Hope William W, Mickiene Diana, Petraitis Vidmantas, Petraitiene Ruta, Kelaher Amy M, Hughes Joanna E, Cotton Margaret P, Bacher John, Keirns James J, Buell Donald, Heresi Gloria, Benjamin Daniel K, Groll Andreas H, Drusano George L, Walsh Thomas J
Immunocompromised Host Section, Pediatric Oncology Branch, CRC, Rm. 1-5750, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Infect Dis. 2008 Jan 1;197(1):163-71. doi: 10.1086/524063.
Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME.
We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation.
Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg.
These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.
血源性念珠菌性脑膜脑炎（HCME）是新生儿播散性念珠菌病相对常见的表现形式，与显著的死亡率和神经发育异常相关。抗真菌治疗后的结果往往不尽人意，治疗选择有限。有限的临床数据表明棘白菌素类药物可能在HCME的治疗中发挥作用。
我们在新生儿HCME兔模型中研究了米卡芬净的药代动力学和药效学，并通过群体药代动力学和蒙特卡洛模拟将结果外推至新生儿。
米卡芬净在0.25 - 16 mg/kg范围内呈现线性血浆药代动力学。米卡芬净可穿透中枢神经系统（CNS）的大部分腔室，但仅在剂量>2 mg/kg时。脑脊液中未可靠检测到米卡芬净。除少数例外情况外，感染和未感染兔子之间药物进入各个CNS亚腔室的情况在统计学上无差异。在脑中呈现剂量 - 微生物反应关系，8 mg/kg剂量时接近最大效应。蒙特卡洛模拟显示，在人类新生儿剂量为12 - 15 mg/kg时可达到接近最大的抗真菌效果。
这些结果为米卡芬净用于新生儿HCME的临床试验提供了基础，并为儿科患者从实验室到床边的抗菌药物桥接研究提供了模型。
