Pfaller Michael A, Carvalhaes Cecilia G, Deshpande Lalitagauri M, Rhomberg Paul R, Castanheira Mariana
Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA.
J Fungi (Basel). 2023 May 25;9(6):608. doi: 10.3390/jof9060608.
Azole resistance in (AFM) is mainly associated with mutations in CYP51A and its promoter region or its homologue CYP51B. We evaluated the in vitro activity of isavuconazole, itraconazole, posaconazole, and voriconazole against 660 AFM collected during 2017-2020. Isolates were tested via CLSI broth microdilution. CLSI epidemiological cutoff values were applied. Non-wildtype (NWT) isolates to azoles were screened for alterations in the CYP51 sequences using whole genome sequencing. Azoles had similar activities against 660 AFM isolates. Overall, AFM displayed WT MIC values to isavuconazole (92.7%), itraconazole (92.9%), posaconazole (97.3%), and voriconazole (96.7%). Only 66 isolates (10.0%) were NWT to 1 or more of the azoles, and 32 harbored one or more alterations in the CYP51 sequences. Of these, 29/32 (90.1%) were NWT to itraconazole, 25/32 (78.1%) were NWT to isavuconazole, 17/32 (53.1%) were NWT to voriconazole, and 11/32 (34.4%) were NWT to posaconazole. The most frequent alteration was CYP51A TR34/L98H, carried by 14 isolates. Four isolates carried the alteration I242V in CYP51A, and G448S; A9T, or G138C was carried by one isolate each. Multiple alterations in CYP51A were detected in five isolates. Alterations in CYP51B were noted in seven isolates. Among 34 NWT isolates without -CYP51 alterations, WT rates to isavuconazole, itraconazole, voriconazole, and posaconazole were 32.4%, 47.1%, 85.3%, and 82.4%, respectively. Ten different CYP51 alterations were detected in 32/66 NWT isolates. Alterations in AFM CYP51 sequences can have variable effects on the in vitro activity of the azoles that are best delineated by testing all triazoles.
烟曲霉（AFM）对唑类药物的耐药性主要与CYP51A及其启动子区域或其同源物CYP51B的突变有关。我们评估了艾沙康唑、伊曲康唑、泊沙康唑和伏立康唑对2017年至2020年期间收集的660株AFM的体外活性。分离株通过CLSI肉汤微量稀释法进行检测。应用CLSI流行病学截断值。使用全基因组测序对唑类药物的非野生型（NWT）分离株进行CYP51序列改变的筛查。唑类药物对660株AFM分离株具有相似的活性。总体而言，AFM对艾沙康唑（92.7%）、伊曲康唑（92.9%）、泊沙康唑（97.3%）和伏立康唑（96.7%）的最低抑菌浓度（MIC）值显示为野生型。只有66株分离株（10.0%）对1种或更多种唑类药物为NWT，32株在CYP51序列中有1种或更多种改变。其中，32株中有29株（90.1%）对伊曲康唑为NWT，25株（78.1%）对艾沙康唑为NWT，17株（53.1%）对伏立康唑为NWT，11株（34.4%）对泊沙康唑为NWT。最常见的改变是CYP51A的TR34/L98H，有14株分离株携带该改变。4株分离株在CYP51A中携带I242V改变，G448S、A9T或G138C改变各有1株分离株携带。在5株分离株中检测到CYP51A的多种改变。在7株分离株中发现了CYP51B的改变。在34株无CYP51改变的NWT分离株中，对艾沙康唑、伊曲康唑、伏立康唑和泊沙康唑的野生型率分别为32.4%、47.1%、85.3%和82.4%。在66株NWT分离株中的32株中检测到10种不同的CYP51改变。AFM CYP51序列的改变对唑类药物的体外活性可能有不同影响，通过对所有三唑类药物进行检测可以最好地描述这些影响。
