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医药导报
医药导报, 2017, 36(2): 149-153
doi: 10.3870/j.issn.1004-0781.2017.02.008
替加环素联合亚胺培南对多重耐药及泛耐药鲍曼不动杆菌体外抗菌作用
In Vitro Activities of Tigecycline in Combination with Imipenem Against Multi-drug Resistant and Pan-drug Resistant Acinetobacter Baumannii Isolates
蔡静, 许静洁, 潘海燕
南京大学医学院附属鼓楼医院药学部,南京 210008
CAI Jing,, XU Jingjie,, PAN Haiyan
Department of Pharmacy,Nanjing Drun Tower Hospital Affiliated to Medical School of Nanjing University,Nanjing 210008, China

作者简介 蔡静(1991-),女,江苏泰州人,药师,学士,主要从事医院药学工作。电话:025-83106666-53701,E-mail:nydcai@126.com。

通信作者 许静洁(1968-),女,江苏南京人,主管药师,学士,主要研究方向:医院药学。电话:025-83106666-53701,E-mail:1176316897@qq.com。
中图分类号: R978     文献标识码: A     文章编号: 1004-0781(2017)02-0149-05
摘要: 目的评价替加环素联合亚胺培南对多重耐药及泛耐药的鲍曼不动杆菌体外抗菌活性,探讨联合用药的可行性,为临床抗菌药物的合理使用提供依据。方法收集南京鼓楼医院2015 年 1—4 月临床分离的多重耐药及泛耐药的鲍曼不动杆菌 16 株,采用棋盘设计微量肉汤稀释法测定替加环素和亚胺培南的单药和联合用药的最低抑菌浓度(MIC),并计算联合药敏指数(FIC),从而判断联合效应。结果替加环素单药平均MIC值(MICG)、MIC50、MIC90分别是1.73,1,4 μg·mL-1,亚胺培南单药MICG、MIC50、MIC90分别是31.00,32,64 μg·mL-1,而在联合用药情况下替加环素MICG、MIC50、MIC90分别是0.24,0.25,0.5 μg·mL-1,亚胺培南MICG、MIC50、MIC90 分别是8.16,8.00,16.00 μg·mL-1,联合用药与单用药比较均明显降低,FIC≤0.5、0.50<FIC≤1分别占 37.50%,62.50%,没有无关和拮抗作用。结论替加环素联合亚胺培南对多重耐药及泛耐药的鲍曼不动杆菌体外抗菌效应主要表现在相加作用和协同作用,提示联合用药对多重耐药及泛耐药鲍曼不动杆菌的治疗可能有效。
关键词: 替加环素 ; 亚胺培南 ; 鲍曼不动杆菌 ; 联合用药 ; 联合药敏指数

Abstract:
ObjectiveTo evaluate the in vitro antimicrobial activity of tigecycline in combination with imipenem against multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolates, so as to discuss the feasibility of drug combination and provide the basis for clinical rational use of antimicrobial agents. MethodsSixteen multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolates were collected between January and April in 2015 from all kinds of infected specimens of Nanjing Drun Tower Hospital. The protocol was designed by checkerboard method, and the minimum inhibitory concentration (MIC) of antibiotics was determined by microdilution broth method, and the fractional inhibitory concentration (FIC) index was calculated according to MIC results. ResultsThe average value of MIC (MICG), MIC50, MIC90 of tigecycline and imipenem single were 1.73,1,4 μg·mL-1and 31.00,32,64 μg·mL-1. When tigecycline was combined with imipenem, MICG, MIC50, MIC90 of tigecycline and imipenem were 0.24,0.25,0.50 μg·mL-1and 8.16,8.00,16.00 μg·mL-1, respectively. Compared with the drug single use groups, MIC was significantly decreased in the drug combination group. In 6 strains (37.50%), synergy effect (FIC≤0.5) was observed, and in 10 strains (62.50%), additive effect (0.5<FIC≤1) was found. No negative and independent effects were shown. ConclusionBoth additive and synergistic action is observed when tigecyclineis combined with imipenem against multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolates. No negative and independent effects are shown. This combination use against multi-drug resistant and pan-drug resistant Acinetobacter baumannii may be an effective therapy for clinical treatment.
Key words: Tigecycline ; Imipenem ; ; Drug combination ; Fractional inhibitory concentration index

