Science Bulletin xxx (xxxx) xxx

Contents lists available at ScienceDirect

Science Bulletin
journal homepage: www.elsevier.com/locate/scib

Review

‘‘Superbugs” with hypervirulence and carbapenem resistance

in Klebsiella pneumoniae: the rise of such emerging nosocomial
pathogens in China
Danni Pu a,b,c, Jiankang Zhao b,c, Kang Chang b,c, Xianxia Zhuo b,c,d, Bin Cao a,b,c,d,e,⇑
a
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
b
Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine,
National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
c
Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
d
Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing 100069, China
e
Tsinghua University-Peking University Joint Center for Life Sciences, Beijing 100084, China

a r t i c l e i n f o a b s t r a c t

Article history: Although hypervirulent Klebsiella pneumoniae (hvKP) can produce community-acquired infections that
Received 7 June 2023 are fatal in young and adult hosts, such as pyogenic liver abscess, endophthalmitis, and meningitis, it
Received in revised form 19 August 2023 has historically been susceptible to antibiotics. Carbapenem-resistant K. pneumoniae (CRKP) is usually
Accepted 26 September 2023
associated with urinary tract infections acquired in hospitals, pneumonia, septicemias, and soft tissue
Available online xxxx
infections. Outbreaks and quick spread of CRKP in hospitals have become a major challenge in public
health due to the lack of effective antibacterial treatments. In the early stages of K. pneumoniae develop-
Keywords:
ment, HvKP and CRKP first appear as distinct routes. However, the lines dividing the two pathotypes are
Klebsiella pneumonia
Hypervirulent
vanishing currently, and the advent of carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) is
Carbapenem resistant devastating as it is simultaneously multidrug-resistant, hypervirulent, and highly transmissible. Most
Prevalence CR-hvKP cases have been reported in Asian clinical settings, particularly in China. Typically, CR-hvKP
Evolution develops when hvKP or CRKP acquires plasmids that carry either the carbapenem-resistance gene or
Nosocomial infection the virulence gene. Alternatively, classic K. pneumoniae (cKP) may acquire a hybrid plasmid carrying both
genes. In this review, we provide an overview of the key antimicrobial resistance mechanisms, virulence
factors, clinical presentations, and outcomes associated with CR-hvKP infection. Additionally, we discuss
the possible evolutionary processes and prevalence of CR-hvKP in China. Given their wide occurrence,
continued surveillance and control measures of such organisms should be assigned a higher priority.
Ó 2023 Science China Press. Published by Elsevier B.V. and Science China Press. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction reported the occurrence of carbapenem-resistant Enterobacteri-

aceae strains, which frequently cause untreatable or difficult-to-
Klebsiella pneumoniae is an opportunistic bacterium that can cure infections in hospital patients because of limited treatment
cause serious organ damage and life-threatening diseases. Based options [5]. In China, carbapenem-resistant K. pneumoniae (CRKP)
on its phenotypic and genotypic features, K. pneumoniae can be cat- strains account for about 90% of clinical carbapenem-resistant
egorized into two types: classic K. pneumoniae (cKP) and hypervir- Enterobacteriaceae (CRE) infections [5]. This high prevalence of
ulent K. pneumoniae (hvKP), each of which presents unique CRKP strains in the healthcare system is expected as widespread
challenges for clinicians [1,2]. CKP commonly causes infections in antimicrobial use gives them a selective advantage. The character-
patients who are immunocompromised, have concomitant condi- istics of hvKP are different from those of cKP. Additionally, most
tions, or have a preexisting barrier breakdown (such as intravascu- reported cases of hvKp infections were contracted in the commu-
lar devices, endotracheal tubes, and surgical incisions) [3,4]. This nity. Characteristics highly suggestive of hvKp infection include
pathotype is able to pick up several components that confer antibi- the ability to infect healthy people of any age and the tendency
otic resistance. The US Centers for Disease Control and Prevention of infected patients to present with multiple infection sites and/
or develop subsequent metastatic spread (such as pyogenic liver
abscess, endophthalmitis, and meningitis) and an unusual occur-
⇑ Corresponding author.
rence for cKP [2,6]. Although patients with hvKP infections often
E-mail address: [email protected] (B. Cao).

https://doi.org/10.1016/j.scib.2023.09.040
2095-9273/Ó 2023 Science China Press. Published by Elsevier B.V. and Science China Press.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: D. Pu, J. Zhao, K. Chang et al., ‘‘Superbugs” with hypervirulence and carbapenem resistance in Klebsiella pneumoniae: the rise of
such emerging nosocomial pathogens in China, Science Bulletin, https://doi.org/10.1016/j.scib.2023.09.040
D. Pu et al. Science Bulletin xxx (xxxx) xxx

