Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA
Duke University Medical Center, Durham, North Carolina, USA.
Antimicrob Agents Chemother. 2019 Aug 23;63(9). doi: 10.1128/AAC.00546-19. Print 2019 Sep.
spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.
spp.，重要的真菌病原体，是导致人类免疫缺陷病毒感染患者真菌感染相关死亡的主要原因，急需新的治疗选择。硫酸伊曲康唑是一种新型三唑类抗真菌药物，研究了其在隐球菌性脑膜脑炎兔模型中的暴露-反应关系。将接受硫酸伊曲康唑治疗的兔子与接受氟康唑治疗的兔子和未接受治疗的对照组进行比较。随着时间的推移，连续测量脑脊液中的真菌负荷，而在治疗结束时，测定脑和眼（房水）中的酵母浓度。使用数学模型来确定硫酸伊曲康唑在兔子中的暴露影响。与未接受治疗的对照组相比，接受硫酸伊曲康唑和氟康唑治疗的兔子的大脑和脑脊液中的真菌负荷均显著降低。在这项研究中，没有观察到硫酸伊曲康唑治疗的剂量依赖性反应。在本研究中，硫酸伊曲康唑治疗隐球菌性脑膜脑炎的效果与氟康唑相似。没有显示出随着时间的推移，酵母的剂量依赖性减少，这限制了我们估计药效学目标的能力。为了进一步描述隐球菌性脑膜脑炎中的暴露-反应关系，需要进行更多的非临床和临床研究。然而，本研究表明，硫酸伊曲康唑与氟康唑一样，在高负荷隐球菌性脑膜脑炎中，可能对巩固和维持治疗有益，而不是诱导单药治疗。
