An optimized method for the detection and spatial distribution of aminoglycoside and vancomycin antibiotics in tissue sections by mass spectrometry imaging.
An optimized method for the detection and spatial distribution of aminoglycoside and vancomycin antibiotics in tissue sections by mass spectrometry imaging.
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一种通过质谱成像检测组织切片中氨基糖苷类和万古霉素抗生素及其空间分布的优化方法。
DOI：
10.1002/jms.4708
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Carter CL
中科院分区：
文献类型：
--
作者：
Wang N;Dartois V;Carter CL
次优抗生素剂量已被确定为已成为全球健康问题的多药耐药（MDR）细菌发展的关键驱动因素之一。氨基糖苷类和万古霉素是用于治疗多种MDR细菌感染的危重患者的广谱抗生素。对这些抗生素的耐药性越来越普遍。为了设计适当的抗生素治疗方案，最大限度地提高疗效，最大限度地减少耐药性的发展，关键是获得感染部位的原位药代动力学-药效学特征。质谱成像（MSI）是实现这一目标的理想技术。由于其结构，氨基糖苷类化合物的电离效率较差。此外，内源性分子的离子抑制作用极大地抑制了氨基糖苷类和万古霉素在治疗水平的检测。在目前的研究中，开发了一种优化的方法，使这些抗生素的MSI检测。组织点样实验表明，卡那霉素，阿米卡星，链霉素和万古霉素，分别在洗涤后的样品中检测灵敏度增加了5倍，15倍，35倍和54倍。利用组织模拟模型来优化洗涤时间和基质添加剂浓度。这些研究确定万古霉素和链霉素的改良检测限为40 - 5 μg/g组织，卡那霉素和阿米卡星的改良检测限为40 - 10 μg/g组织。将优化的方案应用于给予治疗水平的卡那霉素和万古霉素的小鼠的肺切片。清洗方案使MSI首次对氨基糖苷类和万古霉素进行药物分布调查成为可能，为疾病部位抗生素渗透研究铺平了道路。
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.
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