|Symptoms||None, fever, pneumonia, multiple abscesses|
|Complications||Encephalomyelitis, septic shock, acute pyelonephritis, septic arthritis, osteomyelitis|
|Usual onset||1-21 days after exposure|
|Causes||Burkholderia pseudomallei spread by contact to soil or water|
|Risk factors||Diabetes mellitus, thalassaemia, alcoholism, chronic kidney disease, cystic fibrosis|
|Diagnostic method||Growing the bacteria in culture mediums|
|Prevention||Prevention from exposure to contaminated water, antibiotic prophylaxis|
|Treatment||Ceftazidime, meropenem, co-trimoxazole|
|Frequency||165,000 people per year|
|Deaths||89,000 people per year|
Melioidosis is an infectious disease caused by Gram-negative bacterium called Burkholderia pseudomallei. Signs and symptoms can range from none to mild such as fever, skin changes, pneumonia, and abscesses to severe with inflammation of the brain, inflammation of the joints with dangerously low blood pressure which could easily results in death.
The bacteria can be transmitted through wounds, inhalation, and ingestion of polluted water. Person-to-person or animal-to-human transmission is extremely rare. The infection is constantly present in Southeast Asia particularly in northeast Thailand and in northern Australia. In developed countries such as Europe and United States, melioidosis cases are usually imported from countries where melioidosis are constantly present. Diagnosis is usually confirmed by the growth of the bacteria in growth medium. It is important to differentiate the disease clinically from tuberculosis because both shared similar signs and symptoms with similar chest radiograph findings. If the disease is properly treated, death rate is 10%, but if the disease if improperly treated, the death rate could be more than 40%.
Efforts to prevent the disease includes: wearing protective gear while handling contaminated water or apparatus, avoiding direct contact with soil, water, or heavy rain, practising hand hygiene, and drinking boiled water. Antibiotic co-trimoxazole is only used for high risk individuals for getting the disease after being exposed to the bacteria. There is no approved vaccines for melioidosis yet. Treatment if infected is with ceftazidime, meropenem, and co-trimoxazole.
It is estimated that 165,000 people are infected by melioidosis per year. This results in about 89,000 deaths per year. Increased rainfall is associated with increased number of melioidosis cases in endemic areas. The disease was first described by Alfred Whitmore in 1912 in present-day Myanmar.
- 1 Signs and symptoms
- 2 Cause
- 3 Pathogenesis
- 4 Diagnosis
- 5 Prevention
- 6 Treatment
- 7 Prognosis
- 8 Biological warfare potential
- 9 Epidemiology
- 10 History
- 11 Synonyms
- 12 References
- 13 External links
Signs and symptoms
Most of the people who are exposed to the bacteria experience no symptoms. For those children staying in endemic areas, 25% of them experienced seroconversion (the time period needed for antibodies started to form against antigens) in between 6 months to 4 years. This means that high number of asymptomatic people will be tested positive in serology in endemic areas. In Thailand, the seropositivity rate exceeds 50% while for Australia, the seropositivity is only 5%.
The mean incubation period of acute melioidosis was 9 days (range 1–21 days). Symptoms usually appear 2 to 4 weeks after exposure. However, symptoms of melioidosis can also appear in 24 hours for those experienced near drowning in water. Those affected are presented with symptoms of sepsis (predominantly fever) with or without pneumonia, or localised abscess or other focus of infection. The presence of non-specific signs and symptoms has caused melioidosis to be nicknamed as "the great mimicker". 85% of the melioidosis cases are acute.
Those people with diabetes mellitus or occupation or seasonal exposure to the bacteria are at increased risk of developing melioidosis. The disease should be considered in anyone who has fever and staying in endemic areas and those who has abscesses in liver, spleen, prostate, or parotid gland with pneumonia. The clinical manifestation of the disease can range from simple skin changes to severe organ involvement. In northern Australia, 60% of the infected children presented with skin lesions only while 20% of them presented with pneumonia. Among the commonest organs affected are: liver, spleen, lungs, prostate, and kidneys. Bacteremia can occur in 40 to 60% of the people while septic shock occurs in 20% of the cases. Pneumonia is present in 50% of the cases. For those presented with septic shock together with pneumonia, there could be minimal cough. However, for those presented with pneumonia only, prominent cough with sputum and shortness of breath is observed. On chest X-ray, the appearance could range from diffuse nodular infiltrates in those with septic shock to progressive pulmonary consolidation in the upper lobes for those presented with pneumonia only. Pleural effusion and empyema are more common for melioidosis affecting lower lobes of the lungs. Therefore, melioidosis should be differentiated from tuberculosis for those coming from endemic areas because both conditions show radiogical changes on the upper lobes of the lungs. In 10% of the cases, there are secondary pneumonia caused by other bacteria after the primary infection.
