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: 10215475
• 负责人: Julian G Hurdle
• 金额: $ 67.51万
• 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 2023-02-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215475
• 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。2013年，CDC将C. difficile作为一个 紧急威胁，2011年约453，000例病例中造成约29，000例死亡。这些趋势与 流行菌株的出现，特别是流行027。流行病027导致约三分之一的CDI在 美国甲硝唑是CDI最常用的处方药，但经过30年的使用， 与较差的治疗结果相关。甲硝唑治疗效果较差的原因 还不清楚在027流行株的一个子集中进行检测时， 辅因子血红素。同样，在美国，与CDI相关的其他主要流行菌株 在血红素中表达的甲硝唑耐药性。虽然耐药性已经在临床菌株中进化，但 尚不清楚这如何影响甲硝唑治疗CDI的能力。这项研究从医学上解决了这一问题。 重要的问题，通过调查甲硝唑耐药性如何影响治疗结果。首先 检查患者粪便的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。该计划由实验CDI模型补充，即体外人肠道和 具有临床反射性的CDI仓鼠模型。还涉及的问题是， 患者结肠中甲硝唑的浓度不足以用甲硝唑治疗感染， 耐药菌株C.很难表现出抵抗力，目前还不清楚。因此，我们认为， 本研究阐明了C. difficile，使用 结合尖端的遗传算法，以确定基因组数据集中的基因变化， 分离株与敏感分离株相比，并通过分子遗传学方法概括甲硝唑 耐药菌株。公共卫生这项研究的成功完成将立即影响 医疗实践和CDI管理指南。这可以通过改善处方来挽救生命 实践和遵循指南。