Melioidosis

Infectious Disease MONDO:0017775 Pathograph 31 Show in embeddings browser Bacterial Infection

Melioidosis is a frequently severe infection caused by the environmental Gram-negative bacterium Burkholderia pseudomallei, a facultative intracellular saprophyte of soil and surface water in tropical regions (notably Southeast Asia and northern Australia). Infection is acquired through percutaneous inoculation, inhalation, or ingestion of contaminated soil and water and produces a highly protean illness ranging from acute fulminant pneumonia and septicaemia to localised abscesses (lung, liver, spleen, prostate, skin and soft tissue), septic arthritis and osteomyelitis, and neurological disease. Diabetes mellitus is the dominant risk factor. B. pseudomallei is intrinsically resistant to many antibiotics, and treatment requires a prolonged two-stage regimen: an intravenous intensive phase (ceftazidime or a carbapenem) followed by months of oral eradication therapy (trimethoprim-sulfamethoxazole) to prevent relapse from persistent intracellular organisms.

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10
Pathophys.
12
Phenotypes
31
Pathograph
3
Medical Actions
2
References
1
Deep Research
⚙

Pathophysiology

10
Environmental host entry
B. pseudomallei enters the host by percutaneous inoculation, inhalation, or ingestion of contaminated soil and water, initiating local or systemic infection.
symbiont entry into host GO:0044409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased symbiont entry into host (GO:0044409). GO:0044409 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Intracellular invasion and phagosomal escape Following entry, B. pseudomallei invades host cells and escapes into the cytosol.
Show evidence (1 reference)
PMID:29388572 SUPPORT Other
"the route of bacterial entry (skin penetration, inhalation or ingestion)"
The review documents the three portals through which B. pseudomallei enters the host.
Intracellular invasion and phagosomal escape
B. pseudomallei invades epithelial and phagocytic cells and uses a type III secretion system (T3SS-3/Bsa) to escape the endocytic vacuole into the host cytosol, where it replicates as a facultative intracellular pathogen.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
symbiont entry into host cell GO:0046718 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased symbiont entry into host cell (GO:0046718). GO:0046718 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Actin-based motility and cell-to-cell spread Cytosolic bacteria recruit host actin for intracellular movement and spread.
Pneumonia Invasion and intracellular replication in lung tissue produce pneumonia, the most common focal presentation.
Show evidence (2 references)
PMID:16714590 SUPPORT In Vitro
"unable to escape from endocytic vesicles after invasion but still multiplied within the vacuoles"
A Bsa type III secretion system mutant fails to escape the endocytic vacuole, identifying T3SS-3-mediated phagosomal escape as required for the cytosolic intracellular life cycle.
PMID:29388572 SUPPORT Other
"the facultative intracellular lifestyle and virulence factors of B. pseudomallei promote survival and persistence of the pathogen within a broad range of cells"
The review establishes the facultative intracellular lifestyle across many host cell types.
Actin-based motility and cell-to-cell spread
In the cytosol, B. pseudomallei uses the autotransporter BimA to polymerise host actin into a propulsive tail, driving intracellular motility and protrusion into neighbouring cells for direct cell-to-cell spread that avoids the extracellular environment.
actin nucleation GO:0045010 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased actin nucleation (GO:0045010). GO:0045010 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Multinucleated giant cell formation Cell-to-cell spread drives membrane fusion and multinucleated giant cell formation.
Show evidence (2 references)
PMID:30968000 SUPPORT In Vitro
"BimA is required for actin-based motility through its direct interaction with actin, and by mediating actin polymerization at a single pole of the bacterium to promote movement both within and between cells"
BimA-driven polar actin polymerisation is directly demonstrated as the mechanism of intracellular and intercellular motility.
PMID:16714590 SUPPORT In Vitro
"actin tails and membrane protrusions, leading to direct cell-to-cell spreading"
Actin tail formation and membrane protrusions mediate direct cell-to-cell spread.
Multinucleated giant cell formation
Cell-to-cell spread drives fusion of infected host cells into multinucleated giant cells (MNGCs), a characteristic in vitro cytopathic signature of B. pseudomallei that promotes intercellular dissemination while shielding bacteria from humoral immunity.
syncytium formation by cell-cell fusion GO:0000768 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased syncytium formation by cell-cell fusion (GO:0000768). GO:0000768 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Innate immune activation and sepsis Intracellular replication and spread drive innate immune activation and systemic sepsis.
Show evidence (2 references)
PMID:30968000 SUPPORT In Vitro
"inability to form multi-nucleated giant cells in J774.1 cells"
Loss of cell-to-cell spread ablates multinucleated giant cell formation, tying MNGC formation to the actin-motility/spread machinery.
PMID:36814569 SUPPORT In Vitro
"multinucleated giant cell (MNGC) formation efficiency and intracellular multiplication"
MNGC formation is studied as a defining intracellular phenotype of clinical B. pseudomallei isolates.
Innate immune activation and sepsis
Bacterial replication and dissemination trigger strong innate immune activation with pro-inflammatory cytokine release; in severe infection this progresses to bacteraemia, sepsis, and septic shock, the leading cause of death in melioidosis.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Abscess formation Persistent focal infection organises into abscesses in multiple organs.
Sepsis Systemic infection and dysregulated innate immune activation manifest as sepsis.
Septic shock Severe systemic infection progresses to septic shock.
Bacteremia Dissemination of B. pseudomallei into the bloodstream produces bacteraemia.
Fever Innate immune activation and cytokine release produce fever.
Neurological melioidosis Haematogenous seeding of the central nervous system produces neurological melioidosis.
Show evidence (2 references)
PMID:29388572 SUPPORT Human Clinical
"The majority of patients present with sepsis"
Sepsis is the dominant clinical outcome of systemic B. pseudomallei infection.
PMID:21152057 SUPPORT Human Clinical
"116 (21%) developed septic shock"
One in five patients in the Darwin cohort progressed to septic shock.
Abscess formation
Focal suppurative infection produces abscesses in the lungs, liver, spleen, prostate, skin and soft tissue, bones and joints; multi-organ abscesses are a hallmark of disseminated melioidosis.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Liver abscess Focal suppuration in the liver produces hepatic abscesses.
Splenic abscess Focal suppuration in the spleen produces splenic abscesses.
Prostatic abscess Focal suppuration in the prostate produces prostatic abscesses.
Osteomyelitis Focal bone infection produces osteomyelitis.
Septic arthritis Focal joint infection produces septic arthritis.
Skin ulcer Cutaneous suppuration produces skin ulcers and subcutaneous abscesses.
Show evidence (2 references)
PMID:21152057 SUPPORT Human Clinical
"Internal organ abscesses and secondary foci in lungs and/or joints were common"
The prospective cohort documents multi-organ abscesses as a common feature of melioidosis.
PMID:41264536 SUPPORT Human Clinical
"an under-recognised tropical infection that often produces visceral abscesses"
Visceral abscess formation is a characteristic focal manifestation.
B. pseudomallei Peptidoglycan Cross-Linking (Beta-Lactam Target)
B. pseudomallei depends on penicillin-binding-protein transpeptidases to cross-link peptidoglycan during cell-wall synthesis. Ceftazidime and the carbapenems (meropenem, imipenem) acylate these PBPs and anchor the intravenous intensive phase of therapy.
peptidoglycan biosynthetic process GO:0009252 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves peptidoglycan biosynthetic process (GO:0009252). GO:0009252 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"Recommended antibiotic treatment for severe infection is either intravenous Ceftazidime or Meropenem for several weeks"
Ceftazidime and meropenem, the intensive-phase agents, are cell-wall-active beta-lactams acting on PBP transpeptidases.
B. pseudomallei Tetrahydrofolate Synthesis (TMP-SMX Target)
Trimethoprim-sulfamethoxazole, the backbone of the oral eradication phase, blocks the B. pseudomallei folate pathway at two enzymes: sulfamethoxazole inhibits dihydropteroate synthase (DHPS) and trimethoprim inhibits dihydrofolate reductase (DHFR), giving synergistic sequential blockade.
tetrahydrofolate biosynthetic process GO:0046654 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves tetrahydrofolate biosynthetic process (GO:0046654). GO:0046654 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:23627736 SUPPORT Other
"dihydropteroate synthase (DHPS) and dihydrofolate reductase"
Establishes DHPS and DHFR (the sulfamethoxazole and trimethoprim targets) as the enzymes of bacterial folate synthesis this node represents.
PMID:16547571 SUPPORT Other
"oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
TMP-SMX (the DHFR/DHPS-targeting combination) anchors eradication-phase therapy for melioidosis.
Intracellular persistence and eradication-phase requirement
Unlike classic obligate intracellular pathogens, B. pseudomallei is fully susceptible to the cell-wall-active beta-lactams (ceftazidime, carbapenems) that anchor the acute intensive phase. Its facultative intracellular persistence instead gates the second, eradication phase: because surviving intracellular organisms drive relapse and recrudescence, cure requires months of oral therapy with cell-penetrant agents (trimethoprim-sulfamethoxazole, with doxycycline as an alternative) that reach the intracellular niche.
biological process involved in interaction with host GO:0051701 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased biological process involved in interaction with host (GO:0051701). GO:0051701 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:36814569 SUPPORT Human Clinical
"Treatment of melioidosis requires prolonged antibiotic therapy"
Prolonged therapy is required because intracellular B. pseudomallei drives relapse and persistent infection.
PMID:21152057 SUPPORT Human Clinical
"Recurrent melioidosis occurred in 29, mostly attributed to poor adherence to therapy"
Recurrence tracks with inadequate eradication-phase therapy, the clinical rationale for the prolonged oral phase.
Intrinsic antibiotic resistance
B. pseudomallei is intrinsically resistant to many antibiotic classes (aminoglycosides, penicillins, polymyxins, macrolides), in large part through multidrug efflux pumps of the resistance-nodulation-cell-division (RND) family such as AmrAB-OprA. This intrinsic resistance narrows effective therapy to ceftazidime, the carbapenems, and co-trimoxazole.
response to antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
B. pseudomallei Peptidoglycan Cross-Linking (Beta-Lactam Target) Intrinsic resistance excludes most first-line antibiotics, leaving ceftazidime and the carbapenems as the viable PBP-directed options — the reason those specific agents, not penicillins, anchor the intensive phase.
Show evidence (1 reference)
PMID:34181473 SUPPORT Computational
"Dominant intrinsic and acquired multidrug resistance mechanisms are efflux mediated by pumps of the resistance-nodulation-cell division (RND) family"
RND-family efflux pumps are a dominant intrinsic multidrug-resistance mechanism in the B. pseudomallei complex, narrowing effective therapy. Evidence source is COMPUTATIONAL as the paper infers pump conservation from comparative bioinformatic analysis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Melioidosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Cardiovascular 1
Septic shock OCCASIONAL HP:0031273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Septic shock, annotated with Shock (HP:0031273). HP:0031273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"116 (21%) developed septic shock"
One in five patients in the prospective Darwin cohort developed septic shock.
Digestive 1
Liver abscess HP:0100523 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Liver abscess (HP:0100523). HP:0100523 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41264536 SUPPORT Human Clinical
"presenting with liver or splenic abscesses diagnosed by imaging and culture"
A culture-confirmed case series documents hepatic abscesses as a presentation of melioidosis.
Immune 4
Pneumonia FREQUENT HP:0002090 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumonia (HP:0002090). HP:0002090 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"The principal presentation was pneumonia in 278 (51%)"
Pneumonia was the single most common presentation, in 51% of 540 prospectively studied cases.
Sepsis HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29388572 SUPPORT Human Clinical
"The majority of patients present with sepsis"
Sepsis is the predominant clinical presentation of melioidosis.
Osteomyelitis VERY_RARE HP:0002754 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteomyelitis (HP:0002754). HP:0002754 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21152057 SUPPORT Human Clinical
"septic arthritis/osteomyelitis in 20 (4%)"
Osteomyelitis is a recognised musculoskeletal manifestation, grouped with septic arthritis in the cohort.
PMID:40608717 SUPPORT Human Clinical
"B. pseudomallei can cause a wide range of human diseases, including bacteremia, abscesses, osteomyelitis, and septic arthritis"
A case report and literature review confirms osteomyelitis among the manifestations of B. pseudomallei infection.
Neurological melioidosis VERY_RARE Infectious encephalitis HP:0002383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurological melioidosis, annotated with Infectious encephalitis (HP:0002383). HP:0002383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"neurological melioidosis in 14 (3%)"
Neurological melioidosis was the primary presentation in 3% of the Darwin cohort; the HP term Infectious encephalitis is the closest available parent for the encephalomyelitis/CNS-abscess spectrum.
Integument 1
Skin ulcer OCCASIONAL HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin ulcer (HP:0200042). HP:0200042 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"skin infection in 68 (13%)"
Cutaneous/skin infection was the primary presentation in 13% of cases; the cohort records skin infection broadly rather than ulceration specifically, so this supports cutaneous involvement (of which ulcers are the classic form) but not the ulcer subtype directly.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42220795 SUPPORT Human Clinical
"occupational exposure as a farmer, who presented with chronic fever"
Fever is a characteristic presenting symptom, illustrated here in a culture-confirmed case.
Other 4
Bacteremia FREQUENT HP:0031864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bacteremia (HP:0031864). HP:0031864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"298 (55%) were bacteremic and 116 (21%) developed septic shock"
More than half of prospectively studied patients had documented bacteraemia.
Splenic abscess HP:0025059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenic abscess (HP:0025059). HP:0025059 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41264536 SUPPORT Human Clinical
"presenting with liver or splenic abscesses diagnosed by imaging and culture"
The same culture-confirmed series documents splenic abscesses as a presentation.
PMID:42220795 SUPPORT Human Clinical
"Imaging revealed a multiloculated splenic abscess with features of impending rupture"
A culture-confirmed case demonstrates the characteristic multiloculated splenic abscess.
Prostatic abscess OCCASIONAL Prostatitis HP:0000024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prostatic abscess, annotated with Prostatitis (HP:0000024). HP:0000024 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"Prostatic abscesses occurred in 76 (20% of 372 males)"
Prostatic abscesses affected 20% of male patients in the Darwin cohort; the HP term Prostatitis is the closest available ontology parent, so the more specific preferred_term captures the abscess.
Septic arthritis VERY_RARE HP:0003095 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Septic arthritis (HP:0003095). HP:0003095 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"septic arthritis/osteomyelitis in 20 (4%)"
Septic arthritis and osteomyelitis together accounted for 4% of primary presentations in the Darwin cohort.
💊

