🏷

Classifications

Harrison's Part

⚙

Pathophysiology

10

Mucosal Reservoir and Sterile-Site Invasion

K. pneumoniae establishes mucosal or device-associated reservoirs in healthcare settings, and transmitted or selected clones can breach barriers into sterile compartments such as the lower respiratory tract and blood.

lung UBERON:0002048 blood UBERON:0000178

Downstream

Capsule and Siderophore Immune Evasion Once K. pneumoniae reaches a normally sterile site, capsule and siderophore programs help the bacterium survive complement, phagocytosis, and iron limitation.

Pulmonary Klebsiella Bacterial Burden Invasion of the lower airway seeds an expanding pulmonary bacterial burden.

Show evidence (1 reference)

PMID:42127138 SUPPORT Human Clinical

"we estimate at least 879 (57.7%) infections were acquired via nosocomial transmission."

Genomic clustering in neonatal units supports hospital transmission of K. pneumoniae that progresses to invasive sterile-site disease.

Capsule and Siderophore Immune Evasion

Hypervirulent K. pneumoniae can acquire plasmid-encoded regulators of mucoid phenotype and siderophore loci that increase capsule production, hypermucoviscosity, iron acquisition, and resistance to early innate clearance.

Downstream

Pulmonary Klebsiella Bacterial Burden Capsule-mediated antiphagocytic activity lets virulent clones persist and replicate at infected tissue sites.

Hypervirulent Liver Abscess and Metastatic Infection Hypervirulent plasmids carrying capsule and siderophore functions enable invasive clones to cause pyogenic liver abscess and metastatic spread.

Show evidence (2 references)

PMID:42021129 SUPPORT In Vitro

"Functional assays demonstrated that plasmid curing abolished the hypermucoviscous phenotype, reduced capsule production"

CRISPR plasmid curing in the human isolate functionally links the plasmid to hypermucoviscosity and capsule abundance.

PMID:42021129 SUPPORT Model Organism

"completely attenuated virulence in murine models, confirming the plasmid as the principal driver of hypervirulence"

Mouse infection experiments showed that the cured derivative lost the virulence phenotype, complementing the in-vitro capsule and viscosity assays.

Carbapenemase-Mediated Antibiotic Resistance

Carbapenem-resistant K. pneumoniae bloodstream isolates frequently encode KPC, NDM, or OXA-48 carbapenemases, making invasive infection harder to eradicate and shifting therapy away from ordinary carbapenems.

Downstream

Bacteremia and Sepsis Resistance delays or limits active antibiotic therapy and thereby increases the chance that bloodstream infection persists and progresses.

Show evidence (2 references)

PMID:42734011 SUPPORT Human Clinical

"In total, 88.9% (48/54) isolates were detected with KPC carbapenemase, followed by NDM carbapenemase at 7.4% (4/54)."

Quantifies KPC and NDM carbapenemases in a CRKP bloodstream-infection cohort.

PMID:42439974 SUPPORT Human Clinical

"OXA-48 was identified as the predominant carbapenemase, occurring in 50.4% of cases, followed by combinations involving New Delhi metallo-beta-lactamase (NDM) and Klebsiella pneumoniae carbapenemase (KPC)."

Shows that OXA-48 and NDM/KPC combinations also contribute to CRE epidemiology in K. pneumoniae-dominated cohorts.

Klebsiella FMN Riboswitch-Gated Riboflavin Supply (Investigational Target)

K. pneumoniae depends on a flavin mononucleotide riboswitch to gate expression of its riboflavin biosynthesis genes, and that regulatory RNA is a candidate antibacterial target rather than a mechanism of disease. It is recorded here because the vulnerability is specific to this organism in a way that does not generalize: the FMN riboswitch aptamer is poorly conserved across Gram-negative genera, and K. pneumoniae sits at 90 percent identity to the E. coli element while Acinetobacter baumannii sits at 61 percent, which is why the riboswitch-ligand compound series reaches Enterobacteriaceae and not the other Gram-negative ESKAPE pathogens. Entirely investigational: the evidence is in vitro susceptibility of multidrug-resistant clinical isolates, no riboswitch-targeting compound has entered clinical development, and nothing here is a treatment option. The resistance frequency reported for this target in K. pneumoniae is of the same order as in E. coli, so target-site mutation is an expected liability rather than a remote one.

Downstream

Riboswitch Target-Site Resistance in Klebsiella Because the target is the regulatory RNA itself, mutation of the aptamer or expression platform escapes the compound without disabling riboflavin synthesis.

Show evidence (3 references)

PMID:32432858 SUPPORT In Vitro

"Extensive panels of MDR clinical isolates of E. coli (n=42) and K. pneumoniae (n=54) were assessed for their susceptibility to (-)3, also called Ribocil C-PA."

Establishes that a riboswitch-targeting compound was tested against a large panel of multidrug-resistant K. pneumoniae clinical isolates, which is the basis for recording this organism's FMN riboswitch as a candidate target.

PMID:32432858 SUPPORT In Vitro

"sequence identity of aptamer relative to E. coli): K. pneumoniae (90%); E. cloacae (87%); P. aeruginosa (72%); A. baumannii (61%)"

Gives the aptamer conservation figures behind this node's claim that the vulnerability is genus-specific and that K. pneumoniae is among the reachable organisms.

PMID:32432858 SUPPORT In Vitro

"Significant target-based resistance was observed in all of these strains"

Supports the resistance caveat in this node; the cited experiment selected resistant mutants in K. pneumoniae ATCC 27736 alongside two E. coli strains.

Riboswitch Target-Site Resistance in Klebsiella

Selection of K. pneumoniae mutants resistant to the riboswitch-ligand compound series yields target-based resistance at a frequency of the same order as in E. coli, and the resistance maps to the regulatory RNA rather than to a biosynthetic enzyme. This is recorded as an anticipated liability of the investigational target, not as a clinical resistance mechanism of this disease: no riboswitch-targeting compound is in use, so there is no treatment for an isolate to be resistant to. It is distinct from the carbapenemase resistance modelled elsewhere in this entry, which is a present-day clinical problem.

Response to Antibiotic GO:0046677

Show evidence (2 references)

PMID:32432858 SUPPORT In Vitro

"this experiment was conducted in E. coli BW25113, K. pneumoniae ATCC 27736"

Establishes that the resistance-selection experiment included K. pneumoniae, which is what makes this node a claim about this organism rather than an inference from E. coli.

PMID:32432858 SUPPORT In Vitro

"Significant target-based resistance was observed in all of these strains"

Reports that target-based resistance arose in every strain selected, K. pneumoniae among them, which is this node's claim. The reported frequencies at eight times the minimum inhibitory concentration are of the same order in K. pneumoniae as in E. coli; they are not quoted here because the source writes them with characters that do not survive quoting.

Pulmonary Klebsiella Bacterial Burden

Klebsiella pneumoniae reaches the lower respiratory tract, grows as a bacterial burden in lung tissue, and initiates Gram-negative pneumonia.

lung UBERON:0002048

Animal models

Intrapulmonary C57BL/6J mouse K. pneumoniae pneumonia model Mus musculus recapitulates Measures viable K. pneumoniae in lung tissue after controlled intrapulmonary challenge.

Downstream

NLRC4-Dependent IL-1beta Production Intrapulmonary K. pneumoniae challenge induces NLRC4-dependent IL-1beta and chemokine production in the infected lung.

Show evidence (1 reference)

PMID:42439974 SUPPORT Human Clinical

"The majority of the infections were hospital-acquired, with ventilator-associated pneumonia (31.7%) and bloodstream infections (27.8%) being the most prevalent."

Documents K. pneumoniae-dominated CRE infections that commonly presented as ventilator-associated pneumonia.

NLRC4-Dependent IL-1beta Production

The pulmonary response to K. pneumoniae requires the NLRC4 inflammasome for IL-1beta production, neutrophil chemoattractant expression, and survival after lung infection.

neutrophil CL:0000775

interleukin-1 production GO:0032612

Downstream

Neutrophil-Mediated Lung Inflammation

Show evidence (1 reference)

PMID:22547706 SUPPORT Model Organism

"NLRC4 is essential for K. pneumoniae-induced production of IL-1β, IL-17A, and neutrophil chemoattractants (keratinocyte cell-derived chemokines, MIP-2, and LPS-induced CXC chemokines) in the lungs."

Shows that NLRC4 controls IL-1beta and chemoattractant production after K. pneumoniae lung infection.

Neutrophil-Mediated Lung Inflammation

K. pneumoniae infection elicits innate phagocyte recruitment and neutrophil-mediated inflammatory pneumonia in lung tissue.

neutrophil CL:0000775 macrophage CL:0000235

inflammatory response GO:0006954 ↑ INCREASED phagocytosis GO:0006909

lung UBERON:0002048

Downstream

Pneumonia

Bacteremia and Sepsis If lung infection is not contained, viable organisms can disseminate into blood and drive systemic inflammatory organ dysfunction.

Show evidence (1 reference)

PMID:22547706 SUPPORT Model Organism

"In this article, we report that NLRC4 is important for host survival and bacterial clearance, as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae infection."

Identifies neutrophil-mediated lung inflammation as a response to K. pneumoniae infection in the pulmonary model.

Bacteremia and Sepsis

Invasive K. pneumoniae infection can enter the bloodstream, where resistant strains and delayed active therapy are associated with septic physiology, coagulopathy, and high in-hospital mortality.

blood UBERON:0000178

Downstream

Sepsis

Show evidence (1 reference)

PMID:42518856 SUPPORT Human Clinical

"A total of 222 patients (156 male, 70.3%; mean age 66.4 ± 13.6 years) were enrolled. Among them, 106 (47.7%) died during hospitalization."

Quantifies mortality in a human K. pneumoniae bloodstream-infection cohort.

Hypervirulent Liver Abscess and Metastatic Infection

Hypervirulent K. pneumoniae causes pyogenic liver abscess and can disseminate to eye, lung, and central nervous system sites, producing a metastatic invasive syndrome distinct from ordinary nosocomial pneumonia.

liver UBERON:0002107

Downstream

Liver abscess

Show evidence (1 reference)

PMID:41356976 SUPPORT REVIEW SYNTHESIS Human Clinical

"Metastatic infection occurred in 36% of cases, most commonly endophthalmitis (36%), followed by pulmonary (19%) and central nervous system involvement (15%)."

