不动杆菌对替加环素及多黏菌素耐药机制研究进展

不动杆菌属细菌是临床常见的非发酵糖菌,广泛分布于医院环境中,是引起多种院内感染的重要条件致病菌.随着临床抗菌药物的大量使用,不动杆菌逐渐出现了多重耐药甚至全耐药株,有效抗菌药物极少,给临床感染的治疗带来极大困难.近年来发现替加环素和多黏菌素治疗多重耐药革兰阴性菌感染特别是鲍曼不动杆菌有较好疗效,但随着研究的不断深入,逐渐发现不动杆菌对替加环素及多黏菌素也存在耐药性,本文就目前国内外不动杆菌对替加环素及多黏菌素耐药机制进行简要综述.不动杆菌对替加环素耐药机制主要与AdeABC外排泵系统有关,对多黏菌素的耐药机制主要为外膜LPS修饰.还需要针对不动杆菌对替加环素及多黏菌素的耐药机制进一步研究,从而指导临床合理使用抗菌药物.     

双组分调节系统对肺炎克雷伯菌多黏菌素耐药机制影响的研究进展

多黏菌素（多黏菌素B和黏菌素）是目前治疗多重耐药肺炎克雷伯菌的最后一种抗生素,尤其是耐碳青霉烯类肺炎克雷伯菌出现以来。然而,临床分离株中多黏菌素耐药的报告逐渐增加,给临床治疗带来极大的挑战。肺炎克雷伯菌可通过双组分调节系统（two-component regulatory systems, TCSs）修饰脂多糖、mgrB负反馈调节因子、外排泵等介导多黏菌素耐药,在肺炎克雷伯菌多黏菌素耐药过程中扮演了重要角色。本文综述了TCSs信号转导的基础、激活条件及其过表达导致肺炎克雷伯菌最低抑制浓度改变的反馈通路,阐述TCSs导致肺炎克雷伯菌对多黏菌素耐药的机制,对多黏菌素的研究和发现针对临床相关肺炎克雷伯菌感染的潜在药物提供理论基础。     

多黏菌素耐药机制的研究进展

摘要：多黏菌素对多种革兰阴性菌具有很强的杀菌活性,是目前被用于多重耐药和泛耐药细菌感染临床治疗的最后选择, 多黏菌素主要与脂多糖(lipopolysaccharide,LPS)带负电荷的脂质A成分相互作用,并将带正电的残基(例如4-氨基-L-阿拉伯糖、 磷酸乙醇胺和/或半乳糖胺)添加到LPS中,减少细菌表面上的负电荷,从而降低LPS的稳定性并破坏外膜的完整性,以达到杀灭 细菌的目的。然而,随着多黏菌素使用频率的增加,耐药菌株正以惊人的速度出现。革兰阴性菌的大多数多黏菌素耐药机制与 细菌LPS结构的变化有关,多黏菌素耐药性物种产生的LPS本质上含有这些添加物中的一种或多种,这些添加物的产生所需的 基因大多数是染色体编码的,然而,最近已鉴定出携带磷酸乙醇胺转移酶基因(mcr-1~mcr-8)的质粒,这些质粒可能会加快多黏 菌素耐药性的传播速度。独特的是,鲍曼不动杆菌可以通过脂质A生物合成基因lpxA、lpxC或lpxD中的自发突变而不产生LPS或 脂质A,从而对多黏菌素具有高度抗性。此外,在细菌中还发现了一系列其他非LPS依赖性多黏菌素抗性机制,但这些机制通 常仅导致较低水平的抗性,如肺炎克雷伯菌产生的阴离子荚膜多糖,脑膜炎奈瑟菌表达的MtrCDE外排系统,以及少数物种外 膜蛋白表达的改变。鉴于多黏菌素对多重耐药和泛耐药细菌临床治疗的重要性,本文主要对多黏菌素耐药机制的研究进展进行 综述。     