experience worse symptoms than those with cKP because the ill- Genes responsible for capsule production are located on the
ness progresses more quickly, the initial isolates of hvKp are sensi- chromosome’s capsular polysaccharides synthesis (CPS) region.
tive to antimicrobials, and the condition can be controlled quickly Multiple factors in this region can regulate capsule production,
with the use of antibiotics [6]. Recently, clinicians have encoun- including transcriptional antiterminator (rfaH) and a number of
tered an even bigger challenge due to the interaction between proteins involved in capsule biosynthesis, such as Wzi, Wza,
the virulence factors present in hvKP and the antibiotic resistance Wzc, WcaJ, and WbaP [19,20]. Additionally, high capsule produc-
determinants present in cKP. More and more K. pneumoniae strains tivity is also associated with various virulence genes, such as A
with both characteristics have been isolated recently; these strains and B genes (rcsA and rcsB) that regulate capsule synthesis,
cause the development of carbapenem-resistant hypervirulent Klebsiella virulence regulators (kvrA and kvrB), and the regulator
K. pneumoniae (CR-hvKP) and devastating clinical outcomes [7]. of mucoid phenotype A and A2 (rmpA and rmpA2) [21–23]. Previ-
CR-hvKP is a newly reported nosocomial pathogen, first and mainly ously, it was believed that HMV and CPS overproduction had sim-
described in China. This nosocomial pathogen demonstrates charac- ilar characteristics, resulting in the incorrect linking of the rmpA
teristics of both carbapenem resistance and hypervirulence and locus with the HMV phenotype [24]. Notably, not all rmpA/rmpA2
causes serious diseases in hosts and hospital outbreaks [8]. The con- genes can increase the expression of the capsule, and strains carry-
vergence of hypervirulence and carbapenem resistance is the result ing the rmpA/rmpA2 genes but lacking a hypercapsule phenotype
of multiple mechanisms. These mechanisms include the horizontal are also identified [25]. Walker et al. [26] revealed that rmpA stim-
transfer of carbapenem-resistant genes from the CRKP to the hvKP, ulates the activation of a transcriptional regulator that controls the
the acquisition of a hypervirulence plasmid carrying virulence- expression of CPS genes, including rmpD and rmpC. Inactivating
encoding genes by the CRKP, and the development of CR-hvKP from rmpA causes loss of the HMV phenotype as a result of reduced
K. pneumoniae through the uptake of a hybrid plasmid containing expression of rmpD, while a decrease in capsule synthesis is attrib-
both hypervirulence and carbapenem-resistance genes. uted to reduced expression of rmpC. Additionally, the absence of
The objective of this review was to summarize our current rmpC lowers CPS production without affecting the HMV pheno-
knowledge about this threatening and evolving pathogen. To type [27], whereas rmpD, which encodes a small membrane pro-
achieve this, we explored recent progress in research on CR- tein causing HMV phenotype, has no impact on capsule
hvKP, focusing on aspects related to the mechanisms underlying production [26], demonstrating that the development of HMV
hypervirulence and carbapenem resistance in K. pneumoniae, the and CPS are independent features. Although rmpD is functional,
molecular basis for its clinical identification, the clinical features strains with mutations in the CPS biosynthesis genes (wcaJ and
of CR-hvKP infection, as well as the epidemiology of CR-hvKP in manC) also lose HMV, indicating that some components of CPS pro-
China. Additionally, to better understand the traits of CR-hvKP, duction are required for HMV [26]. RmpD can alter Wzc-mediated
we analyzed its evolutionary processes of resistance and virulence. CPS synthesis in larger polysaccharide chains of a more consistent
length, which is a crucial component of the HMV phenotype of
hvKP [28]. Nucci et al. [29] revealed that through mutations in
2. Virulence factors of CR-hvKP
wzc, hvKP and MDR could easily evolve HMV. Recent studies have
shown that when obtaining the plasmid carrying blaKPC-2,
In this section, we discuss factors responsible for the virulence
‘‘CR-hvKP” strains quickly adapt to minimize the energy load by
of CR-hvKP and provide an overview of the various methods used
reducing CPS production and virulence through the mutation of
to distinguish between cKP strains and hvKP strains. These meth-
rfaH and wcaJ in K1 and K2 CR-hvKP, respectively [30]. Mutations
ods include capsule and hypermucoviscosity, siderophore, viru-
in wcaJ have been found in four ST23-K1 CR-hvKP, in which they
lence plasmids and ICEKp, other virulence-associated genes, and
caused little capsule synthesis, virulence decline, low fitness cost,
clinical manifestations, which are presented in Fig. 1.
and high conjugation frequency of the blaKPC-2 plasmid, highlight-
ing that reduced CPS is a potential factor facilitating hyperviru-
2.1. Capsule and hypermucoviscosity lence and carbapenem resistance [9]. Mutations in wzc occur in
ST11-KL64 CR-hvKP strains, causing HMV phenotype, which
The primary factors responsible for the hypermucoviscosity increases virulence and resistance to macrophage phagocytosis
(HMV) phenotype in K. pneumoniae are the polysaccharides in and has a negative effect on bacterial fitness. However, mutations
the outermost capsule, which contribute to its virulence [2,9]. in wcaJ result in a non-mucoid phenotype with reduced virulence
However, the thick hypercapsule can act as a physical obstacle, and resistance against macrophage phagocytosis, and CPS has a
consequently hindering the absorption of DNA and horizontal high impact on mucoid phenotypic alternations [31]. Furthermore,
transfer of genes, which partly explains why hvKP are less prone overexpression of rmpA in rmpA-low-expression cKP isolates can
than cKP to harboring antimicrobial resistant genes [10]. enhance virulence in a mouse infection experiment [32]. All the
At least 79 capsular serotypes have been identified based on studies conducted so far demonstrate that in CR-hvKP strains,
various structures and antigens and various polysaccharide com- CPS can be used as a substitute virulence marker.
ponents of the capsule [11]. The K-types occurring in hvKP isolates Regulation of most of the aforementioned genes is directed at
are fewer than those in cKP strains, with K1, K2, K5, K16, K20, K54, the CPS cluster, which may form a complex network to impact cap-
K57, and KN1 being the most prevalent K-types in hvKP [12,13]. K1 sule synthesis. However, the hypercapsule is not the sole cause of
and K2 are the most common capsular serotypes and the major HMV, and both may serve distinct functions during pathogenesis
pathogenic capsular serotypes that can cause invasive infectious [29,33]. Not all hvKP strains exhibit HMV, and some cKP strains
diseases [14]. The K1and K2 hvKP was significantly more resistant also display an HMV phenotype [34]. Further research is needed
to both intracellular and extracellular killing of neutrophils than to better understand the differences between hypercapsule and
cKP isolates [15]. The serotype is, therefore, a potential virulence HMV in hvKP, which could have implications for the identification
factor, and the capsular serotypes K1 and K2 are representative and treatment of hvKP strains.
of hvKP in general [16]. Recently, a bioconjugate vaccine against
the K1/K2 serotype was developed to treat hvKP infections [17]. 2.2. Siderophore
When CRKP began gaining the hvKP virulence plasmid, hvKP
strains are thought to have increased the variety of capsule types A crucial component needed for vital metabolic activities is the
(e.g., KL47 and KL64), which previously only appeared in cKP [18]. metal iron in bacteria. As the free Fe3+ is insoluble under physiolog-
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D. Pu et al. Science Bulletin xxx (xxxx) xxx

Fig. 1. Virulence features and carbapenem-resistance mechanisms of CR-hvKP. Virulence features (in red) of CR-hvKP include both chromosomal and plasmid-encoded
features that increase virulence. Additional factors that contribute to the pathogenesis of all Klebsiella pneumoniae (in black) include ent, fimbriae, and LPS on the surface. The
carbapenem-resistance mechanisms of CR-hvKP are shown in blue. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative
Commons Attribution 3.0 unported license (creativecommons.org/licenses/by/3.0/).

