Melioidosis
Encyclopedia
Melioidosis is an infectious disease
caused by a Gram-negative
bacterium, Burkholderia pseudomallei
, found in soil
and water. It is of public health importance in endemic areas, particularly in Thailand and northern Australia. It exists in acute and chronic forms. Symptoms may include pain in chest, bones, or joints; cough; skin infections, lung nodule
s and pneumonia.
B. pseudomallei was previously classed as part of the Pseudomonas
genus and until 1992, it was known as Pseudomonas pseudomallei. It is phylogenetically related closely to Burkholderia mallei
which causes glanders
, an infection primarily of horses, donkeys and mules. The name Melioidosis is derived from the Greek melis (μηλις) meaning "a distemper of asses" with the suffixes -oid meaning "similar to" and -osis meaning "a condition", that is, a condition similar to glanders.
, at least five cases have been imported to the UK from that country, which suggests that melioidosis is endemic to that country and that there is a serious problem of underdiagnosis or under-reporting, most likely due to a lack of adequate laboratory facilities.
Northeast Thailand has the highest incidence of melioidosis recorded in the world (21.3 cases of melioidosis per 100,000 people per year). In Northeast Thailand, 80% of children are positive for antibodies
against B. pseudomallei by the age of 4; the figures are lower in other parts of the world.
Melioidosis is a recognised disease in animals, including cats, goats, sheep, and horses. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud. An outbreak at the Paris Zoo in the 1970s ("L’affaire du jardin des plantes") was thought to have originated from an imported panda
.
Burkholderia pseudomallei is normally found in soil and surface water; a history of contact with soil or surface water is therefore almost invariable in patients with melioidosis; that said, the majority of patients who do have contact with infected soil suffer no ill effects. Even within an area, the distribution of B. pseudomallei within the soil can be extremely patchy, and competition with other Burkholderia species has been suggested as a possible reason. Contaminated ground water was implicated in one outbreak in northern Australia. It has been suggested, on the basis of whole genome sequencing, that humans may play a role in moving B. pseudomallei from place to place.
The single most important risk factor for developing severe melioidosis is diabetes mellitus
. Other risk factors include thalassaemia, kidney disease, occupation (rice paddy farmers), and cystic fibrosis
. The mode of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei. Person-to-person spread has been described but is extremely unusual.
There is a clear association with increased rainfall: with the number (and severity) of cases increasing following increased precipitation.
of acute melioidosis was 9 days (range 1–21 days). Patients with latent melioidosis may be symptom free for decades; the longest period between presumed exposure and clinical presentation is 62 years. The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnam time-bomb". There is a wide spectrum of severity; in chronic presentations, symptoms may last months, but fulminant
infection, particularly associated with near-drowning, may present with severe symptoms over hours.
A patient with active melioidosis usually presents with fever. Pain or other symptoms may be suggestive of a clinical focus, which is found in around 75% of patients. Such symptoms include cough or pleuritic chest pain suggestive of pneumonia
, bone or joint pain suggestive of osteomyelitis or septic arthritis, or cellulitis. Intra-abdominal infection (including liver and/or splenic abscesses, or prostatic abscesses) do not usually present with focal pain, and imaging of these organs using ultrasound
or CT
should be performed routinely. In one series of 214 patients, 27.6% had abscesses in the liver or spleen (95% confidence interval
, 22.0% to 33.9%). It has been suggested that B. pseudomallei abscesses have a characteristic "honeycomb" or "swiss cheese" architecture (hypoechoic, multi-septate, multiloculate) on CT
.
There are regional variations in disease presentation: parotid
abscesses characteristically occur in Thai children but this presentation has only been described once in Australia. Conversely, prostatic abscesses are found in up to 20% of Australian males but are rarely described elsewhere. An encephalomyelitis syndrome is recognised in northern Australia.
Patients with melioidosis usually have risk factors for disease, such as diabetes, thalassemia, hazardous alcohol use or renal disease, and frequently give a history of occupational or recreational exposure to mud or pooled surface water. However, otherwise healthy patients, including children, may also get melioidosis.
