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

项目总结/摘要 艰难梭菌感染（CDI）是一种主要的医院获得性疾病，导致严重的发病率， mortality. 2011年，CDC报告称，美国有45.3万例CDI病例，其中2.9万例 死亡流行菌株的出现，特别是NAP 1/027，大大增加了流行率， 疾病的严重程度。C.艰难梭菌对甲硝唑（CDI药物） 和氟喹诺酮类（常用的抗生素）。因此，两种选择力量推动了世界范围内的传播 流行性菌株。现在，这些菌株对万古霉素（首选抗生素）的耐药性越来越强 对于CDI。万古霉素是CDI的重要一线治疗药物， 增加了选择压力。万古霉素耐药性在流行菌株中越来越普遍，特别是 NAP 1/027，我们的研究表明，这些菌株正在国际上传播。这是一个问题，因为这 血统与严重疾病和在医院的快速传播有关。初步调查结果显示， 感染万古霉素耐药菌株的患者具有不良临床结果的可能性是正常人的两倍。基因组 分析表明，这些菌株正在发展初级和次级耐药机制， 以维持预期发生在患者结肠中的药物浓度。关键问题仍然是 理解C的这种新兴形式。困难，这在三个有凝聚力的目标地址。在一个目标中， 使用生物库样本和患者元数据的临床研究和流行病学研究， 在万古霉素治疗期间，这些新出现的病原体影响临床结果和疾病特征。是 由CDI的临床反射性体外和动物模型支持。在第二个目标中，压力将是 进行遗传表征，以描绘导致患者治疗失败的遗传变异。这些 基因签名将在实验室中进行分子验证，并用于基于人群的公众分析。 基因组，以了解患者分离株的全球耐药模式。最后，鉴于 CDI的治疗选择，将研究其他抗生素策略，以提供更多的覆盖面， 万古霉素易失效的微生物。这项研究的结果将是描绘遗传变异， 进化在C。会导致治疗失败这将为分子和基因组研究奠定基础。 快速检测这些菌株，以改善CDI患者的处方方法。公共卫生 这项研究对CDI的诊断和治疗具有重要意义，CDI是一种主要的 公共卫生和经济负担。

PROJECT SUMMARY/ABSTRACT Clostridium difficile infection (CDI) is a major hospital-acquired illness that causes severe morbidity and mortality. In 2011, the CDC reported that there were 453,000 cases of CDI in the United States, with 29,000 deaths. The emergence of epidemic strains, notably NAP1/027, has considerably increased the prevalence and severity of the disease. This clade of C. difficile developed resistance to both metronidazole (a CDI medication) and fluoroquinolones (commonly used antibiotics). As a result, two selection forces drove the worldwide spread of epidemic strains. Now the strains are increasingly becoming resistant to vancomycin, the antibiotic of choice for CDI. Vancomycin is an important first-line treatment for CDI, and increased prescribing of this antibiotic has raised selection pressures. Vancomycin resistance is increasingly more prevalent in epidemic strains, especially NAP1/027, and our study revealed that these strains are spreading internationally. This is concerning since this lineage is associated with severe illness and rapid transmission in hospitals. Preliminary findings indicate that patients infected with vancomycin resistant strains are twice as likely to have poor clinical outcomes. Genome analyses indicate these strains are developing primary and secondary resistance mechanisms that allow them to persist in drug concentrations predicted to occur in the colons of patients. Critical questions remain to understand this emerging form of C. difficile, which address in three cohesive aims. In one goal, we perform clinical studies and epidemiological research using biobanked samples and patient metadata to understand how these emerging pathogens affect clinical outcomes and disease characteristics, during vancomycin therapy. It is supported by clinical reflective in vitro and animas models of CDI. In the second goal, the strains will be genetically characterized to delineate genetic variations that promote treatment failures in patients. These genetic signatures will be molecularly validated in the lab and used in population-based analyses of public genomes to understand global patterns of resistance among patient isolates. Lastly, given there are few treatment options for CDI, other antibiotic strategies will be investigated to provide additional coverage of organisms prone to vancomycin to fail. The outcome of this research will be delineation of genetic variations that evolve in C. difficile that cause therapeutic failure. This will lay the foundation for molecular and genomic diagnostics to rapidly detect these strains to improve prescribing approaches for CDI patients. Public health. This study has significant implications for the diagnosis and treatment of CDI, a disease that imposes a major public health and economic burden in the United States.