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Volume 42 Issue 10
Oct.  2024
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QIAN Shuyu, LI Tiejun. Research progress on resistance mechanisms of carbapenem-resistant Enterobacteriaceae[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(10): 419-425. doi: 10.12206/j.issn.2097-2024.202405005
Citation: QIAN Shuyu, LI Tiejun. Research progress on resistance mechanisms of carbapenem-resistant Enterobacteriaceae[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(10): 419-425. doi: 10.12206/j.issn.2097-2024.202405005

Research progress on resistance mechanisms of carbapenem-resistant Enterobacteriaceae

doi: 10.12206/j.issn.2097-2024.202405005
  • Received Date: 2024-05-06
  • Accepted Date: 2024-09-18
  • Rev Recd Date: 2024-09-10
  • Available Online: 2024-10-24
  • Publish Date: 2024-10-25
  • Carbapenem-resistant Enterobacteriaceae (CRE) is an increasingly serious threat to human health worldwide. CRE usually carries multiple drug resistance genes, which limit the selection of therapeutic drugs, prolong treatment time, require higher treatment costs and greater treatment risks. The epidemiology, resistance mechanisms, current resistance status of CRE and the latest therapeutic drugs for CRE were summarized in this papoer, which provide a basis for the rational use of antibiotics in clinical prevention and treatment of drug-resistant bacterial infections.
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Research progress on resistance mechanisms of carbapenem-resistant Enterobacteriaceae

doi: 10.12206/j.issn.2097-2024.202405005

Abstract: Carbapenem-resistant Enterobacteriaceae (CRE) is an increasingly serious threat to human health worldwide. CRE usually carries multiple drug resistance genes, which limit the selection of therapeutic drugs, prolong treatment time, require higher treatment costs and greater treatment risks. The epidemiology, resistance mechanisms, current resistance status of CRE and the latest therapeutic drugs for CRE were summarized in this papoer, which provide a basis for the rational use of antibiotics in clinical prevention and treatment of drug-resistant bacterial infections.

QIAN Shuyu, LI Tiejun. Research progress on resistance mechanisms of carbapenem-resistant Enterobacteriaceae[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(10): 419-425. doi: 10.12206/j.issn.2097-2024.202405005
Citation: QIAN Shuyu, LI Tiejun. Research progress on resistance mechanisms of carbapenem-resistant Enterobacteriaceae[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(10): 419-425. doi: 10.12206/j.issn.2097-2024.202405005
    • WHO提出抗菌药物耐药性是全球十大健康威胁之一[1],将耐碳青霉烯类肠杆菌(CRE)、耐碳青霉烯铜绿假单胞菌(CRPA)和耐碳青霉烯鲍曼不动杆菌(CRAB)列为最紧迫的威胁。美国疾病控制和预防中心(CDC)将CRE定义为对任何碳青霉烯类抗菌药物不敏感的肠杆菌(即对多利培南、美罗培南或亚胺培南的最低抑制浓度≥4 μg/ml或对厄他培南的最低抑制浓度≥2 μg/ml)或被证明会产生碳青霉烯酶的肠杆菌。碳青霉烯类抗菌药物是一类具有广谱抗菌作用的β-内酰胺类药物,通过抑制青霉素结合蛋白(PBPs)阻碍细菌细胞壁合成[2],曾被许多医院认为是抗菌治疗中的“最后手段”。 目前CRE分离株对大多数临床应用的抗菌药物具有耐药性,从而使临床中抗菌药物的选择受到限制[3]。据统计美国每年有超过13000例CRE感染患者,导致超过1000人死亡[4]。2011年美国CRE感染的发生率为4.2%[5]。2010~2013年欧洲CRE感染的发生率为2.0%[6]。根据抗菌药物耐药性监测网(CHINET)显示,2014年我国CRE感染的发生率为12.5%,2016年为22.9%,2019年则升至26.8%。与2015年相比,2023年中国的CRE发生率增加了58%以上,因此,对CRE的耐药机制的研究值得我们重视。

    • 碳青霉烯酶是一个多样化的β-内酰胺酶家族,具有水解和灭活多种抗菌药物的能力,包括青霉素类、头孢菌素类、单环β-内酰胺类和碳青霉烯类。这些酶与药物结合后破坏四元氮杂二酮环的酰胺键,从而阻止药物与细菌细胞壁青霉素结合蛋白结合[7]。使用Ambler分类系统,碳青霉烯酶可分为A类、B类和D类β-内酰胺酶。

