In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae.
In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae.
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头孢他啶-阿维巴坦对产碳青霉烯酶肺炎克雷伯菌的体内外杀菌活性
DOI：
10.1186/s13756-018-0435-9
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发表时间：
2018
影响因子：
5.5
通讯作者：
Hu F
中科院分区：
文献类型：
--
作者：
Zhang W;Guo Y;Li J;Zhang Y;Yang Y;Dong D;Zhu D;He P;Hu F
近年来，碳青霉烯耐药肠杆菌科（CRE）感染的发病率迅速上升。由于CRE菌株通常对大多数抗微生物药物具有耐药性，因此这种感染的患者通常伴有高死亡率。因此，对临床感染管理提出了严峻的挑战。本研究通过研究头孢他啶-阿维巴坦单用或联用氨曲南对产KPC或NDM碳青霉烯酶肺炎克雷伯菌的体外和体内抑菌活性，探索其耐药菌株所致感染的临床治疗新方案。采用微量稀释肉汤法测定最小抑菌浓度（MIC）。对16株KPC-2菌株和1株OXA-232产碳青霉烯酶肺炎克雷伯菌进行了不同浓度头孢他啶-阿维巴坦的时间杀伤曲线测定。采用棋盘法测定头孢他啶-阿维巴坦联合氨曲南对28株NDM和2株NDM联用产碳青霉烯酶的肺炎克雷伯菌的体外增效杀菌效果。根据计算等级，选择具有协同杀菌作用的药物作为抑菌浓度指标。对其中12株菌株进行头孢他啶-阿维巴坦联合氨曲南的体外杀菌试验。采用小鼠模型研究头孢他啶-阿维巴坦抗生素对产碳青霉烯酶KPC肺炎克雷伯菌Y8感染的影响。时间杀伤试验结果表明，头孢他啶-阿维巴坦在2MIC、4MIC和8MIC浓度下对耐药菌株均有显著的杀菌效果。而在28株NDM和2株NDM合并产碳青霉烯酶的肺炎克雷伯菌中，仅有7株对头孢他啶-阿维巴坦敏感，MIC50和MIC90分别为64 mg/L和256 mg/L。头孢他啶-阿维巴坦联用氨曲南的药敏试验结果显示，90%（27/30）的菌株与头孢他啶-阿维巴坦联用的药物有增效作用，3.3%（1/30）的菌株有加效作用，6.6%（2/30）的菌株无增效作用。未发现拮抗作用。随后的杀菌试验也证实了上述结果。头孢他啶-阿维巴坦治疗小鼠肺炎克雷伯菌Y8感染的疗效显示，感染组小鼠4 d内死亡70%，13 d内全部死亡。细菌负荷测试结果显示，感染组与治疗组血液中细菌数量无显著差异。但治疗组小鼠脾脏和肝脏的CFU计数较感染组低，说明头孢他啶-阿维巴坦对细菌有明显作用，具有一定的治疗效果。本研究表明头孢他啶-阿维巴坦治疗对产碳青霉烯酶的KPC-2和OXA-232肺炎克雷伯菌具有显著的杀菌作用。与氨曲南联合使用时，对NDM产碳青霉烯酶肺炎克雷伯菌具有更强的协同杀菌作用。
In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains. The microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA-232 carbapenemase–producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase–producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase–producing K. pneumoniae strain Y8 Infection was performed in the mouse model. The time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy. This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved.
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在中国上海的一家综合医院中出现和建立KPC-2产生的ST11 klebsiella肺炎。
DOI：
10.1007/s10096-017-3131-4
发表时间：
2018-03
期刊：
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology
影响因子：
--
作者：
Liu J;Yu J;Chen F;Yu J;Simner P;Tamma P;Liu Y;Shen L
通讯作者：
Shen L
影响因子：
4.9
作者：
Albiero, James;Sy, Sherwin K. B.;Bronharo Tognim, Maria Cristina
通讯作者：
Bronharo Tognim, Maria Cristina
影响因子：
4.9
作者：
Shields, Ryan K.;Chen, Liang;Clancy, Cornelius J.
通讯作者：
Clancy, Cornelius J.
影响因子：
4.9
作者：
Bensman, Timothy J.;Wang, Joshua;Beringer, Paul M.
通讯作者：
Beringer, Paul M.
影响因子：
5.2
作者：
Bercot, Beatrice;Poirel, Laurent;Nordmann, Patrice
通讯作者：
Nordmann, Patrice