Relationships Among Metronidazole Resistance, Pharmacodynamics and Treatment Outcomes in Clostridium difficile Infection

艰难梭菌感染甲硝唑耐药性、药效学和治疗结果之间的关系

• 批准号: 9526756
• 负责人: Julian G Hurdle
• 金额: $ 60.76万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9526756
• 关键词: Affect; Aftercare; Animal Model; Animals; Antibiotics; Automobile Driving; Bypass; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Trials; Clostridium difficile; Colon; Data; Diarrhea; Disease; Disease Outbreaks; Epidemic; Evolution; Feces; Frequencies; Genes; Genetic; Genomics; Genotype; Guidelines; Hamsters; Healthcare; Heme; Human; In Vitro; Incidence; Infection; Iron; Kinetics; Knowledge; Laboratories; Link; Metadata; Metronidazole; Metronidazole resistance; Modeling; Molecular; Mutate; Mutation; Outcome; Oxidative Stress; Oxidoreductase; Patient Isolators; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Predisposition; Public Health; Recurrence; Refractory; Resistance; Ribotypes; Severities; Sulfur; Testing; Time; Treatment Failure; Treatment outcome; Validation; Work; analog; biobank; biological adaptation to stress; carbohydrate metabolism; clinically relevant; clinically significant; cofactor; genome wide association study; insight; killings; mutant; novel; pressure; resistant strain; response; therapy development; treatment response; trend

PROJECT SUMMARY/ABSTRACT Clostridium difficile is the main cause of antibiotic-associated diarrhea. Since 2003, the incidence and severity of C. difficile infection (CDI) has risen in the U.S. and globally. In the U.S. in 2011, there were ~29,000 deaths from ~500,000 CDI cases. In 2013 the CDC designated C. difficile as an Urgent Threat. These trends were related to the emergence of epidemic strains, in particular epidemic 027. Epidemic 027 causes about a third of CDI in the U.S. and has a tendency to cause severe disease. The firstline drug metronidazole is now more prone to fail today than 30 years ago. Our study suggests that metronidazole resistance is one hitherto overlooked factor that is driving treatment failures. This proposal seeks to understand the impact of resistance on treatment responses to metronidazole and the genetic basis for metronidazole resistance (MTZ-R) in C. difficile. We discovered that a subset of epidemic 027 strains display decreased susceptibility to metronidazole, when tested in fresh heme. Using fresh heme, we identified other metronidazole-resistant epidemic strains from different lineages. Heme induces the expression of metronidazole resistance that is otherwise not detected. We demonstrate that resistance occurs during therapy in animals and it could be selected in lab- media. This work has significant implications for public health care, because the impact of metronidazole resistance is not well characterized. Our study will provide insights to how resistance affects treatment responses to metronidazole and will unveil how it evolved in epidemic 027 and other lineages. Aim 1. To characterize the clinical impact of MTZ-R. This uses a biobank of patient stools to assess colonization with resistant strains, the on-therapy rise of resistance and if it hinders responses to MTZ. Further validations are done in a clinically reflective in vitro and animal models of CDI. Aim 2. To test if the low colonic levels of MTZ facilitates on-therapy development of MTZ-R and if it is ineffective in CDI with MTZ-R strains. MTZ will be compared to a non-absorbed MTZ analog to quantify the emergence of MTZ-R in low and high drug levels in CDI animals. The non-absorbed MTZ analog will also test the importance of high drug levels in the colon for resolving CDI due to resistant strains. Aim 3. To elucidate the evolution of MTZ-R from laboratory and patient isolates. This aim moves the C. difficile field forward to link phenotypes to their resistance genotypes and elucidates the evolutionary basis of metronidazole resistance in three settings: lab-media, animal models and clinical isolates from patients. It then applies computational genomics and molecular experimentation to identify and validate convergent or divergent paths to resistance. Public health. The

项目摘要/摘要 艰难梭菌是抗生素相关腹泻的主要原因。自2003年以来的发病率和严重性 艰难梭菌感染（CDI）在美国和全球上升。在2011年的美国，有约29,000人死亡 来自约500,000个CDI案件。 2013年，CDC将艰难梭菌指定为紧迫的威胁。这些趋势是 与流行病的出现有关，特别是流行病027。流行病027导致大约三分之一 美国的CDI趋于引起严重疾病。第一期药物甲硝唑现在更多 今天比30年前容易失败。我们的研究表明，甲硝唑耐药性是一种迄今为止 被忽视的因素正在推动治疗失败。该提议试图了解抵抗的影响 关于甲硝唑的治疗反应以及甲硝唑耐药性（MTZ-R）的遗传基础。 艰难的。我们发现，一部分流行病027菌株显示出对甲硝唑的敏感性降低， 当新鲜血红素测试时。使用新鲜血红素，我们确定了其他抗甲硝唑的流行病 来自不同的谱系。血红素诱导甲硝唑抗性的表达，否则不是 检测到。我们证明了在动物治疗期间发生耐药性，可以在实验室中选择 媒体。这项工作对公共卫生保健有重大影响，因为甲硝唑的影响 电阻没有很好地表征。我们的研究将为抗药性如何影响治疗提供见解 对甲硝唑的反应，并将揭示其在流行病和其他谱系中如何发展的。目标1 表征MTZ-R的临床影响。这使用患者粪便的生物库评估与 耐药性菌株，抗药性的上升以及是否阻碍了对MTZ的反应。进一步的验证是 在CDI的临床反射性体外和动物模型中完成。目的2。测试较低的结肠水平是否 MTZ促进了MTZ-R的疗法发展，如果它在具有MTZ-R菌株的CDI中无效。 MTZ 将与未吸收的MTZ类似物进行比较，以量化低毒中MTZ-R的出现 CDI动物的水平。未吸收的MTZ类似物还将测试高药物水平在 由于抗性菌株而解决CDI的结肠。目标3。阐明MTZ-R从实验室的演变 和患者分离株。这个目的将艰难梭菌场向前移动以将表型与它们的抵抗联系起来 基因型并阐明了三种环境中甲硝唑耐药性的进化基础：Lab-Media， 动物模型和患者的临床分离株。然后，它应用计算基因组学和分子 实验以识别和验证收敛或发散的抗性。公共卫生。这