LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant Staphylococcus aureus
LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant Staphylococcus aureus
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LB11058，一种具有高青霉素结合蛋白 2a 亲和力和活性的新型头孢菌素，可治疗均质耐甲氧西林金黄色葡萄球菌引起的实验性心内膜炎
DOI：
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发表时间：
2004
影响因子：
4.9
通讯作者：
P. Moreillon
中科院分区：
文献类型：
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作者：
J. Vouillamoz;J. Entenza;P. Hohl;P. Moreillon
摘要LB 11058是一种新合成的头孢菌素，对葡萄球菌青霉素结合蛋白2a（PBP 2a）具有良好的亲和性。在体外和实验性主动脉心内膜炎大鼠中检测了LB 11058对三种耐甲氧西林金黄色葡萄球菌（MRSA）菌株、一种青霉素酶阴性菌株（COL菌株）和两种产青霉素酶菌株（COL-Bla+和P8-Hom）的抵抗力。LB 11058对微生物的MIC为1 mg/L。万古霉素和头孢曲松的MIC分别为1和≥64 mg/L。在群体分析曲线中，在≥2 mg LB 11058/L时，MRSA菌株均未生长。心内膜炎大鼠治疗5天。LB 11058与大鼠血清蛋白高度结合（≥98%）。然而，结合在250 mg/L的阈值以上是可饱和的。因此，连续输注250 mg/L血清浓度，以确保整个输注期间游离部分（≥5 mg/L）高于药物MIC。对照治疗包括模拟静脉注射万古霉素（1 g，每日两次，游离药物浓度高于MIC，≥90%输注期）或头孢曲松（2 g/24 h，游离药物浓度高于MIC，0%输注期）产生的人血清动力学。LB 11058分别成功治疗了感染COL-Bla+和P8-Hom的10/10（100%）和13/14（93%）大鼠。这与万古霉素相当（分别有8/12只[66%]和6/8只[75%]大鼠绝育）。头孢曲松无活性。血清中低浓度的LB 11058（5和10 mg/L，连续输注）无效，如药效学参数所预测。在适当的剂量下，LB 11058在体外和体内都是高度有效的。这一发现支持开发这种具有高PBP 2a亲和力的β-内酰胺用于治疗MRSA感染。
ABSTRACT LB11058 is a new synthetic cephalosporin with good affinity for staphylococcal penicillin-binding protein 2a (PBP2a). LB11058 was tested in vitro and in rats with experimental aortic endocarditis against three methicillin-resistant Staphylococcus aureus (MRSA) strains, one penicillinase-negative strain (strain COL), and two penicillinase-producing strains (COL-Bla+ and P8-Hom). The MICs of LB11058 for the organisms were 1 mg/liter. The MICs of vancomycin and ceftriaxone were 1 and ≥64 mg/liter, respectively. In population analysis profiles, none of the MRSA strains grew at ≥2 mg of LB11058/liter. Rats with endocarditis were treated for 5 days. LB11058 was highly bound to serum proteins in rats (≥98%). However, binding was saturable above a threshold of 250 mg/liter. Therefore, continuous concentrations of 250 mg/liter in serum were infused to ensure a free fraction (≥5 mg/liter) above the drug's MIC for the entire infusion period. Control treatments included simulation of human serum kinetics produced by intravenous vancomycin (1 g twice daily, free drug concentration above MIC, ≥90% of infusion period) or ceftriaxone (2 g/24 h, free drug concentrations above the MIC, 0% of infusion period). LB11058 successfully treated 10 of 10 (100%) and 13 of 14 (93%) of rats infected with COL-Bla+ and P8-Hom, respectively. This was comparable to vancomycin (sterilization of 8 of 12 [66%] and 6 of 8 [75%] rats, respectively). Ceftriaxone was inactive. Low concentrations of LB11058 (5 and 10 mg/liter, continuously infused) in serum were ineffective, as predicted by the pharmacodynamic parameters. At appropriate doses, LB11058 was highly effective both in vitro and in vivo. This finding supports the development of this beta-lactam with high PBP2a affinity for the treatment of MRSA infections.
影响因子：
11.8
作者：
Chambers HF
通讯作者：
Chambers HF