title: cyp51A-Based mechanisms of Aspergillus fumigatus azole drug resistance present in clinical samples from Germany.
abstract: Since the mid-1990s, a steady increase in the occurrence of itraconazole-resistant Aspergillus fumigatus isolates has been observed in clinical contexts, leading to therapeutic failure in the treatment of aspergillosis. This increase has been predominantly linked to a single allele of the cyp51A gene, termed TR/L98H, which is thought to have arisen through the use of agricultural azoles. Here, we investigated the current epidemiology of triazole-resistant A. fumigatus and underlying cyp51A mutations in clinical samples in Germany. From a total of 527 samples, 17 (3.2%) showed elevated MIC0 values (the lowest concentrations with no visible growth) for at least one of the three substances (itraconazole, voriconazole, and posaconazole) tested. The highest prevalence of resistant isolates was observed in cystic fibrosis patients (5.2%). Among resistant isolates, the TR/L98H mutation in cyp51A was the most prevalent, but isolates with the G54W and M220I substitutions and the novel F219C substitution were also found. The isolate with the G54W substitution was highly resistant to both itraconazole and posaconazole, while all others showed high-level resistance only to itraconazole. For the remaining six isolates, no mutations in cyp51A were found, indicating the presence of other mechanisms. With the exception of the strains carrying the F219C and M220I substitutions, many itraconazole-resistant strains also showed cross-resistance to voriconazole and posaconazole with moderately increased MIC0 values. In conclusion, the prevalence of azole-resistant A. fumigatus in our clinical test set is lower than that previously reported for other countries. Although the TR/L98H mutation frequently occurs among triazole-resistant strains in Germany, it is not the only resistance mechanism present.
authors.affiliation: Institute for Medical Microbiology and German National Reference Centre for Systemic Mycoses, University Medical Center Göttingen, Göttingen, Germany. obader@gwdg.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Bader
authors.forename: Michael
authors.initials: M
authors.lastname: Weig
authors.forename: Utz
authors.initials: U
authors.lastname: Reichard
authors.forename: Raimond
authors.initials: R
authors.lastname: Lugert
authors.forename: Martin
authors.initials: M
authors.lastname: Kuhns
authors.forename: Martin
authors.initials: M
authors.lastname: Christner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Held
authors.forename: Silke
authors.initials: S
authors.lastname: Peter
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schumacher
authors.forename: Dieter
authors.initials: D
authors.lastname: Buchheidt
authors.forename: Kathrin
authors.initials: K
authors.lastname: Tintelnot
authors.forename: Uwe
authors.initials: U
authors.lastname: Groß
mesh_terms: D000483:Alleles; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000453:epidemiology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005858:Germany / Q000453:epidemiology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015995:Prevalence; D011743:Pyrimidines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; 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