Medical Actions

3
Intensive-phase ceftazidime or carbapenem therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ceftazidime CHEBI:3508 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ceftazidime (CHEBI:3508). CHEBI:3508 is a therapeutic agent from Chemical Entities of Biological Interest. meropenem CHEBI:43968 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses meropenem (CHEBI:43968). CHEBI:43968 is a therapeutic agent from Chemical Entities of Biological Interest.
Intravenous ceftazidime, meropenem, or imipenem for at least 10-14 days (longer for deep-seated infection) is the intensive-phase treatment for acute melioidosis.
Mechanism Target:
B. pseudomallei Peptidoglycan Cross-Linking (Beta-Lactam Target) — Ceftazidime and carbapenems acylate B. pseudomallei PBP transpeptidases, blocking peptidoglycan cross-linking.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"intravenous Ceftazidime or Meropenem for several weeks"
The intensive phase uses the cell-wall-active beta-lactams ceftazidime and meropenem.
Show evidence (2 references)
PMID:16547571 SUPPORT Other
"Recommended antibiotic treatment for severe infection is either intravenous Ceftazidime or Meropenem for several weeks"
Guideline-recommended intensive-phase therapy for severe melioidosis.
PMID:41264536 SUPPORT Human Clinical
"intravenous meropenem or ceftazidime followed by oral"
A clinical series confirms the intravenous meropenem/ceftazidime intensive phase in practice.
Eradication-phase trimethoprim-sulfamethoxazole
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trimethoprim CHEBI:45924 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trimethoprim (CHEBI:45924). CHEBI:45924 is a therapeutic agent from Chemical Entities of Biological Interest. sulfamethoxazole CHEBI:9332 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sulfamethoxazole (CHEBI:9332). CHEBI:9332 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral trimethoprim-sulfamethoxazole (co-trimoxazole) for 3-6 months after the intensive phase eradicates persistent organisms and prevents relapse.
Mechanism Target:
B. pseudomallei Tetrahydrofolate Synthesis (TMP-SMX Target) — TMP-SMX blocks DHPS and DHFR in the B. pseudomallei folate pathway.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
The eradication phase is anchored by oral co-trimoxazole, the antifolate combination.
Intracellular persistence and eradication-phase requirement — Cell-penetrant co-trimoxazole reaches persistent intracellular organisms during the prolonged eradication phase.
Show evidence (1 reference)
PMID:36814569 SUPPORT Human Clinical
"Treatment of melioidosis requires prolonged antibiotic therapy"
The prolonged oral eradication phase is required to clear persistent intracellular organisms and prevent relapse.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"rigorous treatment of severe infection with the correct antibiotics in two stages; acute and eradication"
The two-stage acute/eradication structure is the guideline-standard approach, of which oral TMP-SMX is the eradication component.
Eradication-phase doxycycline
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral doxycycline is used in the eradication phase in combination with trimethoprim-sulfamethoxazole (and as an alternative agent). As a cell-penetrant tetracycline it reaches persistent intracellular organisms.
Mechanism Target:
Intracellular persistence and eradication-phase requirement — Cell-penetrant doxycycline reaches persistent intracellular organisms during the prolonged eradication phase.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
Doxycycline is used with co-trimoxazole in the oral eradication phase.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
Doxycycline is a component of the oral eradication regimen for melioidosis.
🌍

Environmental Factors

6
Diabetes mellitus
Diabetes mellitus is the single most important risk factor for melioidosis, present in roughly half of cases and greatly increasing susceptibility.
Show evidence (1 reference)
PMID:29388572 SUPPORT Human Clinical
"Diabetes mellitus is a major risk factor for melioidosis"
Establishes diabetes mellitus as a major predisposing condition.
Mechanism Target:
PREDISPOSES Innate immune activation and sepsis — Diabetes impairs neutrophil/innate immune defence, so an inoculum a healthy host would clear instead establishes invasive, frequently septic infection.
Show evidence (2 references)
PMID:29388572 SUPPORT Human Clinical
"Diabetes mellitus is a major risk factor for melioidosis"
The review identifies diabetes as the dominant host risk factor for melioidosis.
PMID:21152057 SUPPORT Human Clinical
"Risk factors for melioidosis included diabetes"
Diabetes was the leading risk factor in the prospective Darwin cohort.
Chronic kidney disease
Chronic kidney disease is a recognised predisposing comorbidity, associated with impaired neutrophil chemotaxis and bacterial killing.
Show evidence (1 reference)
PMID:40608717 SUPPORT Human Clinical
"Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
Establishes chronic kidney disease as an established predisposing condition for melioidosis.
Mechanism Target:
PREDISPOSES Innate immune activation and sepsis — Renal disease is an established host predisposing factor for invasive melioidosis.
Show evidence (1 reference)
PMID:40608717 SUPPORT Human Clinical
"Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
Renal disease is listed among the established predisposing conditions for melioidosis.
Thalassemia and iron overload
Thalassemia and other iron-overload states predispose to melioidosis, as B. pseudomallei exploits increased host iron availability for intracellular survival.
Show evidence (1 reference)
PMID:40608717 SUPPORT Human Clinical
"Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
Establishes thalassemia and iron overload as an established predisposing condition for melioidosis.
Mechanism Target:
PREDISPOSES Innate immune activation and sepsis — Thalassemia is an established host predisposing factor for melioidosis.
Show evidence (1 reference)
PMID:40608717 SUPPORT Human Clinical
"Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
Thalassemia is listed among the established predisposing conditions for melioidosis.
Hazardous alcohol use
exposure to alcohol consumption ECTO:0001082 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to alcohol consumption (ECTO:0001082). ECTO:0001082 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Hazardous alcohol use is a common comorbidity in melioidosis cohorts and a recognised predisposing factor.
Show evidence (1 reference)
PMID:40608717 SUPPORT Human Clinical
"Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
Establishes hazardous alcohol use as an established predisposing condition for melioidosis.
Mechanism Target:
PREDISPOSES Innate immune activation and sepsis — Alcoholism is an established host predisposing factor for invasive melioidosis.
Show evidence (1 reference)
PMID:40608717 SUPPORT Human Clinical
"Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
Alcoholism is listed among the established predisposing conditions for melioidosis.
Chronic lung disease
Chronic lung disease is a common comorbidity in melioidosis cohorts (26% in the Darwin prospective study) and predisposes to pulmonary and invasive disease.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"chronic lung disease (26%) and chronic renal disease (12%)"
Chronic lung disease was the most common pre-existing comorbidity after diabetes in the Darwin prospective cohort.
Mechanism Target:
PREDISPOSES Innate immune activation and sepsis — Chronic lung disease is an established host predisposing factor for melioidosis.
Show evidence (1 reference)
PMID:21152057 SUPPORT Human Clinical
"chronic lung disease (26%) and chronic renal disease (12%)"
Chronic lung disease was present in 26% of the Darwin cohort, more than chronic renal disease.
Soil and surface water exposure
Occupational and recreational contact with contaminated soil and surface water, especially during the monsoon/rainy season in endemic regions, is the principal route of exposure.
Show evidence (1 reference)
PMID:26877885 SUPPORT Computational
"commonly found in soil in Southeast Asia and Northern"
Contaminated soil is the environmental source of exposure.
Mechanism Target:
TRIGGERS Environmental host entry — Contact with contaminated soil and water is the route by which B. pseudomallei enters the host.
Show evidence (2 references)
PMID:26877885 SUPPORT Computational
"Burkholderia pseudomallei, a highly pathogenic bacterium that causes melioidosis, is commonly found in soil"
Soil is the environmental reservoir contacted during exposure events.
PMID:21152057 SUPPORT Human Clinical
"436 (81%) presented during the monsoonal wet season"
The strong wet-season predominance reflects exposure to water-saturated contaminated soil.
🔬

Diagnosis

2
Culture of Burkholderia pseudomallei
Isolation of B. pseudomallei by culture from blood, sputum, pus, or other clinical samples is the diagnostic gold standard. Because the organism can be misidentified or dismissed as a contaminant (and is a Tier-1 select agent), the microbiology laboratory is central to diagnosis.
Microbial Culture Procedure NCIT:C25300 NCI Thesaurus (NCIT)
Results: Growth of B. pseudomallei from a clinical specimen confirms melioidosis.
Show evidence (2 references)
PMID:16547571 SUPPORT Other
"Diagnosis depends heavily on the clinical microbiology laboratory for culture"
The clinical guideline establishes culture as the mainstay of diagnosis.
PMID:16547571 SUPPORT Other
"is easily cultured from blood, sputum and other clinical samples"
B. pseudomallei is readily cultured from routine clinical specimens.
Serological testing
Serological tests can support a diagnosis of melioidosis but are not definitive on their own, and are limited by high background seropositivity in endemic populations.
serological testing NCIT:C18020 NCI Thesaurus (NCIT)
Results: A positive serology supports but does not confirm melioidosis.
Show evidence (1 reference)
PMID:16547571 SUPPORT Other
"Serological tests can help to support a diagnosis of melioidosis, but by themselves do not provide a definitive diagnosis"
The clinical guideline positions serology as supportive but not definitive.
📊

Prevalence

1
Worldwide
Annual Incidence 2.2 per 100,000 (0.9–5.6) 1–9 per 100,000
Modelled global estimate of ~165,000 human melioidosis cases per year (credible interval 68,000-412,000), of which ~89,000 die; melioidosis is substantially underreported. Rate per 100,000 derived from the modelled annual case count against the contemporaneous global population.
Show evidence (1 reference)
PMID:26877885 SUPPORT Computational
"estimate there to be 165,000 (95% credible interval 68,000-412,000) human melioidosis cases per year worldwide, of which 89,000 (36,000-227,000) die"
Provides the modelled global annual incidence and mortality of melioidosis.
🦠

Infectious Agent

1
Burkholderia pseudomallei
Gram-negative, oxidase-positive, facultative intracellular bacillus and environmental saprophyte that is the causative agent of melioidosis.
Burkholderia pseudomallei NCBITaxon:28450 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:29388572 SUPPORT Other
"Burkholderia pseudomallei is a Gram-negative environmental bacterium and the aetiological agent of melioidosis"
The Nature Reviews Disease Primers review identifies B. pseudomallei as the causative agent of melioidosis.
↔️