1% to 5% of those infected could develop encephalomyelitis or brain abscess, 14 to 28% of the cases could develop acute pyelonephritis, kidney abscess or prostatic abscesses, 0 to 30% would develop neck or parotid gland abscess, 10 to 33% would develop liver, spleen, or paraintestinal abscesses and 4 to 14% of the cases could develop septic arthritis and osteomyelitis. Other rare manifestations could be lymphadenopathy resembling tuberculosis, mediastinal masses, pericardial effusion, mycotic aneurysm, and pancreatitis. Specifically in Australia, up to 20% of the males can get prostatic abscess. Presentation for prostatic abscesses are: pain during urination (dysuria), difficulty in passing urine, and urinary retention requiring catheterization. Rectal examination shows tender and boggy prostate.  In Thailand, 30% of the infected children can get parotid abscess. Subconjunctival abscess and orbital cellulitis may also occur. Encephalomyelitis can occur in healthy people without risk factors. Computed tomography (CT) brain is normal but there is an increase in T2 signal on magnetic resonance imaging (MRI), extending to brain stem and spinal cord. Clinical signs include: unilateral upper motor neuron limb weakness, cerebellar signs, and cranial nerve palsies (VI, VII nerve palsies and bulbar palsy). Some cases presented with flaccid paralysis alone. In northern Australia, all melioidosis with encephalomyelitis cases have elevated white cells in cerebrospinal fluid (CSF), measuring at 30 to 775 cells per microlitres, where majority of the cells are mononuclear cells. CSF protein can be elevated with normal glucose levels.
Chronic melioidosis is usually defined by a duration of symptoms greater than two months and occurs in about 10% of patients. The clinical presentation of chronic melioidosis is protean and includes such presentations as chronic skin infections, chronic lung nodule, and pneumonia. In particular, chronic melioidosis closely mimics tuberculosis, and has sometimes been called "Vietnamese tuberculosis". Other clinical presentations include: fever, weight loss, productive cough with or without bloody sputum with long standing abscesses at multiple body sites.
In latent infection, immunocompetent people have the ability to clear out the infection without showing any symptoms. However, less than 5% of all melioidosis cases has activation after a period of latency. Patients with latent melioidosis may be symptom-free for decades; the longest period between presumed exposure and clinical presentation is 62 years. He was a prisoner of war in Burma-Thailand-Malaysia. The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnam time-bomb". However, subsequent genotyping of the bacteria isolate from the Vietnam veteran showed that the isolate may not come from the Southeast Asia, but from South America. This reinstates a previous report that put the longest latency period for meliodosis as 29 years. Various cormorbidities such as diabetes, renal failure, and alcoholism can predispose to reactivation of melioidosis. In Autralia, the longest recorded latency period was 24 years.
Melioidosis is caused by gram negative, opportunistic, facultative, intracellular, motile saprophyte bacteria named Burkholderia pseudomallei. The bacteria is also aerobic and oxidase test positive. A vacuole located at the centre of the bacteria makes it resembles “safety pin” appearance on gram stain. The bacteria produces glycocalyx polysaccharide capsule which makes it resistant to many types of antibiotics. The bacteria emits a strong soil smell after 24 to 48 hours of incubation. It is generally resistant to gentamicin and colistin antibiotics but is sensitive to Amoxicillin/clavulanic acid (co-amoxiclav). B. pseudomallei is a biosafety level 3 pathogen which requires specialized laboratory handling. In animals, another similar organism named Burkholderia mallei is the causing agent which results in a disease named glanders. B. pseudomallei can be differentiated from another closely related, but less pathogenic species B. thailandensis by its ability to assimilate arabinose. B. pseudomallei is highly adaptable to various host environments. The bacteria has been shown to survive inside Mycorrhiza fungi and amoeba. Thus it has a survival advantage in the human body.
