Efflux pump, the masked side of beta-lactam resistance in Klebsiella pneumoniae clinical isolates.
Efflux pump, the masked side of beta-lactam resistance in Klebsiella pneumoniae clinical isolates.
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DOI：
10.1371/journal.pone.0004817
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Nicolas-Chanoine MH
中科院分区：
文献类型：
--
作者：
Pages JM;Lavigne JP;Leflon-Guibout V;Marcon E;Bert F;Noussair L;Nicolas-Chanoine MH
β-内酰胺酶产生和孔蛋白减少是肺炎克雷伯菌分离株获得性β-内酰胺耐药的公认机制。然而，这些机制在K.对头孢西丁（FOX）不敏感，对阿莫西林+克拉维酸敏感的肺炎分离株。本研究的目的是评估外排泵在β-内酰胺表型中的作用。对包括氯唑西林（CLX）在内的9种β-内酰胺类抗生素和其他抗生素家族的MIC进行了单独测试，并与外排泵抑制剂（EPI）一起测试，然后与CLX（亚抑制浓度）和EPI一起测试11种独特菌血症K。pneumoniae分离株显示不寻常的表型，和2个ATCC菌株。对4株代表菌株进行了CLX和EPI剂量依赖性效应研究。当用EPI测试时，CLX MIC显著降低。在哌拉西林+他唑巴坦中观察到类似的现象，而其他β-内酰胺类药物的MIC仅在EPI和CLX同时存在时显著降低。因此，FOX MIC在K. pneumoniae分离株中，但在ATCC菌株中也是16倍。FOX活性的恢复呈CLX剂量依赖性，表明CLX与其他β-内酰胺类药物在外排方面存在竞争关系。对于氯霉素、红霉素和萘啶酸，其抗性也是由于外排，将CLX添加到EPI中不会增加其活性，表明这些分子的外排过程与β-内酰胺的外排过程之间存在差异。这是首次证实外排机制在临床分离的克雷伯菌β-内酰胺类药物敏感性中起关键作用。肺炎。这些数据清楚地证明，外排泵在β-内酰胺耐药性中的作用在临床分离株中被特别低估。
β-lactamase production and porin decrease are the well-recognized mechanisms of acquired ß-lactam resistance in Klebsiella pneumoniae isolates. However, such mechanisms proved to be absent in K. pneumoniae isolates that are non susceptible to cefoxitin (FOX) and succeptible to amoxicillin+clavulanic acid in our hospital. Assessing the role of efflux pumps in this β-lactam phenotype was the aim of this study. MICs of 9 β-lactams, including cloxacillin (CLX), and other antibiotic families were tested alone and with an efflux pump inhibitor (EPI), then with both CLX (subinhibitory concentrations) and EPI against 11 unique bacteremia K. pneumoniae isolates displaying the unusual phenotype, and 2 ATCC strains. CLX and EPI-dose dependent effects were studied on 4 representatives strains. CLX MICs significantly decreased when tested with EPI. A similar phenomenon was observed with piperacillin+tazobactam whereas MICs of the other β-lactams significantly decreased only in the presence of both EPI and CLX. Thus, FOX MICs decreased 128 fold in the K. pneumoniae isolates but also16 fold in ATCC strain. Restoration of FOX activity was CLX dose-dependent suggesting a competitive relationship between CLX and the other β-lactams with regard to their efflux. For chloramphenicol, erythromycin and nalidixic acid whose resistance was also due to efflux, adding CLX to EPI did not increase their activity suggesting differences between the efflux process of these molecules and that of β-lactams. This is the first study demonstrating that efflux mechanism plays a key role in the β-lactam susceptibility of clinical isolates of K. pneumoniae. Such data clearly evidence that the involvement of efflux pumps in ß-lactam resistance is specially underestimated in clinical isolates.
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