Mechanisms and Circumvention of Daptomycin Resistance in Streptococcus mitis

轻链球菌达托霉素耐药机制及规避

基本信息

批准号：
10064598
负责人：
ARNOLD S BAYER
金额：
$ 45.66万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064598
关键词：
Address Altruism Animals Antibiotic Resistance Antibiotics Bacteremia Blood Circulation Cancer Patient Cardiolipins Cell Death Cell Separation Cells Cephalosporins Clinical Collection Combined Antibiotics Communicable Diseases Community Hospitals Complement Daptomycin Data Development Enterococcus Event Evolution Failure Flow Cytometry Fluorescence Microscopy Frequencies Gene Expression Profiling Genes Genetic Genotype Glycopeptides Goals Grant Heart Valves High Prevalence In Vitro Individual Infection Infective endocarditis Investigation Mediating Medical center Microscopy Modeling Mutation Nosocomial Infections Organism Oryctolagus cuniculus Outcome Pathogenesis Penicillin Resistance Penicillins Pharmacology Phenotype Physiological Population Prevention strategy Regimen Reporting Research Research Personnel Resistance Resort Sepsis Sepsis Syndrome Shock Specialist Staphylococcus aureus Streptococcal Infections Streptococcus Streptococcus Viridans Group Streptococcus mitis Subgroup Suicide Syndrome System Therapeutic Toxic Shock Syndrome United States National Institutes of Health Vancomycin Work antimicrobial bactericide beta-Lactam Resistance beta-Lactams clinically significant conventional therapy design emerging pathogen genomic locus human pathogen in vivo knockout gene pathogen prevent prototype resistant strain suicidal therapy outcome treatment strategy trend uptake virtual whole genome

项目摘要

ABSTRACT Viridans group streptococci (VGS), especially Streptococcus mitis, are pivotal pathogens in a variety of invasive endovascular infections,including: i) “breakthrough bacteremias” and “toxic shock” in neutropenic cancer patients; and ii) infective endocarditis (IE). Given world-wide trends in penicillin-resistance and other β-lactam MIC “creeps” amongst S. mitis strains, the proportion of serious infections caused by relatively or fully β-lactam-resistant-(R) strains is disturbing. Moreover, clinical outcomes in such cases utilizing alternate regimens (e.g., vancomycin) have been disappointing, presumably related to the high prevalence of vancomycin “tolerance” in such strains. This has prompted use of newer bactericidal agents, like daptomycin (DAP) for severe S. mitis syndromes in strains with β-lactam-resistance. Alarmingly, recent recognition of rapid, durable and high-level DAP-R induced by DAP therapy has significantly reduced enthusiasm for such approaches. In addition, DAP MICs in the S. mitis group are 2-10-fold higher than all other VGS groups. The number of reported clinical cases of invasive S. mitis infections in which DAP-R has emerged is limited, due to the relatively infrequent use of DAP in such infections to-date. However, progressive rise in S. mitis β-lactam-R plus the inconsistent outcomes of VANC therapy in such syndromes virtually assures increased DAP use, leading to DAP-R S. mitis infections. Moreover, medical centers with high DAP usage have recently confirmed substantial MIC “creeps” amongst enterococci. Understanding mechanism(s) of emergence of DAP-R in S. mitis, plus strategies to circumvent its evolution are, thus, of great clinical significance. Our Preliminary Data showed that DAP-R outcomes in S. mitis are likely to be multifactorial on both phenotypic and genotypic levels. Most interestingly, we have now shown compelling evidence of two forms of “DAP hyperaccumulation” in which individual cells in a given streptococcal chain can hyper-capture DAP and either die (“altruistic suicide”) or resist DAP killing, in order to protect the remainder of the cell population from DAP exposures and lethality. This is an apparently unique mechanism of DAP-R amongst gram-positive pathogens. In this proposal, we will use strategic fluorescence microscopy, flow cytometry with multidimensional physiologic interrogations, and single cell sorting plus genotyping to divulge mechanisms by which DAP-R S. mitis can resist DAP exposures. Finally, we will use two well-characterized models of endovascular infections, ex vivo (chamber model) and in vivo (experimental rabbit IE), to define DAP regimens to both circumvent emergence of DAP-R and enhance clearance of S. mitis. In summary, these studies will divulge clinical strategies to forestall emergence of DAP-R in S. mitis and perhaps other Gram-positive pathogens.

抽象的草绿色群链球菌 (VGS)，尤其是轻症链球菌，是多种疾病的关键病原体侵袭性血管内感染，包括：i) 中性粒细胞减少症中的“突破性菌血症”和“中毒性休克” 癌症患者；以及 ii) 感染性心内膜炎 (IE)。 β-内酰胺 MIC 在轻链球菌菌株中“蠕动”，相对或完全由β-内酰胺引起的严重感染比例此外，使用替代品的情况下，β-内酰胺抗性（R）菌株的临床结果令人不安。治疗方案（例如万古霉素）令人失望，可能与该病的高患病率有关此类菌株对万古霉素“耐受”，这促使人们使用新的杀菌剂，例如达托霉素。（DAP）用于治疗β-内酰胺耐药菌株的严重轻链球菌综合征。 DAP 治疗诱导的快速、持久和高水平的 DAP-R 显着降低了人们对此类药物的热情此外，轻链球菌组中的 DAP MIC 比所有其他 VGS 组高 2-10 倍。已报告的出现 DAP-R 的侵袭性轻链球菌感染的临床病例数量有限，原因是迄今为止，DAP 在此类感染中的使用相对较少，然而，S. mitis β-内酰胺-R 的数量逐渐增加。再加上 VANC 治疗在此类综合征中的不一致结果实际上确保了 DAP 使用的增加，此外，DAP 使用率高的医疗中心最近也证实了 DAP-R 轻链球菌感染。大量 MIC 在肠球菌中“蔓延”。了解 DAP-R 出现的机制。因此，轻链球菌以及规避其进化的策略具有重要的临床意义。我们的初步数据表明，轻链球菌的 DAP-R 结果可能是多因素的最有趣的是，我们现在已经展示了两种形式的令人信服的证据。 “DAP 超积累”，其中给定链球菌链中的单个细胞可以超捕获 DAP 并要么死亡（“利他自杀”），要么抵抗 DAP 杀伤，以保护剩余的细胞群免受 DAP 暴露和致死率这是 DAP-R 在革兰氏阳性菌中明显独特的机制。病原体。在本提案中，我们将使用战略荧光显微镜、多维流式细胞术生理学询问、单细胞分选加上基因分型，以揭示 DAP-R 的机制 S. mitis 可以抵抗 DAP 暴露。最后，我们将使用两种特征良好的血管内模型。感染，离体（室模型）和体内（实验兔 IE），以确定 DAP 方案规避 DAP-R 的出现并增强轻链球菌的清除总之，这些研究将揭示。预防轻链球菌和其他革兰氏阳性病原体中 DAP-R 出现的临床策略。