Melioidosis

Melioidosis is an infectious disease caused by a Gram-negative bacterium called Burkholderia pseudomallei.[1] Most people infected with B. pseudomallei experience no symptoms; however, those who do experience symptoms have signs and symptoms that range from mild such as fever, skin changes, pneumonia, and abscesses to severe with inflammation of the brain, inflammation of the joints and dangerously low blood pressure that can result in death.[1] Approximately 10% of people with melioidosis develop symptoms that last longer than two months, termed "chronic melioidosis".[1]

Melioidosis
Burkholderia pseudomallei
SpecialtyInfectious disease 
SymptomsNone, fever, pneumonia, multiple abscesses[1]
ComplicationsEncephalomyelitis, septic shock, acute pyelonephritis, septic arthritis, osteomyelitis[1]
Usual onset1-21 days after exposure[1]
CausesBurkholderia pseudomallei spread by contact to soil or water[1]
Risk factorsDiabetes mellitus, thalassaemia, alcoholism, chronic kidney disease, cystic fibrosis[1]
Diagnostic methodGrowing the bacteria in culture mediums[1]
Differential diagnosisTuberculosis[2]
PreventionPrevention from exposure to contaminated water, antibiotic prophylaxis[1]
TreatmentCeftazidime, meropenem, co-trimoxazole[1]
Frequency165,000 people per year[1]
Deaths89,000 people per year[1]

Humans can be infected with B. pseudomallei through coming into contact with polluted water. The bacteria generally enter the body through wounds, inhalation, or ingestion. Person-to-person or animal-to-human transmission is extremely rare.[1] The infection is constantly present in Southeast Asia particularly in northeast Thailand and northern Australia.[1] In developed countries such as Europe and the United States, melioidosis cases are usually imported from countries where melioidosis is more common.[3] The signs and symptoms of melioidosis can resemble tuberculosis, and misdiagnosis is common.[2] Diagnosis is usually confirmed by the growth of B. pseudomallei from an infected person's blood or other bodily fluid.[1] Those with melioidosis are generally treated first with an "intensive phase" course of intravenous antibiotics (most commonly ceftazidime) followed by a several month treatment course of co-trimoxazole.[1] Even if the disease is properly treated, approximately 10% of people with melioidosis die from the disease. If the disease is improperly treated, the death rate could be more than 40%.[1]

Efforts to prevent melioidosis include: wearing protective gear while handling contaminated water, practising hand hygiene, drinking boiled water, and avoiding direct contact with soil, water, or heavy rain.[1] The antibiotic co-trimoxazole is used as a preventative only for individuals at high risk for getting the disease after being exposed to the bacteria.[1] There is no approved vaccine for melioidosis.[1]

Approximately 165,000 people are infected by melioidosis per year, resulting in about 89,000 deaths.[1] Diabetes is a major risk factor for melioidosis; over half of melioidosis cases are in people with diabetes.[1] Increased rainfall is associated with increased number of melioidosis cases in endemic areas.[2] The disease was first described by Alfred Whitmore in 1912 in present-day Myanmar.[4]

Signs and symptoms

Acute

Most people exposed to B. pseudomallei experience no symptoms.[2] For those who do experience symptoms, 85% experience acute melioidosis.[5] The mean incubation period of acute melioidosis is 9 days (range 121 days).[1] However, symptoms of melioidosis can appear in 24 hours for those experienced near drowning in water.[5] Those affected present 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 "the great mimicker".[1]

People with diabetes mellitus or regular exposure to the bacteria are at increased risk of developing melioidosis. The disease should be considered in anyone staying in endemic areas who develops fever, pneumonia, or abscesses in their liver, spleen, prostate, or parotid gland.[1] The clinical manifestation of the disease can range from simple skin changes to severe organ problems.[1] In northern Australia, 60% of the infected children presented with only skin lesions, while 20% presented with pneumonia.[3] The commonest organs affected are: liver, spleen, lungs, prostate, and kidneys. Among the most common clinical signs are presence of bacteria in blood (in 40 to 60% of cases), pneumonia (50%), and septic shock (20%).[1] People with only pneumonia may have a prominent cough with sputum and shortness of breath. Hoewever, those with septic shock together with pneumonia may have minimal coughing.[2] Results of a chest X-ray can range from diffuse nodular infiltrates in those with septic shock to progressive solidification of the lungs in the upper lobes for those with pneumonia only. Excess fluid in the pleural cavity and gathering of pus within a cavity are more common for melioidosis affecting lower lobes of the lungs. Therefore, melioidosis should be differentiated from tuberculosis as both conditions show radiogical changes on the upper lobes of the lungs.[2] In 10% of cases, people develop secondary pneumonia caused by other bacteria after the primary infection.[3]