      A类碳青霉烯酶利用丝氨酸残基水解β-内酰胺结构[8],包括含blaKPC、blaNMC/blaIMI和blaSME基因的3种类型[9],其中,最常见的是含blaKPC基因[10],主要存在于肺炎克雷伯菌中,但也存在于多种其他肠杆菌中,包括弗氏柠檬酸杆菌、阴沟肠杆菌、大肠杆菌、粘质沙雷菌以及假单胞菌等 [9]

      B类金属β-内酰胺酶(MBLs)是锌依赖性的[11],包括含blaVIM、blaIMP和blaNDM基因的三种类型[11-13],它们都存在于可移动的遗传基因上,能够水平传播。金属酶类的β-内酰胺酶能够水解多种β-内酰胺类抗菌药物,但不能水解单环β-内酰胺类抗菌药物,如氨曲南。

      D类碳青霉烯酶包括OXA编码基因的成员,主要存在于不动杆菌中,其中blaOXA-48型也存在于肠杆菌中[14-15],与CRE院内感染相关[16-18]。blaOXA-48型包括OXA-48及其相关变体OXA-181、OXA-162和OXA-232型等。

      在中国,存在blaKPC和blaNDM基因是大多数CRE菌株表型耐药的原因[19-20]。其中肺炎克雷伯菌中产生KPC酶最多,其次为OXA-48酶(37%,310/850)和NDM酶(11%,93/850)。在大肠杆菌中,OXA-48酶(56%,43/77)最为常见,其次为NDM酶(26%,20/77)和KPC酶(18%,14/77)[21]

    • 外排泵是一种主动转运蛋白,主动从细菌中排出抗菌药物,减少了细菌中的药物浓度,使细菌产生耐药性。外排泵基因包括5个家族(SMR、MFS、RND、ABC和MATE家族),其中RND家族临床意义更为重要,它们能识别广泛的底物,与多药耐药相关[22]。最具特征的RND系统是AcrAB-ToIC,由膜融合蛋白AcrA(膜间质蛋白、周浆蛋白)、外排转运蛋白AcrB(内膜蛋白)以及外膜通道蛋白TolC(外膜蛋白)组成的三联体复合物,在肠杆菌中占有绝对优势[23-24]。AcrAB-TolC的调节分为局部抑制和转录因子的全局调控。局部抑制因子AcrR可作为调节剂阻止AcrAB的过表达,AcrR的突变使其抑制作用丧失,可导致AcrAB-TolC的过表达而产生多药耐药[25-26]。其他局部抑制因子还有AcrS/EnvR、组蛋白样核结构蛋白(H-NS)和分裂抑制因子(Sdi)A,但相对影响较小[27]。大肠杆菌中,基因表达主要由多重耐药操纵子MarA控制,在肠沙门氏菌中主要由RamA控制。大肠杆菌中的MarR、MarA和MarB基因参与多种抗菌药物耐药。MarR是一种在没有任何环境信号的情况下阻断自身转录的蛋白质[4],只有当MarR的抑制被破坏时,MarRAB的转录才会发生[28]。MarA的表达导致其调控中的许多基因被激活,包括AcrAB和TolC,从而增加药物外排和多重耐药。此外,氧化应激反应的发生也可能诱导AcrAB,从而产生耐药。

    • 外膜孔蛋白(OMP)的缺乏或突变是碳青霉烯类耐药的潜在重要机制,也是耐碳青霉烯肺炎克雷伯菌、耐碳青霉烯鲍曼不动杆菌等耐碳青霉烯类肠杆菌的重要耐药机制。OmpK35和OmpK36是两种非特异性孔蛋白,抗菌药物及亲水小分子可通过这两种孔蛋白以被动扩散方式进入细菌内而发挥抗菌作用。编码序列或启动子位点的突变、插入、删除或替换会使孔蛋白的翻译过早终止,影响孔蛋白表达从而导致抗菌药物难以进入细菌,产生耐药性。另一种机制是在转录后水平上通过相对较小的sRNAs调节孔蛋白的表达导致耐药,有报道这种现象出现在刺激应激(包括氧化应激)和渗透压、pH值或温度改变下的大肠杆菌分离株与产气肠膜杆菌中[28]。部分研究表明Omp36比Omp35在碳青霉烯耐药中发挥更重要的作用[29-30],它们的缺失或缺乏与AmpC酶的结合可能导致高水平的碳青霉烯类耐药。

