Efficacy of Colistin and Its Combination With Rifampin in Vitro and in Experimental Models of Infection Caused by Carbapenemase-Producing Clinical Isolates of Klebsiella pneumoniae.
Efficacy of Colistin and Its Combination With Rifampin in Vitro and in Experimental Models of Infection Caused by Carbapenemase-Producing Clinical Isolates of Klebsiella pneumoniae.
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DOI：
10.3389/fmicb.2018.00912
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发表时间：
2018
影响因子：
5.2
通讯作者：
Conejo MC
中科院分区：
文献类型：
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作者：
Pachón-Ibáñez ME;Labrador-Herrera G;Cebrero-Cangueiro T;Díaz C;Smani Y;Del Palacio JP;Rodríguez-Baño J;Pascual A;Pachón J;Conejo MC
尽管产碳青霉烯酶肺炎克雷伯菌（CP-Kp）感染具有相关性，但很少有研究评价联合治疗的体内疗效。研究了粘菌素、利福平及其组合对4种克隆无关的CP-Kp临床分离株的杀菌活性（时间-杀灭曲线），分别产生Vim-1、Vim-1 + DHA-1（获得性AmpC β-内酰胺酶）、OXA-48 + CTX-M-15（超广谱β-内酰胺酶）和KPC-3，粘菌素MIC分别为0. 5、64、0. 5和32 mg/L。在鼠腹膜脓毒症模型中测试抗微生物剂在单药治疗和联合治疗中针对所有CP-Kp的功效。在肺炎模型中测试了它们对OXA-48加CTX-M-15生产者的效力。通过体外和体内试验，分析了粘菌素敏感菌株的耐药性发展。体外试验表明，粘菌素与利福平联用24 h对所有菌株均有协同作用.在体内，与对照组相比，利福平单独给药降低了抗Vim-1和OXA-48加CTX-M-15菌株的组织细菌浓度; CMS加利福平降低了这两种CP-Kp和KPC-3菌株的组织细菌浓度。利福平和联合用药增加了对KPC-3菌株的存活率;在肺炎模型中，联合用药也改善了存活率。组合中未出现抗性突变体。总之，CMS加利福平治疗重度腹膜脓毒症模型的疗效较低且不均匀，因为CP-KP产生不同的碳青霉烯酶，仅针对KPC-3菌株增加存活率。该组合在不太严重的肺炎模型中显示出疗效。该组合在体外和体内防止了粘菌素抗性突变体的发展。
Despite the relevance of carbapenemase-producing Klebsiella pneumoniae (CP-Kp) infections there are a scarce number of studies to evaluate in vivo the efficacy of combinations therapies. The bactericidal activity of colistin, rifampin, and its combination was studied (time–kill curves) against four clonally unrelated clinical isolates of CP-Kp, producing VIM-1, VIM-1 plus DHA-1(acquired AmpC β-lactamase), OXA-48 plus CTX-M-15 (extended spectrum β-lactamase) and KPC-3, respectively, with colistin MICs of 0.5, 64, 0.5, and 32 mg/L, respectively. The efficacies of antimicrobials in monotherapy and in combination were tested in a murine peritoneal sepsis model, against all the CP-Kp. Their efficacies were tested in the pneumonia model against the OXA-48 plus CTX-M-15 producers. The development of colistin-resistance was analyzed for the colistin-susceptible strains in vitro and in vivo. In vitro, colistin plus rifampin was synergistic against all the strains at 24 h. In vivo, compared to the controls, rifampin alone reduced tissue bacterial concentrations against VIM-1 and OXA-48 plus CTX-M-15 strains; CMS plus rifampin reduced tissue bacterial concentrations of these two CP-Kp and of the KPC-3 strain. Rifampin and the combination increased the survival against the KPC-3 strain; in the pneumonia model, the combination also improved the survival. No resistant mutants appeared with the combination. In conclusion, CMS plus rifampin had a low and heterogeneous efficacy in the treatment of severe peritoneal sepsis model due to CP-Kp producing different carbapenemases, increasing survival only against the KPC-3 strain. The combination showed efficacy in the less severe pneumonia model. The combination prevented in vitro and in vivo the development of colistin resistant mutants.