A systematic review of hvKp liver abscess cases documents frequent metastatic spread beyond the liver.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

3

Digestive 1

Liver abscess HP:0100523

Show evidence (1 reference)

PMID:41356976 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hypervirulent Klebsiella pneumoniae (hvKp) is an emerging cause of pyogenic liver abscess (PLA), characterized by virulence genes, such as rmpA and rmpA2, as well as capsular types K1/K2 that enhance mucoviscosity and invasiveness."

The hvKp systematic review identifies pyogenic liver abscess as a characteristic human syndrome of hypervirulent K. pneumoniae.

Immune 2

Pneumonia HP:0002090

Show evidence (1 reference)

PMID:42439974 SUPPORT Human Clinical

"The majority of the infections were hospital-acquired, with ventilator-associated pneumonia (31.7%) and bloodstream infections (27.8%) being the most prevalent."

Reports ventilator-associated pneumonia as the most prevalent CRE infection syndrome in a cohort where K. pneumoniae caused almost all infections.

Sepsis HP:0100806

Show evidence (1 reference)

PMID:42127138 SUPPORT Human Clinical

"Klebsiella pneumoniae is the leading cause of sepsis among neonates in low- and middle-income countries (LMICs) in Africa and Asia, contributing substantially to the overall burden of antimicrobial-resistant infections and mortality among neonates globally."

Establishes sepsis as a major human manifestation of invasive neonatal K. pneumoniae infection.

💊

Medical Actions

3

Susceptibility-Guided Antibiotic Therapy

Action: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Directed antibacterial treatment is selected after species identification and susceptibility or resistance testing, especially for extended-spectrum beta-lactamase-producing or carbapenem-resistant Enterobacterales.

Mechanism Target:

INHIBITS Pulmonary Klebsiella Bacterial Burden — Antibiotics are chosen to eradicate the identified K. pneumoniae isolate according to its susceptibility profile.

INHIBITS Bacteremia and Sepsis — Rapid active therapy clears bloodstream organisms and reduces the chance of persistent septic physiology.

Show evidence (1 reference)

PMID:35439291 SUPPORT REVIEW SYNTHESIS Other

"Preferred and alternative treatment recommendations are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known."

IDSA guidance frames therapy for resistant Enterobacterales around organism identification and antibiotic-susceptibility results, which is the core treatment decision for resistant K. pneumoniae pneumonia.

Ceftazidime-avibactam for carbapenem-resistant Enterobacterales bacteremia

Action: Pharmacotherapy NCIT:C15986

Agent: ceftazidime CHEBI:3508 avibactam CHEBI:85984

Platform: Small molecule

Ceftazidime-avibactam is an active beta-lactam/beta-lactamase-inhibitor option for susceptible CRE bloodstream infection, particularly KPC-producing isolates.

Mechanism Target:

INHIBITS Carbapenemase-Mediated Antibiotic Resistance — The avibactam component restores activity against susceptible beta-lactamase-producing Enterobacterales that would otherwise resist carbapenem therapy.

INHIBITS Bacteremia and Sepsis — Active therapy accelerates bloodstream clearance of CRE bacteremia.

Show evidence (1 reference)

PMID:42708480 SUPPORT Human Clinical

"CAZ-AVI showed higher rapid negative conversion for CRE bacteremia in patients with hematologic malignancy, compared to the alternative antibiotics."

A retrospective hematologic-malignancy cohort found faster negative blood culture conversion with ceftazidime-avibactam than with alternative antibiotics.

Intravenous fosfomycin-containing combination regimens

Action: Pharmacotherapy NCIT:C15986

Agent: fosfomycin CHEBI:28915

Platform: Small molecule

Intravenous fosfomycin is used as part of combination therapy for severe carbapenem-resistant Gram-negative infections, including K. pneumoniae hospital-acquired pneumonia, bacteremia, sepsis, and complicated urinary tract infection.

Mechanism Target:

INHIBITS Pulmonary Klebsiella Bacterial Burden — Fosfomycin-containing combinations help treat severe carbapenem-resistant K. pneumoniae infection at pulmonary and bloodstream sites.

INHIBITS Bacteremia and Sepsis — Combination therapy aims to clear carbapenem-resistant Gram-negative bacteremia and sepsis.

Show evidence (1 reference)

PMID:42599357 SUPPORT Human Clinical

"Overall, clinical success was achieved in 79.4% of patients, while the successful clinical response and microbiological cure rates were 87.5% and 81.3% at the end of FOS treatment, respectively."

Shows favorable clinical and microbiological outcomes in a carbapenem-resistant Gram-negative infection cohort in which most patients received fosfomycin as part of combination therapy and K. pneumoniae predominated.

🌍

Environmental Factors

2

Prior broad-spectrum antibiotic and carbapenem exposure

Antibiotic selection pressure, especially prior carbapenem, quinolone, glycopeptide, or beta-lactam/beta-lactamase-inhibitor exposure, is the dominant modifiable risk context for carbapenem-resistant K. pneumoniae infection.

Show evidence (1 reference)

PMID:31525540 SUPPORT Human Clinical

"Immunosuppression, ICU admission, antibiotic exposure (including carbapenems, quinolones, glycopeptides and BL/BLIs), surgery, mechanical ventilation, central venous catheterisation, indwelling catheter and nasogastric intubation were identified as risk factors for CRKP infection and should to..."

Summarizes the meta-analysis evidence that healthcare antibiotic exposure and device-intensive care predispose to CRKP infection.

Mechanism Target:

PREDISPOSES Carbapenemase-Mediated Antibiotic Resistance — Antibiotic exposure selects carbapenemase-carrying lineages in colonized patients and thereby predisposes to infection that resists empiric carbapenem therapy.

Show evidence (1 reference)

PMID:31525540 SUPPORT Human Clinical

"carbapenem exposure, 3.99 (2.86-5.56); quinolone exposure, 1.75 (1.38-2.22); glycopeptide exposure, 3.08 (1.93-4.91)"

A 30-study meta-analysis quantified prior antibiotic classes as risk factors for CRKP infection.

Neonatal-unit nosocomial transmission

K. pneumoniae sepsis in African and South Asian neonatal units is frequently transmitted in nosocomial clusters, linking hospital contact networks to the mucosal reservoirs that seed invasive neonatal infection.

Show evidence (1 reference)

PMID:42127138 SUPPORT Human Clinical

"Nosocomial transmission contributes to a substantial proportion of K. pneumoniae sepsis in neonatal care units in Africa and South Asia."

The cohort conclusion supports neonatal-unit transmission as a documented context for invasive K. pneumoniae disease.

Mechanism Target:

TRIGGERS Mucosal Reservoir and Sterile-Site Invasion — Transmission in neonatal units introduces resistant K. pneumoniae clones into vulnerable hosts, after which colonization can progress to invasive sepsis.

Show evidence (1 reference)

PMID:42127138 SUPPORT Human Clinical

"Overall, we estimated that 1,035 neonatal infections (68.0%) were part of nosocomial transmission clusters."

Quantifies hospital-linked neonatal infections as part of nosocomial clusters inferred from pathogen genomes and timing.

🔬

Diagnosis

3

MALDI-TOF species identification

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry rapidly identifies cultured K. pneumoniae isolates from clinically relevant specimens.

MALDI-TOF mass spectrometry

Show evidence (1 reference)

PMID:27239799 SUPPORT Human Clinical

"A total of 174 K. pneumoniae isolates obtained from clinically relevant material were correctly identified by Bruker MALDI-TOF MS with log (score) >2.0."

Demonstrates MALDI-TOF identification of K. pneumoniae in a 174-isolate diagnostic study.

Blood-culture molecular pathogen and KPC detection

Rapid molecular panels on positive blood cultures can identify bloodstream pathogens and detect resistance determinants such as blaKPC before slower conventional susceptibility workflows finish.

blood culture identification panel

Show evidence (1 reference)

PMID:32305272 SUPPORT Human Clinical

"Among the 100 positively flagged blood cultures, 94% of FilmArray BCID panel results were consistent with the MALDI Biotyper results."

Supports rapid molecular identification from positive blood cultures as concordant with MALDI-TOF in a comparative diagnostic study.

MALDIxin colistin-resistance detection

MALDIxin detects lipid A modifications that mediate K. pneumoniae colistin and polymyxin resistance and can distinguish chromosomal from plasmid MCR mechanisms.

MALDIxin lipid A resistance test

Show evidence (1 reference)

PMID:31580426 SUPPORT Human Clinical

"The optimized method allowed the rapid (<30 min) identification of l-Ara4N- and pEtN-modified lipid A of K. pneumoniae, which are known to be the real triggers of polymyxin resistance."

Shows that MALDIxin can rapidly detect lipid A modifications that confer polymyxin resistance in K. pneumoniae.

🦠

Infectious Agent

1

Klebsiella pneumoniae

Encapsulated Gram-negative bacterium that can colonize mucosal reservoirs, cause human neonatal sepsis and hospital-acquired pneumonia, and acquire carbapenemase or hypervirulence plasmids that intensify invasive disease.

Klebsiella pneumoniae NCBITaxon:573

Show evidence (1 reference)

PMID:42127138 SUPPORT Human Clinical

"Klebsiella pneumoniae is the leading cause of sepsis among neonates in low- and middle-income countries (LMICs) in Africa and Asia, contributing substantially to the overall burden of antimicrobial-resistant infections and mortality among neonates globally."

Establishes K. pneumoniae as a human invasive pathogen in a genomics-supported neonatal-sepsis cohort.

🐁

Animal Models

1

Intrapulmonary C57BL/6J mouse K. pneumoniae pneumonia model Pulmonary challenge model

Male C57BL/6J mice inoculated intrapulmonarily with K. pneumoniae ATCC 43816 develop bronchopneumonia, pulmonary bacterial burden, innate leukocyte recruitment, and survival changes that measure local antibacterial immunity after TLR4 agonist pretreatment.

Species

Mus musculus

Background

C57BL/6J

Pathograph links

Pulmonary Klebsiella Bacterial Burden recapitulates fidelity: moderate observes: organism Measures viable K. pneumoniae in lung tissue after controlled intrapulmonary challenge.