ical conditions, human hosts normally require a siderophore- this gene is common in hvKP strains and is also regarded as a
dependent iron absorption system for iron ingestion. Similarly, potential virulence factor [3]. The various iron transport systems
most bacteria, including K. pneumoniae, have this system that in K. pneumoniae are complementary as they can play a role under
absorbs iron more effectively than the host; it is a common method different microenvironmental conditions during infection.
of collecting iron to survive the host competition [16]. Small mole- The regulatory mechanism of siderophores in hvKP involves a
cules known as siderophores are produced by bacteria inside the complex interplay of iron availability, iron-responsive regulators,
cell and exported to bind iron in the environment with an incred- and two-component systems. Firstly, hvKP strains sense the envi-
ibly high affinity before being brought back into the cell to supply ronmental iron concentration and alter their production of sidero-
the bacterium with iron needed for growth. phores to change their ability to obtain iron from the host, which is
hvKP isolates can produce more siderophores than cKP isolates mostly accomplished through iron-responsive regulators. These
[35]. The hvKP isolates express four siderophores, including enter- regulators sense the iron concentration and modulate the expres-
obactin, yersiniabactin, salmochelin, and aerobactin, among which sion of genes involved in siderophore synthesis and transport.
yersiniabactin, salmochelin, and aerobactin are more common in For example, the ferric uptake regulator (Fur) acts as a repressor
hvKP than in cKP [36]. The genes required for enterobactin and of siderophore production under iron-rich conditions, while the
yersiniabactin biosynthesis are located on the chromosome in demetallating Fur allows efficient acquisition of iron and enhances
the ent cluster and ybt loci, respectively, while the biosynthesis the fitness of the pathogen under iron-poor conditions [38]. Fur-
of salmochelin and aerobactin occurs in iroBCDN and iucABCDiutA thermore, hvKP strains also use two-component systems (QseBC
clusters of virulence plasmids, respectively [37]. In hvKP isolates, and CpxAR) to regulate siderophore production and the expression
aerobactin contributes primarily to hypervirulence under experi- of other virulence genes involved in the development of biofilms,
mental conditions, constituting about 90% of the total siderophore the bacterial type VI secretion system, and type 1/3 fimbriae
synthesis. Additionally, after pneumonic and subcutaneous infec- [39,40]. More interestingly, the CpxAR system can also negatively
tion, mice infected with hvKP mutants with aerobactin deficiency regulate the expression of type 3 fimbriae by modulating cellular
displayed lower susceptibility than mice infected with hvKP iso- iron levels, further demonstrating the complex interactions among
lates deficient in enterobactin, salmochelin, or yersiniabactin [35]. virulence factors [39]. Overall, these mechanisms ensure that hvKP
Furthermore, a new iron transport gene, kfu, was discovered by strains can efficiently scavenge iron from the host environment
studying the genomic sequence of the hvKP NTUH-K2044 strain; and survive in iron-limited conditions.

