Markers predicting response to therapy for KPC-producing Klebsiella pneumoniae

性状（由申请方提供）：产碳青霉烯酶肺炎克雷伯菌。肺炎克雷伯氏菌（KPC-Kp）已成为与高死亡率和治疗失败率相关的重要医院病原体。粘菌素和替加环素在体外对KPC-Kp菌株保持活性，但这些药物的单药治疗导致次优结局。最近的数据表明，联合治疗上级单药治疗，特别是当组合含有碳青霉烯。我们的实验室研究了粘菌素和多利培南（我们医院的处方药碳青霉烯）联合治疗KPC-Kp感染的作用。我们表明，这种方案比其他组合在体外对KPC-Kp分离株的杀灭时间更长，并且更可靠地实现杀菌活性和协同作用。我们还发现，临床KPC-Kp菌株对多利培南的耐药水平（由最低抑菌浓度[MIC]反映）差异很大，这可能会影响对粘菌素-多利培南组合的反应。本项目的目标是系统地表征KPC-Kp菌株对粘菌素和多利培南的耐药性水平，并鉴定 粘菌素-多利培南联合治疗失败的预测因子。我们的中心假设是，对任何一种单独药物的高水平耐药性，如MIC和/或特定耐药机制的存在所证明的，是治疗失败的主要决定因素。我们将通过追求两个具体目标来检验这一假设。首先，我们将粘菌素和多利培南MIC与这些药物的关键耐药机制（粘菌素的脂质A修饰，以及编码多利培南主要孔蛋白的blaKPC和ompK 35/36的表达水平）的存在相关联。其次，我们将把粘菌素-多利培南联合治疗KPC-Kp感染的疗效与单个药物的MIC和耐药机制的存在相关联。为此，我们将审查与KPC-Kp菌血症患者和全身KPC-Kp感染的小鼠与粘菌素-多利培南治疗的结果。我们的初步数据和建议是建立在一个独特的生物储存库超过200临床KPC-Kp菌株。据我们所知，这将是第一项在耐药机制背景下评价联合方案对KPC-Kp菌株的影响的研究。如果成功，该研究将产生数据，为KPC-Kp感染的治疗提供新的见解。在 此外，它将导致未来的研究，链接的分子表征的高度耐药菌株的抗菌药物组合的功效。

DESCRIPTION (provided by applicant): Klebsiella pneumoniae arbapenemase-producing K. pneumoniae (KPC-Kp) has emerged as an important nosocomial pathogen that is associated with high mortality and treatment failure rates. Colistin and tigecycline remain active against KPC-Kp strains in vitro, but monotherapy with these agents results in suboptimal outcomes. Recent data suggest that combination therapy is superior to monotherapy, especially when the combination contains a carbapenem. Our laboratories have studied the role of the combination of colistin and doripenem (the formulary carbapenem at our hospital) against KPC-Kp infections. We showed that this regimen results in greater time-kills than other combinations against KPC-Kp isolates in vitro, and more reliably achieves bactericidal activity and synergy. We also showed that the level of resistance to doripenem (as reflected by minimum inhibitory concentrations [MICs]) varies widely among clinical KPC-Kp strains, and this might impact the response to colistin-doripenem combination. The goal of this project is to systematically characterize the levels of resistance of KPC-Kp strains to colisitin and doripenem, and to identify predictors for treatment failure of the colistin-doripenem combination. Our central hypothesis is that high levels of resistance to either drug alone, as evident by MICs and/or the presence of specific resistance mechanisms, are the primary determinants of treatment failure. We will test this hypothesis by pursuing two specific aims. First, we will correlate colistin and doripenem MICs with the presence of key resistance mechanisms against these agents (lipid A modifications for colistin, and the expression levels of blaKPC and ompK35/36 encoding major porins for doripenem). Second, we will correlate treatment outcomes of the colistin-doripenem combination against KPC-Kp infections with MICs of individual drugs and the presence of resistance mechanisms. For this aim, we will review the outcomes of patients with KPC-Kp bacteremia and mice with systemic KPC-Kp infections treated with colistin-doripenem. Our preliminary data and proposal are built upon a unique biorepository of over 200 clinical KPC-Kp strains. To our knowledge, this will be the first study that evaluates the effect of a combination regimen against KPC-Kp strains in the context of mechanism of resistance. If successful, the study will generate data that will provide new insights into the treatment of KPC-Kp infections. In addition, it will lead to future studies that link molecular characterization of highly drug-resistnt strains with the efficacy of antimicrobial combinations.