Hypervirulent Klebsiella pneumoniae : Epidemiology, virulence factors, and antibiotic resistance

Human infections induced by Klebsiella pneumoniae ( K. pneumoniae ) include pneumonia; urinary tract infections, liver abscesses, bacteremia, and others. The introduction and spread of the hypervirulent K. pneumoniae (hvKp) strains have raised the number of persons who are already susceptible to infections, including those who are healthy or immune-compromised. Infections can occur worldwide; however, they are particularly prevalent in the Asia-Pacific area. Virulence plasmids as well as other conjugal components contain the genetic material that gives hvKp its hypervirulence phenotype. Although the vast majority of hvKp isolates are antibiotic-susceptible, the incidence of virulent as well as resistant isolates, such as carbapenem-resistant hvKp isolates, is continuously growing. Multidrug resistance (MDR) and increased virulence of these strains may be the cause of the subsequent clinical crisis. This study aimed to review and analyse the epidemiology, the factors associated with hypervirulence, and the mechanisms of antibiotic resistance of the hvKp strains in order to provide a better understanding of the basic biology of these strains.


Introduction
The Gram-negative bacterium known as Klebsiella pneumoniae (K. pneumoniae) can impose serious community-acquired diseases, and causes major infections in the immune-compromised individuals (Paczosa and Mecsas, 2016). K. pneumoniae is receiving more attention due to the surge in infections that it causes, in addition to the significant number of strains that are resistant to antibiotic therapy. K. pneumoniae is currently considered as one of the most widespread bacterial causes of pyogenic liver abscesses, a significant clinical problem concerning K. pneumoniae appears to exist. According to the several studies conducted by the US institutions, K. pneumoniae has lately eclipsed Escherichia coli (E. coli) as the main cause of liver abscess (Shon et al., 2013). A previous study reported by Al Kaabi, (2019) that K. pneumoniae species that cause these intrusive infections are generally known as hypervirulent K. pneumoniae (hvKp); however, when grown on agar plates, they have a hypermucoviscous phenotype. This could be attributed to the overabundance of capsule polysaccharides in this bacterium. A relationship has also been discovered between the carriage of virulence plasmids and the hypervirulence phenotype (Tang et al., 2010).

Comparison between hypervirulent and classical K. pneumoniae
The ability of K. pneumoniae to acquire more genetic material is a critical characteristic that has allowed it to evolve. According to Shon et al., (2013), there are two circulating forms of K. pneumoniae: the hvKp and the classical strain of K. pneumoniae (cKp), both of which provide unique challenges to the clinicians. Throughout the past three decades, although the predominance of hvKp infections has steadily grown in the Asia Pacific Rim nations, however these pathotypes remain global bugs (Chang et al., 2012).
Despite the reality that hvKp infections are growing more widespread outside of Asia; however, cKp has long been considered as the most typical source of sickness in the Western countries (Fazili et al., 2016). All clinicians are aware that cKp is an aggressive pathogen that affects the immunecompromised patients, patients who experience a barrier breach in the healthcare settings, and who also have several comorbidities, including intravascular devices, an endotracheal tube, or a surgical wound. The hvKp is best classified as a pathogen that has high virulence (Rossi et al., 2018).
Most hvKp infections are community-acquired. The ability of hvKp to infect healthy persons of any age, as well as those infected patients in several locations and\ or later metastatic spread; all are attributed to hvKp infection, which is distinct from that of the other members of the Enterobacteriaceae. In the absence of a biliary tract illness, the most common clinical affection induced by hvKp infection is a hepatic abscess. On the other hand, hvKp can infect almost all of the body's organs. Non-hepatic abscesses; pneumonia, necrotizing fasciitis, endophthalmitis, and meningitis, are few examples of the infectious disorders (Russo and Marr, 2019).
Initially, it has been thought that hvKp strains may be more specific and sensitive to the positive string test for such a hypermucoviscous phenotype (Fang et al., 2004). Later, this has been discovered to be erroneous, because not all hvKp strains are hypermucoviscous, and some cKp strains exhibit this feature as well (Catalan-Najera et al., 2017;Russo et al., 2018).
HvKp isolates better grow and survive after being introduced into the body than the cKp isolates. Infection can not usually result from simple entering, the bacteria must be able to persist and grow in the presence of host defences. The host's state, the innate virulence of the bacterial strain, and the infecting inoculum, all collaborate to accomplish this invasion. Infection with the virulent strains is possible if its inoculum is high or when the host is injured. In contrast, hvKp has been classified as a specialized pathogen due to its pathogenicity and attacks on the healthy hosts, thus a small inoculum of this pathogen can cause a disease. The capacity of these hvKp species to withstand the bactericidal effects of antimicrobial medicines; complements, and phagocytes in the absence of antibodies is a harmful property (Pomakova et al., 2012).

