碳青霉烯类耐药鲍曼不动杆菌（CRAB）作为21世纪最具挑战性公共卫生问题之一，得到了全世界的广泛关注，是新型抗生素研发首要攻克病原菌[1,2]。CRAB作为院内感染的头号病原菌，以其在医院环境中广泛存在、逃避宿主免疫系统及获得新的抗生素耐药机制等而臭名昭著，因此评估和管理被隔离患者的CRAB感染情况成为临床医生面临的最大难题[3]。首先，很难直观的区分急性感染患者与上呼吸道定植的危重患者，尤其是患有严重免疫缺陷和其他高危因素的患者，因此往往是在临床诊断不明确的时候开始针对CRAB的经验性治疗[4]；其次，大多数CRAB感染表现为肺炎，在CRAB高度流行的地区，不能采用快速分子检测方法检测从呼吸道标本中分离的CRAB，这导致了CRAB肺炎的治疗延迟，进而引起不良的后果[5]；第三，CRAB肺炎需要优化抗菌药物给药剂量，以实现肺泡上皮细胞衬液(ELF)和肺实质内的药代动力学-药效学(PK/PD)靶值，且许多体外具有抗CRAB活性的抗菌药物，因在肺组织的渗透能力差和剂量依赖性毒副作用而受到限制(表1)；第四，CRAB感染相关的生物膜形成通常与耐药表型和毒力增强有关[6]，这强调了清除被CRAB污染的留置装置的重要性[7]；最关键的是针对CRAB分离株的抗菌药物敏感折点没有被确立，且在CLSI和EUCAST的敏感折点存在差异[8-10]。

全球各个国家对CRAB的分离率在30%-80%之间，其中亚洲、东欧和拉丁美洲的分离率最高[11-13] 。CRAB的耐药机制较为复杂，包括固有和获得性β-内酰胺酶、外排泵上调、外膜通透性降低和抗生素靶点改变等[2,12,14] 。研究发现，CRAB通常与编码苯唑西林酶(OXA)(OXA -23和OXA-24/40）的基因水平转移有关，且碳青霉烯耐药率和潜在的耐药机制均具有地理特异性，但随着时间的推移CRAB的主要克隆株也会随之发生变化[11,15-17] 。令人担忧的是，研究人员发现全球CRAB分离株对氨苄西林-舒巴坦和粘菌素等关键抗生素的耐药率正在增加，所以研发治疗CRAB感染的新药及制定有效的治疗方案刻不容缓[16,18] 。我们将治疗CRAB的抗生素按体外活性高低进行排序，包括多粘菌素(粘菌素，多粘菌素B)，四环素(依拉环素，米诺环素，替加环素)和β-内酰胺类(氨苄西林-舒巴坦，碳青霉烯类)[12,19] 。此外，新研发的新型β-内酰胺类抗生素，如头孢地尔和舒巴坦-度洛巴坦，对不同CRAB分离株均表现较强的体外活性，但是两者的敏感折点各不相同且尚未被建立[12,14,20,21] 。以上药物的用药特点及药物副作用见（表1）。

事实上，美国传染病学会(IDSA)抗生素耐药(AMR)治疗指南和欧洲临床微生物学和传染病学会(ESCMID）抗生素耐药治疗指南，都建议对严重的CRAB感染的患者进行至少两种体外活性药物的联合治疗[22,23] 。支持这种联合治疗的依据来自各种抗生素组合在体外的协同效应及其抑制CRAB进一步耐药的可能机制，但这些依据并不能说明体外联合治疗的疗效在体内同样适用[24] 。本文旨在围绕关于侵袭性CRAB感染管理和治疗方面的关键问题，进而提出最全面且最有效的抗生素联合使用方案，而并非一直沿用粘菌素加磷霉素、粘菌素加利福平和以氨基糖苷为主等不能改善患者预后的治疗方案[25-27] 。

1、粘菌素联合美罗培南可否用于治疗CRAB感染？

众所周知粘菌素的毒副作用较大，临床上依然可见粘菌素联合美罗培南用于治疗CRAB感染的方案，因其在治疗广泛的CRAB分离株的体外活性较高且能发挥较强的体外协同作用[28,29]。并且发现这种协同作用是通过粘菌素作用于细菌的细胞膜，使其去极化后增强对碳青霉烯类的摄取活性，允许更多的碳青霉烯类抗生素进入细胞周质间隙并有效地作用于抗生素靶点。但近来在两项大型的临床试验研究中发现，联合治疗的疗效并没有优于单用粘菌素。在其中一组试验中，198例患者接受粘菌素单药治疗和208例接受粘菌素联合美罗培南治疗，其临床治疗失败率分别为83%(125/151) 和81% (130/161)，28天死亡率分别为46%(70/151)和52(84/161)，差异并无统计学意义[30,31]。另一入组423例病患，分析其临床治疗失败比例分别为43%和37%，28天死亡率分别为70%和64%，差异同样不具有统计学意义[32,33]。