鲍曼不动杆菌(Acinetobacter baumannii)属于不动杆菌属,是非发酵的革兰阴性菌,可引起各种严重感染,如呼吸机相关性肺炎、菌血症、脑膜炎、尿路感染、外科伤口感染及软组织感染等,主要发生在重症监护室(ICU)危重患者[1],其次为呼吸内科。鲍曼不动杆菌生长所需的营养很少,并且可以在不同的温度和酸碱度下生长,该菌株也可以在干燥的环境下生存,可广泛定植于医院内各种物品表面[2],是医院感染的重要条件致病菌。根据 2011 年全国耐药监测数据 Mohnarin 报告,鲍曼不动杆菌在医院感染病原菌中位居第四[3]。在不发酵糖革兰阴性杆菌引起的感染中,其分离率仅次于或超过铜绿假单胞菌[4]。替加环素是第一个用于临床的新型甘氨酰四环素类抗生素,它是米诺环素的衍生物,对于致病微生物有着较为广谱的抗菌活性[5]。然而,在临床广泛应用过程中,已出现替加环素耐药的鲍曼不动杆菌分离株。目前《中国鲍曼不动杆菌感染诊治与防控专家共识》对于多重耐药及泛耐药鲍曼不动杆菌推荐多种抗菌药物联合治疗[6]。因此,制定可行的联合用药方案对于治疗由多重耐药及泛耐药鲍曼不动杆菌引起的感染至关重要。常见的两药联合用药方案有多种[7],体外药敏试验结果表明替加环素对多重耐药及泛耐药鲍曼不动杆菌敏感率较高[8-9]。因此,笔者选择临床常用的替加环素联合亚胺培南对临床分离的多重耐药及泛耐药的鲍曼不动杆菌进行药效学研究,旨在为临床合理用药提供依据。

1 材料与方法
1.1 材料

1.1.1 菌株来源 收集从2015年1—4月我院临床分离的鲍曼不动杆菌菌株,采用E-test法进行药敏试验,选取其中表现为多重耐药及泛耐药的菌株16株。

1.1.2 质控菌株 大肠埃希菌(ATCC25922),铜绿假单胞菌(ATCC27853)由我院检验学部提供。

1.1.3 抗菌药物 替加环素灭菌粉末(商品名:泰阁;规格:每瓶50 mg,批号:AIYV/12,分包装厂:John Wyeth and Brother Limited;生产厂家:Wyeth Parenterals Division of Wyeth Holdings Corporation)。亚胺培南/西司他丁钠灭菌粉末(商品名:泰能;规格:亚胺培南 500 mg,西司他丁 500 mg;批号:K009907,分包装厂:杭州默沙东制药有限公司;生产厂家:Merc Sharp&Dohme Corp.U.S.A)。

1.1.4 培养基与仪器 肉汤(批号:150312;由我院检验学部配制),哥伦比亚血琼脂平板(批号:1004471842,青岛海博生物技术有限公司),比浊仪(英国 OXOID 公司),洁净工作台(DL-CJ-2N 型,哈尔滨市东联公司)、隔水式培养箱(GHP-9160 型,上海浦东荣丰科学仪器有限公司)、无菌微量多孔板(Costar,Corning Incorporated)、八导微量加样器(Thermo,ZY38124)等。

1.2 方法

1.2.1 菌液的制备 将临床分离的16株鲍曼不动杆菌、大肠埃希菌(ATCC25922)和铜绿假单胞菌(ATCC27853)分别转种于哥伦比亚血琼脂平板,置37 ℃孵箱内孵育10 h。从过夜新鲜培养的细菌培养基上,用无菌接种环挑取4或5个菌落置于0.9%氯化钠溶液中,用比浊仪校正浊度至0.5 MacFarland(相当于1×108CFU·mL-1),再用MH肉汤稀释至100倍,使每孔最终菌悬液浓度约为1×106 CFU·mL-1。

1.2.2 抗菌药物原液的配置 分别将替加环素和亚胺培南用0.9%氯化钠溶液稀释,使药物浓度均为10 mg·mL-1,分装后置于冰箱内冷藏。替加环素、亚胺培南的母液配制浓度分别是128,1 024 μg·mL-1,由于替加环素配制过程需严格避光,因此替加环素母液宜现配现用。

1.2.3 单药最低抑制浓度(MIC)值的测定 单药孔板的制备:取经灭菌过的96孔微型平板,在 1~12孔每孔各加肉汤100 μL,第 1 列每孔各加128 μg·mL-1替加环素药液100 μL,然后做倍比稀释(取100 μL放入第2孔中,以此类推,11孔吸出的100 μL弃去),使第1~11孔替加环素浓度为0.065~64 μg·mL-1。在1~12孔中各加入配置好的菌悬液100 μL,使得第1~11孔替加环素浓度为0.03~32 μg·mL-1,12孔为阴性对照。用同样的方法制备亚胺培南的单药孔板,使得亚胺培南的最终浓度为0.25~256 μg·mL-1。放入 (35±2)℃温箱中过夜培养,18~24 h观察结果,记录单独应用药物时的MIC。

