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21 January 2023

Carbapenem-Resistant Klebsiella pneumoniae: Virulence Factors, Molecular Epidemiology and Latest Updates in Treatment Options

,
and
1
Microbiology Department, Papanikolaou General Hospital, 57010 Thessaloniki, Greece
2
Microbiology Department, Agios Pavlos General Hospital, 55134 Thessaloniki, Greece
3
Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran 37541-374, Iran
*
Author to whom correspondence should be addressed.
Antibiotics2023, 12(2), 234;https://doi.org/10.3390/antibiotics12020234
This article belongs to the Special Issue Molecular Characterization of Gram-Negative Bacteria: Antimicrobial Resistance, Virulence and Epidemiology
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Abstract

Klebsiella pneumoniae is a Gram-negative opportunistic pathogen responsible for a variety of community and hospital infections. Infections caused by carbapenem-resistant K. pneumoniae (CRKP) constitute a major threat for public health and are strongly associated with high rates of mortality, especially in immunocompromised and critically ill patients. Adhesive fimbriae, capsule, lipopolysaccharide (LPS), and siderophores or iron carriers constitute the main virulence factors which contribute to the pathogenicity of K. pneumoniae. Colistin and tigecycline constitute some of the last resorts for the treatment of CRKP infections. Carbapenemase production, especially K. pneumoniae carbapenemase (KPC) and metallo-β-lactamase (MBL), constitutes the basic molecular mechanism of CRKP emergence. Knowledge of the mechanism of CRKP appearance is crucial, as it can determine the selection of the most suitable antimicrobial agent among those most recently launched. Plazomicin, eravacycline, cefiderocol, temocillin, ceftolozane–tazobactam, imipenem–cilastatin/relebactam, meropenem–vaborbactam, ceftazidime–avibactam and aztreonam–avibactam constitute potent alternatives for treating CRKP infections. The aim of the current review is to highlight the virulence factors and molecular pathogenesis of CRKP and provide recent updates on the molecular epidemiology and antimicrobial treatment options.

1. Introduction

Klebsiella pneumoniae is a non-motile Gram-negative opportunistic pathogen responsible for approximately 10% of nosocomial bacterial infections. Infections caused by carbapenem-resistant K. pneumoniae (CRKP) isolates are a major threat for public health. Such infections can increase the mortality rates of critically ill and debilitated patients hospitalised in intensive care units (ICUs) and can have a negative impact on the financial costs of their hospitalisation all over the world [1,2,3,4]. Remarkably, the mortality rate among patients with pneumonia caused by K. pneumoniae is about 50% [5]. Another major topic for public health is the effect of CRKP infections in disability-adjusted-life-years (DALYs) per 100,000 population, with a median of 11.5 in the European Union, and Greece being among the countries with the highest numbers [6]. The rate of carbapenem resistance for K. pneumoniae isolates reached 66.3% in 2020 in Greece [7]. A recent meta-analysis shows that the prevalence of CRKP colonisation ranges worldwide from 0.13 to 22% with a pooled prevalence of 5.43%, while the incidence of CRKP colonisation ranges from 2% to 73% with a pooled incidence of 22.3% [8]. CRKP isolates are usually classified as multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR), which cause even more difficulty in treating infections. According to the European Center for Disease Prevention and Control (ECDC), MDR is defined as ‘acquired non-susceptibility to at least one agent in ≥ three antimicrobial categories, XDR is defined as ‘non-susceptibility to at least one agent in all but ≤ two antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories)’ and PDR is defined as ‘non-susceptibility to all agents in all antimicrobial categories’ [9]. The molecular epidemiology of CRKP isolates is significant as it can determine potential treatment options [10].
The aim of the current review is to highlight the virulence factors and molecular pathogenesis of CRKP and provide recent updates on the molecular epidemiology and antimicrobial treatment options.