Limitations: The model uses a defined intrapulmonary inoculum in otherwise healthy male mice; it does not reproduce chronic human colonization, device-associated ventilator pneumonia, or resistant plasmid ecology.

Show evidence (1 reference)

PMID:36018281 SUPPORT Model Organism

"Mice received intrapulmonary 3D PHAD (20 μg) or vehicle for 2 consecutive days before challenge with intrapulmonary Klebsiella pneumoniae (2.3 × 10 3 colony-forming units)."

Describes the controlled intrapulmonary mouse challenge used to model K. pneumoniae pneumonia and TLR4 agonist pretreatment.

{ }

Source YAML

click to show

name: Klebsiella Pneumonia
creation_date: "2026-09-25T22:18:26Z"
category: Infectious Disease
description: >-
Klebsiella pneumonia is acute bacterial pneumonia caused by Klebsiella
pneumoniae, an encapsulated Gram-negative ESKAPE pathogen that causes
healthcare-associated pneumonia, bloodstream infection, and
carbapenem-resistant invasive disease, and whose hypervirulent capsule and
siderophore lineages can disseminate to liver and other organs.
disease_term:
preferred_term: Klebsiella pneumonia
term:
id: MONDO:0030602
label: Klebsiella pneumonia
parents:
- Bacterial Pneumonia
- Klebsiella Infectious Disease
synonyms:
- pneumonia due to Klebsiella pneumoniae
- Klebsiella caused pneumonia
- Friedlander pneumonia
infectious_agent:
- name: Klebsiella pneumoniae
description: >-
Encapsulated Gram-negative bacterium that can colonize mucosal reservoirs,
cause human neonatal sepsis and hospital-acquired pneumonia, and acquire
carbapenemase or hypervirulence plasmids that intensify invasive disease.
infectious_agent_term:
preferred_term: Klebsiella pneumoniae
term:
id: NCBITaxon:573
label: Klebsiella pneumoniae
evidence:
- reference: PMID:42127138
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Klebsiella pneumoniae is the leading cause of sepsis among neonates in
low- and middle-income countries (LMICs) in Africa and Asia, contributing
substantially to the overall burden of antimicrobial-resistant infections
and mortality among neonates globally.
explanation: >-
Establishes K. pneumoniae as a human invasive pathogen in a
genomics-supported neonatal-sepsis cohort.
classifications:
harrisons_chapter:
- classification_value: INFECTIOUS_DISEASES
evidence:
- reference: PMID:42178970
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Among the most-concerning multidrug-resistant (MDR) pathogens are the
ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus,
Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa,
and Enterobacter spp.)
explanation: >-
Frames K. pneumoniae as a clinically important bacterial infectious
pathogen rather than a model-only inoculum.

environmental:
- name: Prior broad-spectrum antibiotic and carbapenem exposure
description: >-
Antibiotic selection pressure, especially prior carbapenem, quinolone,
glycopeptide, or beta-lactam/beta-lactamase-inhibitor exposure, is the
dominant modifiable risk context for carbapenem-resistant K. pneumoniae
infection.
influences_mechanisms:
- target: Carbapenemase-Mediated Antibiotic Resistance
environmental_effect: PREDISPOSES
causal_link_type: DIRECT
description: >-
Antibiotic exposure selects carbapenemase-carrying lineages in colonized
patients and thereby predisposes to infection that resists empiric
carbapenem therapy.
evidence:
- reference: PMID:31525540
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
carbapenem exposure, 3.99 (2.86-5.56); quinolone exposure, 1.75
(1.38-2.22); glycopeptide exposure, 3.08 (1.93-4.91)
explanation: >-
A 30-study meta-analysis quantified prior antibiotic classes as risk
factors for CRKP infection.
evidence:
- reference: PMID:31525540
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunosuppression, ICU admission, antibiotic exposure (including
carbapenems, quinolones, glycopeptides and BL/BLIs), surgery, mechanical
ventilation, central venous catheterisation, indwelling catheter and
nasogastric intubation were identified as risk factors for CRKP infection
and should to be considered in clinical practice.
explanation: >-
Summarizes the meta-analysis evidence that healthcare antibiotic exposure
and device-intensive care predispose to CRKP infection.
- name: Neonatal-unit nosocomial transmission
description: >-
K. pneumoniae sepsis in African and South Asian neonatal units is frequently
transmitted in nosocomial clusters, linking hospital contact networks to the
mucosal reservoirs that seed invasive neonatal infection.
influences_mechanisms:
- target: Mucosal Reservoir and Sterile-Site Invasion
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >-
Transmission in neonatal units introduces resistant K. pneumoniae clones
into vulnerable hosts, after which colonization can progress to invasive
sepsis.
evidence:
- reference: PMID:42127138
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, we estimated that 1,035 neonatal infections (68.0%) were part
of nosocomial transmission clusters.
explanation: >-
Quantifies hospital-linked neonatal infections as part of nosocomial
clusters inferred from pathogen genomes and timing.
evidence:
- reference: PMID:42127138
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nosocomial transmission contributes to a substantial proportion of K.
pneumoniae sepsis in neonatal care units in Africa and South Asia.
explanation: >-
The cohort conclusion supports neonatal-unit transmission as a documented
context for invasive K. pneumoniae disease.

pathophysiology:
- name: Mucosal Reservoir and Sterile-Site Invasion
role: trigger
description: >-
K. pneumoniae establishes mucosal or device-associated reservoirs in
healthcare settings, and transmitted or selected clones can breach barriers
into sterile compartments such as the lower respiratory tract and blood.
biological_scale: ORGANISM
locations:
- preferred_term: lung
term:
id: UBERON:0002048
label: lung
- preferred_term: blood
term:
id: UBERON:0000178
label: blood
downstream:
- target: Capsule and Siderophore Immune Evasion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Once K. pneumoniae reaches a normally sterile site, capsule and
siderophore programs help the bacterium survive complement,
phagocytosis, and iron limitation.
- target: Pulmonary Klebsiella Bacterial Burden
causal_link_type: DIRECT
description: >-
Invasion of the lower airway seeds an expanding pulmonary bacterial
burden.
evidence:
- reference: PMID:42127138
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we estimate at least 879 (57.7%) infections were acquired via nosocomial
transmission.
explanation: >-
Genomic clustering in neonatal units supports hospital transmission of
K. pneumoniae that progresses to invasive sterile-site disease.

- name: Capsule and Siderophore Immune Evasion
role: amplifier
description: >-
Hypervirulent K. pneumoniae can acquire plasmid-encoded regulators of
mucoid phenotype and siderophore loci that increase capsule production,
hypermucoviscosity, iron acquisition, and resistance to early innate
clearance.
biological_scale: CELLULAR
downstream:
- target: Pulmonary Klebsiella Bacterial Burden
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Capsule-mediated antiphagocytic activity lets virulent clones persist and
replicate at infected tissue sites.
- target: Hypervirulent Liver Abscess and Metastatic Infection
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Hypervirulent plasmids carrying capsule and siderophore functions enable
invasive clones to cause pyogenic liver abscess and metastatic spread.
evidence:
- reference: PMID:42021129
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genomic analysis identified a 181 kb IncHI1B/IncFIB virulence plasmid
encoding rmpADC and the salmochelin cluster (iroBCDN), but lacking iuc
and rmpA2.
explanation: >-
Identifies the virulence plasmid carried by a human hvKp liver-abscess
isolate.
evidence:
- reference: PMID:42021129
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional assays demonstrated that plasmid curing abolished the
hypermucoviscous phenotype, reduced capsule production
explanation: >-
CRISPR plasmid curing in the human isolate functionally links the plasmid
to hypermucoviscosity and capsule abundance.
- reference: PMID:42021129
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
completely attenuated virulence in murine models, confirming the plasmid
as the principal driver of hypervirulence
explanation: >-
Mouse infection experiments showed that the cured derivative lost the
virulence phenotype, complementing the in-vitro capsule and viscosity
assays.

- name: Carbapenemase-Mediated Antibiotic Resistance
role: amplifier
description: >-
Carbapenem-resistant K. pneumoniae bloodstream isolates frequently encode
KPC, NDM, or OXA-48 carbapenemases, making invasive infection harder to
eradicate and shifting therapy away from ordinary carbapenems.
biological_scale: MOLECULAR
downstream:
- target: Bacteremia and Sepsis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Resistance delays or limits active antibiotic therapy and thereby
increases the chance that bloodstream infection persists and progresses.
evidence:
- reference: PMID:42734011
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In total, 88.9% (48/54) isolates were detected with KPC carbapenemase,
followed by NDM carbapenemase at 7.4% (4/54).
explanation: >-
Quantifies KPC and NDM carbapenemases in a CRKP bloodstream-infection
cohort.
- reference: PMID:42439974
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
OXA-48 was identified as the predominant carbapenemase, occurring in
50.4% of cases, followed by combinations involving New Delhi
metallo-beta-lactamase (NDM) and Klebsiella pneumoniae carbapenemase
(KPC).
explanation: >-
Shows that OXA-48 and NDM/KPC combinations also contribute to CRE
epidemiology in K. pneumoniae-dominated cohorts.