The genome of B. pseudomallei consists of two replicons: chromosome 1 which encodes for housekeeping function of the bacteria such as cell wall synthesis, mobility, and metabolism, and chromosome 2 which encodes for functions that allow the bacteria to adapt to various environments. Horizontal gene transfer between two bacteria causes highly variable genome in B. pseudomallei. Australia has been suggested as the early reservoir for B. psudomallei because of high genetic variability of the bacteria found in this region. The bacteria isolates from Africa, Central and South America seems to have a common ancestor originated from 17th to 19th century. Smaller genomic sequence for B. mallei suggests that it is a clone from B. pseudomallei.
Infection can enter through wounds, inhalation, and ingestion of polluted water. Person-to-person transmission have been reported, but is extremely rare. 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. Birds are also considered as relatively resistant to melioidosis. An outbreak at the Paris Zoo in the 1970s ("L’affaire du jardin des plantes") was thought to have originated from an imported panda or horses from Iran. Transmission from animals to humans (zoonosis) is also rare.
B. pseudomallei is normally found in soil and surface water, and is more abundant at greater than 10 cm from the soil surface up to 80cm to 90 cm. It has been found in soils, ponds, streams, pools, stagnant water, and paddy rice fields. B. pseudomallei can survive in nutrient poor condition such as distilled water, desert, and nutrient depleted soil for more than 16 years. It can also survive in antiseptic and detergent solutions, acidic environments with pH up to 4.5 for 70 days within temperature range from 24 °C (75.2 °F) to 32 °C (89.6 °F). However, the bacteria does not survive in the presence of ultraviolet light. 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. Also implicated are severe weather events such as flooding tsunamis and typhoons. Inadequate chlorination of water supply had been associated with B. pseudomallei outbreak in Northern and Western Australia. The bacteria is also found in unchlorinated water supply in rural Thailand. Irrigation fluid contaminated with B pseudomallei is associated with nosocomial wound infection in hospitals. Based on the whole genome sequencing of the bacteria, humans may play a role in moving B. pseudomallei from place to place.
The inhalation route for melioidosis was first suspected for soldiers exposed to dusts by helicopter rotor blades during Vietnam War. They subsequently developed melioidosis pneumonia. Involvement of lymph nodes in the mediastinum can occur in pneumonia caused by melioidosis. Animal studies also shown that inhalation is possible with high rate of death.
Melioidosis is found in all age groups. For Australia and Thailand, the median age of infection is at 50 years; 5 to 10% of the patients are less than 15 years. The single most important risk factor for developing melioidosis is diabetes mellitus, followed by hazardous alcohol use, chronic kidney disease, and chronic lung disease. In all people with melioidosis, greater than 50% of them have diabetes. Diabetes has 12 folds increased risk of melioidosis. Diabetes decreases the ability of macrophages to fight the bacteria and reduced the ability of T helper cell production. Excessive release of Tumor necrosis factor alpha (TNF) and Interleukin 12 by mononuclear cells causes greater risk of septic shock. The glibenclamide drug taken by diabetes patients can also cause blunting of monocyte’s inflammatory responses. Other risk factors include thalassaemia, occupation (rice paddy farmers), cystic fibrosis,, recreational exposure to soil, water, male, age > 45 years, and prolonged steroids/immunosuppresion. However, 8% of the peadiatrics and 20% of the adult with melioidosis have no risk factors. HIV infection does not predispose to melioidosis. Infant cases have been reported possibly due to mother-to-child transmission, community acquired infection, or healthcare-associated infection.