2. Genomic Pool

Despite the unclear reasons for the high frequency of infections caused by K. pneumoniae compared to other Gram-negative opportunistic bacterial pathogens, there are some suggestions comprising genetic element exchanges with human microbiome populations through DNA molecules, mobile genetic element exchanges bearing genes associated with virulence enhancers and antimicrobial resistance, inherent antimicrobial resistance, starvation tolerance and surpassing other bacterial competitors, which may explain the occurrence of this feature [11,12,13,14,15].
According to genomic investigations, the pan-genome of K. pneumoniae involves a size of about five to six Mbp bearing five to six kilogenes to be encoded. From this number of encodable genes, about seventeen hundred genes are recognized as core genes. The core genome is conserved among bacterial species of K. pneumoniae. Typically, the core genes are present in ≥95% of the members pertaining to a given species. However, the rest genomic pool includes accessory genes. In other words, the accessory genome is known as dispensable, flexible, adaptive or supplementary genome, which varies among Klebsiella spp. The accessory genes are typically present in <95% of the members pertaining to a given species [16,17,18].
Indeed, progression and development in microbial taxonomic approaches provides easier diagnostic and detective methodologies in association with epidemiological studies, public health surveillance and outbreak investigations. Due to this knowledge, effective approaches such as core genome multilocus sequence typing (cgMLST) can be recruited for new advanced techniques, including dual barcoding approach [19,20,21].
The K. pneumoniae species complex based on genomic phylogenetic structure is categorized into seven major phylogroups comprising Kp1 (K. pneumoniae subspecies pneumoniae or K. pneumoniae sensu stricto), Kp2 (K. quasipneumoniae subsp. quasipneumoniae), Kp3 (K. variicola subsp. variicola), Kp4 (K. quasipneumoniae subsp. similipneumoniae), Kp5 (K. variicola subsp. tropica), Kp6 (K. quasivariicola) and Kp7 (K. africana) [17,19]. In this regard, seven housekeeping genes including gapA, infB, mdh, pgi, phoE, rpoB and tonB are sequenced. Moreover, the K-typing or capsule typing can be achieved through wzi gene sequencing or serotyping methods [11].
So, through the MLST typing of the above seven housekeeping genes, several phylo-genetic lineages, e.g., clonal groups (CGs) and/or sequence types, exist [22].
As mentioned above, the antimicrobial-resistant and hypervirulent strains of K. pneumoniae have raised great concern worldwide. On the other hand, Klebsiella spp. are known as significant bacterial agents isolated from patients with ventilator-associated pneumonia (VAP) in ICUs. According to reported results from previous studies, 83% of hospital-acquired pneumonias are associated with VAP [5,23].
Although ß-lactam antimicrobials are known as the first choice for treatment of infections caused by K. pneumoniae, the number of ß-lactamase and especially carbapenemase-producing strains considerably increases. Due to this knowledge, the dissemination of ST258 CRKP is a global concern, as ST258 strains are not completely sensitive towards a wide range of antimicrobials comprising aminoglycosides, fluoroquinolones, etc. [24,25,26,27,28,29,30].
In accordance with the latest studies, the clonal complex (CC) of CC258 is known as the main CRKP comprising ST11, ST258, ST340, ST437 and ST512. Moreover, there are a wide range of MDR clonal groups (CGs), e.g., CG101, CG490, CG147, CG307, CG152, CG14/15, CG231, CG43, CG17/20, CG37 and CG29, which are distributed around the world [31,32,33,34].
According to recorded reports, about 7.5% of STs (or >115 STs) pertaining to CPKP strains have been recognized in different global geographical regions. In addition, CG258 is thepredominant global CPKP strain with 43 ST members. Among them, ST258, ST11, ST340, ST437 and ST512 are the most predominant members of CG258 worldwide. ST11 ranks first in America (Latin) and Asia, while ST258 are the predominant CRKP strains in America (Latin and North) and some European countries. The ST340 has been reported in Greece and Brazil, and ST512 has been identified in Israel, Italy and Colombia [35].
The latest studies depict ≥1452 STs associated with K. pneumoniae, in which 1119 STs are recognized as known strains while the remaining 333 are detected as novel STs. In addition to CG258, CG15 and ST307 carry a huge range of antimicrobial resistance genes that are globally disseminated and are associated with healthcare infectious diseases and nosocomial outbreaks [22].

