多利培南及其联合用药对不同碳青霉烯酶基因鲍曼不动杆菌体外和体内抗菌作用研究
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摘要
鲍曼不动杆菌(Acinetobacterbaumanii,Ab)是非发酵糖类的需氧的革兰阴性杆菌，是导致医院感染最常见的病原菌之一。近年来，随着糖皮质激素、大量抗菌药物等的应用，鲍曼不动杆菌已成为医院感染和机会感染的主要病原菌，给临床医院感染控制带来极大困难。
碳青霉烯类抗生素(carbopenem)是迄今为止抗菌谱最广、抗菌活性最强的一类抗生素，为广谱、小分子的β-内酰胺类药物，由于其对多种β-内酰胺酶高度稳定，因此主要适用于产酶菌和多重耐药菌所致的严重细菌感染。随着广谱抗菌药物，尤其是碳青霉烯类抗生素在临床上的广泛应用，鲍曼不动杆菌耐药性逐渐增强，出现了泛耐药鲍曼不动杆菌和多重耐药鲍曼不动杆菌。多重耐药鲍曼不动杆菌对碳青霉烯抗生素耐药主要是产碳青霉烯酶。碳青霉烯酶可分为三类：A类，为丝氨酸蛋白酶，此类酶尚未在鲍曼不动杆菌中发现； B类，为金属β-内酰胺酶，包括VIM和IMP两种； D类，为苯唑西林酶(OXA-type)，此类酶仅见于不动杆菌，在不动杆菌中共发现20余种，分为四组。不动杆菌产碳青霉烯酶主要是B类和D类。
而近年来，针对泛耐药菌株，耐药突变选择窗理论提出：当两种不同作用机制的抗菌药物同时处于各自的最低抑菌浓度之上，进行联合应用时，细菌需要同时发生两种耐药突变才能生长，从而关闭耐药突变选择窗，从而有效控制细菌耐药。因此，当鲍曼不动杆菌对所有抗菌药物耐药时，联合用药则为治疗的惟一选择。
在以上理论基础上，本实验选取了新型碳青霉烯类广谱抗生素-多利培南，对其进行单药和联合药敏的相关研究。多利培南对绝大多数β-内酰胺酶稳定，相比亚胺培南和美罗培南，诱导细菌产生耐药性的可能性要低。
本研究前期已于临床试验应用江苏正大天晴药业股份有限公司开发研制的注射用多利培南，对比住友制药（苏州）公司生产的注射用美罗培南治疗治疗中、重度呼吸系统急性细菌感染282例。两组病人用药结束时结果：两组呼吸系统病人临床治愈率分别为89.55%和85.07%；两组社区获得性肺炎临床治愈率分别为85.71%和71.43%；两组细菌清除率分别为96.43%和98.21%；两组呼吸系统综合疗效的临床治愈率分别为96.43%和91.30%。
在此基础上，本实验首先检测76株鲍曼不动杆菌的碳青霉烯酶基因，测定多利培南与左氧氟沙星、阿米卡星及舒巴坦的联合用药，对不同基因分型鲍曼不动杆菌的最低抑菌浓度（minimum inhibitory concentration,MIC），通过计算部分抑菌浓度指数（Fractional inhibitory concentration,FIC）来评判其是否具有联合用药的协同效果。同时，进一步通过体内实验，验证联合用药较单药对于鲍曼不动杆菌感染的大鼠是否具有较好的疗效，探讨联合治疗泛耐药鲍曼不动杆菌的组合方式，指导临床治疗。
第一部分76株鲍曼不动杆菌的碳青霉烯酶基因blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2的鉴定
方法：收集2010年7月至2011年5月上海长征医院住院患者的鲍曼不动杆菌标本，RT-PCR检测法扩增测序碳青霉烯酶基因blaOXA-23、blaOXA-24、blaOXA-51、blaOXA-58、blaOXA-27、blaIMP-1、blaIMP-2、blaVIM-2并测序。
结果：在76株菌株中，检测出blaOXA-23阳性53株、blaOXA-24阳性13株、blaOXA-51阳性76株、blaOXA-58阳性10株、blaIMP-1阳性22株、blaIMP-2阳性15株、blaVIM-2阳性23株。比例由高到低依次为：blaOXA-51、blaOXA-23、blaVIM-2、blaIMP-1、blaIMP-2、blaOXA-24、blaOXA-58，比率依次为100.0%、69.7%、30.3%、28.9%、19.7%、17.1%、13.2%。携带1种基因型的有12株，2种基因型的28株，3种基因型的17株，4种基因型的12种，5种基因型的5株,6种基因型的2株。
