鲍曼不动杆菌感染

尚进，谢俊刚华中科技大学同济医学院附属同济医院呼吸与危重症医学科发布于2022-10-20 浏览 8148 收藏

作者：尚进，谢俊刚

单位：华中科技大学同济医学院附属同济医院呼吸与危重症医学科

鲍曼不动杆菌（Acinetobacter baumannii）是一种条件致病菌，主要感染人群为免疫力低下患者，造成机会性感染。在美国和欧洲，由鲍曼不动杆菌引起的感染约占所有与医疗保健相关感染的2%，而在亚洲和中东地区，该比率更高^[1,^2]。尽管其感染率低于其他革兰氏阴性病原体引起的感染率，但在全球范围内，约±45%的鲍曼不动杆菌分离株具有多重耐药性（MDR），耐多药率几乎是其他革兰氏阴性病原体的4倍^[3^{, 4]}。因此，WHO已将耐药的鲍曼不动杆菌列为对人类健康构成最大威胁的细菌列表中的关键组，优先考虑新的抗菌治疗的研发工作^[5]。本文将从鲍曼不动杆菌的毒力机制、传播途径、临床表现、诊断和治疗四方面简单阐述鲍曼不动杆菌感染的相关问题。

一、毒力机制

在过去的10年中，对鲍曼不动杆菌毒力机制的研究主要包括抗干燥性、抵抗消毒、生物膜形成和运动能力，总体来说，鲍曼不动杆菌具有在不利条件下生存的显著能力。最近发现的毒力因子，例如促进鲍曼不动杆菌发病机制的分泌系统、表面糖缀合物和微量营养素获取系统，可能决定了鲍曼不动杆菌菌株的毒力潜力。

1．抗干燥性

抗干燥性即在干燥条件下保持活力的能力，因鲍曼不动杆菌的临床分离株而异，有些分离株可存活近100天^{[6, 7]}。虽然缺乏直接证据，但荚膜多糖很可能有助于鲍曼不动杆菌对干燥的抵抗力^[8]。

2．抵抗消毒

消毒剂（如洗必泰）广泛用于医院和其他医疗卫生机构。鲍曼不动杆菌已被证实可以使用不动杆菌外排蛋白将洗必泰积极泵出细胞^[9]，从而可能促进细菌的存活。

3．生物膜形成

微生物生物膜是包裹在细胞外基质中的群落。鲍曼不动杆菌种群会在皮肤伤口、软组织、封闭敷料、医疗器械（如气管导管，以及聚碳酸酯和不锈钢材质的器材）上形成坚固的生物膜^{[10, 11]}。

4．运动能力

细菌运动与生物体致病的能力密切相关，例如鞭毛对于铜绿假单胞菌来说犹如细菌“马达”，是决定毒力的关键。对鲍曼不动杆菌临床分离株的流行病学研究发现，血液分离株比痰分离株更具运动性^[12]，这表明鲍曼不动杆菌可能也存在一种“马达”影响其运动能力，从而决定其毒力大小。

5．糖缀合物

常见的细菌糖缀合物包括荚膜多糖、糖基化蛋白、脂多糖和聚糖。因为缺乏荚膜的菌株很容易被补体杀死，所以鲍曼不动杆菌的荚膜多糖可以被认为是其主要的毒力因子^[13]。缺乏糖基化系统的细胞在生物膜形成方面存在缺陷^[14]。鲍曼不动杆菌通过改变脂多糖的脂质A，阻止抗生素黏菌素的结合，从而产生耐药性^{[15, 16]}。而菌毛聚糖可能已经进化为保护蛋白质成分免受抗原识别，而且与亚抑制浓度的抗生素接触后，聚糖结构改变，会进一步增强鲍曼不动杆菌的毒力^{[17, 18]}。所以，糖缀合物在鲍曼不动杆菌中具有关键的结构作用，是介导抵御各种不利生存环境、免疫逃避和调节以及毒力的第一道防线。

6．微量营养素采集系统

铁、锰和锌等微量金属元素对生命的所有领域都是必不可少的，也是鲍曼不动杆菌生存所必需的^[19-21]。

7．蛋白质分泌系统

与其他革兰氏阴性病原体类似，鲍曼不动杆菌使用分泌蛋白来促进环境和宿主适应。鲍曼不动杆菌中的蛋白质分泌系统对于黏附宿主细胞、介导肺定植和传播到其他器官、进行细菌竞争等都有重要作用^[22-26]。