    • 青霉素结合蛋白(PBPs)是存在于几乎所有细菌细胞内膜上的一类酶。它们的主要功能是合成细菌细胞壁肽聚糖,形成细胞外骨架。β-内酰胺类抗菌药物的靶蛋白可与细胞内膜上的PBP靶点特异性结合,从而干扰细胞壁肽聚糖的形成,最终导致细菌溶解[31]。PBPs的表达减少或突变可导致抗菌药物MIC值升高,PBPs的突变还可能在导致临床耐药的同时导致孔蛋白产量减少或碳青霉烯酶产生增加,从而发生细菌耐药[32]

    • 氨曲南是单环β-内酰胺类抗菌药物,对产生A类碳青霉烯酶的细菌没有活性,包括高度流行的产KPC碳青霉烯酶的细菌[33]。氨曲南对产生B类和D类碳青霉烯酶的细菌有效,但这些细菌通常携带伴随ESBL基因,可水解氨曲南使其无效,因此作为单一疗法,氨曲南的临床应用通常受到限制[33-34]。氨曲南与新型β-内酰胺酶抑制剂的复合制剂(头孢他啶-阿维巴坦)合用,是一种很有前途的治疗产金属β-内酰胺酶耐药菌的治疗方案。头孢他啶-阿维巴坦单独对金属β-内酰胺酶没有活性,氨曲南对B类碳青霉烯酶有活性但易被其他β-内酰胺酶水解,因此体外,头孢他啶-阿维巴坦和氨曲南之间存在显著的协同作用,可对产金属β-内酰胺酶耐药菌属产生抗菌活性[35]

    • 磷霉素依靠硝酸甘油-3-磷酸转运子(GlpT)和葡萄糖-6-磷酸转运体(UhpT)两种膜转运系统进入细菌内,可同时激活两种转运体使其转运更多磷霉素进入细菌[36]。磷霉素进入细菌后不可逆地竞争性结合丙酮酸-二磷酸尿嘧啶乙酰葡糖胺转移酶(UDP-NrA),参与肽聚糖生物合成的初始步骤[37-39]。肠杆菌科细菌对于磷霉素产生的耐药主要为获得性耐药,即当磷霉素进入细菌的通路发生改变时,细菌就会产生耐药性。例如,大肠埃希菌中编码磷霉素转运体的GlpT、UlpT或UhpT,以及转录上游调控基因UhpA突变都可导致磷霉素进入细菌减少;同时,GlpT和UlpT的表达依赖环磷酸腺苷(cAMP),cAMP表达调控基因ptsl和cyaA的突变导致胞内cAMP浓度降低,从而诱发GlpT和UlpT表达降低,磷霉素进入细菌减少。另外,编码磷霉素水解酶fosA基因也可直接修饰介导肠杆菌对磷霉素的耐药[40-41]

    • 多粘菌素类抗菌药物长期以来一直用于耐药革兰氏阴性菌抗感染治疗,被认为是治疗多重耐药微生物引起感染的一线治疗方案和最后的治疗选择之一,特别是对碳青霉烯类耐药的革兰氏阴性杆菌,其中包括CRE。然而多粘菌素的耐药性正在出现,染色体中点位突变导致细菌脂多糖膜改变或外排泵增加,或由质粒介导的MCR基因改变脂多糖膜中的脂质A导致无法与多粘菌素结合,都会产生耐药性[42-43]。因为多粘菌素具有显著的肾毒性,且通常对携带A类碳青霉烯酶的分离株疗效较低,所以美国感染病学会(IDSA)2023版指南目前不推荐多粘菌素用于治疗CRE。尽管新的抗感染药物已被批准用于临床使用,但世界许多地区都无法获得新药,此时多粘菌素往往还是CRE感染唯一可用的抗菌药物[44-45],因此,其仍被世卫组织认为是“最优先”的至关重要的抗菌药物。

    • 替加环素是在米诺环素核心D环的C9碳处添加了N,N-二甲基甘氨酰胺。因此替加环素有不受四环素类抗菌药物主要耐药机制影响的特性,如四环素特异性外排泵和核糖体保护机制。替加环素通过可逆结合细菌核糖体30S亚基上的螺旋区(H34)来抑制细菌蛋白翻译。随着替加环素在耐碳青霉烯肺炎克雷伯菌感染临床治疗中应用广泛,对肠杆菌科细菌耐药的报道也逐渐增多[46]。替加环素耐药机制有:核糖体蛋白结合位点突变、细胞膜变异、主动外排泵转运系统和修饰酶降解等。在肺炎克雷伯菌、大肠杆菌中,核糖体S10蛋白的编码基因rpsJ突变可介导替加环素耐药[47]。肠杆菌科细菌中,耐药相关外排泵AcrAB-TolC和OqxAB也是细菌对替加环素的敏感性降低的原因之一[48-49]。大肠杆菌中,由IncFIA 质粒编码的RND 型外排泵TMexCD1-TOprJ1可导致替加环素外排增加;另外,核糖体保护蛋白Tet(X)变异体结合可结合性质粒,可以在不同种属的细菌间进行替加环素耐药性的水平传播[50]

