Individualized treatment for patients with parapneumonic pleural effusion via therapeutic drug monitoring and metagenomic analyses

通过治疗药物监测和宏基因组分析对肺炎旁胸腔积液患者进行个体化治疗

• 批准号: 518875532
• 负责人: Dr. Oana Joean
• 金额: --
• 依托单位: Klinik für Pneumologie und Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2023
• 资助国家: 德国
• 起止时间: 2022-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/518875532?language=en
• 关键词: Individualized; treatment; patients; parapneumonic; pleural

Community acquired pneumonia is associated with high morbidity and mortality rates worldwide. It is the world’s leading infectious killer – having claimed 2.5 million lives in 2019. In contrast to tremendous advances in many areas of medicine, little progress has been achieved in pneumonia epidemiology, pathophysiology, or therapy. Accordingly, little has changed in terms of guideline recommendations in the past decades; what we accept as standard of care is often supported by low or moderate quality of evidence. Parapneumonic pleural space infections occur often and are associated with an increased mortality and a higher risk of necessitating intensive care. Current guidelines recommend ß-lactam/ß-lactamase inhibitor combinations for the treatment of this entity. However, the antibiotic pharmacokinetics data for the pleural space are scarce. We plan an in-depth pharmacokinetics characterization of both the protein-bound and free-fractions of the most often used ß-lactams in patients with parapneumonic effusions (Ampicillin/Sulbactam, Piperacillin/Tazobactam, Meropenem) in serum vs. the pleural space compartment. These data will provide much needed guidance concerning choice of antimicrobial substances with optimal penetration in the pleural compartment. Moreover, we aim to develop a prediction algorithm for the attained concentration of free, active antibiotic substance in the pleural compartment based on the trough levels in serum, which are increasingly available in the clinical routine. Such an algorithm will help individualize the dosage regimens in order to obtain optimum pharmacological exposure at the site of infection, thus reducing the risk of treatment failure due to underdosing. Lastly, we will evaluate the added diagnostic value of the 16s rRNA targeted next generation sequencing from parapneumonic pleural fluid compared to the conventional microbiological assays. These data will be further utilized as preliminary results to plan larger ‘Omics’ studies embedded in national cohorts like the Competence Network for Community Acquired Pneumonia (CAPNETZ) with the ultimate aim to attain a better epidemiologic description of this pathology. Achieving these goals would conversely provide support for the choice of empiric treatment.

社区获得性肺炎在世界范围内与高发病率和死亡率有关。它是世界上主要的传染病杀手，在2019年夺走了250万人的生命。与许多医学领域的巨大进步相比，肺炎流行病学、病理生理学或治疗方面的进展甚微。因此，在过去的几十年里，指南建议几乎没有变化；我们接受的护理标准通常是由低质量或中等质量的证据支持的。肺旁胸膜间隙感染经常发生，并与死亡率增加和需要重症监护的高风险相关。目前的指南推荐ß-内酰胺/ß-内酰胺酶抑制剂联合治疗该实体。然而，胸膜腔的抗生素药代动力学数据很少。我们计划对肺旁积液（氨苄西林/舒巴坦，哌拉西林/他唑巴坦，美罗培南）患者血清和胸膜腔室中最常用的ß-内酰胺类药物的蛋白结合和游离部分进行深入的药代动力学表征。这些数据将为选择具有最佳胸膜腔穿透性的抗菌物质提供急需的指导。此外，我们的目标是开发一种基于血清谷水平的胸膜腔内游离活性抗生素物质达到浓度的预测算法，这在临床常规中越来越可用。这样的算法将有助于个体化给药方案，以便在感染部位获得最佳的药理学暴露，从而降低因剂量不足而导致治疗失败的风险。最后，我们将评估来自肺旁胸膜液的16s rRNA靶向下一代测序与传统微生物测定相比的附加诊断价值。这些数据将进一步用作初步结果，以计划纳入社区获得性肺炎能力网络（CAPNETZ）等国家队列的更大规模“组学”研究，最终目的是获得对这种病理的更好的流行病学描述。实现这些目标将反过来为选择经验性治疗提供支持。