Rockwood Neesha, Pasipanodya Jotam G, Denti Paolo, Sirgel Frederick, Lesosky Maia, Gumbo Tawanda, Meintjes Graeme, McIlleron Helen, Wilkinson Robert J
Department of Medicine, Imperial College London, United Kingdom.
Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
Clin Infect Dis. 2017 May 15;64(10):1350-1359. doi: 10.1093/cid/cix158.
There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.
One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).
Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.
PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
几乎没有证据支持为实现最佳结核病治疗效果而设定的目标药物暴露量。因此，我们评估了药代动力学/药效学（PK/PD）参数是否能够预测2个月时的痰培养转阴情况。
对100例肺结核患者（65%合并人类免疫缺陷病毒感染）进行密集采样，以测定治疗7 - 8周后的利福平、异烟肼和吡嗪酰胺血浆浓度，并使用非线性混合效应模型确定PK参数。在基线、2个月和5 - 6个月时收集详细的临床数据和痰标本进行培养。测定基线分离株的最低抑菌浓度（MIC）。采用多因素logistic回归和无假设多变量自适应回归样条法（MARS）确定2个月痰培养转阴的临床和PK/PD预测因素。潜在的PK/PD预测因素包括0至24小时曲线下面积（AUC0 - 24）、最大浓度（Cmax）、AUC0 - 24/MIC、Cmax/MIC以及浓度持续高于MIC的时间百分比（%TMIC）。
26%的患者利福平Cmax<8 mg/L，吡嗪酰胺<35 mg/L，异烟肼<3 mg/L。在调整MIC后，使用多因素logistic回归未发现PK暴露量与2个月痰培养转阴之间存在相关性。然而，MARS法确定异烟肼Cmax与利福平Cmax/MIC比值对2个月痰培养转阴存在负向相互作用。如果异烟肼Cmax<4.6 mg/L且利福平Cmax/MIC<28，则异烟肼浓度对痰培养转阴有拮抗作用。对于异烟肼Cmax>4.6 mg/L的患者，较高的异烟肼暴露量与更高的痰培养转阴率相关。
使用MARS法进行的PK/PD分析确定了异烟肼Cmax和利福平Cmax/MIC阈值，低于该阈值存在浓度依赖性拮抗作用，会降低2个月时的痰培养转阴率。