3. Virulence Factors and Molecular Pathogenesis

In accordance with the latest categorization, K. pneumoniae strains are classified into two major pathotypes, including classical K. pneumoniae and hypervirulent K. pneumoniae (HVKP). Although the classical type is frequent pathogenic agent relating to hospital acquired pneumoniae (HAP), it has limited virulence capability. Furthermore, the classical pathotype easily tends to exchange mobile genetic elements such as plasmids to create MDR strains, while HVKP is recognized as a causative agent of fulminant and invasive diseases and infections in communities. In addition, the HVKP pathotype is capable of bearing plasmids of hypervirulence or carbapenem resistance [36,37,38,39]. Hence, the capability of virulence gene acquisition of CRKP is known as a major means of hypervirulent CRKP strains production [40,41]. According to the latest reports, the main portion of HVKP strains is composed of antibiotic-sensitive populations excluding ampicillin; however, in recent years the number of convergent K. pneumoniae strains is promoting. The convergent K. pneumoniae strains are recognized as MDR HVKP strains bearing aerobactin synthesis locus (iuc) and producing ESBL or carbapenemase enzymes. The convergent K. pneumoniae strains may originate either from those hypervirulent strains which obtained an MDR plasmid or from MDR strains which acquired a virulence plasmid [42].
It is necessary to mention that the identified CPKP strains may bear different genes such as blaIMP, blaKPC and blaNDM, while the blaKPC-bearing CPKP strains involve the major portion of the isolated cases from clinical samples worldwide [43,44]. As an effective example, blaKPC transmission may occur through a wide range of processes including clonal spread, plasmids and mobile small genetic elements such as transposon (e.g., Tn4401) [35]. Indeed, the Tn4401 is a Tn3-based transposon with a length of 10 Kb which is ended via two genes of Tn3 transpoase (tnpA) and Tn3 resolvase (tnpR), and two insertion se-quences of ISKpn6 and ISKpn7 [35,45]. The blaKPC is known as a plasmid-borne gene which can be carried by > 40 plasmids. These plasmids originate from different incompatibility (Inc) groups such as A/C, ColE, FIA, I2, IncFII, L/M, N, P, R, U, W and X. The blaKPC carrier plasmids bear a significant number of antimicrobial resistance genes [35,43]. Moreover, K-typing is normally recruited for HVKP categorization. Although the K1 and K2 types are mostly (~70%) belonging to HVKP and may cause invasive infections, some strains of K1 and K2 types do not pertain to HVKP types [5,46,47,48]. K1, K2, K16, K28, K57 and K63 capsule types are recognized among HVKP strains. The typical phenotypic characteristic of K1 and K2 types is the hypermucoviscous exhibition which can be recognized through a viscous string with a length of more than 5 mm on medium agar [5,49].
Indeed, the integrative conjugal elements and giant plasmids are the effective genetic elements which support the high virulence characteristics in HVKP strains [50,51,52]. K. pneumoniae encompasses four important and effective virulence factors, e.g., adhesive fimbriae (including type 1 type 3 fimbriae), capsule, lipopolysaccharide (LPS) and siderophores [5,23,53,54,55].
Adhesive fimbriae: K. pneumoniae is armed with two important types of fimbriae including type 1 (encoded by fimBEAICDFGH operon) and type 3 (mrkABCDF/mrkABCDEF) fimbriae, which are involved in pathogenesis of the bacteria through attachment to the biotic (human host urothelium) and abiotic (urinary catheter) surfaces to start the process of colonisation, biofilm formation and bacterial invasion (Figure 1) [14,18,56].
Figure 1. Virulence factors in classical/hypervirulent strains of K. pneumoniae [57]. Two types of fimbriae are involved in pathogenesis of the bacteria through attachment to the biotic (human host urothelium) and abiotic (urinary catheter) surfaces to start the process of colonisation, biofilm formation and bacterial invasion. The polysaccharide capsule in K. pneumoniae is known as a pivotal virulence factor which acts as the outermost layer in a bacterial cell and interacts with the host. Lipopolysaccharide (LPS) is an effective protective structure against serum complement proteins in parallel with the presence of capsule.
Capsule: The polysaccharide capsule in K. pneumoniae is known as a pivotal virulence factor which acts as the outermost layer in a bacterial cell and interacts with the host (Figure 1). All types of this acidic polysaccharide capsule are the product of Wzx/Wzy-dependent polymerization pathway encoding by the cps gene cluster. The virulence factor of the capsule covers the K. pneumoniae bacterial cells against the host immune system responses such as phagocytosis, complement proteins, opsonophagocytosis, oxidative killing and antimicrobial peptides. In another word, the encapsulated bacterial cells of K. pneumoniae are capable of evading the host’s immune system through their capsule antigens mimicking the host glycans to survive [27,49,54,55,58,59]. As aforementioned, the K-antigen belonging to K. pneumoniae capsule is an effective criterion for classification and serotyping of the pathogenic strain of K. pneumoniae. Indeed, sequencing of six genes comprising galF, orf2 (cpsACP), wzi, wza, wzb and wzc located at the 5′ end of the cps gene cluster has shown that these genes are highly conserved, while the mid