Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan.
Mycoses. 2022 Dec;65(12):1170-1178. doi: 10.1111/myc.13509. Epub 2022 Aug 25.
Eumycetoma is a neglected tropical disease. It is a chronic inflammatory subcutaneous infection characterised by painless swellings which produce grains. It is currently treated with a combination of itraconazole and surgery. In an ongoing clinical study, the efficacy of fosravuconazole, the prodrug of ravuconazole, is being investigated. For both itraconazole and ravuconazole, no clinical breakpoints or epidemiological cut-off values (ECV) to guide treatment are currently available.
To determine tentative ECVs for itraconazole and ravuconazole in Madurella mycetomatis, the main causative agent of eumycetoma.
Minimal inhibitory concentrations (MICs) for itraconazole and ravuconazole were determined in 131 genetically diverse clinical M. mycetomatis isolates with the modified CLSI M38 broth microdilution method. The MIC distributions were established and used to determine ECVs with the ECOFFinder software. CYP51A sequences were sequenced to determine whether mutations occurred in this azole target gene, and comparisons were made between the different CYP51A variants and the MIC distributions.
The MICs ranged from 0.008 to 1 mg/L for itraconazole and from 0.002 to 0.125 mg/L for ravuconazole. The M. mycetomatis ECV for itraconazole was 1 mg/L and for ravuconazole 0.064 mg/L. In the wild-type population, two CYP51A variants were found for M. mycetomatis, which differed in one amino acid at position 499 (S499G). The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found.
The proposed M. mycetomatis ECV for itraconazole is 1 mg/L and for ravuconazole 0.064 mg/L.
足菌肿是一种被忽视的热带病。它是一种慢性炎症性皮下感染，其特征为无痛性肿胀并产生颗粒。目前，该病采用伊曲康唑联合手术进行治疗。在一项正在进行的临床研究中，正在研究拉夫康唑前体药物福沙伏康唑的疗效。对于伊曲康唑和拉夫康唑，目前都没有指导治疗的临床折点或流行病学 cutoff 值（ECV）。
确定导致足菌肿的主要病原体——外瓶霉的伊曲康唑和拉夫康唑的暂定 ECV。
采用改良 CLSI M38 肉汤微量稀释法测定 131 株遗传多样的临床外瓶霉分离株的伊曲康唑和拉夫康唑最小抑菌浓度（MIC）。建立 MIC 分布，并用 ECOFFinder 软件确定 ECV。测序 CYP51A 序列，以确定唑类药物靶基因是否发生突变，并比较不同 CYP51A 变体与 MIC 分布之间的关系。
伊曲康唑的 MIC 范围为 0.008 至 1mg/L，拉夫康唑的 MIC 范围为 0.002 至 0.125mg/L。外瓶霉的伊曲康唑 ECV 为 1mg/L，拉夫康唑 ECV 为 0.064mg/L。在外瓶霉野生型群体中，发现了两种 CYP51A 变体，它们在 499 位氨基酸上只有一个不同（S499G）。伊曲康唑和拉夫康唑的 MIC 分布在两种变体之间相似。未发现与降低敏感性相关的突变。
建议的外瓶霉伊曲康唑 ECV 为 1mg/L，拉夫康唑 ECV 为 0.064mg/L。
