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首页> 外文OA文献 >Pharmacodynamics of a Novel Des-F(6)-Quinolone, BMS-284756, against Streptococcus pneumoniae in the Thigh Infection Model
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Pharmacodynamics of a Novel Des-F(6)-Quinolone, BMS-284756, against Streptococcus pneumoniae in the Thigh Infection Model

机译：新型Des-F（6）-喹诺酮类药物BMS-284756对大腿感染模型中肺炎链球菌的药效动力学

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BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae. Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 105 to 106 CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates (n = 8) ranged from 0.03 to 2 μg/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, ∼20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against S. pneumoniae, (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.
机译：BMS-284756是一种新型的喹诺酮，它缺少现有化合物中常见的六位氟。尽管有这种结构变化，BMS-284756仍对革兰氏阴性和革兰氏阳性需氧和厌氧性病原体保持有效的抗菌活性。这项研究的目的是确定BMS-284756对肺炎链球菌的药效学特征。通过超滤方法评估小鼠中的蛋白质结合。为了进行药效学研究，使用了中性粒细胞减少的ICR小鼠以及具有免疫功能的小鼠CBA / J，以评估白细胞对感染结果的影响。每只大腿感染了105至106 CFU的小鼠，并在2小时后开始治疗。动物以1.25至100 mg / kg /天的剂量口服BMS-284756，分为一至四剂。在感染后0和24小时，收获大腿用于细菌密度测量。在治疗96小时和治疗后3天再次评估存活率。还对感染的小鼠进行了药代动力学研究。蛋白质结合确定为80％。临床分离株（n = 8）的MIC范围为0.03至2μg/ ml。细菌密度和存活率的变化与药效学参数与血清中药物浓度保持高于MIC，AUC（浓度-时间曲线下的面积）/ MIC之比，峰值/ MIC之比以及最佳响应的预测指标是两种结果指标的AUC / MIC比。总的AUC / MIC比为100到200似乎会产生最大的杀菌效果。在治疗结束时，总的AUC / MIC比值为100（游离AUC / MIC比，〜20）可导致近100％的存活率，而总的AUC / MIC比为200（游离AUC / MIC比，〜40）。 ）是必需的，以确保治疗后3天生存。这些数据证明（i）BMS-284756对肺炎链球菌的体内杀菌活性，（ii）蛋白质结合对BMS-284756的体内药效学评估具有深远影响，以及（iii）AUC / MIC比率200（游离AUC / MIC比率，约40）似乎最能表征所需的动态暴露，以优化杀菌活性和最大存活率。

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