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Study of Mechanisms Leading to Multidrug-Resistant K. pneumoniae and A. baumannii

肺炎克雷伯菌和鲍曼不动杆菌多重耐药机制研究

基本信息

批准号：
7404607
负责人：
JOHN M QUALE
金额：
$ 26.78万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7404607
关键词：
Acinetobacter baumannii Affect Aminoglycosides Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Awareness Bacteria Carbapenems Cephalosporinase Class Clinical DNA Sequence Development Economics Enzymes Exposure to Fluoroquinolones Future Gene Expression Genes Genetic Health care facility Hospitals Hydrolysis Individual Infection Infection Control Investigation Klebsiella pneumonia bacterium Lactamase Lactams Macrolides Measures Membrane Membrane Proteins Molecular Multi-Drug Resistance Mutation New England New York City Nosocomial Infections Pan Genus Patients Plague Pneumonia Polymyxin Resistance Polymyxins Public Health Rate Regulator Genes Reporting Resistance Resistance development Resort Reverse Transcriptase Polymerase Chain Reaction System Tetracycline Tetracyclines Time Toxic effect United States antibiotic efflux antimicrobial drug bacterial resistance beta-Lactamase beta-Lactams efflux pump indium arsenide inhibitor/antagonist major outer membrane protein novel oxytocin, Asp(5)-pathogen porin resistance mechanism restoration transmission process

项目摘要

DESCRIPTION (provided by applicant): Antibiotic resistance rates among hospital-acquired bacteria have reached crisis proportions, particularly in health care facilities in the northeastern United States. In particular, two pathogens, Klebsiella pneumoniae and Acinetobacter baumannii, have developed resistance to all commonly-used antibiotics. Isolates resistant to all beta-lactams (including carbapenems), fluoroquinolones, and aminoglycosides have been documented. Clinicians often resort to the use of polymyxin antibiotics for therapy of these multidrug-resistant bacteria, however toxicity concerns surround these agents, and polymyxin-resistant strains have been reported. For patients with infections with these multidrug-resistant pathogens, no known effective therapy exists. This study will analyze three molecular mechanisms contributing to multidrug resistance in K. pneumoniae and A. baumannii: 1) beta-lactamases, 2) porin deficiencies, and 3) antibiotic efflux systems. Using real time reverse transcriptase PCR, expression of genes encoding beta-lactamases, outer membrane porins, and efflux systems will be measured in highly-resistant strains and their expression will be compared to that found in susceptible isolates. In addition, purported regulatory genes will be characterized by DNA sequencing, to determine if specific mutations affect the genetic control of many of these resistance genes. Ultimately, understanding how these bacteria become so resistant to antibiotics will be important for the development of novel antibacterial agents. For example, the development of novel beta-lactamase inhibitors or efflux system inhibitors may prove useful against some of these isolates. The inter- and intra- hospital transmission of strains of multidrug-resistant K. pneumoniae and A. baumannii has become a serious public health issue. Despite heightened awareness and infection control efforts, the emergence and spread of these pathogens has been relentless. The clinical and economic consequences of nosocomial infections due to multidrug-resistant bacteria are staggering.

描述（由申请人提供）：医院获得性细菌的抗生素耐药率已达到危机比例，特别是在美国东北部的医疗机构。特别是，两种病原体，肺炎克雷伯氏菌和鲍曼不动杆菌，已对所有常用抗生素产生耐药性。已记录了对所有β-内酰胺类（包括碳青霉烯类）、氟喹诺酮类和氨基糖苷类耐药的分离株。临床医生经常求助于使用多粘菌素抗生素来治疗这些多重耐药细菌，然而围绕这些药物的毒性问题，并且已经报道了多粘菌素耐药菌株。对于感染这些多重耐药病原体的患者，没有已知的有效治疗方法。本研究将分析导致克雷伯菌多药耐药的三种分子机制。肺炎链球菌和A.鲍曼不动杆菌：1）β-内酰胺酶，2）孔蛋白缺陷，和3）抗生素外排系统。使用真实的时间逆转录酶PCR，将在高度耐药菌株中测量编码β-内酰胺酶、外膜孔蛋白和外排系统的基因的表达，并将其表达与在敏感分离株中发现的表达进行比较。此外，将通过DNA测序来表征所谓的调控基因，以确定特定突变是否影响许多这些抗性基因的遗传控制。最终，了解这些细菌如何对抗生素产生如此大的耐药性，对于开发新型抗菌药物至关重要。例如，新型β-内酰胺酶抑制剂或外排系统抑制剂的开发可能证明对这些分离株中的一些有用。多重耐药克雷伯氏菌的院内和院内传播。肺炎链球菌和A.鲍曼不动杆菌已成为一个严重的公共卫生问题。尽管提高了认识和感染控制努力，这些病原体的出现和传播一直是无情的。由于多重耐药细菌引起的医院感染的临床和经济后果是惊人的。