Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Healthy, University of Sydney, Sydney, NSW, Australia.
Tuberculosis Research Program, Centenary Institute and Faculty of Medicine and Healthy, University of Sydney, Sydney, NSW, Australia.
Int J Pharm. 2018 Nov 15;551(1-2):158-165. doi: 10.1016/j.ijpharm.2018.09.024. Epub 2018 Sep 14.
Nebulization is currently used for delivery of antibiotics for respiratory infections. Bacteriophages (or phages) are effective predators of pathogens including Pseudomonas aeruginosa commonly found in the lungs of patients with cystic fibrosis (CF). It is known that phages and antibiotics can potentially show synergistic antimicrobial effect on bacterial killing. In the present study, we investigated synergistic antimicrobial effect of phage PEV20 with five different antibiotics against three P. aeruginosa strains isolated from sputum of CF patients. The antibiotics included ciprofloxacin, tobramycin, colistin, aztreonam and amikacin, which are approved by U.S Food and Drug Administration (FDA) for inhaled administration. Phage and antibiotic synergy was determined by assessing bacterial killing performing time-kill studies. Among the different phage-antibiotic combinations, PEV20 and ciprofloxacin exhibited the most synergistic effect. Two phage-ciprofloxacin combinations, containing 1/4 and 1/2 of the minimum inhibitory concentration (MIC) of ciprofloxacin against P. aeruginosa strains FADD1-PA001 (A) and JIP865, respectively were aerosolized using both air-jet and vibrating mesh nebulizers and the synergistic antibacterial activity was maintained after nebulization. Air-jet nebulizer generated droplets with smaller volume median diameters (3.6-3.7 µm) and slightly larger span (2.3-2.4) than vibrating mesh nebulizers (5.1-5.3 µm; 2.1-2.2), achieving a higher fine particle fraction (FPF) of 70%. In conclusion, nebulized phage PEV20 and ciprofloxacin combination shows promising antimicrobial and aerosol characteristics for potential treatment of respiratory tract infections caused by drug-resistant P. aeruginosa.
雾化目前用于传递抗生素治疗呼吸道感染。噬菌体（或噬菌体）是包括铜绿假单胞菌在内的病原体的有效捕食者，铜绿假单胞菌通常存在于囊性纤维化（CF）患者的肺部。已知噬菌体和抗生素对细菌杀伤具有潜在的协同抗菌作用。在本研究中，我们研究了噬菌体 PEV20 与五种不同抗生素对三种从 CF 患者痰液中分离的铜绿假单胞菌菌株的协同抗菌作用。这些抗生素包括环丙沙星、妥布霉素、多粘菌素、氨曲南和阿米卡星，它们均已获得美国食品和药物管理局（FDA）批准用于吸入给药。通过评估细菌杀伤作用进行时间杀伤研究来确定噬菌体和抗生素的协同作用。在不同的噬菌体-抗生素组合中，PEV20 和环丙沙星表现出最强的协同作用。两种噬菌体-环丙沙星组合，含有针对铜绿假单胞菌菌株 FADD1-PA001（A）和 JIP865 的环丙沙星最低抑菌浓度（MIC）的 1/4 和 1/2，分别使用空气射流和振动网式雾化器进行雾化，并且在雾化后保持协同抗菌活性。空气射流雾化器产生的液滴体积中值直径（3.6-3.7μm）略小，跨度（2.3-2.4）略大于振动网式雾化器（5.1-5.3μm；2.1-2.2），实现了更高的细颗粒分数（FPF）为 70%。总之，雾化噬菌体 PEV20 和环丙沙星联合用药具有有前途的抗菌和雾化特性，可潜在用于治疗由耐药铜绿假单胞菌引起的呼吸道感染。
