Chang Ya-Ting, Yang Tsung-Ying, Lu Po-Liang, Lin Shang-Yi, Wang Liang-Chun, Wang Sheng-Fan, Hsieh Ya-Ju, Tseng Sung-Pin
Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan.
Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.
Microorganisms. 2020 Dec 11;8(12):1964. doi: 10.3390/microorganisms8121964.
Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the "last-resort" antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant (CCRKP). Eleven of the 40 isolates harbored carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT-colistin combination could be a potentially favorable therapeutic option for treating CCRKP.
耐碳青霉烯类肠杆菌科细菌（CRE）被世界卫生组织列为紧急威胁，原因是治疗选择有限、耐药机制迅速演变且在全球传播。黏菌素是用于治疗CRE的“最后手段”抗生素中的常用主要药物；然而，CRE中其耐药性的出现使当前困境更加严重。叠氮胸苷（AZT）是一种用于治疗人类免疫缺陷病毒/获得性免疫缺陷综合征的胸苷类似物，已知它对肠杆菌科细菌具有抗菌作用。在本研究中，我们调查了AZT和黏菌素对40株耐黏菌素、耐碳青霉烯类肺炎克雷伯菌（CCRKP）临床分离株的联合作用。40株分离株中有11株携带碳青霉烯酶。体外棋盘法和体内线虫杀伤试验均显示这两种药物之间具有协同活性，每个菌株的分数抑菌浓度指数均≤0.5。此外，与单独使用AZT或黏菌素治疗相比，联合治疗的线虫的风险比显著更低（0.288；<0.0001）。毒性测试表明联合治疗的潜在毒性较低。因此，AZT-黏菌素联合治疗可能是治疗CCRKP的一种潜在有利的治疗选择。