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2.3. Virulence plasmids and ICEKp modeling mice [59]. However, it is likely that the virulence factors
discovered in these numerous mouse models using diverse strains
To date, research on the 224-kb virulence pLVPK from strain of hvKP are only a small portion of the genes that hvKP uses to
CG43 (K2, ST86) and plasmid pK2044 from strain NTUH-K2044 infect healthy hosts. To enhance hvKP diagnostics and find new
(K1, ST23) has been extensive [41,42]. Klebsiella pneumoniae viru- antibacterial targets, a comprehensive picture of virulence deter-
lence plasmids often carry multiple virulence factors, including minants is critically required.
HMV phenotype regulatory genes (rmpA/rmpA2), siderophore-
related gene clusters (iucABCDiutA, iroBCDN, ybtAEPQTUX, and
entABCDEFS), as well as the genes for tellurite and silver resistance 2.5. Definitions of hypervirulence in CR-hvKP
(terABCDEWXZ and silCERS). Among them, the most precise and dis-
tinctive molecular markers on virulence plasmids for identifying Numerous vital virulence factors that promote the pathogenic-
hvKP are iroB, peg-344, iucA, rmpA, and rmpA2 [43]. CRKP strains ity of CR-hvKP have been identified. Currently, the methods for
have acquired virulence plasmids and can cause devastating clini- determining the hypervirulence of CR-hvKP are almost consistent
cal outcomes [8,44]. For example, after acquiring a pK2044 viru- with the methods for determining hvKP.Some virulence traits are
lence plasmid, an ST11-CRKP (JS187) developed a dense capsule, thought to be hallmarks of hypervirulence. A clinical definition of
exhibiting carbapenem resistance and hypervirulence [30]. the hvKP-associated invasive liver abscess syndrome put forth by
Apart from virulence plasmids, a type of mobile genetic element Siu et al. [60] states that the syndrome results in a liver abscess
(MGE) called ICEKp can also spread these virulence factors with extrahepatic consequences, particularly necrotizing fasciitis,
throughout bacterial communities through horizontal gene trans- endophthalmitis, or central nervous system involvement [60].
fer in K. pneumoniae. Fourteen types of ICEKp have been reported However, defining hypervirulence purely based on clinical char-
in hvKP (ICEKp1-ICEKp14), and the yersinia high-pathogenicity acteristics can be challenging. There is an overlap of several clinical
island, on which the ybt locus gene is located, is a significant fea- symptoms, and this is made more challenging by the fact that hvKP
ture of most ICEKp [45]. Apart from ICEKp1 of NTUH-K2044, can induce nosocomial and healthcare-associated infections simi-
ICEKp10, which is similar to KPHPI208 genomic island in liver lar to cKP [61]. The FDA-approved test, the string test, for use in
abscess strain 1084, appears to be the most prevalent ICE in the clinical microbiology laboratory cannot distinguish between
CG23 hvKP [46]. The ICEKp pathogenicity island of most CC23 iso- hvKP strains and cKP strains [34], and some non-K1/K2 strains
lates contains the genes for yersiniabactin, colibactin, and microcin cause pyogenic liver abscess, endogenous endophthalmitis, and
E492 [46]. A polyketide-peptide genotoxin called colibactin causes other related conditions [62]. The hvKP strain is well defined by
typical symptoms of bacterial meningitis and severe DNA damage its virulence gene repertoire [2]. The molecular definition of hvKP
in eukaryotic cells [47]. strains is usually based on the presence of several predictive
biomarkers we mentioned above (e.g., rmpA and iucA-D). Aer-
2.4. Other virulence factors obactin is the main siderophore generated by hvKP strains and is
essential for enhancing virulence both in vitro and in vivo, indicat-
Klebsiella pneumoniae has type 1/3 fimbriae [48]. The hvKP ing that siderophore-related encoding genes, particularly iucA, are
NTUH-2044 genome has seven new fimbrial gene clusters, namely, important markers for hvKP identification [4,43]. Additionally,
kpa, kpb, kpc, kpd, kpe, kpf, and kfg, with kpc being strongly related enhanced capsule synthesis, which is mediated by rmpA or rmpA2,
to K1 serotype hvKP [49]. The small protein KP1_4563 in NTUH- also contributes to the hypervirulent phenotype [24,43]. Therefore,
K2044, which contains the DUF1471 domain, inhibits the activity a combination of markers to define hypervirulence was put for-
of type 3 fimbriae [50]. Additionally, although serotype K1 hyper- ward: rmpA or rmpA2, and/or iuc [30], and genotype, clinical fea-
mucoviscous isolates have genes for type1/3 fimbriae, they have tures, and phenotypes are considered in the current definition of
limited initial adhesion due to the hypercapsule phenotype that hvKP. For example, Liu and Guo [63] used HMV and the presence
could conceal these fimbriae [51]. of aerobactin to define hvKP. Siderophore production greater than
The virulence of K. pneumoniae is boosted by a number of outer 30 lg/ml and peg-344, iroB, iucA, rmpA, and rmpA2 can distinguish
membrane proteins (OMPs), including OmpA, murein lipoprotein hvKp from cKp strains [43]. Additionally, although impractical for
(LppA), and peptidoglycan-associated lipoprotein (Pal) [52]. Simi- the clinical microbiology laboratory, murine, but not Galleria mel-
larly, the downregulation of two important porins, OmpK35 and lonella, models are better suited for assessing the hypervirulence
OmpK36, is responsible for resistance to antibiotics and the sacri- phenotype [43,64].
fice of the bacteria [53,54]. The loss of a new porin, KpnO, can The multiple definitions mentioned above have produced a
result in increased antimicrobial resistance and reduced virulence murky picture of CR-hvKP infection prevalence, detection, and
in NTUH-K2044 [55]. However, it is yet unclear what mechanisms diagnosis. In our opinion, a comprehensive definition of hypervir-
underlie the decreased virulence caused by the absence of these ulence for CR-hvKP should incorporate hypervirulence phenotype
OMPs. in the murine sepsis model, the corresponding virulence gene
The type 6 secretion system (T6SS), a novel virulence-related genotype (e.g., rmpA and iucA), and clinical symptoms of metastatic
factor, has been discovered in hvKP strains recently [56]. Wild- infection. However, the microbiological identification of CR-hvKP
type NTUH-2044 is more virulent than Salmonella typhimurium, strains in clinical laboratories remains challenging. As more
Escherichia coli, and T6SS-null K. pneumoniae in a T6SS-dependent hvKP-specific genes are discovered, additional markers may also
way, and T6SS occurs more frequently in K. pneumoniae strains that become workable substitutes or even more precise. Therefore, sus-
cause liver abscess than in strains that colonize the intestines tained efforts are urgently needed toward establishing a unani-
[56,57], indicating that T6SS may increase the likelihood of hvKP mous definition of hypervirulence for CR-hvKP.
survival. Furthermore, it is hypothesized that T6SS plays a role in
iron import in hvKP as the genes responsible for iron absorption
mechanisms are located close to T6SS-related genes (tssD in 3. Resistance mechanism of CR-hvKP
Kp52.145) [58].
Apart from those mentioned above, some virulence factors, The evolution of CR-hvKP can be attributed to four main path-
such as moaR, mrk fimbriae, kva15 regulators, and kvgAS signaling ways, including synthesis of carbapenemase, downregulation or
systems, have undergone experimental validation in disease- deletion of outer membrane porins, activation of the efflux pump
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system, and altered biofilm components. These mechanisms are deletion of the ompK36 gene lowered the production of OMP and
briefly reviewed in this section. increased carbapenem resistance [88], showing that carbapenem
resistance may be caused by the low expression levels of
3.1. Carbapenemases for extensively drug-resistant ompK35/ompK36. However, in some studies, ompK35/ompK36 defi-
ciency appears to play a minor role in carbapenem resistance, pos-
Extended-spectrum beta-lactamases (ESBLs) are plasmid- sibly serving as a minor cooperative factor alongside ESBLs or
encoded enzymes that hydrolyze b-lactam antibiotics, and the AmpC b-lactamases overexpression [89,90]. These findings suggest
plasmid frequently encodes additional antimicrobial molecules that the regulatory network involved in carbapenem resistance
that confer resistance to cotrimoxazole, fluoroquinolones, and could be highly complex.
aminoglycosides [65]. Although carbapenem antibiotics are effec-
tive against ESBL-containing bacteria, the increased use of these 3.3. Activation of the efflux pump system
antibiotics causes a concomitant emergence of carbapenem-
resistant K. pneumoniae strains [66]. These strains typically carry Efflux of carbapenems via an efflux pump is a key resistance
carbapenemases, which can break down most b-lactam antibiotics mechanism in Enterobacteriaceae strains. Among CRE, the AcrAB-
[67]. Ambler [68] categorized carbapenemases into three classes: TolC pump, consisting of AcrA, AcrB, and TolC, is the classic
A, B, and D. All three classes of enzymes can be transferred resistance-nodulation-cell division (RND) efflux pump [91]. There
between bacteria, leading to a high prevalence of drug-resistant are various regulatory variables that control efflux pumps, includ-
strains. It is common for carbapenem-resistant K. pneumoniae ing acrR, acrD, and rarA [92–94]. Global regulators like soxS, marA,
strains to carry multiple carbapenemase resistance genes. The rob, and ramA are also crucial AcrAB-TolC regulatory elements [84].
prevalence of carbapenemase-positive CR-hvKP strains in China Remarkably, overexpression of acrAB can also reduce ompC and
is summarized in Tables S1 and S2 (online). ompF expression [84]. In K. pneumoniae, Klebsiella-specific efflux
Klebsiella pneumoniae carbapenemase (KPC), the primary class A pumps such as KpnEF and KpnGH pumps also decrease bacterial
enzyme, is the most prevalent carbapenemase worldwide [69]. susceptibility, giving the bacterium time to adjust to its surround-
There are numerous subtypes of KPCs, ranging from KPC-2 to ings [95]. In a 2021 study, a total of 11 CRKP strains causing UTIs,
KPC-157 [70]. When hvKP acquires blaKPC-harboring plasmids, it which are often linked to invasive infections associated with hvKP,
can develop into CR-hvKP with traits that increase both virulence exhibited ramA overexpression and acrB upregulation [96]. Among
and resistance to carbapenem. In China, a remarkable number of these strains, ST11-KL64, the predominant type of CR-hvKP, was
KPC-positive CR-hvKP isolates have been reported since 2010, the most prevalent (5/17) [96]. This suggests that the overexpres-
especially among the KPC-2-producing ST11 K. pneumoniae strains sion of efflux pumps is a potential resistance mechanism in CR-
[71]. The pandemic spread of KPC-2-producing ST11 CR-hvKP hvKP. Unfortunately, the study did not evaluate their virulence
strains in China is mainly associated with horizontal transfer medi- phenotype.
ated by incompatibility group F (IncF) plasmids [72,73].
The primary class B carbapenemase enzymes, commonly
known as metallo-b-lactamases (MBLs), are imipenemase (IMP), 3.4. Altered biofilm components
Verona integron-encoded metallo-b-lactamase (VIM), and New
Delhi metallo-b-lactamases (NDM). Oxacillinases 48 (OXA-48) Biofilm, including lipopolysaccharide (LPS), flagella, and type 1
and 181 (OXA-181) are the two most common class D enzymes and 3 fimbriae, protects bacteria and helps them survive in harsh
[74]. These enzymes only partially hydrolyze carbapenem. In environments. Type 1 and type 3 fimbriae, as well as CPS, are the
China, although KPC-2 is the most predominant carbapenemase, most crucial surface structures in K. pneumoniae [48]. CRKP can
NDM-1/5/7-positive CR-hvKP has also been reported recently inhibit flagellar, fimbriae, and pili proteins in response to merope-
[32,75,76]. Additionally, several cases of OXA-232-producing nem stress, promoting biofilm formation and bacterial survival in
ST15 CR-hvKP have emerged in China, posing a challenge to infec- the presence of drugs [97]. Additionally, among 68 CRKP strains,
tion control [77]. Furthermore, China has occasionally reported the 77.9% and 22% of isolates were strong and middle biofilm produc-
occurrence of IMP-positive and VIM-positive CR-hvKP [78,79]. ers, respectively, suggesting a strong relationship between biofilm
Notably, CR-hvKP strains carrying two or more carbapenemase formation ability and CRKP [98]. Urinary CRKP strains have a
resistance genes, such as blaKPC-2 and blaNDM-1, blaKPC-2 and bla- higher ability to produce polysaccharides (78.57%) and form bio-
film (91.07%) [99]. Therefore, the enhanced biological formation
NDM-5, and blaKPC-2 and blaIMP, are increasingly common
[32,80,81]. Gene recombination, rearrangement, and the assembly ability may render some K. pneumoniae strains even more virulent
of fusion plasmids can transfer plasmids encoding these diverse and antibiotic-resistant. However, some contradictory results have
carbapenem-resistance genes, resulting in more intricate resis- also been reported. Cusumano et al. [100] found that CRKP was 91%
tance mechanisms in CR-hvKP strains [82]. less likely to form a strong biofilm, indicating a negative correla-
tion between biofilm formation and carbapenem resistance. Fang
3.2. Decreased expression or loss of outer membrane porins et al. [101] also reported that CRKP has a weaker biofilm-forming
capacity than cKP due to the absence of the mrkH gene, which reg-
The OMP is a channel on the bacterial outer membrane for ulates type 3 fimbriae.
antibiotics. Reduced or loss of OMP expression affects its size, The above complex findings suggest a correlation between
number, or electrostatic properties, hindering carbapenem entry antibiotic resistance and biofilm formation, an important virulence
and causing antibiotic resistance [83]. OMPs comprise OmpF, factor of hvKP, but the specific biofilm-related mechanisms are
OmpC, LamB, and Pho [84]. Klebsiella pneumoniae is characterized unclear. Therefore, further research is urgently required to deter-
by OmpK35, a member of the OmpF group, and OmpK36, a mem- mine the precise connection between biofilm formation and car-
ber of the OmpC group. In CRKP, decreased expression levels of bapenem resistance in K. pneumoniae.
ompK35/36 could affect antibiotic susceptibility [85]. Two CR-
hvKP strains in Hubei Province presented high resistance to car- 3.5. Additional resistance to other antibiotics
bapenems due to the development of ESBL and low expression of
ompK35/36 [86]. Huang et al. [87] detected mutations in Considering the poor prognosis associated with CR-hvKP infec-
ompK36/37 in a CR-hvKP strain [87]. Wu et al. [88] reported that tious diseases, there is an urgent need for effective antimicrobial
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agent therapies. However, additional counterpart resistance issues burden of this disease has undoubtedly grown due to the increas-
have emerged during clinical treatment. ing spread of CR-hvKP strains in hospitals.
Tigecycline, one of the few remaining treatment options for Underlying comorbidities such as diabetes mellitus and chronic
CRKP, has faced additional resistance issues since its approval in ailments are major risk factors for CR-hvKP infection [129]. Dia-
China [102]. The resistance mechanisms of CR-hvKP to tigecycline betes and age (<65 years) were also independent predictors of sep-
in China primarily involve the overexpression of genes encoding tic ocular or CNS complications [131]. Chinese patients have a
the RND efflux pumps (e.g., AcrAB and OqxAB) or the deactivation higher risk of developing K1 capsule-type liver abscesses than
of negative regulators (ramA and ramR) [103,104]. Other factors, Malay, Indian, or Caucasian patients, according to a study of
including mutated rpsJ and plasmid-borne tet(A) variant genes, also patients in Singapore [13]. However, approximately half of the
contribute to tigecycline insusceptibility [105,106]. patients in a collection of 38 instances seen in the United States
Colistin, also considered a last line of therapy for CRKP [102], were not Asian [60]. Therefore, it is still unknown if the origin
has demonstrated excellent in vitro activity against CR-hvKP and prevalence of CR-hvKP in China are due to this population’s
strains [107]. However, similar to tigecycline, acquired colistin genetic propensity for the disease or environmental variables.
resistance has emerged in Chinese CR-hvKP recently. These mech-
anisms are related to lipid A modification, including the inactiva- 4.2. Adverse clinical outcomes
tion of the MgrB protein, overexpression of the two-component
regulatory systems (PhoPQ and PmrAB) [104,106,108,109], and CR-hvKP is associated with high morbidity and mortality. Du
the acquisition of plasmid-borne mobile colistin resistance genes et al. [132] found that the mortality of CR-hvKP was up to 66.7%
(mcr), which was first recorded in China [110] but has not yet been in patients with BSI. In patients with postoperative K. pneumoniae
found in CR-hvKP. meningitis, the non-CR-hvKP (1/11) and CR-hvKP (5/9) mortality
The use of b-lactam/b-lactamase combo inhibitors, such as cef- rates were substantially different, indicating that the convergence
tazidime/avibactam, has shown high effectiveness against CR-hvKP of carbapenem resistance and hypervirulence causes high mortal-
and provides a hopeful alternative [111,112]. Despite these ity in individuals with K. pneumoniae meningitis [125]. Klebsiella
promising results, the emergence of resistance to ceftazidime/av- pneumoniae infection in patients on hemodialysis is evolving from
ibactam is a cause for concern. CR-hvKP strains can develop resis- the cKP to the CR-hvKP [133]. In oncological patients, strong
tance to ceftazidime/avibactam through various mechanisms, biofilm-producing CRKP infection, as an independent predictor of
including mutations in the blaKPC gene [108]. This underscores mortality, can significantly increase the risk of death [119]. The risk
the need for continued research and development of novel treat- of death is further increased by antimicrobial resistance; in one
ment options to combat the threat of antimicrobial resistance in group of patients infected with isolates that produce carbapene-
CR-hvKP infections. mase, the mortality rate was 100% [8]. Apart from mortality, meta-
static illness can have high morbidity. About 70% of individuals
4. Clinical impacts of CR-hvKP with ocular or CNS metastatic illness will experience long-term
neurological or visual impairment [134].
The clinical presentations of CR-hvKP are varied and intricate, The clinical situation raises many issues that are a cause for
including pyogenic liver abscesses, endophthalmitis, and meningi- concern. First, CR-hvKP outbreaks and rapid transmission in med-
tis caused by hvKP, as well as hospital-acquired urinary tract infec- ical settings present a significant challenge for infection control.
tions, pneumonia, septicemias, and soft tissue infections associated The high level of pathogenicity and resistance frequently leads to
with CRKP. Due to its high resistance and pathogenicity, it can subpar clinical results. Second, CR-hvKP appears to be able to col-
often result in poor clinical outcomes. In this section, we briefly onize the gut and respiratory tract under multiple antibiotic stres-
discussed the pathogen’s clinical characteristics, risk factors, and ses [103,135,136]. These strains pose a high risk of disseminating
adverse consequences. and have the potential to cause severe infection.

