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Bioprocess

2164-5566

Scientific Research Publishing

10.12677/BP.2024.141001

BP-82349

BP20240100000_84587392.pdf

生命科学

肺炎克雷伯菌异质性耐药的研究进展 Research Progress on Heterogeneous Drug Resistance of Klebsiella pneumoniae

潘

菊

² ¹ 阮

奔放

² ¹

浙江工业大学药学院，浙江杭州

null

08 03 2024

14 01 1 6

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

肺炎克雷伯菌是肠杆菌科克雷伯氏菌属(俗称肺炎杆菌)中最重要的一员，也是造成院内感染的主要病原菌之一，可引起肺部、泌尿道、血液、脑部等部位的感染。近年来，由于抗生素的广泛和不合理的使用，肺炎克雷伯菌对多种抗生素产生耐药性且耐药率逐年增高，除了对抗生素耐药之外，肺炎克雷伯菌对多种抗生素的异质性耐药也已出现。异质性耐药被认为是细菌耐药性进化的一个中间过程，是一种特殊的耐药形式，临床检测困难且机制复杂，目前已成为临床抗生素治疗失败的主要原因之一。对异质性耐药进行研究有助于了解临床常见病原菌的耐药发展过程，这对预防和控制细菌耐药及指导临床用药具有重要意义。在本文中，主要对肺炎克雷伯菌异质性耐药的定义、检测方法及可能的耐药机制进行如下综述。 Klebsiella pneumoniae is the most important member of the Enterobacteriaceae genus Klebsiella pneumoniae (commonly known as Klebsiella pneumoniae), and it is also one of the main pathogens causing nosocomial infection. It can cause infections in the lung, urinary tract, blood, brain and other parts. In recent years, due to the widespread and irrational use of antibiotics, Klebsiella pneumoniae has become resistant to a variety of antibiotics and the resistance rate is increasing year by year. In addition to antibiotic resistance, heterogeneous resistance to a variety of antibiotics has also emerged. Heteroresistance is considered to be an intermediate process in the evolution of bacterial resistance. It is a special form of drug resistance, which is difficult to detect clinically and has a complex mechanism. The study of heteroresistance is helpful to understand the development process of drug resistance of common clinical pathogens, which is of great significance for the prevention and control of bacterial resistance and the guidance of clinical medication. In this paper, the definition, detection methods and possible drug resistance mechanisms of Klebsiella pneumoniae heteroresistance are reviewed as follows.

抗生素，肺炎克雷伯菌，异质性耐药, Antibiotics Klebsiella pneumoniae Heteroresistance

摘要

关键词

抗生素，肺炎克雷伯菌，异质性耐药

Research Progress on Heterogeneous Drug Resistance of Klebsiella pneumoniae<sup> </sup>

Ju Pan, Benfang Ruan

College of Pharmacy, Zhejiang University of Technology, Hangzhou Zhejiang

Received: Dec. 29^th, 2023; accepted: Mar. 1^st, 2024; published: Mar. 8^th, 2024

ABSTRACT

Klebsiella pneumoniae is the most important member of the Enterobacteriaceae genus Klebsiella pneumoniae (commonly known as Klebsiella pneumoniae), and it is also one of the main pathogens causing nosocomial infection. It can cause infections in the lung, urinary tract, blood, brain and other parts. In recent years, due to the widespread and irrational use of antibiotics, Klebsiella pneumoniae has become resistant to a variety of antibiotics and the resistance rate is increasing year by year. In addition to antibiotic resistance, heterogeneous resistance to a variety of antibiotics has also emerged. Heteroresistance is considered to be an intermediate process in the evolution of bacterial resistance. It is a special form of drug resistance, which is difficult to detect clinically and has a complex mechanism. The study of heteroresistance is helpful to understand the development process of drug resistance of common clinical pathogens, which is of great significance for the prevention and control of bacterial resistance and the guidance of clinical medication. In this paper, the definition, detection methods and possible drug resistance mechanisms of Klebsiella pneumoniae heteroresistance are reviewed as follows.

