Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP), a type of Klebsiella pneumoniae (KP) that exhibits hypervirulence and carbapenem resistance phenotypes, can cause severe infections, both hospital- and community-acquired infections. CR-hvKP has brought great challenges to global public health and is associated with significant morbidity and mortality. There are many mechanisms responsible for the evolution of the hypervirulence and carbapenem resistance phenotypes, such as the horizontal transfer of the plasmid carrying the carbapenem resistance gene to hypervirulent Klebsiella pneumoniae (hvKP) or carbapenemase-producing Klebsiella pneumoniae (CRKP) acquiring a hypervirulence plasmid carrying a virulence-encoding gene. Notably, KP can evolve into CR-hvKP by acquiring a hybrid plasmid carrying both the carbapenem resistance and hypervirulence genes. In this review, we summarize the evolutionary mechanisms of resistance and plasmid-borne virulence as well as the prevalence of CR-hvKP.

/pdf/epidemiological-characteristics-and-molecular-evolution-q7ovj3au.pdf

Epidemiological characteristics and molecular evolution mechanisms of carbapenem-resistant hypervirulent Klebsiella pneumoniae

To control the emergence and transmission of CRE, it is important to perform retrospective genomic investigations. It is important to evaluate the plasmid diversity, genetic environment, and evolutionary relationships of the blaNDM-positive clinical strains in the early transmission stages. ABSTRACT Incidences of nosocomial infections mediated by New Delhi metallo-β-lactamase (NDM) enzyme-producing Enterobacterales are increasing globally, resulting in a great burden to public health. The carbapenem-resistant Enterobacterales (CRE) were collected from Henan, China during 2013–2016. The blaNDM-positive strains were characterized using PCR, antimicrobial susceptibility testing, conjugation assay, S1 nuclease pulsed-field gel electrophoresis (S1-PFGE), Southern blot, whole-genome sequencing (WGS), and bioinformatics analysis. Eighty-one NDM-producing strains were identified among 391 nonduplicate CRE strains. Among them, four strains cocarried mcr and blaNDM genes, and two carried blaIMP-4 and blaNDM genes. The coexistence of blaNDM-5 and mcr-9 in Enterobacter hormaechei was found for the first time. In total, four blaNDM subtypes were identified. Among them, blaNDM-1 and blaNDM-5 were predominant. There was an obvious increasing trend in blaNDM-5 from 2013 to 2016. Thirteen different bacterial species were found among the 81 strains, and Escherichia coli was the dominant strain. blaNDM genes were located on nine different Inc-type plasmids, most of them on the IncX3 plasmids, except for the Pr-15-2-50 strain, which was located on the chromosome. We characterized two novel plasmids: the IncHI5-like plasmid carrying blaNDM-9 found in K. pneumonia, and the IncI1 blaNDM-5-positive plasmid. These findings provide the genomic basis for the widespread transmission of blaNDM and pave the way for the formulation of more effective monitoring and control methods. IMPORTANCE To control the emergence and transmission of CRE, it is important to perform retrospective genomic investigations. It is important to evaluate the plasmid diversity, genetic environment, and evolutionary relationships of the blaNDM-positive clinical strains in the early transmission stages. This study conducted an in-depth analysis of blaNDM-positive pathogens during a 4-year period using different methods for observing the high prevalence and active transmission of blaNDM-positive CRE. Moreover, we also explored the coexistence of the blaNDM and mcr, a clinically important mobile colistin resistance gene. This study shows that the prevalence of blaNDM-positive pathogens in Henan is high and the isolation rates increase each year. Moreover, plasmid-mediated horizontal transfer plays an important role in blaNDM dissemination. The co-occurrence of multiple resistance genes highlighted a long-lasting evolutionary pathway. Therefore, we have suggested the long-term continuous surveillance of clinical pathogens carrying blaNDM to learn the future transmission trend and curb the public health risk caused by CRE.