4.1. Clinical features and risk factors 5. Mechanisms of the convergence of hypervirulence and
carbapenem resistance
CR-hvKP usually causes healthcare-associated diseases with
unique virulence and is, therefore, associated with high morbidity The formation of CR-hvKP is the result of the ongoing evolution
and mortality. The infamous ST11 CR-hvKP isolated in China was of plasmids containing genes for carbapenem resistance or hyper-
generally disseminated prior to initial reporting and led five virulence [8], which is a cause for concern. This superbug can not
infected individuals to develop deadly ventilator-associated pneu- only cause infections that do not respond to antibiotics but also
monia [8]. Since then, a growing number of nosocomial outbreaks exacerbate the severity of the disease. This evolutionary process
of CR-hvKP have been reported [113–117]. Additionally, there have can occur through three evolutionary paths: K1/K2 hvKP strains
been many reports of patients with liver abscesses [117,118], sev- acquiring carbapenem-resistance plasmids [9], CRKP strains
ere pneumonia [108,119,120], urinary tract infections (UTIs) acquiring virulence plasmids [8], or a combination of carbapenem
[96,103,121], bloodstream infection (BSI) and sepsis resistance and virulence on a single plasmid transmitted by hvKP
[103,104,122,123], meningitis [87,124,125], and skin and soft tis- or CRKP strains [132,137]. In this section, as well as in Fig. 3, we
sue infection [126,127]. CR-hvKP has been less frequently linked reviewed available mechanism-related studies, excluding case
to the seeding of other pelvic and abdominal organs, including reports (Table S1 online), conducted in China. We dissected and
the kidneys [60], spleen [117], prostate, and scrotum [128]. expanded on three fundamental plasmids-related mechanisms
Recently, there was a report of a patient who died of rare acute underpinning the co-occurrence of carbapenem resistance and
purulent pericarditis caused by ST11-KL64 CR-hvKP [129]. In hypervirulence phenotypes.
Argentina, the most common infection sites of hypermucoviscous
CRKP are the urinary and respiratory tracts (34.2%) [130]. Overall, 5.1. Acquisition of virulence plasmids by CRKP
the presentations of CR-hvKP (depicted in Fig. 2) are diverse and
complex, which can simultaneously generate the clinical signs The acquisition of virulence plasmids is a crucial mechanism
and symptoms of both CRKP and hvKP. At the same time, the total underlying the increased virulence of CRKP, which is the most
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D. Pu et al. Science Bulletin xxx (xxxx) xxx