Virulence
The hypermucoviscosity or hypermucoviscous phenotype of hvKp is often attributed to an increase in the capsular polysaccharide production, and the presence of specific virulence genes, such as rmpA (Paczosa and Mecsas, 2016). The 'string test' is typically used to determine the hypermucoviscosity trait. A positive string test is observed when the bacterial colonies growing on an agar plate at 37°C become stretched, and develop a mucoviscous string of > 5mm (Lee et al., 2017).
The genes implicated in virulence have been investigated as possible molecular indicators for hvKp detection (Russo et al., 2018). Peg-344 (metabolic transporter), iuc (biosynthetic genes for such siderophore aerobactin), rmpA, and rmpA2 (regulators that promote the capsule formation), are the most wellknown virulence factors with an experimental evidence for conferring the hypervirulent phenotype (Russo et al., 2015;Bulger et al., 2017).

Factors linked to hvKp hypervirulence
Many hypervirulence-related features are present in the hvKp strains, including the virulence plasmid, a pathogenicity island, sequence types, multiple virulence factors, and capsular serotypes.

KPHP1208 pathogenicity island and pLVPK virulence plasmid
Due to the importance of hvKp isolates in the human infections; especially in people without underlying a disease or an immunodeficiency, it is necessary to use an appropriate laboratory method to obtain an accurate diagnosis of these isolates.
According to Struve et al., (2015), a big virulence plasmid has been detected across all the hvKp clonal lineages, which has its entire genome being sequenced (pLVPK and pK2044-like plasmid). Aerobactin, salmochelin, and rmpA that exist only in the hvKp isolates, are encoded by this plasmid. Lin et al., (2011) observed that a CC23 clonal complex strain missing pLVPK has a considerably reduced virulence, indicating that this plasmid plays a critical function in hvKp. Through genomic research, a new pathogenicity island variation (KPHP1208) has been also discovered that is linked to CC23 clonal complex (Struve et al., 2015).

The mucoid phenotypic regulator A gene (rmpA)
The rmpA (mucoid phenotypic regulator A gene) promotes capsule synthesis, resulting in hypermucoviscosity and pathogenicity of K. pneumoniae (Lin et al., 2020). Two large plasmids carry genes (p-rmpA and p-rmpA2) that are located on the virulence plasmid (pLVPK), in addition to a third gene (c-rmpA) that is carried on the bacterial chromosome, have been discovered in hvKp strains (Hsu et al., 2011). After whole genome sequencing, about 30 hvKp strains that have been recovered from various geographic origins, are positive for rmpA (Struve et al., 2015). Numerous Chinese researchers have discovered that about 92-100 % of the tested hvKp samples are positive for rmpA (Sun et al., 2016;Wu et al., 2017). Regardless of the investigated infection site, most of the hvKp isolates appear to have the rmpA gene (Guo et al., 2016;Wu et al., 2017;Zhan et al., 2017). Although both of hvKp and rmpA have a substantial correlation; however, certain rmpApositive isolates have not shown the hypermucoviscosity phenotype (Yu et al., 2006).

The mucoviscosity-associated gene A (magA)
The magA gene has been identified to be critical for the hypercapsular phenotype in K. pneumoniae strains, which have been isolated from intrusive liver abscesses throughout 2004(Fang et al., 2004. Later, a genetic study and bioinformatic analysis have indicated that magA is indeed the serotype K1 allele (Yeh et al., 2010). MagA has been linked to the capsule serotype K1 in numerous previous studies conducted by Yeh et al., (2006);Guo et al., (2017).

