Institut Pasteur Unité de Recherche Cytokines & Inflammation, Paris, France.
Antimicrob Agents Chemother. 2013 Jul;57(7):3046-59. doi: 10.1128/AAC.01660-12. Epub 2013 Apr 15.
Aspergillus fumigatus causes life-threatening infections, especially in immunocompromised patients. Common drugs for therapy of aspergillosis are polyenes, azoles, and echinocandins. However, despite in vitro efficacy of these antifungals, treatment failure is frequently observed. In this study, we established bioluminescence imaging to monitor drug efficacy under in vitro and in vivo conditions. In vitro assays confirmed the effectiveness of liposomal amphotericin B, voriconazole, and anidulafungin. Liposomal amphotericin B and voriconazole were fungicidal, whereas anidulafungin allowed initial germination of conidia that stopped elongation but allowed the conidia to remain viable. In vivo studies were performed with a leukopenic murine model. Mice were challenged by intranasal instillation with a bioluminescent reporter strain (5 × 10(5) and 2.5 × 10(5) conidia), and therapy efficacies of liposomal amphotericin B, voriconazole, and anidulafungin were monitored. For monotherapy, the highest treatment efficacy was observed with liposomal amphotericin B, whereas the efficacies of voriconazole and anidulafungin were strongly dependent on the infectious dose. When therapy efficacy was studied with different drug combinations, all combinations improved the rate of treatment success compared to that with monotherapy. One hundred percent survival was obtained for treatment with a combination of liposomal amphotericin B and anidulafungin, which prevented not only pulmonary infections but also infections of the sinus. In conclusion, combination therapy increases treatment success, at least in the murine infection model. In addition, our novel approach based on real-time imaging enables in vivo monitoring of drug efficacy in different organs during therapy of invasive aspergillosis.
烟曲霉引起危及生命的感染，尤其是在免疫功能低下的患者中。治疗曲霉病的常用药物是多烯类、唑类和棘白菌素类。然而，尽管这些抗真菌药物在体外具有疗效，但治疗失败的情况经常发生。在这项研究中，我们建立了生物发光成像来监测体外和体内条件下的药物疗效。体外测定证实了脂质体两性霉素 B、伏立康唑和阿尼芬净的有效性。脂质体两性霉素 B 和伏立康唑具有杀菌作用，而阿尼芬净允许初始孢子萌发，但阻止了伸长，同时使孢子保持存活。体内研究采用白细胞减少的小鼠模型进行。通过鼻腔内滴注生物发光报告株（5×10(5)和 2.5×10(5)个孢子）对小鼠进行挑战，并监测脂质体两性霉素 B、伏立康唑和阿尼芬净的治疗效果。对于单一疗法，观察到脂质体两性霉素 B 的治疗效果最高，而伏立康唑和阿尼芬净的疗效强烈依赖于感染剂量。当用不同的药物组合研究治疗效果时，与单一疗法相比，所有组合都提高了治疗成功率。用脂质体两性霉素 B 和阿尼芬净联合治疗可获得 100%的存活率，不仅可以预防肺部感染，还可以预防鼻窦感染。总之，联合治疗至少在小鼠感染模型中增加了治疗成功率。此外，我们基于实时成像的新方法可在侵袭性曲霉病治疗期间，对不同器官中的药物疗效进行体内监测。
