Deshpande Devyani, Srivastava Shashikant, Pasipanodya Jotam Garaimunashe, Gumbo Tawanda
Baylor University Medical Center, Dallas, TX, United States.
Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, United States.
Front Pharmacol. 2022 Oct 18;13:1024608. doi: 10.3389/fphar.2022.1024608. eCollection 2022.
There is need for shorter duration regimens for the treatment of , that can treat patients regardless of multidrug resistance status (pan-tuberculosis). We combined minocycline with tedizolid, moxifloxacin, and rifampin, in the hollow fiber system model of and mimicked each drugs' intrapulmonary pharmacokinetics for 28 days. Minocycline-tedizolid was administered either as a once-a-week or a daily regimen. In order to explore a possible explanation for effectiveness of the once-a-week regimen, we measured systemic and intra-bacterial minocycline pharmacokinetics. Standard daily therapy (rifampin, isoniazid, pyrazinamide) was the comparator. We then calculated or kill slopes for each regimen and ranked the regimens by time-to-extinction predicted in patients. The steepest and shortest time-to-extinction of entire bacterial population was with daily minocycline-rifampin combination. There was no difference in between the minocycline-tedizolid once-a-week the daily therapy ( = 0.85). Standard therapy was predicted to cure 88% of patients, while minocycline-rifampin would cure 98% of patients. Minocycline concentrations fell below minimum inhibitory concentration after 2 days of once-weekly dosing schedule. The shape of minocycline intra-bacterial concentration-time curve differed from the extracellular pharmacokinetic system and lagged by several days, consistent with system hysteresis. Hysteresis explained the persistent microbial killing after hollow fiber system model of concentrations dropped below the minimum inhibitory concentration. Minocycline could form a backbone of a shorter duration once-a-week pan-tuberculosis regimen. We propose a new concept of post-antibiotic microbial killing, distinct from post-antibiotic effect. We propose system hysteresis as the basis for the novel concept of pharmacologic memory, which allows intermittent dosing.
需要有更短疗程的方案来治疗结核病，该方案应能治疗无论是否具有多药耐药性的患者（泛耐药结核病）。我们在结核病的中空纤维系统模型中，将米诺环素与替加环素、莫西沙星和利福平联合使用，并模拟每种药物在肺内28天的药代动力学。米诺环素 - 替加环素采用每周一次或每日给药方案。为了探究每周一次给药方案有效性的可能原因，我们测量了全身和细菌内米诺环素的药代动力学。标准每日疗法（利福平、异烟肼、吡嗪酰胺）作为对照。然后我们计算了每种方案的杀菌或杀灭斜率，并根据预测的患者细菌灭绝时间对方案进行排序。整个细菌群体的杀菌斜率最陡且灭绝时间最短的是每日米诺环素 - 利福平联合用药。米诺环素 - 替加环素每周一次给药方案与每日疗法之间的杀菌斜率没有差异（P = 0.85）。预计标准疗法可治愈88%的患者，而米诺环素 - 利福平可治愈98%的患者。每周一次给药方案在给药2天后米诺环素浓度降至最低抑菌浓度以下。米诺环素在细菌内的浓度 - 时间曲线形状与细胞外药代动力学系统不同，且滞后数天，这与系统滞后现象一致。滞后现象解释了在中空纤维系统模型中米诺环素浓度降至最低抑菌浓度以下后仍持续的微生物杀灭作用。米诺环素可以构成一种更短疗程的每周一次泛耐药结核病治疗方案的基础。我们提出了一种与抗生素后效应不同的抗生素后微生物杀灭的新概念。我们提出系统滞后现象作为药理学记忆新概念的基础，这允许间歇性给药。
