In vitro pharmacodynamics of novel rifamycin ABI-0043 against Staphylococcus aureus
In vitro pharmacodynamics of novel rifamycin ABI-0043 against Staphylococcus aureus
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DOI：
10.1093/jac/dkn133
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发表时间：
2008-07-01
影响因子：
5.2
通讯作者：
Smith, Patrick F.
中科院分区：
文献类型：
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作者：
Tsuji, Brian T.;Yang, Jenny C.;Smith, Patrick F.
目的：ABI-0043是一种新型苯并恶嗪诺霉素衍生物，通过特异性抑制细菌RNA聚合酶而获得其有效的杀菌活性。研究了ABI-0043对临床分离的耐甲氧西林金黄色葡萄球菌（MRSA）和耐甲氧西林金黄色葡萄球菌（MSSA）的体外药效学和杀菌活性。方法：采用大范围浓度ABI-0043的时间杀伤研究，对4株金黄色葡萄球菌临床分离株在24小时内的杀伤活性进行了评估。对所有cfu数据采用综合药代动力学/药效学面积测量，并拟合hill型数学模型来评估药效学。结果：ABI-0043对细菌的杀伤速度快，且呈浓度依赖性。在>= 16倍MIC条件下，对所有菌株均在4小时内具有杀菌活性。对MRSA和MSSA菌株，在b> = 64倍MIC时，细菌减少量最大，因为早在2小时就观察到b> 4 log(10) cfu/mL的减少，并持续整个24小时。ABI-0043的药理学用hill型模型很好地描述了，具有陡峭的s型常数和低EC（50）对所有菌株。结论：ABI-0043对金黄色葡萄球菌临床分离株具有快速、持续的杀菌活性。ABI-0043是一种很有前途的抗葡萄球菌药物，可以对抗严重的金黄色葡萄球菌感染。此外，需要进行药代动力学、药效学和体内研究来确定其在抗菌治疗中的最终地位。
Objectives: ABI-0043 is a novel benzoxazinorifamycin derivative, which derives its potent bactericidal activity by the specific inhibition of bacterial RNA polymerase. We evaluated the in vitro pharmacodynamics and bactericidal activity of ABI-0043 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA).Methods: Using time-kill studies at a wide range of concentrations of ABI-0043, we evaluated the killing activity against four clinical isolates of S. aureus over 24 h. An integrated pharmacokinetic/pharmacodynamic area measure was applied to all cfu data and was fitted to a Hill-type mathematical model to evaluate pharmacodynamics.Results: Bacterial killing for ABI-0043 occurred rapidly and in a concentration-dependent manner. Bactericidal activity was achieved within 4 h at >= 16x MIC against all isolates. Bacterial reductions were greatest at >= 64x MIC against MRSA and MSSA isolates, as a > 4 log(10) cfu/mL reduction was observed as early as 2 h, and sustained throughout 24 h. The pharmacodynamics of ABI-0043 was well described by a Hill-type model, with a steep sigmoidicity constant and a low EC(50) against all isolates.Conclusions: ABI-0043 displayed rapid and sustained bactericidal activity against S. aureus clinical isolates. ABI-0043 represents a promising antistaphylococcal agent to combat serious S. aureus infections. Further, pharmacokinetic, pharmacodynamic and in vivo studies are warranted to determine its ultimate place in antibacterial therapy.