Laboratory of Infectious Diseases, 3rd Department of Pediatrics, Hippokration Hospital, Thessaloniki, Greece.
Mycoses. 2011 Sep;54(5):e486-92. doi: 10.1111/j.1439-0507.2010.01958.x. Epub 2010 Oct 29.
The aim of this study was to evaluate the pharmacokinetics and efficacy of posaconazole (PSC) in combination with granulocyte colony-stimulating factor (G-CSF) in a neutropaenic murine model of disseminated zygomycosis (mucormycosis) due to Rhizopus microsporus. Male BALB/c mice were rendered neutropaenic with cyclophosphamide (200 mg kg(-1), intraperitoneally) administered on days -1 and +5 postinfection. Mice were infected with R. microsporus (5 × 10(4) spores ml(-1)) intravenously. Mice were treated with PSC (40 mg kg(-1) day(-1) by gavage) or G-CSF (300 μg kg(-1) day(-1) subcutaneously) or with the combination of PSC and G-CSF. The fungal burden was assessed by culturing the brain, liver, kidneys and lungs. Blood levels of PSC were measured by high performance liquid chromatography. The survival rates were 33%, 27% and 31% for PSC-treated-, G-CSF-treated- and PSC + G-CSF-treated mice, respectively, as compared to 18% for the controls (P = NS). PSC monotherapy and combination therapy significantly reduced the fungal burden in the kidneys, but not in the rest of the organs. Combination therapy was not superior to PSC monotherapy in terms of either survival or reduction in fungal burden. Serum concentrations of PSC were well-above the MIC of PSC for the particular isolate. PSC monotherapy has a modest efficacy against R. microsporus in reducing fungal burden in neutropaenic mice. Combining G-CSF with PSC does not substantially affect the antifungal activity of PSC.
本研究旨在评估泊沙康唑（PSC）联合粒细胞集落刺激因子（G-CSF）在中性粒细胞减少的播散性毛霉病（毛霉病）鼠模型中的药代动力学和疗效，该模型由微小根毛霉引起。雄性 BALB/c 小鼠用环磷酰胺（200mg/kg，腹腔内）处理，在感染后第-1 天和第+5 天给药，使其中性粒细胞减少。通过静脉内感染 R. microsporus（5×10(4)孢子/ml）感染小鼠。用 PSC（40mg/kg/天，口服）或 G-CSF（300μg/kg/天，皮下）或 PSC 和 G-CSF 联合治疗小鼠。通过培养大脑、肝脏、肾脏和肺来评估真菌负担。通过高效液相色谱法测量 PSC 的血药浓度。PSC 治疗组、G-CSF 治疗组和 PSC+G-CSF 治疗组的存活率分别为 33%、27%和 31%，而对照组为 18%（P=NS）。PSC 单药治疗和联合治疗可显著降低肾脏中的真菌负担，但对其他器官无影响。联合治疗在存活率或真菌负担减少方面并不优于 PSC 单药治疗。PSC 的血清浓度明显高于该特定分离株的 PSC 的 MIC。PSC 单药治疗对中性粒细胞减少的微小根毛霉具有适度的疗效，可降低真菌负担。将 G-CSF 与 PSC 联合使用不会显著影响 PSC 的抗真菌活性。