结论：鲍曼不动杆菌碳青霉烯酶基因分型中，比例由高到低依次为：blaOXA-51、blaOXA-23、blaVIM-2、blaIMP-1、blaIMP-2、blaOXA-24、blaOXA-58，以携带两种基因型的比率最高。
第二部分单药及联合用药对不同碳青霉烯酶基因分型鲍曼不动杆菌药敏的影响
方法：微量肉汤稀释法测定单药左氧氟沙星、阿米卡星、舒巴坦，多利培南、亚胺培南、美罗培南，及多利培南联合左氧氟沙星、阿米卡星、舒巴坦，对76株临床分离鲍曼不动杆菌药的最低抑菌浓度，并计算MIC50、MIC90；利用棋盘法测定联合用药（多利培南+左氧氟沙星，多利培南+阿米卡星，多利培南+舒巴坦）的最低抑菌浓度；比较联合用药FIC的分布，探讨有效的联合方式。
结果：联合用药后，各组MIC50、MIC90均降低。FIC指数分布：多利培南+左氧氟沙星，多利培南+阿米卡星，多利培南+舒巴坦：FIC≤0.5:55.3%、52.6%、60.5%；0.52：5.3%、11.8%、5.3%。3种抗菌药物与多利培南联合用药后,对鲍曼不动杆菌基本表现为协同作用和相加作用,并以协同作用为主,无关作用较少,拮抗作用较少。对于携带blaOXA-58的鲍曼不动杆菌，多利培南联合舒巴坦，FIC较低。对于携带blaOXA-23基因的鲍曼不动杆菌，多利培南联合左氧氟沙星、阿米卡星，FIC较低。
结论：联合用药可降低单药的MIC50、MIC90。联合用药对鲍曼不动杆菌基本表现为协同作用和相加作用,并以协同作用为主。多利培南协同舒巴坦的效果好于左氧氟沙星及阿米卡星。多利培南联合舒巴坦，对携带blaOXA-58基因的鲍曼不动杆菌，敏感性较高。多利培南联合左氧氟沙星、阿米卡星，携带blaOXA-23基因的鲍曼不动杆菌，敏感性较高。
第三部分联合用药对鲍曼不动杆菌感染小鼠的影响
方法：小鼠气道内滴入鲍曼不动杆菌ATCC19606,建立小鼠鲍曼不动杆菌感染模型，在模型建立2天后给予单药左氧氟沙星、阿米卡星、舒巴坦，多利培南、亚胺培南、美罗培南，及联合用药（多利培南+左氧氟沙星，多利培南+阿米卡星，多利培南+舒巴坦），对比对照组及正常组，观察小鼠肺组织病理，体内中性粒细胞计数，TNF-α，MPO，NK细胞活性值变化，从而比较单药及联合用药对体内感染的影响。
结果：鲍曼不动杆菌感染模型中，多利培南联合左氧氟沙星组，与左氧氟沙星组相比，渗出液明显减少，TNF-α、MPO、NK细胞活性值明显降低（P<0.05）；多利培南联合阿米卡星组，与阿米卡星组相比，炎症细胞浸润明显减少，中性粒细胞数、MPO、NK细胞活性明显降低（P<0.05）；多利培南联合舒巴坦组，与舒巴坦组相比，炎症程度有所减轻；中性粒细胞数，TNF-α、NK细胞活性值明显降低（P<0.05）。
结论：多利培南联合左氧氟沙星、阿米卡星、舒巴坦后，较单药相比，炎症程度明显减轻；明显降低了鲍曼不动杆菌小鼠的中性粒细胞数、TNF-α、MPO水平、NK细胞活性（P<0.05）。
综上所述，多利培南的联合用药，可以对不同碳青霉烯酶基因分型鲍曼不动杆菌产生较好的体内和体外疗效。
Acinetobacter baumannii is a sugar-azymic and aerobic Gram-negativefermentation,and one of common pathogens causing hospital infections. In recentyears, with the application of broad-spectrum antimicrobial drugs, glucocorticoids,Acinetobacter Acinetobacter infections have become a major pathogen of hospitalinfections and opportunistic infections, caused great difficulties to clinicalanti-infection treatment and hospital infection control.