    • 头孢他啶-阿维巴坦是一种由第三代头孢菌素头孢他啶与新型β内酰胺酶抑制剂阿维巴坦组成的复合制剂,主要通过阿维巴坦抑制多种类型的β内酰胺酶保护头孢他啶,从而增强头孢他啶杀菌作用[51]。阿维巴坦对于各类β内酰胺酶有广泛的抑制活性,但对于缺乏活性位点丝氨酸残基的B类金属酶(NDM1)无抑制能力[52]。头孢他啶-阿维巴坦对于革兰阴性菌特别是肠杆菌属有较好的抗菌活性,但近年来头孢他啶-阿维巴坦耐药率逐渐上升,其耐药性产生的原因主要是产生金属β内酰胺酶:B类金属酶通过锌离子与β内酰胺类底物结合,可水解所有临床使用的丝氨酸β内酰胺酶抑制剂,包括阿维巴坦;其他原因还包括KPC型碳青霉烯酶基因过表达及β内酰胺酶关键位点氨基酸突变,还存在膜通透性缺陷(即OmpK35、OmpK36和OmpK37的改变)和青霉素结合蛋白突变、外排泵的过表达等原因。

    • 美罗培南-法硼巴坦于2017年获得美国食品药品管理局(FDA)批准,2018年获得欧洲药品管理局(EMA)批准,用于治疗急性胰腺炎、复杂性腹腔感染、医院获得性肺炎、呼吸机相关性肺炎及复杂性尿路感染。法硼巴坦(RPX7009)是一种环状硼酸药效团的β-内酰胺酶抑制剂,其结构与既往上市的其他β-内酰胺酶抑制剂有所不同,法硼巴坦中的硼原子与特定β-内酰胺酶的2-巯基乙酰取代基处的催化丝氨酸形成可逆共价键而发挥作用[53]。法硼巴坦对不同碳青霉烯酶的活性不同,对Ambler A类酶(包括ESBLs、KPCs)有活性,但对B类酶(NDM、VIM、IMP)和D类酶(OXA-48)没有活性[54]。一项2018年的研究结果显示,美罗培南-法硼巴坦对共991珠的KPC阳性肠杆菌科分离物的体外敏感性为99.0%,高于头孢他啶-阿维巴坦(98.2%)和替加环素(95.8%);根据MIC90s数据可得美罗培南-法硼巴坦抗菌效力分别是头孢他啶-阿维巴坦的4倍和美罗培南的64倍[55]。一项多中心、回顾性研究指出比较头孢他啶-阿维巴坦与美罗培南-法硼巴坦治疗成人CRE感染,两种治疗方案30 d和90 d死亡率无差异,但头孢他啶-阿维巴坦单药耐药更为常见[56]。美罗培南-法硼巴坦耐药主要是由于OmpK35/36失活(孔蛋白突变)、blaKPC基因拷贝数增加、抗菌药物的靶点修饰及外排泵的激活[57-59]

    • 亚胺培南-瑞来巴坦于2019年获得FDA批准,2020年获得EMA批准,用于治疗由多重耐药革兰氏阴性菌引起的复杂性尿路感染、复杂性腹腔感染、医院获得性肺炎和呼吸机相关性肺炎。瑞来巴坦(MK-7655)是一种二氮杂双环辛烷抑制剂,结构上相比阿维巴坦在2位羰基上添加了一个哌啶环,其高活性来源于高应变双环脲核与吸电子氨基氧基硫酸盐,但这样的高反应导致其稳定性有限,pH值为4~8时能达到稳定;正常生理pH下,哌啶侧链可以防止瑞来巴坦的细胞外排[56],对A类(如KPC、TEM、SHV和CTX-M)碳青霉烯酶具有有效的体外活性,对B类(MBL、NDM、VIM和IMP)无活性,对D类(OXA-48)碳青霉烯酶的活性有限[54]。与其他新型β-内酰胺不同,亚胺培南-瑞来巴坦对氨苄西林敏感肠球菌和革兰氏阴性厌氧菌具有可靠的抗菌活性,使其成为多重感染患者的潜在首选药物,包括肠球菌、CR-NME和/或DTR铜绿假单胞菌[60]。在所有耐药机制中,B类和D类碳青霉烯酶的产生是CRE中亚胺培南-瑞来巴坦耐药的主要原因。另外亚胺培南-瑞来巴坦耐药也可能由其他机制共同导致,包括碳青霉烯酶突变、碳青霉烯酶过表达、青霉素结合蛋白突变或低表达、外排增加和通透性降低等[54, 57]