以上两组数据表明，粘菌素和碳青霉烯类在治疗侵袭性CRAB感染的体外协同比率高，但在实际临床治疗中这种联合用药并无意义。那么该如何较好地利用粘菌素治疗CRAB感染仍然是个难题，一种方法是使用3药组合，包括氨苄西林-舒巴坦、碳青霉烯类和粘菌素。从机制上讲，粘菌素可能促进氨苄西林-舒巴坦和碳青霉烯类药物的摄取，使两者与青霉素结合蛋白(分别为PBP1/3和PBP2)结合成饱和状态。从时间杀伤效率表明，与单药或2种药物联合相比，3药联合能更快速有效地杀灭病原菌[34] 。此外还发现粘菌素的衍生体—多粘菌素B比前体药物粘菌素更快、更可靠地达到稳态浓度，且神经毒性和肾毒性的副作用较小[35,36] 。因此优化氨苄西林-舒巴坦、多粘菌素B和美罗培南的给药剂量，患者的死亡率明显降低，且能抑制病原菌的耐药发生[34,37] 。但2023年IDSA AMR指南并不提倡使用碳青霉烯类抗生素作为治疗CRAB感染的联合制剂[22] 。

2、舒巴坦治疗CRAB的用药方案

舒巴坦主要作为β-内酰胺酶抑制剂，作用于细菌所产生的β-内酰胺酶，防止酶水解头孢菌素或青霉素类抗生素，通常与β-内酰胺类抗生素组成复方制剂。同时，舒巴坦本身也可以作用于不动杆菌属青霉素结合蛋白PBP1a, PBP1b和PBP3，发挥抗菌作用。复方制剂氨苄西林-舒巴坦抗CRAB的活性取决于其合成比例（2g氨苄西林和1g舒巴坦，2:1）中舒巴坦的量能否达到抗菌的PD靶浓度。例如，在小鼠感染模型中，血清游离舒巴坦浓度高于最低抑菌浓度的时间即fT>MIC是治疗成功的关键因素[38,39]。当患者的肌酐清除率在90至120ml/min，舒巴坦的MIC<4mg /L，治疗目标浓度要达到60% fT>MIC，那么舒巴坦的剂量需要达到1g/6h或2g/8h，持续灌注4h，其治疗效能才能达到90%以上[40]。

有相关研究数据表明，当CRAB分离株对氨苄西林-舒巴坦的药敏结果为敏感(S)或者中介(I)，可以优化氨苄西林-舒巴坦的剂量为3g q4h；耐药R(MIC≥16 mg/L)时，优化舒巴坦的剂量为9g /day[39,41] ，即氨苄西林-舒巴坦9g q8h，持续灌注4h，或27g 24h连续灌注[22] 。近20年来，支持剂量优化的氨苄西林-舒巴坦治疗CRAB感染的证据越来越多，研究人员采用meta分析方法综合比较各试验组中患者临床改善情况、治愈率、死亡率和病原菌的杀灭，发现与其他治疗方案相比，3-8 g/d和高剂量（≥9 g/d）的舒巴坦单药治疗能最高程度的降低CRAB感染患者的死亡率[41-45] 。然而根据CLSI的标准，大部分CRAB临床分离株对氨苄西林-舒巴坦的体外敏感性差，以至于临床医生不会将其作为治疗CRAB的首选药物，这也是目前缺乏氨苄西林-舒巴坦治疗CRAB疗效评估的原因[13] 。同时还发现当折点为MIC≤8/4 mg/L(对应舒巴坦MIC≤4 mg/L)，少于5%的CRAB分离株对氨苄西林-舒巴坦是敏感[13] ；舒巴坦的折点提高到≤8mg/L或者≤16mg/L，只有少于50%的CRAB分离株对氨苄西林-舒巴坦是敏感[40] 。因此高剂量氨苄西林-舒巴坦(定义为至少9 g/d的舒巴坦给药方案)至少应与1种体外有活性的药物联用；当舒巴坦MICs未知或≥16 mg/L时，可选用2种体外有活性的药物联用[46] 。

