头孢洛林与 NXL104 的棋盘组合对产β-内酰胺酶肠杆菌科的活性。
Activity of chequerboard combinations of ceftaroline and NXL104 versus beta-lactamase-producing Enterobacteriaceae.
机构信息
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
出版信息
J Antimicrob Chemother. 2010 Jul;65(7):1428-32. doi: 10.1093/jac/dkq161. Epub 2010 May 17.
BACKGROUND
Ceftaroline is a novel oxyimino-cephalosporin, strongly active against methicillin-resistant staphylococci and pneumococci. It is active against Enterobacteriaceae too, but is labile to common beta-lactamases, including AmpC and extended-spectrum types. To counteract these enzymes, ceftaroline is also being developed combined with NXL104, a beta-lactamase inhibitor.
METHODS
Chequerboard MIC titrations were performed to determine the NXL104 concentrations needed to protect ceftaroline against beta-lactamase-producing Enterobacteriaceae, most of them with ceftaroline MICs >16 mg/L.
RESULTS
All of 60 extended-spectrum beta-lactamase (ESBL) producers were susceptible to ceftaroline + NXL104, 1 + 1 mg/L, as were 5/5 Klebsiella oxytoca with high-level K1 enzyme. Among 30 Enterobacteriaceae with high-level chromosomal AmpC, 18 were susceptible at 1 + 1 mg/L, 28 at 1 + 4 mg/L and all at 4 + 4 mg/L; among 10 with plasmid AmpC enzymes, nine were susceptible at 1 + 1 mg/L and all at 1 + 4 mg/L. None of 10 isolates with combinations of AmpC or ESBL and impermeability was susceptible at 1 + 1 mg/L, but nine were susceptible at 1 + 4 mg/L and all at 4 + 4 mg/L. Among 12 with KPC carbapenemases, only two were susceptible at 1 + 1 mg/L, compared with 10 at 1 + 4 mg/L and 11 at 4 + 4 mg/L; 8/8 with OXA-48 carbapenemase were susceptible at 1 + 1 mg/L whilst 0/5 with metallo-beta-lactamases were inhibited by ceftaroline + NXL104, even at 8 + 4 mg/L. NXL104 potentiated the activity of ceftaroline against many ESBL- and AmpC-negative isolates for which ceftaroline MICs were 1-4 mg/L but not those for which MICs were < or = 0.5 mg/L, probably reflecting the slight lability of this cephalosporin to classical penicillinases, which were present in the former group but not the latter.
CONCLUSIONS
At concentrations of < or = 4 mg/L, NXL104 protected ceftaroline against all relevant beta-lactamases except metalloenzymes.
背景
头孢洛林是一种新型的氧肟基头孢菌素，对耐甲氧西林葡萄球菌和肺炎球菌具有很强的活性。它对肠杆菌科也有活性，但对常见的β-内酰胺酶（包括 AmpC 和超广谱酶）不稳定。为了对抗这些酶，头孢洛林也在与 NXL104 联合开发，NXL104 是一种β-内酰胺酶抑制剂。
方法
采用棋盘微量稀释法测定 NXL104 浓度，以保护头孢洛林免受产生β-内酰胺酶的肠杆菌科的影响，其中大多数头孢洛林 MIC 值>16mg/L。
结果
所有 60 株超广谱β-内酰胺酶（ESBL）产生菌对头孢洛林+NXL104 的 MIC 值为 1+1mg/L 敏感，5/5 株高产 K1 酶的产酸克雷伯菌也敏感。在 30 株高浓度染色体 AmpC 的肠杆菌科中，18 株在 1+1mg/L 时敏感，28 株在 1+4mg/L 时敏感，所有株在 4+4mg/L 时敏感；在 10 株具有质粒 AmpC 酶的菌株中，9 株在 1+1mg/L 时敏感，所有株在 1+4mg/L 时敏感。无 AmpC 或 ESBL 和通透性组合的 10 株分离株在 1+1mg/L 时均不敏感，但在 1+4mg/L 时有 9 株敏感，在 4+4mg/L 时有所有株敏感。在 12 株产 KPC 碳青霉烯酶的菌株中，只有 2 株在 1+1mg/L 时敏感，而 10 株在 1+4mg/L 时敏感，11 株在 4+4mg/L 时敏感；8/8 株产 OXA-48 碳青霉烯酶的菌株在 1+1mg/L 时敏感，而 5 株产金属β-内酰胺酶的菌株则被头孢洛林+NXL104 抑制，即使在 8+4mg/L 时也是如此。NXL104 增强了头孢洛林对许多 ESBL 和 AmpC 阴性分离株的活性，这些分离株的头孢洛林 MIC 值为 1-4mg/L，但对 MIC 值<或=0.5mg/L 的分离株则没有，这可能反映了这种头孢菌素对经典青霉素酶的轻微不稳定性，这些酶存在于前者中，而不存在于后者中。
结论
在浓度<或=4mg/L 时，NXL104 可保护头孢洛林免受除金属酶以外的所有相关β-内酰胺酶的影响。
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