Tsuji Brian T, Yang Jenny C, Forrest Alan, Kelchlin Pamela A, Smith Patrick F
School of Pharmacy and Pharmaceutical Sciences and The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, NY 14260, USA.
J Antimicrob Chemother. 2008 Jul;62(1):156-60. doi: 10.1093/jac/dkn133. Epub 2008 Apr 9.
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).
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.
Bacterial killing for ABI-0043 occurred rapidly and in a concentration-dependent manner. Bactericidal activity was achieved within 4 h at > or =16 x MIC against all isolates. Bacterial reductions were greatest at > or =64 x 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.
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.
ABI - 0043是一种新型苯并恶嗪诺利福霉素衍生物，通过特异性抑制细菌RNA聚合酶发挥强大的杀菌活性。我们评估了ABI - 0043对耐甲氧西林金黄色葡萄球菌（MRSA）和甲氧西林敏感金黄色葡萄球菌（MSSA）临床分离株的体外药效学及杀菌活性。
采用一系列不同浓度的ABI - 0043进行时间 - 杀菌研究，评估其在24小时内对4株金黄色葡萄球菌临床分离株的杀菌活性。将药代动力学/药效学综合面积测量法应用于所有菌落形成单位（cfu）数据，并拟合到希尔型数学模型以评估药效学。
ABI - 0043对细菌的杀灭迅速且呈浓度依赖性。对于所有分离株，在≥16倍最低抑菌浓度（MIC）时，4小时内即可达到杀菌活性。对于MRSA和MSSA分离株，在≥64倍MIC时细菌减少最为显著，早在2小时就观察到≥4 log(10) cfu/mL的减少，并在整个24小时内持续。ABI - 0043的药效学通过希尔型模型得到了很好的描述，对所有分离株具有陡峭的S形常数和低半数有效浓度（EC50）。
ABI - 0043对金黄色葡萄球菌临床分离株显示出快速且持续的杀菌活性。ABI - 0043是一种有前景的抗葡萄球菌药物，可用于对抗严重的金黄色葡萄球菌感染。此外，有必要进行药代动力学、药效学和体内研究，以确定其在抗菌治疗中的最终地位。
