Majithiya J, Sharp A, Parmar A, Denning D W, Warn P A
School of Medicine, University of Manchester, 1.800 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
J Antimicrob Chemother. 2009 Jan;63(1):161-6. doi: 10.1093/jac/dkn431. Epub 2008 Nov 13.
The aim of this study was to assess the dose-response of isavuconazole, voriconazole and fluconazole in disseminated Candida tropicalis and Candida krusei infections.
Mice were immunosuppressed using either one dose [temporarily neutropenic (TN)] or two doses [persistently neutropenic (PN)] of cyclophosphamide. Treatment was started 5 h after infection with oral isavuconazole (6, 15, 30, 60, 90, 120 or 150 mg/kg equivalent active compound), intravenous voriconazole (5, 20 or 40 mg/kg plus grapefruit gavage twice daily) or oral fluconazole (15, 50 or 150 mg/kg) all administered twice daily. Kidney burden was assessed for C. tropicalis, and kidney and brain burden for C. krusei.
Vehicle controls developed a non-lethal infection with high burdens in both models. In the TN models, isavuconazole, voriconazole and fluconazole (>50 mg/kg) reduced kidney burden compared with controls; >60 mg/kg isavuconazole and 50 mg/kg fluconazole were superior to alternative treatments (other than voriconazole 40 mg/kg). Isavuconazole (all doses) reduced brain burden (P<0.05) in the C. krusei model; fluconazole (all doses) and voriconazole (5 and 20 mg/kg) did not. In the C. krusei kidney burden model, isavuconazole 120 and 150 mg/kg and voriconazole 40 mg/kg were superior to controls and fluconazole. In the C. tropicalis model, PN isavuconazole (all doses), voriconazole (>5 mg/kg) and fluconazole (all doses) reduced kidney burden (P<0.05). Only isavuconazole (all doses) and 40 mg/kg voriconazole were effective against C. krusei in the brain, isavuconazole and voriconazole reduced tissue burden (P<0.05). Fluconazole had no significant effect on brain burden even at 150 mg/kg.
Isavuconazole significantly reduced kidney burden in mice infected with C. tropicalis and both kidney and brain burdens in mice infected with C. krusei. Isavuconazole was as effective as voriconazole and much more effective than fluconazole at reducing brain burden.
本研究旨在评估艾沙康唑、伏立康唑和氟康唑在播散性热带念珠菌和克柔念珠菌感染中的剂量反应。
使用单剂量[暂时中性粒细胞减少（TN）]或两剂量[持续中性粒细胞减少（PN）]的环磷酰胺使小鼠免疫抑制。感染后5小时开始治疗，口服艾沙康唑（6、15、30、60、90、120或150mg/kg等效活性化合物）、静脉注射伏立康唑（5、20或40mg/kg加每日两次柚子灌胃）或口服氟康唑（15、50或150mg/kg），均每日给药两次。评估热带念珠菌的肾脏负荷，以及克柔念珠菌的肾脏和脑部负荷。
载体对照组在两种模型中均发生了非致死性感染且负荷较高。在TN模型中，与对照组相比，艾沙康唑、伏立康唑和氟康唑（>50mg/kg）降低了肾脏负荷；>60mg/kg的艾沙康唑和50mg/kg的氟康唑优于其他治疗方法（除40mg/kg的伏立康唑外）。在克柔念珠菌模型中，艾沙康唑（所有剂量）降低了脑部负荷（P<0.05）；氟康唑（所有剂量）和伏立康唑（5和20mg/kg）则未降低。在克柔念珠菌肾脏负荷模型中，120和150mg/kg的艾沙康唑以及40mg/kg的伏立康唑优于对照组和氟康唑。在热带念珠菌模型中，PN艾沙康唑（所有剂量）、伏立康唑（>5mg/kg）和氟康唑（所有剂量）降低了肾脏负荷（P<0.05）。仅艾沙康唑（所有剂量）和40mg/kg的伏立康唑对脑部的克柔念珠菌有效，艾沙康唑和伏立康唑降低了组织负荷（P<0.05）。即使在150mg/kg时，氟康唑对脑部负荷也无显著影响。
艾沙康唑显著降低了感染热带念珠菌小鼠的肾脏负荷，以及感染克柔念珠菌小鼠的肾脏和脑部负荷。在降低脑部负荷方面，艾沙康唑与伏立康唑效果相当，且比氟康唑有效得多。
