fWe describe a large hospital outbreak (93 bloodstream infections) of colistin-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates which was mirrored by increased colistin consumption. The outbreak was mostly traced to the clonal expansion of an mgrB deletion mutant of an ST512 strain that produced KPC-3.
I n Klebsiella pneumoniae bacteria, resistance to carbapenems results in 2 main mechanisms: the production of an extended spectrum β-lactamase or plasmid-borne cephalosporinase associated with a decrease in permeability of the outer membrane (especially through alteration of OmpK35 and OmpK36 porins), or the production of a carbapenemase (1,2). In France, these carbapenemases are Ambler's class A KPC enzymes; class B metallo-β-lactamases of NDM-, VIM-and, to a lesser extent, IMP-type; and Ambler's class D oxacillinases of OXA-48-like type (3,4). K. pneumoniae carbapenemase (KPC) was first identified in United States in the early 2000s (5). Since then, this carbapenemase has spread and has become endemic in several countries, including the United States, Israel, Greece, China, and Italy. It has also been sporadically described in many countries of Europe (1). The worldwide spread of KPC has been linked to the dissemination of a main clone of K. pneumoniae (sequence type [ST] 258) and a singlelocus variant (ST512) (6). In Asia (especially China), ST11, another single-locus variant of ST258, is mostly reported among bla KPC-harboring K. pneumoniae isolates (7). In addition, a recently published study, conducted by the EUSCAPE working group in 2013 in Europe, revealed that the spread of carbapenemaseproducing K. pneumoniae was driven by only a few clones (8). The most prevalent carbapenemase was KPC (45.5% [311/684 isolates]), and 72.7% (229/311) of KPC-producing K. pneumoniae (KPC-Kp) belong to the same clonal group (CG) 258, including ST258 and ST512. Whole-genome sequencing (WGS) analysis has suggested that ST258 and ST512 KPC-Kp spread out in Europe from 2 KPC-endemic countries: Greece (ST258) and Italy (ST512) (6,9-11). However, that study described the epidemiology of KPC in Europe in 2013, whereas the aim of our study was to describe the genomic characteristics of KPC isolates from a more recent period.
Background Klebsiella pneumoniae is a leading cause of intractable hospital-acquired multidrug-resistant infections and carbapenemase-producing K. pneumoniae (CPKp) are particularly feared. Most of the clinical isolates produce capsule as a major virulence factor. Recombination events at the capsule locus are frequent and responsible for capsule diversity within Klebsiella spp. Capsule diversity may also occur within clonal bacterial populations generating differences in colony aspect. However, little is known about this phenomenon of phenotypic variation in CPKp and its consequences. Results Here, we explored the genetic causes of in vitro switching from capsulated, mucoid to non-mucoid, non-capsulated phenotype in eight clinical CPKp isolates. We compared capsulated, mucoid colony variants with one of their non-capsulated, non-mucoid isogenic variant. The two colony variants were distinguished by their appearance on solid medium. Whole genome comparison was used to infer mutations causing phenotypic differences. The frequency of phenotypic switch was strain-dependent and increased along with colony development on plate. We observed, for 72 non-capsulated variants that the loss of the mucoid phenotype correlates with capsule deficiency and diverse genetic events, including transposition of insertion sequences or point mutations, affecting genes belonging to the capsule operon. Reduced or loss of capsular production was associated with various in vitro phenotypic changes, affecting susceptibility to carbapenem but not to colistin, in vitro biofilm formation and autoaggregation. Conclusions The different impact of the phenotypic variation among the eight isolates in terms of capsule content, biofilm production and carbapenem susceptibility suggested heterogeneous selective advantage for capsular loss according to the strain and the mutation. Based on our results, we believe that attention should be paid in the phenotypic characterization of CPKp clinical isolates, particularly of traits related to virulence and carbapenem resistance.
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