- name: Klebsiella FMN Riboswitch-Gated Riboflavin Supply (Investigational Target)
role: therapeutic_vulnerability
conforms_to: "bacterial_riboswitch_targeting#Riboswitch-Gated Essential Gene Expression (Riboswitch Target)"
description: >-
K. pneumoniae depends on a flavin mononucleotide riboswitch to gate
expression of its riboflavin biosynthesis genes, and that regulatory RNA is a
candidate antibacterial target rather than a mechanism of disease. It is
recorded here because the vulnerability is specific to this organism in a way
that does not generalize: the FMN riboswitch aptamer is poorly conserved
across Gram-negative genera, and K. pneumoniae sits at 90 percent identity to
the E. coli element while Acinetobacter baumannii sits at 61 percent, which is
why the riboswitch-ligand compound series reaches Enterobacteriaceae and not
the other Gram-negative ESKAPE pathogens. Entirely investigational: the
evidence is in vitro susceptibility of multidrug-resistant clinical isolates,
no riboswitch-targeting compound has entered clinical development, and
nothing here is a treatment option. The resistance frequency reported for this
target in K. pneumoniae is of the same order as in E. coli, so target-site
mutation is an expected liability rather than a remote one.
biological_scale: MOLECULAR
evidence:
- reference: PMID:32432858
reference_title: Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Extensive panels of MDR clinical isolates of E. coli (n=42) and K.
pneumoniae (n=54) were assessed for their susceptibility to (-)3, also
called Ribocil C-PA.
explanation: >-
Establishes that a riboswitch-targeting compound was tested against a large
panel of multidrug-resistant K. pneumoniae clinical isolates, which is the
basis for recording this organism's FMN riboswitch as a candidate target.
- reference: PMID:32432858
reference_title: Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
sequence identity of aptamer relative to E. coli): K. pneumoniae (90%); E.
cloacae (87%); P. aeruginosa (72%); A. baumannii (61%)
explanation: >-
Gives the aptamer conservation figures behind this node's claim that the
vulnerability is genus-specific and that K. pneumoniae is among the
reachable organisms.
- reference: PMID:32432858
reference_title: Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Significant target-based resistance was observed in all of these strains
explanation: >-
Supports the resistance caveat in this node; the cited experiment selected
resistant mutants in K. pneumoniae ATCC 27736 alongside two E. coli
strains.
downstream:
- target: Riboswitch Target-Site Resistance in Klebsiella
description: >-
Because the target is the regulatory RNA itself, mutation of the aptamer or
expression platform escapes the compound without disabling riboflavin
synthesis.

- name: Riboswitch Target-Site Resistance in Klebsiella
role: adaptive_escape
conforms_to: "bacterial_riboswitch_targeting#Riboswitch Target-Site Resistance"
description: >-
Selection of K. pneumoniae mutants resistant to the riboswitch-ligand
compound series yields target-based resistance at a frequency of the same
order as in E. coli, and the resistance maps to the regulatory RNA rather
than to a biosynthetic enzyme. This is recorded as an anticipated liability of
the investigational target, not as a clinical resistance mechanism of this
disease: no riboswitch-targeting compound is in use, so there is no treatment
for an isolate to be resistant to. It is distinct from the carbapenemase
resistance modelled elsewhere in this entry, which is a present-day clinical
problem.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: Response to Antibiotic
term:
id: GO:0046677
label: response to antibiotic
evidence:
- reference: PMID:32432858
reference_title: Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
this experiment was conducted in E. coli BW25113, K. pneumoniae ATCC 27736
explanation: >-
Establishes that the resistance-selection experiment included K.
pneumoniae, which is what makes this node a claim about this organism
rather than an inference from E. coli.
- reference: PMID:32432858
reference_title: Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Significant target-based resistance was observed in all of these strains
explanation: >-
Reports that target-based resistance arose in every strain selected,
K. pneumoniae among them, which is this node's claim. The reported
frequencies at eight times the minimum inhibitory concentration are of the
same order in K. pneumoniae as in E. coli; they are not quoted here because
the source writes them with characters that do not survive quoting.

- name: Pulmonary Klebsiella Bacterial Burden
role: trigger
description: >-
Klebsiella pneumoniae reaches the lower respiratory tract, grows as a
bacterial burden in lung tissue, and initiates Gram-negative pneumonia.
biological_scale: TISSUE
locations:
- preferred_term: lung
term:
id: UBERON:0002048
label: lung
downstream:
- target: NLRC4-Dependent IL-1beta Production
causal_link_type: DIRECT
description: >-
Intrapulmonary K. pneumoniae challenge induces NLRC4-dependent IL-1beta
and chemokine production in the infected lung.
evidence:
- reference: PMID:42439974
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The majority of the infections were hospital-acquired, with
ventilator-associated pneumonia (31.7%) and bloodstream infections
(27.8%) being the most prevalent.
explanation: >-
Documents K. pneumoniae-dominated CRE infections that commonly presented
as ventilator-associated pneumonia.

- name: NLRC4-Dependent IL-1beta Production
role: amplifier
description: >-
The pulmonary response to K. pneumoniae requires the NLRC4 inflammasome for
IL-1beta production, neutrophil chemoattractant expression, and survival
after lung infection.
biological_scale: CELLULAR
biological_processes:
- preferred_term: interleukin-1 production
term:
id: GO:0032612
label: interleukin-1 production
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
downstream:
- target: Neutrophil-Mediated Lung Inflammation
causal_link_type: DIRECT
evidence:
- reference: PMID:22547706
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
NLRC4 is essential for K. pneumoniae-induced production of IL-1β,
IL-17A, and neutrophil chemoattractants (keratinocyte cell-derived
chemokines, MIP-2, and LPS-induced CXC chemokines) in the lungs.
explanation: >-
Directly connects K. pneumoniae-induced NLRC4 signaling to IL-1beta and
neutrophil-chemoattractant production in infected lungs.
evidence:
- reference: PMID:22547706
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
NLRC4 is essential for K. pneumoniae-induced production of IL-1β, IL-17A,
and neutrophil chemoattractants (keratinocyte cell-derived chemokines,
MIP-2, and LPS-induced CXC chemokines) in the lungs.
explanation: >-
Shows that NLRC4 controls IL-1beta and chemoattractant production after
K. pneumoniae lung infection.

- name: Neutrophil-Mediated Lung Inflammation
role: effector
description: >-
K. pneumoniae infection elicits innate phagocyte recruitment and
neutrophil-mediated inflammatory pneumonia in lung tissue.
biological_scale: TISSUE
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
- preferred_term: phagocytosis
term:
id: GO:0006909
label: phagocytosis
locations:
- preferred_term: lung
term:
id: UBERON:0002048
label: lung
downstream:
- target: Pneumonia
causal_link_type: DIRECT
- target: Bacteremia and Sepsis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
If lung infection is not contained, viable organisms can disseminate into
blood and drive systemic inflammatory organ dysfunction.
evidence:
- reference: PMID:22547706
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In this article, we report that NLRC4 is important for host survival and
bacterial clearance, as well as neutrophil-mediated inflammation in the
lungs following Klebsiella pneumoniae infection.
explanation: >-
Identifies neutrophil-mediated lung inflammation as a response to
K. pneumoniae infection in the pulmonary model.

- name: Bacteremia and Sepsis
role: outcome
description: >-
Invasive K. pneumoniae infection can enter the bloodstream, where resistant
strains and delayed active therapy are associated with septic physiology,
coagulopathy, and high in-hospital mortality.
biological_scale: ORGANISM
locations:
- preferred_term: blood
term:
id: UBERON:0000178
label: blood
downstream:
- target: Sepsis
causal_link_type: DIRECT
evidence:
- reference: PMID:42518856
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 222 patients (156 male, 70.3%; mean age 66.4 ± 13.6 years)
were enrolled. Among them, 106 (47.7%) died during hospitalization.
explanation: >-
Quantifies mortality in a human K. pneumoniae bloodstream-infection
cohort.

- name: Hypervirulent Liver Abscess and Metastatic Infection
role: outcome
description: >-
Hypervirulent K. pneumoniae causes pyogenic liver abscess and can
disseminate to eye, lung, and central nervous system sites, producing a
metastatic invasive syndrome distinct from ordinary nosocomial pneumonia.
biological_scale: ORGANISM
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
downstream:
- target: Liver abscess
causal_link_type: DIRECT
evidence:
- reference: PMID:41356976
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Metastatic infection occurred in 36% of cases, most commonly
endophthalmitis (36%), followed by pulmonary (19%) and central nervous
system involvement (15%).
explanation: >-
A systematic review of hvKp liver abscess cases documents frequent
metastatic spread beyond the liver.

phenotypes:
- name: Pneumonia
description: >-
Hospital-acquired or ventilator-associated bacterial pneumonia can be caused
by K. pneumoniae, including carbapenem-resistant isolates.
phenotype_term:
preferred_term: Pneumonia
term:
id: HP:0002090
label: Pneumonia
evidence:
- reference: PMID:42439974
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The majority of the infections were hospital-acquired, with
ventilator-associated pneumonia (31.7%) and bloodstream infections
(27.8%) being the most prevalent.
explanation: >-
Reports ventilator-associated pneumonia as the most prevalent CRE
infection syndrome in a cohort where K. pneumoniae caused almost all
infections.
- name: Sepsis
description: >-
K. pneumoniae causes neonatal and adult bloodstream infection that can
progress to life-threatening sepsis and in-hospital mortality.
phenotype_term:
preferred_term: Sepsis
term:
id: HP:0100806
label: Sepsis
evidence:
- reference: PMID:42127138
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Klebsiella pneumoniae is the leading cause of sepsis among neonates in
low- and middle-income countries (LMICs) in Africa and Asia, contributing
substantially to the overall burden of antimicrobial-resistant infections
and mortality among neonates globally.
explanation: >-
Establishes sepsis as a major human manifestation of invasive neonatal
K. pneumoniae infection.
- name: Liver abscess
description: >-
Hypervirulent K. pneumoniae can cause pyogenic liver abscess with disabling
metastatic complications such as endophthalmitis.
phenotype_term:
preferred_term: Liver abscess
term:
id: HP:0100523
label: Liver abscess
evidence:
- reference: PMID:41356976
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Hypervirulent Klebsiella pneumoniae (hvKp) is an emerging cause of
pyogenic liver abscess (PLA), characterized by virulence genes, such as
rmpA and rmpA2, as well as capsular types K1/K2 that enhance mucoviscosity
and invasiveness.
explanation: >-
The hvKp systematic review identifies pyogenic liver abscess as a
characteristic human syndrome of hypervirulent K. pneumoniae.