Depending on the course of infection, other severe manifestations can develop. 1% to 5% of those infected develop inflammation of the brain and brain covering or collection of pus in the brain; 14 to 28% develop bacterial inflammation of the kidneys, kidney abscess or prostatic abscesses; 0 to 30% develop neck or salivary gland abscesses; 10 to 33% develop liver, spleen, or paraintestinal abscesses; 4 to 14% develop septic arthritis and osteomyelitis.[1] Other rare manifestations include lymph node disease resembling tuberculosis, mediastinal masses, collection of fluid in the heart covering,[3] abnormal dilatation of blood vessels due to infection,[1] and inflammation of the pancreas.[3] In Australia, up to 20% of infected males develop prostatic abscess characterized by pain during urination, difficulty in passing urine, and urinary retention requiring catheterization.[1] Rectal examination can show inflammation of the prostate.[3] In Thailand, 30% of the infected children develop parotid abscesses.[1] Infections of the eye, such as subconjunctival abscess and orbital cellulitis may also occur.[6] Encephalomyelitis can occur in healthy people without risk factors. Those with melioidosis encephomyelitis tend to have normal computed tomography (CT) scans but increased T2 signal by magnetic resonance imaging (MRI), extending to the 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.[3] In northern Australia, all melioidosis with encephalomyelitis cases had elevated white cells (30 to 775 cells per microlitres) in the cerebrospinal fluid (CSF), mostly mononuclear cells. CSF protein can be elevated with normal glucose levels.[7][8]

Chronic

Chronic melioidosis is usually defined by symptoms lasting greater than two months and occurs in about 10% of patients.[9] The clinical presentation of chronic melioidosis is varied 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".[10][11][12] Other clinical presentations include: fever, weight loss, productive cough with or without bloody sputum and with long-standing abscesses at multiple body sites.[2]

Latent

In latent infection, immunocompetent people can clear the infection without showing any symptoms. However, less than 5% of all melioidosis cases have activation after a period of latency.[1] Patients with latent melioidosis may be symptom-free for decades.[13] Initially, it was thought that the longest period between presumed exposure and clinical presentation is 62 years in a prisoner of war in Burma-Thailand-Malaysia.[13] 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.[14] This reinstates another report that put the longest latency period for melioidosis as 29 years.[15] The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnam time-bomb".[2] In Australia, the longest recorded latency period is 24 years.[3] Various comorbidities such as diabetes, renal failure, and alcoholism can predispose to reactivation of melioidosis.[2]

Cause

Bacteria

Melioidosis is caused by gram-negative, motile, saprophytic bacteria named Burkholderia pseudomallei.[1] The bacteria are generally found in the environment but can be opportunistic, facultative intracellular pathogens.[1] The bacteria are also aerobic and oxidase test positive.[2] A vacuole at the centre of the bacterium makes it resemble a “safety pin” when Gram stained.[2] The bacteria emit a strong soil smell after 24 to 48 hours of growth. B. pseudomallei produces a glycocalyx polysaccharide capsule that makes it resistant to many types of antibiotics.[6] It is generally resistant to gentamicin and colistin but sensitive to amoxicillin/clavulanic acid (co-amoxiclav). B. pseudomallei is a biosafety level 3 pathogen which requires specialized laboratory handling.[2] In animals, another similar organism named Burkholderia mallei is the causative agent of the disease glanders.[1] B. pseudomallei can be differentiated from another closely related, but less pathogenic species B. thailandensis by its ability to assimilate arabinose.[6] B. pseudomallei is highly adaptable to various host environments ranging from inside mycorrhizal fungi spores to amoeba.[2] Its adaptability may give it a survival advantage in the human body.[1]

The genome of B. pseudomallei consists of two replicons: chromosome 1 encodes housekeeping functions of the bacteria such as cell wall synthesis, mobility, and metabolism; chromosome 2 encodes functions that allow the bacteria to adapt to various environments. Horizontal gene transfer among bacteria has resulted in highly variable genomes in B. pseudomallei. Australia has been suggested as the early reservoir for B. pseudomallei because of the high genetic variability of the bacteria found in this region. Bacteria isolated from Africa, Central and South America seem to have a common ancestor that lived in the 17th to 19th centuries.[1] B. mallei is a clone of B. pseudomallei that has lost substantial portions of its genome as it adapted to live exclusively in mammals.[3]

Transmission

Bacteria can enter the body through wounds, inhalation, and ingestion of polluted water.[1] Person-to-person transmission is extremely rare.[2][16][17][18] Melioidosis is a recognised disease in animals including cats,[19] goats, sheep, and horses. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud.[20] Birds are also considered relatively resistant to melioidosis.[6] Transmission from animals to humans is rare.[1][2]

