Li You, Guo Siwei, Li Xin, Yu Yunsong, Yan Bingqian, Tian Miaomei, Xu Bing, Hu Huangdu
Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, PR China; The Third Hospital of Changsha, Changsha, Hunan, PR China.
The Third Hospital of Changsha, Changsha, Hunan, PR China; Institute of Clinical Application of Antibiotics, Changsha, Hunan, PR China.
Microb Pathog. 2022 May;166:105517. doi: 10.1016/j.micpath.2022.105517. Epub 2022 Apr 7.
This study aimed to evaluate the in vitro synergy of polymyxin B (PMB) combined with 11 other antibiotics against PMB-resistant gram-negative bacilli (GNBs).
Thirty-six clinical isolates of PMB-resistant GNBs were used. The MICs of all the antimicrobials tested were determined by the broth microdilution method and the checkerboard assay method. Carbapenemase genes were detected by PCR. In vitro synergy results were interpreted using the fractional inhibitory concentration index (FICI). Four combinations that showed positive interactions were subsequently evaluated in a time-kill study.
Among the 36 strains, 15 harboured the carbapenemase gene, and blaKPC was the predominant carbapenemase. The resistance rates of the 36 strains to tigecycline, meropenem, ceftazidime, and cefepime were 100% (36/36), 97% (35/36), 94% (34/36), and 97% (35/36), respectively. For Enterobacteriaceae and Pseudomonas aeruginosa, the resistance rates to aztreonam and ceftazidime-avibactam (avibactam at a fixed concentration of 4 mg/L) were 95% (19/20) and 25% (5/20), respectively. The PMB-based combinations exhibited synergism to a certain degree. The most synergistic combinations were PMB plus meropenem-avibactam (avibactam at a fixed concentration of 4 mg/L) and PMB plus tigecycline, with the synergy rates of 83.3% and 80.6%, respectively. Compared to tazobactam- and sulbactam-based β-lactam-β-lactamase inhibitor combinations (BL-BLIs), PMB with avibactam-based BL-BLIs exhibited a better synergistic effect. For Acinetobacter baumannii, PMB plus sulbactam exhibited a strong synergism with a 2∼7-fold MIC reduction of PMB. In time-kill studies, the highest degree of synergism was observed for PMB with cefepime-avibactam on all the tested isolates. For isolates with low-level resistance to PMB, PMB combined with other partner antimicrobials also showed a certain degree of synergism.
PMB in combination with tigecycline and avibactam-based BL-BLIs could be a potential clinical option for clinical treatment of infections caused by PMB -resistant GNBs.
本研究旨在评估多粘菌素B（PMB）与其他11种抗生素联合应用对耐PMB革兰氏阴性杆菌（GNBs）的体外协同作用。
使用36株耐PMB的GNB临床分离株。通过肉汤微量稀释法和棋盘稀释法测定所有测试抗菌药物的最低抑菌浓度（MIC）。采用聚合酶链反应（PCR）检测碳青霉烯酶基因。使用分数抑菌浓度指数（FICI）解释体外协同结果。随后在时间杀菌研究中评估显示出阳性相互作用的四种组合。
在36株菌株中，15株携带碳青霉烯酶基因，blaKPC是主要的碳青霉烯酶。36株菌株对替加环素、美罗培南、头孢他啶和头孢吡肟的耐药率分别为100%（36/36）、97%（35/36）、94%（34/36）和97%（35/36）。对于肠杆菌科和铜绿假单胞菌，对氨曲南和头孢他啶-阿维巴坦（阿维巴坦固定浓度为4mg/L）的耐药率分别为95%（19/20）和25%（5/20）。基于PMB的组合表现出一定程度的协同作用。协同作用最强的组合是PMB加美罗培南-阿维巴坦（阿维巴坦固定浓度为4mg/L）和PMB加替加环素，协同率分别为83.3%和80.6%。与基于他唑巴坦和舒巴坦的β-内酰胺-β-内酰胺酶抑制剂组合（BL-BLIs）相比，PMB与基于阿维巴坦的BL-BLIs表现出更好的协同效果。对于鲍曼不动杆菌，PMB加舒巴坦表现出强烈的协同作用，PMB的MIC降低2至7倍。在时间杀菌研究中，在所有测试分离株中观察到PMB与头孢吡肟-阿维巴坦的协同作用程度最高。对于对PMB低水平耐药的分离株，PMB与其他配对抗菌药物联合也显示出一定程度的协同作用。
PMB与替加环素和基于阿维巴坦的BL-BLIs联合应用可能是临床治疗耐PMB GNBs所致感染的一种潜在临床选择。