treatments:
- name: Susceptibility-Guided Antibiotic Therapy
description: >-
Directed antibacterial treatment is selected after species identification
and susceptibility or resistance testing, especially for extended-spectrum
beta-lactamase-producing or carbapenem-resistant Enterobacterales.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Antibiotic Therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
target_mechanisms:
- target: Pulmonary Klebsiella Bacterial Burden
treatment_effect: INHIBITS
description: >-
Antibiotics are chosen to eradicate the identified K. pneumoniae isolate
according to its susceptibility profile.
- target: Bacteremia and Sepsis
treatment_effect: INHIBITS
description: >-
Rapid active therapy clears bloodstream organisms and reduces the chance
of persistent septic physiology.
evidence:
- reference: PMID:35439291
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: OTHER
snippet: >-
Preferred and alternative treatment recommendations are provided with
accompanying rationales, assuming the causative organism has been
identified and antibiotic susceptibility results are known.
explanation: >-
IDSA guidance frames therapy for resistant Enterobacterales around
organism identification and antibiotic-susceptibility results, which is
the core treatment decision for resistant K. pneumoniae pneumonia.
- name: Ceftazidime-avibactam for carbapenem-resistant Enterobacterales bacteremia
description: >-
Ceftazidime-avibactam is an active beta-lactam/beta-lactamase-inhibitor
option for susceptible CRE bloodstream infection, particularly KPC-producing
isolates.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ceftazidime
term:
id: CHEBI:3508
label: ceftazidime
- preferred_term: avibactam
term:
id: CHEBI:85984
label: avibactam
target_mechanisms:
- target: Carbapenemase-Mediated Antibiotic Resistance
treatment_effect: INHIBITS
description: >-
The avibactam component restores activity against susceptible
beta-lactamase-producing Enterobacterales that would otherwise resist
carbapenem therapy.
- target: Bacteremia and Sepsis
treatment_effect: INHIBITS
description: >-
Active therapy accelerates bloodstream clearance of CRE bacteremia.
evidence:
- reference: PMID:42708480
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CAZ-AVI showed higher rapid negative conversion for CRE bacteremia in
patients with hematologic malignancy, compared to the alternative
antibiotics.
explanation: >-
A retrospective hematologic-malignancy cohort found faster negative blood
culture conversion with ceftazidime-avibactam than with alternative
antibiotics.
- name: Intravenous fosfomycin-containing combination regimens
description: >-
Intravenous fosfomycin is used as part of combination therapy for severe
carbapenem-resistant Gram-negative infections, including K. pneumoniae
hospital-acquired pneumonia, bacteremia, sepsis, and complicated urinary
tract infection.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: fosfomycin
term:
id: CHEBI:28915
label: fosfomycin
target_mechanisms:
- target: Pulmonary Klebsiella Bacterial Burden
treatment_effect: INHIBITS
description: >-
Fosfomycin-containing combinations help treat severe carbapenem-resistant
K. pneumoniae infection at pulmonary and bloodstream sites.
- target: Bacteremia and Sepsis
treatment_effect: INHIBITS
description: >-
Combination therapy aims to clear carbapenem-resistant Gram-negative
bacteremia and sepsis.
evidence:
- reference: PMID:42599357
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, clinical success was achieved in 79.4% of patients, while the
successful clinical response and microbiological cure rates were 87.5%
and 81.3% at the end of FOS treatment, respectively.
explanation: >-
Shows favorable clinical and microbiological outcomes in a
carbapenem-resistant Gram-negative infection cohort in which most
patients received fosfomycin as part of combination therapy and
K. pneumoniae predominated.

diagnosis:
- name: MALDI-TOF species identification
description: >-
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
rapidly identifies cultured K. pneumoniae isolates from clinically relevant
specimens.
diagnosis_term:
preferred_term: MALDI-TOF mass spectrometry
evidence:
- reference: PMID:27239799
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 174 K. pneumoniae isolates obtained from clinically relevant
material were correctly identified by Bruker MALDI-TOF MS with log (score)
>2.0.
explanation: >-
Demonstrates MALDI-TOF identification of K. pneumoniae in a 174-isolate
diagnostic study.
- name: Blood-culture molecular pathogen and KPC detection
description: >-
Rapid molecular panels on positive blood cultures can identify bloodstream
pathogens and detect resistance determinants such as blaKPC before slower
conventional susceptibility workflows finish.
diagnosis_term:
preferred_term: blood culture identification panel
evidence:
- reference: PMID:32305272
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the 100 positively flagged blood cultures, 94% of FilmArray BCID
panel results were consistent with the MALDI Biotyper results.
explanation: >-
Supports rapid molecular identification from positive blood cultures as
concordant with MALDI-TOF in a comparative diagnostic study.
- name: MALDIxin colistin-resistance detection
description: >-
MALDIxin detects lipid A modifications that mediate K. pneumoniae colistin
and polymyxin resistance and can distinguish chromosomal from plasmid MCR
mechanisms.
diagnosis_term:
preferred_term: MALDIxin lipid A resistance test
evidence:
- reference: PMID:31580426
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The optimized method allowed the rapid (<30 min) identification of
l-Ara4N- and pEtN-modified lipid A of K. pneumoniae, which are known to
be the real triggers of polymyxin resistance.
explanation: >-
Shows that MALDIxin can rapidly detect lipid A modifications that confer
polymyxin resistance in K. pneumoniae.

animal_models:
- name: Intrapulmonary C57BL/6J mouse K. pneumoniae pneumonia model
species: Mus musculus
background: C57BL/6J
category: Pulmonary challenge model
description: >-
Male C57BL/6J mice inoculated intrapulmonarily with K. pneumoniae ATCC 43816
develop bronchopneumonia, pulmonary bacterial burden, innate leukocyte
recruitment, and survival changes that measure local antibacterial immunity
after TLR4 agonist pretreatment.
modeled_mechanisms:
- target: Pulmonary Klebsiella Bacterial Burden
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Measures viable K. pneumoniae in lung tissue after controlled
intrapulmonary challenge.
limitations: >-
The model uses a defined intrapulmonary inoculum in otherwise healthy
male mice; it does not reproduce chronic human colonization,
device-associated ventilator pneumonia, or resistant plasmid ecology.
evidence:
- reference: PMID:36018281
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mice received intrapulmonary 3D PHAD (20 μg) or vehicle for 2 consecutive
days before challenge with intrapulmonary Klebsiella pneumoniae (2.3 × 10
3 colony-forming units).
explanation: >-
Describes the controlled intrapulmonary mouse challenge used to model
K. pneumoniae pneumonia and TLR4 agonist pretreatment.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Klebsiella Pneumonia · 2026-09-25T22:40:03Z · View source

Created the Klebsiella Pneumonia entry for MONDO:0030602 using research/Klebsiella_Pneumonia-deep-research-openscientist.md. Curated Klebsiella pneumoniae as the infectious agent, an NLRC4/IL-1beta to neutrophilic lung-inflammation mechanism chain, the defining pneumonia phenotype, and susceptibility-guided antibiotic therapy. Validated schema, terms, 8/8 cached snippets, and pathograph targets.

OpenScientist ▸

Klebsiella Pneumonia — Comprehensive Disease Characteristics Report

openscientist-autonomous 37 citations 2026-09-25T15:35:33.724675

Klebsiella Pneumonia — Comprehensive Disease Characteristics Report

Disease: Klebsiella pneumonia (infection caused by Klebsiella pneumoniae) MONDO ID: MONDO:0030602 · Pathogen taxonomy: NCBI:txid573 · Category: Infectious Disease Report type: Multi-iteration autonomous literature synthesis (10 confirmed findings; 46 papers reviewed)

Summary

Klebsiella pneumonia is an acute bacterial infection caused by the encapsulated, non-motile, Gram-negative rod Klebsiella pneumoniae, a member of the Enterobacteriaceae. Clinically the disease is not a single entity but a spectrum: lobar/nosocomial pneumonia, ventilator-associated pneumonia, bloodstream infection (bacteremia/sepsis), urinary tract infection, and — for a distinct hypervirulent pathotype — community-acquired pyogenic liver abscess with metastatic spread. K. pneumoniae is one of the ESKAPE organisms and a WHO critical-priority antimicrobial-resistance (AMR) pathogen, making it a central actor in the global AMR crisis PMID: 42178970. Unlike the Mendelian disorders this template was designed around, Klebsiella pneumonia is an infectious, non-heritable disease: its "causal genes" are bacterial virulence and resistance genes, not human germline variants, and host genetic susceptibility loci are minor relative to healthcare exposures.

The investigation converged on a two-pathotype model. Classical K. pneumoniae (cKp) is an opportunistic nosocomial pathogen that infects debilitated, catheterized, ventilated, or antibiotic-exposed patients and is the leading cause of neonatal sepsis in low- and middle-income countries (LMICs); much of its burden is driven by in-hospital transmission PMID: 42127138. Its danger lies in carbapenem resistance mediated by KPC, NDM, and OXA-48 carbapenemases, which pushes in-hospital mortality of bloodstream infection to 30–50% PMID: 42734011, PMID: 42518856. Hypervirulent K. pneumoniae (hvKp) infects younger, immunocompetent hosts in the community, causing invasive liver abscess through K1/K2 capsule serotypes, rmpADC-driven hypermucoviscosity, and multiple siderophore systems PMID: 42021129. The two pathotypes are converging on mobile plasmids (e.g., ST11 KPC-2 hvKp), an emerging worst-case threat that fuses resistance with virulence PMID: 32576652.

Mechanistically, pathogenesis runs from gut/mucosal colonization → barrier breach → capsule- and siderophore-mediated immune evasion → TLR4- and NLRC4-inflammasome-driven neutrophil/macrophage recruitment → either clearance or, when immunity fails or the organism is resistant, invasive infection, sepsis, and death PMID: 22547706, PMID: 36018281. Diagnosis rests on culture with MALDI-TOF species identification plus molecular/phenotypic resistance detection; treatment is susceptibility-guided, favoring newer β-lactam/β-lactamase-inhibitor combinations (ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam) and cefiderocol for metallo-β-lactamase producers; and prevention hinges on antibiotic stewardship and infection control, because no vaccine is yet licensed.

1. Disease Information

Overview. Klebsiella pneumonia is infection by Klebsiella pneumoniae, historically described by Carl Friedländer (hence "Friedländer's bacillus" / "Friedländer's pneumonia") as a cause of severe lobar pneumonia classically producing thick, blood-tinged "currant-jelly" sputum. Modern disease is dominated by healthcare-associated presentations — hospital-acquired and ventilator-associated pneumonia, catheter-associated UTI, and central-line bloodstream infection — plus community-acquired invasive syndromes driven by the hypervirulent pathotype.