产blaNDM-1肺炎克雷伯菌的高水平多黏菌素耐药株制备及耐药机制研究

摘要：目的 研究产blaNDM-1肺炎克雷伯菌产生多黏菌素耐药的可能性,并对相关机制进行分析。方法 通过黏菌素肉汤 传代培养研究携带blaNDM-1菌株产生多黏菌素耐药的可能性,并对分离出的耐药株通过PCR、Real-time PCR、脉冲场凝胶电泳等 方法进行耐药分子机制研究。结果 通过黏菌素肉汤传代培养,产blaNDM-1肺炎克雷伯菌可进一步表现高水平多黏菌素耐药表 型。检测发现耐药株中膜孔蛋白基因及双组分调节系统中多黏菌素耐药相关基因发生表达水平变化,可能导致菌株对多黏菌素 高水平耐药。结论 产blaNDM-1肺炎克雷伯菌经黏菌素传代诱导培养后可进一步发展多黏菌素耐药,需要引起临床注意。     

多黏菌素E耐药基因mcr-1在我国养殖场的流行及其传播扩散

多黏菌素E是临床上用来治疗多重耐药革兰阴性菌的重要药物之一，特别是用于治疗产超广谱β-内酰胺酶或碳青霉烯酶的多重耐药菌。多黏菌素耐药基因mcr-1的出现，使得细菌对多黏菌素E的耐药性有了水平传播的可能。养殖场被认为是MCR-1阳性菌株传播的源头。食物链和环境是mcr-1基因传播的主要途径。本篇综述重点阐述了mcr-1在我国养殖场的流行情况以及其可能的传播扩散途径，并提出了当下需要解决的一些问题，以期能为今后同行的相关研究提供参考。     

鲍曼不动杆菌对多黏菌素类抗菌药物耐药现状及机制研究进展

多黏菌素类抗菌药物是多重耐药鲍曼不动杆菌的最后防线，但随着临床对多黏菌素类药物使用增多，鲍曼不动杆菌对其耐药的报道也陆续出现，相关耐药机制的研究成为热点。本文对近年来国内外鲍曼不动杆菌对多黏菌素类耐药报道以及耐药机制研究进行综述，以期对临床合理应用多黏菌素类抗菌药物、保持其抗菌活性提供参考。     

多黏菌素B的药动学和药效学与肾毒性的研究进展

近些年,多黏菌素B在其他药物治疗无效的革兰阴性杆菌(如多药耐药细菌和泛耐药细菌)感染的挽救性治疗方案中扮演着重要的角色,其临床价值被重新予以重视。但由于其潜在的肾毒性,在经验性给药方案下难以精准用药,制约着其在临床上合理使用。本文分别对多黏菌素B的药动学(PK)和药效学(PD)、肾毒性机制及影响肾毒性的危险因素进行了分析,阐明了多黏菌素B主要通过非肾途径清除,在临床上对于严重感染的患者需使用负荷剂量,通过控制其他协变量可以减少患者肾毒性的发生率,及多黏菌素B诱导的肾毒性涉及线粒体途径和细胞死亡受体途径,以期为多黏菌素B的临床合理使用提供参考。     

耐多黏菌素肺炎克雷伯菌的研究进展

碳青霉烯类耐药肺炎克雷伯菌导致的感染逐年攀升,使抗菌药物的选择陷入窘境。多黏菌素在临床上被重新启用治疗多重耐药革兰阴性杆菌引发的严重感染。但随其在畜牧业等领域的广泛应用和不合理使用,耐多黏菌素菌株报道逐年增多,耐药相关问题不断涌现。本文将多黏菌素耐药的主要机制和治疗中联合用药组合方式作一综述,以期为临床治疗提供指导。     

多黏菌素B治疗泛耐药肺炎克雷伯菌颅内感染疗效分析

目的 探讨多黏菌素B治疗泛耐药肺炎克雷伯菌颅内感染的临床疗效及愈后,为多黏菌素B在临床合理使用提供借鉴。方法 采用回顾性分析方法,收集34例确诊泛耐药肺炎克雷伯菌颅内感染的病例资料,按药物治疗方案中是否使用多黏菌素分为两组,观察其脑脊液指标恢复情况、临床转归及肾功能指标。结果 以多黏菌素B为基础,联合其他药物治疗泛耐药肺炎克雷伯菌颅内感染,能显著改善脑脊液指标、提高细菌清除率、延长生存时间,且无急性肾功能损伤出现,但是不能降低28d死亡率。多黏菌素使用方法采用静脉注射联合鞘内给药。结论 以多黏菌素B为基础的联合用药治疗泛耐药肺炎克雷伯菌颅内感染有一定疗效,可用于治疗严重颅内感染。     

