Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
Department of Medical Sciences, Hackensack School of Medicine, Nutley, New Jersey, USA.
J Mass Spectrom. 2021 Mar;56(3):e4708. doi: 10.1002/jms.4708.
Suboptimal antibiotic dosing has been identified as one of the key drivers in the development of multidrug-resistant (MDR) bacteria that have become a global health concern. Aminoglycosides and vancomycin are broad-spectrum antibiotics used to treat critically ill patients infected by a variety of MDR bacterial species. Resistance to these antibiotics is becoming more prevalent. In order to design proper antibiotic regimens that maximize efficacy and minimize the development of resistance, it is pivotal to obtain the in situ pharmacokinetic-pharmacodynamic profiles at the sites of infection. Mass spectrometry imaging (MSI) is the ideal technique to achieve this. Aminoglycosides, due to their structure, suffer from poor ionization efficiency. Additionally, ion suppression effects by endogenous molecules greatly inhibit the detection of aminoglycosides and vancomycin at therapeutic levels. In the current study, an optimized method was developed that enabled the detection of these antibiotics by MSI. Tissue spotting experiments demonstrated a 5-, 15-, 35-, and 54-fold increase in detection sensitivity in the washed samples for kanamycin, amikacin, streptomycin, and vancomycin, respectively. Tissue mimetic models were utilized to optimize the washing time and matrix additive concentration. These studies determined the improved limit of detection was 40 to 5 μg/g of tissue for vancomycin and streptomycin, and 40 to 10 μg/g of tissue for kanamycin and amikacin. The optimized protocol was applied to lung sections from mice dosed with therapeutic levels of kanamycin and vancomycin. The washing protocol enabled the first drug distribution investigations of aminoglycosides and vancomycin by MSI, paving the way for site-of-disease antibiotic penetration studies.
抗生素剂量不足已被确定为多药耐药（MDR）细菌发展的关键驱动因素之一，这些细菌已成为全球关注的健康问题。氨基糖苷类和万古霉素是广谱抗生素，用于治疗受多种 MDR 细菌感染的重症患者。这些抗生素的耐药性越来越普遍。为了设计能够最大程度提高疗效并最小化耐药性发展的适当抗生素方案，在感染部位获得原位药代动力学-药效学特征至关重要。质谱成像（MSI）是实现这一目标的理想技术。由于其结构，氨基糖苷类药物的电离效率较差。此外，内源性分子的离子抑制效应极大地抑制了氨基糖苷类和万古霉素在治疗水平下的检测。在当前的研究中，开发了一种优化方法，通过 MSI 可以检测这些抗生素。组织点样实验表明，在经过洗涤的样品中，对卡那霉素、阿米卡星、链霉素和万古霉素的检测灵敏度分别提高了 5 倍、15 倍、35 倍和 54 倍。利用组织模拟模型优化了洗涤时间和基质添加剂浓度。这些研究确定了改进后的检测限为万古霉素和链霉素为 40 至 5μg/g 组织，卡那霉素和阿米卡星为 40 至 10μg/g 组织。优化的方案应用于接受治疗剂量卡那霉素和万古霉素的小鼠肺组织切片。洗涤方案使 MSI 首次能够对氨基糖苷类和万古霉素的药物分布进行研究，为疾病部位抗生素渗透研究铺平了道路。