Carbapenem antibiotics is a small-molecule, efficient, broad-spectrumβ-lactams, most widely and strongest antibacterial activity antibiotics until now, andhighly stable to variety of β-lactamase, it is mainly applicable to serious bacterialinfection caused by multi-resistant bacteria and enzyme production-bacteria.Aswide range applications of antimicrobial agents, especially carbapenems,Acinetobacter baumannii resistantance continuously increased,like multi-drugresistant Acinetobacter baumanii and pan-resistant Acinetobacter baumanii.Resistance of multidrug-resistant Acinetobacter baumanii to carbapenem antibiotic ismainly caused by producing carbapenemases.Carbapenemases,which can bedivided into three categories: A type, is a serine protease; B type, is a metal β-lactamenzyme; D type, is a oxacillin enzyme(OXA-type)， which can only be found inAcinetobacter.A type is not yet in found Acinetobacter genus. Acinetobacterbaumannii producing carbapenemases are type B and D: B type (metalloenzymes)contains VIM and IMP, D type (OXA-type enzyme) were found more than20speciesin Acinetobacter, dividing into four groups.
In recent years, mutants select windows theory considerd: When combination oftwo antimicrobial agents with different mechanisms act, beyond each MIC, thebacteria need have two resistance mutations to close the MSW, in order to controlbacterial resistance effectively. Therefore, when Acinetobacter baumanii resistant toall antimicrobial agents, combination therapy may be best treatment.
As a result, this experiment select a new broad-spectrum carbapenem antibiotics-doripenem,to study its monotherapy and combined sensitivity. Doripenemis stable to mostβ-lactams. Comparing with imipenem and meropenem, possibility ofinduce bacteria producing drug resistance is lower.
The study has clinical trials with doripenem(Zhengdatianqing PharmaceuticalCompany, and meropenem (Zhuyou Pharmaceuticals Company),to treat282cases ofsevere and acute respiratory bacterial infection. Results: clinical curing rate ofrespiratory disease patient are89.55%and85.07%, clinical curing rate ofcommunity-acquired pneumonia are85.71%and71.43%; bacterial clearance rateswere96.43%and98.21%; clinical curing rate of respiratory comprehensive efficacyare96.43%and91.30%.
On this basis, the experiment detect76carbapenemase gene of Acinetobacterbaumannii,detect MIC of monotherapy and combination theapy of doripenem todifferent genotyping of Acinetobacter baumannii, through FIC index to judge whetherit has a synergistic effect. In further vivo experiments, we verify that comparing withsingle-agent,whether combination therapy has a better effect to Acinetobacterbaumannii infection in rats, exploring combination therapy to pan-resistantAcinetobacter baumannii, to guide clinical treatment.
PartI Dection of carbapenemases genes in76Acinetobacter baumannii blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2
Methods: Collecting76Acinetobacter baumannii from July2010to May2011inShanghai Changzheng Hospital,amplified by RT-PCR and assay sequencingcarbapenemase gene: blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2.
Results:In76Acinetobacter baumannii,we decet blaOXA-23、13blaOXA-24、76blaOXA-51、10blaOXA-58、22blaIMP-1、15blaIMP-2、23blaVIM-2,which number are53、13、76、10、22、15、23.From highest to lowest：blaOXA-51、blaOXA-23、blaVIM-2、blaIMP-1、blaIMP-2、blaOXA-24、blaOXA-58，which ratio are100.0%、69.7%、30.3%、28.9%、19.7%、17.1%、13.2%.12plants with1type gene，28plants with2type genes，17plants with3type genes，12plants with4type genes，5plants with5type genes，2plants with6type genes.
Conclusions:In different genotype of Acinetobacter baumannii,ratio from high tolow are: blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2.
PartII Susceptibility of monotherapy and combination to Acinetobacterbaumannii with different carbapenemases genotyping
Methods:We used microdilution method to detect minimum inhibitoryconcentration (MIC) of single agent levofloxacin, amikacin, sulbactam, doripenem,imipenem,meropenem and doripenem combined with levofloxacin, amikacin,sulbactam, to76Acinetobacter baumannii drug, and calculate the MIC50、MIC90; weused checkerboard to decect minimum inhibitory concentration of combination(doripenem+levofloxacin, doripenem+amikacin, doripenem+sulbactam);Comparing combination FIC distribution to explore effective combined way.