Fig. 2. CR-hvKP infection sites. Common sites of primary and metastatic infections caused by CR-hvKP. (Created with BioRender.com).

prevalent among the three mechanisms. The most well-known vir- in infection models involving human lung epithelial cells and G.
ulence plasmids are the 224-kb plasmid pK2044 from K. pneumo- mellonella [18]. Thus, the method by which the virulence plasmid
niae NTUH-K2044 and the 219-kb plasmid pLVPK from is transmitted from hvKP strains to CRKP strains is a point for dis-
K. pneumoniae CG43, on which the virulence-associated loci and cussion. Dong et al. [109] found the presence of homologous
genes are highly conservatively arranged [2]. Such virulence plas- regions between the virulence plasmid and the KPC-2-bearing con-
mids are nonconjugative and absent from cKP due to the lack of jugative MDR plasmid in three ST11 CR-hvKP strains, suggesting
a complete conjugative module comprising tra genes [138]. How- that the nonconjugative virulence plasmid might be transferred
ever, CRKPs acquiring pLVPK-like virulence plasmids have been from hvKP to ST11 CRKP by the co-integrated transfer of these
frequently reported in recent years. Among all the Chinese hyper- two. This can be explained by the fact that the virulence plasmids
virulent and carbapenem-resistant K. pneumoniae, ST11 CR-hvKP themselves cannot spread but are frequently mobilized to access
predominates. Notably, ST11-KL64 gradually displaced ST11- other hosts with the help of other ICEs or conjugative resistance
KL47 as the major subclone prior to 2015 [139]. There were several plasmids that encode the conjugation transfer complexes in the
plasmids with modest fitness costs in the ST11-KL64 CRKP lineages same host cell [141]. Recently, Xu et al. [142] demonstrated that
[140]. Once these CRKP lines acquire the pLVPK-like virulence plas- with the help of conjugative IncF plasmid, pLVPK-like nonconjuga-
mids, they can quickly spread and cause an outbreak in a hospital tive virulence plasmid from hvKP strains can be transferred to ST11
[18]. This study also shows that ST11-KL64 CR-hvKP exhibits sim- CRKP strains in various complex forms, including transferring
ilar traits to hvKP strains K1 and K2 in terms of mucus thickness, alone, co-transferring with IncF plasmid, and transferring in the
siderophore production, and biofilm formation when compared. form of a hybrid plasmid with IncF plasmid. The type IV secretion
Additionally, the hypervirulence of ST11-KL64 hvKP was confirmed system (T4SS) is an important element for the helper plasmid, and