1.2.4 联合用药MIC值测定 按各单药MIC,确定联合药敏试验的药物稀释度。一般选择6个以上稀释度。第1~8孔各加入肉汤50 μL,确定横向(1→8)为亚胺培南降梯度方向,第1列加入512 μg·mL-1亚胺培南溶液均为50 μL,按照倍比稀释的方法,使得第1~8孔亚胺培南浓度为256,128,64,32,16,8,4,2 μg·mL-1。纵向(A-H)为替加环素的降梯度方向,取32 μg·mL-1的替加环素溶液,分别稀释为 32,16,8,4,2,1,0.5,0.25 μg·mL-18 个浓度,依次加入至A-H孔中,每孔50 μL。此时1-8列亚胺培南浓度依次为128,64,32,16,8,4,2,1 μg·mL-1,A-H行替加环素浓度依次为16,8,4,2,1,0.5,0.25,0.125 μg·mL-1,每孔液体100 μL。然后各加入配制好的菌液100 μL,最终亚胺培南横向(1~8)浓度为64~0.5 μg·mL-1,替加环素纵向(A-H)浓度为 8~0.06 μg·mL-1。第9列为阴性对照,只加入肉汤100 μL及 菌液100 μL,第10列及第11列分别为亚胺培南及替加环素单药,按照单药孔板配制倍比稀释的方法,使得亚胺培南竖列的浓度为512~4 μg·mL-1,替加环素竖列的浓度为16~0.12 μg·mL-1,再加入 菌液100 μL,亚胺培南的最终浓度为256~2 μg·mL-1,替加环素的浓度为8~0.06 μg·mL-1,第11孔为空白对照,只加入肉汤200 μL。将配制好的平板放入(35±2)℃温箱中过夜培养,18~24 h观察结果,记录两药联合应用时各自的MIC。

1.2.5 联合药敏指数(FIC)的计算与判读标准 根据MIC值的测定结果,计算替加环素与亚胺培南FIC,判断其联合效应。FIC=甲药联合MIC值/甲药单用MIC值+乙药联合MIC值/乙药单用MIC值。FIC指数≤0.5,为协同作用,即两种抗菌药物联合后的药效大于同样浓度的两种药物抗菌作用的总和。当FIC指数为>0.5~1,为相加作用,即两种药物联合后其活性等于两种药物抗菌作用的总和。当FIC指数为>1~2,为无关作用,即联合药物的活性与单独的抗菌作用相同,FIC指数>2,为拮抗作用,即两种药物联合后的抗菌活性小于单独一种药物的抗菌作用。

1.2.6 统计学方法 采用 SPSS19.0版统计软件进行统计学分析。单用及联用MIC的比较采用t检验,P<0.05为差异有统计学意义。

2 结果
2.1 单用及联用MIC的测定

采用微量肉汤稀释法分别测定替加环素与亚胺培南单用和联用对16株鲍曼不动杆菌的MIC值,见表1。替加环素和亚胺培南联用的MIC值范围、MIC平均值、MIC50 值及 MIC90 值比单用时均有显著下降,均差异有统计学意义(均P<0.05)。

表1 抗菌药物对多重耐药及泛耐药鲍曼不动杆菌的MIC
Tab.1 MICs of the antibiotics against multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolatesμg·mL-1
抗菌药物 MIC
范围
平均		 MIC50 MIC90
单用
替加环素 0.25~8 1.73 1 4
亚胺培南 8~64 31.00 32 64
联用
替加环素 0.06~0.5 0.24 0.25 0.5
亚胺培南 0.5~32 8.16 8 16

表1 抗菌药物对多重耐药及泛耐药鲍曼不动杆菌的MIC

Tab.1 MICs of the antibiotics against multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolatesμg·mL-1

2.2 单用及联用MIC的分布情况

替加环素与亚胺培南单用和联用对16株鲍曼不动杆菌的MIC值分布情况见表2,表3。

表2 替加环素及亚胺培南单用对16株多重及泛耐药鲍曼不动杆菌的MIC分布情况
Tab.2 MIC distributions of tigecycline and imipenem alone against 16 strains of multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolates
MIC/(μg·mL-1) 菌株数 所占百分比/%
替加环素
0.25 3 18.75
0.5 4 25.00
1 3 18.75
2 3 18.75
4 2 12.50
8 1 6.25
亚胺培南
8 2 12.50
16 2 12.50
32 10 62.50
64 2 12.50

表2 替加环素及亚胺培南单用对16株多重及泛耐药鲍曼不动杆菌的MIC分布情况

Tab.2 MIC distributions of tigecycline and imipenem alone against 16 strains of multi-drug resistant and pan-drug resistant Acinetobacter baumannii isolates

表3 替加环素与亚胺培南联用后对16 株鲍曼不动杆菌的MIC分布情况
Tab.3 MIC distributions of tigecycline and imipenem in combination against 16 strains of Acinetobacter baumannii isolates
MIC/(μg·mL-1) 菌株数 所占百分比/%
替加环素
0.06 1 6.25
0.12 6 37.50
0.25 6 37.50
0.5 3 18.75
亚胺培南
0.5 3 18.75
1 1 6.25
4 2 12.50
8 7 43.75
16 2 12.50
32 1 6.25

表3 替加环素与亚胺培南联用后对16 株鲍曼不动杆菌的MIC分布情况

Tab.3 MIC distributions of tigecycline and imipenem in combination against 16 strains of Acinetobacter baumannii isolates

两药联合使用后替加环素的MIC主要分布在0.12和 0.25 μg·mL-1,占37.50%,亚胺培南的MIC值主要分布在8 μg·mL-1,占43.75%,单用药时替加环素主要分布在0.5 μg·mL-1,占25.00%,亚胺培南主要分布在32 μg·mL-1,占62.50%。联合后替加环素的最低MIC值为0.06 μg·mL-1,亚胺培南的最低MIC值为0.5 μg·mL-1,单药替加环素与亚胺培南的最低MIC值为0.25和8 μg·mL-1。两药联合使用后在体外药敏试验中可以明显降低药物各自的MIC值。

