Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla(NDM-5): Preparation for a Postantibiotic Era.
Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla(NDM-5): Preparation for a Postantibiotic Era.
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DOI：
10.1128/mbio.00540-17
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发表时间：
2017-07-25
期刊：
影响因子：
6.4
通讯作者：
Tsuji BT
中科院分区：
文献类型：
--
作者：
Bulman ZP;Chen L;Walsh TJ;Satlin MJ;Qian Y;Bulitta JB;Peloquin CA;Holden PN;Nation RL;Li J;Kreiswirth BN;Tsuji BT
革兰氏阴性菌对碳青霉烯耐药的迅速增加使多粘菌素抗生素的重要性重新显现出来。最近在碳青霉烯耐药肠杆菌科中发现了质粒介导的多粘菌素耐药（mcr-1），这是抗生素黄金时代受到严重威胁的重要标志。我们评估了15种不同的fda批准的抗生素单独和联合多粘菌素B对大肠埃希菌MCR1_NJ的细菌杀灭实验，MCR1_NJ是美国首次报道的同时含有mcr-1和新德里金属β-内酰胺酶基因（blaNDM-5）的分离物。最有希望的方案被推进到空心纤维感染模型（HFIM），其中多粘菌素B、氨曲仑和阿米卡星的人体药代动力学模拟超过240小时。暴露于多粘菌素B单药治疗伴随着MCR1_NJ再生，但没有耐药性扩增（多粘菌素B MIC从0到240小时[MIC0h到MIC240h]为4 mg/l）。而阿米卡星单药治疗引起再生和同时的耐药性扩增（阿米卡星MIC0h为4 mg/l， MIC240h为bb0 64 mg/l）。72小时后，在任何含氮曲南的治疗方案中都没有观察到MCR1_NJ菌落。然而，在单氮曲南治疗和多粘菌素b +氮曲南治疗方案中，HFIM试剂盒都明显浑浊，并且在扫描电镜下明显存在长丝状MCR1_NJ细胞，提示非复制持久型（NRP）表型。相比之下，多粘菌素B、氨曲南和阿米卡星3药联用完全根除（>8-log10 CFU/ml），抑制耐药，防止NRP形成。这是首个综合药代动力学/药效学研究，旨在评估耐多粘菌素和碳青霉烯类耐药大肠杆菌的三联药组合，共同产生MCR-1和NDM-5，并将有助于为所谓的“后抗生素”时代做准备。随着抗生素的黄金时代受到严重威胁，一场全球卫生危机可能即将到来。我们最近在美国报告了首例高度耐药的大肠杆菌所谓的“超级细菌”（MCR1_NJ），它含有两种最令人担忧的抗生素耐药基因，分别编码移动粘菌素耐药性（mcr-1）和新德里金属β-内酰胺酶（blaNDM-5）。令人担忧的是，医学界很容易受到这种新出现的细菌威胁，因为最佳治疗策略尚不明确。在这里，我们报告了使用模拟人剂量的市售抗生素对MCR1_NJ的优化组合的活性。一种独特的三联制剂，包括多粘菌素B、氨曲南和阿米卡星的混合物，根除了产生MCR-1和ndm -5的大肠杆菌。每一种抗菌剂单药或双药联合使用在高接种量时都不能根除MCR1_NJ。据我们所知，这是首次提出针对mcr-1和blaNDM共同携带的超级细菌的三种药物治疗方案的研究，旨在为临床医生为这些病原体的未来发生做好准备。
The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance (mcr-1) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene (blaNDM-5). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance amplification (polymyxin B MIC from 0 to 240 h [MIC0h to MIC240h] of 4 mg/liter), whereas amikacin monotherapy caused regrowth and simultaneous resistance amplification (amikacin MIC0h of 4 mg/liter versus MIC240h of >64 mg/liter). No MCR1_NJ colonies were observed for any of the aztreonam-containing regimens after 72 h. However, HFIM cartridges for both aztreonam monotherapy and the polymyxin B-plus-aztreonam regimen were remarkably turbid, and the presence of long, filamentous MCR1_NJ cells was evident in scanning electron microscopy, suggestive of a nonreplicating persister (NRP) phenotype. In contrast, the 3-drug combination of polymyxin B, aztreonam, and amikacin provided complete eradication (>8-log10 CFU/ml reduction) with suppression of resistance and prevention of NRP formation. This is the first comprehensive pharmacokinetic/pharmacodynamic study to evaluate triple-drug combinations for polymyxin- and carbapenem-resistant E. coli coproducing MCR-1 and NDM-5 and will aid in the preparation for a so-called “postantibiotic” era. A global health crisis may be on the horizon, as the golden era of antibiotics is under serious threat. We recently reported the first case in the United States of a highly resistant, Escherichia coli so-called “superbug” (MCR1_NJ), coharboring two of the most worrying antibiotic resistance genes, encoding mobile colistin resistance (mcr-1) and a New Delhi metallo-β-lactamase (blaNDM-5). Worryingly, the medical community is vulnerable to this emerging bacterial threat because optimal treatment strategies are undefined. Here, we report the activity of an optimized combination using simulated human doses of commercially available antibiotics against MCR1_NJ. A unique triple combination involving a cocktail of polymyxin B, aztreonam, and amikacin eradicated the MCR-1- and NDM-5-producing E. coli. Each antimicrobial agent administered as monotherapy or in double combinations failed to eradicate MCR1_NJ at a high inoculum. To our knowledge, this is the first study to propose 3-drug therapeutic solutions against superbugs coharboring mcr-1 and blaNDM, seeking to prepare clinicians for future occurrences of these pathogens.