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Background

The genus Klebsiella belongs to the tribe Klebsiellae, a member of the


family Enterobacteriaceae. The organisms are named after Edwin Klebs, a
19th century German microbiologist. Klebsiellae are nonmotile, rod-shaped,
gram-negative bacteria with a prominent polysaccharide capsule. This
capsule encases the entire cell surface, accounts for the large appearance
of the organism on gram stain, and provides resistance against many host
defense mechanisms.
Members of the Klebsiella genus typically express 2 types of antigens on
their cell surface. The first is a lipopolysaccharide (O antigen); the other is a
capsular polysaccharide (K antigen). Both of these antigens contribute to
pathogenicity. About 77 K antigens and 9 O antigens exist. The structural
variability of these antigens forms the basis for classification into various
serotypes. The virulence of all serotypes appears to be similar.
Three species in the genus Klebsiella are associated with illness in
humans: Klebsiella pneumoniae, Klebsiella oxytoca, and Klebsiella
granulomatis. Organisms previously known as Klebsiella
ozaenae and Klebsiella rhinoscleromatis are considered nonfermenting
subspecies of K pneumoniae that have characteristic clinical
manifestations. With those exceptions, strains within this genus ferment
lactose, most produce highly mucoid colonies on plates because of the
production of a luxuriant polysaccharide capsule, and all are nonmotile. [1] In
recent years, klebsiellae have become important pathogens in nosocomial
infections. [2] See the image below.

This scanning electron


micrograph (SEM) reveals some of the ultrastructural morphologic features
of Klebsiella pneumoniae. Courtesy of CDC/Janice Carr.

Pathophysiology

Host defense against bacterial invasion depends on phagocytosis by


polymorphonuclear granulocytes and the bactericidal effect of serum,
mediated in large part by complement proteins. Both classic-pathway and
alternate-pathway complement activation have been described, but the
latter, which does not require the presence of immunoglobulins directed
against bacterial antigens, appears to be the more active pathway in K
pneumoniae infections.

Recent data from preclinical studies suggest a role for neutrophil


myeloperoxidase and lipopolysaccharide-binding protein in host defense
against K pneumoniae infection. Neutrophil myeloperoxidase is thought to
mediate oxidative inactivation of elastase, an enzyme implicated in the
pathogenesis of various tissue-destroying diseases. Lipopolysaccharide-
binding protein facilitates transfer of bacterial cell wall components to
inflammatory cells. Investigators showed higher rates of infection in
experimental mice deficient in the genes that control expression of these 2
agents.

The bacteria overcome innate host immunity through several means. They
possess a polysaccharide capsule, which is the main determinant of their
pathogenicity. The capsule is composed of complex acidic polysaccharides.
Its massive layer protects the bacterium from phagocytosis by
polymorphonuclear granulocytes. In addition, the capsule prevents
bacterial death caused by bactericidal serum factors. This is accomplished
mainly by inhibiting the activation or uptake of complement components,
especially C3b. The bacteria also produce multiple adhesins. These may
be fimbrial or nonfimbrial, each with distinct receptor specificity. These help
the microorganism to adhere to host cells, which is critical to the infectious
process.

Lipopolysaccharides (LPS) are another bacterial pathogenicity factor. They


are able to activate complement, which causes selective deposition of C3b
onto LPS molecules at sites distant from the bacterial cell membrane. This
inhibits the formation of the membrane attack complex (C5b-C9), which
prevents membrane damage and bacterial cell death.

Availability of iron increases host susceptibility to K pneumoniae infection.


Bacteria are able to compete effectively for iron bound to host proteins
because of the secretion of high-affinity, low molecular weight iron chelators
known as siderophores. This is necessary because most host iron is bound
to intracellular and extracellular proteins. In order to deprive bacteria of
iron, the host also secretes iron-binding proteins.
Epidemiology of Klebsiellae

Klebsiellae are ubiquitous in nature. In humans, they may colonize the skin,
pharynx, or gastrointestinal tract. They may also colonize sterile wounds
and urine. Carriage rates vary with different studies. Klebsiellae may be
regarded as normal flora in many parts of the colon and intestinal tract and
in the biliary tract. Oropharyngeal carriage has been associated with
endotracheal intubation, impaired host defenses, and antimicrobial use.

K pneumoniae and K oxytoca are the 2 members of this genus responsible


for most human infections. They are opportunistic pathogens found in the
environment and in mammalian mucosal surfaces. The principal
pathogenic reservoirs of infection are the gastrointestinal tract of patients
and the hands of hospital personnel. Organisms can spread rapidly, often
leading to nosocomial outbreaks.

Infection with Klebsiella organisms occurs in the lungs, where they cause
destructive changes. Necrosis, inflammation, and hemorrhage occur within
lung tissue, sometimes producing a thick, bloody, mucoid sputum described
as currant jelly sputum. The illness typically affects middle-aged and older
men with debilitating diseases such as alcoholism, diabetes, or chronic
bronchopulmonary disease. This patient population is believed to have
impaired respiratory host defenses. The organisms gain access after the
host aspirates colonizing oropharyngeal microbes into the lower respiratory
tract.

Klebsiellae have also been incriminated in nosocomial infections. Common


sites include the urinary tract, lower respiratory tract, biliary tract, and
surgical wound sites. The spectrum of clinical syndromes includes
pneumonia, bacteremia, thrombophlebitis, urinary tract infection (UTI),
cholecystitis, diarrhea, upper respiratory tract infection, wound infection,
osteomyelitis, and meningitis. The presence of invasive devices,
contamination of respiratory support equipment, use of urinary catheters,
and use of antibiotics are factors that increase the likelihood of nosocomial
infection with Klebsiella species. Sepsis and septic shock may follow entry
of organisms into the blood from a focal source.
Klebsiella granulomatis (formerly Calymmatobacterium granulomatis) is a
fastidious member of the genus that causes chronic genital ulcerative
disease also known as granuloma inguinale or donovanosis. It is a
relatively rare disease in the United States, with fewer than 100 cases
reported annually. It has long been a recognized cause of genital ulceration
in parts of India, Papua New Guinea, the Caribbean, and South America
(particularly Brazil). Fortunately, the incidence of the disease has
decreased in recent years.

