Reducing Antimicrobial Overuse Through Targeted Therapy for Patients with Community-Acquired Pneumonia

项目总结/摘要 社区获得性肺炎（CAP）是住院和住院患者发病的主要原因， 死亡率在美国。然而，CAP的病原学诊断是具有挑战性的，因为>75%的培养物 阴性，无法鉴定致病病原体。ATS/IDSA指南建议， 经验性抗菌治疗仅限于有耐药病原体危险因素的成年患者。 然而，面对消极的文化和诊断的不确定性，临床医生往往感到不舒服， 逐步升级治疗，因为缩小治疗范围可能会导致覆盖范围不足。的延长 经验性治疗阻碍了抗菌药物管理工作，并鼓励了抗菌药物的开发。 阻力我们的总体目标是通过强调 病原体导向治疗准确的病原学诊断可能有助于2 方法：1）允许最初的窄谱治疗，2）在降级时提供信心 阴性培养后的治疗。快速诊断分析具有提供准确结果的潜力 并因此减少暴露于扩展谱经验疗法的持续时间。多 观察性研究表明，使用分子诊断测定与有利的 结果包括减少抗菌药物使用的总持续时间和住院时间。的 最新的抗菌药物管理实施指南建议使用快速病毒检测， 呼吸道病原体作为一种手段，以减少使用不适当的抗生素。但这些 建议是基于低质量的证据，目前还不清楚是否更广泛的早期 诊断性检测可以减少广谱抗生素的使用和/或及时启动抗病毒治疗。 疗法阴性细菌培养后的降级是另一个抗菌管理目标。而 大多数降级是在鉴定出易感病原体后进行的，ATS/IDSA指南还建议 如果培养物为阴性，则在48小时时降级。然而，这些建议也是基于 观察性研究我们提出了一个大型的，多中心的2 × 2析因群集随机对照试验，以检验 减少CAP患者使用广谱抗生素的两种方法：a）常规使用快速抗生素， 入院时的诊断测试和B）48小时后药剂师领导的临床剂量递减 细菌培养阴性的稳定患者我们的研究将是最大的随机试验，以确定影响 快速诊断测试对抗菌管理和患者的结果。我们的随机试验设计将 使我们能够建立因果关系，并确定广谱抗生素是否可以安全地降低剂量， 稳定的患者。我们拟议试验的结果将产生关于病原体的重要新知识 CAP患者的靶向治疗和抗生素减量。具体来说，从这方面获得的知识 该提案将允许医生限制广谱抗菌药物的使用，并启动靶向治疗。

Project Summary/Abstract Community-acquired pneumonia (CAP) is a leading cause of hospitalizations and inpatient morbidity and mortality in the United States. However, the etiological diagnosis of CAP is challenging as >75% of cultures are negative and a causative pathogen cannot be identified. The ATS/IDSA guidelines recommend that extended spectrum empiric antimicrobial therapy be limited to adult patients with risk factors for resistant pathogens. However, in the face of negative cultures and diagnostic uncertainty, clinicians are often uncomfortable de- escalating therapy, because narrowing treatment could result in inadequate coverage. The prolongation of empiric treatment hampers antimicrobial stewardship efforts and encourages the development of antimicrobial resistance. Our overall goal is to improve antimicrobial prescribing for patients with CAP by emphasizing pathogen-directed therapy. An accurate pathogenic diagnosis could contribute to antimicrobial stewardship in 2 ways: 1) by allowing for initial narrow-spectrum therapy and 2) by providing confidence when de-escalating therapy following negative cultures. Rapid diagnostic assays have the potential to provide accurate results within hours and thereby reduce the duration of exposure to extended spectrum empiric therapy. Multiple observational studies have demonstrated that use of molecular diagnostic assays is associated with favorable outcomes including a reduction in the total duration of antimicrobial use and length of stay in the hospital. The most recent antimicrobial stewardship implementation guidelines recommend the use of rapid viral testing for respiratory pathogens as a means to reduce the use of inappropriate antibiotics. However, these recommendations are based on low quality evidence and it is unknown whether more widespread early diagnostic testing could reduce the use of broad-spectrum antibiotics and/or prompt initiation of antiviral therapy. De-escalation following negative bacterial cultures is another antimicrobial stewardship target. While most de-escalation follows identification of a susceptible pathogen, the ATS/IDSA guidelines also recommend de-escalation at 48 hours if cultures are negative. However, these recommendations are also based on observational studies. We propose a large, multicenter 2 X 2 factorial cluster randomized controlled trial to test both approaches to reducing the use of broad-spectrum antibiotics in patients with CAP: a) routine use of rapid diagnostic testing at the time of admission and b) pharmacist-led de-escalation after 48 hours for clinically stable patients with negative cultures. Our study will be the largest randomized trial to determine the impact of rapid diagnostic testing on antimicrobial stewardship and patient outcomes. Our randomized trial design will allow us to establish causality and determine whether broad spectrum antibiotics can be safely de-escalated in stable patients. Findings from our proposed trials will generate important new knowledge about pathogen targeted therapy and antimicrobial de-escalation in patients with CAP. Specifically, knowledge gained from this proposal will allow physicians to limit the use of broad-spectrum antimicrobials and initiate targeted therapy.