Nicolau David P, Mattoes Holly M, Banevicius Maryanne, Xuan Dawei, Nightingale Charles H
Center for Anti-Infective Research, Office of Research, Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut 06102, USA.
Antimicrob Agents Chemother. 2003 May;47(5):1630-5. doi: 10.1128/AAC.47.5.1630-1635.2003.
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 10(5) to 10(6) 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 micro g/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, approximately 20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, approximately 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, approximately 40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.
BMS-284756是一种新型喹诺酮类药物，缺乏现有化合物典型的6位氟原子。尽管有这种结构变化，BMS-284756对革兰氏阴性和革兰氏阳性需氧及厌氧病原体仍保持强大的抗菌活性。本研究的目的是确定BMS-284756对肺炎链球菌的药效学特征。采用超滤法评估小鼠体内的蛋白结合情况。为进行药效学研究，使用了中性粒细胞减少的ICR小鼠以及具有免疫活性的CBA/J小鼠品系，以评估白细胞对感染结果的影响。小鼠每只大腿感染10(5)至10(6)CFU，感染2小时后开始治疗。动物口服BMS-284756，剂量范围为1.25至100mg/kg/天，分为1至4剂。在感染后0小时和24小时，采集大腿用于测量细菌密度。在治疗的96小时内及治疗后3天评估存活率。还对感染小鼠进行了药代动力学研究。确定蛋白结合率为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血清中药物浓度高于MIC的时间百分比、AUC（浓度-时间曲线下面积）/MIC比值以及峰浓度/MIC比值相关，对于两种结果测量指标，最佳反应预测指标是AUC/MIC比值。总AUC/MIC比值为100至200似乎可产生最大杀菌效果。虽然总AUC/MIC比值暴露值为100（游离AUC/MIC比值，约为20）在治疗结束时导致近100%的存活率，但需要总AUC/MIC比值为200（游离AUC/MIC比值，约为40）以确保治疗后3天存活。这些数据表明：（i）BMS-284756对肺炎链球菌的体内杀菌活性；（ii）蛋白结合对BMS-284756体内药效学评估有深远影响；（iii）AUC/MIC比值为200（游离AUC/MIC比值，约为40）似乎最能表征优化杀菌活性和最大存活率所需的动态暴露情况。