2.3 FIC值的判定

替加环素与亚胺培南联用后,FIC 值显示协同作用(FIC≤0.5)有6株,协同率为37.50%,相加作用(0.5<FIC≤1)有10株,相加率为62.50%,无拮抗与无关作用。因此两药联用以相加和协同作用为主,显示具有增强疗效的作用。

2.4 累积抑菌百分率

替加环素与亚胺培南单用与联用对多重耐药及泛耐药鲍曼不动杆菌累积抑菌百分率曲线见图1。从图1中可看出,替加环素联合亚胺培南的浓度累积抑菌百分率明显向左移,说明两种药物联合对鲍曼不动杆菌主要表现为协同和相加作用。


图1 替加环素与亚胺培南单用和联用对鲍曼不动杆菌累积抑菌百分率曲线

Fig.1 Curves of cumulative inhibition percentage of tigecycline and imipenem alone or in combination against Acinetobacter baumannii isolates

3 讨论

近年来由于鲍曼不动杆菌的分离率、耐药率和患者病死率逐渐增高,已被冠名为“21世纪革兰阴性杆菌MRSA”。在伴有基础疾病或免疫力低下的患者中,鲍曼不动杆菌可以引起严重、致死性的感染,如呼吸机相关肺炎、败血症、伤口感染和泌尿系感染等[10]。碳青霉烯类抗生素具有抗菌作用强、耐酶且稳定等优点,是治疗多重耐药鲍曼不动杆菌较为有效的抗菌药物之一。但自从1991年美国纽约首次报道鲍曼不动杆菌耐碳青霉烯类药物以来,世界各地陆续报道出现耐碳青霉烯类鲍曼不动杆菌(carbapenem-resistant Acinetobacter baumannii,CRAB)[11-12]。鲍曼不动杆菌的耐药机制主要有:产生β-内酰胺酶、外排泵激活、外膜蛋白缺失导致对β-内酰胺类抗生素耐药等[13];产生氨基苷修饰酶(AME)或16SrRNA甲基化酶对氨基苷类耐药;细菌gryA和parC基因的点突变引起对喹诺酮类耐药;产苯唑西林酶(OXA-23,24,40等)、金属酶,是用于临床的新型甘氨酰四环素类抗生素,其作用机制是通过与细菌的30S核糖体结合,阻止转移RNA的进入,使得氨基酸无法结合成肽链,最终阻断细菌蛋白质合成。由于鲍曼不动杆菌的耐药特点,单独应用药物难以达到快速控制广泛耐药菌株感染的目的,且易出现新的耐药菌株,给治疗带来新的困难,替加环素虽然对多重耐药及泛耐药的鲍曼不动杆菌有潜在的抗菌活性,但由于其血药浓度低,通常需要与其他抗菌药物联合使用[14]。碳青霉烯类药物作为临床常用的抗鲍曼不动杆菌药物,近年来耐药率也呈现升高趋势,因此本项研究通过体外实验评价亚胺培南联合替加环素对于多重耐药及泛耐药的鲍曼不动杆菌的临床疗效。

结果显示,联合用药较单用药的MIC值明显降低,提示联合用药强于单独用药。对于本院多重耐药以及泛耐药的鲍曼不动杆菌,替加环素保持着较高的敏感率,这与2012年CHINET监测的报道一致,亚胺培南则表现出高耐药率。FIC主要表现为协同和相加作用,进一步说明替加环素与亚胺培南联合可以增强治疗效果。因此,对于耐药性日益严重的鲍曼不动杆菌引起的感染,亚胺培南联合替加环素可能是一种较为有效的治疗方案。

笔者在本研究选取的菌株均是经过E-test试验法筛选MIC值>6 μg·mL-1的菌株,但是经过微量肉汤稀释法测定,所有菌株的MIC值均<4 μg·mL-1,MIC≤2 μg·mL-1的菌株占总菌株数的81.25%。目前,美国临床和实验室标准协会(Clinical and Laboratory Standard Institute,CLSI)中尚无替加环素药敏检测的操作指南和结果判定标准,替加环素易氧化降解,理化性质不稳定,导致该药的体外药物敏感性检测存在较多的难点和操作误区,因此不易标准化[15],替加环素体外药敏试验操作规程专家共识建议,对CRAB菌株琼脂稀释法、E-test法、Vitek2仪器法、纸片扩散法均不适合检测替加环素的敏感性,对MTS法测定结果也需要谨慎解释,微量肉汤稀释法通常被认为是替加环素体外药敏实验的金标准。有文献报道[16],30家医院临床分离以及实验室保存CRAB30株,采用微量肉汤稀释法测定替加环素MIC50,MIC90分别为2,4 mg·L-1,与本研究测得较为接近。

本研究中替加环素与亚胺培南的协同率与国内相关文献报道的替加环素与美罗培南联合后协同率为29.80%较为接近[17],但也有相关文献显示替加环素与多粘菌素、利福平、舒巴坦等联合后表现为无关作用[18-20],相同研究单位的实验结果存在较大的差异,原因可能是不同地区主要流行菌株耐药表型具有较大差异,不同研究单位采取的实验方法也不尽相同等。