Aerobactin
Hsieh et al., (2008) highlighted that in irondepleted environments; for example in a human host, K. pneumoniae can release some iron-acquiring siderophores (eg. aerobactin, enterobactin, salmochelin, and yersiniabactin). When compared with the cKp strains, hvKp strains have shown a 6 to 10fold higher action of siderophores (Russo et al., 2014). Novel Research in Microbiology Journal, 2023 Over 90 % of the examined enterobacterial isolates have produced enterobactin as a siderophore (Raymond et al., 2003). The majority of hvKp isolates contain salmochelin and aerobactin siderophores (Paczosa and Mecsas, 2016). Despite the fact that hvKp secretes four different types of siderophores; however, aerobactin remains responsible for more than 90 % of the siderophores activity (Russo et al., 2014). Furthermore, aerobactin rather than salmochelin, enterobactin, or yersiniabactin, is essential for growth and retention of the hvKp strains throughout the human ascites fluid or serum, in addition to the in-vivo mouse infection models, indicating that aerobactin is an important virulence factor of hvKp (Russo et al., 2015).

Capsular serotypes K1 and K2
Encapsulated pathogens such as K. pneumonia; use the capsule as a virulence factor. K. pneumoniae has about 78 serotypes of capsular polysaccharides as a minimum (Wyres et al., 2016). Several studies have found a link between both the K1& K2 serotypes and the hvKp (Paczosa and Mecsas, 2016;Catalán-Nájera et al., 2017).
In an in vivo mouse model, serotypes K1 and K2 of K. pneumoniae isolates have substantially more harmful impact than the non-K1/K2 isolates; with recovery rates of 0 vs. 79.2 %, respectively (Yeh et al., 2007). Despite their hypermucoviscosity, both K1 and K2 strains are much more resistant to phagocytosis and to the intracellular death induced by neutrophils and macrophages, compared with the other serotypes (Lee et al., 2014;Paczosa and Mecsas, 2016). Many characteristics have been offered to explain why the K1 and K2 strains are more virulent than the other strains. First, the K1 as well as K2 strains, lack certain mannose residue repeats, which are recognized by the host elements, including the macrophage mannosebinding receptor and the lung-secreted surfactant protein A (SP-A) (Sahly et al., 2008). Second, the surfaces of K1 & K2 strains contain host-specific monosaccharide (sialic acid), which is known to mimic the host cells and helps in avoidance of the immune cells (Lee et al., 2014). Thirdly, the K1 and K2 strains cause the neutrophils to produce fewer reactive oxygen species (ROS) compared with the other serotypes, thus allowing them to live longer in the human tissues (Paczosa and Mecsas, 2016). Fourth, compared with the other K serotype strains, the K1 and K2 strains have more diverse O serotypes, which may help the K1 and K2 viruses to evade the host immune systems (Follador et al., 2016). The non-K1 or K2 serotypes are found in some strains of hvKp (Fang et al., 2007;Shon et al., 2013). Beside the K1 and K2, the other capsular serotypes detected in hvKp, include K5, K16, K20, K28, K54, K57, K63, and KN1 (Guo et al., 2017).
A previous study reported by Yu et al., (2008) has assessed the prevalence and importance of K. pneumoniae virulence determinants in the liver abscesses; among samples with capsular K1\K2 serotypes and samples without the-K1\K2 serotypes. Results have shown that K. pneumoniae isolates with the hypermucoviscosity phenotype in addition to the existence of the rmpA, iucABCD, and iutA genes, have demonstrated significant virulence and lethality for the mouse model; irrespective of the capsular serotypes (Yu et al., 2008).
K. pneumoniae isolates of serotypes K1 and K2 have displayed considerably higher phagocytic resistance and virulence compared with the non-K1\K2 bacteria, demonstrating that the existence of the K1\K2 serotypes is responsible for the enhanced virulence. These findings imply that the presence of K1\K2 serotypes contributes to the hypervirulence of hvKp strains, and their combination with the other hypervirulence-associated characteristics may also Novel Research in Microbiology Journal, 2023 increase the K. pneumoniae virulence (Yeh et al., 2007).