总体来说，鲍曼不动杆菌能够在对许多细菌病原体不利的环境中持续存在的特征，为其在人体定植和随后的感染奠定了基础。

二、传播途径

鲍曼不动杆菌有多种传播途径，包括空气、水和表面接触。鲍曼不动杆菌是一种院内感染常见病原体，其环境污染与干燥或潮湿地区有关^[27]。另外，其存活时间也与特定菌株相关，一些菌株的存活时间为4个月^[28]，受污染的表面和医疗设备和/或患者和医务人员的手卫生可能会成为常见定植部位和有效的传播方式，其中医务人员可充当载体，将细菌从受污染的表面带到患者或患者之间^{[29, 30]}。

三、临床表现

鲍曼不动杆菌感染主要表现为医院获得性肺炎，特别是在气管插管的患者中更易发生，不动杆菌可以在导管上形成生物膜，直接进入肺泡，在组织中建立感染^{[31, 32]}。其次是血流感染。血流感染通常发生在存在中心静脉导管的情况下，或者继发于广泛的肺炎。另外，鲍曼不动杆菌也会引起皮肤和软组织以及手术部位的感染（如骨髓炎、心内膜炎、脑膜炎等），以及与导管相关的尿路感染^[33-37]。这些情况的共同点是解剖屏障的破坏使鲍曼不动杆菌能够直接进入感染部位。由鲍曼不动杆菌引起的社区获得性感染近年也越来越多。社区获得性感染主要发生在温暖、潮湿的热带环境中，特别是在澳大利亚、大洋洲和亚洲的部分地区，包括中国、泰国^{[38, 39]}。但通常出现在有合并症的患者中，包括大量吸烟、过度饮酒、糖尿病、癌症和慢性阻塞性肺疾病患者^{[33, 38]}。社区获得性感染通常表现为急性肺炎，在极少数情况下会出现脑膜炎、蜂窝组织炎或原发性菌血症^[33]。在战争或自然灾害中，鲍曼不动杆菌也经伤口、软组织，侵入血液和骨骼造成感染^{[40, 41]}。另外，还有鲍曼不动杆菌引起坏死性筋膜炎的报道，这些病例主要是HIV、肝硬化、实体器官移植或糖尿病等免疫功能低下的患者^[42-47]。

四、诊断和治疗

对于鲍曼不动杆菌感染的诊断，临床上常采用细菌培养和宏基因组二代测序（mNGS）的检测方法。痰液、肺泡灌洗液、血液、脑脊液、尿液、粪便、咽拭子、肛拭子、引流液、创面分泌物等多种生物标本中均可检出鲍曼不动杆菌。

β-内酰胺类抗生素是鲍曼不动杆菌感染的首选抗菌药物。舒巴坦用于抑制大多数病原体的β-内酰胺酶，对不动杆菌具有直接的抗菌活性。随着舒巴坦耐药率的不断增加，碳青霉烯类药物成为重要的治疗选择。β-内酰胺类抗生素疗效的最佳预测指标是血清药物浓度保持在最低抑制浓度（MIC）以上的时间。所以，对于耐药病原体，延长碳青霉烯类药物的输注可以最大限度地延长高于MIC的时间，从而达到最优化的治疗效果^[48-50]。蒙特卡罗模拟对不动杆菌属的风险分析显示，每8小时给予1 g美罗培南（维持3 h输注）将获得最佳的杀菌率。与快速输注相比，延长碳青霉烯输注时间可降低死亡率，且没有任何证据表明耐药性出现率增加。然而，延长输注时间，药物药代动力学显示药物峰值水平下降^{[49, 51]}。因此，对于MIC为4～16 g/ml的分离株，应延长输注时间，但对于MIC较高的分离株（≥16 g/ml），建议间歇给药，以达到高于MIC的峰值水平。

氟喹诺酮类药物和氨基糖苷类药物不作为经验性治疗的首选，因为鲍曼不动杆菌对这两种药物的耐药率都很高^{[52, 53]}。在敏感性允许的情况下，氨基糖苷类药物可能是一种潜在的治疗选择^[54]。

