Emergence of carbapenem, beta-lactamase inhibitor and cefoxitin resistant lineages from a background of ESBL-producingKlebsiella pneumoniaeandK. quasipneumoniaehighlights different evolutionary mechanisms

AbstractKlebsiella pneumoniaeis recognised as a major threat to public health, with increasing emergence of multidrug-resistant lineages including strains resistant to all available antibiotics. We present an in-depth analysis of 178 extended-spectrum beta-lactamase (ESBL)-producingKlebsiellastrains, with a high background diversity and two dominant lineages, as well as several equally resistant lineages with less prevalence. Neither the overall resistance profile nor the virulence factors explain the prevalence of some lineages; we observe several putative hypervirulence factors across the population, including a reduced virulence plasmid, but this does not correlate with expansion of one or few highly virulent and resistant lineages. Phenotypic analysis of the profiles of resistance traits shows that the vast majority of the phenotypic resistance profiles can be explained by detailed genetic analyses. The main discrepancies are observed for beta-lactams combined with beta-lactamase inhibitors, where most, but not all, resistant strains carry a carbapenemase orampC. Complete genomes for six selected strains, including three of the 21 carbapenem-resistant ones, are reported, which give detailed insights into the early evolution of thebla-NDM-1enzyme, a carbapenemase that was first reported in 2009 and is now globally distributed. Whole-genome based high-resolution analyses of the dominant lineages suggests a very dynamic picture of gene transfer and selection, with phenotypic changes due to plasmid acquisition and chromosomal changes, and emphasize the need to monitor the bacteria at high resolution to understand the rise of high-risk clones, which cannot be explained by obvious differences in resistance profiles or virulence factors.ImportanceCarbapenem-resistant and extended-spectrum beta-lactamase (ESBL) carryingEnterobacteriaceaewere recently highlighted as critical priority fo the development of new treatments by the WHO.Klebsiella pneumoniaeis a member of theEnterobacteriaceaeand has seen a dramatic rise in clinical relevance due to its uncanny ability to accumulate multidrug-resistance plasmids. We present a detailed analysis of a set of ESBL-resistantK. pneumoniaeclinical isolates, and our high-resolution whole-genome sequence analyses highlight that acquisition of drug resistances is not a one-way street inK. pneumoniae, but a highly dynamic process of gain and loss, and that the most successful lineages in the clinic are not necessarily the most resistant or most virulent ones. Analysis of the virulence potential also shows that these strains harbour some, but not all, hallmarks of hypervirulent strains, emphasizing that it is not a clear distinction between hypervirulent and other strains, but equally in flux.