3、四环素类抗生素治疗侵袭性CRAB的用药方案

四环素类抗生素的单一或联合疗法用于治疗CRAB感染的样本量少、非标准化的给药方案及临床感染类型的多样性，导致相关回顾性研究结果存在差异。但近来已有替加环素(TGC)抗CRAB感染的相关临床数据，研究发现与其他抗CRAB感染的治疗方案相比：TGC单药治疗可能导致更高的死亡率，特别是在菌血症或肺炎的情况下[44,47-49]；TGC作为联合治疗的基础，与多粘菌素和舒巴坦联用，能达到较高的临床治愈率[50-51]；与标准剂量相比，较高剂量的TGC(首次剂量200 mg，后续100 mg q12h)与其他体外活性抗生素联用，可以较好地改善患者的预后[52,53]。此外，我们还需考虑TGC在呼吸道、血清和泌尿道中的药物暴露浓度有限以及受非线性血浆蛋白结合的影响[54,55]。并且无论是CLSI或EUCAST都没有关于TGC治疗不动杆菌属的临床药敏折点，然而临床上常常错误地将TGC对肠杆菌科的敏感折点（美国食品药品监督管理局FDA定义的MIC≤2mg/L）作为治疗不动杆菌属的药敏折点依据，导致抗感染的失败。事实上，当TGC MIC≤1mg/L治疗危重病人时，使用标准剂量输注，其PK/PD目标靶值(fAUC:MIC)才能达到90%以上；MIC≥2mg/L时，则需要至少100 mg q12h才能达到相同的靶点[55]。尤其是针对血流感染或者肺炎的患者，当TGC的MIC≤0.5mg/L，加大给药剂量，才能在患者的血清或者ELF达到有效的PK/PD靶浓度[54]。总之，治疗CRAB感染的重症患者，需要选用大剂量并MIC≤1mg/L 的TGC联合其他体外有活性的抗生素，才能达到较高的临床治愈率和较好的预后[22,23]。

与TGC相比，临床上选用米诺环素（MH）治疗CRAB的案例更少。相关报道采用回顾性分析发现，MH MIC≤1mg/L时，200 mg q12h静脉滴注的给药方案，其PK/PD的目标靶值(fAUC:MIC)仅能达到90%；只有MIC≤0.5 mg/L时，治疗CRAB感染的1-log kill的PK/PD靶点才能达到90%以上[56]。因此，MIC值较低且在特殊的感染部位药物暴露浓度能达到PK/PD靶值时，认为MH可以替代TGC作为联合治疗CRAB感染的最佳四环素类抗生素[13,57]，但目前尚未有MH治疗CRAB感染的最佳给药剂量[58]。近来发现，在米诺环素基础上通过化学基团修饰后得到的半合成化合物——奥马环素（Omadacycline），是一种新型9-氨甲基环素类药物，属于四环素类抗生素的一员，但目前还未有治疗侵袭性CRAB的临床相关报道[59,60]。此外依拉环素（Eravacycline）作为一种新型的含氟四环素类抗生素，相关研究监测中发现其MIC值较TGC和MH低，但在治疗侵袭性CRAB感染同样没有临床药敏折点[61,62]，所以推荐使用依拉环素单药或者联合治疗CRAB感染的用药方案，需要被进一步的研究。

总之，四环素类抗生素在治疗CRAB感染方面存在一些优势，如：MH作为四环素类口服制剂，在体外对CRAB具有可靠的活性，同时在非侵袭性感染中，具有口服降阶治疗的优势[59,60]；其次，四环素类通常具有较好地穿透软组织、骨骼和生物膜的活性，为骨关节或假体置换感染，提供了合适的治疗选择[46,63,64]；此外，与其他抗生素相比，四环素类可以降低艰难梭菌的感染风险[65]，因此在艰难梭菌感染风险高的患者中，可以首选以四环素类为主的联合用药；最后，这类药物比基于多粘菌素为基础的联合用药方案，具有更小的肾毒性[46]。

