Characterizing Vancomycin-Resistant C. difficile Strains at Two Geographically Distinct Locations

两个不同地理位置的耐万古霉素艰难梭菌菌株的特征

• 批准号: 10380182
• 负责人: Charles Darkoh
• 金额: $ 70.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380182
• 关键词: African; Americas; Antibiotic Therapy; Antibiotics; Biochemical; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clostridium difficile; Communicable Diseases; Diarrhea; Elements; Epidemiology; Exhibits; Feces; Foundations; Gene Cluster; Genes; Genetic; Genomics; Geography; Goals; Guidelines; Healthcare; Homologous Gene; Hospitals; Incidence; Infection; Intervention; Kenya; Life; Location; Mediating; Mediator of activation protein; Metronidazole; North America; Oral; Outcome; Patients; Peptidoglycan; Pharmaceutical Preparations; Predisposition; Prevention strategy; Public Health; Pulsed-Field Gel Electrophoresis; Recurrence; Reporting; Research; Resistance; Ribotypes; Severity of illness; Societies; Texas; Treatment Failure; Vancomycin; Vancomycin Resistance; Work; alternative treatment; antibiotic-associated diarrhea; base; cost; genetic element; genome sequencing; insight; mortality; pathogen; patient population; prospective; recurrent infection; resistance mechanism; resistant strain; stool sample; treatment response; whole genome

PROJECT SUMMARY Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and death worldwide. As a result, the U.S. CDC has classified C. difficile (CD) as an urgent public health threat. Recent guidelines from Infectious Diseases Society of America and Society for Healthcare Epidemiology of America recommended oral vancomycin or fidaxomicin for both non-severe and severe CDI cases. Because of the high cost of fidaxomicin, vancomycin is now the drug of choice, making it the most important antibiotic for the treatment of CDI. The foundation for this work is based on our recent discovery of CD strains in patients from Texas and Kenya exhibiting reduced susceptibility to both metronidazole and vancomycin. We examined diarrhea CDI stools from 438 patients from Texas and 98 from Kenya for the presence of metronidazole- and vancomycin-non- susceptible CD isolates. Of the stools from Houston, 114/438 (26%) grew CD isolates that were not susceptible to vancomycin, 128/438 (29%) to metronidazole, and 97/438 (22%) to both metronidazole and vancomycin. Among the Kenyan patients, 66/98 (67%) were not susceptible to vancomycin, 83/98 (85%) to metronidazole, and 57/98 (58%) to both antibiotics. Alarmingly, many of the isolates from both locations showed levels of non-susceptibility to these antibiotics that far exceeded their known MICs. Whole-genome sequencing showed the presence of homologs of vanA and vanB gene clusters, common mediators of high-level vancomycin resistance in many hospital-associated pathogens. Until now, such high-level vancomycin non-susceptibility has not been reported in CD strains. The spread of CD strains resistant to vancomycin, a front-line antibiotic for this life-threatening pathogen, will have serious clinical and public health implications. This underscores an urgent need for a comprehensive analysis of the circulating strains, mechanisms of resistance, and how it impacts clinical outcomes to help inform clinical decisions. Our preliminary evidence strongly supports the hypothesis that vancomycin non-susceptible CD strains may be widespread in the CDI patient population and that strains circulating on the African continent may be genetically different from strains circulating in North America. To investigate this hypothesis, we will (i) assess the proportion of CDI patients from Texas and Kenya infected with vancomycin non-susceptible strains and compare the infecting strains; (ii) characterize the genetic elements associated with vancomycin non-susceptibility; and (iii) prospectively follow CDI patients infected with vancomycin non-susceptible strains to assess disease severity, clinical outcome, and rate of recurrence of the infection following treatment. Due to the current importance of vancomycin in CDI treatment, the proposed research will have a major impact on clinical decisions. Importantly, the genetic elements responsible for high-level vancomycin non- susceptibility in CD strains and how it impacts disease severity, clinical outcome, and treatment will be established. This will provide insight into the extent of resistance and open up new avenues for long-term preventative and interventional strategies to mitigate deaths associated with this life-threatening pathogen.

项目摘要 梭状芽胞杆菌艰难梭菌感染（CDI）是抗生素相关腹泻和全球死亡的主要原因。作为 结果，美国疾病预防控制中心将艰难梭菌（CD）归类为紧急的公共卫生威胁。最近的指南 美国传染病学会和美国医疗保健流行病学学会建议口腔 非重生和严重CDI病例的万古霉素或虚拟菌素。由于Fidaxomicin的成本很高， 万古霉素现在是选择的药物，使其成为治疗CDI的最重要抗生素。 这项工作的基础是基于我们最近在得克萨斯州患者和 肯尼亚表现出对甲硝唑和万古霉素的敏感性降低。我们检查了腹泻CDI 来自德克萨斯州438名患者的凳子和来自肯尼亚的98例甲硝唑 - 和万古霉素 - 非 易感CD分离株。在休斯敦的粪便中，114/438（26％）生长的CD分离株不易受到影响 万古霉素，128/438（29％），甲硝唑，甲硝唑和万古霉素均为97/438（22％）。之中 肯尼亚患者，66/98（67％）不易万古霉素，甲硝唑83/98（85％）和57/98 （58％）两种抗生素。令人震惊的是，来自两个位置的许多分离株都表现出不敏感的水平 这些远远超过其已知麦克风的抗生素。全基因组测序显示 VANA和VANB基因簇的同源物，许多在许多人中的高级万古霉素耐药性的常见介体 医院相关的病原体。迄今 CD菌株。 CD菌株对万古霉素有抗性的传播，万古霉素是一种威胁生命的前线抗生素 病原体将具有严重的临床和公共卫生影响。这强调了迫切需要 循环菌株，耐药机制及其如何影响临床结果的全面分析 帮助临床决策。我们的初步证据强烈支持万古霉素的假设 不敏感的CD菌株可能在CDI患者人群中广泛存在，并且在循环 非洲大陆可能与北美循环的菌株在遗传上不同。调查 这个假设，我们将（i）评估来自得克萨斯州和肯尼亚感染万古霉素的CDI患者的比例 不敏感的菌株并比较感染菌株； （ii）表征与 万古霉素不敏感性； （iii）前瞻性地跟踪感染万古霉素不易感染的CDI患者 评估疾病严重程度，临床结果和治疗后感染复发率的菌株。 由于当前的万古霉素在CDI治疗中的重要性，拟议的研究将具有主要 对临床决策的影响。重要的是，负责高级万古霉素非 - 的遗传因素 CD菌株的敏感性及其如何影响疾病的严重程度，临床结果和治疗 已确立的。这将提供有关抵抗程度的洞察力，并为长期开放新的途径 减轻与这种威胁生命的病原体相关的死亡的预防和介入策略。