The changing epidemiology of carbapenemase-producing<i>Klebsiella pneumoniae</i>in Italy: toward polyclonal evolution with emergence of high-risk lineages

Pilato, Vincenzo Di; Errico, Giulia; Monaco, Monica; Giani, Tommaso; Grosso, María Del; Antonelli, Alberto; David, Sophia; Lindh, Erika; Camilli, Romina; Aanensen, David M.; Rossolini, Gian María; Pantosti, Annalisa; Manso, Esther; Pedna, Maria Federica; Mungiguerra, M; Moscati, Presidio Ospedaliero G; Mosca, Adriana; Vailati, Francesca; Aschbacher, Richard; Imbriani, A; Sartore, P; Cittadella, Ospedale Civile di; Giraldi, Cristina; Cosenza, Azienda Ospedaliera di; Piana, Federica; Pecile, Patrizia; Careggi, Ospedale; Nittis, Rosella De; Pini, Beatrice; Manzoni, Ospedale A; Mirri, Paola; Bianchi, Emanuela; Restelli, A; Morelli, Daniela; Tumori, Istituto; Catania, Maria Rosaria; Barbaro, Anna; Bernaschi, Paola; Parisi, Gabriella; Gualdi, Paola; Dusi, Pier Andrea; Bona, Rosalba; Paolo, Ospedale S; D’Andrea, Marco Maria; Cavallo, Rossana; Lanzafame, Paolo; Sartor, Anna L.; Grandesso, Stefano; Milano, F

doi:10.1093/jac/dkaa431

Cited by 53 publications

(46 citation statements)

References 26 publications

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“…Our data also confirmed previous reports that this clade likely spread from the USA to Europe and the Middle East (26) where it dominated the resistant KP population in some countries over several years (e.g. Italy and Israel) (18,27). Notably, the ST258/512 phylogeny also suggested that there have been multiple reversion events of L3 insertions, represented by genomes lacking a particular L3 insertion amidst a clade carrying that insertion ( Figure 3B ).…”

Section: Resultssupporting

confidence: 92%

“…Several of the L3 insertion acquisition events (most notably of GD) are associated with subsequent clonal expansions. For example, the clade consisting largely of ST512 that encodes a GD insertion became highly successful as evident in the phylogeny and supported by multiple surveillance reports (18,27). Our data also confirmed previous reports that this clade likely spread from the USA to Europe and the Middle East (26) where it dominated the resistant KP population in some countries over several years (e.g.…”

Section: L3 Insertions Are Associated With Clonal Expansions In Mdr L...supporting

confidence: 90%

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Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae

David

Wong

Sanchez‐Garrido

et al. 2022

Preprint

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Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. In a murine pneumonia model, KP mutants harbouring L3 insertions have a competitive disadvantage relative to a strain expressing wild-type OmpK36 in the absence of antibiotics. This explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.

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Section: Resultssupporting

confidence: 92%

Section: L3 Insertions Are Associated With Clonal Expansions In Mdr L...supporting

confidence: 90%

Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae

David

Wong

Sanchez‐Garrido

et al. 2022

Preprint

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“…This endemicity was mostly caused by the successful clonal expansion of a K pneumoniae carbapenemase (KPC)-producing K pneumoniae clone and belonging to clonal complex 258. 5 Within the past decade, clonal complex 258 has been compounded by the emergence of additional KPC-producing K pneumoniae clones (eg, ST307 and ST101), 6 whereas CPE producing other types of carbapenemases (eg, OXA-48 and metalloβ-lactamases) have remained sporadic or at most been responsible for small outbreaks. 7 Since November 2018, however, a large outbreak of CPE-producing NDM-type carba penemases (NDM-CPE) emerged in Tuscany, Italy.…”

Section: Introductionmentioning

confidence: 99%

Resistome and virulome accretion in an NDM-1-producing ST147 sublineage of Klebsiella pneumoniae associated with an outbreak in Tuscany, Italy: a genotypic and phenotypic characterisation