Results: After combination therapy, MIC50、MIC90decreased. The FIC indexdistribution: the doripenem+levofloxacin, doripenem+amikacin, doripenem+sulbactam:FIC≤0.5:55.3%,52.6%,60.5%;0.52：5.3%、11.8%、5.3%.combination of antimicrobial drugswith doripenem, showed synergistic and additive effect, especially synergies, lowunrelated effect and antagonism effect. According to blaOXA-58Acinetobacterbaumannii, doripenem combind with sulbactam had lower FIC ratio. To blaOXA-58Acinetobacter baumannii, doripenem combind with levofloxacin, amikacin had lowerFIC ratio.
Conclusions: After combination of antimicrobial drugs with doripenem,it showedsynergistic and additive effect, especially synergies, low unrelated effect andantagonism effect. Towards blaOXA-58gene, Doripenem combined with sulbactam, hada high sensitivity.Towards blaOXA-23gene, Doripenem combined with levofloxacin oramikacin, had a high sensitivity.
PartIII Effect of combination therapy to mice with Acinetobacter baumanniiinfections
Methods:In airway of mouse,we instilled Acinetobacter baumanniiATCC19606,to create mice infection model of Acinetobacter baumannii. Two daysafter model set up,we given single drug levofloxacin, amikacin, sulbactam, doripenem, meropenem,imipenem, and combination therapy (doripenem+levofloxacin, doripenem+amikacin, doripenem+sulbactam), comparing with controlgroup and normal group, observing mice lung tissue pathology, neutralgranulocyte,TNF-α, MPO, NK cytoactive to compare effect of single-agent andcombination therapy to body infection.
Results:In Acinetobacter baumannii infection models, doripenem combinedwith levofloxacin group,compared with levofloxacin group, inflammatory extravasatedecreasing,TNF-α, MPO, NK cytoactive decreased significantly(P <0.05);doripenemcombined with amikacin group, compared with amikacin group, inflammatoryinfiltration decreasing;neutrophils number, MPO,NK cytoactive are significantlylower(P <0.05); doripenem combined with sulbactam, compared with sulbactamgroup,inflammation decreasing obviously;neutrophils number, TNF-α is significantlylower(P <0.05).
Conclusions:After doripenem combined with levofloxacin, amikacin, sulbactam,comparing with single drug,it could not only obviously reduce mice plumonaryinflammation;but significantly reduce neutrophils,TNF-α,MPO,NK cytoactive ofAcinetobacter baumannii mice (P <0.05).
In summary,combination of doripenem can produce better internal and externalefficacy towards carbapenemases with different genotyping Acinetobacter baumannii.