The hvKp strains and creation of a biofilm
A bacterial biofilm is a clump of cells that can exist on a surface and is coated with layers of polysaccharides; proteins, and DNA. The ability of bacteria to form a biofilm increases their resistance to the host defence elements and to the antimicrobials, and is well-recognized as a key virulence trait (Thornton et al., 2012). Biofilm production has been proven to be a key factor in the closed-space infections even when there is no foreign body exists (Yamanaka et al., 2011). A slimy extracellular matrix that is made up of extracellular polymeric molecules (EPS) surrounds the adhering cells in a biofilm. The hvKp strains make much more biofilm than the cKp strains, indicating that biofilm formation may play a role in the hvKp pathogenesis (Wu et al., 2011).

Antibiotic resistance in K. pneumoniae
There are two forms of antibiotic resistance observed in K. pneumoniae. Production of extendedspectrum β-lactamases (ESBLs) is a technique that renders the bacteria resistant to cephalosporins and monobactams. The development of carbapenemases by K. pneumoniae represents a more dangerous route of antibiotic resistance, which renders this bacterium resistant to practically all known ß-lactams, including the carbapenems.

Extended-spectrum β-lactamases
K. pneumoniae resistance to ampicillin as well as to carbenicillin is attributed to the manufacture of SHV-1-β-lactamase, which is encoded on the chromosome. The development of extended-spectrum β-lactamases (ESBLs) is the primary cause of the third-generation cephalosporin resistance. Penicillins, first, second, and third-generation cephalosporins, in addition to aztreonam, are hydrolyzed mainly by these plasmid-mediated enzymes. ESBLs producing K. pneumoniae are resistant to cefoxitin and carbapenems, however they're susceptible to β-lactamase inhibitors. Resistance to cotrimoxazole, fluoroquinolones, and aminoglycosides, are among the other resistance mechanisms that are encoded by ESBLs-carrying plasmids (Hennequin and Robin, 2016).
The ESBL enzymes SHV-1 and TEM-2 genetic variants have been discovered in most ESBLproducing K. pneumonia. The widespread use of gene sequencing to locate the lactamase genes in the clinical isolates has led to the discovery of several variations of the common TEM and SHV enzymes. Recently, about 243 TEM and 228 SHV variants have been discovered; however not all of them exhibit the ESBL phenotype (Castanheira et al., 2021). In the 1990s, a new ESBL family known as the CTX-M has been introduced. The CTX-M enzymes have emerged as the most popular types of ESBL; with CTX-M-15 being the most common in K. pneumoniae (Calbo and Garau, 2015). In K. pneumoniae, the development of β-lactamase is the earliest mechanism of resistance to β-lactams, followed by the permeability changes and the efflux pump extrusion (Mejía-Zambrano, 2022).

Carbapenems
In the late 1980s, carbapenems have been introduced to the hospitals, and proved to be particularly successful in treating K. pneumoniae infections that produce ESBLs (Paterson et al., 2004). The carbapenem resistant Enterobacteriaceae (CRE) produces MBL IMP-1, which is a carbapenemhydrolyzing enzyme that is encoded on plasmids, and can be transmitted from one species to another. Verona integron-encoded metallo-β-lactamase (VIM-1) has been identified in the Enterobacteriaceae family of bacteria (Bahmani, 2019). In 1996, a carbapenemresistant K. pneumoniae strain has been discovered in the United States, and this strain has developed K. pneumoniae carbapenemase (KPC) as a new carbapenemase (Yigit et al., 2001). This plasmidencoded KPC gene is capable of efficiently hydrolyzing both the oxyimino-cephalosporins and the carbapenems. K. pneumoniae bacterium that causes KPC has spread throughout the United States and in many other countries, thus generating outbreaks and endemicity in these areas (Munoz-Price et al., 2013). OXA-48 is a new group of carbapenemases, which has appeared in the early 2000s and spreads mostly to K. pneumoniae in the Mediterranean nations; coinciding with the rise in KPC inside the United States and across the world (Mlynarcik et al., 2020).
NDM (New Delhi metallolactamase) has been detected in carbapenem-resistant K. pneumoniae as well as in E. coli in a patient who has been relocated in 2009 from India (Yong et al., 2009). Later, NDM-1 has rapidly spread throughout South Asia and the rest of the world (Nordmann et al., 2011). The most frequent cause of carbapenem resistance in Gramnegative bacteria is the production of carbapenemase. Carbapenemase synthesis usually leads to clinically substantial carbapenem resistance (Iovleva and Doi, 2017).

