1. Introduction:

Hypervirulent Klebsiella pneumoniae (hvKp) is an increasingly recognized pathotype of Klebsiella pneumoniae characterized clinically by its ability to cause organ- or life-threatening infections in healthy hosts from the community. Presentations with multiple sites of infection or subsequent metastatic spread is another defining feature. Infectious syndromes include hepatic abscess (in the absence of biliary disease), non-hepatic abscesses, pneumonia, and less commonly necrotizing fasciitis, endophthalmitis, and meningitis [1].

hvKp is differentiated genetically from classical K. pneumoniae (cKp), which presently is the most common K. pneumoniae pathotype in Western countries, by its acquisition of a cluster of virulence factors encoded on a virulence plasmid and other mobile chromosomally integrated genetic elements. Clinically, cKp primarily affects people in the hospital setting with comorbid conditions rather than healthy individuals.

“Superbug” has long been used to describe strains of bacteria that are resistant to the majority of antibiotics commonly used today, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. Several XDR enteric Gram-negative bacilli have come to public attention in the past two decades. One of the most famous superbugs to emerge within the past two decades has been multidrug-resistant (MDR) and extensively drug-resistant cKp, which may express extended spectrum beta lactamases (ESBL), a variety of carbapenemases, and the colistin resistance gene mcr-1. Treatment of superbugs such as XDR cKp is difficult due to the paucity of therapeutic options available and the toxicity of last-resort drugs. However, most of these Gram-negative pathogens have been largely isolated to the healthcare environment and are of relatively low virulence, producing invasive infection only in opportunistic settings or after extensive antimicrobial exposure. In contrast, hvKp is difficult to treat despite the health of the host or its antimicrobial sensitivity. Challenges in the treatment of hvKp are to curtail its spread by the rapid initiation of therapy, detect occult metastases that may require source control, and to utilize appropriate site-specific antimicrobials. When hvKp strains were first recognized, they were largely antimicrobial susceptible. Unfortunately, this is changing. An increasing number of reports describe hvKp isolates that have acquired ESBL or carbapenemases or, conversely, XDR-cKp strains that have acquired hvKp virulence determinants. For such isolates, the combination of virulence and antimicrobial resistance is highly problematic.

2. The emergence of the hypervirulent Klebsiella pneumoniae pathotype

hvKp was first recognized in Taiwan in 1986 [2], although genomic analyses suggest it existed unrecognized as early as the 1920s [3]. Throughout the past three decades, hvKp has undergone epidemic spread in Asia, especially South Korea, Japan and China, with sporadic but increasing rates reported elsewhere. Like cKp, hvKp colonization is requisite but does not necessarily lead to subsequent infection. In one study, putative hvKp strains comprised 9.8% of intestinal K. pneumoniae isolates in healthy adults from Asian countries [4]. It is unknown why only selected colonized individuals develop infection and the mechanism by which this occurs, other than probable aspiration in the setting of pneumonia.

Approximately 70% of hvKp isolates are capsule types K1 or K2. The hvKp K1 capsule type isolates are clustered uniformly within a monophyletic clade of clonal group 23 (CG23), while hvKp K2 capsule type strains are more genetically diverse [5]. Despite clade and capsular type, all hvKp isolates share homologues of the large virulence plasmid pLVK [5], underscoring its importance to the hypervirulent phenotype.

Complete epidemiologic data on carriage, transmission, and incidence of invasive disease are not available, in part because a biomarker that can accurately differentiate cKp from hvKp has not been defined. Clinical laboratories are unable to differentiate between cKp and hvKp strains, nor is there is a commercially available assay that reliably distinguishes the two. However, several biomarkers, including peg-344, iroB, iucA, _prmpA, _prmpA2, and quantitative siderophore production greater than 30 μg/mL have been found to predict hvKp strains with excellent sensitivity and specificity [6]. These biomarkers could lead to the development of a diagnostic test, and if FDA approved, can be utilized by clinical laboratories for patient care, as well as for use in epidemiologic surveillance and research studies. Prior to this report, many studies defined hvKp as isolates that demonstrated a positive “string test,” in which a colony on an agar plate produces viscous strings of 5 mm or greater when stretched with an inoculating loop. However this hypermucoviscous phenotype has been shown not to be optimally accurate, especially in areas with a low prevalence of hvKp infection [6].

The prevalence of hvKp asymptomatic fecal carriage and the incidence of hvKp infection are higher in the Asian Pacific Rim, which may be attributed to increased acquisition, genetic susceptibility, or some combination of both. Multiple features of the hvKp epidemic indirectly support a genetic predisposition to infection. Those of East Asian descent are disproportionately infected even when residing outside endemic areas [7]. Conversely, Indian immigrants to Singapore suffered 1.4% of hvKp liver abscesses despite comprising 7.4% of the population [7]. Nonetheless, differences in travel, diet, and exposures remain alternative considerations for these observations.

