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

项目总结/摘要 艰难梭菌是腹泻的主要原因。自2003年以来， 梭艰难梭菌感染（CDI）在美国和全球范围内有所上升。在美国，2011年有约29，000人死亡 约50万例CDI病例。2013年，CDC将C.这是一个紧迫的威胁。这些趋势 与流行菌株的出现有关，特别是流行027。027年流行病导致大约三分之一的 CDI在美国并有导致严重疾病的倾向。一线药物甲硝唑现在更多 比30年前更容易失败我们的研究表明，甲硝唑耐药是迄今为止， 被忽视的因素是导致治疗失败的原因。该提案旨在了解抵抗的影响 对甲硝唑的治疗反应和甲硝唑耐药的遗传基础（MTZ-R）在C。 很难我们发现流行性027菌株的一个子集显示出对甲硝唑的敏感性降低， 当在新鲜血红素中测试时。使用新鲜血红素，我们鉴定了其他甲硝唑耐药流行株 来自不同的血统血红素诱导甲硝唑耐药的表达，否则不会 检测到我们证明了耐药性发生在动物治疗过程中，它可以在实验室中选择， 媒体这项工作对公共卫生保健具有重要意义，因为甲硝唑的影响 抗性没有很好地表征。我们的研究将为耐药性如何影响治疗提供见解 对甲硝唑的反应，并将揭示它如何在流行病027和其他谱系中进化。目标1.到 描述MTZ-R的临床影响。该研究使用患者粪便的生物库来评估 耐药菌株，治疗中耐药性的上升，以及是否阻碍了对MTZ的反应。进一步验证包括 在CDI的临床反映性体外和动物模型中进行。目标2.为了测试结肠内低水平的 MTZ促进MTZ-R的治疗发展，如果它在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MTZ-R在低剂量和高剂量药物中的出现。 CDI动物的水平。非吸收的MTZ类似物也将测试高药物水平在治疗中的重要性。 结肠用于解决由于耐药菌株引起的CDI。目标3.阐明MTZ-R在实验室条件下的进化过程 和患者分离物。这一目标使C。将表型与耐药性联系起来 基因型并阐明了在三种环境中甲硝唑抗性的进化基础：实验室培养基， 动物模型和来自患者的临床分离物。然后将计算基因组学和分子生物学 实验，以确定和验证收敛或发散路径的阻力。公共卫生的