title: Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure.
abstract: Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate was detected in 1999 in Manchester, UK. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p<0.001). Of the 34 itraconazole-resistant isolates we studied, 65% (22) were cross-resistant to voriconazole and 74% (25) were cross-resistant to posaconazole. Thirteen of 14 evaluable patients in our study had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable). Eighteen amino acid alterations were found in the target enzyme, Cyp51A, 4 of which were novel. A population genetic analysis of microsatellites showed the existence of resistant mutants that evolved from originally susceptible strains, different cyp51A mutations in the same strain, and microalterations in microsatellite repeat number. Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.
authors.affiliation: Regional Mycology Laboratory, Manchester, UK.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Howard
authors.forename: Dasa
authors.initials: D
authors.lastname: Cerar
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Ahmed
authors.initials: A
authors.lastname: Albarrag
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Fisher
authors.forename: Alessandro C
authors.initials: AC
authors.lastname: Pasqualotto
authors.forename: Michel
authors.initials: M
authors.lastname: Laverdiere
authors.forename: Maiken C
authors.initials: MC
authors.lastname: Arendrup
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.forename: David W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics*; D001393:Azoles / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D025141:Drug Resistance, Fungal; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole