Lee Sie Huey, Teo Jeanette, Heng Desmond, Ng Wai Kiong, Zhao Yanli, Tan Reginald B H
Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore.
Department of Laboratory Medicine, National University Hospital, Singapore, Singapore.
J Pharm Sci. 2016 Apr;105(4):1501-12. doi: 10.1016/j.xphs.2016.02.007.
Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 μm-3.4 ± 0.1 μm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa.
耐多药（MDR）超级细菌引起的肺部感染在全球呈上升趋势，临床后果非常严峻。它们的耐多药特性使治疗选择极为有限。尽管作为一种高毒性抗生素，黏菌素如今被用作对抗这些难以治疗的耐多药病原体的“最后一线”治疗药物，但它正迅速失去效力。因此，这项研究旨在识别并量身定制有用的联合用药方案（可能具有可轮换性和协同性），作为应对耐药率上升的有吸引力的替代策略。确定了三种可能可轮换的三元干粉吸入器制剂（每种制剂都包含黏菌素和另外两种从利福平、美罗培南和替加环素中选出的不同类别的抗生素）（具有独特的互补杀菌机制），通过喷雾干燥进行共配制，使用下一代撞击器评估其气溶胶性能，并测试它们对多种耐多药病原体的疗效。粉末颗粒具有可吸入尺寸（d50，3.1±0.3μm - 3.4±0.1μm），形态上主要为皱缩状。当通过模型干粉吸入器（Aerolizer(®)）以60 L/min的速度分散时，这些粉末显示出体外沉积，细颗粒分数约为53% - 70%。所有制剂在实验室中均成功测试出对耐多药病原体具有高效性。此外，在针对耐多药铜绿假单胞菌进行测试时，在所有三种制剂中都检测到了良好的协同相互作用。