Key identifiers. - MONDO: MONDO:0030602 (Klebsiella pneumonia) - Pathogen (NCBI Taxonomy): Klebsiella pneumoniae txid573 - MeSH: Klebsiella Infections (D007710); Pneumonia, Bacterial - ICD-10: J15.0 (Pneumonia due to Klebsiella pneumoniae); A49.8/B96.1 (Klebsiella as cause of disease classified elsewhere) - ICD-11: CA40 (bacterial pneumonia) with pathogen extension; infection codes under 1B/1C - OMIM / Orphanet: Not applicable — this is an acquired infectious disease, not a Mendelian disorder. There is no OMIM phenotype entry; Orphanet does not list it as a rare genetic disease.

Synonyms / alternative names. Friedländer's pneumonia; Friedländer's bacillus infection; Klebsiella pneumoniae infection; Klebsiella infection (when generalized); (for the invasive pathotype) hypervirulent Klebsiella pneumoniae infection / invasive Klebsiella syndrome.

Data source type. The evidence base is overwhelmingly aggregated disease-level — surveillance cohorts, genomic epidemiology, meta-analyses, and clinical guidelines — supplemented by individual case reports/series for the hypervirulent syndrome. It is not derived from a single-patient EHR data file.

2. Etiology

Primary cause — infectious. The disease is caused by infection with K. pneumoniae. There is no human germline genetic cause. Two ecological/virulence pathotypes drive distinct etiologies:

Feature	Classical (cKp)	Hypervirulent (hvKp)
Typical host	Debilitated, hospitalized, immunocompromised	Younger, often immunocompetent
Setting	Nosocomial	Community-acquired
Hallmark syndrome	HAP/VAP, BSI, UTI, neonatal sepsis	Pyogenic liver abscess, metastatic (endophthalmitis, meningitis)
Key genetics	Carbapenemases (KPC/NDM/OXA-48)	K1/K2 capsule, rmpADC, aerobactin/salmochelin/yersiniabactin
Mortality driver	Antibiotic resistance	Dissemination/metastasis

Risk factors (host/environmental — quantified). A meta-analysis of 30 studies (5,075 cases) established that carbapenem-resistant K. pneumoniae (CRKP) infection is driven by healthcare exposures and prior antibiotics, not host demographics PMID: 31525540:

Risk factor	Odds ratio (95% CI)
Carbapenem exposure	3.99 (2.86–5.56)
ICU admission	3.25 (2.36–4.47)
Glycopeptide exposure	3.08 (1.93–4.91)
Central venous catheterization	2.93 (2.00–4.28)
Mechanical ventilation	2.91 (1.96–4.31)
Indwelling (urinary) catheter	2.62 (1.65–4.17)
Any prior antibiotic exposure	2.53 (1.56–4.11)
Nasogastric intubation	2.38 (1.22–4.62)
β-lactam/β-lactamase-inhibitor exposure	2.28 (1.37–3.80)
Quinolone exposure	1.75 (1.38–2.22)
Surgery	1.59 (1.08–2.34)
Immunosuppression	1.47 (1.14–1.90)

Notably, age, sex, and diabetes mellitus were NOT associated with CRKP infection in this meta-analysis (a useful negative finding) — although diabetes is a well-recognized risk factor specifically for hvKp liver abscess in the Asian literature. Additional exposure-based risks include prolonged mechanical ventilation and prolonged ECMO support, where prior antibiotic use before ECMO (RR 1.25) and longer ventilation (RR 1.31) independently predicted healthcare-associated infection PMID: 42685911.

Genetic risk factors (human). No robust, replicated human susceptibility loci for K. pneumoniae disease were identified in this investigation. Innate-immune pathway integrity (TLR4, NLRC4/inflammasome, IL-1β signaling) is mechanistically protective in models, implying that host defects in these pathways would increase susceptibility, but this remains inferred rather than demonstrated in human genetic association studies.

Protective factors. Intact mucosal barriers, a diverse gut microbiome that resists colonization by multidrug-resistant Enterobacterales, and competent innate immunity are protective. Gut microbiome composition modulates intestinal colonization by MDR Enterobacterales PMID: 41009869, PMID: 38659243 — implying microbiome preservation (avoiding unnecessary broad-spectrum antibiotics) is protective. No validated protective human genetic variant was found.

Gene–environment interaction. The dominant interaction is antibiotic exposure × bacterial resistance genotype: antibiotic pressure selects for carbapenemase-carrying clones in the gut reservoir, which then cause endogenous infection or spread nosocomially. This is an environment-(bacterial)genotype interaction rather than a human GxE effect.

3. Phenotypes

Phenotypes are clinical manifestations of infection, varying by syndrome. Onset is typically acute; severity ranges moderate to severe; frequency figures are syndrome-dependent.

Phenotype	Type	Syndrome	Suggested HPO term
Pneumonia / productive cough	Clinical sign	HAP/VAP, CAP	HP:0002090 (Pneumonia); HP:0031246 (Productive cough)
Fever	Symptom	All	HP:0001945 (Fever)
Dyspnea	Symptom	Pneumonia, sepsis	HP:0002094 (Dyspnea)
"Currant-jelly" / bloody sputum	Clinical sign	Friedländer pneumonia	HP:0002105 (Hemoptysis)
Sepsis / septic shock	Clinical sign	BSI	HP:0100806 (Sepsis)
Bacteremia	Laboratory	BSI	HP:0031864 (Bacteremia)*
Liver abscess	Physical/imaging	hvKp	HP:0100523 (Hepatic abscess)*
Leukocytosis	Laboratory	All	HP:0001974 (Leukocytosis)
Elevated D-dimer / coagulopathy	Laboratory	Severe BSI	HP:0003581-adjacent (coagulation abnormality)
Urinary tract infection	Clinical sign	Catheter-associated	HP:0000010 (Recurrent UTI)
Neonatal sepsis	Clinical sign	LMIC neonates	HP:0001945 + neonatal onset
Metastatic endophthalmitis / meningitis	Clinical sign	hvKp dissemination	HP:0000623 / HP:0001287

*Term suggestions; verify exact HPO ID before ingestion.

Age of onset. Bimodal — neonatal (LMIC sepsis) and older adults (nosocomial; mean age ≈66 years, male predominance ≈70% in BSI cohorts). hvKp liver abscess tends to occur in middle-aged adults.

Quality-of-life impact. Severe infection causes ICU-level morbidity, prolonged hospitalization, and long-term functional impairment in survivors of sepsis; disease-specific QoL instruments were not identified in the literature reviewed.

4. Genetic / Molecular Information (bacterial)

Because this is an infectious disease, the relevant genetics are the pathogen's virulence and resistance determinants, not human variants.

Resistance genes (carbapenemases). Carbapenem resistance is mediated chiefly by three carbapenemase families PMID: 42734011, PMID: 42439974: - KPC (blaKPC; class A) — dominant in many regions; 88.9% (48/54) of CRKP BSI isolates in a Chinese cohort. - NDM (blaNDM; class B metallo-β-lactamase) — 7.4% in the same cohort; alters therapy because MBLs hydrolyze most β-lactams and are not inhibited by avibactam/vaborbactam. - OXA-48 (blaOXA-48; class D) — predominant (50.4%) in a southern Saudi Arabia CRE cohort, illustrating strong geographic variation. Additional/associated genes: blaVIM (MBL), blaSHV and blaCTX-M (ESBLs).

Virulence genes. In CRKP BSI, virulence genes ycfM, wabG, and entB were present in all strains; fimH 98.15%, mrkD 96.30%, uge 92.60%, kpn 92.60% PMID: 42734011. For hvKp, the defining loci are the capsular polysaccharide serotypes K1/K2, the regulator of mucoid phenotype operon rmpADC (drives hypermucoviscosity), and multiple siderophore systems — aerobactin, salmochelin (iroBCDN), and yersiniabactin (ybt) — frequently carried on large virulence plasmids. A characterized ST111 hvKp isolate harbored a 181 kb IncHI1B/IncFIB virulence plasmid encoding rmpADC and salmochelin (iroBCDN) plus yersiniabactin; CRISPR/Cas9 plasmid curing followed by murine infection confirmed the plasmid's causal contribution to hypervirulence PMID: 42021129.

Lineages (multilocus sequence types). hvKp liver abscess is canonically linked to ST23, ST65, ST86; convergent resistance-plus-virulence clones include ST11 (KPC-2-producing hvKp).

Epigenetics / chromosomal abnormalities / human modifier genes. Not applicable to this infectious disease. (Bacterial DNA methylation/restriction-modification systems exist but are not disease-defining here.)

5. Environmental Information

Infectious agent. Klebsiella pneumoniae (NCBI:txid573), Gram-negative, encapsulated, non-motile, lactose-fermenting, oxidase-negative rod of the Enterobacteriaceae.

Environmental reservoirs & transmission. The gastrointestinal tract is the principal reservoir; the organism also colonizes the oropharynx and skin, and persists on hospital surfaces and medical devices, enabling patient-to-patient nosocomial transmission via healthcare-worker hands and equipment. Genomic clustering of neonatal isolates across 27 units in 13 countries confirmed extensive nosocomial spread PMID: 42127138.

Lifestyle / host-environment factors. Alcohol use and diabetes are associated with invasive hvKp disease in Asian populations; broad-spectrum antibiotic exposure is the dominant modifiable environmental driver of resistant infection (see Section 2). Timor-Leste and Ethiopian surveillance underscore that third-generation cephalosporin and emerging carbapenem resistance are widespread, particularly in LMIC settings PMID: 42662930, PMID: 42594141.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating event → clinical manifestation)

Gut/mucosal colonization by K. pneumoniae (often a resistant or hypervirulent clone selected by prior antibiotics) establishes a reservoir in the GI tract PMID: 32576652, PMID: 42127138.
Barrier breach — via micro-aspiration into the lung, a urinary/vascular catheter, surgery, or translocation across a compromised gut epithelium — allows the organism to reach a normally sterile site (inferred from reservoir + device risk-factor data).
At the tissue site, the polysaccharide capsule and hypermucoviscosity (hvKp: K1/K2, rmpADC) resist phagocytosis and complement, while siderophores (aerobactin, salmochelin, yersiniabactin) scavenge host iron, enabling bacterial survival and replication PMID: 42021129.
Bacterial ligands (LPS) engage TLR4 on epithelium/macrophages, which triggers NF-κB signaling and cytokine/chemokine release (KC, MIP-2, LIX), recruiting neutrophils and monocytes/macrophages to the lung PMID: 36018281.
In parallel, the NLRC4 inflammasome senses the organism and drives IL-1β (and IL-17A) production, which is essential for neutrophil-mediated clearance and host survival PMID: 22547706.
Branch A — effective immunity: neutrophil/macrophage phagocytosis and inflammasome/IL-1β signaling clear the infection → recovery.
Branch B — failed immunity or antibiotic-resistant organism: the bacterium evades clearance and disseminates into blood → bacteremia/sepsis, activating coagulation (elevated D-dimer) and causing organ dysfunction and death (30–50% in resistant BSI) PMID: 42518856, PMID: 42734011.
Branch C — hypervirulent dissemination: hvKp seeds the liver (pyogenic abscess) and metastasizes to eye (endophthalmitis), meninges, lung, producing invasive syndrome even in immunocompetent hosts PMID: 41356976.