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D. Pu et al. Science Bulletin xxx (xxxx) xxx

Fig. 3. Proposed mechanisms for the convergence of hypervirulence and carbapenem resistance. (a) Mechanisms of formation of CR-hvKP with the help of conjunctive
resistance plasmid (usually IncF plasmid) and further proposed model of the mobilization of virulence plasmid to Klebsiella pneumoniae and Escherichia coli. (b) Transmission
of nonconjugative virulence/resistance plasmids mediated by a self-transferable IncN3 plasmid. (c) Formation of CR-hvKP through Outer membrane vesicles (OMVs)-
mediated horizontal transfer.

the helper plasmid can also use the oriT of the mobilized virulence remain unchanged, and the competition ability within and
plasmid to complete the mobilization [142,143]. Additionally, high between species enhances even further [8,71,139,149]. However,
extracellular polysaccharide production in K. pneumoniae could most CR-hvKP isolates are not hypercapsule-positive, which is an
limit the transfer of virulence plasmids, and E. coli could act as important virulence factor in CR-hvKP [30,31]. The convergence
an intermediate vector to facilitate this transfer process [142]. of carbapenem resistance and hypervirulence results from the evo-
Wang et al. [144] reported that coexisting nonconjugative viru- lution of the capsule [9]. Therefore, these CR-hvKP may not be as
lence/resistance plasmids can also be mobilized by the IncN3 con- virulent as was initially believed after the loss of the hypercapsule.
jugative plasmid, either directly or via an intermediary E. coli in
two ways: a hybrid plasmid fused with IncN3 or a cotransfer with 5.2. HvKP strains with acquired carbapenem-resistance plasmids
the assistance plasmid, IncN3. Furthermore, Wyres et al. [10]
demonstrated that multidrug-resistant bacteria are more inclined The development of CR-hvKP can be caused by the horizontal
than hypervirulent strains to create a range of surface polysaccha- transfer of plasmids, transposons, phages, and insertion elements
ride sites through chromosomal recombination and acquire viru- carrying mobile carbapenem-resistance genes from CRKP to hvKP
lence plasmids [10]. Outer membrane vesicles (OMVs) play a strains. Klebsiella pneumoniae can transfer a resistance plasmid to
significant role in the transmission of bacterial virulence factors, sensitive Enterobacteriaceae through OMVs [150]. Another study
leading to inflammation and damage during K. pneumoniae infec- demonstrated that OMVs derived from CRKP can carry and deliver
tions [145,146]. More importantly, K. pneumoniae may develop blaNDM-1 to other K. pneumoniae strains, such as hvKP [151], which
CR-hvKP because of the coexistence of virulence and enriches our understanding of the formation mechanism of CR-
carbapenem-resistance genes due to OMVs-mediated horizontal hvKP. The regional distribution characteristics of carbapenemases
transfer of the virulence plasmid phvK2115 [147]. When hvKP- indicate that similar regional characteristics can also be seen in
OMVs carrying virulence genes are transferred to ESBL-producing the carbapenem-resistance phenotype acquired by hvKP [156]. In
cKP, the transformed strains display high virulence and China, for example, KPC is the most prevalent carbapenemase,
multidrug-resistant characteristics [148]. These findings indicate and KPC-positive CR-hvKP strains are also frequently reported
that OMVs-mediated horizontal transfer may serve as a pivotal [152]. After obtaining virulence plasmids carrying the blaKPC-2 gene
mechanism contributing to the formation of CR-hvKP. or a movable DNA fragment carrying blaKPC-2, five K1 hvKP strains
The pLVPK/pLVPK-like virulence plasmid acquisition can dra- transformed into K1 CR-hvKP [153]. Yan et al. [154] isolated an
matically increase the pathogenicity of CRKP, but survival rates ST23-K1 CR-hvKP strain ZJ27003 from the sputum of an elderly
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D. Pu et al. Science Bulletin xxx (xxxx) xxx

