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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections
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Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

机译：Tebipenem的药效学：多药抗革兰阴性感染口腔治疗的新选择

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Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli, n = 6; Klebsietto pneumoniae, n = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve (fAUC(0-24))/MIC corrected for the length of the dosing interval (fAUC(0-24)/MIC . 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum beta-lactamases versus the wild type. The median fAUC(0-24)/MIC . 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An fAUC(0-24)/MIC . 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI.
机译：Tebipenem Pivoxil HBr（TBPM-PI-HBR）是一种新型口腔生物可获得的Carbapenem。活性部分是TebipeNem。 Tebipenem Pivoxil在耳朵，鼻子和咽喉感染和呼吸道感染的儿童中使用了许可。 HBR盐设计用于改善药物物质和药物产品性质，包括稳定性。现在正在开发TBPM-PI-HBR作为治疗成人复杂的泌尿道感染（CUTI）的代理商。在特征在于特征的中性细胞鼠Thigh感染模型中研究了TebipeNem的药代动力学 - 药效学。使用液相色谱 - 串联质谱法测量血浆药物浓度。在建立剂量 - 反应关系后进行剂量分馏实验。使用11种肠杆菌（大肠杆菌，N = 6; Klebsietto Pneumoniae，N = 5），建立了瘀滞所需的药物暴露的幅度。在空心纤维感染模型（HFIM）中建立了药物暴露与抗性出现的关系。 Tebipenem表现出最佳的药物动力学，其在浓度 - 时间曲线下最好由游离药物区域（Fauc（0-24））/ MIC校正给药间隔的长度（Fauc（0-24）/ MIC。1 / tau）。 TebipeNem的药效学与大肠杆菌和K.肺炎的肺炎是可比的，同等是具有扩展光谱β-内酰胺酶与野生型的菌株的响应。中位数Fauc（0-24）/ MIC。在11株中实现瘀滞的1 / TAU值为23. HFIM中逐步的分级方案导致抑制抗性。 Fauc（0-24）/ MIC。 1 / TAU值为34.58至51.87导致对数杀死和抑制阻力。这些数据和分析将用于定义成人患者Cuti患者的第III期研究方案。

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