Klebsiella Pneumoniae and Hypervirulent Derivatives

Klebsiella Pneumoniae and Hypervirulent Derivatives

Virulence, pathogenesis, host susceptibility and means for control.

1-Introduction

Klebsiella pneumoniae is one of the Enterobacteriaceae group which are a large, diverse group of facultative Gram-negative rods (1). It’s a gram-negative, encapsulated, non-motile bacterium(2, 3), resides in the environment; soil, surface waters and medical devices (2). It readily colonizes human mucosal surfaces, including the GIT and oropharynx (2), as well as the respiratory tract and feces of about 5% of normal individuals (4). From these sites, it can gain entry to other tissues and cause severe infections (2). K. pneumonia is extremely resilient, whose pathogenicity success seems to follow the model of “the best defense is a good defense rather than “the best defense is a good offense.” (2). This is presented by its ability to escape and survive (instead of actively suppressing) different components of the immune system and grow at variable host sites(2). It’s an opportunistic pathogen that causes a wide range of infections (5). It’s a common cause of nosocomial and community acquired infections especially in immunocompromised patients (6). The importance of K. pneumoniae increased in the last few decades with the emergence of a new hypervirulent variant of the pathogen that’s causing serious, life-threatening community-acquired infection in younger healthy individuals (7). That hypervirulent variant (hvKP)(5), was first described in the Asian Pacific Rim (7), but currently it’s increasingly reported worldwide (5). The emergence of hvKP together with the worldwide problem of increased antibiotic resistance and the fear of resistance transfer to hvKP (most hvKP strains are antibiotic susceptible (5)), makes K. pneumoniae a real terror.

2-History

The pathogen was first described by Carl Friedlander in 1882(3, 7)who described an encapsulated bacillus isolated from the lungs of patients who died from pneumonia(7). This predated the Gram stain technique, which was developed in 1884 (7). It was, at first, named Friedlander’s bacillus (7) or Friedlander’s bacterium(2), later changed to Klebsiella in 1886 (7). During the pre-antibiotic era, K. pneumoniae was known as a cause of pneumonia, mainly in alcoholics and diabetic patients (7). It was also an established uro-pathogen, and a cause of biliary tract infections, osteomyelitis and bacteremia (7). In the antibiotic era, the epidemiology of K. pneumoniae infections has evolved with most infections, particularly in developed Western countries, occurring in hospitals and long-term care facilities (7). Urinary tract, lungs, abdominal cavity, intra-vascular devices, surgical sites, soft tissues and resultant bacteremia were the most common involved sites of infection (7). Due to their propensity for acquiring antimicrobial resistance determinants these “classic” K. pneumoniae (cKP) strains have received increased notoriety and became more challenging (7). The spread of New Delhi metallo-β-lactamase (NDM-1)-containing strains from India associated with medical tourism and more recently the extreme drug-resistant K. pneumoniae outbreak at the Clinical Center Hospital on the NIH campus have captured the awareness of scientists, physicians, and press (7). The new hvKP was first reported in the mid-1980s (5, 7), reports from Taiwan indicated a unique clinical syndrome of community-acquired Klebsiella pneumoniae infections (5, 7). Patients with clear history of hepatobiliary disease presented with community-acquired pyogenic liver abscesses (CA-PLA)(5, 7)with tendency for metastatic spread to distant sites (7), an unusual feature for enteric Gram-negative bacilli in the non-immunocompromised (7). An increasing number of cases are being reported from North America, South America, the Caribbean, Europe, the Middle East, Australia, Africa and South Africa (7).