Transmission

1
Environmental acquisition from soil and water
Human infection is acquired from the environment through percutaneous inoculation of contaminated soil or water, inhalation of aerosols, or ingestion, rather than by person-to-person spread.
Show evidence (2 references)
PMID:26877885 SUPPORT Computational
"Burkholderia pseudomallei, a highly pathogenic bacterium that causes melioidosis, is commonly found in soil"
The global distribution model establishes soil as the environmental reservoir from which infection is acquired.
PMID:29388572 SUPPORT Other
"the route of bacterial entry (skin penetration, inhalation or ingestion)"
The review enumerates the three environmental routes of acquisition.
{ }

Source YAML

click to show 
name: Melioidosis
creation_date: "2026-08-08T00:00:00Z"
category: Infectious Disease
parents:
- Bacterial Infection
synonyms:
- Whitmore disease
- Whitmore's disease
- Burkholderia pseudomallei infection
- Nightcliff gardener's disease
description: >-
  Melioidosis is a frequently severe infection caused by the environmental
  Gram-negative bacterium Burkholderia pseudomallei, a facultative intracellular
  saprophyte of soil and surface water in tropical regions (notably Southeast
  Asia and northern Australia). Infection is acquired through percutaneous
  inoculation, inhalation, or ingestion of contaminated soil and water and
  produces a highly protean illness ranging from acute fulminant pneumonia and
  septicaemia to localised abscesses (lung, liver, spleen, prostate, skin and
  soft tissue), septic arthritis and osteomyelitis, and neurological disease.
  Diabetes mellitus is the dominant risk factor. B. pseudomallei is intrinsically
  resistant to many antibiotics, and treatment requires a prolonged two-stage
  regimen: an intravenous intensive phase (ceftazidime or a carbapenem) followed
  by months of oral eradication therapy (trimethoprim-sulfamethoxazole) to
  prevent relapse from persistent intracellular organisms.
disease_term:
  preferred_term: melioidosis
  term:
    id: MONDO:0017775
    label: melioidosis
references:
- reference: PMID:29388572
  title: "Melioidosis."
- reference: PMID:21152057
  title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
infectious_agent:
- name: Burkholderia pseudomallei
  description: >-
    Gram-negative, oxidase-positive, facultative intracellular bacillus and
    environmental saprophyte that is the causative agent of melioidosis.
  infectious_agent_term:
    preferred_term: Burkholderia pseudomallei
    term:
      id: NCBITaxon:28450
      label: Burkholderia pseudomallei
  evidence:
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Burkholderia pseudomallei is a Gram-negative environmental bacterium and the aetiological agent of melioidosis"
    explanation: The Nature Reviews Disease Primers review identifies B. pseudomallei as the causative agent of melioidosis.
transmission:
- name: Environmental acquisition from soil and water
  description: >-
    Human infection is acquired from the environment through percutaneous
    inoculation of contaminated soil or water, inhalation of aerosols, or
    ingestion, rather than by person-to-person spread.
  evidence:
  - reference: PMID:26877885
    reference_title: "Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Burkholderia pseudomallei, a highly pathogenic bacterium that causes melioidosis, is commonly found in soil"
    explanation: The global distribution model establishes soil as the environmental reservoir from which infection is acquired.
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the route of bacterial entry (skin penetration, inhalation or ingestion)"
    explanation: The review enumerates the three environmental routes of acquisition.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.2
  rate_low: 0.9
  rate_high: 5.6
  notes: >-
    Modelled global estimate of ~165,000 human melioidosis cases per year
    (credible interval 68,000-412,000), of which ~89,000 die; melioidosis is
    substantially underreported. Rate per 100,000 derived from the modelled
    annual case count against the contemporaneous global population.
  evidence:
  - reference: PMID:26877885
    reference_title: "Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "estimate there to be 165,000 (95% credible interval 68,000-412,000) human melioidosis cases per year worldwide, of which 89,000 (36,000-227,000) die"
    explanation: Provides the modelled global annual incidence and mortality of melioidosis.
pathophysiology:
- name: Environmental host entry
  description: >-
    B. pseudomallei enters the host by percutaneous inoculation, inhalation, or
    ingestion of contaminated soil and water, initiating local or systemic
    infection.
  biological_processes:
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
    modifier: INCREASED
  evidence:
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the route of bacterial entry (skin penetration, inhalation or ingestion)"
    explanation: The review documents the three portals through which B. pseudomallei enters the host.
  downstream:
  - target: Intracellular invasion and phagosomal escape
    causal_link_type: DIRECT
    description: Following entry, B. pseudomallei invades host cells and escapes into the cytosol.
- name: Intracellular invasion and phagosomal escape
  description: >-
    B. pseudomallei invades epithelial and phagocytic cells and uses a type III
    secretion system (T3SS-3/Bsa) to escape the endocytic vacuole into the host
    cytosol, where it replicates as a facultative intracellular pathogen.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
    modifier: INCREASED
  evidence:
  - reference: PMID:16714590
    reference_title: "Identification of Burkholderia pseudomallei genes required for the intracellular life cycle and in vivo virulence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "unable to escape from endocytic vesicles after invasion but still multiplied within the vacuoles"
    explanation: A Bsa type III secretion system mutant fails to escape the endocytic vacuole, identifying T3SS-3-mediated phagosomal escape as required for the cytosolic intracellular life cycle.
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the facultative intracellular lifestyle and virulence factors of B. pseudomallei promote survival and persistence of the pathogen within a broad range of cells"
    explanation: The review establishes the facultative intracellular lifestyle across many host cell types.
  downstream:
  - target: Actin-based motility and cell-to-cell spread
    causal_link_type: DIRECT
    description: Cytosolic bacteria recruit host actin for intracellular movement and spread.
  - target: Pneumonia
    causal_link_type: DIRECT
    description: >-
      Invasion and intracellular replication in lung tissue produce pneumonia,
      the most common focal presentation.
- name: Actin-based motility and cell-to-cell spread
  description: >-
    In the cytosol, B. pseudomallei uses the autotransporter BimA to polymerise
    host actin into a propulsive tail, driving intracellular motility and
    protrusion into neighbouring cells for direct cell-to-cell spread that avoids
    the extracellular environment.
  biological_processes:
  - preferred_term: actin nucleation
    term:
      id: GO:0045010
      label: actin nucleation
    modifier: INCREASED
  evidence:
  - reference: PMID:30968000
    reference_title: "Burkholderia pseudomallei BimC Is Required for Actin-Based Motility, Intracellular Survival, and Virulence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "BimA is required for actin-based motility through its direct interaction with actin, and by mediating actin polymerization at a single pole of the bacterium to promote movement both within and between cells"
    explanation: BimA-driven polar actin polymerisation is directly demonstrated as the mechanism of intracellular and intercellular motility.
  - reference: PMID:16714590
    reference_title: "Identification of Burkholderia pseudomallei genes required for the intracellular life cycle and in vivo virulence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "actin tails and membrane protrusions, leading to direct cell-to-cell spreading"
    explanation: Actin tail formation and membrane protrusions mediate direct cell-to-cell spread.
  downstream:
  - target: Multinucleated giant cell formation
    causal_link_type: DIRECT
    description: Cell-to-cell spread drives membrane fusion and multinucleated giant cell formation.
- name: Multinucleated giant cell formation
  description: >-
    Cell-to-cell spread drives fusion of infected host cells into multinucleated
    giant cells (MNGCs), a characteristic in vitro cytopathic signature of B.
    pseudomallei that promotes intercellular dissemination while shielding
    bacteria from humoral immunity.
  biological_processes:
  - preferred_term: syncytium formation by cell-cell fusion
    term:
      id: GO:0000768
      label: syncytium formation by cell-cell fusion
    modifier: INCREASED
  evidence:
  - reference: PMID:30968000
    reference_title: "Burkholderia pseudomallei BimC Is Required for Actin-Based Motility, Intracellular Survival, and Virulence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "inability to form multi-nucleated giant cells in J774.1 cells"
    explanation: Loss of cell-to-cell spread ablates multinucleated giant cell formation, tying MNGC formation to the actin-motility/spread machinery.
  - reference: PMID:36814569
    reference_title: "Phenotypic and genetic alterations of Burkholderia pseudomallei in patients during relapse and persistent infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "multinucleated giant cell (MNGC) formation efficiency and intracellular multiplication"
    explanation: MNGC formation is studied as a defining intracellular phenotype of clinical B. pseudomallei isolates.
  downstream:
  - target: Innate immune activation and sepsis
    causal_link_type: DIRECT
    description: Intracellular replication and spread drive innate immune activation and systemic sepsis.
- name: Innate immune activation and sepsis
  description: >-
    Bacterial replication and dissemination trigger strong innate immune
    activation with pro-inflammatory cytokine release; in severe infection this
    progresses to bacteraemia, sepsis, and septic shock, the leading cause of
    death in melioidosis.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients present with sepsis"
    explanation: Sepsis is the dominant clinical outcome of systemic B. pseudomallei infection.
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "116 (21%) developed septic shock"
    explanation: One in five patients in the Darwin cohort progressed to septic shock.
  downstream:
  - target: Abscess formation
    causal_link_type: DIRECT
    description: Persistent focal infection organises into abscesses in multiple organs.
  - target: Sepsis
    causal_link_type: DIRECT
    description: Systemic infection and dysregulated innate immune activation manifest as sepsis.
  - target: Septic shock
    causal_link_type: DIRECT
    description: Severe systemic infection progresses to septic shock.
  - target: Bacteremia
    causal_link_type: DIRECT
    description: Dissemination of B. pseudomallei into the bloodstream produces bacteraemia.
  - target: Fever
    causal_link_type: DIRECT
    description: Innate immune activation and cytokine release produce fever.
  - target: Neurological melioidosis
    causal_link_type: DIRECT
    description: Haematogenous seeding of the central nervous system produces neurological melioidosis.
- name: Abscess formation
  description: >-
    Focal suppurative infection produces abscesses in the lungs, liver, spleen,
    prostate, skin and soft tissue, bones and joints; multi-organ abscesses are a
    hallmark of disseminated melioidosis.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Internal organ abscesses and secondary foci in lungs and/or joints were common"
    explanation: The prospective cohort documents multi-organ abscesses as a common feature of melioidosis.
  - reference: PMID:41264536
    reference_title: "Melioidosis presenting as hepatosplenic abscesses: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an under-recognised tropical infection that often produces visceral abscesses"
    explanation: Visceral abscess formation is a characteristic focal manifestation.
  downstream:
  - target: Liver abscess
    causal_link_type: DIRECT
    description: Focal suppuration in the liver produces hepatic abscesses.
  - target: Splenic abscess
    causal_link_type: DIRECT
    description: Focal suppuration in the spleen produces splenic abscesses.
  - target: Prostatic abscess
    causal_link_type: DIRECT
    description: Focal suppuration in the prostate produces prostatic abscesses.
  - target: Osteomyelitis
    causal_link_type: DIRECT
    description: Focal bone infection produces osteomyelitis.
  - target: Septic arthritis
    causal_link_type: DIRECT
    description: Focal joint infection produces septic arthritis.
  - target: Skin ulcer
    causal_link_type: DIRECT
    description: Cutaneous suppuration produces skin ulcers and subcutaneous abscesses.
- name: B. pseudomallei Peptidoglycan Cross-Linking (Beta-Lactam Target)
  description: >-
    B. pseudomallei depends on penicillin-binding-protein transpeptidases to
    cross-link peptidoglycan during cell-wall synthesis. Ceftazidime and the
    carbapenems (meropenem, imipenem) acylate these PBPs and anchor the
    intravenous intensive phase of therapy.
  role: therapeutic_vulnerability
  conforms_to: "bacterial_cell_wall_synthesis_inhibition#Peptidoglycan Cross-Linking by Penicillin-Binding Proteins"
  biological_processes:
  - preferred_term: peptidoglycan biosynthetic process
    term:
      id: GO:0009252
      label: peptidoglycan biosynthetic process
  evidence:
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recommended antibiotic treatment for severe infection is either intravenous Ceftazidime or Meropenem for several weeks"
    explanation: Ceftazidime and meropenem, the intensive-phase agents, are cell-wall-active beta-lactams acting on PBP transpeptidases.
- name: B. pseudomallei Tetrahydrofolate Synthesis (TMP-SMX Target)
  description: >-
    Trimethoprim-sulfamethoxazole, the backbone of the oral eradication phase,
    blocks the B. pseudomallei folate pathway at two enzymes: sulfamethoxazole
    inhibits dihydropteroate synthase (DHPS) and trimethoprim inhibits
    dihydrofolate reductase (DHFR), giving synergistic sequential blockade.
  role: therapeutic_vulnerability
  conforms_to: "bacterial_folate_synthesis_inhibition#Bacterial Tetrahydrofolate Synthesis (Antifolate Target)"
  biological_processes:
  - preferred_term: tetrahydrofolate biosynthetic process
    term:
      id: GO:0046654
      label: tetrahydrofolate biosynthetic process
  evidence:
  - reference: PMID:23627736
    reference_title: "Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "dihydropteroate synthase (DHPS) and dihydrofolate reductase"
    explanation: Establishes DHPS and DHFR (the sulfamethoxazole and trimethoprim targets) as the enzymes of bacterial folate synthesis this node represents.
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
    explanation: TMP-SMX (the DHFR/DHPS-targeting combination) anchors eradication-phase therapy for melioidosis.
- name: Intracellular persistence and eradication-phase requirement
  description: >-
    Unlike classic obligate intracellular pathogens, B. pseudomallei is fully
    susceptible to the cell-wall-active beta-lactams (ceftazidime, carbapenems)
    that anchor the acute intensive phase. Its facultative intracellular
    persistence instead gates the second, eradication phase: because surviving
    intracellular organisms drive relapse and recrudescence, cure requires months
    of oral therapy with cell-penetrant agents (trimethoprim-sulfamethoxazole,
    with doxycycline as an alternative) that reach the intracellular niche.
  role: therapeutic_vulnerability
  conforms_to: "intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials"
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
    modifier: INCREASED
  evidence:
  - reference: PMID:36814569
    reference_title: "Phenotypic and genetic alterations of Burkholderia pseudomallei in patients during relapse and persistent infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of melioidosis requires prolonged antibiotic therapy"
    explanation: Prolonged therapy is required because intracellular B. pseudomallei drives relapse and persistent infection.
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent melioidosis occurred in 29, mostly attributed to poor adherence to therapy"
    explanation: Recurrence tracks with inadequate eradication-phase therapy, the clinical rationale for the prolonged oral phase.
- name: Intrinsic antibiotic resistance
  description: >-
    B. pseudomallei is intrinsically resistant to many antibiotic classes
    (aminoglycosides, penicillins, polymyxins, macrolides), in large part through
    multidrug efflux pumps of the resistance-nodulation-cell-division (RND)
    family such as AmrAB-OprA. This intrinsic resistance narrows effective therapy
    to ceftazidime, the carbapenems, and co-trimoxazole.
  role: intrinsic_resistance
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
    modifier: INCREASED
  evidence:
  - reference: PMID:34181473
    reference_title: "Conservation of Resistance-Nodulation-Cell Division Efflux Pump-Mediated Antibiotic Resistance in Burkholderia cepacia Complex and Burkholderia pseudomallei Complex Species."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Dominant intrinsic and acquired multidrug resistance mechanisms are efflux mediated by pumps of the resistance-nodulation-cell division (RND) family"
    explanation: RND-family efflux pumps are a dominant intrinsic multidrug-resistance mechanism in the B. pseudomallei complex, narrowing effective therapy. Evidence source is COMPUTATIONAL as the paper infers pump conservation from comparative bioinformatic analysis.
  downstream:
  - target: B. pseudomallei Peptidoglycan Cross-Linking (Beta-Lactam Target)
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Intrinsic resistance excludes most first-line antibiotics, leaving
      ceftazidime and the carbapenems as the viable PBP-directed options — the
      reason those specific agents, not penicillins, anchor the intensive phase.
phenotypes:
- name: Pneumonia
  description: >-
    Pneumonia is the most common clinical presentation of melioidosis, ranging
    from acute fulminant lobar pneumonia to a chronic cavitary illness resembling
    tuberculosis.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The principal presentation was pneumonia in 278 (51%)"
    explanation: Pneumonia was the single most common presentation, in 51% of 540 prospectively studied cases.
- name: Sepsis
  description: >-
    Bacteraemic melioidosis frequently presents as severe sepsis and septic
