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

项目概要/摘要 艰难梭菌是抗生素相关性腹泻的主要原因。自 2003 年以来，发病率和严重程度 在美国和全球范围内，艰难梭菌感染 (CDI) 的比例有所上升。 2011 年美国约有 29,000 人死亡 约 500,000 例 CDI 病例。 2013 年，疾病预防控制中心将艰难梭菌指定为紧急威胁。这些趋势是 与流行病株的出现有关，特别是流行病 027。流行病 027 导致约三分之一 CDI 在美国有导致严重疾病的倾向。现在一线药物甲硝唑比较多 今天比 30 年前更容易失败。我们的研究表明，迄今为止，甲硝唑耐药性是一种 导致治疗失败的被忽视的因素。该提案旨在了解阻力的影响 甲硝唑治疗反应和甲硝唑耐药性（MTZ-R）的遗传基础。 艰难梭菌。我们发现流行 027 菌株的一个子集对甲硝唑的敏感性降低， 在新鲜血红素中进行测试时。使用新鲜血红素，我们鉴定了其他耐甲硝唑的流行菌株 来自不同的血统。血红素诱导甲硝唑耐药性的表达，否则不会 检测到。我们证明，在动物治疗过程中会出现耐药性，并且可以在实验室中进行选择 媒体。这项工作对公共卫生保健具有重大影响，因为甲硝唑的影响 耐药性尚未得到很好的表征。我们的研究将深入了解耐药性如何影响治疗 对甲硝唑的反应，并将揭示其在流行病 027 和其他谱系中的演变。目标 1. 至 描述 MTZ-R 的临床影响。该方法使用患者粪便生物库来评估定植情况 耐药菌株、治疗中耐药性的上升以及是否阻碍对 MTZ 的反应。进一步验证是 在 CDI 的临床反映体外和动物模型中完成。目标 2. 测试结肠中的低水平是否 MTZ 促进 MTZ-R 的治疗发展，如果它对 MTZ-R 菌株的 CDI 无效。 MTZ 将与非吸收的 MTZ 类似物进行比较，以量化 MTZ-R 在低和高药物中的出现 CDI 动物中的水平。非吸收的 MTZ 类似物还将测试高药物水平在 结肠用于解决耐药菌株引起的 CDI。目标 3. 阐明实验室中 MTZ-R 的演变 和患者隔离。这一目标推动艰难梭菌领域向前发展，将表型与其耐药性联系起来 基因型并阐明了三种环境下甲硝唑耐药性的进化基础：实验室介质、 动物模型和患者的临床分离物。然后应用计算基因组学和分子生物学 通过实验来识别和验证抵抗的趋同或发散路径。公共卫生。这