治疗耐药鲍曼不动杆菌的一种选择药物是替加环素。虽然替加环素对鲍曼不动杆菌菌株的MIC（2 g/ml）通常较低，但该药物的血清浓度也较低，即使MIC为2 g/ml，在使用替加环素治疗时结果可能较差，如增加死亡率，无法清除菌血症和发生突破性菌血症^[55]。一项系统评价和荟萃分析（非特定于不动杆菌感染）也发现，替加环素治疗会导致较高的住院死亡率、较低的微生物根除率和住院时间延长的趋势^[56]。

目前，多黏菌素通常是耐药鲍曼不动杆菌的最后治疗选择。研究发现，多黏菌素在肺泡内的药物浓度相对较差，静脉输注2小时后采集的支气管肺泡灌洗标本中，尚未检测到多黏菌素^[57]。且多黏菌素具有较明显的肾毒性和神经毒性，所以雾化多黏菌素被用于临床治疗中。相较于静脉用药，雾化多黏菌素可能会在肺部达到非常高的浓度，最大限度地减少全身暴露和毒性，同时，鲍曼不动杆菌肺炎患者得到了良好的治疗效果^{[58, 59]}。但需要注意，多黏菌素可能对肺组织有毒并诱导支气管痉挛，并且累积剂量依然有发生肾毒性的可能^{[60, 61]}。

事实上，鲍曼不动杆菌对替加环素和多黏菌素的耐药率也逐年上升，联合治疗成为改善治疗结果的选择。2012年《中国鲍曼不动杆菌感染诊治与防控专家共识》指出，对于MDR，可选用舒巴坦或碳青霉烯类药物联合氟喹诺酮类或氨基糖苷类药物。对于广泛耐药（XDR），可选择舒巴坦联合下述任何一种：米诺环素（或多西环素），多黏菌素，氨基糖苷类，碳青霉烯类抗生素；或多黏菌素联合下述任何一种：舒巴坦，碳青霉烯类抗生素；抑或替加环素联合下述任何一种：舒巴坦，碳青霉烯类，多黏菌素，喹诺酮类，氨基糖苷类抗生素；甚至三药联合：舒巴坦+多西环素+碳青霉烯类抗生素，或者亚胺培南+利福平+多黏菌素或妥布霉素^[67]。在所有联合方案中，最合理的一种可能是多黏菌素联合碳青霉烯类，在多项体外研究中均发现其具有协同作用^[62-66]，这种协同作用尤其适用于对碳青霉烯类具有中等耐药性的分离株（例如碳青霉烯类MIC为4～16 g/ml）^[63]。在非菌血症XDR不动杆菌肺炎病例中，作为碳青霉烯类或其他药物全身治疗的辅助手段，可以考虑添加吸入性多黏菌素。