In up to 25% of patients, no focus of infection is found and the diagnosis is usually made on blood cultures or throat swab. Melioidosis is said to be able to affect any organ in the body except the heart valves (endocarditis). Although meningitis
has been described secondary to ruptured brain abscesses, primary meningitis has not been described. Less common manifestations include intravascular infection, lymph node
abscesses (1.2–2.2%), pyopericardium and myocarditis, mediastinal infection, and thyroid and scrotal abscesses and ocular infection.
, sometimes being called "Vietnamese tuberculosis
". Chronic melioidosis can mimic tuberculous pericarditis
.
A definite history of contact with soil may not be elicited as melioidosis can be dormant for many years before manifesting. Attention should be paid to a history of travel to endemic areas in returned travellers. Some authors recommend considering possibility of melioidosis in every febrile patient with a history of traveling to and/or staying at endemic areas.
A complete screen (blood culture, sputum
culture, urine culture, throat swab and culture of any aspirated pus) should be performed on all patients with suspected melioidosis (culture on blood agar as well as Ashdown's medium
). A definitive diagnosis is made by growing B. pseudomallei from any site. A throat swab is not sensitive but is 100% specific if positive, and compares favourably with sputum culture. The sensitivity of urine culture is increased if a centrifuged specimen is cultured, and any bacterial growth should be reported (not just growth above 104 organisms/ml which is the usual cut off). Very occasionally, bone marrow culture may be positive in patients who have negative blood cultures for B. pseudomallei, but these are not usually recommended. A common error made by clinicians unfamiliar with melioidosis is to only send a specimen from the affected site (which is the usual procedure for most other infections) instead of sending a full screen.
Ashdown's medium, a selective medium containing gentamicin
, may be required for cultures taken from non-sterile sites. Burkholderia cepacia medium may be a useful alternative selective medium in non-endemic areas, where Ashdown's is not available. A new medium derived from Ashdown known as Francis medium may help differentiate B. pseudomallei from B. cepacia and may help in the early diagnosis of melioidosis, but has not yet been extensively clinically validated.
Many commercial kits for identifying bacteria may mis-identify B. pseudomallei (see Burkholderia pseudomallei for a more detailed discussion of these issues).
There is also a serological test
for melioidosis (indirect haemagglutination), but this is not commercially available in most countries. A high background titre may reduce the positive predictive value of serological tests in endemic countries. A specific direct immunofluorescent test and latex agglutination, based on monoclonal antibodies, are used widely in Thailand but are not available elsewhere. There is almost complete cross-reactivity with B. thailandensis. There exists a commercial ELISA
kit for melioidosis which appears to perform well. but no ELISA test has yet been clinically validated as a diagnostic tool.
It is not possible to make the diagnosis on imaging studies alone (X-rays and scans), but imaging is routinely performed to assess the full extent of disease. Imaging of the abdomen using CT scans or ultrasound is recommended routinely, as abscesses may not be clinically apparent and may coexist with disease elsewhere. Australian authorities suggest imaging of the prostate
specifically due to the high incidence of prostatic abscesses in northern Australian patients. A chest x-ray is also considered routine, with other investigations as clinically indicated. The presence of honeycomb abscesses in the liver are considered characteristic, but are not diagnostic.
The differential diagnosis
is extensive; melioidosis may mimic many other infections, including tuberculosis
.
Intravenous intensive phase.
Eradication phase.
, co-trimoxazole
and doxycycline
; this regimen is associated with a mortality rate of 80% and should no longer be used unless no other alternatives are available. All four drugs are bacteriostatic (they stop the bacterium from growing but do not kill it) and the action of co-trimoxazole antagonizes both chloramphenicol and doxycycline.
or meropenem
), the septicemic form of melioidosis has a mortality rate that exceeds 90%. With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with bacteraemia or severe sepsis. It seems certain that access to intensive care facilities is also important, and probably at least partially explains why total mortality is 20% in Northern Australia but 40% in Northeast Thailand. Response to appropriate antibiotic treatment is slow with the average duration of fever following treatment being 5–9 days.
Recurrence occurs in 10 to 20% of patients. While molecular studies have established that the majority of recurrences are due to the original infecting strain, a significant proportion of recurrences (perhaps up to a quarter) in endemic areas may be due to reinfection, particularly after 2 years. Risk factors include severity of disease (patients with positive blood cultures or multifocal disease have a higher risk of relapse), choice of antibiotic for eradication therapy (doxycycline monotherapy and fluoroquinolone therapy are not as effective), poor compliance with eradication therapy and duration of eradication therapy less than 8 weeks.