Keywords:Antibiotics, Klebsiella pneumoniae, Heteroresistance

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

肺炎克雷伯菌(Klebsiella pneumoniae, KP)是一种常见的革兰氏染色阴性，不能运动的，周围有多糖荚膜包囊的杆状芽孢杆菌，属于克雷伯氏菌属和肠杆菌科，其广泛存在于自然环境中。肺炎克雷伯菌不具备传染性，是一种条件致病菌，能够正常存在于人体的呼吸道及肠道中，在机体免疫力减退、滥用抗生素或进行气管插管等情况下，通过吞咽、吸入、插管等方式可使致病菌进入肺部引起感染 [ 1 ] 。肺炎克雷伯菌是医院感染的重要致病菌之一，近年来随着抗生素在临床的大量及不合理使用，肺炎克雷伯菌的耐药性问题日趋严重。在过去的几年里，越来越多的表达高粘液表型的高毒力肺炎克雷伯菌(hvKP)分离株被反复报道，这些分离株现在被认为是对公共健康的严重威胁 [ 2 ] 。这些耐药菌株的出现会导致临床抗菌药物的治疗失败和病程迁延 [ 3 ] [ 4 ] 。

研究发现，肺炎克雷伯菌还存在另一种耐药情况，即细菌异质性耐药(heteroresistance, HR)。在过去几年内，全球范围内已出现多例异质性耐药肺炎克雷伯菌株 [ 5 ] ，然而由于异质性耐药表型和遗传的不稳定性及耐药机制尚未明确一直难以进行检测和研究 [ 6 ] 。本文简要综述肺炎克雷伯菌异质性耐药的研究进展，为其评估治疗方案和指导临床抗菌药物的合理使用提供参考。

2. 异质性耐药的发现及定义

自1928年青霉素问世以来，抗生素的使用已成为现代医疗的重要手段，但随着抗生素使用的增加，细菌对抗生素的耐药问题也在越来越严重 [ 7 ] 。最初在1947年就有报道描述了革兰阴性细菌流感嗜血菌的异质性耐药现象 [ 8 ] ，但这一词首次被提出是在1970年 [ 9 ] 。自此以后，不断发现各种细菌对多种不同抗生素产生异质性耐药现象。但是由于缺乏对异质性耐药精确的定义，以及缺乏对其机制的理解，阻碍了我们研究和掌握这种现象所带来的临床威胁。

异质性耐药被认为是细菌耐药性进化过程中的一个中间过程，机制复杂，其定义尚无统一标准。广义的异质性耐药是指在细菌群体中具有一个亚群或几个亚群的耐药性与主要群体相比，这些亚群表现出更高的抗生素耐药性水平 [ 10 ] 。现通常以，El-Halfawy等 [ 11 ] 定义的标准作为参考，即测试菌株可分离出不同耐药程度的细菌亚群，其中一个或多个亚群对某一抗菌药物的耐药程度高于菌株主要亚群的耐药程度，其对某种抗生素的最小抑菌浓度(minimum inhibitory concentration, MIC)值高于相应菌株主要亚群至少8倍且细菌群体中异质性耐药亚群的比例应 ≥ 10⁻⁷，以此能够更合理地描述异质性耐药 [ 12 ] 。除此之外，在定义异质性耐药时，耐药亚群的稳定性和克隆性也是需要考虑的因素。当耐药亚群在没有抗生素压力的情况下，在50代内能够恢复到亲代耐药水平，则为不稳定型异质性耐药，反之如果在没有抗生素压力的情况下，亚群的耐药性没有降低或恢复到亲代耐药水平，则为稳定型异质性耐药 [ 13 ] [ 14 ] 。区分多克隆异质性耐药和单克隆异质性耐药对于从机制上研究异质性耐药具有重要意义，多克隆异质性耐药包括耐药突变和对抗生素敏感性不同的菌株感染，这样产生的耐药性通常是稳定的。而单克隆异质性耐药性是由细菌群体内的异质性引起的，在维持数代后常常丢失其耐药性 [ 10 ] [ 15 ] 。

3. 异质性耐药的检测方法 3.1. 表型耐药检测

异质性耐药的常用表型耐药检测方法有K-B纸片扩散法、E-test法和群体普分析法(population analysis profiling, PAP) [ 16 ] 。目前检测异质性耐药主要通过K-B法或E-test法进行初步检测，当抑菌圈内出现耐药亚群菌落即为疑似异质性耐药菌株，再对存在该现象的疑似菌株采用PAP法来进行确认。PAP被认为是确定异质性耐药的“金标准”，是指将待测菌株于不同浓度梯度抗生素的琼脂培养基或液体培养基中进行培养，观察其生长情况并进行单菌落计数，以完全抑制细菌生长的抗生素浓度与开始抑制细菌生长的抗生素浓度之间的差值来描述细菌异质性耐药情况。目前常以耐药亚群频率 > 10⁻⁷且MIC值高于主要亚群MIC值的8倍作为判断异质性耐药的标准 [ 11 ] 。