    shock, the major cause of mortality.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients present with sepsis"
    explanation: Sepsis is the predominant clinical presentation of melioidosis.
- name: Septic shock
  description: >-
    A substantial minority of patients progress to septic shock, the principal
    driver of the high case-fatality rate of severe melioidosis.
  phenotype_term:
    preferred_term: Septic shock
    term:
      id: HP:0031273
      label: Shock
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "116 (21%) developed septic shock"
    explanation: One in five patients in the prospective Darwin cohort developed septic shock.
- name: Bacteremia
  description: >-
    Bloodstream infection with B. pseudomallei is common in severe melioidosis
    and predicts poor outcome.
  phenotype_term:
    preferred_term: Bacteremia
    term:
      id: HP:0031864
      label: Bacteremia
  frequency: FREQUENT
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "298 (55%) were bacteremic and 116 (21%) developed septic shock"
    explanation: More than half of prospectively studied patients had documented bacteraemia.
- name: Liver abscess
  description: >-
    Hepatic abscesses, often multiple and characteristically multiloculated
    ("honeycomb" or "Swiss cheese" appearance), are a feature of disseminated
    melioidosis.
  phenotype_term:
    preferred_term: Liver abscess
    term:
      id: HP:0100523
      label: Liver abscess
  evidence:
  - reference: PMID:41264536
    reference_title: "Melioidosis presenting as hepatosplenic abscesses: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with liver or splenic abscesses diagnosed by imaging and culture"
    explanation: A culture-confirmed case series documents hepatic abscesses as a presentation of melioidosis.
- name: Splenic abscess
  description: >-
    Splenic abscesses, frequently multiple, are a common site of visceral
    dissemination in melioidosis.
  phenotype_term:
    preferred_term: Splenic abscess
    term:
      id: HP:0025059
      label: Splenic abscess
  evidence:
  - reference: PMID:41264536
    reference_title: "Melioidosis presenting as hepatosplenic abscesses: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with liver or splenic abscesses diagnosed by imaging and culture"
    explanation: The same culture-confirmed series documents splenic abscesses as a presentation.
  - reference: PMID:42220795
    reference_title: "Melioidosis Presenting As a Chronic Splenic Abscess: A Diagnostic Challenge."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging revealed a multiloculated splenic abscess with features of impending rupture"
    explanation: A culture-confirmed case demonstrates the characteristic multiloculated splenic abscess.
- name: Prostatic abscess
  description: >-
    Prostatic abscess is a distinctive genitourinary manifestation of melioidosis,
    occurring in a substantial fraction of male patients (notably in Australian
    cohorts).
  phenotype_term:
    preferred_term: Prostatic abscess
    term:
      id: HP:0000024
      label: Prostatitis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prostatic abscesses occurred in 76 (20% of 372 males)"
    explanation: >-
      Prostatic abscesses affected 20% of male patients in the Darwin cohort; the
      HP term Prostatitis is the closest available ontology parent, so the more
      specific preferred_term captures the abscess.
- name: Septic arthritis
  description: >-
    Septic arthritis occurs in a substantial minority of patients, part of the
    musculoskeletal involvement of melioidosis.
  phenotype_term:
    preferred_term: Septic arthritis
    term:
      id: HP:0003095
      label: Septic arthritis
  frequency: VERY_RARE
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "septic arthritis/osteomyelitis in 20 (4%)"
    explanation: Septic arthritis and osteomyelitis together accounted for 4% of primary presentations in the Darwin cohort.
- name: Osteomyelitis
  description: >-
    Osteomyelitis is a recognised deep-seated focal manifestation, often
    accompanying septic arthritis.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  frequency: VERY_RARE
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "septic arthritis/osteomyelitis in 20 (4%)"
    explanation: Osteomyelitis is a recognised musculoskeletal manifestation, grouped with septic arthritis in the cohort.
  - reference: PMID:40608717
    reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "B. pseudomallei can cause a wide range of human diseases, including bacteremia, abscesses, osteomyelitis, and septic arthritis"
    explanation: A case report and literature review confirms osteomyelitis among the manifestations of B. pseudomallei infection.
- name: Skin ulcer
  description: >-
    Cutaneous melioidosis presents with skin ulcers, pustules, and subcutaneous
    abscesses, especially after percutaneous inoculation.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin infection in 68 (13%)"
    explanation: >-
      Cutaneous/skin infection was the primary presentation in 13% of cases; the
      cohort records skin infection broadly rather than ulceration specifically,
      so this supports cutaneous involvement (of which ulcers are the classic
      form) but not the ulcer subtype directly.
- name: Fever
  description: >-
    Fever is a characteristic presenting symptom of melioidosis.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:42220795
    reference_title: "Melioidosis Presenting As a Chronic Splenic Abscess: A Diagnostic Challenge."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occupational exposure as a farmer, who presented with chronic fever"
    explanation: Fever is a characteristic presenting symptom, illustrated here in a culture-confirmed case.
- name: Neurological melioidosis
  description: >-
    Neurological melioidosis (brain abscess and brainstem encephalomyelitis) is
    an uncommon but distinctive and severe manifestation.
  phenotype_term:
    preferred_term: Neurological melioidosis
    term:
      id: HP:0002383
      label: Infectious encephalitis
  frequency: VERY_RARE
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurological melioidosis in 14 (3%)"
    explanation: >-
      Neurological melioidosis was the primary presentation in 3% of the Darwin
      cohort; the HP term Infectious encephalitis is the closest available parent
      for the encephalomyelitis/CNS-abscess spectrum.
environmental:
- name: Diabetes mellitus
  description: >-
    Diabetes mellitus is the single most important risk factor for melioidosis,
    present in roughly half of cases and greatly increasing susceptibility.
  influences_mechanisms:
  - target: Innate immune activation and sepsis
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Diabetes impairs neutrophil/innate immune defence, so an inoculum a healthy
      host would clear instead establishes invasive, frequently septic infection.
    evidence:
    - reference: PMID:29388572
      reference_title: "Melioidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diabetes mellitus is a major risk factor for melioidosis"
      explanation: The review identifies diabetes as the dominant host risk factor for melioidosis.
    - reference: PMID:21152057
      reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Risk factors for melioidosis included diabetes"
      explanation: Diabetes was the leading risk factor in the prospective Darwin cohort.
  evidence:
  - reference: PMID:29388572
    reference_title: "Melioidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diabetes mellitus is a major risk factor for melioidosis"
    explanation: Establishes diabetes mellitus as a major predisposing condition.
- name: Chronic kidney disease
  description: >-
    Chronic kidney disease is a recognised predisposing comorbidity, associated
    with impaired neutrophil chemotaxis and bacterial killing.
  influences_mechanisms:
  - target: Innate immune activation and sepsis
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Renal disease is an established host predisposing factor for invasive
      melioidosis.
    evidence:
    - reference: PMID:40608717
      reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
      explanation: Renal disease is listed among the established predisposing conditions for melioidosis.
  evidence:
  - reference: PMID:40608717
    reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
    explanation: Establishes chronic kidney disease as an established predisposing condition for melioidosis.
- name: Thalassemia and iron overload
  description: >-
    Thalassemia and other iron-overload states predispose to melioidosis, as B.
    pseudomallei exploits increased host iron availability for intracellular
    survival.
  influences_mechanisms:
  - target: Innate immune activation and sepsis
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Thalassemia is an established host predisposing factor for melioidosis.
    evidence:
    - reference: PMID:40608717
      reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
      explanation: Thalassemia is listed among the established predisposing conditions for melioidosis.
  evidence:
  - reference: PMID:40608717
    reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
    explanation: Establishes thalassemia and iron overload as an established predisposing condition for melioidosis.
- name: Hazardous alcohol use
  exposure_term:
    preferred_term: exposure to alcohol consumption
    term:
      id: ECTO:0001082
      label: exposure to alcohol consumption
  description: >-
    Hazardous alcohol use is a common comorbidity in melioidosis cohorts and a
    recognised predisposing factor.
  influences_mechanisms:
  - target: Innate immune activation and sepsis
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Alcoholism is an established host predisposing factor for invasive
      melioidosis.
    evidence:
    - reference: PMID:40608717
      reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
      explanation: Alcoholism is listed among the established predisposing conditions for melioidosis.
  evidence:
  - reference: PMID:40608717
    reference_title: "Diabetic foot osteomyelitis caused by Burkholderia pseudomallei: first case report from Türkiye and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diabetes mellitus, renal disease, alcoholism, liver cirrhosis, and thalassemia are known predisposing factors"
    explanation: Establishes hazardous alcohol use as an established predisposing condition for melioidosis.
- name: Chronic lung disease
  description: >-
    Chronic lung disease is a common comorbidity in melioidosis cohorts (26% in
    the Darwin prospective study) and predisposes to pulmonary and invasive
    disease.
  influences_mechanisms:
  - target: Innate immune activation and sepsis
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Chronic lung disease is an established host predisposing factor for
      melioidosis.
    evidence:
    - reference: PMID:21152057
      reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "chronic lung disease (26%) and chronic renal disease (12%)"
      explanation: Chronic lung disease was present in 26% of the Darwin cohort, more than chronic renal disease.
  evidence:
  - reference: PMID:21152057
    reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic lung disease (26%) and chronic renal disease (12%)"
    explanation: Chronic lung disease was the most common pre-existing comorbidity after diabetes in the Darwin prospective cohort.
- name: Soil and surface water exposure
  description: >-
    Occupational and recreational contact with contaminated soil and surface
    water, especially during the monsoon/rainy season in endemic regions, is the
    principal route of exposure.
  influences_mechanisms:
  - target: Environmental host entry
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Contact with contaminated soil and water is the route by which B.
      pseudomallei enters the host.
    evidence:
    - reference: PMID:26877885
      reference_title: "Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Burkholderia pseudomallei, a highly pathogenic bacterium that causes melioidosis, is commonly found in soil"
      explanation: Soil is the environmental reservoir contacted during exposure events.
    - reference: PMID:21152057
      reference_title: "The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "436 (81%) presented during the monsoonal wet season"
      explanation: The strong wet-season predominance reflects exposure to water-saturated contaminated soil.
  evidence:
  - reference: PMID:26877885
    reference_title: "Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "commonly found in soil in Southeast Asia and Northern"
    explanation: Contaminated soil is the environmental source of exposure.
diagnosis:
- name: Culture of Burkholderia pseudomallei
  description: >-
    Isolation of B. pseudomallei by culture from blood, sputum, pus, or other
    clinical samples is the diagnostic gold standard. Because the organism can be
    misidentified or dismissed as a contaminant (and is a Tier-1 select agent),
    the microbiology laboratory is central to diagnosis.
  diagnosis_term:
    preferred_term: Microbial Culture Procedure
    term:
      id: NCIT:C25300
      label: Microbial Culture Procedure
  results: Growth of B. pseudomallei from a clinical specimen confirms melioidosis.
  evidence:
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis depends heavily on the clinical microbiology laboratory for culture"
    explanation: The clinical guideline establishes culture as the mainstay of diagnosis.
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "is easily cultured from blood, sputum and other clinical samples"
    explanation: B. pseudomallei is readily cultured from routine clinical specimens.
- name: Serological testing
  description: >-
    Serological tests can support a diagnosis of melioidosis but are not
    definitive on their own, and are limited by high background seropositivity in
    endemic populations.
  diagnosis_term:
    preferred_term: serological testing
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: A positive serology supports but does not confirm melioidosis.
  evidence:
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Serological tests can help to support a diagnosis of melioidosis, but by themselves do not provide a definitive diagnosis"
    explanation: The clinical guideline positions serology as supportive but not definitive.
treatments:
- name: Intensive-phase ceftazidime or carbapenem therapy
  description: >-
    Intravenous ceftazidime, meropenem, or imipenem for at least 10-14 days
    (longer for deep-seated infection) is the intensive-phase treatment for acute
    melioidosis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ceftazidime
      term:
        id: CHEBI:3508
        label: ceftazidime
    - preferred_term: meropenem
      term:
        id: CHEBI:43968
        label: meropenem
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: B. pseudomallei Peptidoglycan Cross-Linking (Beta-Lactam Target)
    description: >-
      Ceftazidime and carbapenems acylate B. pseudomallei PBP transpeptidases,
      blocking peptidoglycan cross-linking.
    evidence:
    - reference: PMID:16547571
      reference_title: "Clinical guideline for diagnosis and management of melioidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "intravenous Ceftazidime or Meropenem for several weeks"
      explanation: The intensive phase uses the cell-wall-active beta-lactams ceftazidime and meropenem.
  evidence:
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recommended antibiotic treatment for severe infection is either intravenous Ceftazidime or Meropenem for several weeks"
    explanation: Guideline-recommended intensive-phase therapy for severe melioidosis.
  - reference: PMID:41264536
    reference_title: "Melioidosis presenting as hepatosplenic abscesses: A case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intravenous meropenem or ceftazidime followed by oral"
    explanation: A clinical series confirms the intravenous meropenem/ceftazidime intensive phase in practice.
- name: Eradication-phase trimethoprim-sulfamethoxazole
  description: >-
    Oral trimethoprim-sulfamethoxazole (co-trimoxazole) for 3-6 months after the
    intensive phase eradicates persistent organisms and prevents relapse.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: B. pseudomallei Tetrahydrofolate Synthesis (TMP-SMX Target)
    description: >-
      TMP-SMX blocks DHPS and DHFR in the B. pseudomallei folate pathway.
    evidence:
    - reference: PMID:16547571
      reference_title: "Clinical guideline for diagnosis and management of melioidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
      explanation: The eradication phase is anchored by oral co-trimoxazole, the antifolate combination.
  - target: Intracellular persistence and eradication-phase requirement
    description: >-
      Cell-penetrant co-trimoxazole reaches persistent intracellular organisms
      during the prolonged eradication phase.
    evidence:
    - reference: PMID:36814569
      reference_title: "Phenotypic and genetic alterations of Burkholderia pseudomallei in patients during relapse and persistent infections."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment of melioidosis requires prolonged antibiotic therapy"
      explanation: The prolonged oral eradication phase is required to clear persistent intracellular organisms and prevent relapse.
  evidence:
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "rigorous treatment of severe infection with the correct antibiotics in two stages; acute and eradication"
    explanation: The two-stage acute/eradication structure is the guideline-standard approach, of which oral TMP-SMX is the eradication component.
- name: Eradication-phase doxycycline
  description: >-
    Oral doxycycline is used in the eradication phase in combination with
    trimethoprim-sulfamethoxazole (and as an alternative agent). As a
    cell-penetrant tetracycline it reaches persistent intracellular organisms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Intracellular persistence and eradication-phase requirement
    description: >-
      Cell-penetrant doxycycline reaches persistent intracellular organisms
      during the prolonged eradication phase.
    evidence:
    - reference: PMID:16547571
      reference_title: "Clinical guideline for diagnosis and management of melioidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
      explanation: Doxycycline is used with co-trimoxazole in the oral eradication phase.
  evidence:
  - reference: PMID:16547571
    reference_title: "Clinical guideline for diagnosis and management of melioidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oral treatment with a combination of trimethoprim-sulphamethoxazole and doxycycline"
    explanation: Doxycycline is a component of the oral eradication regimen for melioidosis.
📚

