Quncuo Chilie, Ye Wei Dan, Yang Jing, He Jian-Qing
Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China.
State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, China.
Infection. 2025 Aug 13. doi: 10.1007/s15010-025-02620-x.
Therapeutic drug monitoring (TDM) is increasingly recommended for managing multidrug-resistant tuberculosis (MDR-TB) due to significant interindividual pharmacokinetic variability. However, data on plasma concentration variability and associated patient factors for second-line anti-TB drugs remain limited.
We conducted a retrospective observational study including 74 patients with MDR-TB at West China Hospital, Sichuan University, from January 2022 to December 2024. Plasma concentrations of second-line drugs (levofloxacin, cycloserine, clofazimine, bedaquiline, and linezolid) were measured at steady-state. We analyzed therapeutic target attainment rates, evaluated correlations between drug concentrations and patient baseline characteristics, and explored predictors of drug exposure using multivariable linear regression.
Significant interindividual variability in drug exposure was observed across the studied second-line anti-TB drugs. Clofazimine demonstrated the highest therapeutic target attainment (72.7%), while bedaquiline had the lowest (21.1%). For levofloxacin, 29.8% of patients achieved therapeutic concentrations, whereas cycloserine reached target levels in 43.2% of cases. Age was positively correlated with cycloserine concentrations (ρ = 0.328, p = 0.030). Multivariable regression identified age and liver enzymes (ALT and AST) as independent predictors of levofloxacin exposure. Specifically, elevated ALT was associated with lower levofloxacin levels (B = -0.191, 95% CI: -0.337 to -0.045), while elevated AST was linked to higher levels (B = 0.292, 95% CI: 0.080 to 0.503). Linezolid trough concentrations showed a negative correlation with RBC count, and peak concentrations were positively associated with ESR. Additionally, bedaquiline concentrations correlated positively with CRP levels.
Our findings highlight substantial pharmacokinetic variability among second-line anti-TB drugs, influenced by patient age, liver function, and systemic inflammation. These results underscore the potential importance of individualized dosing and routine TDM in optimizing drug exposure and minimizing toxicity in patients with MDR-TB.
由于个体间药代动力学存在显著差异，治疗药物监测（TDM）越来越多地被推荐用于管理耐多药结核病（MDR-TB）。然而，关于二线抗结核药物血浆浓度变异性及相关患者因素的数据仍然有限。
我们进行了一项回顾性观察研究，纳入了2022年1月至2024年12月在四川大学华西医院就诊的74例耐多药结核病患者。在稳态下测量二线药物（左氧氟沙星、环丝氨酸、氯法齐明、贝达喹啉和利奈唑胺）的血浆浓度。我们分析了治疗目标达成率，评估了药物浓度与患者基线特征之间的相关性，并使用多变量线性回归探索药物暴露的预测因素。
在所研究的二线抗结核药物中观察到显著的个体间药物暴露变异性。氯法齐明的治疗目标达成率最高（72.7%），而贝达喹啉最低（21.1%）。对于左氧氟沙星，29.8%的患者达到治疗浓度，而环丝氨酸在43.2%的病例中达到目标水平。年龄与环丝氨酸浓度呈正相关（ρ = 0.328，p = 0.030）。多变量回归确定年龄和肝酶（ALT和AST）是左氧氟沙星暴露的独立预测因素。具体而言，ALT升高与左氧氟沙星水平降低相关（B = -0.191，95%CI：-0.337至-0.045），而AST升高与水平升高相关（B = 0.292，95%CI：0.080至0.503）。利奈唑胺谷浓度与红细胞计数呈负相关，峰浓度与血沉呈正相关。此外，贝达喹啉浓度与CRP水平呈正相关。
我们的研究结果突出了二线抗结核药物之间存在显著的药代动力学变异性，这受到患者年龄、肝功能和全身炎症的影响。这些结果强调了个体化给药和常规TDM在优化耐多药结核病患者药物暴露和最小化毒性方面的潜在重要性。