In endemic areas, people (rice-paddy farmers in particular) are warned to avoid contact with soil, mud and surface water where possible. Case clusters have been described following flooding and cyclones and probably relate to exposure. Other case clusters have related to contamination of drinking water supplies. Populations at risk include patients with diabetes mellitus
, chronic renal failure
, chronic lung disease or patients with an immune deficiency of any kind. The effectiveness of measures to reduce exposure to the causative organism have not been established. A vaccine is not yet available.
and grepafloxacin
have been shown to be effective in animal models.
There are no vaccines currently licensed for the prevention of melioidosis.
. It is classed by the US Centers for Disease Control (CDC) as a Category B agent. B. pseudomallei, like its relative B. mallei which causes Glanders
, was studied by the U.S. as a potential biological warfare agent, but was never weaponized. It has been reported that the Soviet Union
was also experimenting with B. pseudomallei as a biological warfare agent.
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
caused by a Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacterium, Burkholderia pseudomallei
Burkholderia pseudomallei
Burkholderia pseudomallei is a Gram-negative, bipolar, aerobic, motile rod-shaped bacterium. It infects humans and animals and causes the disease melioidosis. It is also capable of infecting plants....
, found in soil
Soil
Soil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics...
and water. It is of public health importance in endemic areas, particularly in Thailand and northern Australia. It exists in acute and chronic forms. Symptoms may include pain in chest, bones, or joints; cough; skin infections, lung nodule
Nodule (medicine)
For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure....
s and pneumonia.
B. pseudomallei was previously classed as part of the Pseudomonas
Pseudomonas
Pseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...
genus and until 1992, it was known as Pseudomonas pseudomallei. It is phylogenetically related closely to Burkholderia mallei
Burkholderia mallei
Burkholderia mallei is a gram-negative bipolar aerobic bacterium, a Burkholderia-genus human and animal pathogen causing Glanders; the Latin name of this disease gave name to the causative agent species...
which causes glanders
Glanders
Glanders is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats...
, an infection primarily of horses, donkeys and mules. The name Melioidosis is derived from the Greek melis (μηλις) meaning "a distemper of asses" with the suffixes -oid meaning "similar to" and -osis meaning "a condition", that is, a condition similar to glanders.
Epidemiology
Melioidosis is endemic in parts of southeast Asia (including Thailand, Laos and southern China, Singapore, Malaysia, Burma and Vietnam), Taiwan and northern Australia. Multiple cases have also been described in Hong Kong and Brunei India, and sporadic cases in Central and South America, the Middle East, the Pacific and several African countries. Although only one case of melioidosis has ever been reported in BangladeshBangladesh
Bangladesh , officially the People's Republic of Bangladesh is a sovereign state located in South Asia. It is bordered by India on all sides except for a small border with Burma to the far southeast and by the Bay of Bengal to the south...
, at least five cases have been imported to the UK from that country, which suggests that melioidosis is endemic to that country and that there is a serious problem of underdiagnosis or under-reporting, most likely due to a lack of adequate laboratory facilities.
Northeast Thailand has the highest incidence of melioidosis recorded in the world (21.3 cases of melioidosis per 100,000 people per year). In Northeast Thailand, 80% of children are positive for antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against B. pseudomallei by the age of 4; the figures are lower in other parts of the world.
Melioidosis is a recognised disease in animals, including cats, goats, sheep, and horses. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud. An outbreak at the Paris Zoo in the 1970s ("L’affaire du jardin des plantes") was thought to have originated from an imported panda
Panda
Panda or Panda bear most often refers to:*Giant panda, an animal in the Bear familyPanda may also refer to:*Red panda, the only living member in the Ailuridae family-In biology:* Species related to the Giant panda...
.
Burkholderia pseudomallei is normally found in soil and surface water; a history of contact with soil or surface water is therefore almost invariable in patients with melioidosis; that said, the majority of patients who do have contact with infected soil suffer no ill effects. Even within an area, the distribution of B. pseudomallei within the soil can be extremely patchy, and competition with other Burkholderia species has been suggested as a possible reason. Contaminated ground water was implicated in one outbreak in northern Australia. It has been suggested, on the basis of whole genome sequencing, that humans may play a role in moving B. pseudomallei from place to place.