Antibiotic-resistant hvKp
Except for ampicillin resistance, many hvKp strains are antibiotics sensitive and resistant to the commonly used antimicrobial medications (Paczosa and Mecsas, 2016 Paczosa and Mecsas, (2016) reported that to induce infection, K. pneumoniae should overcome the mechanical barriers, in addition to the cellular and humeral innate immune systems. The mechanical mucociliary elevator, which consists of mucus covering the respiratory system that catches the particles and germs and then shuttles them up and out through the ciliary lining, represents one of the first human defences against the respiratory tract diseases. In addition, the flow of urine through the genitourinary tract exerts strong mechanical stress on K. pneumonia.

Host immune defences
Accordingly, after passing through these early mechanical hurdles, K. pneumoniae must cross the cellular and humeral inherent defences. The antimicrobial factors produced by the immune system have a variety of functions, including those that are opsonic, bactericidal, and bacteriostatic, and they make up the humeral defences. For example, the complement system is a humeral defence that can kill Novel Research in Microbiology Journal, 2023 the bacteria through a variety of methods (Merle et al., 2015). For the immunological effector cells, the proinflammatory mediators and chemo-attractants are also generated when the complement cascade becomes initiated. Some complement components can also operate as opsonins that facilitate phagocytosis through binding to the pathogens (Clegg and Murphy, 2017).
A previous study by Coya et al., (2015) added that two more humeral defences are used to prevent the bacterial infections, such as defensins, which are bactericidal proteins that exist in the lungs and destroy the bacterial membrane, in addition to transferrin, which is a bacteriostatic factor that adsorbs iron; a vital element for growth of bacteria. Both of the surfactants and immunoglobulins can operate as phagocytosis opsonins. Within the lungs, the surfactant protein A (SP-A) and allocation of the SP-B proprotein can enhance the neutrophil enrolment and K. pneumoniae killing.

Pathogenesis of infection
Acquisition, which results in bacterial colonization, is most likely the first step required for eventual endogenous hvKp infection (Shon et al., 2013). The infection rates in hvKp-colonized patients are unknown, just as the time interval between acquisition and infection. The gastrointestinal system is much more commonly colonized, whereas the oropharynx and skin are less commonly colonized (Fung et al., 2012).
According to a previous study conducted on other Enterobacteriaceae, such as E. coli and cKp, the food, water, personal transmission, and animal-to-person transmission are all plausible pathways for bacterial acquisition and subsequent colonization by these bacteria (Johnson and Russo, 2005). Although hvKp infection is most common in the ambulatory persons; however, it has been reported also in the healthcare facilities (Lee et al., 2006). Furthermore, due to the hvKp's inherent virulence; infection in patients with co-morbidities (e.g. cancer) may lead to a serious disease. As a result, contact with the healthcare workers or inanimate items within the facility may be a cause of infection by hvKp, and thus effective infection control measures should be addressed (Lin et al., 2010).
The next essential step in hvKp pathogenesis is the entry into an extra-intestinal organ or location. The cKp as well as other Enterobacteriaceae use a variety of invasive mechanisms, including bowel disruption, to allow the bacteria to colonize the gastrointestinal tract in order to invade the peritoneal cavity. In addition, macro-or micro-spiration of the oropharyngeal inhabitants to the respiratory tract, in addition to interference with the integrity of the skin barriers, are possible mechanisms of bacterial invasion and infection (Johnson and Russo, 2005). The oropharyngeal colonization and micro-or macroaspiration often cause pneumonia. Although some hvKp patients appear to have aspiration pneumonia; however this is not always the case (Lin et al., 2010).