Genes essential for the hvKp hyperviruent phenotype are clustered on mobile genetic elements, thus facilitating transfer of virulence factors to other strains [3]. The full complement of gene products responsible for this phenotype is still under investigation. However, the most critical factors identified to date, which are encoded on a large virulence plasmid, are increased production of capsule and molecules called siderophores that enable iron acquisition needed for infection.

The siderophore aerobactin accounts for greater than 90% of hvKp’s total siderophore production, while enterobactin, salmochelin, and yersiniabactin account for the remaining minority [8]. Using isogenic constructs that variably express these siderophores, only aerobactin significantly enhances survival in human ascites, serum, and in outbred mouse systemic and pulmonary infection models [8]. This suggests that the primary virulence determinant among hvKp’s siderophores is aerobactin. The regulators of the mucoid phenotype rmpA and rmpA2, which increase capsule production, also have been shown to increase hvKp virulence, perhaps by impairing phagocytosis and enabling survival within macrophages [9]. Additional hvKp-specific virulence factors identified include colibactin, which contributes to invasion of the central nervous system [10] and the putative metabolite transporter peg-344, which contributes to virulence in pulmonary infection models [11]. The mechanisms responsible for hvKp’s relatively unique ability to infect multiple sites and metastatically spread are still poorly defined.

3. The increasing prevalence of MDR and XDR hvKp is problematic

cKp has reached public attention in recent years as a superbug capable of expressing cephalosporin, carbapenem, and colistin resistance. cKp easily acquires drug resistance by acquisition of any of hundreds of known compatible antimicrobial resistance (AMR) plasmids. Rates of AMR plasmid carriage in cKp vary by strain and geographic region, but they are increasing globally at a staggering rate.

Fortunately, less drug resistance has been observed in hvKp. The majority of hvKp strains have retained antimicrobial susceptibility to multiple drug classes. Population genomics data suggests that incorporation of antimicrobial resistance plasmids to hvKp is more difficult that in cKP. Postulated barriers are the hyper-expression of capsule, which may provide a physical barrier, and CRISPR systems [3]. However, the barrier to plasmid acquisition is incomplete. In the face of antibiotic selection pressure, reports of hvKp possessing ESBL, carbapenemase, and even colistin-resistance plasmids are increasing. Zhang and others have reported cases of acquisition of a KPC-2 plasmid by hvKp, with fatal outcome to the patients [12]. In this case report, an antimicrobial resistance determinant integrated into the hvKp virulence plasmid via an insertion sequent (IS) element. This mechanism circumvents potential plasmid incompatibilities that would prevent concurrent transmission of the hypervirulent and MDR phenotypes [12]. Conversely, Gu and colleagues [13] have reported acquisition of a hvKp virulence plasmid by a carbapenem-resistant cKp strain, which caused an outbreak of 5 cases in a Chinese hospital ICU, and uniformly fatal outcomes in the patients affected. A strain of hvKp possessing bla_NDM-5 has also been described [14]. In light of these data, it is probable that further convergence of multidrug resistance genes with hypervirulent K. pneumoniae will occur.

4. Discussion

Hypervirulent Klebsiella pneumoniae poses a serious public health threat. While it is carried and spread asymptomatically within the community, it can also cause organ and life-threatening, invasive disease in the same healthy population. With the increasingly reported cases of MDR and XDR hvKp, the possibility of losing antimicrobial treatment options for this virulent pathogen is becoming a reality. Protecting patients from hvKp requires action from all levels of the healthcare system. Clinicians need to be cognizant of hvKp clinical syndromes, which should prompt thorough investigations for, and management of, occult metastatic infections, including appropriate site-specific antimicrobial treatment, especially for meningitis, brain abscess, and endophthalmitis. A commercially available, FDA approved assay for reliable identification of the hvKP is needed to aid clinicians in recognizing healthcare associated infection or in individuals with co-morbidities, settings in which hvKp is not usually considered. More studies are needed on appropriate screening and infection control practices to minimize hvKP transmission in the healthcare setting or among close contacts. Lastly, minimizing further emergence of MDR and XDR hvKp requires vigilant antimicrobial stewardship. In an era of increasing drug resistance and relative stagnation of antimicrobial development, appropriate and effective management of “superbugs” requires awareness of current and future threats as well as preemptive action.

Acknowledgments

Footnotes

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