References & Deep Research

References

2
PMID:29388572
Melioidosis.
No top-level findings curated for this source.
PMID:21152057
The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Melioidosis: Comprehensive Disease Characteristics Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 62 citations 2026-08-08T14:36:17.929750

Melioidosis: Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview. Melioidosis is a life-threatening infectious disease caused by Burkholderia pseudomallei, a Gram-negative, motile, facultative intracellular saprophytic bacillus that lives naturally in tropical/subtropical soil and fresh water. It is acquired via percutaneous inoculation, inhalation, or ingestion of the organism from contaminated environmental sources, and can affect virtually any organ system, ranging from localized cutaneous abscess to fulminant septic shock. Wiersinga et al. (Nat Rev Dis Primers 2018) note it is "a life-threatening infection that is estimated to account for approximately 89,000 deaths per year worldwide," with disease that "can vary greatly and may mimic those of tuberculosis or common forms of pneumonia" (Nature Reviews Disease Primers, 2018; PMID for the primer series generally cited as 29388606). A more recent mechanistic and epidemiological update is Meumann et al., Burkholderia pseudomallei and melioidosis, Nat Rev Microbiol 2024;22:155-169 (PMID:37749352).

Key identifiers: - MONDO: MONDO:0017775 - Disease Ontology: DOID:5052 - OMIM: 615557 ("MELIOIDOSIS, SUSCEPTIBILITY TO" — a susceptibility-locus entry, not a Mendelian disease entry; OMIM notes host TLR/TNF variants as susceptibility modifiers, not causal mutations, since the causal agent is infectious, not genetic) - Orphanet: ORPHA:31202 - ICD-11: 1C42 (Melioidosis) - ICD-10: A24.0 (Melioidosis, general); A24.1 (Acute/fulminating melioidosis); A24.2 (Subacute and chronic melioidosis); A24.3 (Other melioidosis); A24.4 (Melioidosis, unspecified) - MeSH: D008554 (Melioidosis) - NCBI Taxonomy (causative organism): Burkholderia pseudomallei, Taxonomy ID 28450

Synonyms/alternative names: Whitmore's disease (after Alfred Whitmore, who first described it in Rangoon, Burma, in 1911–1912); "Nightcliff gardener's disease" (Darwin, Australia, regional term); pseudoglanders; Vietnamese time bomb / Vietnamese time-bomb disease (referring to reactivation years after exposure).

Data source type. Most published knowledge is derived from aggregated disease-level clinical cohorts and registries (e.g., the 20+ year Darwin Prospective Melioidosis Study in Australia's Northern Territory, the Sunpasitthiprapa Hospital cohort in Thailand, and India's national melioidosis case series), rather than individual-EHR mining — reflecting its status as an endemic infectious disease of low/middle-income tropical regions with limited EHR infrastructure. Global burden modeling (Limmathurotsakul et al. 2016; Birnie et al. 2019) is ecological/geospatial, combining environmental suitability modeling with reported incidence.

2. Etiology

Disease Causal Factor

Melioidosis is a purely infectious disease — there is no genetic or purely mechanistic causal pathway independent of infection by B. pseudomallei. Transmission routes are: - Percutaneous inoculation — the dominant route in most series — through skin abrasions/wounds contacting contaminated soil or water. - Inhalation of aerosolized bacteria/contaminated dust, notably during severe weather events (typhoons, monsoons) — associated with more severe, rapidly fulminant pneumonic disease. - Ingestion of contaminated water — implicated especially in pediatric suppurative parotitis in Thailand. - Rare nosocomial, laboratory-acquired, and person-to-person transmission (the latter is exceptionally rare; melioidosis is fundamentally a sapronosis, not a classic zoonosis — "both animals and humans can independently be infected by this endemic soil and water bacterium" rather than transmitting to one another) (Merck Veterinary Manual; Aust Vet J 2025 review).

Risk Factors

Genetic/host risk factors (susceptibility loci, not causal mutations): - TLR4 region variants: TLR4 −1196C>T associated with protection; other TLR4-region SNPs associated with susceptibility (Genes Immun 2011; PMID for the TLR4 study is commonly cited as West et al., PMID 21430785). - TLR5 R392X nonsense polymorphism: paradoxically protective against in-hospital death and organ failure in a cohort of ~600 Thai patients — "hypofunctional TLR5 was associated with decreased organ failure and improved survival," though the same allele increases susceptibility to invasive aspergillosis and Legionnaires' disease (tradeoff/pleiotropy). - TNF and NOD2 polymorphisms linked to disease severity. - Cellular GWAS approaches (lymphoblastoid cell lines infected with B. pseudomallei) are being used to identify additional host regulators (grant: NIH R21-AI133171, T. West). - HLA associations are less well characterized than for many other infections; the strongest and most replicated genetic signal remains the TLR/TNF innate-immunity axis rather than an adaptive-immunity HLA locus.