碳青霉烯类抗生素(carbopenem)是迄今为止抗菌谱最广、抗菌活性最强的一类抗生素，为广谱、小分子的β-内酰胺类药物，由于其对多种β-内酰胺酶高度稳定，因此主要适用于产酶菌和多重耐药菌所致的严重细菌感染。随着广谱抗菌药物，尤其是碳青霉烯类抗生素在临床上的广泛应用，鲍曼不动杆菌耐药性逐渐增强，出现了泛耐药鲍曼不动杆菌和多重耐药鲍曼不动杆菌。多重耐药鲍曼不动杆菌对碳青霉烯抗生素耐药主要是产碳青霉烯酶。碳青霉烯酶可分为三类：A类，为丝氨酸蛋白酶，此类酶尚未在鲍曼不动杆菌中发现； B类，为金属β-内酰胺酶，包括VIM和IMP两种； D类，为苯唑西林酶(OXA-type)，此类酶仅见于不动杆菌，在不动杆菌中共发现20余种，分为四组。不动杆菌产碳青霉烯酶主要是B类和D类。
而近年来，针对泛耐药菌株，耐药突变选择窗理论提出：当两种不同作用机制的抗菌药物同时处于各自的最低抑菌浓度之上，进行联合应用时，细菌需要同时发生两种耐药突变才能生长，从而关闭耐药突变选择窗，从而有效控制细菌耐药。因此，当鲍曼不动杆菌对所有抗菌药物耐药时，联合用药则为治疗的惟一选择。
在以上理论基础上，本实验选取了新型碳青霉烯类广谱抗生素-多利培南，对其进行单药和联合药敏的相关研究。多利培南对绝大多数β-内酰胺酶稳定，相比亚胺培南和美罗培南，诱导细菌产生耐药性的可能性要低。
本研究前期已于临床试验应用江苏正大天晴药业股份有限公司开发研制的注射用多利培南，对比住友制药（苏州）公司生产的注射用美罗培南治疗治疗中、重度呼吸系统急性细菌感染282例。两组病人用药结束时结果：两组呼吸系统病人临床治愈率分别为89.55%和85.07%；两组社区获得性肺炎临床治愈率分别为85.71%和71.43%；两组细菌清除率分别为96.43%和98.21%；两组呼吸系统综合疗效的临床治愈率分别为96.43%和91.30%。
在此基础上，本实验首先检测76株鲍曼不动杆菌的碳青霉烯酶基因，测定多利培南与左氧氟沙星、阿米卡星及舒巴坦的联合用药，对不同基因分型鲍曼不动杆菌的最低抑菌浓度（minimum inhibitory concentration,MIC），通过计算部分抑菌浓度指数（Fractional inhibitory concentration,FIC）来评判其是否具有联合用药的协同效果。同时，进一步通过体内实验，验证联合用药较单药对于鲍曼不动杆菌感染的大鼠是否具有较好的疗效，探讨联合治疗泛耐药鲍曼不动杆菌的组合方式，指导临床治疗。
第一部分76株鲍曼不动杆菌的碳青霉烯酶基因blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2的鉴定
方法：收集2010年7月至2011年5月上海长征医院住院患者的鲍曼不动杆菌标本，RT-PCR检测法扩增测序碳青霉烯酶基因blaOXA-23、blaOXA-24、blaOXA-51、blaOXA-58、blaOXA-27、blaIMP-1、blaIMP-2、blaVIM-2并测序。
结果：在76株菌株中，检测出blaOXA-23阳性53株、blaOXA-24阳性13株、blaOXA-51阳性76株、blaOXA-58阳性10株、blaIMP-1阳性22株、blaIMP-2阳性15株、blaVIM-2阳性23株。比例由高到低依次为：blaOXA-51、blaOXA-23、blaVIM-2、blaIMP-1、blaIMP-2、blaOXA-24、blaOXA-58，比率依次为100.0%、69.7%、30.3%、28.9%、19.7%、17.1%、13.2%。携带1种基因型的有12株，2种基因型的28株，3种基因型的17株，4种基因型的12种，5种基因型的5株,6种基因型的2株。
结论：鲍曼不动杆菌碳青霉烯酶基因分型中，比例由高到低依次为：blaOXA-51、blaOXA-23、blaVIM-2、blaIMP-1、blaIMP-2、blaOXA-24、blaOXA-58，以携带两种基因型的比率最高。
第二部分单药及联合用药对不同碳青霉烯酶基因分型鲍曼不动杆菌药敏的影响
方法：微量肉汤稀释法测定单药左氧氟沙星、阿米卡星、舒巴坦，多利培南、亚胺培南、美罗培南，及多利培南联合左氧氟沙星、阿米卡星、舒巴坦，对76株临床分离鲍曼不动杆菌药的最低抑菌浓度，并计算MIC50、MIC90；利用棋盘法测定联合用药（多利培南+左氧氟沙星，多利培南+阿米卡星，多利培南+舒巴坦）的最低抑菌浓度；比较联合用药FIC的分布，探讨有效的联合方式。
结果：联合用药后，各组MIC50、MIC90均降低。FIC指数分布：多利培南+左氧氟沙星，多利培南+阿米卡星，多利培南+舒巴坦：FIC≤0.5:55.3%、52.6%、60.5%；0.5
结论：联合用药可降低单药的MIC50、MIC90。联合用药对鲍曼不动杆菌基本表现为协同作用和相加作用,并以协同作用为主。多利培南协同舒巴坦的效果好于左氧氟沙星及阿米卡星。多利培南联合舒巴坦，对携带blaOXA-58基因的鲍曼不动杆菌，敏感性较高。多利培南联合左氧氟沙星、阿米卡星，携带blaOXA-23基因的鲍曼不动杆菌，敏感性较高。
第三部分联合用药对鲍曼不动杆菌感染小鼠的影响
方法：小鼠气道内滴入鲍曼不动杆菌ATCC19606,建立小鼠鲍曼不动杆菌感染模型，在模型建立2天后给予单药左氧氟沙星、阿米卡星、舒巴坦，多利培南、亚胺培南、美罗培南，及联合用药（多利培南+左氧氟沙星，多利培南+阿米卡星，多利培南+舒巴坦），对比对照组及正常组，观察小鼠肺组织病理，体内中性粒细胞计数，TNF-α，MPO，NK细胞活性值变化，从而比较单药及联合用药对体内感染的影响。
结果：鲍曼不动杆菌感染模型中，多利培南联合左氧氟沙星组，与左氧氟沙星组相比，渗出液明显减少，TNF-α、MPO、NK细胞活性值明显降低（P<0.05）；多利培南联合阿米卡星组，与阿米卡星组相比，炎症细胞浸润明显减少，中性粒细胞数、MPO、NK细胞活性明显降低（P<0.05）；多利培南联合舒巴坦组，与舒巴坦组相比，炎症程度有所减轻；中性粒细胞数，TNF-α、NK细胞活性值明显降低（P<0.05）。
结论：多利培南联合左氧氟沙星、阿米卡星、舒巴坦后，较单药相比，炎症程度明显减轻；明显降低了鲍曼不动杆菌小鼠的中性粒细胞数、TNF-α、MPO水平、NK细胞活性（P<0.05）。
综上所述，多利培南的联合用药，可以对不同碳青霉烯酶基因分型鲍曼不动杆菌产生较好的体内和体外疗效。
