Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark.
Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark
Antimicrob Agents Chemother. 2020 Dec 16;65(1). doi: 10.1128/AAC.01527-20.
Olorofim is a novel antifungal drug in phase 2 trials. It has shown promising activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Here, we explored the MIC variability in more detail and prospectively investigated the susceptibility of contemporary clinical mold isolates, as population data are needed for future epidemiological cutoff (ECOFF) settings. Fifteen isolates previously found with low/medium/high MICs (≤0.002 to 0.25 mg/liter) were tested repeatedly and EUCAST MICs read in a blinded fashion by three observers. , encoding the olorofim target enzyme dihydroorotate dehydrogenase (DHODH), was sequenced. A total of 1,423 mold isolates (10 species complexes [including 1,032 isolates] and 105 other mold/dermatophyte isolates) were examined. Olorofim susceptibility (modal MIC, MIC, MIC, and wild-type upper limits [WT-ULs] [species complexes with ≥15 isolates]) was determined and compared to that of four comparators. MICs (mg/liter) were within two 2-fold dilutions (0.016 to 0.03) for 473/476 determinations. The MIC range spanned four dilutions (0.008 to 0.06). No significant mutations were found. Modal MIC/WT-UL (mg/liter) values were 0.03/0.06 ( and ), 0.06/0.125 ( and ), and 0.06/0.25 ( and ). The MIC range for spp. was 0.008 to 0.25. Olorofim susceptibility was similar for azole-resistant and -susceptible isolates of but reduced for and (MICs of >1). With experience, olorofim susceptibility testing is robust. The testing of isolates from our center showed uniform and broad-spectrum activity. Single-center WT-ULs are suggested.
奥洛福米是一种处于 2 期临床试验阶段的新型抗真菌药物。它对各种霉菌（except for Mucorales 除外）显示出有前景的活性。最初，我们观察到了广泛的 EUCAST MIC 值。在这里，我们更详细地探讨了 MIC 值的可变性，并前瞻性地研究了当代临床霉菌分离株的敏感性，因为未来需要进行流行病学临界值（ECOFF）设置。对 15 株先前发现的 MIC 值较低/中/高（≤0.002 至 0.25 毫克/升）的分离株进行了重复测试，并由三位观察者以盲法方式读取 EUCAST MIC 值。，编码奥洛福米的靶酶二氢乳清酸脱氢酶（DHODH），进行了测序。总共检查了 1423 株霉菌分离株（10 个种复合体[包括 1032 株分离株]和 105 株其他霉菌/皮肤癣菌分离株）。确定了奥洛福米的敏感性（模态 MIC、MIC、MIC 和野生型上限[WT-ULs] [种复合体中≥15 株分离株]），并与四种比较剂进行了比较。MIC 值（毫克/升）在两次 2 倍稀释度（0.016 至 0.03）之间，用于 473/476 次测定。MIC 范围跨越四个稀释度（0.008 至 0.06）。未发现显著的突变。模态 MIC/WT-UL（毫克/升）值为 0.03/0.06（和）、0.06/0.125（和）和 0.06/0.25（和）。的 MIC 范围为 0.008 至 0.25。奥洛福米对唑类耐药和敏感的分离株的敏感性相似，但对和（MIC 值>1）的敏感性降低。随着经验的积累，奥洛福米的药敏试验是可靠的。我们中心分离株的检测显示出均匀的广谱活性。建议使用单中心 WT-ULs。
