Objectives

Mycobacterium avium complex (MAC) bacteria can cause chronic pulmonary disease (PD). Current treatment regimens of azithromycin, ethambutol and rifampicin have culture conversion rates of around 65%. Dynamic, preclinical models to assess the efficacy of treatment regimens are important to guide clinical trial development. The hollow fibre system (HFS) has been applied but reports lack experimental details.

Methods

We simulated the human pharmacokinetics of azithromycin, ethambutol and rifampicin both in plasma and epithelial lining fluid (ELF) in a HFS, exposing THP-1 cells infected with M. avium to the triple-drug regimen for 3 weeks. We accounted for drug–drug interactions and protein-binding and provide all laboratory protocols. We differentiated the effects on the intracellular and extracellular mycobacterial population.

Results

The antibiotic concentrations in the HFS accurately reflected the time to peak concentration (T_max), the peak concentration (C_max) and half-life of azithromycin, rifampicin and ethambutol in plasma and ELF reported in literature. We find that plasma drug concentrations fail to hold the MAC bacterial load static (ΔLog10 CFU/mL_{Control:Regimen} = 0.66 ± 0.76 and 0.45 ± 0.28 at 3 and 21 days); ELF concentrations do hold the bacterial load static for 3 days and inhibit bacterial growth for the duration of the experiment (ΔLog10 CFU/mL_{Control:Regimen} = 1.1 ± 0.1 and 1.64 ± 0.59 at 3 and 21 days).

Discussion

In our model, the current therapy against MAC is ineffective, even when accounting for antibiotic accumulation at the site of infection and intracellularly. New treatment regimens need to be developed and be compared with currently recommended regimens in dynamic models prior to clinical evaluation. With the publication of all protocols we aim to open this technology to new users.

中文翻译：

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鸟分枝杆菌复合肺病的标准疗法在模拟人血浆和上皮衬里液药代动力学的开源中空纤维系统中显示出有限的疗效

目标

鸟分枝杆菌复合体 (MAC) 细菌可引起慢性肺病 (PD)。目前阿奇霉素、乙胺丁醇和利福平的治疗方案的培养转化率约为 65%。用于评估治疗方案疗效的动态临床前模型对于指导临床试验的开发非常重要。中空纤维系统（HFS）已被应用，但报告缺乏实验细节。

方法

我们在 HFS 中模拟了血浆和上皮衬里液 (ELF) 中阿奇霉素、乙胺丁醇和利福平的人体药代动力学，将感染鸟分枝杆菌的 THP-1 细胞暴露于三药方案 3 周。我们考虑了药物-药物相互作用和蛋白质结合，并提供了所有实验室方案。我们区分了对细胞内和细胞外分枝杆菌种群的影响。

结果

HFS 中的抗生素浓度准确反映了文献报道的血浆和 ELF 中阿奇霉素、利福平和乙胺丁醇的达峰时间 (T _max )、峰浓度 (C _max ) 和半衰期。我们发现血浆药物浓度无法保持 MAC 细菌负荷静态（ΔLog10 CFU/mL_{对照：方案} = 0.66 ± 0.76 和 0.45 ± 0.28 在第 3 天和第 21 天）；ELF 浓度确实使细菌负载保持静态 3 天，并在实验期间抑制细菌生长（ΔLog10 CFU/mL_{对照：方案} = 1.1 ± 0.1 和 1.64 ± 0.59 在第 3 天和第 21 天）。

讨论

在我们的模型中，目前针对 MAC 的治疗是无效的，即使考虑到感染部位和细胞内的抗生素积累。在临床评估之前，需要开发新的治疗方案并与当前推荐的动态模型中的方案进行比较。随着所有协议的发布，我们的目标是向新用户开放这项技术。