Personalized antibiotherapy: development and evaluation of a microfluidic biosensor platform for non-invasive, multianalyte on-site diagnostics

抗生素治疗在人类医学中的重要性不断增加。在本文中，个体化抗生素治疗（包括抗生素剂量和给药间隔以及持续时间）在抗感染治疗的功效中起决定性作用。然而，由于缺乏床旁浓度监测的方法，抗生素剂量仅适应于患者的体重。在这种情况下，一个主要的问题是在医院的发展多药耐药性作为一个不理想的抗生素使用的结果。一个非侵入性的方法，使这种诊断在非侵入性收集的体液，如呼出气冷凝液（EBC），尿液和唾液，将是非常需要的个性化抗生素治疗。在这方面，微流控芯片实验室（Lab-on-a-chip，简称CQs）平台可以加速各种分析物的特异性和灵敏度定量沿着具有低样品消耗、更快的样品到结果时间以及复杂实验室功能的轻松集成。因此，所提出的项目的目标是实施和临床前评估微流体多路复用生物传感器平台，用于非侵入性地现场定量一组参数，包括各种β-内酰胺抗生素以及肾脏和炎症生物标志物，以允许个性化的抗生素治疗。以及白细胞介素-6和急性期蛋白（例如，血清淀粉样蛋白A、C反应蛋白和前降钙素）用于细菌炎症，将评估其敏感性和选择性。此外，在研究各种抗生素剂量的大型动物实验中，将在血液、组织和非侵入性收集的EBC样品中进行炎症标志物和抗生素药代动力学的准实时监测。因此，该项目包括实现一种用于快速和非侵入性标本采集的EBC采样装置。计划中的微流控微流控装置与高性能生物分子传感系统的成功实施可能会改变抗生素治疗的游戏规则。因为它将使炎症进展和抗生素药代动力学的（非侵入性）分析成为可能，因此可以为个性化抗生素治疗铺平道路。此外，这可能是全球对抗抗生素耐药性的重要里程碑。

Antibiotherapy achieves constantly increasing importance in human medicine. Herein, an individualized antibiotherapy, comprising the antibiotic dose and the dosing interval as well as the duration, plays a decisive role in the efficacy of the anti-infective therapy. However, due to the lack of the methods for bedside concentration monitoring, antibiotic dosages are, if at all, adapted only to the body weight of the patients. In this context, a major problem is the in-hospital development of multidrug resistance as a consequence of suboptimal antibiotic use.A non-invasive approach, enabling such diagnostics in non-invasively collected body fluids such as exhaled breath condensate (EBC), urine and saliva, would be highly desirable for a personalized antibiotherapy. In this respect, microfluidic lab-on-a-chip (LOC) platforms provide an acceleration of the specific and sensitive quantification of various analytes along with a low sample consumption, faster sample-to-result times and an easy integration of complex laboratory functions. Therefore, the goal of the proposed project is the implementation and pre-clinical evaluation of a microfluidic multiplexed biosensor platform for the non-invasive, on-site quantification of a panel of parameters, comprising various ß-lactam antibiotics, as well as renal and inflammation biomarkers, in order to allow a personalized antibiotherapy.In this project, various endogenous biomarkers including creatinine and cystatin C for renal function, and interleukin-6 and acute phase proteins (e.g., serum amyloid A, C-reactive protein and procalcitonin) for bacterial inflammation will be evaluated regarding their sensitivity and selectivity. Furthermore, in large animal experiments, investigating various antibiotic dosages, the quasi real-time surveillance of inflammation markers and antibiotic pharmacokinetics will be carried out in blood, tissue and non-invasively collected EBC samples. Hence, this project includes the realization of an EBC sampling device for rapid and non-invasive specimen collection.A successful implementation of the planned microfluidic LOC device in combination with a performant biomolecular sensing system could be a game-changer in the antibiotherapy. Since it would enable the (non-invasive) profiling of the inflammation progress and the antibiotic pharmacokinetics and thus, could pave the way for a personalized antibiotherapy. Furthermore, this could be a significant landmark on the global combat against the antibiotic resistance.