最后，目前迫切需要对联合治疗进行前瞻性随机研究，进一步确定联合方案是否有用，联合治疗方案是否优于单一治疗，以便指导今后如何选择药物治疗。

参考文献

[1] Magill S S, Edwards J R, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections[J]. N Engl J Med, 2014, 370(13):1198-1208.
[2] Lob S H, Hoban D J, Sahm D F, et al. Regional differences and trends in antimicrobial susceptibility of Acinetobacter baumannii[J]. Int J Antimicrob Agents, 2016, 47(4):317-323.
[3] Giammanco A, Calà C, Fasciana T, et al. Global Assessment of the Activity of Tigecycline against Multidrug-Resistant Gram-Negative Pathogens between 2004 and 2014 as Part of the Tigecycline Evaluation and Surveillance Trial[J]. mSphere, 2017. 2(1):e00310-16.
[4] Rolain J M, Diene S M, Kempf M, et al. Real-time sequencing to decipher the molecular mechanism of resistance of a clinical pan-drug-resistant Acinetobacter baumannii isolate from Marseille, France[J]. Antimicrob Agents Chemother, 2013, 57(1):592-596.
[5] Baraldi E, Lindahl O, Savic M, et al. Antibiotic Pipeline Coordinators[J]. J Law Med Ethics, 2018, 46(1_suppl):25-31.
[6] Giannouli M, Antunes L C S, Marchetti V, et al. Virulence-related traits of epidemic Acinetobacter baumannii strains belonging to the international clonal lineages Ⅰ-Ⅲ and to the emerging genotypes ST25 and ST78[J]. BMC Infect Dis, 2013, 13:282.
[7] Antunes L C S, Imperi F, Carattoli A, et al. Deciphering the multifactorial nature of Acinetobacter baumannii pathogenicity[J]. PLoS One, 2011, 6(8):e22674.
[8] Espinal P, Martí S, Vila J. Effect of biofilm formation on the survival of Acinetobacter baumannii on dry surfaces[J]. J Hosp Infect, 2012, 80(1):56-60.
[9] Hassan K A, Jackson S M, Penesyan A, et al. Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins[J]. Proc Natl Acad Sci U S A, 2013, 110(50):20254-20259.
[10] Thompson M G, Black C C, Pavlicek R L, et al. Validation of a novel murine wound model of Acinetobacter baumannii infection[J]. Antimicrob Agents Chemother, 2014, 58(3):1332-1342.
[11] Greene C, Wu J, Rickard A H, et al. Evaluation of the ability of Acinetobacter baumannii to form biofilms on six different biomedical relevant surfaces[J]. Lett Appl Microbiol, 2016, 63(4):233-239.
[12] Vijayakumar S, Rajenderan S, Laishram S, et al. Biofilm Formation and Motility Depend on the Nature of the Acinetobacter baumannii Clinical Isolates[J]. Front Public Health, 2016, 4:105.
[13] Lees-Miller R G, Iwashkiw J A, Scott N E, et al. A common pathway for O-linked protein-glycosylation and synthesis of capsule in Acinetobacter baumannii[J]. Mol Microbiol, 2013, 89(5):816-830.
[14] Iwashkiw J A, Seper A, Weber B S, et al. Identification of a general O-linked protein glycosylation system in Acinetobacter baumannii and its role in virulence and biofilm formation[J]. PLoS Pathog, 2012, 8(6):e1002758.
[15] Adams M D, Nickel G C, Bajaksouzian S, et al. Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component system[J]. Antimicrob Agents Chemother, 2009, 53(9):3628-3634.
[16] Beceiro A, Llobet E, Aranda J, et al. Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system[J]. Antimicrob Agents Chemother, 2011, 55(7):3370-3379.
[17] Piepenbrink K H, Lillehoj E, Harding C M, et al. Structural Diversity in the Type Ⅳ Pili of Multidrug-resistant Acinetobacter[J]. J Biol Chem, 2016, 291(44):22924-22935.
[18] Geisinger E, Isberg R R. Antibiotic modulation of capsular exopolysaccharide and virulence in Acinetobacter baumannii[J]. PLoS Pathog, 2015, 11(2):e1004691.
[19] Antunes L C S, Imperi F, Towner K J, et al. Genome-assisted identification of putative iron-utilization genes in Acinetobacter baumannii and their distribution among a genotypically diverse collection of clinical isolates[J]. Res Microbiol, 2011,162(3):279-284.
[20] Zackular J P, Chazin W J, Skaar E P. Nutritional Immunity: S100 Proteins at the Host-Pathogen Interface[J]. J Biol Chem, 2015, 290(31):18991-18998.
[21] Juttukonda L J, Chazin W J, Skaar E P. Acinetobacter baumannii Coordinates Urea Metabolism with Metal Import To Resist Host-Mediated Metal Limitation[J]. mBio, 2016, 7(5):e01475-16.
