磷霉素和替加环素对产肺炎克雷伯菌碳青霉烯酶肺炎克雷伯菌的联合药物敏感试验
Antimicrobial activity of fosfomycin combined with tigecycline against Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae
目的:评价磷霉素和替加环素对产肺炎克雷伯菌碳青霉烯酶(KPC 酶)肺炎克雷伯菌的体外联合抗菌效应并研究其对磷霉素的耐药机制。方法微量肉汤稀释法分别测定磷霉素和替加环素单药对42株肺炎克雷伯菌(20株产 KPC 酶,22株 KPC 酶阴性)的最低抑菌浓度(MIC)。采用棋盘法设计测定不同浓度组合的抗菌药物的联合药物敏感试验,计算分级抑菌浓度指数(FICI)并判定联合效应。FICI=MIC磷霉素联合/MIC磷霉素单药+MIC替加环素联合/MIC替加环素单药。相关判读标准:FICI≤0.5为协同作用,0.5<FICI≤1.0为相加作用,1<FICI≤2为无关作用,FICI>2为拮抗作用。对磷霉素耐药的产 KPC酶肺炎克雷伯菌进行常见磷霉素耐药基因筛选。数据比较采用 t 检验。结果产 KPC 酶肺炎克雷伯菌对磷霉素的敏感率为35.0%(7/20),替加环素敏感率为70.0%(14/20)。联合用药后,敏感率分别增至50.0%(10/20)和95.0%(19/20),且各自 MIC 值均有所下降。替加环素在联合后 MIC 值下降明显,与单药 MIC 比较差异有统计学意义(t=-2.596,P =0.013),而磷霉素联合前后 MIC 比较差异无统计学意义(t =-1.274,P =0.211)。FICI 显示,2种抗菌药物的协同、相加效应共计60%,无关效应占40%,未发现拮抗作用。22株 KPC 酶阴性菌株2种抗菌药物联合无关作用占54.5%,相加、协同效应分别为31.8%和13.6%,无拮抗作用。2株携带 fosA 耐药基因的菌株,其 fosA 与 KPC 酶基因均定位于同一质粒上,质粒分别为138.9 kb 与104.5 kb。结论产 KPC 酶肺炎克雷伯菌对替加环素敏感性较高。替加环素联合磷霉素以协同作用和相加作用为主,提示该联合用药方案对产 KPC 酶肺炎克雷伯菌具有一定的抑制效应。
更多Objective To evaluate antimicrobial activity of fosfomycin combined with tigecycline against Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae and study the mechanism of drug resistance to fosfomycin. Methods Broth microdilution method was used to independently determine the minimum inhibitory concentrations (MIC)of fosfomycin and tigecycline against 42 Klebsiella pneumoniae isolates (including 20 KPC-producing and 22 KPC non-producing isolates).Checkerboard design method was applied to evaluate combined effect of different concentrations on antimicrobial susceptibility and calculate the fractional inhibitory concentration index (FICI).FICI=MICfosfomycin joint/MICfosfomycin monotherapy +MICtigecycline joint/MICtigecycline monotherapy .Related interpretation criteria were as following:FICI≤0.5 means synergy;0.5 <FICI≤1 .0 means additive;1 <FICI≤2 means indifference;FICI> 2 means antagonism.The fosfomycin resistant genes in KPC-producing Klebsiella pneumoniae isolates were screened.The data were analyzed by t test.Results Antimicrobial susceptibility testing results indicated the fosfomycin and tigecycline susceptibility rates in KPC-producing isolates were 35 .0%(7/20)and 70.0% (14/20 ),respectively.The susceptibility rates of drug combination increased to 50.0% (10/20 )and 95 .0% (19/20 ),respectively,with both MIC decreased.MIC of tigecycline decreased significantly after combination therapy and showed a statistical significance compared with the MIC of monotherapy (t = - 2.596,P = 0.013 ),whereas there was no significant difference between single and combined therapy of fosfomycin (t=-1 .274,P =0.211).FICI indicated that a total of 60.0%isolates showed synergy and additive effects between two antimicrobial agents,followed by indifference (40.0%),but there was no antagonism effect.Among 22 KPC non-producing isolates,there were 54.5 %showing indifference effects,followed by additive (31 .8%)and synergy (13.6%)effects.No antagonism effect was found.The study also identified two isolates with fosA resistant gene which located on the same plasmid as well as the bla KPC gene.The plasmid sizes in the two isolates were 138.9 kb and 104.5 kb, respectively.Conclusions KPC-producing Klebsiella pneumoniae are more susceptible to tigecycline. Combined use of two antimicrobial agents mainly exerts synergy and additive effect rather than antagonism,which may suggest the combination therapy strategy could inhibit the activity of KPC-producing Klebsiella pneumoniae .
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