The bacteria has the ability to infect various types of cells and to evade human immune response. When skin is broken, B pseudomallei first enters and replicates in the epithelial cells of the broken skin. In the host, Protease-activated receptor-1 (PAR-1) expressed on the surface of endothelial cells, platelets, and monocytes helps B. pseudomallei invasion. The bacteria then can infect both phagocytes and non-phagocytes in the blood stream. The bacteria enters these cells through endocytosis inside an endocytic vesicle. B. pseudomallei has multiple secretory systems and can be transported across cellular membranes, aiding invasion into a host cell. B. pseudomallei uses Type III secretion system (T3SS) system effector proteins for invasion into a cell. T3SS is a molecular syringe that injects effector proteins into host cells. The effector proteins rearrange the host cytoskeleton to facilitate invasion.The cell entry is aided by flagella, LPS, type IV pilin, and adhesion proteins BoaA and BoaB. The T3SS effector protein bopA helps to disrupt endocytic vesicle and thus avoid the bacteria from being digested by lysosomes inside the cell. The bacteria then replicates inside the cytoplasm of the cell. The bacteria are also able to withstand high oxidative stress in an endocytic vesicle by creating an acidic environment. Once inside cytoplasm, BimA autotransporter proteins protein helps escape the bacteria from phagosome. Premature killing of macrophage can also cause the evasion of B. pseudomallei from being digested. Besides, the delayed degradation of infected neutrophils ingested by macrophages also causes the bacteria to proliferate inside the host cells.
The bacteria then proceeds to spread from cell to cell from cell cytoplasm. The bacteria rearrange the host cell cytoskeleton using Bim A to allow the latter to form a membranous protusions that extends into neighbouring cells. The bacteria then travel into another cell using actin. The action of these bacteria causes the fusion of the adjacent cells which leads to the formation of multinucleated giant cells (MNGCs). When MNGCs lyse, they form plaques (a central clear area with a ring of fused cells). These plaques then provide shelter for the bacteria for further replication or latent infection. With the help of Bim A autotrasporter protein, the bacteria are able to travel through nerve roots in the spinal cord and brain, thus leading to encephalomyelitis (inflammation of the brain and spinal cord).
Besides spreading from cell to cell, the bacteria can also spread through blood stream, causing sepsis. The bacteria can survive in antigen presenting cells and dendritic cells. Thus, these cells acts as vehicles that transport the bacteria into the lymphatic system, causing widespread dissemination of the bacteria in the human body.
Melioidosis infection induces humoral immunity through the release of interferon gamma (IFN) and cell-mediated immunity. Macrophages activated by IFN has improved killing of B. pseudomallei via the production of inducible nitric oxide synthase (NOS). Neutrophils, dendritic cells, B cell and T cells activate the human complement membrane attack complex (MAC) and coagulation cascade. However, the complement activity is hampered by external capsule and lipopolysaccharide (LPS) of the bacteria. These two features of the bacteria are also resistant to lysosomal degradation, thus enabling the survival of the bacteria in human phagocytes. Although activation of coagulation cascade is helpful in containing melioidosis infection, overactivation coagulation cascade can cause disseminated intravascular coagulation (DIC). Human Toll-like receptor (TLRs) such as TLR2, TLR4, TLR 5 recognizes the pathogen-associated molecular pattern (PAMPs) of the bacteria such as LPS and flagella, thus initiating immune response against the bacteria. As a result, Interleukin 1 beta (IL-1β) and Interleukin 18 (IL-18) are produced. Once B. pseudomallei escaped from the lysosomal destruction, it enters the cytosol of the cell. Meanwhile, inside the human cell, Pattern recognition receptors of the cytosol namely NOD-like receptors detects the Damage-associated molecular pattern (DAMP)s of the bacteria. As a result, inflammasomes which contains Caspase 1 are released to digest the bacteria. Activation of Caspase 1 enables the pyroptosis of the bacteria and increases the production of Interleukin 1 beta (IL-1β) and Interleukin 18 (IL-18). IL-18 increases IFN production through natural killer cells while IL-1beta reduces the IFN production. Thus, reduction in IFN gamma contributes to the persistence of the bacteria intra-cellularly. CD4 T cells and cytotoxic CD8 T cells are important to keep melioidosis at bay. Reduction of these cells is associated with higher risk of death. However, HIV infection is not a risk factor for melioidosis. Although macrophages show deregulated cytokine response in individuals with HIV infection, bacterial internalization and intracellular killing are still effective.
B. pseudomallei can remain latent in the human body from 19 to 29 years until it is reactivated during human immunosuppression or stress response. The mechanism of latent infection remains unclear as of 2018. Amongst mechanisms suggested are: residing in the nucleus of the cell to prevent being digested, entering a stage of slower growth rate, antibiotic resistance, and genetic adaption to the host environment. Granulomas (containing neutrophils, macrophages, lymphocytes, and multinucleated giant cells) formed at the infection site in melioidosis has been associated with latent infection in human body.
