodology and interpreted using the EUCAST breakpoints.
  
  
  RESULTS
  Three-hundred and sixty-four of the 952 strains (38%) were resistant to azoles. Of these, 225 contained the TR34/L98H mutation, 98 contained the TR(46)/Y121F/T289A mutation and 39 had no cyp51A mutations. Two isolates harboured other cyp51A mutations, of which one (P216L) has been shown to confer azole resistance. Of the TR(34)/L98H isolates, 99.6% (224/225) were resistant to itraconazole (MICs >2 mg/L), 92.4% (208/225) were resistant to voriconazole (MICs >2 mg/L) and 97.8% (220/225) were resistant to posaconazole (MICs >0.25 mg/L). All TR(46)/Y121F/T289A isolates were resistant to voriconazole (MICs >16 mg/L), 82.7% (81/98) were resistant to itraconazole with a bimodal MIC distribution and 94.9% (93/98) were resistant to posaconazole. The MICs of amphotericin B, anidulafungin and terbinafine were not affected by the presence of azole-resistance mechanisms.
  
  
  CONCLUSIONS
  The TR(34)/L98H and TR(46)/Y121F/T289A cyp51A genotypes of A. fumigatus show distinct resistance phenotypes. The mechanisms behind low-level itraconazole resistance in TR(46)/Y121F/T289A isolates warrant future research. The potential of increased azole dosing for disease caused by low-level resistant strains should be investigated.
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jakko
authors.initials: J
authors.lastname: van Ingen
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Henrich A
authors.initials: HA
authors.lastname: van der Lee
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ton A J
authors.initials: TA
authors.lastname: Rijs
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Zoll
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Leenstra
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands paul.verweij@radboudumc.nl.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D001393:Azoles / Q000494:pharmacology*; D025141:Drug Resistance, Fungal; D054714:Echinocandins / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D009426:Netherlands; D011090:Polyenes / Q000494:pharmacology*; D058886:Sterol 14-Demethylase / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D054714:Echinocandins; D011090:Polyenes; D058886:Sterol 14-Demethylase
keywords: A. fumigatus; MICs; itraconazole; posaconazole; voriconazole