Detail by category

Molecular pathways: TLR4 → MyD88 → NF-κB (pro-inflammatory transcription); NLRC4 inflammasome → caspase-1 → IL-1β/IL-18 maturation.
Cellular processes: acute inflammation, neutrophil chemotaxis and phagocytosis, macrophage activation, pyroptosis (inflammasome-linked cell death).
Immune involvement: innate immunity is decisive; NLRC4-derived IL-1β specifically (not IL-18 or IL-17A) partially rescued survival and neutrophil accumulation in NLRC4−/− mice PMID: 22547706. TLR4-agonist (3D-PHAD) pretreatment increased phagocytic innate cells, reduced lung CFU, and improved survival PMID: 36018281.
Bacterial "protein dysfunction": capsule and siderophore systems are gain-of-virulence; carbapenemases are enzymatic drug-inactivation.
Tissue damage: neutrophilic inflammation, abscess/necrosis (liver in hvKp), and sepsis-associated microvascular injury/coagulopathy.

Suggested ontology terms. GO:0006954 (inflammatory response); GO:0002224/GO:0038123 (toll-like receptor signaling); GO:0072559 (NLRP/NLRC4-type inflammasome complex — verify exact ID); GO:0006935 (chemotaxis); GO:0006909 (phagocytosis). Cell types (CL): CL:0000775 (neutrophil), CL:0000235 (macrophage), CL:0000583 (alveolar macrophage), CL:0000066 (epithelial cell). Anatomy (UBERON): UBERON:0002048 (lung), UBERON:0002107 (liver), UBERON:0000178 (blood).

7. Anatomical Structures Affected

Primary organs: lung (UBERON:0002048) — pneumonia; blood (UBERON:0000178) — bacteremia; urinary tract/bladder (UBERON:0001255) — UTI.
hvKp target organs: liver (UBERON:0002107) — pyogenic abscess; with metastasis to eye (UBERON:0000970, endophthalmitis) and meninges/CNS (UBERON:0002360, meningitis).
Body systems: respiratory, cardiovascular (sepsis), hepatobiliary, urinary, and (neonatal) systemic.
Tissues/cells: respiratory and urinary epithelium (adhesion via type 1/type 3 fimbriae fimH/mrkD); recruited neutrophils (CL:0000775) and macrophages/alveolar macrophages (CL:0000235/CL:0000583).
Subcellular compartments (host innate response): cytosolic inflammasome complex, plasma-membrane TLR4 receptor; (bacterial) outer-membrane capsule and LPS.
Lateralization: pneumonia may be lobar (classically upper-lobe in Friedländer pneumonia) or bilateral; liver abscess is often solitary right-lobe.

8. Temporal Development

Onset: typically acute (hours–days). Neonatal sepsis presents early/late neonatal period; nosocomial pneumonia after device exposure/ICU stay.
Progression: can be rapid, progressing to sepsis and septic shock, particularly with resistant organisms or delayed effective therapy. hvKp abscess may be subacute but disseminate.
Course: acute and, with treatment, often self-limited to the treatment course; complicated/resistant infections have prolonged courses. Not relapsing-remitting or chronic in the Mendelian sense.
Critical intervention window: early appropriate (susceptibility-matched) antimicrobial therapy is the key modifiable determinant of survival; delays worsen outcome. Faster microbiological clearance with ceftazidime-avibactam (HR 2.475; 95% CI 1.493–4.102) underscores the value of rapid, correct therapy PMID: 42708480.

9. Inheritance and Population

Inheritance. Not applicable — infectious, non-heritable. No AD/AR/X-linked pattern; no penetrance/expressivity/ anticipation/founder-effect/consanguinity considerations for the human host.

Epidemiology. - K. pneumoniae is the leading cause of neonatal sepsis in LMICs in Africa and Asia; in a genomic study of 1,523 isolates from 27 neonatal units across 13 countries, an estimated 68.0% (1,035/1,523) of neonatal infections were part of nosocomial transmission clusters, with ≥57.7% (879) acquired via nosocomial transmission PMID: 42127138. - In ICU/ECMO cohorts, K. pneumoniae is repeatedly among the top VAP/HAP pathogens; VAP reached 31.1 cases/1,000 ECMO-days PMID: 42685911. - CRKP bloodstream infection incidence was ~2.2/100,000 patient-days in one Chinese study PMID: 42734011.

Demographics. BSI cohorts show male predominance (~67–70%) and older age (mean ≈64–66 years) PMID: 42518856, PMID: 42563676. Geographic variation in carbapenemase type is pronounced: KPC-dominant in East Asia/parts of the Americas, OXA-48-dominant in the Middle East/Mediterranean, NDM widespread in South Asia. hvKp invasive liver-abscess syndrome is most reported in East/Southeast Asia.

10. Diagnostics

Culture + identification. The reference approach is culture with MALDI-TOF MS identification plus molecular/phenotypic resistance detection. MALDI-TOF correctly identified 174/174 K. pneumoniae isolates with log score >2.0, 100% concordant with reference systems PMID: 27239799.

Rapid molecular panels. BioFire FilmArray Blood Culture Identification from positive blood cultures showed 94% concordance with MALDI Biotyper and detects blaKPC PMID: 32305272.

Resistance detection. PCR/WGS identify carbapenemase genes (blaKPC, blaNDM, blaOXA-48, blaVIM); phenotypic tests include the modified Carbapenem Inactivation Method (mCIM). The MALDIxin test detects lipid A modifications (L-Ara4N/pEtN) underlying colistin resistance in <30 min and distinguishes chromosomal vs MCR-mediated resistance PMID: 31580426. Strain typing (rep-PCR, WGS/MLST) supports outbreak investigation PMID: 21568752.

Biomarkers / labs. Leukocytosis, elevated CRP/procalcitonin; elevated D-dimer is an independent prognostic marker in BSI (see Section 11). Imaging: chest radiograph/CT for pneumonia (classic bulging-fissure lobar consolidation); abdominal CT/ultrasound for hvKp liver abscess.

Differential diagnosis. Other Gram-negative pneumonias/BSI (E. coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Serratia), S. aureus pneumonia, and other causes of liver abscess (E. coli, anaerobes, amebic abscess).

11. Outcome / Prognosis

Mortality is high, especially for resistant bloodstream infection.

Outcome metric	Value	Source
In-hospital mortality, KP BSI (n=222)	47.7% (106/222)	PMID: 42518856
28-day mortality, BSI in acute-on-chronic liver failure	49.1%	PMID: 42717128
Donor-derived / hospital-acquired pneumonia in lung transplant	50%	PMID: 42781399

Prognostic factors. Independent predictors and correlates of death include elevated D-dimer (adjusted HR 1.04 per unit, 95% CI 1.03–1.07; high vs low group HR 2.14, 95% CI 1.27–3.59) PMID: 42518856; capsular type K47/K64 and KPC-plasmid features in CRKP bacteraemia PMID: 42216056; disease severity scores (MELD, Pitt bacteremia score, APACHE II); and choice of therapy — non-polymyxin regimens achieved higher clinical cure than polymyxin-based therapy in CRKP bacteraemia (58.4% vs 15.4%; p=0.02) PMID: 42455851.

Complications. Septic shock, multi-organ failure, DIC/coagulopathy; for hvKp, metastatic endophthalmitis, meningitis, and septic emboli. Recovery is achievable with early appropriate therapy but is compromised by resistance and host frailty.

12. Treatment

Susceptibility-guided antibiotic therapy is the cornerstone. For non-metallo-β-lactamase CRE, IDSA 2022 guidance and the German MDRO guideline recommend ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam as first-choice agents; metallo-β-lactamase (e.g., NDM) production must be detected or excluded because it changes therapy to cefiderocol or ceftazidime-avibactam plus aztreonam PMID: 35439291, PMID: 42661422.

Scenario	Preferred therapy	NCIT-type intervention
Susceptible K. pneumoniae	β-lactam per susceptibility (e.g., ceftriaxone)	Cephalosporin therapy
ESBL producer	Carbapenem	Carbapenem therapy
CRE (non-MBL: KPC/OXA-48)	Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam	β-lactam/β-lactamase-inhibitor therapy
MBL (NDM/VIM)	Cefiderocol, or ceftazidime-avibactam + aztreonam	Siderophore-cephalosporin therapy
Adjunct / renal-sparing	IV fosfomycin-containing regimens	Fosfomycin therapy

Ceftazidime-avibactam produced faster microbiological clearance than alternatives PMID: 42708480. IV fosfomycin combination regimens achieved 79.4% clinical success and were associated with reduced acute kidney injury versus colistin-heavy regimens PMID: 42599357, PMID: 42482780. Colistin/polymyxins are now later-line owing to nephrotoxicity and inferior cure rates PMID: 42455851.

Source control (drainage of liver abscess/empyema, removal of infected catheters/lines) is essential, particularly for hvKp.

Adjunctive/experimental. In a murine model, atorvastatin added to imipenem provided additional benefit in Gram-negative pneumonia PMID: 29463546; immunomodulation of the ICOS pathway influenced airway-pathogen pathogenesis PMID: 29378030. TLR4-agonist innate stimulation was protective in mice PMID: 36018281. These are pre-clinical.

