Novel Diagnostics to Improve Antimicrobial Stewardship for Acute Respiratory Tract Infections in Resource-Limited Settings

项目摘要/摘要 急性呼吸道感染(ARTIS)是全球抗生素过度使用的主要原因。快速、准确 确定病原体可以减少ARTIS的抗生素过度使用，但在可用情况下并不总是可行的 诊断。在低收入或中等收入国家(LMIC)，ARTI的诊断因有限而进一步复杂化 实验室基础设施。此前，申请人表明，提供快速的基于抗原的 在LMIC环境中进行流感检测与抗生素使用的显著减少有关；然而， 大多数流感阳性患者仍然接受了抗生素处方。医生后来引用了诊断 关于细菌感染是抗生素过量处方的主要原因的不确定性。为了更有效地 尽量减少ARTIS的抗生素使用，将感染大致归类为细菌或病毒的诊断可能会发挥作用 重要的角色。申请者的长期目标是成为一名独立的调查员 在LMIC环境中使用新的诊断方法改善抗菌药物管理的有效策略。这项工作 在本申请中提出的将在LMIC中执行，目标为1)定义以下流行病 ARTIS，2)提炼一种新的基于宿主的基因表达分析，区分病毒和细菌 ARTIS，以及3)确定降钙素原的性能特征和基因签名 区分病毒性和细菌性关节炎。为了达到这些目标，申请者将执行 在基因组学、传染病诊断、抗生素耐药性专家的指导下进行的项目 管理和全球健康。拟议的具体目标将在SRI的一家三级护理医院实施。 并包括以下内容：1)确定呼吸道病毒和细菌的频率分布 急性发热性呼吸道疾病患者中的感染，2)改进基因表达分类器以 区分病毒性和细菌性关节炎，以及3)前瞻性地招募ARTI患者队列以评估 降钙素原和基因表达分类器在区分病毒和病毒时的性能特征 细菌性关节炎。通过开展这项工作，申请人建议填补一个重要的知识空白 关于以宿主为基础的技术在南亚LMIC人群中诊断ARTIS的适用性。 拟议的全面五年计划包括授课课程、动手实验室和 生物信息学工作，抗菌药物管理和临床试验培训，以及结构化指导以发展 作为一名独立且成功的研究人员的候选人。这些目标的完成和收购 培训期间的技能培训将使申请者处于竞争地位，可以申请未来的R01 资金问题。在授权期结束时，申请人将对 了解基于主机的技术如何在南亚、LMIC环境中诊断ARTIS，以及 将成为改进抗生素合理使用的有效策略的领导者 在资源有限的情况下。

Project Summary/ Abstract Acute respiratory tract infections (ARTIs) are a leading cause of antibiotic overuse worldwide. Rapid, accurate identification of a pathogen can reduce antibiotic overuse for ARTIs, but is not always possible with available diagnostics. In low- or middle-income countries (LMICs), ARTI diagnosis is further complicated by limited laboratory infrastructure. Previously, the applicant showed that providing access to rapid antigen-based influenza testing in a LMIC setting was associated with a significant decrease in antibiotic use; however, the majority of influenza-positive patients still received antibiotic prescriptions. Physicians later cited diagnostic uncertainty regarding bacterial infection as a major reason for antibiotic over-prescription. To more effectively minimize antibiotic use for ARTIs, diagnostics that broadly classify infections as bacterial or viral may play an important role. The long-term goal of the applicant is to become an independent investigator developing effective strategies for using novel diagnostics to improve antimicrobial stewardship in LMIC settings. The work proposed in this application will be carried out in a LMIC with the objectives of 1) defining the epidemiology of ARTIs, 2) refining a novel host-based gene expression assay that differentiates between viral and bacterial ARTIs, and 3) determining the performance characteristics of procalcitonin and gene signatures at differentiating between viral and bacterial ARTIs. To accomplish these goals, the applicant will carry out the project under the mentorship of experts in genomics, infectious disease diagnostics, antibiotic resistance/ stewardship, and global health. The proposed Specific Aims will be carried out at a tertiary care hospital in Sri Lanka and include the following: 1) Determine the frequency distribution of viral and bacterial respiratory infections among patients with acute febrile respiratory illness, 2) Refine a gene expression classifier to distinguish viral and bacterial ARTIs, and 3) Prospectively enroll a cohort of ARTI patients to assess the performance characteristics of procalcitonin and gene expression classifiers at differentiating between viral and bacterial ARTIs. By conducting this work, the applicant proposes to fill an important gap in knowledge regarding the applicability of host-based technologies for diagnosing ARTIs in a South Asian, LMIC population. The proposed comprehensive five-year plan includes didactic sessions, hands-on laboratory and bioinformatics work, antimicrobial stewardship and clinical trials training, and structured mentorship to develop the candidate as an independent and successful researcher. The completion of these aims and the acquisition of skills during the training period would place the applicant in a competitive position to apply for future R01 funding. By the conclusion of the award period, the applicant will have contributed significantly to the knowledge of how host-based technologies perform at diagnosing ARTIs in a South Asian, LMIC setting, and will be poised to become a leader in developing effective strategies for improving the rational use of antibiotics in resource-limited settings.