Decoding the clinical impact of the recent evolution of metronidazole resistance on Clostridium difficile infection

解读甲硝唑耐药性的最新演变对艰难梭菌感染的临床影响

• 批准号: 9767021
• 负责人: Julian G Hurdle
• 金额: $ 69.67万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767021
• 关键词: Address; Adopted; Affect; Anaerobic Bacteria; Animals; Bypass; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Trials; Clostridium difficile; Colon; Complement; Complex; DNA Sequence Alteration; Data; Detection; Drug Prescriptions; Environment; Epidemic; Evolution; Feces; Genes; Genetic; Genetic Programming; Genotype; Guideline Adherence; Hamsters; Healthcare; Heme; Human; In Vitro; Incidence; Infection; Intestines; Iron; Light; Medical; Medical center; Metabolism; Metadata; Metronidazole; Metronidazole resistance; Modeling; Molecular; Molecular Genetics; Mutagenesis; Mutate; Mutation; Outcome; Oxidative Stress; Oxidoreductase; Pathogenesis; Pathway interactions; Patient Isolators; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Practice Guidelines; Predisposition; Public Health; Refractory; Research; Resistance; Ribotypes; Savings; Severities; Subgroup; Sulfur; Testing; Texas; Treatment outcome; United States; Validation; absorption; analog; antibiotic-associated diarrhea; biobank; clinically significant; cofactor; dynamical evolution; gene function; genetic resistance; genome wide association study; genomic data; improved; infection management; mutant; pressure; prevent; resistance gene; resistant strain; response; sugar; 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 2013 the CDC designated C. difficile as an Urgent Threat, which caused ~29,000 deaths from ~453,000 cases in 2011. These trends were related to the emergence of epidemic strains, particularly epidemic 027. Epidemic 027 causes about a third of CDI in the U.S. Metronidazole is the most commonly prescribed drug for CDI, but after 30 years of use, it is now associated with poorer treatment outcomes. Reasons for the now poorer outcomes for metronidazole therapy is unclear. A subset of epidemic 027 strains show decreased susceptibility to metronidazole, when tested in the cofactor heme. Similarly, other dominant epidemic strains associated with CDI in the United States have evolved metronidazole resistance that is expressed in heme. While resistance has evolved in clinical strains, it is unclear how this impacts the ability to treat CDI with metronidazole. This study addresses this medically important question, by investigating how metronidazole resistance affects treatment outcomes. Firstly, a biobank of patient stools is examined for metronidazole-resistant strains, heme levels and patient metadata for clinical outcomes. This plan is complemented by experimental CDI models, namely the in vitro human gut and hamster models of CDI that are clinically reflective. Also addressed is the question of whether the low concentrations of metronidazole in the colon of patients is inadequate to treat infections with metronidazole- resistant strains. The genetic mechanisms adopted by C. difficile to display resistance is still unclear. Hence, this study elucidates the genetic basis for the evolution of metronidazole resistance in C. difficile, using a combination of cutting-edge genetic algorithms to identify gene changes in the genomic data sets for resistant isolates when compared to sensitive isolates and by molecular genetics to recapitulate metronidazole resistance in naïve strains. Public health. The successful completion of this study will immediately impact healthcare practices and the guidelines for CDI management. This could save lives by improving prescribing practices and guideline adherence.

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。 2013 年，CDC 将艰难梭菌指定为 紧急威胁，2011 年约 453,000 例病例中造成约 29,000 人死亡。这些趋势与 流行病株的出现，特别是流行病 027。流行病 027 导致了大约三分之一的 CDI 美国甲硝唑是 CDI 最常用的处方药物，但经过 30 年的使用，现在已 与较差的治疗结果相关。目前甲硝唑治疗效果较差的原因 尚不清楚。流行病 027 菌株的一个子集在进行测试时显示出对甲硝唑的敏感性降低 辅因子血红素。同样，美国其他与 CDI 相关的主要流行毒株 进化出甲硝唑耐药性，表现为血红素。虽然临床菌株已产生耐药性，但 目前尚不清楚这如何影响甲硝唑治疗 CDI 的能力。这项研究在医学上解决了这个问题 通过调查甲硝唑耐药性如何影响治疗结果，我们提出了一个重要的问题。首先，一个 检查患者粪便生物库中的甲硝唑耐药菌株、血红素水平和患者元数据 临床结果。该计划得到了实验性 CDI 模型的补充，即体外人类肠道和 具有临床意义的 CDI 仓鼠模型。还解决了是否低的问题 患者结肠中甲硝唑的浓度不足以治疗甲硝唑感染 耐药菌株。艰难梭菌表现出耐药性的遗传机制仍不清楚。因此， 这项研究阐明了艰难梭菌甲硝唑耐药性进化的遗传基础，使用 结合尖端遗传算法来识别基因组数据集中的基因变化以抵抗耐药性 与敏感分离株进行比较并通过分子遗传学概括甲硝唑 幼稚菌株的耐药性。公共卫生。这项研究的成功完成将立即产生影响 医疗保健实践和 CDI 管理指南。这可以通过改善处方来挽救生命 实践和准则遵守情况。