Rhinoscleroma and ozena are 2 other infections caused


by Klebsiella species. These diseases are rare. Rhinoscleroma is a chronic
inflammatory process involving the nasopharynx, whereas ozena is a
chronic atrophic rhinitis characterized by necrosis of nasal mucosa and
mucopurulent nasal discharge.

K oxytoca has been implicated in neonatal bacteremia, especially among


premature infants and in neonatal intensive care units. Increasingly, the
organism is being isolated from patients with neonatal septicemia.

Extensive use of broad-spectrum antibiotics in hospitalized patients has led


to both increased carriage of klebsiellae and, subsequently, the
development of multidrug-resistant strains that produce extended-spectrum
beta-lactamase (ESBL). These strains are highly virulent, show capsular
type K55, and have an extraordinary ability to spread. Most outbreaks are
due to a single clone or single gene; the bowel is the major site of
colonization with infection of the urinary tract, respiratory tract, and wounds.
Bacteremia and significant increased mortality have resulted from infection
with these species.

In addition to prior antibiotic use, risk factors for infection include the
presence of an indwelling catheter, feeding tube, or central venous
catheter; poor health status; and treatment in an intensive care unit or
nursing home. Acquisition of these species has become a major problem in
most hospitals because of resistance to multiple antibiotics and potential
transfer of plasmids to other organisms.

Carbapenem-resistant Enterobacteriaceae (CRE), which are sometimes


known as K pneumoniae carbapenemase (KPC) and New Delhi metallo-
beta-lactamase (NDM), are a family of bacteria that are difficult to treat
because of their high levels of resistance to antibiotics. Some CRE bacteria
have become resistant to most available antibiotics and cause mortality
rates of up to 50%.

Frequency

United States

In some parts of the world, K pneumoniae is an important cause of


community-acquired pneumonia in elderly persons. Studies conducted in
Malaysia and Japan estimate the incidence rate in elderly persons to be
15-40%, which is equal to, if not greater than, that of Haemophilus
influenzae. However, in the United States, these figures are different.
Persons with alcoholism are the main population at risk, and they constitute
66% of people affected by this disease. Mortality rates are as high as 50%
and approach 100% in persons with alcoholism and bacteremia.

Klebsiellae are also important in nosocomial infections among adult and


pediatric populations. Klebsiellae account for approximately 8% of all
hospital-acquired infections. In the United States, depending on the study
reviewed, they comprise 3-7% of all nosocomial bacterial infections, placing
them among the top 8 pathogens in hospitals. Klebsiellae cause as many
as 14% of cases of primary bacteremia, second only to Escherichia coli as
a cause of gram-negative sepsis. They may affect any body site, but
respiratory infections and UTIs predominate.

Of 145 reported epidemic outbreaks of nosocomial bacteremias during


1983-1991, 13 were attributed to Klebsiella organisms. The US Centers for
Disease Control and Prevention report that Klebsiella strains were
responsible for 3% of all pathogenic epidemic outbreaks.

An investigation of Klebsiella pneumoniae carbapenemase (KPC)-


producing Enterobacteriaceae among patients of acute and long-term
acute care hospitals was conducted in 2011. The investigation found
extensive spread of KPC-producing Enterobacteriaceae throughout 4
adjacent counties in Indiana and Illinois over a 1-yr period. Long-term acute
care hospitals played a central role in the outbreak, suggesting that
guidelines for controlling KPC should be expanded to include long-term
care facilities. Education of personnel and coordinated regional efforts
among health care facilities are crucial for KPC control. [3]
Another multihospital study on transmission risk found that patients
admitted to acute care hospitals from high-acuity long-termcare facilities
were more likely to be colonized with KPC-producing Enterobacteriaceae
than were patients admitted from the community. [4]

K oxytoca is among the top 4 pathogens that cause infection in patients in


neonatal intensive care units. It is the second most frequent cause of gram-
negative neonatal bacteremia.

International

Outbreaks of neonatal septicemia occur worldwide. Infection with K


pneumoniae also has a worldwide distribution. Infection with K
rhinoscleromatis is not common in the United States, although it has a
worldwide distribution and is usually observed in areas of eastern Europe,
southern Asia, central Africa, and Latin America. K granulomatis is more
common outside the United States in countries such as India, Papa New
Guinea, Caribbean, South America, Zambia, Zimbabwe, South Africa,
Southeast Asia, and some parts of Australia.

Mortality/Morbidity

Klebsiella pneumonia is a necrotizing process with a predilection for


debilitated people. It has a high mortality rate of approximately 50% even
with antimicrobial therapy. The mortality rate approaches 100% for persons
with alcoholism and bacteremia.

Klebsiella bacteremia and sepsis produce clinical manifestations similar to


those caused by other gram-negative enteric organisms. Morbidity and
mortality rates are comparable to those for other gram-negative organisms
that cause sepsis and septic shock. In neonatal units, outbreaks caused by
ESBL-producing strains present a more serious problem and may be
associated with increased mortality.

Age

Community-acquired Klebsiella (Friedlnder) pneumonia is a disease of


debilitated middle-aged and older men with alcoholism.
Nosocomial infections may affect adults or children, and they occur more
frequently in premature infants, patients in neonatal intensive care units,
and hospitalized individuals who are immunocompromised.