Carbapenem-resistant K. pneumoniae exhibiting clinically undetected amikacin and meropenem heteroresistance leads to treatment failure in a murine model of infection
Carbapenem-resistant K. pneumoniae exhibiting clinically undetected amikacin and meropenem heteroresistance leads to treatment failure in a murine model of infection
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DOI：
10.1016/j.micpath.2021.105162
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发表时间：
2021-08-30
影响因子：
3.8
通讯作者：
Zhou, Yingshun
中科院分区：
文献类型：
--
作者：
Zhang, Feiyang;Ding, Manlin;Zhou, Yingshun
异耐药是一种尚不清楚的耐药性机制，它指的是一种现象，即看似等基因的细菌的不同亚群对特定抗生素表现出一系列的敏感性。在目前的研究中，我们鉴定了一株多重耐药、碳青霉烯酶阳性的肺炎克雷伯菌SWMUF35，该菌株临床诊断为对阿米卡星敏感和美罗培南耐药，但具有不同的表型耐药细胞亚群，并具有形成生物膜的能力。种群分析结果显示，SWMUF35对阿米卡星和美罗培南均有异耐，可认为是共异耐肺炎克雷伯菌。体外双PAP、双时间杀伤、棋盘试验等实验表明，阿米卡星联合美罗培南可有效对抗SWMUF35。重要的是，通过腹膜炎小鼠体内模型，我们发现阿米卡星或美罗培南单药治疗无法挽救感染SWMUF35的小鼠。抗生素联合治疗可能是一种合理的策略，使用临床批准的抗生素，当单一治疗失败。此外，我们的数据警告说，抗生素敏感性测试结果可能不可靠，因为未检测到异耐药，这可能导致治疗失败，而检测这种表型是正确选择抗生素以支持成功治疗结果的先决条件。
Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic. In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail. Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.