13. Prevention

Primary prevention. Antibiotic stewardship (limiting carbapenem/glycopeptide/quinolone pressure — the strongest modifiable risk factors, Section 2) and infection prevention and control: hand hygiene, contact precautions, device-care bundles (ventilator, central-line, urinary-catheter), and environmental cleaning to interrupt nosocomial transmission PMID: 42127138, PMID: 42685911.

Secondary prevention. Active surveillance cultures / rectal screening for CRKP carriage in high-risk units; early detection of carbapenemase producers enables cohorting and rapid appropriate therapy.

Vaccines (investigational). No licensed Klebsiella vaccine exists. Candidates target capsular polysaccharides, O-antigen (LPS), and the MrkA type-3 fimbrial subunit. A pVAX1-MrkA DNA vaccine protected 80% of mice against sepsis (p=0.0373), identifying MrkA as a lead antigen PMID: 42634491; reverse-vaccinology antigen discovery is ongoing PMID: 42511741, PMID: 42453653.

Microbiome-based prevention (emerging). Because the gut is the reservoir, strategies preserving/restoring a colonization-resistant microbiome are under investigation PMID: 41009869.

14. Other Species / Natural Disease

Taxonomy of pathogen: Klebsiella pneumoniae (NCBI:txid573); related species K. oxytoca, K. variicola, K. aerogenes.
Host range: broad — K. pneumoniae naturally infects humans and many animals (cattle mastitis, equine and companion-animal infections, primates, wildlife) and colonizes environmental niches (water, soil, plants). It is an important One Health organism, with resistance genes shared across human, animal, agricultural, and environmental compartments PMID: 42568440.
Zoonotic/cross-species transmission: plausible via the environment and food chain; direct zoonosis is less defined than the environmental resistance-gene flow. No single human ortholog gene is relevant (infectious disease).

15. Model Organisms

Mouse (murine) models are the primary system for pathogenesis and immunity: pulmonary infection models demonstrated the essential role of NLRC4/IL-1β PMID: 22547706 and TLR4-agonist protection PMID: 36018281; sepsis models validated the MrkA DNA vaccine PMID: 42634491 and atorvastatin+imipenem adjunctive therapy PMID: 29463546.
Genetic host models: knockout mice (e.g., Nlrc4−/−, Icos−/−) dissect host-defense pathways PMID: 29378030.
Bacterial genetic tools: CRISPR/Cas9 plasmid curing established causality of the hvKp virulence plasmid PMID: 42021129.
Phenotype recapitulation: murine pneumonia/sepsis models reproduce neutrophilic lung inflammation, bacteremia, and (for hvKp) dissemination, and predict vaccine/therapy efficacy. Limitations: mouse innate immunity and microbiome differ from humans; models may not capture chronic colonization dynamics, human device-associated disease, or the full breadth of resistance-plasmid ecology. General animal-model reviews are available PMID: 38559342.

Mechanistic Model / Interpretation

    ┌─────────────────────────────────────────────────────────┐
    │  ANTIBIOTIC PRESSURE (carbapenem OR≈4.0, ICU, catheters) │
    └───────────────────────────┬─────────────────────────────┘
                                 ▼
   GUT / MUCOSAL RESERVOIR  ──(prior antibiotics select resistant/hvKp clones)──►  colonization
                                 │
             barrier breach (aspiration, catheter, surgery, translocation)
                                 ▼
           BACTERIUM AT STERILE SITE (lung / blood / liver / urine)
                                 │
    ┌───────────────── capsule (K1/K2) + rmpADC + siderophores ──────────────────┐
    │                  resist phagocytosis/complement; scavenge iron              │
    ▼                                                                             ▼
   HOST INNATE SENSING:  TLR4→NF-κB  +  NLRC4 inflammasome→caspase-1→IL-1β
    │
    ▼
   NEUTROPHIL + MACROPHAGE recruitment & phagocytosis
    │
   ┌────────┴─────────┬──────────────────────────────┐
   ▼                  ▼                              ▼
 CLEARANCE       FAILED IMMUNITY / RESISTANCE     HYPERVIRULENT DISSEMINATION
 (recovery)      → bacteremia → SEPSIS            → liver abscess → metastasis
 → coagulopathy (↑D-dimer)          (eye, meninges, lung)
 → 30–50% MORTALITY

The unifying insight is that two epidemiologically distinct pathotypes share a common virulence toolkit (capsule + siderophores) and a common gut reservoir, but differ in their principal threat: cKp weaponizes antibiotic resistance against debilitated hosts, whereas hvKp weaponizes capsule-based hypervirulence against healthy hosts. Their convergence on mobile plasmids (resistant and hypervirulent, e.g., ST11 KPC-2 hvKp) is the field's chief emerging concern.

Evidence Base

PMID	Contribution	Role
42127138	Neonatal sepsis, 68% nosocomial clusters across 13 countries	Establishes burden & nosocomial transmission
42734011	KPC 88.9%, NDM 7.4% in CRKP BSI; virulence gene profile	Resistance & virulence genetics
42439974	OXA-48 predominant (50.4%) in Saudi CRE	Geographic resistance variation
42021129	ST111 hvKp; 181 kb virulence plasmid; CRISPR curing	hvKp causal genetics
41356976	53-case systematic review of hvKp liver abscess	hvKp clinical phenotype
22547706	NLRC4/IL-1β essential for pulmonary defense	Host mechanism
36018281	TLR4 agonist protective in mice	Host mechanism / therapy lead
42518856	47.7% BSI mortality; D-dimer HR 1.04	Prognosis/biomarker
42455851	Non-polymyxin cure 58.4% vs 15.4%	Treatment outcome
42216056	K47/K64 + KPC-plasmid features & mortality	Prognostic genetics
35439291	IDSA 2022 CRE treatment guidance	Treatment standard
42661422	German MDRO guideline first-line agents	Treatment standard
42708480	CAZ-AVI faster clearance HR 2.475	Treatment efficacy
31525540	Meta-analysis of CRKP risk factors	Etiology/risk
27239799	MALDI-TOF 174/174 identification	Diagnostics
32305272	FilmArray BCID 94% concordance, blaKPC	Diagnostics
31580426	MALDIxin colistin-resistance test	Diagnostics
32576652	Stool reservoir of ST11 KPC-2 hvKp	Reservoir/convergence
42634491	MrkA DNA vaccine 80% protection	Prevention
42178970	ESKAPE priority designation	Public-health framing

Limitations and Knowledge Gaps

Template mismatch. This template is designed for Mendelian/genetic diseases; sections on human causal genes, inheritance, penetrance, chromosomal abnormalities, and germline variants are not applicable to an infectious disease and were reframed to bacterial genetics.
Human host-susceptibility genetics are underexplored — no replicated GWAS loci were identified; the protective role of TLR4/NLRC4 is inferred from mouse models, not human association data.
Geographic bias. Resistance and hvKp data skew toward East Asia, the Middle East, and select LMIC surveillance sites; global prevalence/incidence per 100,000 is not uniformly quantified.
Prognostic evidence derives largely from single-center retrospective cohorts (risk of confounding by indication for therapy choices).
Vaccine and adjunctive-therapy data are pre-clinical (murine); none is licensed or validated in humans.
Convergent resistant-hypervirulent clones (e.g., ST11 KPC-2 hvKp) are documented but their population-level frequency and outcome impact remain incompletely quantified.

Proposed Follow-up Experiments / Actions

Human host-genetics study: targeted or genome-wide association analysis of TLR4, NLRC4/NLRP, IL1B, and complement variants against severe K. pneumoniae sepsis to test the inferred protective pathways in humans.
Prospective, multicenter trial comparing ceftazidime-avibactam-based vs fosfomycin-combination vs polymyxin-based regimens for CRKP BSI, powered for mortality and nephrotoxicity, stratified by carbapenemase class.
Reservoir-interruption trial: evaluate microbiome-preserving stewardship or decolonization strategies to reduce endogenous CRKP/hvKp infection in ICU cohorts.
Convergent-clone surveillance: systematic WGS monitoring for resistant-plus-hypervirulent plasmids (rmpADC + carbapenemase) to quantify emergence and outcomes.
Advance MrkA/capsule/O-antigen vaccine candidates toward first-in-human immunogenicity trials, prioritizing high-risk populations (neonates in LMICs, ICU/transplant patients).
Validate D-dimer and capsular-type (K47/K64) prognostic markers in prospective cohorts and integrate into a clinical risk-stratification tool.

Report generated from a 5-iteration autonomous literature synthesis (10 confirmed findings, 46 papers). Evidence types span human clinical cohorts/meta-analyses, genomic epidemiology, murine model studies, and in-vitro diagnostics. All quantitative claims are attributed to the cited PMIDs.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome	Count
References checked	37
Resolved	37
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	37
On topic	18
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	30
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	22
Terms named correctly	14
Terms named as a different term	2
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

UBERON:0002048 (2 mentions) - the report calls it "lung", "Primary organs: lung"; UBERON calls it lung
UBERON:0002107 (2 mentions) - the report calls it "liver", "hvKp target organs: liver"; UBERON calls it liver

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0100523 (1 mention) - the report calls it "Hepatic abscess"; HP calls it Liver abscess, and lists "Hepatic abscess" among its other names
HP:0001974 (1 mention) - the report calls it "Leukocytosis"; HP calls it Increased total leukocyte count, and lists "Leukocytosis" among its other names
HP:0000010 (1 mention) - the report calls it "Recurrent UTI"; HP calls it Recurrent urinary tract infections, and lists "Recurrent UTIs" among its other names
GO:0038123 (1 mention) - the report calls it "toll-like receptor signaling"; GO calls it toll-like receptor TLR1:TLR2 signaling pathway
GO:0072559 (1 mention) - the report calls it "NLRP/NLRC4-type inflammasome complex — verify exact ID"; GO calls it NLRP3 inflammasome complex
UBERON:0001255 (1 mention) - the report calls it "urinary tract/bladder"; UBERON calls it urinary bladder

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0000775 - called "neutrophil", "neutrophils"
UBERON:0002048 - called "lung", "Primary organs: lung"
UBERON:0002107 - called "liver", "hvKp target organs: liver"

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Klebsiella Pneumonia — Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information (bacterial)

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating event → clinical manifestation)

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently