Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA
Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania.
Antimicrob Agents Chemother. 2017 Aug 24;61(9). doi: 10.1128/AAC.00305-17. Print 2017 Sep.
Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-β-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits ( < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone ( < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone ( < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-β-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights ( = 0.764; < 0.001), and pulmonary infarct score ( = 0.911; < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-β-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent.
侵袭性肺曲霉病（IPA）是免疫功能低下患者发病率和死亡率的重要原因。我们假设，通过抗真菌三唑伊曲康唑（ISA）和棘白菌素米卡芬净（MFG）分别抑制真菌细胞膜中麦角固醇的生物合成和细胞壁中（1→3）-β-D-葡聚糖，可能会改善持续性中性粒细胞减少兔实验性 IPA 的结果。治疗包括 20mg/kg/天（ISA20）、40mg/kg/天（ISA40）和 60mg/kg/天（ISA60）的 ISA；2mg/kg/天（MFG2）的 MFG；ISA20 和 MFG2、ISA40 和 MFG2 以及 ISA60 和 MFG2 的组合；以及未治疗（未治疗对照组[UC]）。测量半乳甘露聚糖指数（GMI）和血清中（1→3）-β-D-葡聚糖水平。与 MFG2 治疗或 UC 兔相比，ISA20、ISA40、ISA60、ISA20-MFG2、ISA40-MFG2 和 ISA60-MFG2 治疗的兔中的真菌残留负担（每克 CFU 数）显著降低（<0.01）。与单独用 ISA40 或 MFG2 治疗的兔相比，ISA40-MFG2 治疗的兔中的机体介导的肺损伤、肺重和肺梗死评分降低（<0.01）。与单独用 ISA40 或 MFG2 治疗的兔相比，ISA40-MFG2 治疗的兔的存活率延长（<0.01）。在治疗过程中，GMI 和血清（1→3）-β-D-葡聚糖水平的显著下降与这些结果变量直接相关。GMI 与机体介导的肺损伤、肺重（=0.764；<0.001）和肺梗死评分（=0.911；<0.001）呈正相关。总之，与接受伊曲康唑单药治疗的兔相比，接受伊曲康唑和米卡芬净联合治疗的兔的真菌残留负担显著降低，肺损伤减少，存活率延长，GMI 降低，血清（1→3）-β-D-葡聚糖水平降低。
