Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
Clin Infect Dis. 2018 Nov 13;67(11):1743-1749. doi: 10.1093/cid/ciy346.
Bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies.
Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints.
We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC ≥0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC ≥0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC ≥100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range.
Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines.
细菌敏感性分为敏感、中介敏感剂量依赖性（ISDD）和耐药。策略是在 ISDD 类别中使用一线药物的较高剂量，从而保留这些药物的使用。该系统尚未应用于抗结核药物。最近，药代动力学/药效学（PK/PD）目标暴露与蒙特卡罗实验一起确定了异烟肼的敏感截止点为 0.0312mg/L，利福平为 0.0625mg/L，吡嗪酰胺为 50mg/L。这些已经在临床研究中得到证实。
使用蒙特卡罗实验进行目标达标研究，以调查增加利福平、异烟肼和吡嗪酰胺剂量是否会使 >90%的 10000 名由细菌引起的肺结核患者达到 PK/PD 目标，从而揭示了提议的和传统的截止点之间的最小抑菌浓度（MIC）。
我们发现，每天 900 毫克异烟肼剂量确定了一个新的 ISDD MIC 范围为 0.0312-0.25mg/L，MIC≥0.5mg/L 为耐药。每天 1800 毫克利福平会导致 ISDD 的 MIC 范围为 0.0625-0.25mg/L，MIC≥0.5mg/L 为耐药。每天 4 克吡嗪酰胺的剂量时，ISDD 的 MIC 范围为 37.5-50mg/L，MIC≥100mg/L 为耐药。基于 MIC 分布，93%（异烟肼）、78%（利福平）和 27%（吡嗪酰胺）的分离物将处于 ISDD 范围内。
通过 2 种浓度的药物敏感性测试来确定 ISDD 范围，然后使用较高的剂量，可以防止切换到毒性更大的二线治疗。确认性临床研究将提供改变治疗指南的证据。