4、头孢地尔治疗CRAB感染的用药指南

头孢地尔作为新研发的一种β-内酰胺类抗生素，在临床上能够发挥有效的治疗碳青霉烯类耐药病原菌感染的作用，同时也被期许能作为治疗CRAB感染的首选药物[66]。近来对头孢地尔的监测数据表明，当MIC≤4 mg/L时，对CRAB表现普遍高敏感性[19,67,68]，但其在体外的活性并未在临床治疗CRAB感染的疗效中凸显[67,69]。为了准确评估头孢地尔治疗CRAB感染的疗效，研究者们通过逆概率加权法(IPTW)弱化临床样本的选择偏差性和实验设计的局限性，得出单用头孢地尔抗感染的失败率高于单用粘菌素[70]，单用头孢地尔的抗感染失败率高于联合治疗，更容易发生头孢地尔耐药[71,72]。事实上，临床上头孢地尔治疗CRAB感染的耐药情况已有报道[72-74]。研究发现，在抗生素体外药敏试验中，各种药物与头孢地尔联用时显示出较高的协同作用[68,75,76]。如在小鼠的大腿感染模型中，头孢地尔与氨苄西林-舒巴坦、头孢他啶-阿维巴坦或美罗培南联合，用于治疗CRAB分离株的杀菌效果优于单用头孢地尔，并且头孢地尔联合氨苄西林-舒巴坦或头孢他啶-阿维巴坦可以有效的阻止头孢地尔耐药情况的发生[70,77]。头孢地尔PK/PD研究中，发现头孢地尔的MIC≤2mg /L时，在ELF中实现PK/PD靶目标(fT>MIC)的概率很高[78]。值得注意的是，头孢地尔治疗CRAB的fT>MIC靶值(88% )显著高于治疗其他碳青霉烯类耐药病原菌的fT>MIC(≤70% )[79]。综上所述，由于头孢地尔治疗CRAB感染存在的体外活性、安全性以及联合治疗潜在的有利条件，可将其作为联合用药的重要组成成分，但不支持单药治疗[70,71]；在所有使用头孢地尔治疗的患者中，强烈建议密切观察其耐药性[72]；CLSI、EUCAST和FDA定义的头孢地尔药敏折点各不相同[66]，在临床实践中确定准确且有效的药敏折点成为一个重大且迫切的挑战。

5、治疗CRAB感染的用药新方案

目前FDA批准的新型β-内酰胺酶抑制剂(阿维巴坦、瑞莱巴坦或法硼巴坦)均不可有效地抑制OXA碳青霉烯酶活性。度洛巴坦（未被FDA批准）是新一代二氮杂环辛酮(DBO) β-内酰胺酶抑制剂，不仅可抑制D类OXA碳青霉烯酶，同样对A类和C类丝氨酸酶都有强有效的抑制活性[80]。研究发现将度洛巴坦与舒巴坦联合时，可以增强舒巴坦对抗CRAB的活性[13]。针对全球分离的2570株CRAB菌株，舒巴坦-度洛巴坦的MIC50和MIC90分别为1mg/L和4mg/L[13]。这些体外试验数据给临床提供了安全用药依据，即舒巴坦-度洛巴坦联合用药剂量为：1g舒巴坦和1g度洛巴坦，q6h 持续输注3h[81]；舒巴坦-度洛巴坦MIC≤4mg/L时，所有被检测菌株的治疗结果达标率超过90%，且得出舒巴坦和度洛巴坦在ELF的渗透率，分别占总药物浓度的53%和37%[82]。另一组关于舒巴坦-度洛巴坦联合亚胺培南-西司他丁与粘菌素联合亚胺培南-西司他丁的比较中发现，舒巴坦-度洛巴坦组的临床治愈率明显高于粘菌素组（62%vs40%），死亡率(19%vs32%)和肾毒性(13%vs38%)均明显低于粘菌素组[83]。未来的研究还需要确定亚胺培南-西司他丁是否对舒巴坦-度洛巴坦在治疗CRAB感染方面有协同效应。虽然针对舒巴坦-度洛巴坦的完整性研究结果尚未发表，且度洛巴坦还未经FDA批准上市，但它会成为未来治疗侵袭性CRAB感染的最新突破点[84,85]。