Environmental/behavioral/comorbidity risk factors (these dominate over genetic risk in melioidosis, unusually for an infectious disease): - Diabetes mellitus (mostly type 2) — the single strongest risk factor; diabetic patients have ~3-fold to 12-fold increased risk across studies (meta-analysis RR 3.40, 95% CI 2.92–3.87; Nat Rev Dis Primers cites up to 12-fold), and diabetes is present in roughly half of all culture-confirmed cases (51% in one 321-patient cohort). - Hazardous alcohol use — present in ~32% of a representative cohort. - Chronic kidney disease — ~13% of cases; mechanistically, "in the milieu of advanced chronic kidney disease, neutrophils display impaired chemotaxis, reduced phagocytic ability, decreased generation of reactive oxygen intermediates during oxidative burst." - Chronic lung disease. - Thalassemia / iron-overload states — "conditions with increased iron stores, such as thalassemia, are considered to increase the risk to acquire melioidosis," and B. pseudomallei actively "modulates host iron homeostasis to facilitate iron availability and intracellular survival" (PLOS NTD, PMID 29228001). - Corticosteroid/immunosuppressive therapy. - Occupational/behavioral exposure: rice farming, gardening, other soil/water contact occupations; agricultural, laboratory, healthcare, veterinary, and construction workers; drinking untreated water; open wounds contaminated with soil/water; outdoor exposure during/after severe weather (typhoons increase incidence because "the bacteria would spread more easily with strong wind and storms"). - Male sex and older age (>45 years) are consistently overrepresented in adult cohorts. - Notably, HIV/immunosuppression from HIV is not a major reported risk factor in most endemic-region series (in contrast to many other opportunistic infections), though this varies by cohort.

Protective Factors

  • The TLR5 R392X and TLR4 −1196C>T variants noted above.
  • No validated dietary/lifestyle protective factor is established; primary prevention (below) centers on exposure avoidance rather than an identified protective exposure.

Gene-Environment Interactions

The dominant G×E pattern in melioidosis is host metabolic/iron dysregulation (diabetes, thalassemia) interacting with environmental exposure dose and route: hyperglycemia impairs neutrophil function and intracellular bacterial killing, so an environmental inoculum that a healthy host would clear establishes invasive infection in a diabetic host. Innate-immunity SNPs (TLR4/TLR5) modulate the inflammatory response magnitude once infection is established, influencing whether an exposure event progresses to septic shock versus a milder/localized course.

3. Phenotypes

Melioidosis has an extraordinarily protean presentation ("the great mimicker" in the literature), spanning localized cutaneous disease to fulminant multi-organ septic shock. Of 624 culture-confirmed patients in one large series, 51% presented with pneumonia as the primary diagnosis — the single most common organ manifestation.

Symptoms/Clinical Signs (Phenotype type: symptom/sign)

Phenotype Suggested HP term
Fever HP:0001945
Sepsis HP:0100806
Septic shock / Shock HP:0031273
Acute infectious pneumonia HP:0200114
Lung abscess HP:0031367
Liver abscess HP:0410033 (or "Hepatic abscess")
Splenic abscess HP:0100804 (Abnormality of the spleen) / splenic abscess (specific term may require search)
Cutaneous abscess HP:0031292
Cellulitis HP:0100658
Osteomyelitis (incl. foot osteomyelitis) HP:0002754
Septic arthritis HP:0002718
Parotitis / suppurative parotitis (pediatric hallmark, Thailand) HP:0100786 (Parotitis)
Prostatitis related genitourinary abnormality term
Brain abscess HP:0007183
Encephalitis / rhombencephalitis / brainstem encephalitis HP:0002383 (Encephalitis)
Hepatitis HP:0012115
Lymphadenitis HP:0100827 (or general lymphadenopathy term)
Cough HP:0012735
Headache HP:0002315
Myalgia HP:0003326
Arthralgia HP:0002829

Phenotype Characteristics

  • Age of onset: Any age; adult predominance overall, but with distinct pediatric syndrome (below). In endemic zones, cases cluster in the wet/monsoon season — 80% of pediatric Australian cases presented during the wet season.
  • Severity: Highly variable — from indolent chronic ulcerative skin disease to fulminant septic shock with death within 24–48 hours.
  • Progression pattern: Acute presentation in ~88% of cases; chronic (symptoms >2 months, often mimicking tuberculosis) in ~22% — note these can overlap/co-occur in the literature's classification. Notorious for relapse after treatment if eradication-phase therapy is inadequate.
  • Frequency/regional variation (a distinctive feature of melioidosis phenotype epidemiology — presentation differs qualitatively by geography):
  • Northern Australia (adults): pneumonia is the most common organ presentation (~51% in the large series above); genitourinary involvement (especially prostatic abscess) more prominent than in SE Asia.
  • Thailand (adults): bacteremia in ~64%, pneumonia ~62%, internal-organ abscess ~49%, soft tissue ~22%, joint ~7%.
  • Northern Australia (children): cutaneous manifestation is the most common presentation (60% vs. 13% in adults); bacteremia less common than in adults (16% vs. 59%); brainstem encephalitis occurred in 3/45 children in a 24-year Northern Territory series (Clin Infect Dis 2015;60:21, PMID 25234519).
  • Thailand (children): acute suppurative parotitis in ~one-third of pediatric cases, plus liver abscess, likely from ingestion of contaminated water.
  • Neurological melioidosis (an important, distinct sub-phenotype): unusual overall but a recognized encephalomyelitis syndrome with variable brainstem, cerebellar, and spinal cord involvement. Brainstem (34%) and frontal lobe (34%) are the most affected locations; rim-enhancing lesions on contrast MRI in 78%; CSF shows mononuclear pleocytosis (64%), elevated protein (93%), normal glucose (66%); mortality ~20% (systematic review, PLoS Negl Trop Dis 2019, PMID 30870428; and Meumann et al., Clin Infect Dis 2024, PMID 37788335, on the bimABm allele's influence on CNS presentation/outcome).

Quality of Life Impact

Direct disease-specific QoL instrument data (EQ-5D/SF-36) for melioidosis specifically was not identified in this search; QoL burden is inferred indirectly from the very high DALY estimates (see Epidemiology, below) driven by mortality and by long courses of IV/oral antibiotic therapy (up to 20 weeks total), amputation/debridement for severe cutaneous/osteoarticular disease, and neurological sequelae after CNS melioidosis.

4. Genetic/Molecular Information

Melioidosis is not a Mendelian genetic disease; there is no single causal gene. The "genetic" dimension relevant to a knowledge-base entry is (a) host susceptibility variants and (b) pathogen virulence-factor genetics.

Host Susceptibility Variants (not disease-causing, but modify risk/severity)

  • TLR4 (HGNC:11850) region SNPs, including −1196C>T (protective) and other TLR4-region variants (susceptibility-associated) — Genes Immun 2011.
  • TLR5 (HGNC:11851) R392X nonsense polymorphism — protective against organ failure/death, at the cost of increased susceptibility to Aspergillus and Legionella.
  • TLR1 and TLR2 coding variants — studied but a large multicenter cohort found no association between TLR1/TLR5 coding variants and mortality (PMC11066355), illustrating cohort-dependent heterogeneity in this literature.
  • TNF (HGNC:11892) promoter polymorphisms — linked to severity.
  • NOD2 (HGNC:5331) polymorphisms — linked to severity.
  • These are best modeled in dismech schema terms as susceptibility/modifier genetic context (relationship_type: SUSCEPTIBILITY or MODIFIER), not causal, consistent with OMIM's own framing of entry 615557 as "MELIOIDOSIS, SUSCEPTIBILITY TO."

Variant Classification / Population Frequency

Because these are common regulatory/coding SNPs in innate-immunity genes rather than rare Mendelian variants, ACMG pathogenicity classification, gnomAD rare-variant framing, and somatic/germline distinctions are not directly applicable in the usual dismech sense — allele frequencies for these SNPs should instead be sourced from population-genetics/GWAS literature (dbSNP/1000 Genomes) if precise curation is required.

Pathogen Genetics (arguably more central to "genetic/molecular information" for an infectious disease entry)

  • B. pseudomallei genome: two chromosomes (~7.2 Mb total), notable for encoding three Type III Secretion Systems (T3SS-1, -2, -3) and six Type VI Secretion Systems. T3SS-3 (the bsa locus, homologous to Salmonella SPI-1-type systems) is the one required for pathogenesis in mammals.
  • T3SS-3 regulatory hierarchy: bspR (BPSL1105) → bprP (BPSS1553) → bsaN/bicA (BPSS1546/BPSS1533) → effector operons bopC, bopE, bopA, and bapA/bapB/bapC (organized BPSS1516–BPSS1552).
  • Key effector proteins: BopE (a Rho-GTPase-mimicking GEF that promotes actin-dependent invasion and, per recent work, suppresses the Rab32-dependent host defense pathway — mSphere 2024); BopA (mediates evasion of LC3-associated phagocytosis/autophagy; PMC3055895); BipC (actin modulation and translocation).
  • Capsular polysaccharide loci (at least two of four described polysaccharide structures contribute to virulence — Type I O-PS is implicated in serum resistance/anti-phagocytosis).
  • Quorum sensing: three acyl-homoserine-lactone (AHL) synthase genes (bpsI1, bpsI2, bpsI3) plus five regulator genes; principal AHLs are N-octanoyl-HSL and N-(3-hydroxy-decanoyl)-HSL; quorum sensing negatively regulates multinucleate giant cell formation during intracellular growth.
  • bimA gene (actin-based motility, VirG/BimA family) — the bimABm allele specifically has been shown to influence CNS presentation and outcome of neurological melioidosis (Clin Infect Dis 2024, PMID 37788335).

Functional Consequences / Mechanistic Framing for dismech

For a dismech entry, host TLR4/TLR5/TNF/NOD2 variants map cleanly to GeneticContext.functional_impact_category (e.g., TLR5 R392X = truncating/LOSS_OF_FUNCTION variant with a paradoxically protective phenotype), while the pathogen virulence apparatus (T3SS-3, quorum sensing, capsule) is best modeled as biological_processes/molecular_functions on pathophysiology nodes (see Mechanism section) rather than as host genetic context, since it is bacterial rather than host biology.

Epigenetics / Chromosomal Abnormalities

No epigenetic or chromosomal-abnormality mechanism specific to melioidosis was identified in this search; this section is not applicable beyond the innate-immune SNP framework above.

5. Environmental Information

  • Primary environmental reservoir: B. pseudomallei is a saprophytic soil and freshwater organism, endemic in a band across tropical/subtropical latitudes, especially Southeast Asia (Thailand, especially the northeast; Malaysia; Singapore; Vietnam; Laos; Cambodia; Myanmar) and northern Australia, with increasing recognition in South Asia (India — "highest total burden," 1.6 million DALYs), sub-Saharan Africa, and parts of the Americas.
  • Environmental exposure routes: contact with contaminated soil/mud/surface water via skin abrasions; inhalation of aerosolized soil dust or water droplets, particularly during severe weather (typhoons, monsoon storms — "infection cases are more common after typhoons or storms"); ingestion of contaminated (especially untreated) water.
  • Occupational/behavioral exposures: rice-paddy farming, gardening, other agriculture, construction/soil excavation, veterinary work, laboratory work with the organism (BSL-3 required for virulent strains).
  • Climate change and epidemiological transition: emerging literature (PMC10128909, "Drivers of melioidosis endemicity: epidemiological transition, zoonosis, and climate change") links expanding endemic range and case counts to climate-driven changes in soil/water ecology and extreme-weather frequency.
  • Suggested ECTO term: exposure to contaminated soil/water (an ECTO term analogous to other soil/water-sapronosis exposures used elsewhere in dismech, e.g. the arsenic-water exposure pattern) — exact ECTO CURIE should be verified via OAK lookup at curation time.
  • Infectious agent: Burkholderia pseudomallei (NCBI Taxon:28450), Gram-negative bacillus, family Burkholderiaceae. Recognized biothreat status: CDC Tier 1 Select Agent and a Category B, Tier-1 biothreat agent, owing to environmental persistence, aerosol infectivity, and intrinsic resistance to many first-line antibiotics.

