Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.
Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.
复制标题
DOI：
10.1093/cid/ciw471
复制
发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Swaminathan S;Pasipanodya JG;Ramachandran G;Hemanth Kumar AK;Srivastava S;Deshpande D;Nuermberger E;Gumbo T
背景：药物浓度在儿童结核病临床预后中的作用尚不清楚。 剂量优化的目标浓度未知。方法：采用房室药代动力学分析法对印度结核病儿童的血浆药物浓度进行建模。 对儿童进行随访，直至治疗结束，以确定治疗失败或死亡。使用包括随机森林在内的人工智能算法集成，从30个临床、实验室和药代动力学变量中识别临床结局的预测因子。结果：在143名已知结果的儿童中，异烟肼、利福平和吡嗪酰胺浓度的儿童间变异性较高：110名（77%）完成治疗，24名（17%）治疗失败，9名（6%）死亡。 治疗失败或死亡的主要预测因素是吡嗪酰胺峰浓度<38.10 mg/L和利福平峰浓度<3.01 mg/L。低于这些峰浓度阈值的不良结局的相对风险为3.64（95%置信区间[CI]，2.28-5.83）。异烟肼与利福平和吡嗪酰胺具有浓度依赖性拮抗作用，在拮抗浓度范围内，治疗失败的校正比值比为3.00（95% CI，2.08-4.33）。仅就死亡作为结局而言，相同的药物浓度加上z评分（营养不良的指标）和年龄<3岁是高度排名的预测因子。在<3岁的儿童中，异烟肼0- 24小时浓度-时间曲线下面积<11.95 mg/L ×小时和/或利福平峰值<3.10 mg/L是治疗失败的最佳预测因子，相对风险为3.43（95% CI，0.99 -11.82）。结论：我们已经确定了新的抗生素目标浓度，这是与儿童结核病治疗失败和死亡相关的潜在生物标志物。
Background. The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. Methods. Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables. Results. Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28–5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08–4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99–11.82). Conclusions. We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.
登录
查看更多内容
影响因子：
11.8
作者：
Pasipanodya, Jotam G.;Srivastava, Shashikant;Gumbo, Tawanda
通讯作者：
Gumbo, Tawanda
DOI：
10.1093/cid/ciw473
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
DOI：
10.1093/cid/ciw474
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
影响因子：
11.5
作者：
Alsultan, Abdullah;Peloquin, Charles A.
通讯作者：
Peloquin, Charles A.
影响因子：
6.4
作者：
Srivastava, Shashikant;Pasipanodya, Jotam G.;Gumbo, Tawanda
通讯作者：
Gumbo, Tawanda