3.2. 分子耐药检测

近年来，各种先进的技术被用来评估异质性耐药细菌，通过比较多种抗菌药物浓度下的单个细菌生长情况，准确识别异质性耐药。全基因组测序是检测临床分离株耐药亚群的一种越来越常用的方法 [ 17 ] [ 18 ] 。此外，利用拉曼光谱技术可对直接对样本中分离出的病原菌进行逐一检测，可准确测量个体细菌在测试药物作用下的异质性变化 [ 19 ] 。微液滴数字PCR技术(ddPCR)也是一种较为灵敏的检测方法，其是基于泊松(Poisson)分布原理的核酸分子绝对定量技术，可以检测与耐药性相关的基因或点突变 [ 20 ] 。

4. 肺炎克雷伯菌的异质性耐药机制 4.1. 碳青霉烯类抗菌药物的异质性耐药机制

肺炎克雷伯菌对碳青霉烯类抗菌药物的耐药机制与其携带不同的耐药基因有关，其主要机制有四种：产生能灭活碳青霉烯的碳青霉烯酶，外膜孔蛋白基因突变或基因缺失引起的外膜通透性的改变、膜外排泵基因上调表达以及抗生素作用蛋白靶点的突变。在上述几种机制中，产碳青霉烯酶是肺炎克雷伯菌碳青霉烯类耐药最主要的机制，肺炎克雷伯菌主要的碳青霉烯酶(KPC)是最常见的A类丝氨酸β-内酰胺酶，由携带在质粒上的blaKPC基因编码，并通过Tn4401转座子转运，这有助于其在细菌分离物之间的有效转移 [ 21 ] 。除KPC外，肺炎克雷伯菌还可产生不同的金属β-内酰胺酶，包括亚胺烯酶(IMP)、新德里金属β-内酰胺酶(NDM)、维罗纳整合子编码的金属-b-内酰胺酶(VIM)和oxy-48样碳青霉烯酶 [ 3 ] [ 21 ] 。膜孔蛋白是肺炎克雷伯菌细胞外膜上一种特殊的水溶性通道蛋白，主要由OmpK35和OmpK36基因编码。有研究表明，肺炎克雷伯菌对碳青霉烯类抗菌药物的耐药机制可能与编码外膜孔蛋白OmpK35和OmpK36的基因突变或缺失相关 [ 22 ] 。Adams-Sapper等人研究发现了OmpK36孔蛋白减少所导致的产KPC-2肺炎克雷伯菌菌株，相比于敏感菌株而言，其对亚胺培南的MIC增加了32倍 [ 23 ] 。

4.2. 黏菌素类抗菌药物的异质性耐药机制

近年来的研究已经发现，肺炎克雷伯菌中粘菌素异质性耐药的机制与粘菌素耐药亚群中基因phoP [ 24 ] 、phoQ、PmrA [ 25 ] 、yciM [ 26 ] 、lpxM等发生多种特异性的基因突变有关。而近年的研究则表明，在产KPC的肺炎克雷伯菌中，多粘菌素耐药最为常见的耐药机制是基因mgrB的失活。mgrB是一段编码跨膜蛋白的基因，它作为PhoPQ系统的负调节因子，它的失活会导致pmrHFIJKLM操纵子过表达 [ 27 ] 。此外mgrB基因的失活也可能使细菌产生厚荚膜以保护细菌免受粘菌素的侵害 [ 28 ] 。除了基因突变的机制外，粘菌素的异质性也可能与肺炎克雷伯菌生物膜形成过程中出现的小菌落变异表型有关 [ 29 ] 。生物膜具有保护细菌免受外界环境的影响和攻击的功能，是抗生素的物理屏障。生物膜的复杂结构有利于形成具有不同基因表达形式的异质性耐药亚群。