Genomic Epidemiology Insights on NDM-Producing Pathogens Revealed the Pivotal Role of Plasmids on blaNDM Transmission

The emergence of carbapenem-resistant Enterobacterales (CRE) that coexpress serine- and metallo-carbapenemases is a severe threat to the efficacy of ceftazidime-avibactam (CZA), which has been proven to be extremely effective against KPC-producing Enterobacterales strains. Our study described the cooccurrence of KPC-2, a serine β-lactamase, and IMP-4, a metallo-β-lactamase (MBL), on a conjugative hybrid plasmid from a clinical carbapenem-resistant K. quasipneumoniae strain, and it revealed an alternative route for IncHI5 plasmid to evolve by recombining with other plasmids to form a hybrid plasmid. ABSTRACT Generation of hybrid MDR plasmids accelerated the evolution and transmission of resistance genes. In this study, we characterized a blaKPC-2- and blaIMP-4-coharboring conjugative hybrid plasmid constituted of an IncHI5 plasmid-like region, an IncFII(Yp)/IncFIA plasmid-like region, and a KPN1344 chromosome-like region from a clinical ST852-KL18 Klebsiella quasipneumoniae strain. The blaIMP-4 gene was captured by a novel integron In1965, and the blaKPC-2 gene was located on a new non-Tn4401 group I NTEKPC element. Both blaKPC-2- and blaIMP-4-containing genetic architectures were distinguished from classical structures, highlighting the constant evolution of these genetic elements. IMPORTANCE The emergence of carbapenem-resistant Enterobacterales (CRE) that coexpress serine- and metallo-carbapenemases is a severe threat to the efficacy of ceftazidime-avibactam (CZA), which has been proven to be extremely effective against KPC-producing Enterobacterales strains. Our study described the cooccurrence of KPC-2, a serine β-lactamase, and IMP-4, a metallo-β-lactamase (MBL), on a conjugative hybrid plasmid from a clinical carbapenem-resistant K. quasipneumoniae strain, and it revealed an alternative route for IncHI5 plasmid to evolve by recombining with other plasmids to form a hybrid plasmid. Moreover, this hybrid plasmid can be transferred into other Klebsiella species and stably persist during passage. The propagation of two important carbapenemase genes with a new genetic background using well-evolved plasmids in the clinical setting promotes the emergence of superbugs that require careful monitoring.

Characterization of a Conjugative Hybrid Plasmid Coharboring blaKPC-2 and blaIMP-4 in a Klebsiella quasipneumoniae Clinical Isolate

Colistin was considered as the last-resort drug against severe clinical infections caused by multidrug-resistant Gram-negative pathogens. Mobile colistin resistance (mcr) genes and its variants carried by plasmids have been reported in diverse niches in recent years, and yet few studies reported carriage of mcr-10 in ECC strains of companion animal origin. ABSTRACT Mobile colistin resistance (mcr) genes mediated by plasmids have widely disseminated throughout the world. Recently, 10 mcr genes (mcr-1 to mcr-10) and a large number of variants have been identified in more than 60 countries. However, only a few instances of Enterobacter cloacae complex (ECC) bearing mcr-10 from animal origin have been reported globally. The aim of this study was to fill a knowledge gap in mcr-10-positive ECC of animal origin and analyze the potential transmission trend and different characteristics between human and companion animal isolates. The mcr-10 gene was identified on a self-transmissible plasmid in the human isolate and non-transmissible plasmids in other three animal strains. mcr-10 was adjacent to a XerC-type tyrosine recombinase-gene, and various insertion sequences were located on the downstream of core conservative structure xerC-mcr-10, thus indicating this region might be a candidate for insertions of mobile genetic elements and mcr-10 might be mobilized by IS-mediated mechanisms. Moreover, phylogenetic analysis found that mcr-10-positive isolates were mainly distributed in the clade of Enterobacter roggenkampii, exhibiting significant species specificity. These findings indicated that mcr-10 has emerged among Enterobacter spp. within humans and companion animals, highlighting that the importance of taking effective control measures to monitor the dissemination and evolution of mcr genes. IMPORTANCE Colistin was considered as the last-resort drug against severe clinical infections caused by multidrug-resistant Gram-negative pathogens. Mobile colistin resistance (mcr) genes and its variants carried by plasmids have been reported in diverse niches in recent years, and yet few studies reported carriage of mcr-10 in ECC strains of companion animal origin. How plasmid-borne mcr-10 transmitted in opportunistic pathogens and different characteristics of mcr-10-bearing strains isolated from humans and companion animals are not well understood. In this study, we discovered mcr-10-harboring strains in multidrug-resistant ECC isolates of companion animal origin for the first time and conducted a comprehensive analysis of the genetic environment of mcr-10 from multiple countries around the world, providing the potential basis for formulating control measures to slow down the spread of colistin resistance.

