Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Antimicrob Agents Chemother. 2011 Apr;55(4):1527-32. doi: 10.1128/AAC.01524-10. Epub 2011 Jan 31.
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 ∼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.
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可能不足以杀死人类体内的细胞内分枝杆菌。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。在感染后 28 天开始每周给药 5 次，共 4 周。异烟肼的人类等效剂量使两种物种的肺部细菌数量减少了 10 倍。人类等效剂量的 1/4 和 1/2 的吡嗪酰胺的活性最小，而人类等效剂量使两种物种的肺部细菌数量减少了约 1.0 个对数（10）。将吡嗪酰胺的人类等效剂量增加一倍，可使小鼠和豚鼠的肺部细菌负荷分别减少 1.7 和 3.0 个对数（10）。与人类和小鼠一样，吡嗪酰胺在豚鼠中与利福平表现出显著的协同作用。需要进行临床研究，以调查更高剂量吡嗪酰胺联合结核病方案的杀菌活性和耐受性。