Low white blood cell count, raised liver enzymes, increased bilirubin levels (indicates liver dysfunction), raised urea and creatinine levels (indicates kidney dysfunction), hypoglycemia and acidosis represents poorer prognosis in those infected with melioidosis. C-reactive protein(CRP) and procalcitonin levels are not reliable in predicting the severity of melioidosis infection.
Bacterial culture is the definitive diagnosis of melidosis. It is important not misinterpret the bacterial growth as Pseudomonas or Bacillus spp. B. pseudomallei is never part of human flora. Therefore, any growth of the bacteria should be regarded as diagnostic of melioidosis. Blood culture is the most important sample for culture because the bacteria are usually found in blood. Other samples such as throat, rectal swabs, pus from abscesses, and sputum can also be used for culture. Blood cultures can be positive in 50 to 60% of the cases. For those strongly suspected of melioidosis but with initial negative culture, repeated cultures should be taken because the culture can become positive subsequently. The agar plates should be incubated at 37 °C (98.6 °F) in air  and inspected daily for four days. B. pseudomallei can be grown on sheep blood agar, MacConkey agar, Ashdown's medium (containing gentamicin), or Ashdown's broth (containing colistin). On agar plates, B. pseudomallei will be seen as creamy, non-haemolytic, with shape similar to a rod on Day 2 of incubation. On Day 4 of incubation, the colonies will appear dry and wrinkled. Francis medium is a modification of Ashdown medium, where the concentration of gentamicin is increased from 4mg/L to 8 mg/L. Colonies of B. pseudomallei that are grown on Francis medium are yellow. For laboratories located outside endemic areas, Burkholderia cepacia selective agar or Pseudomonas selective agar can be used as alternative if Ashdown's medium is not available. Besides, B pseudomallei in culture can be identified by Analytical profile index 20NE or 20E biochemical kit. It is a screening system for rapidly identifying those with high possibility of melioidosis infection. The screening system contains information on Gram stain, oxidase test, typical growth characteristics, and resistance to certain antibiotics of the bacteria. Molecular methods such as 16S rDNA probe and polymerase chain reaction (PCR) can be used to detect B. pseudomallei bacteria in culture but only available in research and reference laboratories. The B. pseudomallei bacteria can be accurately identified using PCR by targeting the T3SS system gene cluster of the bacteria.
B. pseudomallei can be observed under microscopy. The organism is described as gram negative rod shaped bacterium with bipolar staining similar to safety pin appearance. However, light microscopy is both not specific and not sensitive. Immunofluorescent microscopy approaches 100% in specificity and while achieved less than 50% sensitivity. A lateral flow immunoassay has been developed but not extensively evaluated.
Serological tests such as indirect haemagglutination test has been used to detect the presence of antibodies against B. pseudomallei. However, the test suffered from poor sensitivity and specificity because those staying in melioidosis endemic areas usually shows high background antibody titres. For Autralia, the cut-off point of antibody titer is 1:40. In Thailand, the cut-off antibody titre is 1:160. Thailand also uses direct immunofluorescent antibody test (IFAT) and latex agglutination. In IFAT, both B. pseudomallei antigen and B. thailandensis can be used to quantity the amount of antibodies produced against the bacteria. Therefore, the results have to be interpreted with caution as there could be false positive reaction when the human body is exposed to non-pathogenic B. thailandensis infection. Latex agglutination is useful in screening for suspected B. pseudomallei colonies. A commercial ELISA kit for melioidosis 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 (such as X-rays, ultrasound, and CT scans), but imaging is routinely performed to assess the extent of disease spread. 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 is considered characteristic, but is not diagnostic.
Person-to-person transmission is exceedingly unusual; and patients with melioidosis should not be considered contagious. Lab workers should handle B. pseudomallei under BSL-3 isolation conditions, as laboratory-acquired melioidosis has been described. There are also several cases of hospital-acquired infection of melioidosis. Therefore, healthcare providers are still recommended to practice hand hygiene and universal precautions.
Large scale water chlorination has been successful in Australia. In middle to low income countries, water should be boiled before consumption. In high income countries, water could be treated with ultraviolet light for those at risk of contracting melioidosis. Those who are high risk of contact with the bacteria should wear protective gear (such as boots and gloves) during work. Those who are staying in endemic areas should avoid direct contact with soil, and outdoor exposure to heavy rain, or dust clouds. Bottled water or boiled water are preferred as drinking water.