6. Mechanism / Pathophysiology

Overall Causal Chain

Environmental inoculation (percutaneous/inhalational/ingestion) → local bacterial adherence and invasion of host cells (phagocytic and non-phagocytic) → phagosomal/endosomal escape mediated by T3SS-3 → intracellular replication and cell-to-cell spread via actin-based motility → host innate immune sensing (TLR4/TLR5, inflammasome) → either effective early containment (localized abscess, chronic granulomatous disease) or immune dysregulation and systemic dissemination (bacteremia, septic shock, multi-organ abscess formation) depending on host factors (diabetes, iron overload, TLR/TNF genotype) and bacterial inoculum/virulence factors.

Molecular Pathways / Cellular Processes

  1. Adhesion and invasion: B. pseudomallei adheres to and invades both phagocytic (macrophages, neutrophils) and non-phagocytic cells (epithelial cells, fibroblasts) using flagella and adhesins.
  2. T3SS-3-mediated vacuolar escape: Following endocytosis/phagocytosis, T3SS-3 (bsa locus) delivers effectors (BopE, BipD, BipC) that trigger actin rearrangement and disrupt the phagosomal membrane, allowing bacterial escape into the cytosol before lysosomal fusion — "T3SS-3 mutants exhibit delayed vacuolar escape phenotypes" (Infect Immun 2008, PMID 18443088).
  3. Autophagy evasion: BopA disrupts LC3-associated phagocytosis (a form of xenophagy); bopA mutants show increased LC3 co-localization and reduced intracellular survival (PMC3055895).
  4. Actin-based intracellular/intercellular motility: BimA nucleates host actin at one bacterial pole, propelling the organism through the cytoplasm and into adjacent cells, producing characteristic multinucleated giant cells (MNGCs) via cell-cell fusion — a histopathological hallmark. Quorum sensing negatively regulates MNGC formation (PMC3660431).
  5. Inflammasome activation: Cytosolic B. pseudomallei activates the NLRC4 inflammasome early in macrophage infection (caspase-1-dependent, NLRC4-dependent), transitioning to NLRP3-dependent, NLRC4-independent activation at later time points, producing IL-1β/IL-18 and pyroptotic macrophage death (PLoS Pathog 2014, PMID 24626296). A non-canonical caspase-11 pathway in lung epithelial cells drives protective epithelial pyroptosis distinct from macrophage caspase-1-mediated pyroptosis (PLoS Pathog 2018, "Caspase-11-dependent pyroptosis of lung epithelial cells protects from melioidosis while caspase-1 mediates macrophage pyroptosis and production of IL-18").
  6. Systemic cytokine response: Severe/septic melioidosis is characterized by a Th1-polarized cytokine storm — elevated IFN-γ and the IFN-γ-inducing cytokines IL-18, IL-12, IL-15, alongside TNF-α and IL-6; APACHE II score together with IL-6 or IL-10 concentration are independent predictors of mortality (PMID 10669346).
  7. Iron acquisition/host iron manipulation: The organism actively modulates host iron homeostasis to increase iron availability for intracellular survival (PLoS Negl Trop Dis 2018, PMID 29228001) — mechanistically linking the thalassemia/iron-overload risk factor above to bacterial nutritional virulence.
  8. Capsule- and LPS-mediated serum resistance: Type I capsular O-polysaccharide confers resistance to complement-mediated killing and phagocytosis, permitting bacteremic dissemination.
  9. Quorum sensing (AHL-mediated): Coordinates biofilm formation, virulence factor expression, and (as above) restrains excessive giant-cell formation, implying a role in balancing acute cytotoxicity against sustained chronic/latent infection.

Cell Types Involved (suggested CL terms)

  • Macrophage (CL:0000235) — primary intracellular replicative niche and site of pyroptosis.
  • Neutrophil (CL:0000775) — first responder, impaired function in diabetes/CKD hosts.
  • Epithelial cell, respiratory (CL:0000082 or more specific alveolar epithelial terms) — site of caspase-11-dependent protective pyroptosis.
  • Dendritic cell (CL:0000451) — antigen presentation, Th1 polarization.
  • Fibroblast (CL:0000057) — non-phagocytic host cell also invaded.

Biological Processes (suggested GO terms)

  • Phagocytosis (GO:0006909)
  • Actin filament-based movement / actin-based cell motility (GO:0030036)
  • Inflammasome complex assembly (GO:0131015)
  • Pyroptosis (GO:0070269)
  • Positive regulation of interferon-gamma production (GO:0032729)
  • Response to lipopolysaccharide (GO:0032496)
  • Iron ion homeostasis (GO:0055072)
  • Quorum sensing (GO:0009372)

Tissue Damage Mechanisms

Direct cytotoxicity from intracellular replication and pyroptotic cell death; abscess formation via neutrophilic/granulomatous containment attempts; multinucleated giant cell formation as a histopathological correlate of cell-to-cell spread; septic shock physiology (vasodilation, capillary leak, disseminated intravascular coagulation in the most severe cases) in bacteremic disease.

Molecular Profiling

Specific transcriptomic/proteomic/metabolomic datasets for human melioidosis were not deeply catalogued in this search pass; the PepSeq multiplexed antigen-discovery platform (Front Immunol 2025) represents a relevant proteomics-adjacent effort for vaccine/diagnostic antigen discovery.

7. Anatomical Structures Affected

  • Organ level (primary): Lung (pneumonia — most common single-organ presentation), skin/soft tissue (cellulitis, cutaneous abscess), liver (abscess), spleen (abscess), prostate (prostatic abscess — a distinctive and diagnostically useful finding, more common in Australian cohorts), kidney (renal abscess), bone/joint (osteomyelitis, septic arthritis), parotid gland (suppurative parotitis, especially pediatric Thailand), brain/CNS (abscess, brainstem encephalitis/encephalomyelitis), lymph nodes (lymphadenitis).
  • Body systems involved: Respiratory, integumentary, hepatobiliary, genitourinary, musculoskeletal, central nervous, and (in severe disease) the vascular/hematologic system via sepsis/DIC.
  • Suggested UBERON terms: lung (UBERON:0002048), liver (UBERON:0002107), spleen (UBERON:0002106), prostate gland (UBERON:0002367), parotid gland (UBERON:0001832), brain stem (UBERON:0002298), skin of body (UBERON:0002097), bone tissue (UBERON:0002481).
  • Tissue/cell level: Alveolar epithelium and macrophages (pulmonary disease); hepatic/splenic parenchyma with microabscess formation; synovium (septic arthritis); bone marrow/cortical bone (osteomyelitis).
  • Subcellular level (GO Cellular Component): phagosome (GO:0045335), cytosol (GO:0005829, site of intracellular replication post-vacuolar escape), inflammasome complex (GO:0061702).
  • Localization/laterality: Generally not laterality-specific in the classic congenital-anomaly sense; CNS disease has a distinctive predilection for the brainstem/rhombencephalon.

8. Temporal Development

  • Onset: Any age; incubation period estimated at 1–21 days from inoculating injury in most acute presentations, though this is highly variable with inoculum/route/host factors.
  • Latency controversy — the "Vietnamese time bomb": Melioidosis acquired notoriety during the Vietnam War (an estimated 225,000 U.S. personnel potentially exposed; 343 confirmed cases in U.S. troops by 1973) for apparently reactivating years to decades after the exposure ended, with case reports of activation after 18 years (Vietnam veteran) and 28 years (WWII veteran), and extreme outlier claims of latency up to 62 years. However, a 2024 reassessment (Am J Trop Med Hyg 2024;111:156, PMID 38806042) concludes the "Time Bomb" phenomenon has largely not materialized at the scale predicted, and argues many historically reported "reactivation from latency" cases more likely represent undiagnosed chronic, relapsing-remitting melioidosis rather than truly dormant, asymptomatic infection.
  • Progression/course pattern: Acute fulminant presentation (~88% of cases) with rapid progression to sepsis/septic shock over hours to days, vs. chronic presentation (~22%, symptoms >2 months) mimicking tuberculosis with indolent pulmonary or cutaneous disease.
  • Relapse: A defining clinical feature — relapse after treatment is common if eradication-phase (oral) antibiotic therapy is inadequate in dose or duration; optimized co-trimoxazole regimens (1920 mg twice daily) reduce relapse to as low as ~3.2% monotherapy / 4.6% combination with doxycycline, versus substantially higher rates historically with shorter or lower-dose regimens.
  • Critical periods for intervention: Early recognition and initiation of appropriate IV antibiotics (ceftazidime or meropenem) within the acute phase is the single greatest modifiable determinant of survival, since delayed diagnosis (a common failure mode given the nonspecific presentation) drives the high case-fatality rates seen outside specialist centers.

9. Inheritance and Population

Melioidosis is an acquired infectious disease with no Mendelian inheritance pattern; the OMIM entry (615557) explicitly frames genetics as susceptibility, not inheritance of the disease itself. Penetrance/expressivity/anticipation/germline mosaicism/founder-effect/carrier-frequency concepts (as classically defined for monogenic disease) are not applicable; "carrier frequency" instead corresponds to population allele frequency of the TLR4/TLR5/TNF/NOD2 susceptibility SNPs discussed in Section 4.

Epidemiology

  • Global burden (2015 estimate, Limmathurotsakul et al. 2016; refined by Birnie et al., Lancet Infect Dis 2019, PMID 31285144): an estimated 165,000 cases and ~89,000 deaths per year worldwide — comparable in mortality burden to measles (~95,600 deaths/year) and exceeding leptospirosis (~50,000/year) and dengue (~12,500/year).
  • Regional burden: The WHO South-East Asia region accounts for >60% of the estimated global burden; India carries the highest total burden, estimated at 1.6 million DALYs.
  • Incidence: Median annual incidence across endemic-area studies is 20.5 cases per 100,000 population; the highest reported subgroup incidence is in Indigenous Australians, at 103.6 per 100,000 in 2011–12.
  • Mortality rate: Highly setting-dependent, ranging 9%–70% globally; state-of-the-art care (early diagnosis, ICU support, appropriate antibiotics) can reduce mortality to <10%, whereas resource-limited settings without ceftazidime/meropenem access see mortality >40%.

Population Demographics

  • Sex ratio: Male predominance is consistently reported across adult endemic-area cohorts (reflecting occupational/behavioral exposure patterns — agriculture, outdoor labor).
  • Age distribution: Adult predominance, typically >45 years, correlating with peak prevalence of diabetes/comorbidities; pediatric cases represent a minority (~5% in the 24-year Northern Territory series) but have a distinct clinical phenotype (Section 3).
  • Geographic distribution: Core endemic "melioidosis belt" — Southeast Asia (Thailand, especially Ubon Ratchathani/northeast region; Malaysia; Singapore; Vietnam; Laos; Cambodia; Myanmar) and northern Australia (Darwin/Northern Territory, Far North Queensland); increasingly recognized in South Asia (India), sub-Saharan Africa, and parts of Central/South America and the Caribbean as surveillance and diagnostic capacity improve; environmental suitability modeling suggests substantial under-recognition in Africa.

10. Diagnostics

Clinical/Laboratory Tests

  • Culture (gold standard): Blood, sputum, urine, pus/wound swabs, or throat swab cultured on selective media — Ashdown's agar (Trypticase soy agar + 4% glycerol, neutral red indicator, crystal violet, gentamicin as selective agents) is the classic selective medium enabling identification from non-sterile sites. Blood culture sensitivity is only ~60% in latent-class diagnostic-accuracy modeling, meaning a negative blood culture does not exclude disease.
  • Molecular (PCR): Real-time PCR targeting the TTS1 (T3SS-1) locus for direct detection from clinical specimens; automated molecular platforms are now being evaluated for point-of-care/near-patient use.
  • Serology: IgG/IgM ELISA and polysaccharide-based latex agglutination assays exist but "serological diagnosis of melioidosis remains challenging" due to background seropositivity in endemic populations and variable in-house/commercial assay performance; primarily useful as an adjunct, not a stand-alone diagnostic.
  • Environmental/soil detection: Culture- and PCR-based soil testing methods are used for environmental surveillance/source-tracing in endemic regions.

Genetic Testing

Not applicable in the conventional sense (no causal human gene); TLR4/TLR5/TNF/NOD2 genotyping is a research tool for risk/prognosis stratification, not a clinical diagnostic test.

