耐多药和利福平耐药肺结核患者体内贝达喹啉血药浓度及其与近期疗效和安全性的相关性

The relationship between the efficacy, safety and serum concentration of bedaquiline during the treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis

目的前瞻性观察含贝达喹啉方案治疗耐多药和利福平耐药肺结核(MDR/RR-PTB)患者体内贝达喹啉血药浓度情况, 并探索疗效和不良反应与血药浓度的相关性。方法选择2019年9月至2021年8月在重庆市公共卫生医疗救治中心住院, 并使用含贝达喹啉方案治疗的37例MDR/RR-PTB患者, 其中男23例, 女14例, 年龄15~60岁。采用超高效液相色谱质谱联用技术测定贝达喹啉血药浓度。观察患者体内贝达喹啉血药浓度情况, 并对患者近期疗效、不良反应的发生情况与血药浓度的相关性进行分析。贝达喹啉血药浓度最佳截断值采用受试者工作特征曲线进行分析, 并应用SPSS 26.0软件对数据进行统计分析, P<0.05为差异有统计学意义。结果 37例患者服药后2 h(C2 h)、6 h(C6 h)、下次服药前(C24 h)的贝达喹啉血药浓度分别为0.01~6.52、0.88~7.60、0.11~4.14 mg/L。C6 h显著高于C2 h和C24 h, 差异均有统计学意义(P<0.05)。37例患者中, 30例痰结核菌培养转阴成功、1例转阴失败, 3例因QTcF≥500 ms停药、3例失访, 痰结核菌培养首次转阴时间2~12(6.00±2.79)周, 12周痰结核菌培养转阴率为94.60%。C24 h与痰结核菌培养首次转阴时间、C6 h与病灶改善和其他不良反应(除QT间期)情况呈正相关(P<0.05)。C24 h与影像学改善和不良反应、C6 h与QT间期情况不相关(P>0.05), 但高C24 h组病灶改善(显著吸收+吸收)和空洞改善(闭合+缩小)、不良反应的比例均多于低C24 h组;高C6 h组整体QTcF值高于低C6 h组、发生QT间期延长的患者亦多于低C6 h组。结论应用贝达喹啉治疗西南地区MDR/RR-PTB患者的总体治疗效果和安全性较好, 当贝达喹啉C24 h>0.78 mg/L时, 患者首次转阴时间可能更短;贝达喹啉C6 h>2.85 mg/L时, 可能更有利于病灶吸收、但同时不良反应发生率可能更高。并且随着血药浓度增加, 患者可能存在治疗效果更好、不良反应更多的趋势。

Objective To observe the serum concentration of bedaquiline in multidrug-resistant and rifampicin-resistant pulmonary tuberculosis(PTB)patients,and to explore the correlation between efficacy,safety and serum concentration.Methods A total of 37 MDR/RR-PTB patients hospitalized in Chongqing Public Health Medical Center from September 2019 to August 2021 were selected and treated with bedaquiline,including 23 males and 14 females,aged 15-60 years.The serum concentration of bedaquiline was determined by ultra performance liquid chromatography-mass spectrometry.The serum concentration and the correlation between efficacy,safety and serum concentration of bedaquiline were evaluated.The optimal cut-off value of bedaquiline concentration was analyzed by receiver operating characteristic curve.SPSS 26.0 statistical software was used for data analysis,and P<0.05 was considered statistically significant.Results The serum concentration of bedaquiline in 2 hours(C2 h),6 hours(C6 h)and next time of taking medicine(C24 h)were 0.01-6.52,0.88-7.60,0.11-4.14 mg/L,respectively.Among the 37 patients,sputum culture turned negative in 30,but one case was still tested positive for Mycobacterium tuberculosis,while the drug was stopped in 3 cases due to QTcF≥500 ms,and another 3 cases were lost to follow-up.The sputum culture negative conversion time was 2-12(6.00±2.79)weeks,and the sputum culture negative conversion rate in 12 weeks was 94.60%.Correlation analysis showed that C24 h of bedaquiline was positively correlated with the sputum culture negative conversion time,and C6 h of bedaquiline was positively correlated with improvement of lesions and adverse reactions(all P<0.05).Although there was no statistically significant difference,the constituent ratio of lesions and cavities in lung and adverse reaction in high C24 h group were more than that those in low C24 h group,and the QTcF and the constituent ratio of QT interval prolonged were higher in the high C6 h group.Conclusions The overall efficacy and safety of bedaquiline in the treatment of MDR/RR-PTB were satisfactory.The sputum culture negative conversion time might be shorter when C24 h was more than 0.78 mg/L.Meanwhile,C6 h above 2.85 mg/L was beneficial to improvement of lesions,but the rate of adverse reactions might be higher.There was a trend of correlation between serum concentration and short-term efficacy and safety.