Girard A E, Girard D, Gootz T D, Faiella J A, Cimochowski C R
Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
Antimicrob Agents Chemother. 1995 Oct;39(10):2210-6. doi: 10.1128/AAC.39.10.2210.
The interesting in vitro antimicrobial activity and pharmacokinetics of the new quinolone trovafloxacin (CP-99,219) warranted further studies to determine its in vivo efficacy in models of infectious disease. The significance of the pharmacokinetic and in vitro antimicrobial profiles of trovafloxacin was shown through efficacy in a series of animal infection models by employing primarily oral therapy. Against acute infections, trovafloxacin was consistently more effective than temafloxacin, ciprofloxacin, and ofloxacin against Streptococcus pneumoniae and other gram-positive pathogens while maintaining activity comparable to that of ciprofloxacin against gram-negative organisms. In a model of murine pneumonia, trovafloxacin was more efficacious than temafloxacin, while ciprofloxacin failed against S. pneumoniae (50% protective doses, 2.1, 29.5, and >100 mg/kg, respectively). In addition to its inherent in vitro potency advantage against S. pneumoniae, these data were supported by a pharmacokinetic study that showed levels of trovafloxacin in pulmonary tissue of S. pneumoniae-infected CF1 mice to be considerably greater than those of temafloxacin and ciprofloxacin (twice the maximum drug concentration in serum; two to three times the half-life, and three to six times the area under the concentration-time curve). Against localized mixed anaerobic infections, trovafloxacin was the only agent to effectively reduce the numbers of recoverable CFU of Bacteroides fragilis ( >1,000-fold), Staphylococcus aureus (1,000-fold), and Escherichia coli ( >100-fold) compared with ciprofloxacin, vancomycin, metronidazole, clindamycin, cefoxitin, and ceftriaxone. The in vitro and in vivo antimicrobial activities of trovafloxacin and its pharmacokinetics in laboratory animals provide support for the ongoing and planned human phase II and III clinical trials.
新型喹诺酮曲伐沙星（CP - 99,219）有趣的体外抗菌活性和药代动力学特性，使得有必要进行进一步研究，以确定其在传染病模型中的体内疗效。通过主要采用口服疗法，在一系列动物感染模型中证实了曲伐沙星的药代动力学和体外抗菌谱的重要性。针对急性感染，曲伐沙星在对抗肺炎链球菌和其他革兰氏阳性病原体方面始终比替马沙星、环丙沙星和氧氟沙星更有效，同时对革兰氏阴性菌保持与环丙沙星相当的活性。在小鼠肺炎模型中，曲伐沙星比替马沙星更有效，而环丙沙星对肺炎链球菌无效（50%保护剂量分别为2.1、29.5和>100 mg/kg）。除了其对肺炎链球菌固有的体外效力优势外，一项药代动力学研究也支持了这些数据，该研究表明，在感染肺炎链球菌的CF1小鼠肺组织中，曲伐沙星的水平明显高于替马沙星和环丙沙星（血清中最大药物浓度的两倍；半衰期的两到三倍，浓度 - 时间曲线下面积的三到六倍）。针对局部混合厌氧菌感染，与环丙沙星、万古霉素、甲硝唑、克林霉素、头孢西丁和头孢曲松相比，曲伐沙星是唯一能有效减少脆弱拟杆菌（>1000倍）、金黄色葡萄球菌（1000倍）和大肠杆菌（>100倍）可恢复CFU数量的药物。曲伐沙星的体外和体内抗菌活性及其在实验动物中的药代动力学为正在进行和计划中的人类II期和III期临床试验提供了支持。
