Itraconazole resistance in Aspergillus fumigatus
Itraconazole resistance in Aspergillus fumigatus
复制标题
DOI：
10.1128/aac.41.6.1364
复制
发表时间：
1997-06-01
影响因子：
4.9
通讯作者：
Kelly, SL
中科院分区：
文献类型：
--
作者：
Denning, DW;Venkateswarlu, K;Kelly, SL
侵袭性曲霉病是免疫功能低下患者中日益频繁的机会性感染。只有两种药物，即曲霉素B和伊曲康唑被许可用于治疗，伊曲康唑通过抑制进行甾醇14 α去甲基化的P-450酶起作用。烟曲霉对伊曲康唑的体外耐药性与体内结果相关，此前尚未描述过。对于烟曲霉的三个分离株（AF 72、AF 90和AF 91）。结果表明，两例侵袭性曲霉病患者的烟曲霉菌对伊曲康唑的MIC值均高于正常对照组，用小鼠模型建立MIC值的有效性，用随机扩增多态性DNA进行分型。甾醇的分析，抑制无细胞甾醇的生物合成从[C-14]甲羟戊酸，定量的P-450含量，和[H-3]伊曲康唑浓度在菌丝球被用来确定抗性的机制。三种耐药分离株的MIC>16 μ g/ml。分子分型结果表明，AF 72菌株的麦角甾醇含量较敏感菌株低，甾醇中间体含量较高，在无细胞麦角甾醇生物合成中对伊曲康唑的敏感性相似，胞内[H-3]伊曲康唑浓度较敏感菌株低。AF 91和AF 92具有略高的麦角甾醇和较低的中间甾醇浓度，在无细胞系统中对伊曲康唑对甾醇14 α去甲基化作用的抗性增加了5倍，并且在敏感分离株中发现了细胞内[H-3]伊曲康唑浓度。烟曲霉中对伊曲康唑的抗性在体外可检测到并且存在于轻度油菜分离株中，并且至少有两种抗性机制是负责的。
Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients, Only two agents, amphotericin B and itraconazole, are licensed for therapy, Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14 alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described, For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated, A neutropenic murine model was used to establish the validity of the MICs, The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [C-14]mevalonate, quantitation of P-450 content, and [H-3]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 mu g/ml. In vitro resistance was confirmed in vivo for all three isolates, Molecular typing showed the isolates from the two patients to he genetically distinct, Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [H-3]itraconazole concentration, In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14 alpha demethylation, and intracellular [H-3]itraconazole concentrations found in susceptible isolates, Resistance to itraconazole in A, fumigatus is detectable in vitro and is present in mild-rape isolates, and at least two mechanisms of resistance are responsible.