The single most important risk factor for developing severe melioidosis is diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. Other risk factors include thalassaemia, kidney disease, occupation (rice paddy farmers), and cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
. The mode of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei. Person-to-person spread has been described but is extremely unusual.
There is a clear association with increased rainfall: with the number (and severity) of cases increasing following increased precipitation.
Acute melioidosis
In the subgroup of patients where an inoculating event was noted, the mean incubation periodIncubation period
Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...
of acute melioidosis was 9 days (range 1–21 days). Patients with latent melioidosis may be symptom free for decades; the longest period between presumed exposure and clinical presentation is 62 years. The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnam time-bomb". There is a wide spectrum of severity; in chronic presentations, symptoms may last months, but fulminant
Fulminant
Fulminant is any event or process that occurs suddenly and quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character. The word comes from Latin fulmināre, to strike with lightning...
infection, particularly associated with near-drowning, may present with severe symptoms over hours.
A patient with active melioidosis usually presents with fever. Pain or other symptoms may be suggestive of a clinical focus, which is found in around 75% of patients. Such symptoms include cough or pleuritic chest pain suggestive of pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, bone or joint pain suggestive of osteomyelitis or septic arthritis, or cellulitis. Intra-abdominal infection (including liver and/or splenic abscesses, or prostatic abscesses) do not usually present with focal pain, and imaging of these organs using ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
or CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
should be performed routinely. In one series of 214 patients, 27.6% had abscesses in the liver or spleen (95% confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
, 22.0% to 33.9%). It has been suggested that B. pseudomallei abscesses have a characteristic "honeycomb" or "swiss cheese" architecture (hypoechoic, multi-septate, multiloculate) on CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
.
There are regional variations in disease presentation: parotid
Parotid gland
The paired parotid glands are the largest of the salivary glands. They are each found wrapped around the mandibular ramus, and secrete saliva through Stensen's ducts into the oral cavity, to facilitate mastication and swallowing and to begin the digestion of starches.-Location:The parotid glands...
abscesses characteristically occur in Thai children but this presentation has only been described once in Australia. Conversely, prostatic abscesses are found in up to 20% of Australian males but are rarely described elsewhere. An encephalomyelitis syndrome is recognised in northern Australia.
Patients with melioidosis usually have risk factors for disease, such as diabetes, thalassemia, hazardous alcohol use or renal disease, and frequently give a history of occupational or recreational exposure to mud or pooled surface water. However, otherwise healthy patients, including children, may also get melioidosis.
In up to 25% of patients, no focus of infection is found and the diagnosis is usually made on blood cultures or throat swab. Melioidosis is said to be able to affect any organ in the body except the heart valves (endocarditis). Although meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
has been described secondary to ruptured brain abscesses, primary meningitis has not been described. Less common manifestations include intravascular infection, lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
abscesses (1.2–2.2%), pyopericardium and myocarditis, mediastinal infection, and thyroid and scrotal abscesses and ocular infection.
Chronic melioidosis
Chronic melioidosis is usually defined by a duration of symptoms greater than 2 months and occurs in approximately 10% of patients. The clinical presentation of chronic melioidosis is protean and includes such presentations as chronic skin infection, skin ulcers and lung nodules or chronic pneumonia, closely mimicking tuberculosisTuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, sometimes being called "Vietnamese tuberculosis
Vietnamese tuberculosis
Vietnamese tuberculosis refers to certain forms of chronic melioidosis that look clinically very similar to tuberculosis. It is derived from the clinical appearance of the disease in American soldiers returning from the Vietnam war....
". Chronic melioidosis can mimic tuberculous pericarditis
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...
.
Diagnosis
A definitive diagnosis is made by culturing the organism from any clinical sample, because the organism is never part of the normal human flora.A definite history of contact with soil may not be elicited as melioidosis can be dormant for many years before manifesting. Attention should be paid to a history of travel to endemic areas in returned travellers. Some authors recommend considering possibility of melioidosis in every febrile patient with a history of traveling to and/or staying at endemic areas.
