Modifiable Risk Factors for the Emergence of Resistance to Pseudomonas aeruginosa

出现铜绿假单胞菌耐药性的可改变风险因素

• 批准号: 10425430
• 负责人: Pranita Tamma
• 金额: $ 20.34万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425430
• 关键词: Antibiotic Therapy; Antibiotics; Antimicrobial susceptibility; Area; Bacterial Chromosomes; Binding Sites; Case Series; Case Study; Ceftazidime; Clinical; Cloning; Combined Antibiotics; Complex; Data; Decision Trees; Dependence; Development; Dialysis procedure; Dose; Drug resistance; Exhibits; Exposure to; Frequencies; Future; Genetic Markers; Hospitals; Hour; Imipenem; Infection; Infusion procedures; Investigation; K-Series Research Career Programs; Laboratories; Machine Learning; Medical; Minimum Inhibitory Concentration measurement; Monobactams; Morbidity - disease rate; Mutation; Observational Study; Patients; Pharmaceutical Preparations; Point Mutation; Predisposition; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Psychological reinforcement; Regrets; Reporting; Research Design; Research Personnel; Resistance; Risk Factors; Site; Site-Directed Mutagenesis; Source; Tazobactam; Test Result; Testing; Time; United States; VDAC1 gene; Validation; Vulnerable Populations; Work; base; beta-Lactams; carbapenem resistance; clinical investigation; cohort; combat; design; drug development; effective therapy; experience; genome sequencing; genomic locus; individual patient; innovation; modifiable risk; mortality; novel; novel diagnostics; pathogen; pre-clinical; respiratory; urinary; validation studies; whole genome

Project Summary Carbapenem-resistant Pseudomonas aeruginosa (CR-P. aeruginosa) contributes to significant mortality in hospitalized patients. Only four β-lactam agents with activity against CR-P. aeruginosa are available in the US, of which ceftolozane-tazobactam (C-T) is the most frequently used to treat CR-P. aeruginosa. Pre-clinical investigations indicate C-T had activity against >90% of P. aeruginosa isolates; after clinical use, reports of P. aeruginosa that initially tested susceptible to C-T but became resistant during therapy emerged. Our preliminary data indicate that amongst 28 consecutive patients infected with CR-P. aeruginosa with isolates initially susceptible to C-T, 50% of patients had subsequent P. aeruginosa isolates with > 4-fold increase in C-T minimum inhibitory concentrations (MICs) up to 30 days after C-T exposure. We identified genetic markers contributing to resistance through whole genome sequencing (WGS) – notably mutations in the ampC-ampR region and in PBP3. Alarmingly, 86% of P. aeruginosa isolates initially susceptible to another novel antibiotic, ceftazidime-avibactam (C-A), exhibited resistance to C-A after C-T exposure - in the absence of C-A exposure. This is concerning as the emergence of resistance to one novel agent could eliminate the few remaining treatment options. We explored modifiable risk factors that could reduce the frequency of C-T resistance and found that 30% of patients who received C-T over 1 hour had subsequent C-T resistant isolates, whereas no patients who received the drug over 3 hours developed resistant isolates. We would like to repeat this exploratory work and include experimental validation studies in a cohort of 260 patients across seven hospitals who have paired P. aeruginosa clinical isolates stored at -80°C and were prescribed C-T. In Aim 1, WGS will identify the genetic loci associated with C-T resistance comparing paired CR-P. aeruginosa isolates from the same patient before and up to 30 days after C-T exposure. Validation will occur through cloning and site-directed mutagenesis work. Broth microdilution will determine susceptibility testing results for the three other β-lactams with activity against CR-P. aeruginosa to quantify the emergence of cross-resistance. In Aim 2, we will capitalize on diverse C-T administration strategies at participating sites and develop a machine learning derived decision tree to inform clinicians how to prescribe C-T most effectively to reduce the likelihood of acquired resistance. The following are some risk factors that will be investigated for potential inclusion: (1) infusion of C-T over 3 hours, (2) high-dose C-T, (3) combination antibiotic therapy, (4) dialysis dependency, (5) source of infection and source control, (6) number of days of C-T exposure. This work will (1) inform future drug development by identifying areas of the bacterial chromosome highly prone to resistance and in need of additional reinforcement and (2) identify modifiable risk factors that can be used by clinicians to enable novel antibiotics to remain effective treatment options for extended periods of time.

项目摘要 抗碳青霉烯酸铜绿假单胞菌（Cr-p。eruginosa）有助于显着死亡的死亡率 住院的患者。只有四种β-内酰胺剂具有针对Cr-P的活性。铜绿可在美国可用， 其中最常用于治疗CR-P的Ceftolozane-Tazobactam（C-T）。铜绿。临床前 研究表明，C-T具有> 90％的铜绿假单胞菌分离株的活性；临床使用后，P。 最初测试了易受C-T但在治疗过程中具有耐药性的铜绿物。 我们的初步数据表明，在28例连续感染CR-P的患者中。铜绿 分离株最初容易受到C-T的影响，其中50％的患者随后患有铜绿假单胞菌分离株，大于4倍 C-T暴露后30天，C-T最小抑制浓度（MIC）的增加。我们确定了 通过整个基因组测序（WGS）导致抗性的遗传标记 - 尤其是突变 AMPC-AMPR区域和PBP3。令人震惊的是，有86％的铜绿假单胞菌分离株最初容易受到另一种的影响 新颖的抗生素，头孢氨酸-Avibactam（C-A）在C-T暴露后暴露于C-A的耐药性 - 在不存在的情况下 C-A暴露。这是因为对一个新型剂的抵抗力的出现可能消除第二种 剩余的治疗选择。我们探索了可修改的风险因素，这些因素可能会降低C-T的频率 阻力，发现30％在1小时内接受C-T的患者随后具有抗C-T 分离株，而没有接受该药物的患者在3小时内会产生抗性分离株。我们想 重复这项探索性工作，并包括在260名患者的队列中进行实验验证研究 七家与铜绿假单胞菌临床分离株配对的医院储存在-80°C下，并开了C -T。 在AIM 1中，WGS将确定与比较配对Cr-P比较C-T电阻相关的遗传位置。铜绿 C-T暴露后30天后，从同一患者分离出来。验证将通过 克隆和定向诱变工作。肉汤微稀释将确定易感性测试结果 其他三个β-内酰胺具有针对Cr-P的活性。铜绿可量化交叉抗性的出现。 在AIM 2中，我们将利用参与站点的潜水员C-T管理策略，并开发 机器学习派生的决策树，以告知临床医生如何最有效地准备C-T以减少 获得抵抗的可能性。以下是一些危险因素 包含：（1）在3小时内输注C-T，（2）高剂量C-T，（3）组合抗生素治疗，（4）透析 依赖性，（5）感染和来源控制的来源，（6）C-T暴露天数。 这项工作将（1）通过识别细菌染色体的区域来告知未来的药物开发 容易抵抗和需要其他强化，（2）确定可改变的风险因素 临床医生用来使新型抗生素能够长时间保持有效的治疗选择。