Wiederhold Nathan P, Najvar Laura K, Matsumoto Satoru, Bocanegra Rosie A, Herrera Monica L, Wickes Brian L, Kirkpatrick William R, Patterson Thomas F
University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA South Texas Veterans Health Care System, San Antonio, Texas, USA.
Antimicrob Agents Chemother. 2015 May;59(5):2875-81. doi: 10.1128/AAC.04857-14. Epub 2015 Mar 9.
ASP9726 is an investigational echinocandin with in vitro activity against Aspergillus species. We evaluated the pharmacokinetics and efficacy of this agent in an established guinea pig model of invasive pulmonary aspergillosis. ASP9726 plasma concentrations were measured in guinea pigs administered either a single dose or multiple doses of this agent at 2.5, 5, and 10 mg/kg of body weight/day by subcutaneous injection. Immunosuppressed guinea pigs were inoculated with A. fumigatus AF293, and ASP9726 (2.5, 5, and 10 mg/kg/day), voriconazole (10 mg/kg by oral gavage twice daily), or caspofungin (3 mg/kg/day by intraperitoneal injection) was administered for 8 days. Changes in fungal burden were measured by enumerating CFU and by quantitative PCR of specimens from within the lungs, as well as by analysis of serum (1 → 3)-β-D-glucan and galactomannan. Lung histopathology was also evaluated. ASP9726 plasma concentrations increased in a dose-proportional manner, and the drug was well tolerated at each dose. Each dose of ASP9726, voriconazole, and caspofungin significantly reduced pulmonary fungal burden as measured by quantitative PCR and by determining (1 → 3)-β-D-glucan and galactomannan levels, but only voriconazole significantly reduced numbers of CFU. ASP9726 at 5 mg/kg also significantly improved survival. Histopathology demonstrated morphological changes in hyphae in animals exposed to ASP9726 and caspofungin, consistent with the activities of the echinocandins. These results suggest that ASP9726 may be efficacious for the treatment of invasive pulmonary aspergillosis.
ASP9726是一种具有体外抗曲霉菌活性的研究性棘白菌素。我们在已建立的豚鼠侵袭性肺曲霉病模型中评估了该药物的药代动力学和疗效。通过皮下注射，以2.5、5和10mg/kg体重/天的剂量给豚鼠单次或多次给药ASP9726后，测定其血浆浓度。对免疫抑制的豚鼠接种烟曲霉AF293，然后给予ASP9726（2.5、5和10mg/kg/天）、伏立康唑（口服灌胃10mg/kg，每日两次）或卡泊芬净（腹腔注射3mg/kg/天），持续8天。通过计数菌落形成单位（CFU）、对肺内标本进行定量PCR以及分析血清（1→3）-β-D-葡聚糖和半乳甘露聚糖来测量真菌负荷的变化。还对肺组织病理学进行了评估。ASP9726的血浆浓度呈剂量比例增加，且在每个剂量下药物耐受性良好。通过定量PCR以及测定（1→3）-β-D-葡聚糖和半乳甘露聚糖水平发现，ASP9726、伏立康唑和卡泊芬净的每个剂量均能显著降低肺部真菌负荷，但只有伏立康唑能显著减少CFU数量。5mg/kg的ASP9726也能显著提高生存率。组织病理学显示，暴露于ASP9726和卡泊芬净的动物中，菌丝出现形态变化，这与棘白菌素的活性一致。这些结果表明，ASP9726可能对侵袭性肺曲霉病的治疗有效。
