1.3. Infections caused by K. Pnemoniae (400)
K. pneumoniae is notorious for causing serious infections such as pneumonia, urinary tract infections (UTIs), bacteremia, pyogenic liver abscess and meningitis. While both classical and HV K. pneumoniae strains are frequent etiological agents of these infections, some are much more likely to be caused by HV than classical strains (3). Classical K. pneumoniae strains are a frequent cause of serious nosocomial infection around the world, leading to primary pneumonias, UTIs and bacteremias, as well as secondary bacteremias caused by spread from primary infection sites in the bladder or lungs (4, 5). In contrast, HV strains typically cause community acquired infections in apparently healthy individuals, particularly in those residing in Southeast Asia (6). classic hv infections include..
K. pneumoniae is an opportunistic pathogen, often targeting individuals with weakened immune systems, which would be particularly prevelant in hospital or other health care settings.
Pneumonia caused by Klebsiella bacteria can be divided into two categories – hospital-acquired pneumonias (HAPs) and community-acquired pneumonias (CAPs). HAPs are defined as lower respiratory infections presenting clinically >48 hours after hospitalization in individuals with no pneumonia symptoms prior to admission (3). Pneumonias that present sooner should be considered as CAPs. Studies have shown that bacterial HAPs are some of the most frequent healthcare-associated infections, being a leading cause of mortality among infections in hospitals (3). A 2014 study by Magill et al. showed that K. pneumoniae was the underlying cause of approximately 11.8% of HAPs, and was the third most common pathogen in nosocomial infections among 183 surveyed hospitals (4). Due to the increased numbers of patients treated with antibiotics (resulting in more antibiotic resistant flora), there is a much higher risk of K. pneumoniae being multidrug resistant in nosocomial than community acquired infections (5).
K. pneumoniae is a prevalent cause of CAPs in Asia and Africa, causing approximately 15% of infections. In contrast, the bacteria is only thought to cause roughly 3-5% of CAPs in Europe, Australia and the USA (3, 6, 7). It has been suggested that the increased prevalence of CAPs seen in Africa and Asia likely corresponds to the increased prevalence of HV strains in these regions (6).
Clinical manifestations of K. pneumoniae pneumonia include cough, fever, chest pain, leukocytosis, and production of a characteristic ‘currant jelly sputum’, a viscous and blood-tinged mucous formed due to significant inflammation and necrosis of the lungs (6–8).
K. pneumoniae is a major cause of UTIs, with studies claiming it to be the second most frequent cause, behind Escherichia coli (9, 10). Infections are thought to be caused by seeding of the bacteria from the GI tract, resulting in symptoms such as dysuria, hematuria, increased frequency and urgency of urination and fever (10, 11). K. pneumoniae is estimated to cause up to 6% and 7% of nosocomial and community-acquired UTIs respectively, which can generally be treated by antibiotics. However, rising prevalence of ESBL-producing and CRE K. pneumoniae strains in intestines could increase these statistics due to seeding of antibiotic resistant strains into the bladder, thereby increasing UTI morbidity (10, 12).
K. pnuemoniae is known to be a major cause of morbidity and mortality in Gram-negative bacteremia.
Pyogenic liver abscess and meningitis
1.4 Patient Risk Factors
Alcoholic
x
The high rate of klebsiella pathogens is strongly related to
alcoholism. A significant specific distribution of CAP related
to K. pneumoniae was found in the group of alcoholic patients
compared to nonalcoholic patients (88% versus 12%,(7)
1.5 Host Immune Defence against KP
In order for K. pneumoniae to establish infection, it must overcome a number of obstacles including mechanical barriers and humoral and cellular defences of the host’s innate immune system.
1.5.1 Mechanical Barriers
Mechanical barriers are one of the first lines of defence used to prevent microbial invasion in mammals. Mucous membranes of the respiratory, GI and genitourinary tracts constitute a large proportion of these barriers, providing protection to the host. In the respiratory tract, cells secrete mucus that traps microbes and other particles entering the airways. Cilia then move the mucus-trapped particles up and out through the throat and nose, in a mechanism termed the ‘mucociliary elevator’. The GI tract utilizes a similar mechanism, with mucus preventing microbial binding to epithelial cells, and peristalsis propelling nonadherent microbes out of the tract. In the genitourinary tract, both the flow and the low pH of urine provide strong mechanical and chemical forces to remove K. pneumoniae and other microbes and prevent their entry to bladder (13).
1.5.2 Humoral Innate Immune Defence
Pathogens that overcome mechanical and chemical barriers face the next line of innate defence consisting of humoral and cellular components, in addition to triggering acute inflammation in the host.
Humoral defences involve a range of antimicrobial factors such as the complement cascade, defensins and other antimicrobial peptides, that can play opsonic, bacteriostatic or bactericidal roles in controlling pathogens (3). The complement system is arguably the most important component of humoral immunity, utilizing a number of mechanisms to kill pathogens. Depending on how it is triggered, the cascade can act through three different pathways called classical, lectin and alternative pathways. These are activated by antigen-antibody complexes, mannose-binding lectin binding to mannose on bacterial surfaces, and microbial cell surfaces, respectively. All pathways converge on the lysis of C3 to C3b and C3a, culminating in opsonization of bacteria for increased phagocytosis, activation of membrane attack complexes to lyse bacteria via insertion of pores, and increased inflammation via proinflammatory mediator and chemoattractant release (13). For example, K. pneumoniae’s surface exposed lipopolysaccharide (LPS) and outer membrane proteins (OPMs) are targets for C3b deposition, which bind to complement receptors on phagocytes and trigger bacterial killing by phagocytosis (14). Additionally, humoral defences such as defensins kill bacteria by damaging their cell membrane, and immunoglobulins and surfactants can opsonize bacteria to increase phagocytosis (3). K. pneumoniae has developed strategies to evade a number of these defences, such as increased resistance to opsonophagocytosis and complement-mediated lysis. Merino et al. demonstrated one such strategy, in which K. pneumoniae strains whose LPS molecules were masked by K antigens failed to activate compliment and so were resistant to its mechanisms of killing (15).
1.5.3 Cellular Innate Immune Defences
Innate immune cells are critical players in combatting K. pneumoniae infection. In addition to phagocytosing encountered pathogens, macrophages produce cytokines and chemokines that orchestrate the immune response. Neutrophils are among the first cells recruited to K. pneumoniae infection sites by macrophage-secreted chemokines including interleukin-8 (IL-8), IL-23 and CXCL1 (2, 3). This has been demonstrated in mouse models of K. pneumoniae lung infection, where alveolar macrophages recruit neutrophils in an attempt to contain and clear the infection (16). To control bacterial infection, neutrophils are known to use phagocytosis alongside release of antimicrobial factors such as reactive oxygen species (ROS), serine proteases that disrupt the structural integrity of microbes, and neutrophil extracellular traps composed of nuclear chromatin and bactericidal proteins that bind microbes and aid in their killing (3, 17). Dendritic cells (DCs) are known to play a role in K. pneumoniae lung infection, with murine models suggesting that Toll-like Receptor 9 (TLR-9) is needed for effective immune response (18). TLRs are critical in bacterial invasion, with their downstream activation of MyD88, TRIF and TIRAP being needed to produce inflammatory cytokines that control infection. TLR4 recognises LPS of Gram negative bacteria, and is known to be crucial in K. pneumoniae clearance with mouse models defective in the TLR showing increased bacterial loads and mortality rates