AAC：揭示绿脓杆菌β内酰胺酶抵御抗生素杀菌的分子机制

刊登在国际杂志Antimicrobial Agents and Chemotherapy上的一篇研究报告中，来自哥本哈根大学医学院的研究者揭示了绿脓杆菌中，高水平的β-内酰胺酶可以高效改变β-内酰胺类抗生素的活性。

该项研究以标题“High beta-lactamase levels change the pharmacodynamics of beta-lactam antibiotics in Pseudomonas aeruginosa biofilms” 刊登于该杂志10月刊上。相关研究对于理解细菌对于抗生素的耐药性以及开发新型抗生素有一定帮助。

在绿脓杆菌感染的肺部纤维化囊肿病人身上，细菌对β-内酰胺类抗生素的抗性普遍存在，这种耐药性主要取决于细菌染色体编码的β-内酰胺酶的产生以及细菌生物被膜的产生。

研究者Niels Hoiby表示，他们开展这项研究的目的在于研究抗生素头孢他啶及亚胺培南作为β-内酰胺类抗生素在对于绿脓杆菌的生物被膜形成的影响、药代动力学以及药效学。

在文章中，研究者使用野生型菌株PAO1以及β内酰胺酶过量产生的突变体菌株PAΔDDh2Dh3进行实验研究，研究者用不同浓度的头孢他啶及亚胺培南作用于两种菌株，并且观察其生物被膜的产生量。结果显示，头孢他啶在杀灭野生型细菌和突变体菌株上表现出时间依赖性，而亚胺培南在抑制野生型菌株和突变体菌株生成生物被膜上表现出事件依赖性。

而β内酰胺酶的接种效应在绿脓杆菌的浮游菌株和生物被膜都有发现，而头孢他啶对于

突变体菌株PAΔDDh2Dh3的效应比对野生型PAO1的效应更为明显。相关的研究为研究者揭示细菌对抗生素产生耐药性以及开发新型抵御细菌感染的抗生素提供了希望和帮助。

doi:10.1128/​AAC.01393-12
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High beta-lactamase levels change the pharmacodynamics of beta-lactam antibiotics in Pseudomonas aeruginosa biofilms

Wang Hengzhuang1↴, Oana Ciofu2, Liang Yang3,5, Hong Wu1,2,5, Zhijun Song1, Antonio Oliver4 and Niels Høiby1,2,6

Resistance to β-lactam antibiotics is a frequent problem in P. aeruginosa lung infection of cystic fibrosis (CF). This resistance is mainly due to the hyper-production of chromosomally encoded β-lactamase and biofilm formation. The purpose of this study was to investigate the role of β-lactamase in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ceftazidime and imipenem on P. aeruginosa biofilms. PAO1 and its corresponding β-lactamase-overproducing mutant PAΔDDh2Dh3 were used in this study. Biofilms of these two strains in flow-chamber, microtiter-plate, and alginate beads were treated with different concentrations of ceftazidime and imipenem. The kinetics of antibiotics on biofilms was investigated in vitro by time-kill methods. Time-dependent killing of ceftazidime was observed in PAO1 biofilms, but concentration-dependent killing activity of ceftazidime was observed for β-lactamase-overproducing biofilms of P. aeruginosa in all the three models. Ceftazidime showed time-dependent killing on both planktonic PAO1 and PAΔDDh2Dh3. This difference is probably due to the special distribution and accumulation of β-lactamase in the biofilm matrix which can hydrolyze the β-lactam antibiotics. The PK/PD indices of AUC/MBIC and Cmax/MBIC (AUC, area under curve; Cmax, maximum concentration; MBIC, minimal biofilm inhibitory concentration) are probably best to describe the effect of ceftazidime in β-lactamase-overproducing P. aeruginosa biofilms. Meanwhile imipenem showed time-dependent killing on both PAO1 and PAΔDDh2Dh3 biofilms. Inoculum effect of β-lactams was found in both planktonic and biofilm P. aeruginosa. The inoculum effect of ceftazidime for β-lactamase-overproducing mutant PAΔDDh2Dh3 biofilms was more obvious than PAO1 biofilms with the requirement of higher antibiotic concentration and longer period treatment.

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