3-Pathogenesis

3-1-Acquisition resulting in colonization

This is the first step necessary for subsequent endogenous K. pneumoniae infection (7). Data from cKP and other Enterobacteriaceae, suggests that the vehicle(s) for acquisition and subsequent colonization are some combination of food, water, person-to-person (family members or sexual partners) and animal-to-person transmission (e.g. pets-owners) (7). Limited data supporting that the same is happening with hvKP(7). Mechanisms for cKP, entering the site of infection include; ascension from the perineum into the bladder; disruption of the bowel enabling GIT colonizers entry into the peritoneal cavity; micro- or macro-aspiration of oro -pharyngeal colonizers into the respiratory tract; or disruption in the skin barrier(7). For hvKP, entering the lungs through aspiration from oropharyngeal colonization seems plausible also(7). Regarding the common presentation of hvKP, (PLA), the ability to invade across an intact intestinal mucosa, though seems plausible, but the regular abscence of biliary tract disease, (a prominent feature of patients with hvKP-mediated PLA), makes it less likely and suggests the possibility of entry from a non-intestinal site (7).

Skin break that might be overt or occult, resulting in bacteremia, similar to what occurs in invasive Staphylococcus aureus infection is another possibility(7). It’s not-possible, in many cases, to distinguish the primary site of infection from metastatic spread (7). Cases with multiple organs/sites are most likely seeded from the initial bacteremia (7). Interestingly, till now, no recorded cases of laboratory acquisition (7).

3-2-Clinical diseases (infections)(2, 7) .

K. pneumoniae is associated with wide range of community and healthcare acquired infections. Table 1 is giving a summary for the most common K. pneumoniae infections and its geographical distribution (2). In addition to the infections mentioned in the table, the pathogen is also involved in other infections including, Splenic abscess, Spontaneous bacterial peritonitis(both may be primary or metastatic  to PLA and mainly hvKP is involved), Empyema/complicated parapneumonic effusion (secondary to pneumonia or PLA ),  Endophthalmitis (via hematogenous dissemination, first described in 1986 and was one of the first hints that something was different with K. pneumoniae and the appearance of hvKP) and other CNS infections (brain abscess, subdural empyema, and epidural abscess) (2). A case of native valve endocarditis due to hvKP and another one case of Lemierre syndrome (septic internal jugular venous thrombophlebitis), possibly  due to hvKP, have also been reported(7).

Table 1: Characteristics of nosocomial and community-acquired K. pneumoniae infections(2).

4-Host susceptibility (Patient risk factors)(2).

Immunodeficiency patients are at a much greater risk for cKP infections (both community and health acquired (2)) than healthy population. Immunodeficiencies with higher risk  for healthcare acquired cKP bacteremia include; diabetes, malignancy, solid organ transplantation, chronic liver disease, dialysis, corticosteroids-therapy, chemotherapy (possibly overlapping  malignancy), and other treatments or conditions resulting in neutropenia (2).Colonization of the oropharyngeal tract (less commonly, the GIT) is a risk factor for both CAPs and HAPs, as aspiration is the primary route for bacterial lung infection (2). The risk of aspirating microbes increases with alcohol intoxication, radiation therapy, endotracheal intubation, and defects in the defenses of the respiratory tract, (e.g. deficiency in muco-ciliary clearance)(2). Neonates and elderly are at risk for K. pneumoniae infection. Neonates (particularly those who are premature or in the ICU) due to immature immune defenses, relatively high permeability of the GIT mucosa and lack of established microbiota. the, while in elderly, aging of immune responses make them less efficacious at controlling pathogens. Use of medical devises like endotracheal intubation (associated with VAB) and urinary catheter (associated with UTIs) increase patient risk for cKP infections. (2).

On the contrary to cKP, hvKP can cause serious, life-threatening community-acquired infection in younger healthy hosts (without any kind of prior immunodeficiency or predisposing factors)(5, 7).

5-Virulence factors

Four major  virulence factors’ classes have been well studied in Kllebsiella pneumoniae; capsule (including hyper capsule production in hv strains); lipopolysaccharides (LPS); siderophores; and fimbriae (also known as pili) (2). Other factors were identified as being important for K. pneumoniae virulence however their mechanisms of action and clinical significance are not yet fully understood. These include Porins, OMPs, iron transport systems, efflux pumps, and genes involved in allantoin metabolism (2).

