Alm Richard A, McLaughlin Robert E, Kos Veronica N, Sader Helio S, Iaconis Joseph P, Lahiri Sushmita D
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA, USA
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA, USA.
J Antimicrob Chemother. 2014 Aug;69(8):2065-75. doi: 10.1093/jac/dku114. Epub 2014 Apr 28.
Ceftaroline, approved in Europe in 2012, has activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC90 values of 1-2 mg/L depending on geographical location. During a global 2010 surveillance programme, conducted prior to the European launch, 4 S. aureus isolates, out of 8037 tested, possessing ceftaroline MIC values of >2 mg/L were identified. The objective of this study was to characterize these four isolates to elucidate the mechanism of ceftaroline resistance.
MIC determinations were performed using broth microdilution and whole genome sequencing was performed to enable sequence-based analyses.
The only changes in proteins known to be required for full expression of methicillin resistance that correlated with the ceftaroline MIC were in penicillin-binding protein 2a (PBP2a). Isolates with a ceftaroline MIC of 2 mg/L had a Glu239Lys mutation in the non-penicillin-binding domain whereas the four isolates with ceftaroline MIC values of 8 mg/L carried an additional Glu447Lys mutation in the penicillin-binding domain. The impact of these mutations was analysed using the known X-ray structure of S. aureus PBP2a and a model for ceftaroline resistance proposed. Analysis of the core genomes showed that the isolates with reduced susceptibility to ceftaroline were epidemiologically related.
Mutations in PBP2a can affect the activity of ceftaroline against MRSA. Although a rare event, based on surveillance studies, it appears a first-step change in the non-penicillin-binding domain together with a second-step in the penicillin-binding domain may result in elevation of the ceftaroline MIC to >2 mg/L.
头孢洛林于2012年在欧洲获批，对耐甲氧西林金黄色葡萄球菌（MRSA）具有活性，其MIC90值为1 - 2mg/L，具体数值因地理位置而异。在2010年欧洲上市前开展的一项全球监测计划中，从8037株受试金黄色葡萄球菌分离株中，鉴定出4株头孢洛林MIC值>2mg/L的菌株。本研究的目的是对这4株分离株进行特性分析，以阐明头孢洛林耐药机制。
采用肉汤微量稀释法测定MIC，并进行全基因组测序以进行基于序列的分析。
与头孢洛林MIC相关的、已知对甲氧西林耐药完全表达所必需的蛋白质中，唯一的变化发生在青霉素结合蛋白2a（PBP2a）。头孢洛林MIC为2mg/L的分离株在非青霉素结合结构域有一个Glu239Lys突变，而4株头孢洛林MIC值为8mg/L的分离株在青霉素结合结构域还存在一个额外的Glu447Lys突变。利用已知的金黄色葡萄球菌PBP2a X射线结构和提出的头孢洛林耐药模型，分析了这些突变的影响。核心基因组分析表明，对头孢洛林敏感性降低的分离株在流行病学上相关。
PBP2a中的突变可影响头孢洛林对MRSA的活性。基于监测研究，尽管这是一个罕见事件，但非青霉素结合结构域的第一步变化以及青霉素结合结构域的第二步变化可能导致头孢洛林MIC升高至>2mg/L。