碳青霉烯类异质性耐药铜绿假单胞菌的耐药机制研究

摘要：目的 筛选铜绿假单胞菌临床分离株的碳青霉烯类异质性耐药菌株,并分析相关机制。方法 采用E-test纸条法、 群体分析法(PAP)法对30株铜绿假单胞菌临床分离株进行亚胺培南异质性耐药的初筛和复筛、肉汤微量稀释法测定异质性耐药菌 株对亚胺培南及其他药物的MIC值、全基因组测序分析碳青霉烯类异质性耐药菌株的可能耐药机制。结果 通过E-test纸条法和 PAP法鉴别筛选出8株亚胺培南异质性耐药铜绿假单胞菌,检测发现异质性耐药菌株对多黏菌素B、头孢他啶、美罗培南耐药率 较高,对环丙沙星等更敏感。全基因组测序分析发现碳青霉烯类异质性耐药铜绿假单胞菌无可确证的基因突变,但可能与延伸 因子P基因有关。     

多黏菌素异质性耐药的研究进展及临床意义

Due to the extensive use of antibiotics, bacterial resistance is constantly emerging. Nowadays, polymyxins have become the last-resort to defend against multidrug-resistant bacteria, especially carbapenem-resistant Gram-negative bacteria. However, in recent years, there are more and more reports about polymyxin resistance, and the heteroresistance of polymyxins has been found to be a severe situation. Heteroresistance is the intermediate process from sensitivity to drug resistance. Routine clinical tests cannot effectively detect the heteroresistance, which poses a huge threat to the clinical treatment of drugs, resulting in repeated infections and drug failure. However, there are few researches on its mechanism. At present, it is mainly related to the mutations of LPS related genes on chromosomes, the unstable amplification of drug-resistant genes, and the efflux pump system. In this paper, we summarize the related research of bacterial heteroresistance, especially heteroresistance of polymyxins and its clinical     

RecA inactivation as a strategy to reverse the heteroresistance phenomenon in clinical isolates of Escherichia coli

RecA inhibition could be an important strategy to combat antimicrobial resistance because of its key role in the SOS response, DNA repair and homologous recombination contributing to bacterial survival. This study evaluated the impact of RecA inactivation on heteroresistance in clinical isolates of Escherichia coli and their corresponding recA-deficient isogenic strains to multiple classes of antimicrobial agents. A high frequency (>30%) of heteroresistance was observed in this collection of clinical isolates. Deletion of the recA gene led to a marked reduction in heteroresistant subpopulations, especially against quinolones or β-lactams. The molecular basis of heteroresistance was associated with an increase in copy number of plasmid-borne resistance genes (bla_TEM-1B) or tandem gene amplifications (qnrA1). Of note, in the absence of the recA gene, the increase in copy number of resistance genes was suppressed. This makes the recA gene a promising target for combating heteroresistance.     

多粘菌素对泛耐药革兰阴性杆菌严重感染临床应用新进展

目的：了解多粘菌素的相关特点,为制定合理的给药方案,提高临床疗效和安全性提供参考。方法：通过查阅文献,总结多粘菌素B及E的药理学特点、临床应用新进展、不良反应及耐药性,并提出相应的防治对策。结果：多粘菌素类对泛耐药革兰阴性菌感染,特别对多药耐药的鲍曼不动杆菌和铜绿假单胞菌所致感染有较好疗效。其肾毒性及神经肌肉阻滞反应的发生率较以前降低。由于多粘菌素类的广泛应用,革兰阴性菌中已出现耐药菌株。结论：多粘菌素类使用时应注意剂量、与其他药物联用以及肾功能不全患者安全合理使用等问题。     

多黏菌素类药物的肾毒性及其优化给药方案研究进展

多重耐药及泛耐药革兰阴性菌的流行给临床抗感染治疗带来了巨大挑战.由于新型抗菌药物研究开发缓慢,多黏菌素这类曾因严重的神经毒性和肾毒性而逐渐停止使用的抗生素又重回人们视野,并成为了治疗重症难治性革兰阴性菌感染的主要药物.然而,肾毒性仍严重影响此类药物的临床治疗效果.其肾毒性机制复杂,并且临床上存在着许多肾毒性危险因素,因...     