4.3. 四环素类抗菌药物的异质性耐药机制

肺炎克雷伯菌对四环素产生异质性耐药的机制与耐药亚群中外排泵相关基因表达水平增加或活性增强有关。研究表明，四环素耐药机制包括外排泵AcrAB、OqxAB和MacAB的过表达。AcrAB和oqxAB基因的表达受全局转录激活因子如RAMA、SOXS和MARA的调控 [ 30 ] [ 31 ] 。有研究人员发现依拉环素(一种新型的氟四环素类抗生素)异质性耐药可由OqxAB和MacAB外排泵以及转录调节剂RamA的过表达引起 [ 30 ] 。

4.4. 氨基糖苷类抗菌药物的异质性耐药机制

对质粒编码的16SrRNA甲基化酶和氨基糖苷类修饰酶(Ames)基因的存在是肺炎克雷伯菌产生氨基糖苷类耐药的主要原因 [ 32 ] 。16SrRNA能够阻断氨基糖苷类抗生素与16SrRNA靶点的结合，使得药物与其靶点不能结合，从而引起肺炎克雷伯菌对氨基糖苷类抗生素的耐药性。肺炎克雷伯菌的氨基糖苷类异质性耐药主要是由于携带在质粒上并编码氨基糖苷乙酰转移酶(AAC)的AMEs基因扩增引起 [ 14 ] ，然而这种耐药表型并不稳定，在无抗生素压力的情况下传代40代后，菌株可减少拷贝数或丢失质粒而恢复敏感。

4.5. 磷霉素异质性耐药

肺炎克雷伯菌对磷霉素产生异质性耐药产生的机制是耐药亚群中磷霉素靶酶MurA活性位点特别是磷霉素结合位点的突变，包括周边氨基酸替换变导致磷霉素摄取系统缺陷及磷霉素耐药基因MurA过度表达，磷霉素异质性耐药表型的发生和变化部分是由菌株的突变增加导致的 [ 33 ] [ 34 ] 。

5. 肺炎克雷伯菌耐异质性耐药的治疗策略

最近的研究结果表明，临床批准的抗生素组合可能会根除与异质性耐药肺炎克雷伯菌相关的感染 [ 25 ] [ 35 ] [ 36 ] 。Cheong等人研究发现，美罗培南与粘菌素联合使用可能是治疗异质性耐粘菌素肺炎克雷伯菌感染的一种选择 [ 36 ] 。美罗培南可单独根除一株异质性耐药分离株，但其与粘菌素的联合使用效果更好。此外田等人研究了多粘菌素B和替加环素对肺炎克雷伯菌分离株的联合作用，这些分离株对这两种抗生素都表现出双重异质耐药性 [ 36 ] 。对这些分离株进行时间杀灭实验，对于对多粘菌素B具有异质性耐药性的菌株，在多粘菌素B单药治疗的前4小时至10小时内达到了杀灭效果，但它们在10小时后迅速再生。替加环素单药治疗对菌株有短暂的抑制作用，随后细菌生长也缓慢增加。结果表明抗生素单一疗法(多粘菌素B或替加环素)具有短暂的抑制作用，敏感细菌被杀死，耐药亚群却没有被消除。但是减少剂量的多粘菌素B和替加环素的联合使用导致分离株的细菌CFU显著减少，成功地根除了敏感和耐药亚群。这些结果表明，多种抗生素联合使用可能是治疗异质性耐药肺炎克雷伯菌感染的一种有效方法。

6. 总结

近年来的研究显示，肺炎克雷伯菌对抗生素的耐药率呈逐年快速上升的趋势 [ 37 ] 。到目前为止，仍然缺少异质性耐药异质的标准定义和检测方法，这限制了异质性耐药的进一步研究。同时，异质性耐药机制十分复杂，不同种属细菌对同种抗生素异质性耐药机制各不相同，即使是同种细菌对同种抗生素异质性耐药机制也不尽相同。如果异质性耐药菌株不能给予及时发现和有效控制，异质性耐药将最终进展至完全耐药，影响临床用药选择及治疗效果。因此，建立规范化、快速的异质性耐药实验室检测技术迫在眉睫，并且需要进一步探究肺炎克雷伯菌异质性耐药的机制，防止肺炎克雷伯菌异质性耐药菌感染的传播。

文章引用

潘菊,阮奔放. 肺炎克雷伯菌异质性耐药的研究进展 Research Progress on Heterogeneous Drug Resistance of Klebsiella pneumoniae[J]. 生物过程, 2024, 14(01): 1-6. https://doi.org/10.12677/BP.2024.141001

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