Firsov Alexander A, Alferova Irene V, Smirnova Maria V, Lubenko Irene Yu, Portnoy Yury A, Zinner Stephen H
Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
Int J Antimicrob Agents. 2005 May;25(5):409-13. doi: 10.1016/j.ijantimicag.2005.02.004.
The kinetics of killing of Streptococcus pneumoniae exposed to ABT492 or levofloxacin were compared. S. pneumoniae ATCC 49619 and four ciprofloxacin-resistant clinical isolates, S. pneumoniae 1149, 391, 79 and 804, were exposed to ABT492 and levofloxacin as a single dose in a dynamic model that simulates human pharmacokinetics of the quinolones. With S. pneumoniae ATCC 49619 eight-fold ranging AUC/MIC ratios (60-500 h) were simulated for each quinolone. In addition, two larger AUC/MICs, i.e., 1080 and 2150 h for ABT492 and 1460 and 3660 h for levofloxacin which correspond to 100 and 200 mg doses of ABT492 and 200 and 500 mg doses of levofloxacin, respectively, were mimicked. Each ciprofloxacin-resistant organism was exposed to the clinical doses of ABT492 (400 mg) and levofloxacin (500 mg); the respective AUC/MIC ratios were from 580 to 3470 h and from 28 to 110 h. At comparable AUC/MICs (from 60 to 500 h), regrowth of S. pneumoniae ATCC 49619 followed initial killing, and the times to regrowth were longer with levofloxacin than ABT492. However, no regrowth of S. pneumoniae ATCC 49619 occurred at the higher AUC/MICs of ABT492 (1080 and 2150 h) and levofloxacin (1460 and 3660 h). Killing of S. pneumoniae 1149, 391 and 79 without bacterial regrowth, was provided by ABT492 (AUC/MIC 3470, 2310 and 1160 h, respectively) but not levofloxacin (AUC/MIC 55, 110 and 28 h, respectively). Regrowth of S. pneumoniae 804 was observed with both ABT492 and levofloxacin (AUC/MIC 580 and 55 h, respectively). Areas between the control growth curve and the time-kill curve (ABBCs) for ABT492 against S. pneumoniae 1149, 391 and 79 were 2.6-4.2 times larger than the respective ABBCs for levofloxacin, whereas similar ABBCs were found with S. pneumoniae 804 exposed to both quinolones. These findings predict significantly greater efficacy of ABT492 than levofloxacin at clinically achievable AUC/MIC ratios against ciprofloxacin-resistant S. pneumoniae and similar efficacies of the two quinolones against susceptible organisms.
比较了暴露于ABT492或左氧氟沙星的肺炎链球菌的杀菌动力学。肺炎链球菌ATCC 49619和4株耐环丙沙星的临床分离株，即肺炎链球菌1149、391、79和804，在模拟喹诺酮类药物人体药代动力学的动态模型中接受ABT492和左氧氟沙星单剂量处理。对于肺炎链球菌ATCC 49619，针对每种喹诺酮模拟了8倍范围的AUC/MIC比值（60 - 500小时）。此外，还模拟了两个更大的AUC/MIC值，即ABT492的1080和2150小时以及左氧氟沙星的1460和3660小时，分别对应100和200毫克剂量的ABT492以及200和500毫克剂量的左氧氟沙星。每种耐环丙沙星的菌株接受ABT492（400毫克）和左氧氟沙星（500毫克）的临床剂量处理；各自的AUC/MIC比值分别为580至3470小时和28至110小时。在相当的AUC/MIC值（60至500小时）下，肺炎链球菌ATCC 49619在初始杀菌后出现再生长，且左氧氟沙星处理后的再生长时间比ABT492长。然而，在ABT492（1080和2150小时）和左氧氟沙星（1460和3660小时）的较高AUC/MIC值下，肺炎链球菌ATCC 49619未出现再生长。ABT492对肺炎链球菌1149、391和79的杀菌作用（无细菌再生长），其AUC/MIC分别为3470、2310和1160小时，而左氧氟沙星（AUC/MIC分别为55、110和28小时）则未达到此效果。肺炎链球菌804在ABT492和左氧氟沙星处理后均出现再生长（AUC/MIC分别为580和55小时）。ABT492针对肺炎链球菌1149、391和79的对照生长曲线与时间 - 杀菌曲线之间的面积（ABBCs）比左氧氟沙星相应的ABBCs大2.6 - 4.2倍，而肺炎链球菌804暴露于两种喹诺酮时的ABBCs相似。这些发现预示，在临床可达到的AUC/MIC比值下，ABT492对耐环丙沙星肺炎链球菌的疗效显著高于左氧氟沙星，而两种喹诺酮对敏感菌的疗效相似。