A complete screen (blood culture, sputum
Sputum
Sputum is mucus that is coughed up from the lower airways. It is usually used for microbiological investigations of respiratory infections....
culture, urine culture, throat swab and culture of any aspirated pus) should be performed on all patients with suspected melioidosis (culture on blood agar as well as Ashdown's medium
Ashdown's medium
Ashdown's medium is a selective culture medium for the isolation and characterisation of Burkholderia pseudomallei .Ashdown's medium was first described by LR Ashdown in 1979....
). A definitive diagnosis is made by growing B. pseudomallei from any site. A throat swab is not sensitive but is 100% specific if positive, and compares favourably with sputum culture. The sensitivity of urine culture is increased if a centrifuged specimen is cultured, and any bacterial growth should be reported (not just growth above 104 organisms/ml which is the usual cut off). Very occasionally, bone marrow culture may be positive in patients who have negative blood cultures for B. pseudomallei, but these are not usually recommended. A common error made by clinicians unfamiliar with melioidosis is to only send a specimen from the affected site (which is the usual procedure for most other infections) instead of sending a full screen.
Ashdown's medium, a selective medium containing gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
, may be required for cultures taken from non-sterile sites. Burkholderia cepacia medium may be a useful alternative selective medium in non-endemic areas, where Ashdown's is not available. A new medium derived from Ashdown known as Francis medium may help differentiate B. pseudomallei from B. cepacia and may help in the early diagnosis of melioidosis, but has not yet been extensively clinically validated.
Many commercial kits for identifying bacteria may mis-identify B. pseudomallei (see Burkholderia pseudomallei for a more detailed discussion of these issues).
There is also a serological test
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
for melioidosis (indirect haemagglutination), but this is not commercially available in most countries. A high background titre may reduce the positive predictive value of serological tests in endemic countries. A specific direct immunofluorescent test and latex agglutination, based on monoclonal antibodies, are used widely in Thailand but are not available elsewhere. There is almost complete cross-reactivity with B. thailandensis. There exists a commercial ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
kit for melioidosis which appears to perform well. but no ELISA test has yet been clinically validated as a diagnostic tool.
It is not possible to make the diagnosis on imaging studies alone (X-rays and scans), but imaging is routinely performed to assess the full extent of disease. Imaging of the abdomen using CT scans or ultrasound is recommended routinely, as abscesses may not be clinically apparent and may coexist with disease elsewhere. Australian authorities suggest imaging of the prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
specifically due to the high incidence of prostatic abscesses in northern Australian patients. A chest x-ray is also considered routine, with other investigations as clinically indicated. The presence of honeycomb abscesses in the liver are considered characteristic, but are not diagnostic.
The differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
is extensive; melioidosis may mimic many other infections, including tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
.
Current treatment
The treatment of melioidosis is divided into two stages, an intravenous high intensity phase and an eradication phase to prevent recurrence.Intravenous intensive phase.
- Intravenous ceftazidimeCeftazidimeCeftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
is the current drug of choice for treatment of acute melioidosis. MeropenemMeropenemMeropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
, imipenemImipenemImipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...
and cefoperazone-sulbactam (Sulperazone) are also active. Intravenous amoxicillin-clavulanate (co-amoxiclavCo-amoxiclavAmoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...
) may be used if none of the above four drugs are available, but it produces inferior outcomes. Intravenous antibioticAntibioticAn antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s are given for a minimum of 10 to 14 days, and are not usually stopped until the patient's temperature has returned to normal for more than 48 hours. Even with appropriate antibiotic therapy, fevers often persist for weeks or months, and patients may continue to develop new lesions even while on appropriate treatment. The median fever clearance time in melioidosis is 10 days: and failure of the fever to clear is not a reason to alter treatment. It is not uncommon for patients to require parenteralParenteralParenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
treatment continuously for a month or more.
- Intravenous meropenemMeropenemMeropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
is routinely used in Australia: outcomes appear to be good and meropenem is currently being tested with ceftazidime in a Thai clinical trial (ATOM).