6、侵袭性CRAB感染的辅助疗法

为了更有效的治疗侵袭性CRAB感染，临床上应用了几种辅助疗法，包括吸入雾化抗生素、噬菌体和单克隆抗体的使用，但因为缺乏有效的数据支持，这些辅助方法的疗效并未可知[22,23]。针对感染CRAB的肺炎患者，吸入雾化氨基糖苷类药物和粘菌素可以减少负荷菌量，虽然尚未显示可显著改善临床结局，但却有益于包括结构性肺组织病的慢性感染者的后续抗感染治疗[86,87]。例如，给上呼吸道定植的肺移植患者，雾化吸入治疗CRAB的预防性抗生素[88]。未来我们还可以使用振动网喷雾器吸入雾化粘菌素并联合使用静脉注射其他抗生素，来观察评估治疗侵袭性CRAB感染的疗效[89]。增强机体对CRAB的固有免疫是克服CRAB感染的一种新疗法，为此近来研究发现几种单克隆抗体（MAbs）[90-92]，包括MAb 8和MAb 65两种已被证实可以提高存活率的小鼠感染模型[91,92]。然而，两种单抗组合只能覆盖不到50%的CRAB筛选分离株，这表明未来的免疫治疗需要将多种单抗组合成单一鸡尾酒疗法，以有效对抗不同的分离菌株。此外，我们还发现噬菌体在侵袭性CRAB抗感染治疗中发挥的作用令人瞩目，然而缺乏广泛的试验数据进行论证[93-95]。

7、侵袭性CRAB感染的首选治疗方案

近20年来，临床医生在很大程度上依赖经验用药来指导CRAB感染的治疗。近来几项关于治疗CRAB感染的随机临床试验分析、同时期的PK/PD研究及新型抗生素的研发，都将有助于指导临床医生对CRAB感染治疗的选择[22,23,46]。虽然以往的用药方案依然在被沿用，但我们同时也在寻找更多更有效的治疗CRAB感染的新方案，包括保留多粘菌素有效治疗的联合用药方案[46]；优化舒巴坦剂量达到9g/d，来促进其治疗不动杆菌属的活性；头孢地尔作为治疗CRAB感染的药物联合制剂具有较好的耐受性，建议因感染组织部位的不同而制定不同的临床敏感折点[70]；临床上治疗CRAB感染，疗效最为显著的是舒巴坦-度洛巴坦复方制剂，不仅能降低CRAB感染的死亡率，减低药物的毒副作用，同时还提高患者的临床治愈率[83]。

总之，CRAB感染的治疗应围绕以舒巴坦为主的联合用药方案，可以联用强效β-内酰胺酶抑制剂度洛巴坦（如果获批FDA），或与1种或多种体外活性抗生素联合使用[22] 。再者强调确定体外活性不应仅仅依赖敏感折点，而应是进一步了解抗菌药物PK/PD靶点和感染部位药物暴露情况。例如，根据目前CLSI定义米诺环素的折点MIC≤4mg/L即为敏感，但事实上当MIC>1mg/L时，其感染部位的抗生素浓度已无法达到治疗浓度[56] 。考虑到这些因素，我们需要结合药敏试验结果、感染部位和对当地流行病学的调查结果，制定个性化的治疗方案。

治疗侵袭性CRAB感染的一线首选药物因组织不同而异，首选方案包括大剂量氨苄西林-舒巴坦联合头孢地尔、多粘菌素B或替加环素，并根据PK/PD模型优化的剂量、药敏试验的结果和感染部位进行区分[22,23,46] 。例如， 治疗CRAB相关肺炎，首选氨苄西林-舒巴坦联合替加环素或头孢地尔；CRAB相关血流感染，首选氨苄西林-舒巴坦联合头孢地尔或多粘菌素B；CRAB相关骨关节感染，首选氨苄西林-舒巴坦联合替加环素；其他部位的感染也同样适用，包括腹腔感染，可选用氨苄西林-舒巴坦联合替加环素或头孢地尔；尿路感染可选用氨苄西林-舒巴坦联合粘菌素。如以上治疗方案无效或者患者复发感染CRAB，目前暂不建议联合使用第三种抗生素。无论选择何种治疗方案，均需要及时控制感染源并密切监测患者的临床反应和药物的毒副作用。研究指明，针对侵袭性CRAB感染的患者，在没有其他单一疗法或特定的联合治疗药物问世前，舒巴坦-度洛巴坦（如能获批FDA）可能是作为联合治疗的最佳选择。

表一（点击图片放大查看）

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摘译自Clinical Infectious Diseases.2023:76 (Suppl 2) 《Navigating Available Treatment Options for Carbapenem-Resistant Acinetobacterbaumannii-calcoaceticus Complex Infections》

译者简介

徐巧丽

医学硕士，临床抗感染与免疫方向。福建省漳州市医院检验科主管技师 ，从事临床微生物检验工作多年，目前在北京大学人民医院检验科微生物组进修。

编译：徐巧丽（福建省漳州市医院）；审校：陈宏斌（北京大学人民医院）

本文转载自订阅号「京港感染论坛」

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