总之,鲍曼不动杆菌的耐药问题日益严重,在选择联合应用抗菌药物治疗多重耐药及泛耐药鲍曼不动杆菌引起的院内感染时,首先应根据药物的MIC值选择联合后可以产生协同效应的抗菌药物,避免产生拮抗作用的联合用药;其次应尽可能了解当地的主要流行菌株耐药表型,以便针对不同的耐药机制合理选择联合药物。体外药敏试验结果表明,对于多重耐药及泛耐药鲍曼不动杆菌的治疗,替加环素联合碳青霉烯类抗生素可能是一种有效治疗方案,供临床参考。

The authors have declared that no competing interests exist.
参考文献
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Acinetobacter baumannii has been increasingly reported as a significant causative organism of various nosocomial infections. Here we describe an outbreak of carbapenem-resistant A. baumannii (CRAB) in the ICUs of a Korean university hospital, along with a successful outbreak control program. From October 2007 through July 2008, CRAB was isolated from 57 ICU patients. Nineteen patients were diagnosed as being truly infected with CRAB, four of whom were presumed to have died due to CRAB infection, producing a case-fatality rate of 21.1%. In surveillance of the environment and the healthcare workers (HCWs), CRAB was isolated from 24 (17.9%) of 135 environmental samples and seven (10.9%) of 65 HCWs. The pulsed field gel electrophoresis patterns showed that the isolates from patients, HCWs, and the environment were genetically related. Control of the outbreak was achieved by enforcing contact precautions, reducing environmental contamination through massive cleaning, and use of a closed-suctioning system. By August 2008 there were no new cases of CRAB in the ICUs. This study shows that the extensive spread of CRAB can happen through HCWs and the environmental contamination, and that proper strategies including strict contact precautions, massive environmental decontamination, and a closed-suctioning system can be effective for controlling CRAB outbreaks.
DOI:10.3346/jkms.2010.25.7.999      PMID:2890899      URL    
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正近20年来,鲍曼不动杆菌已 经成为医院感染中重要的病原菌[1]。由于鲍曼不动杆菌具有快速获得对多种抗菌药物耐药的能力,多重耐药、泛耐药的鲍曼不动杆菌分离株不断在医院中出现, 已成为威胁公众健康的重要问题,而对其多重耐药及播散机制的研究也日趋深入[2]。鲍曼不动杆菌的固有耐药途径包括:酶的降解作用,靶位修饰或保护,降低 对抗菌药物的通透或增加对抗菌药物的主动泵出;
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目的了解2012年我国不同地区15所医院临床分离不动杆菌属细菌的构成、分布及其耐药性。方法共收集15所教学医院临床分离的8 739株不动杆菌属,其中鲍曼不动杆菌7 827株（89.6%）。按照统一方案,采用纸片扩散法或自动化仪器法进行药敏试验,结果按CLSI 2013年版标准判读,采用WHONET5.6软件进行数据分析。结果 8 739株不动杆菌属细菌主要分离自住院患者,占85.4%,门急诊患者占14.6%。26.4%不动杆菌属分离自ICU,其次为内科病房（22.0%）。鲍曼不动杆菌对替加环素、米诺环素和头孢哌酮-舒巴坦的耐药率最低,分别为10.9%、35.2%和35.7%,其次为阿米卡星（43.4%）;对亚胺培南和美罗培南的耐药率分别为63.5%和68.2%。不同医院不动杆菌属细菌对抗菌药物的耐药率也有不同,不同科室分离株的耐药率也有不同,其中以ICU分离株耐药率最高。出现较多多重耐药（45.0%,3 521/7 827）和泛耐药（20.0%,1 567/7 827）株。结论鲍曼不动杆菌是不动杆菌属中最常见的菌种,检出率呈逐年增长的趋势。该菌对于除米诺环素、阿米卡星和头孢哌酮-舒巴坦外的大多数抗菌药物的耐药率在60.0%以上,且耐药率有逐年增高的趋势。不同地区医院鲍曼不动杆菌的耐药率相差较大,不同科室菌株的耐药率也有很大差异。
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The dawn of a troubling post-antibiotic era likely is on the horizon, fuelled by a rise in bacterial resistance to existing antibiotic therapy alongside a waning pipeline of novel . Tigecycline, a new glycylcycline with an expanded broad spectrum of in vitro activity, was recently approved for the treatment of complicated skin and (cSSTIs) and complicated (cIAIs). This review will examine how tigecycline evades the common mechanisms of antibiotic resistance, the metabolism and pharmacokinetics of tigecycline, and its spectrum of in vitro activity. The results of randomized clinical trials for the treatment of cSSTIs and cIAIs with tigecycline are also described, as is the patient safety and tolerability observed during these studies. Tigecycline monotherapy has been shown to be as effective as its comparators and, against a backdrop of rising bacterial resistance, the role for tigecycline in monotherapy of from Gram-positive, Gram-negative and anaerobic is a meaningful .
