Petraitiene Ruta, Petraitis Vidmantas, Hope William W, Walsh Thomas J
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical Center of Cornell University, New York, New York.
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
Clin Infect Dis. 2015 Dec 1;61 Suppl 6(Suppl 6):S643-51. doi: 10.1093/cid/civ817.
The current standard of treatment of invasive candidiasis with echinocandins requires once-daily therapy. To improve quality of life, reduce costs, and improve outcome, we studied the pharmacokinetics (PK), efficacy, and safety of alternate dosing regimens of micafungin (MFG) for the treatment of experimental subacute disseminated candidiasis.
MFG was administered for 12 days starting 24 hours after intravenous inoculation of 1 × 10(3) Candida albicans blastoconidia. Study groups consisted of MFG at 1 mg/kg every 24 hours (MFG1), 2 mg/kg every 48 hours (MFG2), and 3 mg/kg every 72 hours (MFG3), and untreated controls. PK of MFG were determined on day 7 by high-performance liquid chromatography and modeled using nonparametric adaptive grid program. A 2-compartment PK model with volume of the central compartment (Vc), clearance (SCL), and the intercompartmental rate constants Kcp and Kpc was used. The fungal burden in 7 tissues was determined 312 hours after the initiation of therapy.
PK of MFG were linear and the parameter means ± SD were Vc = 0.41 ± 0.18 L, Kcp = 2.80 ± 1.55/hour, Kpc = 1.71 ± 0.93/hour, and SCL = 0.16 ± 0.003 L/hour (r(2) = 0.99). The area under the plasma drug concentration - time curve for MFG1, MFG2, and MFG3 was 198.7 ± 19.8, 166.3 ± 36.7, and 192.8 ± 46.2 mg × hour/L, respectively (P = .24). All treatment groups showed significant and comparable resolution of (1→3)-β-D-glucan levels and clearance of C. albicans from liver, spleen, kidney, brain, lung, vitreous humor, and vena cava in comparison to untreated controls (P ≤ .05). There were no differences in hepatic or renal function among study groups.
Less fractionated MFG regimens of every 48 and 72 hours are safe and as effective in experimental disseminated candidiasis as once-daily therapy in neutropenic hosts.
目前棘白菌素治疗侵袭性念珠菌病的标准疗法为每日一次给药。为了改善生活质量、降低成本并提高治疗效果，我们研究了米卡芬净（MFG）不同给药方案治疗实验性亚急性播散性念珠菌病的药代动力学（PK）、疗效及安全性。
静脉接种1×10³白色念珠菌芽生孢子24小时后开始给予MFG，持续给药12天。研究组包括每24小时给予1mg/kg MFG（MFG1组）、每48小时给予2mg/kg MFG（MFG2组）、每72小时给予3mg/kg MFG（MFG3组），以及未治疗的对照组。在第7天通过高效液相色谱法测定MFG的药代动力学，并使用非参数自适应网格程序进行建模。采用具有中央室容积（Vc）、清除率（SCL）以及室间速率常数Kcp和Kpc的二室药代动力学模型。治疗开始312小时后测定7个组织中的真菌负荷。
MFG的药代动力学呈线性，参数均值±标准差为Vc = 0.41±0.18L，Kcp = 2.80±1.55/小时，Kpc = 1.71±0.93/小时，SCL = 0.16±0.003L/小时（r² = 0.99）。MFG1组、MFG2组和MFG3组的血浆药物浓度 - 时间曲线下面积分别为198.7±19.8、166.3±36.7和192.8±46.2mg×小时/L（P = 0.24）。与未治疗的对照组相比，所有治疗组的（1→3）-β-D-葡聚糖水平均显著且相当程度地下降，白色念珠菌从肝脏、脾脏、肾脏、大脑、肺、玻璃体液和腔静脉中清除（P≤0.05）。研究组之间肝功能或肾功能无差异。
每48小时和每72小时给药的MFG较少分割的给药方案在实验性播散性念珠菌病中是安全的，并且在中性粒细胞减少宿主中与每日一次治疗同样有效。