After exposure to B. pseudomallei (particularly following a laboratory accident), treatment with co-trimoxazole is recommended. Alternatively, co-amoxiclav and doxycycline can be used for those who is intolerant co-trimoxazole. In view of possibility of severe side effects caused by co-trimoxazole, only high risk individuals will receive such treatments. Low risk individuals would receive frequent monitoring instead.
Several vaccine candidates are being researched; but as of 2018, there is no vaccine approved for public use. There is a fear that when a vaccine is licensed, financial constraints will make the vaccination an unrealistic factor for many countries that are suffering from high rates of melioidosis.
The treatment of melioidosis is divided into two stages, an intravenous intensive phase and an eradication phase to prevent recurrence. The choice of antibiotics depends upon the susceptibility of the bacteria to various types of antibiotics. B. pesudomallei are generally susceptible to ceftazidime, meropenem, imipenem, and co-amoxiclav. These drugs are designed to kill the bacteria. B. pseudomallei is also susceptible to doyxcycline, chloramphenicol, and co-trimoxazole. These drugs are designed to inhibit the growth of the bacteria. However, the bacteria is resistant to penicillin, ampicillin, 1st and 2nd generation cephalosporin, gentamicin, streptomycin, tobramycin, macrolides, and polymyxins. On the other hand, B. pseudomallei isolates from the region of Sarawak, Malaysia are susceptible to gentamicin. Optimal therapy for melioidosis have been determined as a result from clinical trials in Thailand.
Intravenous ceftazidime is the current drug of choice for treatment of acute melioidosis and should be administered 10 to 14 days after getting the infection. Meropenem, imipenem and the cefoperazone-sulbactam combination (Sulperazone) are also effective. Intravenous amoxicillin-clavulanate (co-amoxiclav) may be used if none of the above four drugs is available. However, co-amoxiclav produces same efficacy as ceftazidime in preventing deaths. Intravenous antibiotics are given for a minimum of 10 to 14 days. The median fever clearance time in melioidosis is 9 days.
Meropenem is the preferred antibiotic therapy for neurological melioidosis and those presented with septic shock and is admitted into intensive care unit (ICU). Co-trimoxazole is recommended for neurological melidosis, osteomyelitis, septic arthritis, skin and gastrointestinal infection, and deeply seated abscess. For deep seated infections such as abscesses of internal organs, osteomyelitis, septic arthritis, and neurological melioidosis, the duration of antibiotics given should be longer (up to 4 to 8 weeks). The time taken for fever to be resolved can be more than 10 days in those with deep seated infection. The dosage for intravenous ceftazidime is 2g 6 hourly in adults (50 mg/kg up to 2g in children less than 15 years old). The dosage for meropenem is 1g 8 hourly in adults (25 mg/kg up to 1g in children). Resistance to ceftazidime, carbapenems, and co-amoxiclav are rare in intensive phase but is more prominent in eradication therapy. There is no differences when using cefoperazone/sulbactam or ceftazidime to treat melioidosis as both of them shows similar death rates and disease progression following treatment. For those with kidney impairment, the dosage of ceftazidime, meropenem, and co-trimoxazole should be lowered. Once the clinical condition improved, meropenem can be switched back to ceftazidime.
Following the treatment of the acute disease, eradication (or maintenance) treatment with co-trimoxazole is the drug of choice which should be used for at least 3 months. For those with neurological melioidosis and osteomyelitis, duration more than 6 months. Co-amoxiclav and doxycycline are drugs of second choice. Co-trimoxazole should not be used in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency as it can cause haemolytic anemia. Other side effects such as rash, hyperkalemia, renal dysfunction, and gastrointestinal symptoms should prompt the reduction of co-trimoxazole doses. Chloramphenicol is no longer routinely recommended for this purpose. Co-amoxiclav is an alternative for those patients who are unable to take co-trimoxazole and doxycycline (e.g., pregnant women and children under the age of 12), but is not as effective and has higher relapse rate. Single agent treatment with a fluoroquinolone (e.g., ciprofloxacin) or doxycycline for the oral maintenance phase is ineffective.