Emergence and Transmission of Plasmid-Mediated Mobile Colistin Resistance Gene mcr-10 in Humans and Companion Animals

It is well known that carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a more problematic public health issue due to its widespread spread worldwide. In China, ST11-type CRKP is the most prevalent CRKP, but ST15-type CRKP, a recently prevalent high-risk clone, has emerged widely throughout China, posing a serious public health risk. Therefore, we conducted an epidemiological of an outbreak of ST15 CRKP of producing CTX-M-15, KPC-2 and SHV-106 in a tertiary hospital in Anhui, China, to Understanding the potential risks of the current STT15 CRKP outbreak.From July 2021 to December 2021, 13 ST15 CRKP isolates were identified by collecting non-repeated clinical multidrug-resistant isolates, with all capsular typing of serotype KL19. All ST15 CRKP isolates were resistant to cephalosporins, carbapenems and quinolones, but were sensitive to amikacin, tigecycline and polymyxin B. In addition, isolates carried blaSHV-106 (100%), blaKPC-2 (69%), blaCTX-M-15 (69%), blaTEM-1B (69%), blaOXA-1 (62%) and blaLAP-2 (8%), as well as iron chelators (iutA, ybt, fyuA, ent, fepA, irp1, irp2, 100%) were detected. In phenotyping experiments, all ST15 CRKP exhibited lower growth rates than NTUH-K2044, and all ST15 CRKP did not exhibit mucoviscositty characteristics. However, in the Galleria mellonella infection model, isolates 21081212, 21081241 and 21091216 were more lethal than the hypervirulent isolates NTUH-K2044. Sequencing results showed that the genetic environment surrounding the genes blaSHV-106, blaKPC-2, blaCTX-M-15, blaOXA-1 and blaTEM-1B were all identical in the ST15 CRKP isolates. Phylogenetic analysis showed that 13 ST15 CRKP isolates were divided into three subgroups, and when placed in global analysis, 10 of them were highly homologous to isolates from Jiangsu, two were highly homologous to isolates from Zhejiang, and one was homologous to an isolate from an unlabelled region.Our research shows that ST15 CRKP, which carries multiple β-lactamases genes and siderophores-encoding genes, may be evolving to hypervirulence and may have spread widely in localised areas. Therefore, environmental surveillance and clinical infection control in hospitals should be strengthened to prevent further spread of ST15 CRKP. 

/pdf/epidemiology-of-carbapenem-resistant-klebsiella-pneumoniae-hdbtlmc1.pdf

Epidemiology of carbapenem-resistant Klebsiella pneumoniae ST15 of producing KPC-2, SHV-106 and CTX-M-15 in Anhui, China

Methylobacterium radiotolerans has only been identified in blood samples from end-stage renal failure or leukaemia patients in clinic. Here, we report a case of infective endocarditis (IE) caused by M. radiotolerans. 16S rRNA sequencing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used to identify the bacteria isolated from cardiac vegetation. A drug sensitivity test was conducted by disk diffusion on blood Mueller-Hinton agar. This isolate was identified as M. radiotolerans, which was susceptible to aminoglycosides and ciprofloxacin. Our findings also suggest that M. radiotolerans can cause infection in a patient with normal immune function.

