title: Epidemiological cutoffs and cross-resistance to azole drugs in Aspergillus fumigatus.
abstract: Antifungal susceptibility testing of molds has been standardized in Europe and in the United States. Aspergillus fumigatus strains with resistance to azole drugs have recently been detected and the underlying molecular mechanisms of resistance characterized. Three hundred and ninety-three isolates, including 32 itraconazole-resistant strains, were used to define wild-type populations, epidemiological cutoffs, and cross-resistance between azole drugs. The epidemiological cutoff for itraconazole, voriconazole, and ravuconazole for the wild-type populations of A. fumigatus was < or =1 mg/liter. For posaconazole, the epidemiological cutoff was < or =0.25 mg/liter. Up till now, isolates susceptible to itraconazole have not yet displayed resistance to other azole drugs. Cross-resistance between azole drugs depends on specific mutations in cyp51A. Thus, a substitution of glycine in position 54 of Cyp51A confers cross-resistance between itraconazole and posaconazole. A substitution of methionine at position 220 or a duplication in tandem of a 34-bp fragment in the cyp51A promoter combined with a substitution of leucine at position 98 for histidine confers cross-resistance to all azole drugs tested. The results obtained in this study will help to develop clinical breakpoints for azole drugs and A. fumigatus.
authors.affiliation: Servicio de Micologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Ctra Majadahonda Pozuelo km 2, 28220 Majadahonda, Spain. jlrtudela@isciii.es
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Rodriguez-Tudela
authors.forename: Laura
authors.initials: L
authors.lastname: Alcazar-Fuoli
authors.forename: Emilia
authors.initials: E
authors.lastname: Mellado
authors.forename: Ana
authors.initials: A
authors.lastname: Alastruey-Izquierdo
authors.forename: Araceli
authors.initials: A
authors.lastname: Monzon
authors.forename: Manuel
authors.initials: M
authors.lastname: Cuenca-Estrella
mesh_terms: D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D001393:Azoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics; D005800:Genes, Fungal; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000592:standards; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D011743:Pyrimidines; D013844:Thiazoles; D014230:Triazoles; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; C104066:ER 30346; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole