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.

异抗性是一种鲜为人知的耐药机制，它指的是存在不同亚群的看似同基因细菌的现象，这些亚群对特定抗生素表现出一系列敏感性。

在目前的研究中，我们鉴定出一株耐多药、碳青霉烯酶阳性的肺炎克雷伯菌 SWMUF35 菌株，该菌株被临床诊断归类为对阿米卡星敏感和对美罗培南耐药，但含有不同的表型耐药细胞亚群，并具有形成生物膜的能力. 群体分析概况 (PAP) 表明 SWMUF35 对阿米卡星和美罗培南表现出异抗性，这被认为是共同抗性肺炎克雷伯菌拉紧。双PAP、双倍杀灭试验和棋盘试验等体外实验表明，抗生素联合治疗（阿米卡星联合美罗培南）可有效对抗SWMUF35。重要的是，使用腹膜炎的体内小鼠模型，我们发现阿米卡星或美罗培南单一疗法无法挽救感染 SWMUF35 的小鼠。当单一疗法失败时，抗生素联合疗法可能是使用临床批准的抗生素的合理策略。

此外，我们的数据警告说，由于未检测到异种耐药性，抗生素药敏试验结果可能不可靠，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。