title: Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles.
abstract: BACKGROUND
  Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus.
  
  
  METHODS
  Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles.
  
  
  RESULTS
  Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration ≥16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites.
  
  
  CONCLUSIONS
  We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jan W M
authors.initials: JW
authors.lastname: van der Linden
authors.forename: Simone M T
authors.initials: SM
authors.lastname: Camps
authors.forename: Greetje A
authors.initials: GA
authors.lastname: Kampinga
authors.forename: Jan P A
authors.initials: JP
authors.lastname: Arends
authors.forename: Yvette J
authors.initials: YJ
authors.lastname: Debets-Ossenkopp
authors.forename: Pieter J A
authors.initials: PJ
authors.lastname: Haas
authors.forename: Bart J A
authors.initials: BJ
authors.lastname: Rijnders
authors.forename: Ed J
authors.initials: EJ
authors.lastname: Kuijper
authors.forename: Frank H
authors.initials: FH
authors.lastname: van Tiel
authors.forename: János
authors.initials: J
authors.lastname: Varga
authors.forename: Anna
authors.initials: A
authors.lastname: Karawajczyk
authors.forename: J
authors.initials: J
authors.lastname: Zoll
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000368:Aged; D000391:Air Microbiology; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D001228:Aspergillosis / Q000175:diagnosis* / Q000188:drug therapy / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D002648:Child; D025141:Drug Resistance, Fungal; D005260:Female; D005800:Genes, Fungal; D005838:Genotype; D006761:Hospitals; D006801:Humans; D008297:Male; D008875:Middle Aged; D058889:Molecular Typing; D016533:Mycological Typing Techniques; D009426:Netherlands; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012111:Residence Characteristics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D011795:Surveys and Questionnaires; D017211:Treatment Failure; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole
keywords: Aspergillus fumigatus; azole resistance; invasive aspergillosis; prevalence; voriconazole