Achaogen, Inc., 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, USA.
Antimicrob Agents Chemother. 2011 Apr;55(4):1728-33. doi: 10.1128/AAC.00862-10. Epub 2011 Jan 31.
Aminoglycosides are broad-spectrum antibiotics with particular clinical utility against life-threatening infections. As resistance to antibiotics, including aminoglycosides, continues to grow, there is a need for new and effective antimicrobial agents. ACHN-490 is a novel aminoglycoside in clinical development with activity against multidrug-resistant Gram-negative and select Gram-positive pathogens. Here we assess the in vivo efficacy of ACHN-490 against a variety of common pathogens in two murine models: the septicemia and neutropenic thigh models. When its activity against a gentamicin-susceptible strain of Escherichia coli was tested in the septicemia model, ACHN-490 improved 7-day survival with a dose-response profile similar to that of gentamicin, with 100% survival seen at doses of 1.6 mg/kg of body weight and above. In animals infected with a gentamicin-susceptible strain of Pseudomonas aeruginosa, treatment with either ACHN-490 or gentamicin led to 100% survival at doses of 16 mg/kg and above in the septicemia model. ACHN-490 was also effective in the neutropenic thigh model, reducing multidrug-resistant Enterobacteriaceae family and methicillin-resistant Staphylococcus aureus strains, as well as broadly susceptible strains, to static levels with dose-dependent activity. Against gentamicin-sensitive Enterobacteriaceae and methicillin-resistant S. aureus, the efficacy of ACHN-490 was comparable to that of gentamicin. However, gentamicin-resistant Enterobacteriaceae strains and those harboring the Klebsiella pneumoniae carbapenemase responded to ACHN-490 but not gentamicin, with static doses ranging from 12 mg/kg to 64 mg/kg for ACHN-490. These results suggest that ACHN-490 has the potential to become a clinically useful agent against drug-resistant pathogens, including Enterobacteriaceae, P. aeruginosa, and methicillin-resistant S. aureus, and support further development of this promising novel aminoglycoside.
氨基糖苷类抗生素是一种广谱抗生素，对危及生命的感染具有特殊的临床应用价值。随着抗生素耐药性的不断增加，包括氨基糖苷类抗生素在内，我们需要新的、有效的抗菌药物。ACHN-490 是一种新型的临床开发中的氨基糖苷类抗生素，对多种多药耐药革兰氏阴性和选择性革兰氏阳性病原体具有活性。在这里，我们在两种小鼠模型（败血症和中性粒细胞减少性大腿模型）中评估了 ACHN-490 对多种常见病原体的体内疗效。当在败血症模型中测试其对氨基糖苷类敏感的大肠杆菌菌株的活性时，ACHN-490 改善了 7 天的存活率，其剂量反应曲线与庆大霉素相似，在 1.6mg/kg 及以上剂量下，100%的动物存活。在感染氨基糖苷类敏感的铜绿假单胞菌的动物中，ACHN-490 或庆大霉素治疗在败血症模型中，16mg/kg 及以上剂量可使 100%的动物存活。ACHN-490 在中性粒细胞减少性大腿模型中也有效，对多药耐药肠杆菌科和耐甲氧西林金黄色葡萄球菌菌株以及广泛敏感的菌株具有剂量依赖性的杀菌活性，使其达到静态水平。对氨基糖苷类敏感的肠杆菌科和耐甲氧西林金黄色葡萄球菌，ACHN-490 的疗效与庆大霉素相当。然而，对氨基糖苷类耐药的肠杆菌科菌株和携带肺炎克雷伯菌碳青霉烯酶的菌株对 ACHN-490 有反应，但对庆大霉素没有反应，ACHN-490 的静态剂量范围为 12mg/kg 至 64mg/kg。这些结果表明，ACHN-490 有可能成为一种对抗耐药病原体（包括肠杆菌科、铜绿假单胞菌和耐甲氧西林金黄色葡萄球菌）的临床有用药物，并支持进一步开发这种有前途的新型氨基糖苷类抗生素。