Fig-1 The four well-studied virulence factors in cKP and hv KP(2).

5-1-Capsule

Capsule, a polysaccharide matrix that coats the cell, is necessary for K. pneumoniae virulence and is the most thoroughly studied virulence factor of K. pneumoniae (2). Capsule protects against the host immunity through; inhibiting phagocytosis (polysaccharides are poor immunogens   and also acts like a slimy football jersey, that is hard to grasp and tears away when grabbed by phagocytes (8)), stoping activation of the early immune response, and abolishing lysis by complement and antimicrobial peptides (by binding to them, thus prevents its interaction with the bacterial surface)(2).

According to strain-specific capsular polysaccharides termed K antigens, there are 78 known serotypes of K. pneumoniae (2, 5, 7). K1 and K2 strains are generally more virulent than others (2, 5, 7), and they are the most common in hvKP which are characterized by overproduction of its polysaccharide capsule (5) and also by its hyper-muco-viscosity (not all hvKP strains are hyper-muco-viscous) (5).

5-2-Lipopolysaccharide

LPS, (also known as endotoxin) (2), are a major and necessary component of the outer layer of the cell membrane of all Gram-negative bacteria. Though considerable variation in LPS structures among bacterial species, it’s usually consists of an O antigen, a core oligosaccharide, and lipid A. (2). 8-12 LPS serotypes have been described in K. pneumoniae (7), and O1 is the most common (2). LPS rule involves both benefiting and hindering for K. pneumoniae during infection. Though It’s an important virulence factor that protect against humoral defenses but it’s also a strong immune activator. The lipid portion of bacterial LPS, lipid A, is a potent ligand of TLR4, a pattern recognition receptor (2). Certain Klebsiella pneumoniae strains use capsule for partially shielding  their LPS from detection by TLRs (2). No data are available on whether LPS contributes to the increased virulence of hvKP strains (7). LPS is the primary means of protection against complement through its O-antigen, which protects against C3 by binding C3b, (a component of complement system that’s act as both, an opsonin and part of the pore-forming process) (2).

5-3-Fimbriae

Type 1 and 3 fimbriae are the main adhesive structures that have been characterized as pathogenicity factors in K. pneumoniae (2). Other structures have been also noted for K. pneumoniae adhesion, including another fimbria called KPF-28, a nonfimbrial factor called CF29K, and a capsule-like material (2). Type 1 fimbriae are thin, thread-like protrusions on the bacterial cell surface. They’re expressed in 90% of both clinical and environmental K. pneumoniae isolates (2). Type 3 fimbriae are helix-like filament (2). Type 1 fimbriae contribute to the invasion of bladder cells and biofilm formation in the bladder by K. pneumoniae during UTIs but they’re not needed for early colonization (2). During biofilm formation on catheters, type 3 fimbriae are expressed, while the expression of type 1 fimbriae is controversial (2). Type 3 and, possibly, type 1 fimbriae may also contribute to the delivery, entry, and persistence of K. pneumoniae in VAPs (2).

5-4-Siderophores

These are molecules that possess a higher affinity for iron (which is essential for bacterial growth and plays a crucial role in the progression of infection(5)), than host transport proteins do (2). Several siderophores are expressed in K. pneumoniae; enterobactin, yersiniabactin, salmochelin, and aerobactin (2). Production of more than one siderophore by K. pneumoniae is a means of optimizing successful colonization of different tissues and/or avoiding host neutralization of one siderophore (2). Enterobactin has the highest affinity for iron, while aerobactin is the lowest (2). enterobactin expression is almost ubiquitous among both cKP and hvKP strains and is therefore considered to be the primary iron uptaking system utilized by K. pneumoniae (2), but it’s neutralized by the host-secreted molecule lipocalin-2. Yersiniabactin is overrepresented in K. pneumoniae isolates from the respiratory tract, and is not deactivated by lipocalin-2, but it’s unable to acquire enough iron in the presence of the host protein transferrin (2). Salmochelin is a c-glucosylated form of enterobactin (2). This modification prevents its binding of by lipocalin-2, thus preventing siderophore neutralization(2). Aerobactin is a citrate-hydroxamate siderophore, that’s rarely expressed in cKP clinical isolates, (only about 6%), yet it’s present in 93 to 100% of hvKP isolates(2).