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Author information: (1)Division of Infectious Diseases and HIV Medicine, University Hospitals, Case Medical Centers, Cleveland, OH, USA.
DOI:10.1128/AAC.01464-06      PMID:2043292      URL    
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一、概述:共识目的和意义鲍曼不动杆菌具有强大的获得耐药性和克隆传播的能力,多重耐药、广泛耐药、全耐药鲍曼不动杆菌呈世界性流行[1],已成为我国院内感染最重要的病原菌之一.多重耐药鲍曼不动杆菌( Multidrugresistant Acinetobacter baumannii MDRAB)是指对下列五类抗菌药物中至少三类抗菌药物耐药的菌株,包括:抗假单胞菌头孢菌素、抗假单胞菌碳青霉烯类抗生素、含有β内酰胺酶抑制剂的复合制剂(包括哌拉西林/他唑巴坦、头孢哌酮/舒巴坦、氨苄西林/舒巴坦)、氟喹诺酮类抗菌药物、氨基糖苷类抗生素.广泛耐药鲍曼不动杆菌( Extensively Drug Resistant A.baumannii,XDRAB)是指仅对1～2种潜在有抗不动杆菌活性的药物[主要指替加环素和(或)多黏菌素)敏感的菌株.
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ABSTRACT The in vitro activities of tigecycline and selected antimicrobials were evaluated against a variety of multiple-drug-resistant clinical isolates, including extended-spectrum beta-lactamase- and/or metallo-beta-lactamase-producing gram-negative strains, colistin-resistant strains, vancomycin- and/or linezolid-resistant enterococci, and methicillin-resistant Staphylococcus aureus (MRSA). Tigecycline showed excellent activity against a collection of difficult-to-treat pathogens currently encountered in the hospital setting.
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[9] 张小江, 徐英春, 原英,等.替加环素等 14 种抗菌药物对多重耐药菌的体外抗菌活性研究[J].中国感染与化疗杂志,2009,9(5):365-368.
目的评价替加环素等14种抗菌药物对多重耐药细菌的体外抗菌活性。方法采用微量肉汤稀释法测定替加环素对临床分离的214株多重耐药细菌（MRSA、肠球菌属细菌、鲍曼不动杆菌、产ESBLs大肠埃希菌、产ESBLs肺炎克雷伯菌和肠杆菌属细菌）的MIC,并与其他13种抗菌药物进行比较。数据分析采用WHONET5.4软件。结果多重耐药的MRSA对替加环素、万古霉素和利奈唑胺的敏感性均为100%。多重耐药的肠球菌属（粪肠球菌和屎肠球菌）对替加环素和利奈唑胺的敏感率均为100%,万古霉素敏感率为93.1%,2株万古霉素耐药的多重耐药屎肠球菌对替加环素和利奈唑胺均呈敏感,MIC90值分别为0.064mg/L和1mg/L。37株多重耐药鲍曼不动杆菌对替加环素的敏感率为97.3%,MIC90值为2mg/L,其中16株耐美罗培南的鲍曼不动杆菌对替加环素的敏感率仍为100%,MIC90值为2mg/L。产ESBLs大肠埃希菌和肺炎克雷伯菌对替加环素和美罗培南的敏感率均为100%,但替加环素的MIC90值均高于美罗培南。多重耐药的肠杆菌属细菌（阴沟肠杆菌和产气肠杆菌）对替加环素的敏感率为86.5%,MIC90值为4mg/L。结论替加环素对多重耐药的常见需氧革兰阳性球菌和革兰阴性杆菌均有良好的体外抗菌活性。
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<h2 class="secHeading" id="section_abstract">Summary</h2><p id="">Institutional outbreaks caused by <em>Acinetobacter baumannii</em> strains that have acquired multiple mechanisms of antimicrobial drug resistance constitute a growing public-health problem. Because of complex epidemiology, infection control of these outbreaks is difficult to attain. Identification of potential common sources of an outbreak, through surveillance cultures and epidemiological typing studies, can aid in the implementation of specific control measures. Adherence to a series of infection control methods including strict environmental cleaning, effective sterilisation of reusable medical equipment, attention to proper hand hygiene practices, and use of contact precautions, together with appropriate administrative guidance and support, are required for the containment of an outbreak. Effective antibiotic treatment of <em>A baumannii</em> infections, such as ventilator-associated pneumonia and bloodstream infections, is also of paramount importance. Carbapenems have long been regarded as the agents of choice, but resistance rates have risen substantially in some areas. Sulbactam has been successfully used in the treatment of serious <em>A baumannii</em> infections; however, the activity of this agent against carbapenem-resistant isolates is decreasing. Polymyxins show reliable antimicrobial activity against <em>A baumannii</em> isolates. Available clinical reports, although consisting of small-sized studies, support their effectiveness and mitigate previous concerns for toxicity. Minocycline, and particularly its derivative, tigecycline, have shown high antimicrobial activity against <em>A baumannii</em>, though relevant clinical evidence is still scarce. Several issues regarding the optimum therapeutic choices for multidrug-resistant <em>A baumannii</em> infections need to be clarified by future research.</p>