zone of the cps loci encompasses a variable region of nucleotide sequences producing proteins which participate in assembly and polymerization of capsule blocks. Due to this fact, the K-typing method is considered an effective categorization technique. Up to now, >80 serotypes are recognized among pathogenic strains of K. pneumoniae according to K-antigen capsule [49,55,58,60,61]. However, up to 70% of K. pneumoniae isolated bacterial cells are able to produce a novel capsule or not capable to express any capsule. Hence, this portion of K. pneumoniae strains are not typeable through serological methods. Instead, through the contribution of molecular techniques and sequencing technologies, we are able today to investigate the capsule synthesis loci or K-loci belonging to more than 2500 whole genomes of K. pneumoniae. The recorded results from previous investigations show 134 distinct K-loci encoding minimally 134 different K-types which can be effective in epidemiological studies in association with K. pneumoniae [62]. Capsule is involved in bacterial biofilm formation; the results reported from previous studies depict that unencapsulated strains of K. pneumoniae are highly sensitive to host immune responses. Furthermore, the unencapsulated strains of K. pneumoniae show reduction in their pathogenicity in mice models [23,54].
The gene clusters encoding capsule are located on chromosome or plasmids. In this regard, the wzy-K1, wzx, wzc, wza, wzb, wzi, gnd, wca, cpsA, cpsB, cpsG and galF encode exopolysaccharide portion of capsule and are located on chromosome (wza, wzb, wzc, gnd, wca, cpsA, cpsB, cpsG and galF constitute the cps chromosomal operon gene), while the rmpA, rmpB and rmpA2 genes involved in capsule biosynthesis are locatedon both chromosome and plasmid. Moreover, the genes of kvrA, kvrB, rcsA, rcsB, c-rmpA and c-rmpA2 contribute to capsule biosynthesis and are situated on chromosome. Finally, the genes of p-rmpA and p-rmpA2, which participate in capsule biosynthesis, are plasmid-borne. C-rmpA, c-rmpA2, p-rmpA and p-rmpA2 and wzy-K1 positively regulate the process of hypercapsulation through affecting the transcripts producing via cps chromosomal operon gene. KvrA, kvrB and rcsB genes regulate the capsule production through controlling effect on rmpA promoter. Indeed, rmpA and rmpA2 regulate the mucoidal property in K. pneumoniae [54].
Lipopolysaccharide (LPS): LPS is a Gram-negative bacterial endotoxin which is composed of lipid A, O-antigen and an oligosaccharide core. Each constructive part of LPS is respectively encoded by lpx, wbb and waa gene clusters. LPS is an effective protective structure against serum complement proteins in parallel with the presence of capsule (Figure 1). LPS is also a bacterial protector in opposition to the human host humoral immune system. Furthermore, LPS is known as an important inducer biomolecule for toll-like receptor 4 (TLR4), which may activate the expression and secretion of different cytokines and interleukins [23,54,63,64,65,66,67].
Siderophores or iron carriers: The pivotal role of iron related to virulence and pathogenesis of pathogenic microorganisms has been detected. In this regard, there are effective interactions between the iron metabolism and immune cells which affect the pathogenesis of microbial agents (Figure 1) [68,69,70]. Iron molecules are recognized as competitive resources for pathogenic bacteria, e.g., K. pneumoniae survival within their host during a successful infection. Therefore, acquiring and recruiting host iron metals by the pathogenic bacteria is an effective strategy to survive and establish infection within the host in the presence of immune cells, e.g., macrophages (MΦs and neutrophils) and molecules. Indeed, as a first line defensive mechanism in a healthy human host immune system, the iron molecules are normally not free within the plasma. To protect the host from the virulence of pathogenic bacterial cells of K. pneumoniae, the iron metals are linked to iron transporters of transferrins and iron-binding immunoglycoproteins of lactoferrins [23,68,70,71,72,73].
Iron as an essential element is necessary for both human and microbial pathogens. Iron contributes to different biological features including DNA biosynthesis or replication, transcription, production of energy within mitochondria, central metabolism and enzymatic reactions [73,74]. Hence, the human host body has iron-chelating proteins to bind the iron metals while the pathogens encompass siderophores or iron carriers which bind to iron metal with high affinity. Interestingly, bacterial iron binding proteins are effective competitors to human host iron-chelating proteins. Some bacterial pathogens such as K. pneumoniae possess stealth iron carriers. Up to now, several iron scavengers known as siderophores have been recognized among Gram-negative microbial pathogens including enterobactin, aerobactin, yersinobactin, salmochelin, etc., with different levels of affinity for iron molecules. However, K. pneumoniae is able to recruit these four iron carriers. According to previous reported results, enterobactin as a highly conserved iron scavenger is the most common siderophore secreted by ~90% of isolated Enterobacterales members. Among the aforementioned iron carriers, enterobactin (encoded by entABCDEF gene cluster upon the chromosome and transported via fepABCDG) has the strongest affinity for iron molecules [54,73,75,76,77,78].

