Multidrug-Resistant Acinetobacter baumannii

描述(申请人提供)：鲍曼不动杆菌是一种革兰氏阴性、非乳糖发酵的微生物，可引起严重的医院感染，如呼吸机相关性肺炎和菌血症。鲍曼不动杆菌的特点是对各种类型的抗菌剂产生抗药性，而这些抗菌剂本来对鲍曼不动杆菌有效。在匹兹堡，对亚胺培南和阿米卡星耐药的鲍曼不动杆菌激增，需要使用粘菌素和替格环素等抢救剂。尽管这些多药耐药(MDR)鲍曼不动杆菌菌株造成了潜在的问题，但对美国鲍曼不动杆菌对这些抗菌药的耐药机制知之甚少。目前使用脉冲场凝胶电泳法(PFGE)的流行病学研究表明，鲍曼不动杆菌可引起医院内暴发，主要通过接触医护人员受污染的手或医院环境而在患者之间传播。在监测研究中需要一种比PFGE更规范、更客观的分子分型方法，以调查鲍曼不动杆菌的国内和国际流行病学。应用的假设是：(1)OXA型碳青霉烯酶(如OXA-23)和ArmA 16S核糖体RNA甲基酶是鲍曼不动杆菌对亚胺培南和阿米卡星产生耐药性的主要机制；(2)多位点可变数目串联重复序列分析(MLVA)分子分型方法准确可靠地区分鲍曼不动杆菌临床菌株，具有优于PFGE的优势。为了解决这些假说，我们制定了以下具体目标：(1)研究鲍曼不动杆菌临床分离株对亚胺培南和阿米卡星耐药的分子机制；(2)对鲍曼不动杆菌客观分子分型方法进行评价。MLVA的分型结果将与PFGE和MLST进行比较。拟议的研究将提高对鲍曼不动杆菌如何获得多重耐药的理解，并导致最佳利用现有类别的抗菌药来管理感染的战略。这也将成为努力设计新的治疗剂和战略的基础，这些药物和战略将克服或逃避现有的和新出现的耐药机制。目的分子分型方法将成为未来研究鲍曼不动杆菌全球流行病学的重要工具。相关性(见说明)：鲍曼不动杆菌是一种有问题的病原体，会导致住院患者的严重感染。该项目旨在检查它是如何对两种重要的抗生素亚胺培南和阿米卡星产生抗药性的，并开发一种客观的方法来对菌株进行“指纹”鉴定。这些知识将有助于优化现有抗生素的使用和改进感染控制做法。

DESCRIPTION (provided by applicant): Acinetobacter baumannii is a Gram-negative, non-lactose-fermenting organism that causes serious nosocomial infections such as ventilator-associated pneumonia and bacteremia. A. baumannii is characterized by its tendency to acquire resistance to various classes of antimicrobials that are otherwise effective against this organism. In Pittsburgh, there is a surge in imipenem-resistant and amikacin-resistant A. baumannii, necessitating use of salvage agents such as colistin and tigecycline. Despite the potential magnitude of the problem caused by these multidrug-resistant (MDR) A. baumannii strains, little is known about the mechanisms of resistance to these antimicrobials in A. baumannii in the United States. Current epidemiological studies using pulsed-field gel electrophoresis (PFGE) reveal that A. baumannii causes nosocomial outbreaks, spreading from patient to patient mostly by contact with the contaminated hands of healthcare workers or the hospital environment. A molecular typing method that is more standardized and objective than PFGE is needed for use in surveillance studies to investigate national and international epidemiology of A. baumannii. The hypotheses of the application are: (1) OXA-type carbapenemases (e.g., OXA-23) and ArmA 16S ribosomal RNA methylase are the primary mechanisms by which A. baumannii develops resistance to imipenem and amikacin, (2) The multi-locus variable number of tandem repeats analysis (MLVA) scheme of molecular typing accurately and reliably discriminates clinical strains of A. baumannii and offers advantages over PFGE. To address these hypotheses, the following specific aims have been formulated: (1) Characterize the molecular mechanisms of imipenem and amikacin resistance in MDR A. baumannii clinical strains, (2) Evaluate objective molecular typing methods of A. baumannii. Typing results for MLVA will be compared with PFGE and MLST. The proposed study will enhance the level of understanding in how A. baumannii acquires multidrug resistance and lead to a strategy to best utilize the existing classes of antimicrobials to manage the infections. This will also form the basis for efforts in designing novel therapeutic agents and strategies that will overcome or evade the existing and emerging resistance mechanisms. Objective molecular typing methods will serve as an essential tool for future studies that will address the global epidemiology of MDR A. baumannii. RELEVANCE (See instructions): Acinetobacter baumannii is a problematic pathogen that causes serious infections in patients admitted to hospitals. The project aims to examine how it acquires resistance to two important antibiotics, imipenem and amikacin, and also develop an objective method to "fingerprint" the strains. Such knowledge will help in optimizing use of existing antibiotics and improving infection control practices.