Verhasselt Hedda Luise, Thissen Lara, Scharmann Ulrike, Dittmer Silke, Rath Peter-Michael, Steinmann Joerg, Kirchhoff Lisa
Institute of Medical Microbiology, Excellence Center for Medical Mycology (ECMM), University Hospital Essen, University of Duisburg-Essen, Virchowstraße 179, 45147, Essen, Germany.
Institute of Clinical Microbiology, Infectious Diseases and Infection Control, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany.
Mycopathologia. 2025 Apr 5;190(2):34. doi: 10.1007/s11046-025-00941-x.
Numbers of infections with azole-resistant Aspergillus fumigatus (ARAf) were rising in the last decades. We assessed ARAf susceptibility trends towards five antifungal agents (amphotericin B (AMB), itraconazole (ITR), voriconazole (VCZ), olorofim (OLO) and manogepix (MGX)) over twelve years in a German Excellence Center for Medical Mycology (ECMM). In addition, underlying mutations were studied and correlated with trends in minimum inhibitory concentration (MIC). Broth microdilution (BMD) was performed following EUCAST guidelines for 143 clinical ARAf isolates collected between the years 2011 and 2022 in a West German tertiary care centre. BMD was carried out for all antifungal agents in the following concentration ranges: 0.016-8 mg/L for AMB, ITR and VCZ as well as 0.001-0.5 mg/L for OLO and 0.004-2 mg/L for MGX. Molecular assays on mutations associated with antifungal resistance were performed for all 143 isolates (AsperGenius® 1.0, Pathonostics, Maastricht, The Netherlands) and for a total of ten non TR/L98H and TR/Y121F/T289A mutated ARAf isolates additional cyp51A sequencing was carried out. For all isolates, microdilution revealed a MIC of > 8 mg/L for ITR, 4 mg/L for VCZ, 0.03 mg/L for OLO, 0.016 mg/L for MGX, and 0.5 mg/L for AMB. Considering EUCAST breakpoints, 97.9% of the strains (n = 140) were resistant to VCZ, 1.4% (n = 2) towards AMB and 92.3% towards ITR (n = 132). Molecular assays revealed 123 (86%) isolates with the azole resistance underlying mutation TR/L98H, 10 (7%) with a TR/Y121F/T289A mutation and 10 (7%) with other cyp51A mutations. A comparison of triazole MICs of isolates collected from 2011 to 2019 with the MICs of isolates collected between 2020 and 2022 revealed no significant differences for itraconazole (p = 0.543) and for voriconazole (p = 0.148),with a trend of increased geometric mean for ITR and VCZ MICs over time. MICs for OLO and MGX did not significantly differ between isolates with the distinct azole-resistance underlying mutations. Before 2016, the azole resistance underlying mutations were mainly TR/L98H, but the portion of isolates with TR/Y121F/T289A and other Cyp51A mutated isolates increased afterwards. We showed almost stable MICs for ITR and VCZ over twelve years in ARAf isolates from West Germany while occurring azole resistance underlying mutations varied with an increase in the proportion of TR/Y121F/T289A and other Cyp51A mutations after 2016.
在过去几十年中，耐唑类烟曲霉（ARAf）的感染数量不断上升。我们在德国一家医学真菌学卓越中心（ECMM）评估了12年间ARAf对五种抗真菌药物（两性霉素B（AMB）、伊曲康唑（ITR）、伏立康唑（VCZ）、奥洛菲姆（OLO）和马尼地平（MGX））的药敏趋势。此外，还研究了潜在突变，并将其与最低抑菌浓度（MIC）趋势相关联。按照欧洲抗菌药物敏感性试验委员会（EUCAST）指南，对2011年至2022年间在德国西部一家三级护理中心收集的143株临床ARAf分离株进行了肉汤微量稀释（BMD）试验。对所有抗真菌药物进行BMD试验的浓度范围如下：AMB、ITR和VCZ为0.016 - 8mg/L，OLO为0.001 - 0.5mg/L，MGX为0.004 - 2mg/L。对所有143株分离株进行了与抗真菌耐药相关突变的分子检测（AsperGenius® 1.0，Pathonostics，荷兰马斯特里赫特），对总共10株非TR/L98H和TR/Y121F/T289A突变的ARAf分离株额外进行了cyp51A测序。对于所有分离株，微量稀释法显示ITR的MIC>8mg/L，VCZ为4mg/L，OLO为0.03mg/L，MGX为0.016mg/L，AMB为0.5mg/L。根据EUCAST断点，9