patient with COPD. This strain contains an IncP1 plasmid, and a gene blaKPC-2, in an ST11-KL64 CRKP strain in China [137].
p27003_KPC, carrying blaKPC-2, which can be transferred to Pseu- This plasmid harbored multiple IS26 sequences that regulated
domonas aeruginosa PAO1, rendering the receptor resistant to car- the recombination of the fragments carrying blaKPC-2 and virulence
bapenem. A KPC-2-mediated carbapenem-resistant ST36 hvKP genes, as well as the reversal of the large sequence fragment [137].
clinical isolate was described by Feng et al. [155]. Similarly, Liu As a result, the formation of hybrid plasmids is accomplished
et al. [81] presented an NDM-1 and KPC-2 coproducing ST86-K2 through recombination between gene fragments that contain
CR-hvKP strain containing four plasmids. Apart from an IncHI1/ insertion elements. Recently, Xu et al. [142] identified the mecha-
IncFIB virulence plasmid that is identical to pLVPK, the strain also nisms for the formation of hybrid plasmids, by which two single-
acquired two carbapenemase-producing plasmids, including a bla- chain segments change at unique fusion sites or undergo homolo-
NDM-1-carrying IncN plasmid and an IncFIIK plasmid carrying KPC-2 gous recombination.
[127]. Notably, a study reported a tigecycline-resistant and IMP-4 Apart from the acquisition of virulence plasmids, the integra-
carbapenemase-producing CR-hvKP isolate, XH210, recovered tion of these plasmids into bacterial chromosomes can also occur,
from human blood[156]. The ST17-K38 serotype and the conjuga- leading to the evolution of highly virulent strains. The integration
tive resistance plasmid pXH210-IMP with the blaIMP-4 gene were process involves the insertion of plasmid DNA into the chromo-
used to identify this CR-hvKP strain. Furthermore, strain XH210 some and can be mediated by various MGEs. This integration can
exhibited a hypervirulent phenotype in the G. mellonella and result in the acquisition of new genetic material and the evolution
mouse infection models but lacked the distinctive characteristics of new phenotypes that may confer a selective advantage to the
often linked with hypervirulence. This study highlighted the bacteria. Recent studies have shed light on the mechanisms
urgent need to increase active surveillance of CR-hvKP strains involved in the integration of virulence plasmids into bacterial
and identify possibly hypervirulent isolates more accurately [156]. chromosomes. In 2021, whole-genome sequencing of two hvKP
These investigations provide examples of how hvKP clones strains revealed that hypervirulence genes, such as iroBCDN,
acquired resistance plasmids that were later shown to be conjuga- iucABCDiutA, rmpA/rmpA2, and peg-344, were all put into specific
tive. It appears that hvKP strains are more prone to acquiring resis- areas of the chromosome [164]. Furthermore, a recent study by
tance genes than CRKP strains acquiring nonconjugative virulence Tang et al. [165] in 2023 found that in a CR-hvKP strain, the classic
plasmids. However, evidence suggests the opposite. Several out- virulence genes were located on a novel T4SS type ICE embedded
breaks of infection caused by CR-hvKP strains, particularly ST11- within the chromosomes. This highlights the diversity of mecha-
CR-hvKP, have been documented in a number of Chinese hospitals nisms involved in the integration of virulence plasmids into bacte-
[8,116]. In contrast, CR-hvKP infections seem to result in fewer rial chromosomes and emphasizes the importance of
hospital outbreaks and are reported less frequently, particularly understanding the molecular mechanisms underlying these pro-
in China. Numerous factors are possibly to blame for bacteria’s sur- cesses. The integration of virulence plasmids into bacterial chro-
vival and predominance in hospitals. Moreover, these CR-hvKP mosomes can have important consequences for public health.
strains may not be hypervirulent and carbapenem resistant, The evolved highly virulent strains can be transmitted vertically
although they have related genes. Relative to the ST11-KL64 CR- [164], leading to the emergence of new epidemics. Therefore,
hvKP strain, the K1/K2 hypervirulent lineages demonstrate a note- understanding the mechanisms involved in the integration of viru-
worthy distinction in terms of resistance determinants and antibi- lence plasmids into bacterial chromosomes is critical for develop-
otic resistance levels. The K1/K2 lineages exhibit a substantial ing effective strategies for the prevention and control of highly
reduction in the number of resistance determinants and show virulent and multidrug-resistant strains.
low-level resistance to antibiotics [18]. Tian et al. [30] showed that
the K1 type hvKP strain with HMV lacked corresponding car-
bapenem resistance initially after acquiring the resistance plasmid 6. Epidemiology and genetic backgrounds
but acquired high resistance to carbapenems when the HMV was
lost, while the mucoid phenotype was lost in the K2 type hvKP Recently, the incidence of CR-hvKP has been increasing world-
strain that had the KPC plasmid. Furthermore, such CR-hvKP wide [7]. China has been identified as the main epidemic area for
strains attenuated their virulence in mice and larvae in vivo after CR-hvKP, with the largest number of reported cases [166]. To com-
the loss of HMV [30]. Liu et al. [157] recently demonstrated that prehensively assess the epidemiology of CR-hvKP, we conducted a
ST15 CR-hvKP clinical strains with the ‘‘red, dry and rough” mor- thorough search of PubMed, Web of Science, MEDLINE, CNKI, and
photype, which was due to a G579D substitution in the BcsA pro- Wanfang database for English-language literature published
tein, were less virulent than that with typical morphologies. between January 2013 and March 2023, using the following search
strategy (‘‘hypervirulence” [All Fields] OR ‘‘hypervirulent” [All
5.3. The fusion plasmid carrying genes both for virulence and Fields]) AND (‘‘Klebsiella pneumoniae” [MeSH Terms] OR ‘‘Klebsiella
carbapenem resistance pneumoniae” [All Fields]) AND (‘‘carbapenem resistance” [All Fields]
OR ‘‘carbapenem resistant” [All Fields]). We filtered and categorized
Numerous recent investigations have found hybrid plasmids these papers in accordance with the year of isolation, province, iso-
carrying both resistance and virulence genes in K. pneumoniae lation type, carbapenem-resistance determinant, virulence determi-
strains of various sequence types, including cKP clone types, such nant, serotype, STs, and isolation number in Table S1 (online), which
as ST11, ST101, and ST147 [158,159], and hvKP clone types like will be frequently referenced throughout this section.
ST23 and ST86 [153,160]. Some of these hybrid plasmids are As shown in Tables S1 and S2 (online), the prevalence of
formed by combining conjugative resistance plasmids of the IncF CR-hvKP has been increasing since 2012 in more than half of the
family with virulence plasmids [161]. Yang et al. [162] discovered Chinese regions with significant regional variation. The highest
one such hybrid plasmid in a clinical strain of K. variicola strain and incidence was observed in the Zhejiang (553 (28.5%) of 1940 iso-
verified its capacity for self-transduction. In a different investiga- lates), Jiangsu (377 (19.4%) of 1940 isolates), and Beijing (229
tion, a clinical K. pneumoniae strain underwent homologous recom- (9.7%) of 1940 isolates), followed by Henan (188 (9.7%) of 1940 iso-
bination between a virulence plasmid and an IncFIA plasmid, lates), Shandong (114 (5.9%) of 1940 isolates), and Hebei (105
resulting in a conjugative hybrid plasmid [163]. In addition, one (5.4%) of 1940 isolates).
study identified a hybrid plasmid, pCRHV-C2244, carrying a collec- The carbapenem-resistance determinant in CR-hvKP is primar-
tion of virulence genes, including iucABCDiutA, iroBCDN, and rmpA2, ily attributed to the widespread presence of the blaKPC-2 gene, with
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D. Pu et al. Science Bulletin xxx (xxxx) xxx

a detection rate as high as 80.7% (1565/1940). The detection rates erature. Danni Pu wrote the manuscript. Bin Cao and Jiankang Zhao
of NDM, OXA, IMP, and VIM carbapenemase genes were 2.5% conceptualized and led the discussion of the review. Jiankang Zhao,
(48/1940), 1.8% (34/1940), 0.1% (2/1940), and 0% (1/1940), respec- Xianxia Zhuo, and Kang Chang described and revised the manu-
tively. Multiple carbapenem-resistance genes were detected in script critically. All authors have read and approved the
1.8% (35/1940) of the isolates, and other mechanisms were manuscript.
detected in 0.09% (17/1940) of the isolates. Carbapenem-
resistance analysis was not performed in 4.9% (96/1940) of the
CR-hvKP strains. Our epidemiological analysis, in concurrence with Appendix A. Supplementary materials
that of a previous study [71] on CR-hvKP in China, revealed that the
majority of CR-hvKP strains belonged to the ST11-KL64 type. ST11 Supplementary materials to this review can be found online at
is the most common clone of CRKP in China, with a rate of 80.7% https://doi.org/10.1016/j.scib.2023.09.040.
(1565/1940), followed by ST23 at 2.4% (46/1940) and ST15 at
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