Adaptive resistance to cationic compounds in Pseudomonas aeruginosa

Adaptive resistance is an autoregulated phenomenon characterised by induction of resistance in the presence of drug and reversal to the sensitive phenotype in its absence. This type of resistance is well documented for polycationic antibiotics, including aminoglycosides and polymyxins, in Pseudomonas aeruginosa and other aerobic Gram-negative bacilli. It is not caused by selection of resistant mutants but rather by phenotypic alterations in order to survive the lethal drug effect. Adaptive resistance to aminoglycosides is mainly mediated by the MexXY-OprM efflux pump that is rapidly upregulated in bacteria surviving the first exposure to aminoglycosides and is downregulated when bacteria are no longer in contact with the drug. A two-component regulatory system designated ParR-ParS plays a major role in adaptive resistance induced by cationic peptides. In the presence of cationic peptides, ParR-ParS activates the lipopolysaccharide modification operon (arnBCADTEF) leading to increased resistance in polymyxins and aminoglycosides. The bactericidal kinetics related to adaptive resistance have important clinical implications and provide a rationale for administering cationic antibiotics in larger initial and longer interval bolus dosing. A better understanding of this phenomenon and the molecular mechanisms responsible will be essential not only for optimum use of cationic antibiotics but also for developing new agents with ability to counteract the detrimental effects of adaptive resistance and thus enhance the therapeutic efficacy of polycationic compounds.     

New information about the polymyxin/colistin class of antibiotics

Infections by multidrug resistant Gram-negative bacilli (MDR-GNB) have become a major threat for patients hospitalized in intensive care units, representing a prevalent cause of morbimortality in the critically ill, since these microorganisms have developed resistance to most available antimicrobial agents. In this respect, very few therapeutic innovations have been developed in recent years, and it is not foreseen that any new drugs will be commercialized in the near future. Tigecycline represents an effective alternative in this setting, but lacks activity against Pseudomonas aeruginosa, and its use has not been validated for all organ-specific infections. Frequently, only old antibiotics like colistin remain a valid option. New pharmaceutical formulations and dosage regimens of polymyxins have considerably reduced the toxicity previously attributed to these antimicrobials, and have made it possible to reintroduce them into clinical practice. Nonetheless, the effectiveness of polymyxins is still suboptimal, and the expansion of heteroresistance and pan-drug-resistant strains of gram-negative bacilli is of concern. Improvements in dosing, alternative methods of administration and different synergic antimicrobial combinations have been proposed in recent literature, among other measures, to enhance the effectiveness of polymyxins. The latest data regarding polymyxins and their clinical use are discussed in this review.     

多黏菌素抗菌机理及耐药机制研究进展

多黏菌素是临床治疗多重耐药的革兰阴性菌感染的最后一道防线。但随着多黏菌素在临床、畜牧业及农业上使用的逐年增加以及一些抗生素滥用情况的发生，导致其对革兰阴性菌的治疗效果相对下降，出现了多种多黏菌素耐药的革兰阴性菌。本文就多黏菌素的抗菌机理、副作用机制、对不同耐药菌的耐药机制进行综述。     

细菌药物主动外排系统在生物被膜耐药中的作用

摘要：细菌生物被膜的产生使传统抗菌药物难以对其进行有效的清除,进而导致严重感染的复发和持续性感染, 是人类目 前面临的又一新的挑战。生物被膜细菌中由于营养物质和代谢产物的积累,促使药物主动外排系统相关基因表达明显增加, 使 外排泵转运多种不同类型的化合物能力增强,从而产生多重耐药表型,是引起细菌耐药的主要机制之一;外排泵基因的表达对 生物被膜细菌的生长和耐药性增强方面有着重要作用。本文从生物被膜耐药的影响因素、药物主动外排系统参与生物被膜形成 及其影响、外排泵抑制剂对生物被膜耐药的影响几个方面对细菌药物主动外排系统在生物被膜耐药中的作用进行综述。     

非编码sRNA在细菌耐药机制方面的研究进展

近年来的研究发现,细菌应答抗生素压力时会产生特异的非编码小RNA(small RNA, sRNA)谱,进而可能调控下游基因的表达,帮助细菌克服抗生素压力。sRNA以各种方式调控细菌耐药相关基因(如抗生素转运蛋白、药物外排泵、细胞被膜的合成与修饰),参与细菌耐药网络。因此,sRNA及其相关因子(如Hfq)可能被用作抗菌治疗的靶标。本文将从sRNA应答抗生素压力并产生抗生素耐药及其作为药物靶点的前景等方面,综述sRNA在细菌耐药调控方面的研究进展。