Epidemiology and clinical diseases
Complete understanding of the frequency and scope of hvKp disease is lacking, due to the lack of an objective diagnostic tests. The lack of unambiguous genotypic\ phenotypic markers for hvKp has made it difficult to gain a thorough grasp of the diseases caused by hvKp. Although the best available laboratory-based surrogate measure is the positive "string test," which shows the hypermucoviscous phenotype; however, it is uncertain if all hvKp strains have this characteristic or not. Furthermore, this test is not performed regularly in the clinical laboratories (Wyres et al., 2016).
HvKp infections cause severe morbidity and death.
Community-acquired pneumonia with bacteremia and necrotizing fasciitis are both remarkable infections that have high fatality rates (Lin et al., 2010). Furthermore, the survivors of hvKpassociated infections in the crucial areas frequently experience severe morbidities, including visual loss and neurologic sequelae (Cheng et al., 2012).
Novel Research in Microbiology Journal, 2023

Pyogenic liver abscess (PLA)
The defining symptom that led to the diagnosis of hvKp is the primary pyogenic liver abscess (PLA), which has been observed in the ambulatory patients without biliary illness (Shon et al., 2013). HvKp is most likely hematogenously transmitted through the portal or systemic circulation. There are several reports of re-infections at the same or different sites; often by the same strain, months to even more than a year after completion of therapy, which are circumstantial but interesting and require more investigation (Fierer et al., 2011;Harada et al., 2011). HvKp also causes splenic abscesses that could be attributed to primary or secondary infections (Lee et al., 2011).

Pneumonia
Community acquired pneumonia caused by hvKp with or without primary lung abscesses, has been rarely documented. A recent study has been conducted by Hirai et al., (2020), which included a literature review has recorded only 10 reported cases of pneumonia in total; with 5 of these patients having bacteremia and 5 experiencing septic shock. About 50 % of these patient cases have unfortunately died. Among the 10 cases, 4 have had diabetes as a comorbidity. The studies in this review have been all recorded in South America, Japan, and Taiwan (Hirai et al., 2020;Fliss et al., 2022).

Endophthalmitis
The PLA patients have a 0.83-11 % chance of having endogenous endophthalmitis (EE), which results from the hematogenous dissemination (Sng et al., 2008). EE develops in 4.8 % of individuals suffering from hvKp bacteremia (Lee et al., 2006). Even with intensive therapy, the prognosis of EE is miserable with diminished vision and blindness being the most typical outcomes (Serban et al., 2021).

Meningitis
In the absence of neurosurgery or head trauma, K. pneumoniae appears to become a frequent source of community-acquired meningitis (Chang et al., 2012). In the context of meningitis, subdural empyema; brain abscess, and epidural abscess, all have all been reported and documented either alone or in combination (Doud et al., 2009).

Soft tissue and musculoskeletal system diseases
The hvKp has appeared as a common agent of the necrotizing fasciitis; with an identical number of instances and a higher death rate than group A Streptococcus (Cheng et al., 2012), psoas abscess (Mita et al., 2012, septic arthritis (Kishibe et al., 2016), and osteomyelitis (Chang et al., 2001). All these soft tissue and musculoskeletal system infections have been described and may be the source sites of bacterial infection.

Urinary tract
HvKp bacteremia has been connected to the urinary tract infections (Lee et al., 2006). Bacteremic spread towards the kidneys; perinephric area, and prostate that culminates in the formation of an abscess, has been widely documented (Shon et al., 2013).

Treatment options
The hvKp strains could be the next emerging "superbugs". The necessity to drain abscesses/closed space infections is a key principle of the infectious disease treatment. Because hvKp strains are known to cause abscesses, source control is an important part of the overall therapeutic strategy. Opening surgical drainage is unusual in the today's era of interventional radiology and percutaneous draining of the treatable abscesses. However, the hvKp's physical feature of hypermucoviscosity may make draining of catheter difficult (Shon et al., 2013).