    • 普拉佐米星(原ACHN-490)是一种新型的半合成氨基糖苷类抗菌药物,于2018年获得美国FDA批准,用于复杂性尿路感染,尚未获得EMA的批准。普拉佐米星对肠杆菌具有广谱活性,包括产ESBL酶或多种CRE肠杆菌,包括A类(KPC),B类(VIM, IMP)和D类(OXA-48)β-内酰胺酶[60];但对于产NDM-1酶的菌株,因为它们通常产生16S rRNA甲基转移酶,所以抗菌活性变化差异较大,因此对NDM-1流行地区的临床应用可能有限[60]。氨基糖苷类抗菌药物的耐药性通常是通过氨基糖苷修饰酶(AMEs)发生的,该酶降低了药物对核糖体靶标的结合亲和力。普拉佐米星具有几种结构修饰,可阻止大多数AMEs的活性,从而降低AMEs介导的耐药风险。但普拉佐米星不能克服16s核糖体甲基转移酶引起的修饰,这些基因可以通过质粒水平转移造成普拉佐米星的耐药[61]

    • 依拉环素(原TP-434)是一种新型四环素,于2018年获得美国FDA批准,用于复杂性尿路感染,其结构类似于替加环素,通过结合核糖体30s亚基抑制细菌蛋白质合成,对除假单胞菌之外的好氧和厌氧的革兰氏阳性与阴性菌有广谱活性[62]。依拉环素对含A类(KPC)、B类(VIM,NDM-1)和D类(OXA-48)β-内酰胺酶的CRE仍有活性[63]。四环素类抗菌药物的耐药性是通过获得编码在质粒和结合转座子或整合子上的抗性基因而发生的,因此可以在物种和属之间转移。目前已知的四环素类耐药机制有4种:外排、核糖体保护蛋白、核糖体突变和酶失活。外排是导致新型四环素耐药的主要原因。依拉环素可以避开易导致其他新型四环素在肠杆菌科和不动杆菌属中耐药的TetA外排泵;虽然葡萄球菌表达的TetK泵对依拉环素有作用,但通常不引起耐药[64-65]。另外,革兰氏阴性细菌与拟杆菌属中发现的Tet(X)酶是一种对依拉环素有活性的四环素破坏酶,可在人类肠道菌群中以无症状携带的形式存在,表明依拉环素的耐药性具有可传播性[66]

    • 头孢地尔是一种新型的铁载体头孢菌素,2019年获得美国FDA批准,用于治疗复杂性尿路感染和医院获得性肺炎和呼吸机相关性肺炎。头孢地尔通过铁转运系统主动转运,以及少量膜孔蛋白通道途径逃避细菌防御系统进入细菌细胞[67]。头孢地尔进入细胞后靶向结合青霉素结合蛋白,主要是PBP-3[68],其结构C3和C7侧链的修饰使其对多数丝氨酸和金属β -内酰胺酶(包括KPC、NDM、VIM、IMP和OXA-48)具有高度稳定性,抑制肽聚糖合成并最终导致细胞死亡[69]。近年体外研究发现,头孢地尔对CRE敏感性高[70-71]。2022年一篇有关肠杆菌中头孢地尔敏感性降低机制的综述提到某些β-内酰胺酶(尤其是NDM或KPC变体)的产生,铁载体摄取系统的修饰,以及PBP靶点的罕见突变可能会成为头孢地尔耐药的原因[72]

    • 耐碳青霉烯类肠杆菌的传播是一个紧迫的公共卫生问题,对全世界的抗菌药物疗效构成威胁。氨曲南、磷霉素、多粘菌素、替加环素与头孢哌酮阿维巴坦是国内常见的治疗药物。但上述药物耐药性逐年攀升。过去几年FDA批准上市的新型β-内酰胺和β-内酰胺酶抑制剂组合,以及新型的氨基糖苷类、四环素类和头孢菌素类药物等新药的耐药率低,或可缓解耐碳青霉烯类肠杆菌的耐药困境。

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