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

社区获得性肺炎与世界范围内的高发病率和死亡率有关。它是世界上最大的传染性杀手-在2019年夺走了250万人的生命。与许多医学领域的巨大进步形成对比的是，肺炎流行病学、病理生理学或治疗方面的进展甚微。因此，在过去几十年中，指南建议几乎没有变化；我们接受的护理标准往往得到低质量或中等质量的证据的支持。肺炎旁胸腔感染经常发生，并与死亡率增加和需要重症监护的风险增加有关。目前的指南建议将伯内酰胺/伯内酰胺酶抑制剂组合用于该实体的治疗。然而，关于胸膜腔的抗生素药代动力学数据很少。我们计划对肺炎旁积液(氨苄西林/舒巴坦、哌拉西林/他唑巴坦、美罗培南)患者血清和胸腔中最常用的β-内酰胺类药物的蛋白结合组分和游离组分进行深入的药代动力学表征。这些数据将为选择在胸膜腔内具有最佳渗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中谷值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有用。这种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物暴露，从而降低因剂量不足而导致治疗失败的风险。最后，我们将评估从肺炎旁胸液中提取的16S rRNA靶向下一代测序与传统的微生物检测相比所增加的诊断价值。这些数据将被进一步用作初步结果，以计划嵌入到社区获得性肺炎能力网络(CAPNETZ)等国家队列中的更大规模的OMICS研究，最终目的是获得对这种病理的更好的流行病学描述。相反，实现这些目标将为选择经验性待遇提供支持。

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.