[22] Bentancor L V, Camacho-Peiro A, Bozkurt-Guzel C, et al. Identification of Ata, a multifunctional trimeric autotransporter of Acinetobacter baumannii[J]. J Bacteriol, 2012, 194(15):3950-3960.
[23] Weber B S , Miyata S T, Iwashkiw J A, et al. Genomic and functional analysis of the type Ⅵ secretion system in Acinetobacter[J]. PLoS One, 2013, 8(1):e55142.
[24] Carruthers M D, Nicholson P A, Tracy E N, et al. Acinetobacter baumannii utilizes a type Ⅵ secretion system for bacterial competition[J]. PLoS One, 2013, 8(3):e59388.
[25] Harding C M, Kinsella R L, Palmer L D, et al. Medically Relevant Acinetobacter Species Require a Type II Secretion System and Specific Membrane-Associated Chaperones for the Export of Multiple Substrates and Full Virulence[J]. PLoS Pathog, 2016, 12(1):e1005391.
[26] Tilley D, Law R, Warren S, et al. CpaA a novel protease from Acinetobacter baumannii clinical isolates deregulates blood coagulation[J]. FEMS Microbiol Lett, 2014, 356(1):53-61.
[27] Cheon S, Kim M J, Yun S J, et al. Controlling endemic multidrug-resistant Acinetobacter baumannii in Intensive Care Units using antimicrobial stewardship and infection control[J]. Korean J Intern Med, 2016, 31(2):367-374.
[28] Wendt C, Dietze B, Dietz E, et al. Survival of Acinetobacter baumannii on dry surfaces[J]. J Clin Microbiol, 1997, 35(6):1394-1397.
[29] Peleg A Y, Seifert H, Paterson D L. Acinetobacter baumannii: emergence of a successful pathogen[J]. Clin Microbiol Rev, 2008, 21(3):538-582.
[30] Tacconelli E, Cataldo M A, Dancer S J, et al. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients[J]. Clin Microbiol Infect, 2014, 20 Suppl 1:1-55.
[31] Raad I I, Mohamed J A, Reitzel R A, et al. The prevention of biofilm colonization by multidrug-resistant pathogens that cause ventilator-associated pneumonia with antimicrobial-coated endotracheal tubes[J]. Biomaterials, 2011, 32(11):2689-2694.
[32] Gil-Perotin S, Ramirez P, Marti V, et al. Implications of endotracheal tube biofilm in ventilator-associated pneumonia response: a state of concept[J]. Crit Care, 2012, 16(3):R93.
[33] Joly-Guillou M-L. Clinical impact and pathogenicity of Acinetobacter[J]. Clin Microbiol Infect, 2005, 11(11):868-873.
[34] Sievert D M, Ricks P, Edwards J R, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010[J]. Infect Control Hosp Epidemiol, 2013, 34(1):1-14.
[35] Davis K A, Moran K A, McAllister C K, et al. Multidrug-resistant Acinetobacter extremity infections in soldiers[J]. Emerg Infect Dis, 2005, 11(8):1218-1224.
[36] Yun H C, Branstetter J G, Murray C K. Osteomyelitis in military personnel wounded in Iraq and Afghanistan[J]. J Trauma, 2008, 64(2 Suppl):S163-S168; discussion S168.
[37] de Carvalho V C, de Oliveira P R D, Dal-Paz K, et al. Gram-negative osteomyelitis: clinical and microbiological profile[J]. Braz J Infect Dis, 2012, 16(1):63-67.
[38] Falagas M E, Karveli E A, Kelesidis I, et al. Community-acquired Acinetobacter infections[J]. Eur J Clin Microbiol Infect Dis, 2007, 26(12):857-868.
[39] Peng C, Zong Z, Fan H. Acinetobacter baumannii isolates associated with community-acquired pneumonia in West China[J]. Clin Microbiol Infect, 2012, 18(12):E491-E493.
[40] Centers for Disease Control and Prevention (CDC). Acinetobacter baumannii infections among patients at military medical facilities treating injured U.S. service members, 2002-2004[J]. MMWR Morb Mortal Wkly Rep, 2004, 53(45):1063-1066.
[41] Oncül O, Keskin O, Acar H V, et al. Hospital-acquired infections following the 1999 Marmara earthquake[J]. J Hosp Infect, 2002, 51(1):47-51.
[42] Nonaka Y, Nagae M, Omae T, et al. Community-acquired necrotizing fasciitis caused by Acinetobacter calcoaceticus: a case report and literature review[J]. J Infect Chemother, 2014, 20(5):330-335.
[43] Sinha N, Niazi M, Lvovsky D. A fatal case of multidrug resistant acinetobacter necrotizing fasciitis: the changing scary face of nosocomial infection[J]. Case Rep Infect Dis, 2014, 2014:705279.
[44] Corradino B, Toia F, di Lorenzo S, et al. A difficult case of necrotizing fasciitis caused by Acinetobacter baumannii[J]. Int J Low Extrem Wounds, 2010, 9(4):152-154.
