左旋阿伐他星及其前药阿伐他汀是属于喹诺酮的苯并喹利嗪亚类的新型广谱抗MRSA药物,配制用于静脉和口服给药,分别。各种体外和体内研究已经建立了他们的抗临床显著革兰氏阳性,革兰氏阴性,非典型的,和厌氧病原体。左旋阿霉素对MRSA的有效活性,耐喹诺酮金黄色葡萄球菌,和异万古霉素中间菌株是其充分分化的作用机制的结果,涉及优先靶向DNA促旋酶。在临床相关的实验条件下,如酸性pH值,也观察到了左氟沙星的有效抗葡萄球菌活性。细胞内环境,和生物膜,提示该药物具有治疗难治疗MRSA感染的功能.左旋阿霉素还保留了临床上对耐药呼吸道病原体如大环内酯和青霉素耐药肺炎链球菌的相关活性,化脓性链球菌,流感嗜血杆菌,和卡他莫拉菌,结合临床确定的同类最佳人上皮肺液浓度,在治疗顽固性呼吸道感染方面具有很好的潜力。有吸引力的特点,比如对诺拉流出的抵抗力,金黄色葡萄球菌的不同作用机制,对高接种物培养的杀伤力,和低突变预防浓度,可能会赋予两种药物有利的抗性抑制特征。体内研究在急性细菌皮肤和皮肤结构感染模型中显示出有希望的疗效,呼吸道感染,肾盂肾炎,和人类等效小鼠剂量的腹膜炎。两种制剂在多个I期研究中均具有良好的耐受性,并且总体上显示出剂量依赖性暴露。特别是,口服阿拉沃纳沙星显示出优异的生物利用度(〜90%),几乎反映了静脉内左旋甲氧氟沙星的药代动力学特征,表明前药的无缝吸收和有效裂解以释放活性母体药物。肝功能损害研究表明,对于不同程度的肝功能损害,不需要调整左旋纳沙星/阿莱文纳帕沙星的临床剂量。随着左旋纳地沙星和阿伐纳地沙星的II期和III期研究的成功完成,它们代表了用于治疗由多重耐药革兰氏阳性生物体引起的感染的临床上有吸引力的治疗选择.在这里,我们回顾了目前关于左旋阿伐那霉素和阿伐那霉素的治疗吸引力的证据,这是基于一系列非临床的体外和体内研究和临床研究。
Levonadifloxacin and its prodrug alalevonadifloxacin are novel broad-spectrum anti-MRSA agents belonging to the benzoquinolizine subclass of quinolone, formulated for intravenous and oral administration, respectively. Various in vitro and in vivo studies have established their antimicrobial spectrum against clinically significant Gram-positive, Gram-negative, atypical, and anaerobic pathogens. The potent activity of
levonadifloxacin against MRSA, quinolone-resistant Staphylococcus aureus, and hetero-vancomycin-intermediate strains is an outcome of its well-differentiated mechanism of action involving preferential targeting to DNA gyrase. Potent anti-staphylococcal activity of levonadifloxacin was also observed in clinically relevant experimental conditions such as acidic pH, the intracellular environment, and biofilms, suggesting that the drug is bestowed with enabling features for the treatment of difficult-to-treat MRSA infections.
Levonadifloxacin also retains clinically relevant activity against resistant respiratory pathogens such as macrolide- and penicillin-resistant Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis and, in conjunction with clinically established best-in-class human epithelial lung fluid concentration, has promising potential in the management of recalcitrant respiratory infections. Attractive features, such as resistance to NorA efflux, divergent mechanism of action in S. aureus, cidality against high-inoculum cultures, and low mutant prevention concentration, are likely to confer favorable resistance-suppression features to both agents. In vivo studies have shown promising efficacy in models of acute bacterial skin and skin structure infection, respiratory infections, pyelonephritis, and peritonitis at human-equivalent mouse doses. Both formulations were well tolerated in multiple phase I studies and overall showed a dose-dependent exposure. In particular, oral alalevonadifloxacin showed excellent bioavailability (~90%), almost mirroring the pharmacokinetic profile of intravenous levonadifloxacin, indicating the prodrug\'s seamless absorption and efficient cleavage to release the active parent drug. Hepatic impairment studies showed that clinical doses of
levonadifloxacin/alalevonadifloxacin are not required to be adjusted for various degrees of hepatic impairment. With the successful completion of phase II and phase III studies for both levonadifloxacin and alalevonadifloxacin, they represent clinically attractive therapeutic options for the treatment of infections caused by multi-drug-resistant Gram-positive organisms. Herein, we
review the current evidence on therapeutically appealing attributes of
levonadifloxacin and alalevonadifloxacin, which are based on a range of non-clinical in vitro and in vivo investigations and clinical studies.