Azole resistance is an emerging problem in Aspergillus fumigatus and is associated with a high probability of treatment failure. An azole resistance mechanism typically decreases the activity of multiple azole compounds, depending on the mutation. As alternative treatment options are limited and in some isolates the minimum inhibitory concentration (MIC) increases by only a few two-fold dilutions steps, we investigated if voriconazole and posaconazole have a role in treating azole-resistant Aspergillus disease. The relation between resistance genotype and phenotype, pharmacokinetic and pharmacodynamic properties, and (pre)clinical treatment efficacy were reviewed. The results were used to estimate the exposure needed to achieve the pharmacodynamic target for each MIC. For posaconazole adequate exposure can be achieved only for wild type isolates as dose escalation does not allow PD target attainment. However, the new intravenous formulation might result in sufficient exposure to treat isolates with a MIC of 0.5 mg/L. For voriconazole our analysis indicated that the exposure needed to treat infection due to isolates with a MIC of 2 mg/L is feasible and maybe isolates with a MIC of 4 mg/L. However, extreme caution and strict monitoring of drug levels would be required, as the probability of toxicity will also increase.

中文翻译：

---

唑类化合物在耐唑类曲霉病管理中的作用：从工作台到床边。

唑耐性是烟曲霉中新出现的问题，并且与治疗失败的可能性较高相关。取决于突变，对唑的抗性机制通常会降低多种唑化合物的活性。由于替代疗法的选择受到限制，并且在某些分离物中，最低抑菌浓度（MIC）仅增加了几倍的稀释倍数，因此我们研究了伏立康唑和泊沙康唑是否在治疗对唑耐药的曲霉病中起作用。综述了耐药基因型与表型，药代动力学和药效学性质以及（临床前）疗效之间的关系。结果用于估计实现每个MIC的药效学目标所需的暴露量。对于泊沙康唑，仅对于野生型分离株才能获得足够的暴露，因为剂量递增无法达到PD靶标。但是，新的静脉内制剂可能会导致足够的暴露，以治疗MIC为0.5 mg / L的分离株。对于伏立康唑，我们的分析表明，由于MIC为2 mg / L的分离株，治疗感染所需的暴露是可行的，也许MIC为4 mg / L的分离株。但是，由于毒性的可能性也会增加，因此需要非常谨慎并严格监控药物水平。对于伏立康唑，我们的分析表明，由于MIC为2 mg / L的分离株，治疗感染所需的暴露是可行的，也许MIC为4 mg / L的分离株。但是，由于毒性的可能性也会增加，因此需要非常谨慎并严格监控药物水平。对于伏立康唑，我们的分析表明，由于MIC为2 mg / L的分离株，治疗感染所需的暴露是可行的，也许MIC为4 mg / L的分离株。但是，由于毒性的可能性也会增加，因此需要非常谨慎并严格监控药物水平。