DOI:10.1016/S1473-3099(08)70279-2      Magsci    
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Abstract Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a major global health problem. Polymyxin antibiotics such as colistin have resurfaced as effective last-resort antimicrobials for use against MDR Gram-negative pathogens, including Acinetobacter baumannii. Here we show that A. baumannii can rapidly develop resistance to polymyxin antibiotics by complete loss of the initial binding target, the lipid A component of lipopolysaccharide (LPS), which has long been considered to be essential for the viability of Gram-negative bacteria. We characterized 13 independent colistin-resistant derivatives of A. baumannii type strain ATCC 19606 and showed that all contained mutations within one of the first three genes of the lipid A biosynthesis pathway: lpxA, lpxC, and lpxD. All of these mutations resulted in the complete loss of LPS production. Furthermore, we showed that loss of LPS occurs in a colistin-resistant clinical isolate of A. baumannii. This is the first report of a spontaneously occurring, lipopolysaccharide-deficient, Gram-negative bacterium.
DOI:10.1128/AAC.00834-10      PMID:20855724      URL    
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The increasing problem of infections due to multidrug-resistant Gram-negative bacteria has led to re-use of polymyxins in several countries. However, there are already clinical isolates of Gram-negative bacteria that are resistant to all available antibiotics, including polymyxins. We present a case series of patients with infections due to pathogens resistant to all antimicrobial agents tested, including polymyxins. An isolate was defined as pandrug-resistant (PDR) if it exhibited resistance to all 7 anti-pseudomonal antimicrobial agents, i.e. antipseudomonal penicillins, cephalosporins, carbapenems, monobactams, quinolones, aminoglycosides, and polymyxins. Clinical cure of the infection due to pandrug-resistant (PDR) Gram-negative bacteria, namely Pseudomonas aeruginosa or Klebsiella pneumoniae was observed in 4 out of 6 patients with combination of colistin and beta lactam antibiotics. Colistin, in combination with beta lactam antibiotics, may be a useful agent for the management of pandrug-resistant Gram-negative bacterial infections. The re-use of polymyxins, an old class of antibiotics, should be done with caution in an attempt to delay the rate of development of pandrug-resistant Gram-negative bacterial infections.
DOI:10.1186/1471-2334-5-24      PMID:1087841      URL    
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[13] 张辉, 张小江, 徐英春,等. 2011年中国CHINET不动杆菌属细菌耐药性监测[J]. 中国感染与化疗杂志,2013,13(5):342-348.
目的 了解2011年我国不同地区1 5所医院临床分离不动杆菌属细菌分布及其耐药性.方法 共收集15所教学医院临床分离的6 723株不动杆菌属细菌,其中鲍曼不动杆菌5 958株(88.6％).按照统一方案,采用纸片扩散法进行药敏试验,结果按CLSI 2012年版标准判读,采用WHONET5.6软件进行数据分析.结果 6 723株不动杆菌属细菌中,分离自住院患者6 003株(89.3％),分离自门急诊患者720株(10.7％). 33.9％不动杆菌属细菌分离自ICU,其次为内科病房(29.3％).鲍曼不动杆菌对头孢哌酮-舒巴坦和米诺环素的耐药率最低,分别为43.4％和 31.1％,其次为阿米卡星(52.4％);对亚胺培南和美罗培南的耐药率分别为65.2％和66.2％.不同医院、不同科室分离的细菌对抗菌药物的耐药 率不同.科室中以ICU分离耐药菌株耐药率最高.出现较多多重耐药(51.7％,3 081/5 958)和泛耐药(27.4％,1 635/5 958)株.结论 鲍曼不动杆菌是不动杆菌属中最常见的菌种,该菌除对米诺环素和头孢哌酮-舒巴坦外的大多数抗菌药物的耐药率在60.0％以上,且检出率呈逐年增长的趋势. 不同地区医院、不同科室分离的鲍曼不动杆菌对抗菌药物的耐药率相差较大.