5-5-Porins

Downregulation of OmpK35 and OmpK36 porins appears to provide an advantage for K. pneumoniae in the face of antibiotics, perhaps because they serve as a channel that allows entry of antibiotics into the bacteria (2).

5-6-Outer membrane proteins (OMPs)

Several OMPs have been studied and noted to be important for K. pneumoniae virulence, but studies on them seems to give conflict results(2).

5-7-Pumps and Transporters

AcrAB is an efflux pump that has implication in both K. pneumoniae virulence and resistance to antibiotics(2). Kfu is an ABC iron transport system, that’s involved in iron acquisition by K. pneumoniae, and there’s a strong association between its expression and hvKP(2).

5-8-Allantoin Metabolism

It’s a process through which bacteria can secure carbon and nitrogen from their environment. An operon containing genes involved in this process was identified in a search for K. pneumoniae genes whose transcription was upregulated in hvKP strains compared to cKP (2).

6-Means of control

Being an MDRO or XDRO (mainly cKP more than hvKP) (5, 7), patients with K. pneumonia infections or colonization with high risk of transmission, need to undergo (in addition to standard precautions) contact isolation precaution while with in healthcare facilities (9). This includes single patient room (or cohort with similar patients when un-available) (9). HCP caring for patients should wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient’s environment (9). Donning gown and gloves upon room entry and discarding before exiting the patient room (9).

Protecting patients from HAP and VAP (including those by K. pneumoniae) need additional precautions include; Respiratory therapy equipment maintenance, Avoidance of endotracheal intubation, subglottic secretion drainage, reduction in the use of nasogastric tubes and elevation of the bed’s head. (10).

Bibliography

.

1. Miller D. 2014. APIC Text of Infection Control and Epidemiology, Chapter 75, Enterobacteriaceae,.

2. Paczosa MK, Mecsas J.2016. Klebsiella pneumoniae: Going on the Offense with a Strong Defense. Microbiol Mol Biol Rev 80:629-61.

3. Ashurst JA, Dawson A.2018. Pneumonia, Klebsiella. StatPearls [Internet].

4. Carroll KC, Morse SA, Mietzner TA, Miller S. 2016. Medical Microbiology.

5. Lee CR, Lee JH, Park KS, Jeon JH, Kim YB, Cha CJ, Jeong BC, Lee SH.2017. Antimicrobial Resistance of Hypervirulent Klebsiella pneumoniae: Epidemiology, Hypervirulence-Associated Determinants, and Resistance Mechanisms. Front Cell Infect Microbiol 7:483.

6. Shankar C, Veeraraghavan B, Nabarro LEB, Ravi R, Ragupathi NKD, Rupali P.2018. Whole genome analysis of hypervirulent Klebsiella pneumoniae isolates from community and hospital acquired bloodstream infection. BMC Microbiol 18:6.

7. Shon AS, Bajwa RP, Russo TA.2013. Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed. Virulence 4:107-18.

8. MURRAY PR, ROSENTHAL KS, PFALLER MA. 2016. MEDICAL MICROBIOLOGY.

9. Siegel JD, Rhinehart E, Jackson M, Chiarello L. 2006. Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006. Healthcare Infection Control Practices Advisory Committee (HICPAC) / CDC.

10. Peyrani P. 2014. APIC Text of Infection Control and Epidemiology,  chapter 36. Pneumonia | Prevention Measures for Healthcare-Associated Infections. The Association for Professionals in Infection Control and Epidemiology.