Applied Research in Antimicrobial Resistance: Studies of Susceptibility Testing

描述（由申请人提供）：尽管今天使用了大量有效的抗生素，但“后抗菌时代”已经迫在眉睫了十多年，因为患者，特别是重症监护病房（icu）的患者，越来越多地发生由多药耐药（MDR）病原体引起的感染。这种感染与死亡率增加、发病率增加和费用增加有关。革兰氏阴性杆菌（GNB），如铜绿假单胞菌、肺炎克雷伯菌和不动杆菌（本项目感兴趣的病原体），可通过常规药敏试验确定对所有抗菌剂产生耐药性。这个项目的目标是：1)确定改善耐多药gnb感染患者治疗的策略，从而改善此类感染的临床和微生物预后；(2)评估哪些体外抗菌药物敏感性测试的实验室算法与耐多药gnb感染的改善结果最密切相关；(3)评估医疗保健专业人员如何实际使用体外敏感性数据来选择和修改耐多药gnb感染的治疗方案。本研究设计是一项前瞻性观察性研究，研究对象为耐多药gnb感染重地纽约市纽约长老会医院（New York- Presbyterian Hospital， NYPH）重症监护病房（ICU）院内获得性肺炎和耐多药gnb血流感染患者。NYPH是纽约市最大的医疗中心，拥有16个ICU， 383个ICU床位，每年有14,800名患者入住ICU，其中约40-50人患有耐多药gnb感染。具体目的和研究方法如下：目的1将观察耐多药- gnb感染的治疗策略，并通过巢式病例对照研究确定与选定治疗方案相关的耐多药- gnb感染受试者的结果，并将其与非耐多药- gnb感染受试者的结果进行比较。目标2将确定体外药敏试验策略（从目标1中对耐多药- gnb进行），以最好地预测成功的临床和微生物学结果，并可能导致不同的治疗选择。测试策略将包括NYPH临床微生物实验室目前使用的辅助测试（例如，粘菌素和替加环素的测试）以及研究分析（例如，参考肉汤微稀释协同研究，测试协同研究和最小杀菌浓度测试）。目标3将调查NYPH的医疗保健专业人员，以确定他们对抗菌药物敏感性测试策略的知识、态度和实践，并确定与使用测试结果相关的因素。为此，将对150名ICU医生、传染病专科医生和临床药剂师进行电子匿名调查。本项目提出的仔细开展的观察性研究，辅以潜在临床相关的体外药敏试验，有望改善耐多药gnb感染患者的治疗。患者，特别是重症监护病房的患者，越来越多地出现由耐多药微生物引起的感染。这些感染与死亡率增加、发病率增加和费用增加有关。仔细进行的观察性研究和临床相关的体外抗菌药物敏感性测试，最有希望改善对多药耐药生物感染患者的治疗。

DESCRIPTION (provided by applicant): Despite the large numbers of effective antibiotics in use today, the 'post-antimicrobial era' has been looming for well over a decade as patients, particularly in intensive care units (ICUs), are increasingly developing infections caused by multidrug-resistant (MDR) pathogens. Such infections are associated with increased mortality, increased morbidity, and increased cost. Gram negative bacilli (GNB), such as Pseudomonas aeruginosa, Klebsiella pneumonia and Acinetobacter spp. (the pathogens of interest in this project), may become resistant to all antimicrobial agents as determined by routine susceptibility testing. The goals of this project are to: 1) determine strategies to improve the treatment of patients infected with MDR-GNB and thus improve clinical and microbiological outcomes of such infections, (2) assess which laboratory algorithms for in vitro antimicrobial susceptibility testing most closely correlate with improved outcomes for MDR-GNB infections, and (3) evaluate how healthcare professionals actually use in vitro susceptibility data to choose and modify treatment regimens for MDR-GNB infections. The research design is a prospective observational study of ICU patients with hospital-acquired pneumonia and bloodstream infections caused by MDR-GNB at New York- Presbyterian Hospital (NYPH) in New York City, the epicenter of MDR-GNB infections. NYPH is the largest medical center in NYC and has 16 ICUs, 383 ICU beds, and 14,800 patients admitted to the ICU each year of whom approximately 40-50 develop MDR-GNB infections. The specific aims and research methods are as follows: Aim 1 will observe the treatment strategies used for MDR-GNB infections and determine the outcomes of subjects with MDR-GNB infections associated with selected treatment regimens and as compared with the outcomes of subjects with non-MDR-GNB infections by performing a nested case-control study. Aim 2 will determine the in vitro susceptibility testing strategies (performed on MDR-GNB from Aim 1) that best predict successful clinical and microbiologic outcomes and potentially lead to different treatment choices. Testing strategies will include ancillary testing currently used by NYPH clinical microbiology laboratories (e.g., Etest for colistin and tigecycline) as well as research assays (e.g., reference broth microdilution synergy studies, Etest synergy studies, and minimal bactericidal concentration testing). Aim 3 will survey healthcare professionals at NYPH to determine their knowledge, attitudes, and practices regarding antimicrobial susceptibility testing strategies and determine factors associated with the use of test results. To do so, an electronic, anonymous survey will be administered to 150 ICU physicians, infectious diseases sub-specialists, and clinical pharmacists. The carefully conducted observational studies proposed in this project, supplemented by potentially clinically relevant in vitro susceptibility testing, hold the greatest promise to improve the treatment of patients infected with MDR-GNB. Patients, particularly in intensive care units, are increasingly developing infections caused by multidrug-resistant organisms. These infections are associated with increased mortality, increased morbidity, and increased cost. Carefully conducted observational studies and clinically relevant in vitro antimicrobial susceptibility testing, hold the greatest promise to improve the treatment of patients infected with mutidrug-resistant organisms.