Acinetobacter baumannii is a sugar-azymic and aerobic Gram-negativefermentation,and one of common pathogens causing hospital infections. In recentyears, with the application of broad-spectrum antimicrobial drugs, glucocorticoids,Acinetobacter Acinetobacter infections have become a major pathogen of hospitalinfections and opportunistic infections, caused great difficulties to clinicalanti-infection treatment and hospital infection control.
Carbapenem antibiotics is a small-molecule, efficient, broad-spectrumβ-lactams, most widely and strongest antibacterial activity antibiotics until now, andhighly stable to variety of β-lactamase, it is mainly applicable to serious bacterialinfection caused by multi-resistant bacteria and enzyme production-bacteria.Aswide range applications of antimicrobial agents, especially carbapenems,Acinetobacter baumannii resistantance continuously increased,like multi-drugresistant Acinetobacter baumanii and pan-resistant Acinetobacter baumanii.Resistance of multidrug-resistant Acinetobacter baumanii to carbapenem antibiotic ismainly caused by producing carbapenemases.Carbapenemases,which can bedivided into three categories: A type, is a serine protease; B type, is a metal β-lactamenzyme; D type, is a oxacillin enzyme(OXA-type)， which can only be found inAcinetobacter.A type is not yet in found Acinetobacter genus. Acinetobacterbaumannii producing carbapenemases are type B and D: B type (metalloenzymes)contains VIM and IMP, D type (OXA-type enzyme) were found more than20speciesin Acinetobacter, dividing into four groups.
In recent years, mutants select windows theory considerd: When combination oftwo antimicrobial agents with different mechanisms act, beyond each MIC, thebacteria need have two resistance mutations to close the MSW, in order to controlbacterial resistance effectively. Therefore, when Acinetobacter baumanii resistant toall antimicrobial agents, combination therapy may be best treatment.
As a result, this experiment select a new broad-spectrum carbapenem antibiotics-doripenem,to study its monotherapy and combined sensitivity. Doripenemis stable to mostβ-lactams. Comparing with imipenem and meropenem, possibility ofinduce bacteria producing drug resistance is lower.
The study has clinical trials with doripenem(Zhengdatianqing PharmaceuticalCompany, and meropenem (Zhuyou Pharmaceuticals Company),to treat282cases ofsevere and acute respiratory bacterial infection. Results: clinical curing rate ofrespiratory disease patient are89.55%and85.07%, clinical curing rate ofcommunity-acquired pneumonia are85.71%and71.43%; bacterial clearance rateswere96.43%and98.21%; clinical curing rate of respiratory comprehensive efficacyare96.43%and91.30%.