[45] Gouraud A, Bernard N, Millaret A, et al. Multidrug-resistant Acinetobacter baumannii causing necrotizing fasciitis in a pancreas-kidney transplant recipient: a case report[J]. Transplantation, 2012, 94(6):e37-e38.
[46] Charnot-Katsikas A, Dorafshar A H, Aycock J K, et al. Two cases of necrotizing fasciitis due to Acinetobacter baumannii[J]. J Clin Microbiol, 2009, 47(1):258-263.
[47] Sullivan D R, Shields J, Netzer G. Fatal case of multi-drug resistant Acinetobacter baumannii necrotizing fasciitis[J]. Am Surg, 2010, 76(6):651-653.
[48] Mattoes H M, Kuti J L, Drusano G L, et al. Optimizing antimicrobial pharmacodynamics: dosage strategies for meropenem[J]. Clin Ther, 2004, 26(8):1187-1198.
[49] Lomaestro B M, Drusano G L. Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation[J]. Antimicrob Agents Chemother, 2005, 49(1):461-463.
[50] Lee L S, Kinzig-Schippers M, Nafziger A N, et al. Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation[J]. Diagn Microbiol Infect Dis, 2010, 68(3):251-258.
[51] Falagas M E, Tansarli G S, Ikawa K, et al. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis[J]. Clin Infect Dis, 2013, 56(2):272-282.
[52] Vila J, Ruiz J, Goñi P, et al. Quinolone-resistance mutations in the topoisomerase IV parC gene of Acinetobacter baumannii[J]. J Antimicrob Chemother, 1997, 39(6):757-762.
[53] Hujer K M, Hujer A M, Endimiani A, et al. Rapid determination of quinolone resistance in Acinetobacter spp[J]. J Clin Microbiol, 2009, 47(5):1436-1442.
[54] Fishbain J, Peleg A Y. Treatment of Acinetobacter infections[J]. Clin Infect Dis, 2010, 51(1):79-84.
[55] Gordon N C, Wareham D W. A review of clinical and microbiological outcomes following treatment of infections involving multidrug-resistant Acinetobacter baumannii with tigecycline[J]. J Antimicrob Chemother, 2009, 63(4):775-780.
[56] Ni W, Han Y, Zhao J, et al. Tigecycline treatment experience against multidrug-resistant Acinetobacter baumannii infections: a systematic review and meta-analysis[J]. Int J Antimicrob Agents, 2016, 47(2):107-116.
[57] Imberti R, Cusato M, Villani P, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically Ill patients after IV colistin methanesulfonate administration[J]. Chest, 2010, 138(6):1333-1339.
[58] Kuo S-C, Lee Y-T, Yang S-P, et al. Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study[J]. Clin Microbiol Infect, 2012, 18(9):870-876.
[59] Korbila I P, Michalopoulos A, Rafailidis P I, et al. Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study[J]. Clin Microbiol Infect, 2010, 16(8):1230-1236.
[60] Lu Q, Luo R, Bodin L, et al. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii[J]. Anesthesiology, 2012, 117(6):1335-1347.
[61] Choi H K, Kim Y K, Kim H Y, et al. Inhaled colistin for treatment of pneumonia due to colistin-only-susceptible Acinetobacter baumannii[J]. Yonsei Med J, 2014, 55(1):118-125.
[62] Zusman O, Avni T, Leibovici L, et al. Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems[J]. Antimicrob Agents Chemother, 2013, 57(10):5104-5111.
[63] Oleksiuk L M, Nguyen M H, Press E G, et al. In vitro responses of Acinetobacter baumannii to two- and three-drug combinations following exposure to colistin and doripenem[J]. Antimicrob Agents Chemother, 2014, 58(2):1195-1199.
[64] Batirel A,Balkan I I, Karabay O, et al. Comparison of colistin-carbapenem, colistin-sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections[J]. Eur J Clin Microbiol Infect Dis, 2014, 33(8):1311-1322.
[65] Dinc G, Demiraslan H, Elmali F, et al. Antimicrobial efficacy of doripenem and its combinations with sulbactam, amikacin, colistin, tigecycline in experimental sepsis of carbapenem-resistant Acinetobacter baumannii[J]. New Microbiol, 2015, 38(1):67-73.
[66] Le Minh V, Nhu N T K, Phat V V, et al. In vitro activity of colistin in antimicrobial combination against carbapenem-resistant Acinetobacter baumannii isolated from patients with ventilator-associated pneumonia in Vietnam[J]. J Med Microbiol, 2015, 64(10):1162-1169.
[67] 陈佰义, 何礼贤, 胡必杰, 等. 中国鲍曼不动杆菌感染诊治与防控专家共识[J]. 中华医学杂志, 2012, 92(2):76-85.