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.

中文翻译：

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一种质谱成像检测组织切片中氨基糖苷类和万古霉素抗生素空间分布的优化方法

不理想的抗生素剂量已被确定为多重耐药 (MDR) 细菌发展的关键驱动因素之一，该细菌已成为全球健康问题。氨基糖苷类和万古霉素是广谱抗生素，用于治疗被多种 MDR 细菌感染的危重患者。对这些抗生素的耐药性正变得越来越普遍。为了设计适当的抗生素方案以最大限度地提高疗效并最大限度地减少耐药性的发展，获得感染部位的原位药代动力学-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。氨基糖苷类由于其结构的原因，其电离效率很差。此外，内源性分子的离子抑制作用极大地抑制了治疗水平的氨基糖苷类和万古霉素的检测。在当前的研究中，开发了一种优化方法，能够通过 MSI 检测这些抗生素。组织点样实验表明，在洗涤后的样品中，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、15、35 和 54 倍。组织模拟模型用于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进检测限为 40 至 5 μg/g 组织，卡那霉素和阿米卡星为 40 至 10 μg/g 组织。将优化的方案应用于小鼠的肺切片，这些小鼠接受了治疗水平的卡那霉素和万古霉素。