4. Mechanisms of Antimicrobial Resistance

K. pneumoniae isolates present resistance to antimicrobial agents through one or more of the following mechanisms:
(a)
production of specified enzymes (e.g., β-lactamases or aminoglycoside modifying enzymes) [79,80].
(b)
decreased cell permeability through loss of Omps [81].
(c)
overexpression of efflux pumps, which are transmembrane proteins, with the antimicrobial agent being usually excreted out of the bacterial cell through an energy-consuming process. For example, an efflux pump called KpnGH contributes to antimicrobial resistance in K. pneumoniae [82].
(d)
modification of the target of the antimicrobial agent [83].

4.1. B-Lactams—Ambler Classification of β-Lactamases

B-lactam antimicrobials contain a β-lactam ring in their chemical structure. In this group, the following antimicrobials are classified: (a) penicillin and its derivatives (semisynthetic penicillins), (b) cephalosporins and cephamycins, (c) monobactams and (d) carbapenems (imipenem, meropenem, ertapenem and doripenem). B-lactamases are enzymes that hydrolyse the β-lactam ring, inhibiting the action of these antimicrobials [84].
There are two classification schemes of β-lactamases. Initially, according to the initial functional classification system proposed by Bush, β-lactamases are classified in three major groups, based on their substrate and inhibitor profiles. These functional attributes have been associated with molecular structure in a dendrogram for those enzymes with known amino acid sequences [85].
However, the revised molecular classification proposed by Ambler is the most widely used. Based on this classification, only amino acid sequence determination could provide information upon which a molecular phylogeny could be based. According to preliminary data, β-lactamases have a polyphyletic origin. Thus, they are classified in four different classes, designated A, B, C and D [86,87].
Class A β-lactamases are serine-based enzymes. This class includes simple β-lactamases, such as sylfhydryl variable (SHV), temoneira (TEM), cefotaxime hydrolysing capabilities (CTX-M), Pseudomonas extended-resistant (PER), Guiana extended-spectrum (GES), Vietnamese extended-spectrum β-lactamase (VEB), integron-borne cephalosporinase (IBC), Serratia fonticola (SFO), Brazil extended-spectrum (BES), Belgium extended-spectrum (BEL) and Tlahuicas Indians (TLA). All these β-lactamases are inhibited both in vivo and in vitro by β-lactamase inhibitors (clavulanate, tazobactam, sulbactam). SHV and TEM can act, due to point mutations, as extended spectrum β-lactamases (ESBLs), while CTX-M is considered the newest ESBL. All the rest could act as ESBLs with milder hydrolytic capacity. ESBLs can potentially be inhibited by clavulanate, but they have an in vivo therapeutic effect only for urinary tract infections (UTIs). Inhibitor-resistant TEMs (IRTs) and inhibitor-resistant SHVs (IRSs), as well as carbapenemases called K. pneumoniae carbapenemases (KPCs), are classified in this group [88,89]. KPCs are distinguished in 12 subtypes [90].
Class B β-lactamases include carbapenemases which are called metallo-β-lactamases (MBLs). Their action is based on zinc ions (Zn+2). MBLs hydrolyse all β-lactams except aztreonam, which belongs to monobactams. The most well-known MBLs detected so far are Imipenemase (IMP), Verona integron-encoded MBL (VIM), German imipenemase (GIM), Sao Paulo MBL (SPM), Seoul imipenemase (SIM), Australia imipenemase (AIM), Dutch imipenemase (DIM), New-Delhi MBL (NDM), and the recently detected Tripoli MBL (TMB) and Florence imipenemase (FIM) [91,92,93,94,95,96,97,98,99]. MBLs are classified further in three subgroups: B1, B2 and B3 [87].
Class C β-lactamases include serine-based enzymes, called cephalosporinases or AmpC β-lactamases. They are distinguished as stable and inducible, and they can be either chromosomally or plasmid-located (AmpC-like). The production of inducible AmpC depends on whether the inducer is weak or strong. They are not inhibited by β-lactamase inhibitors, and they are sensitive to cefepime and carbapenems. K. pneumoniae strains mainly transfer AmpC-like enzymes, which are considered to have been transmitted from a bacterial chromosome through plasmid conjugation. AmpC β-lactamases are distinguished in various classes [100].
Class D β-lactamases include serine-based enzymes which are called oxacillinases (OXA). These enzymes are characterized by high heterogeneity regarding their structure and their biochemical characteristics. Therefore, they display a large variety concerning their hydrolytic potential depending on the subtype they belong. They are not inhibited by β-lactamase inhibitors. Some of them act as carbapenemases with a milder hydrolytic capacity compared to carbapenemases belonging to other classes. However, they can provide a high grade of resistance when they co-exist with other resistance mechanisms [101].