First case of infective endocarditis caused by Methylobacterium radiotolerans

The emergence of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) was regarded as an emerging threat in clinical settings. Here, we investigated the prevalence of CRKP strains among inpatients in a new hospital over 1 year since its inception with various techniques, and carried out a WGS-based phylogenetic study to dissect the genomic background of these isolates. The genomes of three representative blaNDM-1-positive strains and the plasmids of four blaKPC-2-positive strains were selected for Nanopore long-read sequencing to resolve the complicated MDR structures. Thirty-five CRKP strains were identified from 193 K. pneumoniae isolates, among which 30 strains (85.7%) harbored blaKPC-2, whereas the remaining five strains (14.3%) were positive for blaNDM-1. The antimicrobial resistance profiles of blaNDM-1-positive isolates were narrower than that of blaKPC-2-positive isolates. Five isolates including two blaNDM-1-positive isolates and three blaKPC-2-positive strains could successfully transfer the carbapenem resistance phenotype by conjugation. All CRKP strains were categorized into six known multilocus sequence types, with ST11 being the most prevalent type. Phylogenetic analysis demonstrated that the clonal spread of ST11 blaKPC-2-positive isolates and local polyclonal spread of blaNDM-1-positive isolates have existed in the hospital. The blaNDM-1 gene was located on IncX3, IncFIB/IncHI1B, and IncHI5-like plasmids, of which IncFIB/IncHI1B plasmid has a novel structure. By contrast, all ST11 isolates shared the similar blaKPC-2-bearing plasmid backbone, and 11 of them possessed pLVPK-like plasmids. In addition, in silico virulome analysis, Galleria mellonella larvae infection assay, and siderophore secretion revealed the hypervirulence potential of most blaKPC-2-positive strains. Given that these isolates also had remarkable environmental adaptability, targeted measures should be implemented to prevent the grave consequences caused by hv-CRKP strains in nosocomial settings.

Deciphering the Epidemiological Characteristics and Molecular Features of blaKPC-2- or blaNDM-1-Positive Klebsiella pneumoniae Isolates in a Newly Established Hospital.

The spread of plasmid-mediated carbapenem-resistant clinical isolates is a serious threat to global health. In this study, an emerging NDM-encoding IncHI5-like plasmid from Klebsiella pneumoniae of infant patient origin was characterized, and the plasmid was compared to the available IncHI5-like plasmids to better understand the genetic composition and evolution of this emerging plasmid. Clinical isolate C39 was identified as K. pneumoniae and belonged to the ST37 and KL15 serotype. Whole genome sequencing (WGS) and analysis revealed that it harbored two plasmids, one of which was a large IncHI5-like plasmid pC39-334kb encoding a wide variety of antimicrobial resistance genes clustered in a single multidrug resistance (MDR) region. The blaNDM-1 gene was located on a ΔISAba125-blaNDM-1-bleMBL-trpF-dsbC structure. Comparative genomic analysis showed that it shared a similar backbone with four IncHI5-like plasmids and the IncHI5 plasmid pNDM-1-EC12, and these six plasmids differed from typical IncHI5 plasmids. The replication genes of IncHI5-like plasmids shared 97.06% (repHI5B) and 97.99% (repFIB-like) nucleotide identity with those of IncHI5 plasmids. Given that pNDM-1-EC12 and all IncHI5-like plasmids are closely related genetically, the occurrence of IncHI5-like plasmid is likely associated with the mutation of the replication genes of pNDM-1-EC12-like IncHI5 plasmids. All available IncHI5-like plasmids harbored 262 core genes encoding replication and maintenance functions and carried distinct MDR regions. Furthermore, 80% of them (4/5) were found in K. pneumoniae from Chinese nosocomial settings. To conclude, this study expands our knowledge of the evolution history of IncHI5-like plasmids, and more attention should be paid to track the evolution pathway of them among clinical, animal, and environmental settings.

/pdf/characterization-of-a-blandm-1-bearing-inchi5-like-plasmid-1dpyf2ceau.pdf

Characterization of a blaNDM-1-Bearing IncHI5-Like Plasmid From Klebsiella pneumoniae of Infant Origin.

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First case of infective endocarditis caused by Methylobacterium radiotolerans

Deciphering the Epidemiological Characteristics and Molecular Features of blaKPC-2- or blaNDM-1-Positive Klebsiella pneumoniae Isolates in a Newly Established Hospital.

Characterization of a blaNDM-1-Bearing IncHI5-Like Plasmid From Klebsiella pneumoniae of Infant Origin.