Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, Seville, Spain; Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain; Department of Medicine, University of Seville, Seville, Spain.
Int J Antimicrob Agents. 2019 Oct;54(4):507-512. doi: 10.1016/j.ijantimicag.2019.07.006. Epub 2019 Jul 9.
Due to the significant increase in antimicrobial resistance in Gram-negative bacilli (GNB), development of non-antimicrobial therapeutic alternatives, which can be used together with the few and non-optimal available antimicrobial agents such as colistin, has become an urgent need. In this context, dysregulation of the bacterial cell wall could be a therapeutic adjuvant to the activity of colistin. The aim of this study was to analyse the activity of oxyclozanide, an anthelmintic drug, in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) GNB. Three Col-S reference strains and 13 clinical isolates (1 Col-S, 12 Col-R) of Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were studied. Microdilution assays and time-kill curves were performed to examine the activity of oxyclozanide in combination with colistin. The outer membrane protein (OMP) profile, membrane permeability and cell wall structure of Col-S and Col-R A. baumannii, P. aeruginosa and K. pneumoniae in the presence of oxyclozanide were assessed by SDS-PAGE, fluorescence microscopy and transmission electron microscopy, respectively. Oxyclozanide in combination with colistin increased the activity of colistin against Col-S and Col-R A. baumannii, P. aeruginosa and K. pneumoniae. Time-kill curves showed synergistic activity between oxyclozanide and colistin against these bacterial isolates. Moreover, Col-R A. baumannii, P. aeruginosa and K. pneumoniae in the presence of oxyclozanide presented greater permeability and disruption of their cell wall than Col-S strains, without modification of their OMP profile. These data suggest that combination of oxyclozanide and colistin may be a new alternative for the treatment of Col-R GNB infections.
由于革兰氏阴性菌 (GNB) 对抗微生物药物的耐药性显著增加，开发非抗微生物治疗替代品已成为当务之急，这些替代品可以与少数非最佳可用的抗微生物药物（如黏菌素）一起使用。在这种情况下，细菌细胞壁的失调可能是黏菌素活性的治疗辅助剂。本研究旨在分析驱虫药奥克昔隆与黏菌素联合应用对黏菌素敏感 (Col-S) 和黏菌素耐药 (Col-R) GNB 的活性。研究了 3 株 Col-S 参考菌株和 13 株临床分离株（1 株 Col-S、12 株 Col-R）的鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌。通过微量稀释法和时间杀伤曲线检测奥克昔隆与黏菌素联合应用的活性。通过 SDS-PAGE、荧光显微镜和透射电子显微镜分别评估 Col-S 和 Col-R 鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌的外膜蛋白 (OMP) 谱、膜通透性和细胞壁结构。奥克昔隆与黏菌素联合使用增加了黏菌素对 Col-S 和 Col-R 鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌的活性。时间杀伤曲线显示奥克昔隆与黏菌素对这些细菌分离株具有协同活性。此外，与 Col-S 菌株相比，奥克昔隆存在时，Col-R 鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌的通透性增加，细胞壁破坏更大，但其 OMP 谱没有改变。这些数据表明，奥克昔隆与黏菌素联合使用可能是治疗 Col-R GNB 感染的新选择。