- There are theoretical reasons for believing that mortality might be lower in patients treated with imipenem: first, there is less endotoxinEndotoxinEndotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
released by dying bacteria during imimipenem treatment, and the minimum inhibitory concentrationMinimum inhibitory concentrationIn microbiology, minimum inhibitory concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. Minimum inhibitory concentrations are important in diagnostic laboratories to confirm resistance of microorganisms...
for imipenem is lower than for ceftazidime. However, no clinically relevant difference was found in mortality between imipenem and ceftazidime treatment. The MIC of meropenem is higher for B. pseudomallei than for many other organisms, and patients being haemofiltered will need more frequent or higher doses.
- MoxifloxacinMoxifloxacinMoxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion...
, cefepimeCefepimeCefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents...
, tigecyclineTigecyclineTigecycline is a glycylcycline antibiotic developed by Francis Tally and marketed by Wyeth under the brand name Tygacil. It was given a U.S. Food and Drug Administration fast-track approval and was approved on June 17, 2005...
and ertapenemErtapenemErtapenem is a carbapenem antibiotic marketed by Merck as Invanz. It is structurally very similar to meropenem in that it possess a 1-β-methyl group.-Indications:...
do not appear to be effective in vitro. Piperacillin-sulbactamPiperacillinPiperacillin is an extended spectrum beta-lactam antibiotic of the ureidopenicillin class.It is normally used together with a beta-lactamase inhibitor such as tazobactam. The combination drug piperacillin/tazobactam is commercially available as e.g. Tazocin, Zosyn, Brodactam, Piptaz and as Trezora...
, doripenemDoripenemDoripenem is an ultra-broad spectrum injectable antibiotic. It is a beta-lactam and belongs to the subgroup of carbapenems. It was launched by Shionogi Co. of Japan under the brand name Finibax in 2005 and is being marketed outside Japan by Johnson & Johnson...
and biapenemBiapenemBiapenem is a carbapenem antibiotic. It has in vitro activity against anaerobes.Approved in Japan in 2001.-External links:...
appear to be effective in vitro, but there is no clinical experience on which to recommend their use.
- Adjunctive treatment with GCSFGranulocyte colony-stimulating factorGranulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
or co-trimoxazoleCo-trimoxazoleTrimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
were not associated with decreased fatality rates in trials in Thailand.
Eradication phase.
- Following the treatment of the acute disease, it is recommended that eradication (or maintenance) treatment with co-trimoxazoleCo-trimoxazoleTrimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
and doxycyclineDoxycyclineDoxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
be used for 12 to 20 weeks to reduce the rate of recurrence. ChloramphenicolChloramphenicolChloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
is no longer routinely recommended for this purpose. Co-amoxiclav is an alternative for those patients who are unable to take co-trimoxazole and doxycyclineDoxycyclineDoxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
(e.g., pregnant women and children under the age of 12), but is not as effective. Single agent treatment with a fluoroquinolone (e.g., ciprofloxacinCiprofloxacinCiprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
) or doxycycline for the oral maintenance phase is ineffective.
- In Australia, co-trimoxazole is used on its own for eradication therapy, with relapse rates that are lower than those seen in Thailand; there is also in vitro evidence to suggest that co-trimoxazole and doxycycline are antagonistic, and that co-trimoxazole on its own may be preferable. A randomised controlled trial (MERTH) to compare this with the current standard of co-trimoxazole and doxycycline started in 2006 and is due for completion in 2008. Studies reinforce the need for adequate follow up and good adherence to the eradication phase of therapy. Dosing for co-trimoxazole is based on weight: (<40 kg: 160/800 mg every 12 hours; 40–60kg: 240/1200 mg every 12 hours, >60 kg: 320/1600 mg every 12 hours).
Surgical treatment
Surgical drainage is usually indicated for prostatic abscesses and septic arthritis, may be indicated for parotid abscesses and not usually indicated for hepatosplenic abscesses. In bacteraemic melioidosis unresponsive to intravenous antibiotic therapy, splenectomy has been attempted, but there is only anecdotal evidence to support this practice.Historical treatment
Prior to 1989, the standard treatment for acute melioidosis was a three-drug combination of chloramphenicolChloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
, co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
and doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
; this regimen is associated with a mortality rate of 80% and should no longer be used unless no other alternatives are available. All four drugs are bacteriostatic (they stop the bacterium from growing but do not kill it) and the action of co-trimoxazole antagonizes both chloramphenicol and doxycycline.