In Australia, co-trimoxazole is used in children and could also be used in pregnant mothers after the first 12 weeks of pregnancy. Meanwhile, in Thailand, co-amoxiclav is the drug of choice for children and pregnancy women. However, B. pseudomallei can easily acquire resistance when this drug is used. The dosing regimen for co-trimoxazole (trimethoprim/sulfamethoxazole) in eradication phase is 6/30 mg/kg, up to maximum 240/1200 mg in children, 240/1200 mg in adults weighing 40 to 60 kg, and 320/1600 mg in adults weighing more than 60 kg, taken orally every 12 hours. In children, co-trimoxazole is taken together with folic acid (0.1 mg/kg up to 5mg in children). There are also cases where melioidosis is successfully treated with co-trimoxazole for 3 months without going through intensive therapy provided that there is only skin manifestations without involvement of internal organs or sepsis. Resistance to cotrimoxazole is quite rare in Australia.
Surgical drainage is indicated for single, large abscess in the liver, muscle, and prostate. However, for multiple abscesses in the liver, spleen, and kidney, surgical drainage may not be possible or necessary. For septic arthritis, arthrotomy washout and drainage is required. Surgical debridement may be necessary. For those with mycotic aneurysm, urgent surgery is required for prosthetic vascular grafts. Life-long therapy with co-trimoxazole may be needed for those with prosthetic vascular grafts. Other abscesses rarely need to be drained because majority of them can resolve with antibiotic treatment. In Australia, prostate abscess may require routine imaging and drainage.
Immunomodulating therapies such as granulocyte colony-stimulating factor (G-CSF), Interleukin 7 (IL-7), and anti-PDI (programmed cell death) could be useful in melioidosis treatment especially for those with septic shock. This is because these drugs could help to boost the human body immune function against the bacteria.
In resourceful settings, where the disease can be detected and treated early, the risk of death is 10%. Meanwhile, in resource poor settings, the risk of death from the disease is more than 40%.
For those with incomplete treatment, reppearance of symptoms after a period of disease remission (recrudescence) can occur. Then, hospital admission is needed for intravenous antibiotics. For those completed treatment successfully, recurrence can also occur due to recrudescence or new melioidosis infection. With better therapies, the recrudescence rate has reduced from 10% to 5%. New infection is now more common than recrudescence. Risk factors of recrudescence 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.
Underlying medical conditions such as diabetes mellitus, chronic kidney disease, and cancer can worsens the long term survival and disability of those recovered from infection. The most severe complication of melioidosis is encephalomyelitis. It can cause quadriparesis (muscle weakness in all the limbs) or partial, flaccid paraparesis (muscle weakness of both legs) or foot drop. For those with previous melioidosis associated bones and joints infections, complications such as sinus tract infection, bones and joint deformities with limited range of motion can occur. Acute parotitis in children may be complicated with facial nerve paralysis. It has been reported only once in Australia.
Biological warfare potential
Interest in melioidosis has been expressed because it has the potential to be developed as a biological weapon. It is classified by the US Centers for Disease Control (CDC) as a category B, Tier 1 select agent. Another similar bacteria, Burkholderia mallei was used by the Germans in World War I to infect livestocks shipped to Allied countries. Deliberate infection of human prisoners of war (POW) and animals using B. mallei were made in Pingfang District, China by the Japanese during World War II. Soviet Union reportedly used B. mallei during Soviet–Afghan War in 1982 and 1984. B. pseudomallei, like B. mallei, was studied by both US and Soviet Union as a potential biological warfare agent, but never weaponized. Other countries such as Iran, Iraq, North Korea, and Syria may potentially have investigated the properties of the bacteria for biological weapons. The bacterium is readily available in the environment and is cost-effective to produce. It can also be aerosolized and transmitted via inhalation. However, the bacterium has never been used in biological warfare.
Melioidosis is an understudied disease which remained endemic in developing countries. In 2015, International Melioidosis Society (IMS) was formed to raise awareness regarding the disease. As of 2018, melioidosis is not included in the WHO list of neglected tropical diseases. Melioidosis is endemic in parts of southeast Asia (including Thailand, Laos, Singapore, Brunei, Malaysia, Burma and Vietnam), China, Taiwan and northern Australia. Flooding can increase its extent, including flooding in central 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. The disease is clearly associated with increased rainfall, with the number (and severity) of cases rising following increased precipitation.
