耐多粘菌素、耐碳青霉烯类鲍曼不动杆菌可被三种单独无活性的药物联合使用所根除。
Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity.
作者信息
Lenhard Justin R, Thamlikitkul Visanu, Silveira Fernanda P, Garonzik Samira M, Tao Xun, Forrest Alan, Soo Shin Beom, Kaye Keith S, Bulitta Jürgen B, Nation Roger L, Li Jian, Tsuji Brian T
机构信息
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences and School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.
California Northstate University College of Pharmacy, Elk Grove, CA, USA.
出版信息
J Antimicrob Chemother. 2017 May 1;72(5):1415-1420. doi: 10.1093/jac/dkx002.
OBJECTIVES
The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii . The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities.
METHODS
Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactam-resistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations.
RESULTS
Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg of >2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth.
CONCLUSIONS
To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.
目的
多粘菌素耐药性的出现可能使临床医生在对抗耐药鲍曼不动杆菌时几乎无药可用。本研究的目的是确定多粘菌素耐药性的体外出现情况，并确定一种能够根除无明显药敏的鲍曼不动杆菌的联合用药方案。
方法
评估了从一名重症患者身上分离出的两株克隆相关、配对的鲍曼不动杆菌，该患者在一项临床群体药代动力学研究中接受甲磺酸多粘菌素治疗时出现了对粘菌素的耐药性：一株是治疗前分离出的鲍曼不动杆菌（03 - 149.1，对多粘菌素敏感，MIC为0.5mg/L），另一株是治疗后分离出的（03 - 149.2，对多粘菌素耐药，MIC为32mg/L，对碳青霉烯类耐药，对氨苄西林/舒巴坦耐药）。利用患者独特的药代动力学，在中空纤维感染模型（HFIM）中重现患者在临床实际接受的治疗方案，以追踪针对03 - 149.1的多粘菌素耐药性的出现情况。随后在HFIM中，单独以及以两药和三药联合的方式，用多粘菌素B、美罗培南和氨苄西林/舒巴坦对泛耐药的03 - 149.2菌株进行挑战。
结果
尽管达到了粘菌素稳态目标，即AUC0 - 24>60mg·h/L且Cavg>2.5mg/L，但粘菌素群体分析图谱证实了多粘菌素耐药性的临床发展。在HFIM中模拟患者的粘菌素治疗方案时，未实现杀菌效果，且在96小时时观察到多粘菌素耐药性增强。对于耐多粘菌素菌株，在HFIM中，多粘菌素B、美罗培南和氨苄西林/舒巴坦的三联组合在96小时时根除了鲍曼不动杆菌，而单一疗法和双联组合则导致细菌再生。
结论
为对抗耐多粘菌素鲍曼不动杆菌，多粘菌素B、美罗培南和氨苄西林/舒巴坦的三联组合具有很大的前景。
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