High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis
High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis
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DOI：
10.1128/aac.03085-15
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发表时间：
2016-07-01
影响因子：
4.9
通讯作者：
Nuermberger, Eric
中科院分区：
文献类型：
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作者：
Lanoix, Jean-Philippe;Tasneen, Rokeya;Nuermberger, Eric
吡嗪酰胺 (PZA) 是一种前药，需要通过 pncA 编码的酰胺酶转化为吡嗪酸 (POA)，才能发挥体外活性。 pncA 突变是临床分离株中 PZA 耐药的最常见原因。为了确定 POA 的全身递送或宿主介导的 PZA 向 POA 的转化是否可以规避这种耐药性，我们评估了口服给药和宿主衍生的 POA 的体内功效。在 BALB/c 和 C3HeB/FeJ 小鼠中测定了剂量范围的血浆和肺内 POA 药代动力学以及口服 POA 或 PZA 治疗对 PZA 敏感结核病的疗效。在感染 pncA 缺失突变体并用 PZA 处理的兔子中评估了宿主来源的 POA 的活性。小鼠给予150mg/kg体重的PZA和POA后，从0小时到无穷大的浓度-时间曲线下面积(AUC(0-无穷大))的中位血浆POA值分别为139至222μg.h/ml和178至287μg.h/ml。施用 POA 和 PZA 后，感染小鼠的上皮衬里液 POA 浓度相当。在慢性感染的 BALB/c 小鼠中，4 周后，150 mg/kg 的 PZA 使肺 CFU 计数减少>2 log(10)。 POA 仅在 450 mg/kg 剂量下有效，使肺 CFU 计数减少约 0.7 log(10)。 POA 对 C3HeB/FeJ 小鼠没有明显的杀菌活性，对感染 PZA 抗性突变体的兔子也没有给予 PZA。口服 POA 给药和宿主介导的 PZA 转化为 POA 产生的血浆 POA 暴露与 PZA 给药相当，但效果显着低于 PZA。这些结果表明，细菌内递送 POA 以及在感染部位产生更高的 POA 浓度将是最大化 POA 功效的更有效策略。
Pyrazinamide (PZA) is a prodrug requiring conversion to pyrazinoic acid (POA) by an amidase encoded by pncA for in vitro activity. Mutation of pncA is the most common cause of PZA resistance in clinical isolates. To determine whether the systemic delivery of POA or host-mediated conversion of PZA to POA could circumvent such resistance, we evaluated the efficacy of orally administered and host-derived POA in vivo. Dose-ranging plasma and intrapulmonary POA pharmacokinetics and the efficacy of oral POA or PZA treatment against PZA-susceptible tuberculosis were determined in BALB/c and C3HeB/FeJ mice. The activity of host-derived POA was assessed in rabbits infected with a pncA-null mutant and treated with PZA. Median plasma POA values for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) were 139 to 222 mu g.h/ml and 178 to 287 mu g.h/ml after doses of PZA and POA of 150 mg/kg of body weight, respectively, in mice. Epithelial lining fluid POA concentrations in infected mice were comparable after POA and PZA administration. In chronically infected BALB/c mice, PZA at 150 mg/kg reduced lung CFU counts by >2 log(10) after 4 weeks. POA was effective only at 450 mg/kg, which reduced lung CFU counts by similar to 0.7 log(10). POA had no demonstrable bactericidal activity in C3HeB/FeJ mice, nor did PZA administered to rabbits infected with a PZA-resistant mutant. Oral POA administration and host-mediated conversion of PZA to POA producing plasma POA exposures comparable to PZA administration was significantly less effective than PZA. These results suggest that the intrabacillary delivery of POA and that producing higher POA concentrations at the site of infection will be more effective strategies for maximizing POA efficacy.