Dose-Dependent Activity of Pyrazinamide in Animal Models of Intracellular and Extracellular Tuberculosis Infections
Dose-Dependent Activity of Pyrazinamide in Animal Models of Intracellular and Extracellular Tuberculosis Infections
复制标题
DOI：
10.1128/aac.01524-10
复制
发表时间：
2011-04-01
影响因子：
4.9
通讯作者：
Karakousis, Petros C.
中科院分区：
文献类型：
--
作者：
Ahmad, Zahoor;Fraig, Mostafa M.;Karakousis, Petros C.
最近的体外药代动力学数据表明，目前推荐的吡嗪酰胺剂量对于杀死人体细胞内杆菌来说可能不是最佳剂量。我们分别在慢性感染的小鼠和豚鼠中评估了一系列吡嗪酰胺剂量对细胞内和细胞外结核分枝杆菌的作用。从感染后 28 天开始，每周给予抗生素 5 次，持续 4 周。人类等效剂量的异烟肼可使每个物种的肺部细菌数量减少 10 倍。给予人类当量剂量的 1/4 和 1/2 的吡嗪酰胺活性最低，而人类当量剂量使每个物种的肺部细菌计数减少了大约 1.0 log(10)。将吡嗪酰胺的人体等效剂量加倍后，小鼠和豚鼠的肺部细菌负荷分别减少了 1.7 和 3.0 log(10)。与在人类和小鼠中一样，吡嗪酰胺在豚鼠中显示出与利福平显着的协同作用。有必要进行临床研究来调查结核病联合治疗方案中较高剂量吡嗪酰胺的灭菌活性和耐受性。
Recent in vitro pharmacokinetic data suggest that the currently recommended dose of pyrazinamide may be suboptimal for killing intracellular bacilli in humans. We evaluated a range of pyrazinamide doses against intracellular and extracellular Mycobacterium tuberculosis in chronically infected mice and guinea pigs, respectively. Antibiotics were given five times weekly for 4 weeks beginning 28 days after infection. Human-equivalent doses of isoniazid reduced lung bacterial counts 10-fold in each species. Pyrazinamide given at 1/4 and 1/2 the human-equivalent dose was minimally active, while human-equivalent doses reduced lung bacterial counts by similar to 1.0 log(10) in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log(10) in mice and guinea pigs, respectively. As in humans and mice, pyrazinamide showed significant synergy with rifampin in guinea pigs. Clinical studies are warranted to investigate the sterilizing activity and tolerability of higher doses of pyrazinamide in combination tuberculosis regimens.