Lesion Penetration and Activity Limit the Utility of Second-Line Injectable Agents in Pulmonary Tuberculosis.
Lesion Penetration and Activity Limit the Utility of Second-Line Injectable Agents in Pulmonary Tuberculosis.
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DOI：
10.1128/aac.00506-21
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发表时间：
2021-09-17
影响因子：
4.9
通讯作者：
Dartois V
中科院分区：
文献类型：
--
作者：
Ernest JP;Sarathy J;Wang N;Kaya F;Zimmerman MD;Strydom N;Wang H;Xie M;Gengenbacher M;Via LE;Barry CE 3rd;Carter CL;Savic RM;Dartois V
阿米卡星和卡那霉素是二线注射剂，用于治疗耐多药结核病（MDR-TB），其基础是另一种氨基糖苷类和一线抗结核药物链霉素的临床效用。虽然链霉素在第一次结核病控制临床试验中作为单一药物进行了测试，但在将阿米卡星和卡那霉素引入耐多药结核病治疗方案之前没有进行随机对照试验。最近的一项大型回顾性荟萃分析显示，与没有任何注射药物的方案相比，阿米卡星提供了适度的益处，卡那霉素与更差的结局相关。尽管长期使用这些药物会导致不可逆的耳毒性，但它们仍然是耐多药结核治疗方案的一部分，因为它们在防止对其他药物产生耐药性方面发挥作用。为了量化阿米卡星和卡那霉素对二线治疗方案的贡献，我们应用二维基质辅助激光解吸电离（MALDI）质谱成像在大的肺部病变，量化药物暴露在肺和病变的兔活动性TB，并测量所需的浓度杀死或抑制居民细菌种群的生长。使用这些指标，我们应用了作用部位药代动力学和药效学（PK-PD）概念，并模拟了患者肺部病变的药物覆盖范围。结果为两种药物的有限临床效用提供了药理学解释，并揭示了阿米卡星比卡那霉素更好的PK-PD病变覆盖范围，与治疗成功的回顾性数据一致。连同最近的机制研究解剖抗菌活性从氨基糖苷类耳毒性，链霉素，阿米卡星，卡那霉素的有限，但快速渗透到TB疾病的网站支持开发类似物具有改善的疗效和耐受性。
Amikacin and kanamycin are second-line injectables used in the treatment of multidrug-resistant tuberculosis (MDR-TB) based on the clinical utility of streptomycin, another aminoglycoside and first-line anti-TB drug. While streptomycin was tested as a single agent in the first controlled TB clinical trial, introduction of amikacin and kanamycin into MDR-TB regimens was not preceded by randomized controlled trials. A recent large retrospective meta-analysis revealed that compared with regimens without any injectable drug, amikacin provided modest benefits, and kanamycin was associated with worse outcomes. Although their long-term use can cause irreversible ototoxicity, they remain part of MDR-TB regimens because they have a role in preventing emergence of resistance to other drugs. To quantify the contribution of amikacin and kanamycin to second-line regimens, we applied two-dimensional matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging in large lung lesions, quantified drug exposure in lung and in lesions of rabbits with active TB, and measured the concentrations required to kill or inhibit growth of the resident bacterial populations. Using these metrics, we applied site-of-action pharmacokinetic and pharmacodynamic (PK-PD) concepts and simulated drug coverage in patients’ lung lesions. The results provide a pharmacological explanation for the limited clinical utility of both agents and reveal better PK-PD lesion coverage for amikacin than kanamycin, consistent with retrospective data of contribution to treatment success. Together with recent mechanistic studies dissecting antibacterial activity from aminoglycoside ototoxicity, the limited but rapid penetration of streptomycin, amikacin, and kanamycin to the sites of TB disease supports the development of analogs with improved efficacy and tolerability.