Prognosis
Without access to appropriate antibiotics (principally ceftazidimeCeftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
or meropenem
Meropenem
Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
), the septicemic form of melioidosis has a mortality rate that exceeds 90%. With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with bacteraemia or severe sepsis. It seems certain that access to intensive care facilities is also important, and probably at least partially explains why total mortality is 20% in Northern Australia but 40% in Northeast Thailand. Response to appropriate antibiotic treatment is slow with the average duration of fever following treatment being 5–9 days.
Recurrence occurs in 10 to 20% of patients. While molecular studies have established that the majority of recurrences are due to the original infecting strain, a significant proportion of recurrences (perhaps up to a quarter) in endemic areas may be due to reinfection, particularly after 2 years. Risk factors include severity of disease (patients with positive blood cultures or multifocal disease have a higher risk of relapse), choice of antibiotic for eradication therapy (doxycycline monotherapy and fluoroquinolone therapy are not as effective), poor compliance with eradication therapy and duration of eradication therapy less than 8 weeks.
Prevention
Person-to-person transmission is exceedingly unusual; and patients with melioidosis should not be considered contagious. Lab workers should handle Burkholderia pseudomallei under BSL-3 isolation conditions, as laboratory acquired melioidosis has been described.In endemic areas, people (rice-paddy farmers in particular) are warned to avoid contact with soil, mud and surface water where possible. Case clusters have been described following flooding and cyclones and probably relate to exposure. Other case clusters have related to contamination of drinking water supplies. Populations at risk include patients with diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
, chronic lung disease or patients with an immune deficiency of any kind. The effectiveness of measures to reduce exposure to the causative organism have not been established. A vaccine is not yet available.
Post-exposure prophylaxis
After exposure to B. pseudomallei (particularly following a laboratory accident) combined treatment with co-trimoxazole and doxycycline is recommended. TrovafloxacinTrovafloxacin
Trovafloxacin is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity...
and grepafloxacin
Grepafloxacin
Grepafloxacin hydrochloride was a oral broad-spectrum quinoline antibacterial agent used to treat bacterial infections...
have been shown to be effective in animal models.
Vaccination
There are no vaccines currently licensed for the prevention of melioidosis.
Biological warfare potential
There has been interest in melioidosis because it has the potential to be developed as a biological weaponBiological warfare
Biological warfare is the use of biological toxins or infectious agents such as bacteria, viruses, and fungi with intent to kill or incapacitate humans, animals or plants as an act of war...
. It is classed by the US Centers for Disease Control (CDC) as a Category B agent. B. pseudomallei, like its relative B. mallei which causes Glanders
Glanders
Glanders is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats...
, was studied by the U.S. as a potential biological warfare agent, but was never weaponized. It has been reported that the Soviet Union
Soviet Union
The Soviet Union , officially the Union of Soviet Socialist Republics , was a constitutionally socialist state that existed in Eurasia between 1922 and 1991....
was also experimenting with B. pseudomallei as a biological warfare agent.
Synonyms
- pseudoglanders
- Whitmore's disease (after Captain Alfred WhitmoreAlfred WhitmoreMajor Alfred Whitmore was an English pathologist who, together with C.S. Krishnaswami, identified Burkholderia pseudomallei, the causative agent of melioidosis in opium addicts in Rangoon in 1911...
, who first described the disease) - Nightcliff gardener's disease (Nightcliff is a suburb of Darwin, AustraliaDarwin, Northern TerritoryDarwin is the capital city of the Northern Territory, Australia. Situated on the Timor Sea, Darwin has a population of 127,500, making it by far the largest and most populated city in the sparsely populated Northern Territory, but the least populous of all Australia's capital cities...
where melioidosis is endemic) - Paddy-field disease
- Morphia injector's septicaemia
See also
In episode 9 season 5 of TV show House M.D. the hostage taker who seeks a diagnosis from House has melioidosis (ironically, the stubborn man has the "distemper of asses").External links
- Virginia Tech pathogen database - Burkholderia pseudomallei
- Center for Biosecurity Agent Fact Sheet
- Burkholderia pseudomallei genomes and related information at PATRIC, a Bioinformatics Resource Center funded by NIAID