Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P < 0.01, P < 0.001, and P < 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P < 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P < 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (P < 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P < 0.001), 85% of RVC10-treated rabbits (P < 0.001), and 50% of AMB-treated rabbits (P < 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

中文翻译：

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不断增加剂量的雷伏康唑赖氨酸磷酸酯静脉内给药治疗持续性中性粒细胞减少症兔实验性肺曲霉病的功效，安全性和血浆药代动力学。

拉伏康唑是一种新型的抗真菌三唑，具有广谱活性和较长的血浆半衰期。我们研究了递增剂量的雷伏康唑赖氨酸磷酸酯的抗真菌功效，安全性和药代动力学，用于治疗持续性嗜中性白血球减少症兔由于烟曲霉而引起的侵袭性肺曲霉病。治疗组包括以2.5（RVC2.5），5（RVC5）和10（RVC10）mg / kg体重/天的剂量治疗的兔子，以1 mg / kg / day的两性霉素B（AMB）治疗的兔子或未经处理的对照。与未治疗的对照组相比，RVC5-，RVC10和AMB处理的兔子的肺残余真菌负荷（每克CFU）呈剂量依赖性降低（分别为P <0.01，P <0.001和P <0.01） 。这些发现与未经处理的对照组和RVC2.5处理的兔中进行性半乳甘露聚糖抗原血症，RVC5-和RVC10处理的兔中较低的半乳甘露聚糖指数（GMI）以及AMB处理的兔中类似的低GMI相关（P <0.01） 。用RVC5，RVC10和AMB治疗的兔子，与未治疗的对照组相比，通过梗死评分和肺重量衡量，还显示出了生物体介导的肺损伤的减轻（P <0.001）。与未治疗的对照组相比，通过计算机断层摄影术检测到的RVC5和RVC10治疗的兔子肺部浸润减少，从而支持了这些结果（P <0.05）。整个研究中的生存率达到了95％的RVC5处理的兔子（P <0.001），85％的RVC10处理的兔子（P <0.001）和50％的AMB处理的兔子（P <0）。05）与未处理的对照组相比。拉伏康唑显示线性血浆药代动力学和大量分布，同时在整个给药间隔中维持血浆中浓度高于MIC。在拉伏康唑治疗的动物中，没有肝毒性或肾毒性的证据。静脉给药雷伏康唑赖氨酸磷酸酯对持续性中性粒细胞减少症兔的侵袭性肺曲霉病具有剂量依赖性疗效和出色的安全性。