PDF(Pubmed)
Abstract：
BACKGROUND: Gram-negative bacteria (GNB) are becoming increasingly resistant to a wide variety of antibiotics. There are currently limited treatments for GNB, and the combination of antibiotics with complementary mechanisms has been reported to be a feasible strategy for treating GNB infection. The inability to cross the GNB outer membrane (OM) is an important reason that a broad spectrum of Gram-positive only class of antibiotics (GPOAs) is lacking. Polymyxins may help GPOAs to permeate by disrupting OM of GNB.
OBJECTIVE: To identify what kind of GPOAs can be aided to broaden their anti-GNB spectrum by polymyxins, we systematically investigated the synergy of eight GPOAs in combination with colistin (COL) and polymyxin B (PMB) against GNB in vitro.
METHODS: The synergistic effect of COL or PMB and GPOAs combinations against GNB reference strains and clinical isolates were determined by checkerboard tests. The killing kinetics of the combinations were assessed using time-kill assays.
RESULTS: In the checkerboard tests, polymyxins-GPOAs combinations exert synergistic effects characterized by species and strain specificity. The synergistic interactions on P. aeruginosa strains are significantly lower than those on strains of A. baumannii, K. pneumoniae and E. coli. Among all the combinations, COL has shown the best synergistic effect in combination with dalbavancin (DAL) or oritavancin (ORI) versus almost all of the strains tested, with FICIs from 0.16 to 0.50 and 0.13 to < 0.28, respectively. In addition, the time-kill assays demonstrated that COL/DAL and COL/ORI had sustained bactericidal activity.
CONCLUSIONS: Our results indicated that polymyxins could help GPOAs to permeate the OM of specific GNB, thus showed synergistic effects and bactericidal effects in the in vitro assays. In vivo combination studies should be further conducted to validate the results of this study.
OBJECTIVE: To identify what kind of GPOAs can be aided to broaden their anti-GNB spectrum by polymyxins, we systematically investigated the synergy of eight GPOAs in combination with colistin (COL) and polymyxin B (PMB) against GNB in vitro.
METHODS: The synergistic effect of COL or PMB and GPOAs combinations against GNB reference strains and clinical isolates were determined by checkerboard tests. The killing kinetics of the combinations were assessed using time-kill assays.
RESULTS: In the checkerboard tests, polymyxins-GPOAs combinations exert synergistic effects characterized by species and strain specificity. The synergistic interactions on P. aeruginosa strains are significantly lower than those on strains of A. baumannii, K. pneumoniae and E. coli. Among all the combinations, COL has shown the best synergistic effect in combination with dalbavancin (DAL) or oritavancin (ORI) versus almost all of the strains tested, with FICIs from 0.16 to 0.50 and 0.13 to < 0.28, respectively. In addition, the time-kill assays demonstrated that COL/DAL and COL/ORI had sustained bactericidal activity.
CONCLUSIONS: Our results indicated that polymyxins could help GPOAs to permeate the OM of specific GNB, thus showed synergistic effects and bactericidal effects in the in vitro assays. In vivo combination studies should be further conducted to validate the results of this study.
摘要：
背景：革兰氏阴性菌（GNB）对多种抗生素的耐药性越来越高。目前针对GNB的治疗方法有限，据报道，抗生素与互补机制的组合是治疗GNB感染的可行策略。无法穿过GNB外膜（OM）是缺乏广谱革兰氏阳性唯一类抗生素（GPOAs）的重要原因。多粘菌素可能通过破坏GNB的OM来帮助GPOA渗透。
目的：为了确定多粘菌素可以帮助扩大其抗GNB谱，我们系统地研究了8种GPOAs与粘菌素（COL）和多粘菌素B（PMB）在体外对GNB的协同作用。
方法：通过棋盘测试确定COL或PMB和GPOAs组合对GNB参考菌株和临床分离株的协同作用。使用时间-杀灭测定评估组合的杀灭动力学。
结果：在棋盘测试中，多粘菌素-GPOAs组合发挥以物种和菌株特异性为特征的协同作用。铜绿假单胞菌菌株的协同相互作用显著低于鲍曼不动杆菌菌株,肺炎克雷伯菌和大肠杆菌。在所有的组合中，与几乎所有测试的菌株相比，COL与达巴万星（DAL）或奥利万星（ORI）组合显示出最佳的协同作用。FICI分别为0.16至0.50和0.13至<0.28。此外,时间杀灭试验表明，COL/DAL和COL/ORI具有持续的杀菌活性。
结论：我们的结果表明多粘菌素可以帮助GPOAs渗透特定GNB的OM，因此在体外试验中显示出协同作用和杀菌作用。应进一步进行体内联合研究以验证本研究的结果。
目的：为了确定多粘菌素可以帮助扩大其抗GNB谱，我们系统地研究了8种GPOAs与粘菌素（COL）和多粘菌素B（PMB）在体外对GNB的协同作用。
方法：通过棋盘测试确定COL或PMB和GPOAs组合对GNB参考菌株和临床分离株的协同作用。使用时间-杀灭测定评估组合的杀灭动力学。
结果：在棋盘测试中，多粘菌素-GPOAs组合发挥以物种和菌株特异性为特征的协同作用。铜绿假单胞菌菌株的协同相互作用显著低于鲍曼不动杆菌菌株,肺炎克雷伯菌和大肠杆菌。在所有的组合中，与几乎所有测试的菌株相比，COL与达巴万星（DAL）或奥利万星（ORI）组合显示出最佳的协同作用。FICI分别为0.16至0.50和0.13至<0.28。此外,时间杀灭试验表明，COL/DAL和COL/ORI具有持续的杀菌活性。
结论：我们的结果表明多粘菌素可以帮助GPOAs渗透特定GNB的OM，因此在体外试验中显示出协同作用和杀菌作用。应进一步进行体内联合研究以验证本研究的结果。