On this basis, the experiment detect76carbapenemase gene of Acinetobacterbaumannii,detect MIC of monotherapy and combination theapy of doripenem todifferent genotyping of Acinetobacter baumannii, through FIC index to judge whetherit has a synergistic effect. In further vivo experiments, we verify that comparing withsingle-agent,whether combination therapy has a better effect to Acinetobacterbaumannii infection in rats, exploring combination therapy to pan-resistantAcinetobacter baumannii, to guide clinical treatment.
PartI Dection of carbapenemases genes in76Acinetobacter baumannii blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2
Methods: Collecting76Acinetobacter baumannii from July2010to May2011inShanghai Changzheng Hospital,amplified by RT-PCR and assay sequencingcarbapenemase gene: blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2.
Results:In76Acinetobacter baumannii,we decet blaOXA-23、13blaOXA-24、76blaOXA-51、10blaOXA-58、22blaIMP-1、15blaIMP-2、23blaVIM-2,which number are53、13、76、10、22、15、23.From highest to lowest：blaOXA-51、blaOXA-23、blaVIM-2、blaIMP-1、blaIMP-2、blaOXA-24、blaOXA-58，which ratio are100.0%、69.7%、30.3%、28.9%、19.7%、17.1%、13.2%.12plants with1type gene，28plants with2type genes，17plants with3type genes，12plants with4type genes，5plants with5type genes，2plants with6type genes.
Conclusions:In different genotype of Acinetobacter baumannii,ratio from high tolow are: blaOXA-23、blaOXA-24、blaOXA-58、blaOXA-51、blaIMP-1、blaIMP-2、blaVIM-2.
PartII Susceptibility of monotherapy and combination to Acinetobacterbaumannii with different carbapenemases genotyping
Methods:We used microdilution method to detect minimum inhibitoryconcentration (MIC) of single agent levofloxacin, amikacin, sulbactam, doripenem,imipenem,meropenem and doripenem combined with levofloxacin, amikacin,sulbactam, to76Acinetobacter baumannii drug, and calculate the MIC50、MIC90; weused checkerboard to decect minimum inhibitory concentration of combination(doripenem+levofloxacin, doripenem+amikacin, doripenem+sulbactam);Comparing combination FIC distribution to explore effective combined way.
Results: After combination therapy, MIC50、MIC90decreased. The FIC indexdistribution: the doripenem+levofloxacin, doripenem+amikacin, doripenem+sulbactam:FIC≤0.5:55.3%,52.6%,60.5%;0.5
Conclusions: After combination of antimicrobial drugs with doripenem,it showedsynergistic and additive effect, especially synergies, low unrelated effect andantagonism effect. Towards blaOXA-58gene, Doripenem combined with sulbactam, hada high sensitivity.Towards blaOXA-23gene, Doripenem combined with levofloxacin oramikacin, had a high sensitivity.
PartIII Effect of combination therapy to mice with Acinetobacter baumanniiinfections
Methods:In airway of mouse,we instilled Acinetobacter baumanniiATCC19606,to create mice infection model of Acinetobacter baumannii. Two daysafter model set up,we given single drug levofloxacin, amikacin, sulbactam, doripenem, meropenem,imipenem, and combination therapy (doripenem+levofloxacin, doripenem+amikacin, doripenem+sulbactam), comparing with controlgroup and normal group, observing mice lung tissue pathology, neutralgranulocyte,TNF-α, MPO, NK cytoactive to compare effect of single-agent andcombination therapy to body infection.
Results:In Acinetobacter baumannii infection models, doripenem combinedwith levofloxacin group,compared with levofloxacin group, inflammatory extravasatedecreasing,TNF-α, MPO, NK cytoactive decreased significantly(P <0.05);doripenemcombined with amikacin group, compared with amikacin group, inflammatoryinfiltration decreasing;neutrophils number, MPO,NK cytoactive are significantlylower(P <0.05); doripenem combined with sulbactam, compared with sulbactamgroup,inflammation decreasing obviously;neutrophils number, TNF-α is significantlylower(P <0.05).
Conclusions:After doripenem combined with levofloxacin, amikacin, sulbactam,comparing with single drug,it could not only obviously reduce mice plumonaryinflammation;but significantly reduce neutrophils,TNF-α,MPO,NK cytoactive ofAcinetobacter baumannii mice (P <0.05).
In summary,combination of doripenem can produce better internal and externalefficacy towards carbapenemases with different genotyping Acinetobacter baumannii.
引文
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