Although only one case of melioidosis has ever been reported in Bangladesh, at least five cases have been imported to the UK from that country. Recent news reports indicate B. pseudomallei has been isolated from soil in Bangladesh, but this remains to be verified scientifically. This suggests that melioidosis is endemic to Bangladesh and that a problem of underdiagnosis or under-reporting exists there. most likely due to a lack of adequate laboratory facilities in affected rural areas. A high isolation frequency (percentage of positive soil samples) was found in east Saravan in rural Lao PDR distant from the Mekong River, thought by the investigators to be the highest geometric mean concentration in the world (about 464 (25-10,850 CFU/g soil). In the United States, two historical cases (1950 and 1971) and three recent cases (2010, 2011, 2013) have been reported amongst people that did not travel overseas. Despite extensive investigations, the source of melioidosis was never confirmed. One possible explaination is that importation of medicinal plant products and exotic reptiles could resulted in the spread of melioidosis in United States.
A statistical model indicated that the incidence will be 165,000 cases per year in 2016 (95% confidence interval, 68,000 to 412,000), with 138,000 of those occurring in East and South Asia and the Pacific. In about half of those cases (54% or 89,000), people will die. Northeast Thailand has the highest incidence of melioidosis recorded in the world (an average incidence of 12.7 cases 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. Under-reporting is a prevalent problem because only 1,300 cases were reported worldwide since 2010, which is less than 1% of the projected incidence based on modeling. Besides, lack of laboratory diagnositic capabilities and the lack of disease awareness amongst health care providers also causes underdiagnosis. Even if the culture turns positive for B. pesudomallei, it could discarded as contaminant especially in laboratories in non-endemic areas.
Pathologist Alfred Whitmore and assistant Krishnaswami first reported the disease among beggars and morphine addicts at autopsy in Rangoon, present-day Myanmar, in a report published in 1912. Arthur Conan Doyle may have read the 1912 report before writing a short story that involved the fictitious tropical disease "Tapanuli fever" in a Sherlock Holmes adventure. In the story of “The Dying Detective”, Holmes received a box designed to inoculate the victim with “Tanapuli fever” upon opening. “Tanapuli fever” was thought by many to represent melioidosis. The term “melioidosis” was first coined in 1921. They distinguished it from glanders, a disease of humans and animals that is similar in presentation, but caused by a different micro-organism. B. pseudomallei, also known as the Whitmore bacillus, was identified in 1917 in Kuala Lumpur. First human case of melioidosis was reported in Sri Lanka in 1927. In 1932, 83 cases were reported in South and Southeast Asia with 98% mortality. In 1936, first animal (sheep) case of melioidosis was reported in Madagascar, South Africa. In 1937, soil and water are identified as habitat of B. pseudomallei. During Vietnam War from 1967 to 1973, 343 American soldiers were reported with melioidosis, with about 50 cases reported to have transmitted through inhalation. First evidence of B. pseudomallei (in soil) in Brazil was reported in 1983.
Prior to 1989, the standard treatment for acute melioidosis was a three-drug combination of chloramphenicol, co-trimoxazole and doxycycline; this regimen is associated with a mortality rate of 80% and is no longer be used unless no other alternatives are available. All three 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. Aerosolised B. pseudomallei was first isolated in 1989. In the same year, Ceftazidime had been shown to reduce the risk of death of melioidosis from 74% to 37%. B. pseudomallei was previously classified as part of the genus Pseudomonas; until 1992. In 1992, the pathogen was formally named B. pseudomallei. 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. In 2002, B. pseudomallei was classified as "Category B agent". Live attenuated vaccine was developed in mice in the same year. In 2003, multilocus sequence typing for B. pseudomallei was developed. In 2012, B pseudomallei was classified as "Tier 1 select agent" by CDC. In 2014, co-trimoxazole was established as the oral eradication therapy. In 2015, B. pseudomallei DNA was detected in filtered air using quantitative PCR. In 2016, a statistical model was developed to predict the occurrence of global melioidosis per year. In 2017, whole genome sequencing points to Australia as the early reservoir for melioidosis.
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- Nightcliff gardener's disease (Nightcliff is a suburb of Darwin, Australia where melioidosis is endemic)
- Paddy-field disease
- Morphia injector's septicaemia
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