Tally F P, Zeckel M, Wasilewski M M, Carini C, Berman C L, Drusano G L, Oleson F B
Cubist Pharmaceuticals, Inc., 24 Emily Street, Cambridge, MA 02139, USA.
Expert Opin Investig Drugs. 1999 Aug;8(8):1223-38. doi: 10.1517/13543784.8.8.1223.
The alarming increase in the incidence of Gram-positive infections, including those caused by resistant bacteria, has sparked renewed interest in novel antibiotics. One such agent is daptomycin, a novel lipopeptide antibiotic with proven bactericidal activity in vitro against all clinically relevant Gram-positive bacteria. These include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediately susceptible Staphylococcus aureus (GISA), coagulase-negative staphylococci (CNS) and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives. Daptomycin provides rapid, concentration-dependent killing and a relatively prolonged concentration-dependent post-antibiotic effect in vitro. Spontaneous acquisition of resistance to daptomycin occurs rarely. Daptomycin exhibits linear pharmacokinetics, minimal accumulation with once-daily dosing, and low plasma clearance and volume of distribution. Phase II clinical trials indicate that daptomycin at doses of 2 mg/kg q24 h and 3 mg/kg q12 h is efficacious against skin and soft tissue infections and bacteremia, respectively. In addition, results in endocarditis suggested potential efficacy with higher doses. On the basis of clinical trials to date, it appears that daptomycin has an excellent safety profile, with the incidence and nature of serious adverse events comparable to those observed with conventional therapy. Adverse events associated with other classes of antimicrobials (nephrotoxicity, local irritation, ototoxicity, hypersensitivity, and gastrointestinal effects) were uncommon with daptomycin. Minimal skeletal muscle toxicity was seen at only the highest dose tested (4 mg/kg q12 h), predicted by elevations in serum creatinine phosphokinase, and readily reversible upon discontinuation of treatment. There were no signs of toxicity in cardiac or smooth muscle. Phase II and III clinical trials are underway to evaluate daptomycin for the treatment of Gram-positive bacteremia and complicated skin and soft tissue infections, respectively. Daptomycin holds promise as a rapidly acting and highly effective antibiotic for Gram-positive infections.
革兰氏阳性菌感染的发病率惊人上升，包括由耐药菌引起的感染，这引发了人们对新型抗生素的新兴趣。达托霉素就是这样一种药物，它是一种新型脂肽抗生素，在体外对所有临床相关的革兰氏阳性菌均具有已证实的杀菌活性。这些细菌包括耐药病原体，如万古霉素耐药肠球菌（VRE）、耐甲氧西林金黄色葡萄球菌（MRSA）、糖肽中介敏感金黄色葡萄球菌（GISA）、凝固酶阴性葡萄球菌（CNS）和青霉素耐药肺炎链球菌（PRSP），针对这些病原体几乎没有其他治疗选择。达托霉素在体外能提供快速、浓度依赖性的杀菌作用以及相对较长的浓度依赖性抗生素后效应。对达托霉素自发产生耐药性的情况很少见。达托霉素呈现线性药代动力学，每日一次给药时极少蓄积，血浆清除率低且分布容积小。II期临床试验表明，剂量为2mg/kg q24h和3mg/kg q12h的达托霉素分别对皮肤和软组织感染以及菌血症有效。此外，心内膜炎的研究结果表明更高剂量可能有效。基于迄今为止的临床试验，达托霉素似乎具有出色的安全性，严重不良事件的发生率和性质与传统治疗相当。与达托霉素相关的其他类抗菌药物的不良事件（肾毒性、局部刺激、耳毒性、超敏反应和胃肠道效应）并不常见。仅在测试的最高剂量（4mg/kg q12h）时观察到最小程度的骨骼肌毒性，表现为血清肌酐磷酸激酶升高，停药后可迅速逆转。心脏或平滑肌没有毒性迹象。目前正在进行II期和III期临床试验，分别评估达托霉素治疗革兰氏阳性菌血症和复杂性皮肤及软组织感染的效果。达托霉素有望成为治疗革兰氏阳性菌感染的快速起效且高效的抗生素。
