Emergence of TonB-dependent receptor mediated cefiderocol resistance among multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates.

多重耐药 (MDR) 铜绿假单胞菌临床分离株中 TonB 依赖性受体介导的头孢地罗耐药性的出现。

• 批准号: 10646641
• 负责人: William R Miller
• 金额: $ 17.17万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646641
• 关键词: Active Biological Transport; Affect; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biological; Biological Assay; Blood; Carbapenems; Caring; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Clinical; Clinical Data; Clinical Microbiology; Cohort Studies; Collection; Data; Detection; Development; Diameter; Diffusion; Dose; Drug Exposure; Drug Kinetics; Endothelium; Evaluation; Exposure to; Fiber; Gene Mutation; Genetic Polymorphism; Genomics; Geographic Locations; Geography; Goals; Growth; Healthcare; Hospital Referrals; Human; Infection; Integral Membrane Protein; Intensive Care Units; Intermediate resistance; International; Iron; Label; Laboratories; Link; Liquid substance; Lung; Mediating; Medical; Membrane; Methods; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Mutation; Nonsense Codon; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Population Analysis; Predisposition; Prevalence; Proteins; Pseudomonas; Pseudomonas aeruginosa; Receptor Gene; Regimen; Regulation; Regulatory Pathway; Reporting; Resistance; Risk; Route; Series; Siderophores; Site; Source; Stream; System; Test Result; Testing; Therapeutic Uses; Toxic effect; Treatment Failure; Variant; assay development; beta-Lactamase; beta-Lactams; carbapenem resistance; clinical development; clinical practice; clinically relevant; genome analysis; genome sequencing; healthcare-associated infections; in vitro activity; inhibitor; insertion/deletion mutation; medical vulnerability; multi-drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; mutant; novel; pathogen; periplasm; prevent; prospective; protein function; public health emergency; receptor; resistance mechanism; screening; tool; uptake; whole genome

Project Summary The rise of antibiotic resistance among healthcare associated pathogens has created a public health emergency and is a major challenge to the provision of effective medical care. Multidrug-resistant (MDR) Pseudomonas aeruginosa is labeled as a serious threat by the Centers for Disease Control and Prevention, and disproportionately impacts medically vulnerable patients such as those in the intensive care unit. The emergence of resistance to front-line antibiotics, including carbapenems and recently introduced β-lactam/β- lactamase inhibitor combinations, has led to the use of alternate regimens with decreased efficacy and increased toxicity. Cefiderocol (FDC) is a novel siderophore cephalosporin that retains in vitro activity against MDR-P. aeruginosa. This antibiotic mimics the iron binding molecules P. aeruginosa requires for growth, and is actively transported into the periplasmic space by proteins on the outer membrane of the bacteria called TonB dependent receptors (TBDR). Resistance to FDC has been linked to a loss of expression of these TBDRs in clinical isolates of P. aeruginosa. Further, an analysis of genomes of P. aeruginosa collected before the approval of FDC found that mutations predicted to lead to decreased expression of TBDR genes were present in carbapenem-resistant isolates. Using population analysis profiles (PAP), several strains of P. aeruginosa with TBDR mutations showed heteroresistance to FDC, or growth of a small population of bacteria at antibiotic concentrations above the clinical resistance breakpoint despite testing susceptible on standard susceptibility testing. In two major specific aims, this proposal will investigate the hypothesis that mutations in TBDR genes are present across clinical isolates of P. aeruginosa from diverse geographic areas and lead to the emergence of resistance on exposure to FDC. In the first aim, the prevalence of TBDR gene mutations will be evaluated in a collection of nearly one thousand carbapenem-resistant P. aeruginosa from the Prospective Observational Pseudomonas study (POP). Alterations in this pathway will be linked to FDC susceptibility testing results, an assessment of heteroresistance using PAP, and clinical features of P. aeruginosa colonization and infection. In the second aim, we will investigate strategies to understand and mitigate the emergence of resistance associated with TBDR mutations. First, a disk diffusion-based method to identify heteroresistant isolates will be developed as a screening test for the clinical microbiology laboratory. Second, a hollow fiber infection model simulating human pharmacokinetics of FDC will be used to evaluate the emergence of FDC resistance at clinically relevant drug concentrations. This proposal will provide important information on the distribution and prevalence of mutations associated with resistance to FDC in P. aeruginosa. The development of an assay to identify isolates at risk of resistance, and an understanding of the mechanism by which resistance emerges at human drug exposures, can form the basis for rational therapeutic use of FDC at the patient bedside.

项目摘要 医疗保健相关病原体中抗生素抗性的兴起创造了公共卫生 紧急情况，是提供有效医疗服务的主要挑战。耐药（MDR） 铜绿假单胞菌被标记为疾病控制与预防中心的严重威胁， 不成比例地影响医学脆弱的患者，例如重症监护病房的患者。这 对前线抗生素的抗性的出现，包括碳青霉烯，最近引入了β-内酰胺/β- 乳糖酶抑制剂组合已导致使用效率降低的替代方案，并且 毒性增加。 Cefiderocol（FDC）是一种新型的铁载体头孢菌素，它保留了体外活性 MDR-P。铜绿。这种抗生素模拟了铁结合分子P.铜绿假单胞菌需要生长，并且 通过蛋白质在称为tonb的细菌的外膜上积极运输到周围空间 依赖受体（TBDR）。对FDC的抗性已与这些TBDR的表达丧失有关 铜绿假单胞菌的临床分离株。此外，对在此之前收集的铜绿假单胞菌的基因组进行了分析 FDC的批准发现，预测会导致TBDR基因表达改善的突变存在 在抗碳青霉烯的分离株中。使用种群分析曲线（PAP），几种铜绿假单胞菌菌株 TBDR突变显示出对FDC的杂质或抗生素中少量细菌的生长 临床阻力断裂点以上的浓度在易受标准敏感性的测试前面测试 测试。在两个主要的特定目的中，该提案将研究TBDR基因突变的假设 存在于潜水区地理区域的铜绿假单胞菌的临床分离株中，并导致出现 暴露于FDC的阻力。在第一个目标中，将评估TBDR基因突变的流行率 从预期观察性的 假单胞菌研究（POP）。该途径中的改变将与FDC易感性测试结果有关 使用PAP和铜绿假单胞菌定殖和感染的临床特征评估异质症。在 第二个目的，我们将调查了解和减轻抵抗的出现的策略 与TBDR突变有关。首先，一种基于磁盘扩散的方法来识别异抗分离株将是 开发为临床微生物实验室的筛查测试。第二，一个空心纤维感染模型 模拟FDC的人类药代动力学将用于评估FDC耐药性的出现 临床相关的药物浓度。该建议将提供有关分销和 铜绿假单胞菌中与FDC抗性相关的突变的患病率。开发分析 识别有抵抗风险的隔离物，以及对抗电阻出现机制的理解 人类药物暴露，可以构成患者床边使用FDC合理治疗的基础。