Antimicrobials
The effective management of hvKp infections demands on combination of sufficient source control and ongoing antibiotic treatment. The length of Novel Research in Microbiology Journal, 2023 treatment varies from two to six weeks; depending on the extent and location of the infection. Drainage of liver abscesses has been linked with a lower risk of metastatic infection and mortality. It is essential to note that all K. pneumoniae strains have inherent resistance to ampicillin. No studies have specifically assessed the most effective antibiotics for treating hvKp infections, thus the physicians should consider the local antimicrobial resistance patterns and the site of infection when selecting an empirical antibiotic therapy (Choby et al., 2020). There is a lack of data and trials to determine the best antibacterials for treating hvKP infections. Meanwhile, the occurrence of multi drug resistance (MDR) in hvKP is increasing along with health care-associated infections.
Recommendations have been made to use newer combinations of antibacterials, including ceftazidimeavibactam, meropenem-vaborbactam, and imipenemrelebactam, for effective treatment of CR-Kp infections. However, these antibacterials are not effective in treating infections caused by class βcarbapenemases, which are a major factor of carbapenem resistance in these isolates; as demonstrated in this study conducted by Banerjee et al., (2021), and in other studies from several developing countries. It's vital to remember that due to the low penetration ability of some antibacterials, several hvKp-infected locations pose more therapeutic problems. Based on the susceptibility data, ceftriaxone and meropenem are effective antimicrobial agents for treatment of central nervous system (CNS) infections. Several antibiotics, including trimethoprimsulfamethoxazole, fluoroquinolones, and\or fosfomycin, can produce therapeutic concentrations in the prostate. However, the ocular infection has been treated with a mixture of systemic and intravitreal medications (e.g., cefazolin, ceftazidime, aminoglycosides, and imipenem). Moreover, the use of intraocular steroid therapy has been reported (Xu et al., 2018).

Passive immunization
The increasing incidence of extensive drugresistance (XDR) and pan-drug-resistant (PDR) strains, in addition to the increased development and usage of monoclonal antibodies (MAbs) for treating many medical problems, have raised the interest of hvKp antibody-based treatment (Wang-Lin et al., 2017). MAbs directed against the K1 bacterial capsule have been used efficiently in vitro to treat and\ or prevent hvKp infection (Diago-Navarro et al., 2017). Passive immunization must resist the antigenic diversity of the bacterial surface polysaccharides to avoid hvKp infection (Follador et al., 2016).

Phage therapy
The current incidence and inadequate treatment choices for MDR hvKp necessitate finding potential alternative approaches. The use of phages has been well reported and is a proven strategy across the globe to fight MDR pathogens. Bacteriophages are natural predators of bacteria with the self-replicating ability and rigorous specificity to spot and destroy the bacterial host through taking over the cellular machinery (Aslam et al., 2021). Different structural components of the bacteriophages are responsible for lysis of the bacterial host, including endolysins, holins, and spanins. These components play a significant part in the assembly and release of the bacteriophages from the host bacteria. The endolysins degrade the peptidoglycans, whereas the holins and spanins disrupt the cell membrane. These specific particles efficiently kill the bacteria without causing any harm to the human microbiota; so unlike the antibiotics, the bacteriophages have no side effects, i.e., antibioticassociated diarrhea. Additionally, the bacteriophages neither produce any type of toxins nor disseminate antibiotic resistance genes (Aslam et al., 2022).

Conclusion
The progressive hvKps diseases have some dangerous traits that are not observed in cKp infections. HvKP infects people who are young or who do not have any co-morbidity. The hvKp strains are mostly associated with the community-associated infections. In addition, hvKp infections have a mortality incidence of 3 to 42 %, and are frequently linked to deadly disseminated infections. These pathogenic features of hvKp may be primarily involved in its hypervirulence. Many virulence factors, including the K1\K2 serotypes, RmpA, and aerobactin, appear to be closely related to hvKp hypervirulence. The precise hvKp's phenotypic and genotypic traits must be defined, and the determinants of hvKp hypervirulence need to be investigated further. These hypervirulence-related parameters of hvKp can be used to develop new therapeutics. HvKp infection management is challenging; therefore the morbidity and death rates will continue to rise. A combination of hypervirulence and multiple or pan-drug resistance in hvKp infection may lead to a "post-antibiotic" situation.

Conflict of interest
There have been no documented conflicts of interest by any author about this study.

Funding
No financial support was received for this work.

Ethical approval
Non-applicable.