Abstract
The treatment of multidrug-resistant Gram-negative infections is based on colistin. As result, COL-resistance (COL-R) can develop and spread. In Acinetobacter baumannii, a crucial step is to understand COL-R onset and stability, still far to be elucidated. COL-R phenotypic stability, onset modalities, and phylogenomics were investigated in a clinical A. baumannii sample showing a COL resistant (COLR) phenotype at first isolation. COL-R was confirmed by Minimum-Inhibitory-Concentrations as well as investigated by Resistance-Induction assays and Population-Analysis-Profiles (PAPs) to determine: (i) stability; (ii) inducibility; (iii) heteroresistance. Genomics was performed by Mi-Seq Whole-Genome-Sequencing, Phylogenesis, and Genomic Epidemiology by bioinformatics. COLR A. baumannii were subdivided as follows: (i) 3 A. baumannii with stable and high COL MICs defining the “homogeneous-resistant” onset phenotype; (ii) 6 A. baumannii with variable and lower COL MICs displaying a “COL-inducible” onset phenotype responsible for adaptive-resistance or a “subpopulation” onset phenotype responsible for COL-heteroresistance. COL-R stability and onset strategies were not uniquely linked to the amount of LPS and cell envelope charge. Phylogenomics categorized 3 lineages clustering stable and/or unstable COL-R phenotypes with increasing genomic complexity. Likewise, different nsSNP profiling in genes already associated with COL-R marked the stable and/or unstable COL-R phenotypes. Our investigation finds out that A. baumannii can range through unstable or stable COLR phenotypes emerging via different “onset strategies” within phylogenetic lineages displaying increasing genomic mosaicism.
Highlights
In the last twenty years, Acinetobacter baumannii has become a major threat as an important pathogen associated with nosocomial and community infections at various body sites, including the bloodstream, respiratory tract, urinary tract, surgical sites, and wounds [1], and because it poses a huge challenge in clinical settings due to its intrinsic and acquired antimicrobial resistance
The overuse and inappropriate consumption of colistin strongly correlate with the emergence of COLR A. baumannii [18]
We investigated the stability of colistin resistance (COL-R) phenotypes in A. baumannii phenotypically outlining the different onset strategies and genomically characterizing the phylogenetic lineages having different “stability and onset phenotypes”
Summary
In the last twenty years, Acinetobacter baumannii has become a major threat as an important pathogen associated with nosocomial and community infections at various body sites, including the bloodstream, respiratory tract, urinary tract, surgical sites, and wounds [1], and because it poses a huge challenge in clinical settings due to its intrinsic and acquired antimicrobial resistance. And not unexpectedly, the emergence of colistin-resistant (COLR) A. baumannii was reported worldwide [3] and it is caused by mutations or altered expression of diverse genes—mainly pmr and lpx genes [4] as well as galU [5]—or the acquisition of the plasmidic gene mcr [6]. Heteroresistance is usually defined as the presence of subpopulations with MIC values higher (variably defined as equal to or more than two- to eight-fold) than the MIC in the main population, is often associated with the previous use of the drug, and represents major trouble in clinical settings as resistant subpopulations can emerge during treatment, resulting in treatment failure. Adding to the complexity in fully understanding the COLR A. baumannii threat, there are cases where COL minimum inhibitory concentration (MIC) values vary over time for the same A. baumannii strain, ranging from values lower than the susceptibility cut-off to higher values [11] even in the absence of heteroresistant subpopulations
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