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

社区获得性肺炎与全球高发病率和死亡率相关。它是世界上主要的传染性杀手-在2019年夺去了250万人的生命。与许多医学领域的巨大进步相反，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，指南的建议几乎没有改变;我们接受的护理标准往往得到低质量或中等质量证据的支持。胸膜旁间隙感染经常发生，并与死亡率增加和需要重症监护的风险较高相关。目前的指南推荐β-内酰胺/β-内酰胺酶抑制剂联合治疗这种疾病。然而，胸膜腔的抗生素药代动力学数据很少。我们计划对胸膜旁积液患者血清中最常用的β-内酰胺类药物（氨苄西林/舒巴坦、曲拉西林/他唑巴坦、美罗培南）的蛋白结合和游离部分与胸膜腔室进行深入的药代动力学表征。这些数据将提供急需的指导有关的抗菌物质的选择与胸膜腔室的最佳渗透。此外，我们的目标是开发一种预测算法，根据血清中的谷水平，在胸膜室中获得的游离活性抗生素物质的浓度，这是越来越多地在临床常规。这样的算法将有助于个体化给药方案，以在感染部位获得最佳药理学暴露，从而降低由于剂量不足而导致治疗失败的风险。最后，我们将评估与传统微生物检测相比，16 s rRNA靶向下一代测序对胸膜旁积液的诊断价值。这些数据将进一步用作初步结果，以计划在国家队列中嵌入更大的“组学”研究，如社区获得性肺炎能力网络（CAPNETZ），最终目的是更好地描述这种病理学。相反，实现这些目标将为经验性治疗的选择提供支持。

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.