title: Azole resistance in allergic bronchopulmonary aspergillosis and Aspergillus bronchitis.
abstract: Oral azole antifungal therapy is used extensively for all forms of aspergillosis, including allergic bronchopulmonary aspergillosis (ABPA). However, long-term therapy may increase the risk of resistance. Here we report itraconazole and voriconazole resistance with reduced susceptibility to posaconazole in Aspergillus fumigatus in two patients exposed to itraconazole. Patients were diagnosed with ABPA and Aspergillus bronchitis related to innate immune defects. An azole susceptible strain was initially isolated from patient 1, but later a genetically different azole-resistant strain was cultured, possibly related to sub-therapeutic itraconazole levels, which could be a trigger for selection of resistance. The mechanism of resistance identified in this case was an L98H change in Cyp51A, accompanied by a tandem repeat in the promoter region of cyp51A leading to increased expression. No cyp51A mutation was found in azole-resistant isolates recovered from patient 2. Both patients responded to posaconazole, with plasma levels of >1.0 mg/L. Subsequently, susceptible strains of different molecular types were cultured from both patients, suggesting eradication and replacement.
authors: The University of Manchester, The Manchester Academic Health Science Centre, Manchester, UK. susan.j.howard@manchester.ac.uk
authors: S J
authors: SJ
authors: Howard
authors: A C
authors: AC
authors: Pasqualotto
authors: D W
authors: DW
authors: Denning
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000302:isolation & purification; D001393:Azoles / Q000494:pharmacology* / Q000627:therapeutic use; D001991:Bronchitis / Q000188:drug therapy / Q000382:microbiology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D025141:Drug Resistance, Fungal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008875:Middle Aged; D020125:Mutation, Missense; D010949:Plasma / Q000737:chemistry; D011743:Pyrimidines / Q000494:pharmacology; 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; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole