Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA.
Pharmacy Practice Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
Toxins (Basel). 2020 Jan 22;12(2):69. doi: 10.3390/toxins12020069.
Toxins produced by community-associated methicillin-resistant (CA-MRSA) contribute to virulence. We developed a statistical approach to determine an optimum sequence of antimicrobials to treat CA-MRSA infections based on an antimicrobial's ability to reduce virulence. In an in vitro pharmacodynamic hollow fiber model, expression of six virulence genes (, , , , , and in CA-MRSA USA300 was measured by RT-PCR at six time points with or without human-simulated, pharmacokinetic dosing of five antimicrobials (clindamycin, minocycline, vancomycin, linezolid, and trimethoprim/sulfamethoxazole (SXT)). Statistical modeling identified the antimicrobial causing the greatest decrease in virulence gene expression at each time-point. The optimum sequence was SXT at T0 and T4, linezolid at T8, and clindamycin at T24-T72 when was weighted as the most important gene or when all six genes were weighted equally. This changed to SXT at T0-T24, linezolid at T48, and clindamycin at T72 when was weighted as unimportant. The empirical -value for each optimum sequence according to the different weights was 0.001, 0.0009, and 0.0018 with 10,000 permutations, respectively, indicating statistical significance. A statistical method integrating data on change in gene expression upon multiple antimicrobial exposures is a promising tool for identifying a sequence of antimicrobials that is effective in sustaining reduced CA-MRSA virulence.
社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）产生的毒素有助于其毒力。我们开发了一种统计方法，根据抗生素降低毒力的能力，确定治疗 CA-MRSA 感染的最佳抗生素序贯疗法。在体外药效学中空纤维模型中，通过 RT-PCR 测定了 CA-MRSA USA300 中六个毒力基因（、、、、、和）在六个时间点的表达，在有无人类模拟、药代动力学剂量的五种抗生素（克林霉素、米诺环素、万古霉素、利奈唑胺和复方磺胺甲噁唑（SXT））的情况下进行检测。统计模型确定了每个时间点抗生素导致毒力基因表达下降最大的抗生素。当权重最高的基因为或所有六个基因为同等权重时，最佳顺序为 T0 和 T4 时的 SXT、T8 时的利奈唑胺和 T24-T72 时的克林霉素。当权重为不重要时，最佳顺序变为 T0-T24 时的 SXT、T48 时的利奈唑胺和 T72 时的克林霉素。根据不同权重，每种最佳序列的经验 P 值分别为 0.001、0.0009 和 0.0018，经 10000 次置换检验，均具有统计学意义。一种整合了多种抗生素暴露后基因表达变化数据的统计方法是一种很有前途的工具，可以确定一种能持续降低 CA-MRSA 毒力的抗生素序贯疗法。