4.2. Decreased Cell Permeability through Loss of Omps

The contribution of OMP deficiency is considered a secondary mechanism conferring mainly a low level of resistance itself. OmpA, OmpK35, OmpK36 and OmpK37 are the most important OMPs in K. pneumoniae strains, with a global concern [102].
OmpA alterations confer resistance to antimicrobial agents, but not to carbapenems [103]. The mutations of OmpK35 in combination with these of OmpK36 usually act as a supplementary mechanism of resistance in the emergence of CRKP isolates [104,105]. The downregulation of OmpK37 has a minor contribution to the appearance of CRKP [106].

4.3. Transport of Antimicrobial Resistance Genes

The antimicrobial resistance genes are encompassed in mobile elements such as plasmids, transposons and integrons. These elements are crucially important, as they are involved in the vertical transmission of these genes from K. pneumoniae to its descendants, as well as in the horizontal transmission of the genes from a certain K. pneumoniae strain to another.
Most plasmids are usually circular double-stranded DNA molecules, but linear plasmids are also detected. The conjugative plasmids are crucial in the transport of antimicrobial resistance genes from a specific K. pneumoniae strain to another and they encode all the appropriate factors for this transfer [107]. There is a strong correlation between specific antimicrobial resistance genes and their integration in certain plasmids. Several of them can transfer many copies of these resistance genes, providing even higher grade of resistance [108]. Transposons are small DNA fragments. They are transported from one DNA site to another but do not have the ability of self-replication. The transfer can be conducted either through transposon duplicate and transport of the copy or through cut and transfer of the whole transposon [109].
Integrons are larger genetic elements which can encompass antimicrobial resistance cassettes and are classified in five classes [110]. They can also be incorporated in other mobile genetic elements such as transposons and conjugative plasmids [111].

7. Conclusions

CRKP infections constitute a significant threat for public health. The knowledge of the exact mechanism of CRKP emergence is crucial for the selection of the most appropriate antimicrobial among those most recently launched. Plazomicin, eravacycline, cefiderocol, temocillin, ceftolozane–tazobactam, imipenem–cilastatin/relebactam, meropenem-vaborbactam, ceftazidime–avibactam and aztreonam–avibactam constitute potent alternatives for treating CRKP infections. The evolution of the molecular epidemiology of CRKP strains is dynamic and data and information around it should be continuously updated to diminish the spread of these isolates.

Author Contributions

T.K., K.T. and P.B. have equally contributed to the conception and design of the work and have approved the submitted version of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

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