et al. 2022

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Background Carbapenemase-producing Enterobacterales (CPE), particularly those producing metallo-β-lactamases, are among the most challenging antibiotic-resistant pathogens, causing outbreaks of difficult-to-treat nosocomial infections worldwide. Since November 2018, an outbreak of New Delhi metallo-β-lactamases-positive CPE (NDM-CPE) has emerged in Tuscany, Italy. In this study, we aimed to investigate the NDM-CPE associated with the outbreak and characterise the responsible Klebsiella pneumoniae clone.Methods We used whole-genome sequencing and bioinformatic analysis to characterise NDM-CPE isolates that caused bloodstream infections in 53 patients at 11 hospitals in Tuscany and that were collected between Jan 1, 2018, and July 5, 2019 (ie, the early phase of the outbreak and preceding months). The CPE isolates characterised in this study were isolated and identified at the species level and as NDM producers by six diagnostic microbiology laboratories that serve the 11 hospitals. We used comparative genomic analysis, antimicrobial susceptibility testing, plasmid conjugal transfer assays, evaluation of virulence potential in the Galleria mellonella infection model, and serum bactericidal assays to further characterise the clone causing the outbreak. FindingsThe outbreak was sustained by an ST147 K pneumoniae producing NDM-1, which had a complex resistome that mediated resistance to most antimicrobials (except cefiderocol, the aztreonam-avibactam combination, colistin, and fosfomycin). The clone belonged to a sublineage of probably recent evolution, occurred by the sequential acquisition of an integrative and conjugative element encoding the yersiniabactin siderophore, an FIB(pQil)-type multiresistance plasmid carrying bla NDM-1 , and a transferable chimeric plasmid, derived from virulence elements of hypervirulent K pneumoniae, carrying several resistance and virulence determinants. Infection of G mellonella larvae revealed a variable virulence potential. The behaviour in serum bactericidal assays was different from typical hypervirulent K pneumoniae strains, with variable grades of serum resistance apparently associated with mutations in specific chromosomal loci (csrD, pal, and ramR).Interpretation This description of a sublineage of ST147 K pneumoniae with a complex resistome and virulome that is capable of sustaining a large regional outbreak adds to existing research on the evolutionary trajectories within high-risk clones of K pneumoniae. Global surveillance programmes are warranted to track the dissemination of these lineages, and to prevent and control their spread.

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“…However, p3347689I_1 was missing the IS CR1-aph(3 ' )-VI -IS Aba125-bla NDM-1 -Δ ble- qacEΔ1-sul1 region, suggesting an acquisition event in p3347558_1 ( Figure 1B ). Finally, we note that ST395 is a globally successful lineage that usually carries bla OXA-48 and bla KPC carbapenemase encoding-genes [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

A Patient With Multiple Carbapenemase Producers Including an Unusual Citrobacter sedlakii Hosting an IncC blaNDM-1- and armA-carrying Plasmid

Moser

Keller

Campos-Madueno

et al. 2021

PAI

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Background. Patients colonized with multiple species of carbapenemase-producing Enterobacterales (CPE) are increasingly observed. This phenomenon can be due to the high local prevalence of these pathogens, the presence of important host risk factors, and the great genetic promiscuity of some carbapenemase genes. Methods. We analyzed 4 CPE (Escherichia coli, Klebsiella pneumoniae, Providencia stuartii, Citrobacter sedlakii), 1 extended-spectrum cephalosporin-resistant K. pneumoniae (ESC-R-Kp), and 1 carbapenemase-producing Acinetobacter baumannii simultaneously isolated from a patient transferred from Macedonia. Susceptibility tests were performed using a microdilution MIC system. The complete genome sequences were obtained by using both short-read and long-read whole-genome sequencing technologies. Results. All CPE presented high-level resistance to all aminoglycosides due to the expression of the armA 16S rRNA methylase. In C. sedlakii and E. coli (ST69), both the carbapenemase blaNDM-1 and armA genes were located on an identical IncC plasmid of type 1a. The K. pneumoniae (ST268) and P. stuartii carried chromosomal blaNDM-1 and blaOXA-48, respectively, while the ESC-R-Kp (ST395) harbored a plasmid-located blaCTX-M-15. In the latter 3 isolates, armA-harboring IncC plasmids similar to plasmids found in C. sedlakii and E. coli were also detected. The A. baumannii strain possessed the blaOXA-40 carbapenemase gene. Conclusions. The characterization of the genetic organization of IncC-type plasmids harbored by 3 different species from the same patient offered insights into the evolution of these broad- host-range plasmids. Moreover, we characterized here the first complete genome sequence of a carbapenemase-producing C. sedlakii strain, providing a reference for future studies on this rarely reported species.

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The changing epidemiology of carbapenemase-producingKlebsiella pneumoniaein Italy: toward polyclonal evolution with emergence of high-risk lineages

Cited by 53 publications

References 26 publications

Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae

Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae

Resistome and virulome accretion in an NDM-1-producing ST147 sublineage of Klebsiella pneumoniae associated with an outbreak in Tuscany, Italy: a genotypic and phenotypic characterisation

A Patient With Multiple Carbapenemase Producers Including an Unusual Citrobacter sedlakii Hosting an IncC blaNDM-1- and armA-carrying Plasmid

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