Seyedmousavi Seyedmojtaba, Brüggemann Roger J M, Meis Jacques F, Melchers Willem J G, Verweij Paul E, Mouton Johan W
Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands.
Department of Pharmacy, Radboud UMC, Nijmegen, the Netherlands.
Antimicrob Agents Chemother. 2015 May;59(5):2855-66. doi: 10.1128/AAC.04907-14. Epub 2015 Mar 9.
Azole resistance is an emerging problem in Aspergillus fumigatus which translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. The in vivo efficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg/kg of body weight/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg/kg/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinical A. fumigatus isolates: a wild-type isolate (ISA MICEUCAST, 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in the cyp51A gene: G54W (ISA MIC(EUCAST), 0.5 mg/liter), M220I (ISA MIC(EUCAST), 4 mg/liter), and TR34/L98H (ISA MIC(EUCAST), 8 mg/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W mutant, and 256 mg/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR34/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC(0-24)/MIC(EUCAST) ratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC(0-24)/MIC) can be used to optimize the treatment of human infections by A. fumigatus, including strains with decreased susceptibility.
唑类耐药是烟曲霉中一个新出现的问题，这会导致治疗失败。对于侵袭性曲霉病（IA），即使是对当前唑类药物敏感性降低的菌株，使用新型唑类进行替代治疗可能会改善治疗效果。在免疫功能正常的IA小鼠模型中，评估了通过灌胃给予体重为0.25、1、4、16、64、128、256和512mg/kg/天的前药硫酸艾沙康唑（BAL8557）（分别相当于0.12、0.48、1.92、7.68、30.7、61.4、122.9和245.8mg/kg/天的艾沙康唑[ISA]）对4株临床烟曲霉菌株的体内疗效：一株野生型菌株（ISA MICEUCAST，0.5mg/L）和三株在cyp51A基因中存在替代突变的唑类耐药菌株：G54W（ISA MIC(EUCAST)，0.5mg/L）、M220I（ISA MIC(EUCAST)，4mg/L）和TR34/L98H（ISA MIC(EUCAST)，8mg/L）。对于野生型菌株，前药硫酸艾沙康唑剂量为64mg/kg时达到最大效果（100%存活）；对于G54W突变株，剂量为128mg/kg时达到最大效果；对于M220I突变株，剂量为256mg/kg，每天两次（q12）时达到最大效果。对于TR34/L98H菌株，使用最高剂量的前药硫酸艾沙康唑（256mg/kg q12）未达到最大反应。对于50%的存活率，ISA总药物的有效AUC(0 - 24)/MIC(EUCAST)比值为24.73（95%置信区间，22.50至27.18）。艾沙康唑的疗效取决于药物暴露量和分离株的艾沙康唑MIC。暴露量与效果之间的定量关系（AUC(0 - 24)/MIC）可用于优化烟曲霉引起的人类感染的治疗，包括敏感性降低的菌株。