Imaging

CT/MRI for organ abscess detection (liver, spleen, prostate, brain); contrast-enhanced MRI with T2-weighted sequences is the modality of choice for suspected CNS melioidosis, showing hyperintense brainstem/frontal lobe lesions with a characteristic rim-enhancing pattern in 78% of cases.

Clinical Criteria / Differential Diagnosis

No single validated clinical scoring system for diagnosis exists (diagnosis is microbiological); the key clinical challenge is that melioidosis mimics tuberculosis (chronic pulmonary cavitary disease), community-acquired pneumonia, and other causes of multi-organ abscess/sepsis, making a high index of suspicion in returning travelers or residents of endemic areas essential.

Screening

No population-level screening program exists; risk-based prevention counseling (below) substitutes for screening in high-risk groups (diabetics in endemic areas).

11. Outcome/Prognosis

  • Mortality: 9–70% depending on setting; <10% achievable with optimal care; historically cited overall figure "up to 40%."
  • Prognostic factors/biomarkers: APACHE II score, IL-6 and IL-10 plasma concentrations (and their ratios to TNF-α), plasma lactate, presence of bacteremia/septicemia, pneumonia as the presenting focus, older age, elevated serum urea and bilirubin, low lymphocyte count, low bicarbonate, and low serum albumin are each independently associated with mortality (PMID 10669346 and related cohort literature).
  • CNS melioidosis-specific mortality: ~20% in the systematic IPD review (PMID 30870428).
  • Relapse as a distinct "morbidity" outcome: 3–5% with modern optimized eradication-phase co-trimoxazole regimens; historically higher with suboptimal dosing/duration — relapse functions almost as a second disease phase in the natural history rather than a rare complication.
  • Recovery potential: Full recovery is achievable with prompt, adequate combined acute-phase IV and eradication-phase oral therapy; delayed or inadequate treatment is associated with both higher acute mortality and higher relapse-driven long-term morbidity.
  • Complications: Amputation/disfigurement from severe cutaneous/osteoarticular disease; neurological sequelae from CNS involvement (cranial nerve deficits from brainstem lesions); chronic organ abscess recurrence.

12. Treatment

Melioidosis treatment follows a well-established two-phase regimen (summarized in the LSHTM review "Treatment and prophylaxis of melioidosis," PMC4236584, and updated network meta-analyses).

Acute (Intensive) Phase — parenteral, ≥10–14 days (often 2–4 weeks)

  • Ceftazidime 2 g IV every 8 hours (40 mg/kg/dose in children) — mainstay first-line agent.
  • Suggested NCIT: NCIT:C15986 (Pharmacotherapy) + therapeutic_agent CHEBI term for ceftazidime (CHEBI:471415 or similar — verify via OAK).
  • Meropenem 1 g IV every 8 hours (25 mg/kg) — used preferentially in severe/septic-shock presentations or as second-line after treatment failure; carbapenems reserved for the most severe infections.
  • Co-amoxiclav (amoxicillin-clavulanate) — second-line/alternative acute-phase agent, particularly in pregnancy or where cephalosporins/carbapenems are unavailable.

Eradication Phase — oral, total antibiotic course to ~20 weeks

  • Co-trimoxazole (trimethoprim-sulfamethoxazole) — preferred eradication-phase agent; optimal dosing (1920 mg twice daily in adults) minimizes both relapse and mortality; typical duration 3–6 months (minimum duration for low relapse risk ≈ 3 months).
  • Suggested NCIT: NCIT:C15986 (Pharmacotherapy) + CHEBI therapeutic_agent for co-trimoxazole components (sulfamethoxazole CHEBI:9328, trimethoprim CHEBI:9679).
  • Doxycycline as an alternative or combination eradication agent, though co-trimoxazole monotherapy shows lower relapse rates than combination regimens in recent network meta-analysis (PLoS Negl Trop Dis 2023, PMID 37585472).
  • Co-amoxiclav as an alternative eradication-phase drug where co-trimoxazole is contraindicated (e.g., sulfa allergy, pregnancy, renal impairment).

Surgical/Interventional

Drainage of large abscesses (splenic, hepatic, prostatic, soft-tissue) is often required as an adjunct to antibiotics; debridement for severe cutaneous/soft-tissue disease.

Supportive Care

ICU-level sepsis management (fluid resuscitation, vasopressor support, mechanical ventilation) is central to reducing mortality in septic-shock presentations; this is reflected in the strong prognostic value of APACHE II scoring.

Experimental/Investigational

No approved vaccine or targeted immunotherapy exists yet; treatment remains purely antimicrobial + supportive.

Treatment Outcomes / Pharmacogenomics

Direct pharmacogenomic (drug-metabolism-variant) data specific to melioidosis antimicrobial dosing was not identified in this search; dosing adjustments are driven by renal function (relevant given CKD is itself a risk factor) rather than germline pharmacogenomic variants.

13. Prevention

Primary Prevention

  • Exposure avoidance: protective clothing (boots, gloves) for occupational soil/water contact in endemic areas; avoidance of soil/water exposure during and after severe weather events; immediate and thorough cleaning of any soil/water-contaminated skin wounds.
  • Water safety: avoiding consumption of untreated water; ensuring safe drinking water infrastructure in endemic communities.
  • Targeted diabetic prevention programs: The PREMEL trial (stepped-wedge cluster-randomized controlled trial) tested a multifaceted prevention program specifically for diabetics in an endemic area, reflecting the recognition that diabetes-focused prevention messaging is a rational primary-prevention strategy given the outsized attributable risk of diabetes.
  • No vaccine currently licensed (see below).

Secondary Prevention / Screening

No population-based screening program for melioidosis exists (unlike genetic or cancer screening); the closest analogue is targeted health education for identified high-risk groups (diabetics, agricultural workers) in endemic regions, and clinician education to raise diagnostic suspicion (reducing time-to-treatment, which is itself a major secondary-prevention lever against mortality).

Tertiary Prevention

Adequate-duration eradication-phase antibiotics (above) to prevent relapse constitutes the primary tertiary-prevention intervention in this disease.

Vaccine Development (active area, no licensed product as of 2025–2026)

  • Leading subunit candidate: CPS-CRM197/Hcp1 glycoconjugate (capsular polysaccharide conjugated to CRM197 carrier, plus Hcp1 protein antigen), developed at University of Nevada, Reno, with a planned/ongoing Phase I trial in Oxford, UK, in ~36 healthy adult volunteers (with and without diabetes), with a planned Phase 1b extension in Ubon Ratchathani, Thailand.
  • A second promising candidate emerged from a multi-institution collaboration (Tulane University, Northern Arizona University, UC Irvine, Charles Darwin University), reported to show preclinical promise (late-2025 press coverage).
  • PepSeq antigen-discovery platform (Front Immunol 2025) is being used for rational antigen selection for next-generation candidates.
  • Stakeholder-attitude research in Thailand (Ubon Ratchathani) has specifically assessed community and clinician readiness for future melioidosis vaccine trials (PMC10646340).
  • An active observational natural-history study (NCT06089668, "An Observational Study to Evaluate Clinical Characteristics of Adult Patients With Suspected or Confirmed Melioidosis") is ongoing to characterize the modern clinical spectrum, likely to inform future trial endpoints.

Public Health / Biosecurity

Because B. pseudomallei is a CDC Tier 1 Select Agent / Category B biothreat agent, public health prevention also intersects with biosecurity: laboratory-acquired infection monitoring programs exist for occupational exposures (PMID 36776750), and BSL-3 containment is mandated for research with virulent strains.

14. Other Species / Natural Disease

  • Taxonomy of causative organism: Burkholderia pseudomallei (NCBI Taxon:28450).
  • Naturally susceptible species: Melioidosis occurs naturally and commonly in sheep, goats, and pigs (the three most commonly affected livestock species); also reported in cattle, buffalo, horses, mules, deer, camels, alpacas, dogs, cats, dolphins, wallabies, koalas, nonhuman primates, birds, tropical fish, and reptiles (Merck Veterinary Manual; Aust Vet J 2025 companion-animal case series, PMID pending/DOI 10.1111/avj.70097 — 45 Australian cases: 24 dogs, 21 cats, 1997–2025).
  • Species-specific presentation: In goats, mastitis or pneumonia is most common, with aortic aneurysm also reported; in sheep, respiratory tract involvement predominates (fever, severe cough, respiratory distress, mucopurulent nasal/ocular discharge). Sheep and goats' particular susceptibility drives the requirement for pasteurization of tropical commercial goat's milk.
  • Veterinary/One Health relevance: A 2025 IJID One Health review frames melioidosis explicitly as a "One Health" issue given shared environmental exposure across species (IJID One Health 2025, S2949-9151(25)00040-X).
  • Transmission mode across species: Infection is sapronotic (environmental-source-driven) rather than classically zoonotic — animal-to-human and human-to-human transmission are both extremely rare; each host species acquires infection independently from the shared soil/water reservoir. This is an important point for accurate dismech curation: melioidosis should not be modeled with an animal-to-human transmission edge, but rather with parallel independent-exposure edges from a shared environmental reservoir.
  • Comparative pathology: The multinucleated giant cell / actin-based intracellular motility mechanism (Section 6) is conserved across the mammalian hosts studied (mice, hamsters, and natural livestock/companion-animal infection), supporting cross-species mechanistic conservation despite phenotypic (organ-tropism) variation.

15. Model Organisms

Mouse Models (the dominant experimental system)

  • BALB/c mice — highly susceptible; recapitulate acute human melioidosis: rapidly progressive bacteremia leading to death by ~96 hours post-infection; LD50 as low as 4 organisms.
  • C57BL/6 mice — relatively resistant; recapitulate chronic human melioidosis: typically remain asymptomatic for up to 6 weeks post-infection; LD50 ≈ 2.5 × 10⁴ organisms. Peritoneal exudate cells (PEC) from C57BL/6 mice show greater microbicidal efficiency against B. pseudomallei than BALB/c PECs, and resistance is proposed to have "a genetic basis," making this strain pair a classic acute-vs-chronic comparative model (Immunol Cell Biol 1998, PMID 9600859; and follow-up characterization studies PMC5325312, PMC3123849).
  • Low-dose aerosol C57BL/6 exposure specifically models chronic human melioidosis (PMC3123849), useful for studying the latency/chronicity question raised in Section 8.
  • Sex and age significantly modulate outcome in these models (PMC7168040, "The Impact of Age and Sex on Mouse Models of Melioidosis") — an important covariate for translational interpretation, and a candidate HUMAN_MODEL_MISMATCH consideration if mouse-model conclusions about sex/age effects are extrapolated directly to the strongly male-skewed human epidemiology.
  • Both inhalational and intraperitoneal challenge routes are used and produce differing kinetics/severity (PMID 28182634/PMC5325312).

Other Model Systems

  • Hamster models: used for capsule-mutant attenuation studies (PMID 26836271) and are generally considered highly susceptible, acute-lethality models useful for vaccine/therapeutic efficacy screening.
  • RAW 264.7 murine macrophage-like cell line and J774.2 murine macrophages: the standard in vitro cellular infection models for dissecting T3SS-3-dependent vacuolar escape, intracellular replication, and autophagy evasion (BopA) mechanisms.
  • Human primary macrophage-based infection models: used specifically to confirm that canonical NLRP3/NLRC4 inflammasome activation observed in mouse/cell-line systems is recapitulated in human cells (PLoS Negl Trop Dis 2020).
  • Avirulent/attenuated strains for biosafety: e.g., the ΔpurM strain with atypical type B LPS (PMC5461690), engineered specifically to permit non-BSL-3 study of aspects of melioidosis biology — a useful "model limitation" note, since findings from attenuated-strain studies may not fully generalize to virulent-strain pathogenesis.

Model Limitations

The BALB/c-acute/C57BL/6-chronic dichotomy is a well-validated and widely used proxy for the human acute/chronic clinical spectrum, but (a) inbred mouse LD50 values are many orders of magnitude apart from typical human environmental inoculum estimates, (b) the pronounced human comorbidity-driven risk architecture (diabetes, thalassemia, CKD) is not fully recapitulated in standard inbred immunocompetent mouse challenge models without additional metabolic-disease mouse-model crossing, and (c) the human "Vietnamese time bomb" multi-decade latency question (Section 8) has no validated long-duration animal model equivalent — the closest surrogate (low-dose C57BL/6 chronic aerosol exposure) models weeks, not years, of latency.

Sources