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[14] 梅宏波, 严星, 潘海媛. 比阿培南联合替加环素治疗广泛耐药鲍曼不动杆菌临床疗效[J].医药前沿, 2014,(24):210-211.
目的：观察比阿培兰联合替加环素治疗肺部广泛耐药鲍曼不动杆菌感染的临床 疗效及安全性。方法分析2013年1月-2014年6月在我院呼吸内科住院期间肺部感染广泛耐药鲍曼不动杆菌患者采取比阿培兰联合替加环素抗感染治疗的疗 效和安全性。结果：肺部广泛耐药鲍曼不动杆菌感染患者共12例，均为医院获得性肺炎，比阿培兰联合替加环素抗感染治疗时间7-20天，8例痊愈，2例好 转，2例无效死亡。其中3例出现不良反应，经对症处理均好转。结论比阿培兰联合替加环素治疗广泛耐药鲍曼不动杆菌效果较好。
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[15] 王辉, 俞云松, 王明贵,等. 替加环素体外药敏试验操作规程专家共识[J].中华检验医学杂志,2013,36(7):584-587.
替加环素是一种甘氨酰环素类抗生素,于2005年在美国批准上市,全球共有50多个国家和地区批准和上市 了替加环素,2012年初在中国批准上市.目前批注的适应证:(1)复杂性皮肤和皮肤软组织感染;(2)复杂性腹腔内感染;(3)社区获得性细菌性肺炎. 由于替加环素具有广谱、抗菌活性强的特点,对于临床常见多重耐药菌感染有非常好的疗效,且临床使用方便,不需根据肾功能受损情况调整剂量,因此该抗菌药物 将会在临床抗感染治疗中被广泛使用.
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[16] 杜小幸,王海萍,傅鹰,等. 不同药敏方法检测替加环素对鲍曼不动杆菌敏感性的比较[J].中华检验医学杂志, 2013,36(7):598-603.
目的 比较不同药敏方法检测替加环素对鲍曼不动杆菌的敏感性.方法 回顾性选取2010年1至12月全国30家医院临床分离以及本实验室保存的碳青霉烯类抗生素敏感鲍曼不动杆菌(CSAB)和耐药鲍曼不动杆菌(CRAB) 各30株,采用微量肉汤稀释法、Etest法、琼脂稀释法、MIC测试条(MTS)法、Vitek 2仪器法和纸片扩散法测定替加环素对鲍曼不动杆菌的敏感性,并以微量肉汤稀释法结果为标准进行比较,同时比较M-H和ISO培养基对药敏结果的影响.结果 CSAB微量肉汤稀释法、Etest法、琼脂稀释法、MTS法、Vitek 2仪器法测定替加环素MIC50/MIC90分别为0.125/0.25 mg/L、0.125/0.25 mg/L、0.5/1 mg/L、0.125/0.25 mg/L、0.5/0.5 mg/L,与微量肉汤稀释法比较,按照美国食品药品监督局(FDA)/欧洲药敏试验委员会(EUCAST)判断标准,所有药敏方法分类一致性(CA) ≥90％,未出现非常严重误差(VME).CRAB微量肉汤稀释法、Etest法、琼脂稀释法、MTS法、Vitek 2仪器法测定替加环素MIC50/MIC90分别为2/4 mg/L、4/4 mg/L、4/4 mg/L、1/2 mg/L、2/4mg/L,按照FDA/EUCAST判断标准,MTS法产生3.3％(1/30)/6.7％ (2/30) VME,没有一种药敏方法CA≥90％.按照Jones判断标准,纸片扩散法结果与微量肉汤稀释法结果分类一致性高于FDA标准,但对CRAB菌株CA仅 为66.7％ (20/30),未出现VME.采用M-H琼脂测得的替加环素MIC高于ISO琼脂.结论 对CRAB菌株,琼脂稀释法、Etest法、Vitek 2仪器法、纸片扩散法均不适合检测替加环素的敏感性,其检测中介或耐药菌株需用微量肉汤稀释法进一步确认,对MTS法测定结果也需要谨慎解释.
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[17] 王风娟,吕媛,李耘. 替加环素联合5种抗菌药物对多重耐药鲍曼不动杆菌的体外活性[J].中国临床药理学杂志, 2013,29(5):345-349.
目的 评价替加环素分别联合5种临床常用抗不动杆菌属抗菌药物对57株多重耐药鲍曼不动杆菌的体外抗菌作用.方法 琼脂棋盘稀释法测定替加环素分别联合美罗培南、阿米卡星、环丙沙星、粘菌素、舒巴坦对57株对美罗培南、阿米卡星、环丙沙星、米诺环素均耐药的多重耐药鲍 曼不动杆菌的最低抑菌浓度(MIC),并计算部分抑菌浓度指数(FICI).结果 替加环素与5种抗菌药物联合后表现为协同或不相关作用,其中协同率较高的组合为替加环素+阿米卡星组,50.9％；其次为替加环素+美罗培南 组,29.8％,未发现拮抗现象.结论 替加环素与5种抗菌药物联合对本组多重耐药鲍曼不动杆菌主要表现为不相关作用,但与阿米卡星联合具有相对较高的协同率.
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[18] OZBEK B, OTUK G.In vitro activities of tigecycline alone and in combination with colistin sulfate or sulbactam against carbapenem-susceptible and resistant Acinetobacter baumannii strains isolated from Intensive Care Units[J]. Int J Antimicrob Agents, 2010, 36(2):191-192.
Ozbek B, Otük G.
DOI:10.1016/j.ijantimicag.2010.04.004      PMID:20537868      URL    
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[19] PRINCIPE L, D'AREZZO S, CAPONE A, et al. In vitro activity of tigecycline in combination with various antimicrobials against multidrug resistant Acinetobacter baumannii[J].Ann Clin Microbiol Antimicrob , 2009, 8(1): 18.
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[20] LIM T P.In vitro activity of polymyxin B, rifampicin, tigecycline alone and in combination against carbapenem-resistant Acinetobacter baumannii in singapore[J]. PLoS One, 2011, 6(4): e18485.
Objective Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. Methods AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. Results 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. Conclusion Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations.
DOI:10.1371/journal.pone.0018485      PMID:3080872      URL    
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关键词（key words）
替加环素
亚胺培南
鲍曼不动杆菌
联合用药
联合药敏指数
Tigecycline
Imipenem
Drug combination
Fractional inhibitory con...
作者
蔡静
许静洁
潘海燕
CAI Jing
XU Jingjie
PAN Haiyan