Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Malawi-Liverpool-Wellcome Clinical Research Programme, Kamuzu University of Health Sciences, Blantyre, Malawi.
Clin Infect Dis. 2022 Oct 29;75(9):1520-1528. doi: 10.1093/cid/ciac228.
Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi.
Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models.
Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified.
Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.
与血浆药代动力学相比，肺内药代动力学可能更能解释结核病（TB）治疗的反应。我们通过在马拉维进行的一线治疗的成年患者的痰中细菌清除率模型来探索这些关系。
使用分枝杆菌生长指示剂管中痰的时间至阳性的线性混合效应模型来估计细菌消除率（BER），这些痰是在治疗强化阶段（0-8 周）收集的，用于微生物学确诊的 TB。在第 8 和第 16 周时使用血浆和肺内药物水平的群体药代动力学模型。使用个体水平的药物暴露（浓度-时间曲线下面积[AUC]和 Cmax）来研究药物暴露的药代动力学-药效学关系，作为分枝杆菌消除模型中的协变量，包括利福平、异烟肼、吡嗪酰胺和乙胺丁醇在血浆、上皮衬里液和肺泡细胞中的药物暴露。
在 157 名参与者中（58%合并人类免疫缺陷病毒[HIV]感染），血浆或肺泡细胞中的药物暴露与痰中细菌清除无关。上皮衬里液中利福平或异烟肼的峰浓度（Cmax）或暴露（AUC）较高与更快的细菌清除和痰转阴时间较短有关。基线胸部 X 光片上更广泛的疾病与更慢的细菌清除有关。在 133 名参与者中记录了临床结局，其中 15 名（11%）记录了不良结局（复发性 TB、治疗失败或死亡）。未发现 BER 与晚期临床结局之间存在关系。
上皮衬里液中利福平或异烟肼的肺内药物暴露增加与更快的细菌清除有关。更高剂量的利福平或异烟肼可能导致持续的高肺内药物暴露、快速的细菌清除、缩短治疗时间和更好的治疗结果。