B. pseudomallei is normally found in soil and surface water, and is most abundant at soil depths of 10 cm to 90 cm.[1][6] It has been found in soils, ponds, streams, pools, stagnant water, and paddy rice fields.[2] B. pseudomallei can survive in nutrient-poor conditions such as distilled water, desert soil, and nutrient-depleted soil for more than 16 years.[1] It can also survive in antiseptic and detergent solutions, acidic environments (pH 4.5 for 70 days), and in environments at temperatures ranging from 24 °C (75.2 °F) to 32 °C (89.6 °F). However, the bacteria do not survive in the presence of ultraviolet light.[6] A history of contact with soil or surface water is, therefore, almost invariable in patients with melioidosis;[21] 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,[22][23] and competition with other Burkholderia species has been suggested as a possible reason.[24] Contaminated ground water was implicated in one outbreak in northern Australia.[25] Also implicated are severe weather events such as flooding[26] tsunamis[27] and typhoons.[28][29] Inadequate chlorination of water supply had been associated with B. pseudomallei outbreak in Northern and Western Australia. The bacteria have also been found in an unchlorinated water supply in rural Thailand. Irrigation fluid contaminated with B pseudomallei is associated with nosocomial wound infection in hospitals.[1] Based on the whole genome sequencing of the bacteria, humans may play a role in moving B. pseudomallei from place to place.[30]

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 have also shown that inhalation is associated with a high rate of death.[3]

Pathogenesis

B. pseudomallei has the ability to infect various types of cells and to evade human immune responses.[1] Bacteria first enter at a break in the skin or mucous membrane and replicate in the epithelial cells.[1] From there, they use flagellar motility to spread and infect various cell types. In the blood stream, the bacteria can infect both phagocytes and non-phagocytes. B. pseudomallei use their flagella to move near host cells, then attach to the cells using various adhesion proteins, including the type IV pilus protein PilA as well as adhesion proteins BoaA and BoaB. Additionally, adhesion of the bacteria partially depends on the presence of the host protein Protease-activated receptor-1 which is present on the surface of endothelial cells, platelets, and monocytes.[1] Once bound, the bacteria enter host cells through endocytosis, ending up inside an endocytic vesicle. As the vesicle acidifies, B. pseudomallei uses its Type 3 secretion system (T3SS) to inject effector proteins into the host cell, disrupting the vesicle and allowing the bacteria to escape into the host cytoplasm.[1] Within the host cytoplasm, the bacteria evade being killed by host autophagy using various T3SS effector proteins, including BopA.[1] The bacteria replicate in the host cytoplasm.[1]

Inside the host cell, the bacteria move by inducing the polymerization of host actin behind them, propelling the bacteria forward.[1] This actin-mediated motility is accomplished with the autotransporter BimA which interacts with actin at the tail-end of the bacterium.[1] Propelled by actin, the bacteria push against the host membrane, creating protusions that extend into neighbouring cells. These protrusions cause neighboring cells to fuse, leading to the formation of multinucleated giant cells (MNGCs). When MNGCs lyse, they form plaques (a central clear area with a ring of fused cells) which provide shelter for the bacteria for further replication or latent infection. This same process in infected neurons can allow bacteria to travel through nerve roots in the spinal cord and brain, leading to inflammation of the brain and spinal cord.[1] Besides spreading from cell to cell, the bacteria can also spread through the 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.[1]

While B. pseudomallei can survive in phagocytic cells, these cells can kill B. pseudomallei by several mechanisms. Macrophages activated by interferon gamma (IFN) have improved killing of B. pseudomallei via the production of inducible nitric oxide synthase.[1] Acidification of the endosome and degradation of the bacteria is also possible, however the bacterial capsule and LPS makes B. pseudomallei resistant to lysosomal degradation. Once B. pseudomallei escapes into the host cytosol it can be recognized by pattern recognition receptors such as NOD-like receptors, triggering formation of the inflammasome and activation of caspase 1, which induces death of the host cell by pyroptosis and further activation of the immune system.[1] Several systemic host defenses also contribute to the immune response. B. pseudomallei triggers both the complement system and coagulation cascade, however the thick bacterial capsule prevents deposition of the complement membrane attack complex.[1]

Additional elements of the immune system are activated by host toll-like receptors such as TLR2, TLR4, and TLR5 that recognize the conserved pieces of the bacteria such as LPS and flagella. This activation results in the production of cytokines such as Interleukin 1 beta (IL-1β) and Interleukin 18 (IL-18).[1] IL-18 increases IFN production through natural killer cells while IL-1beta reduces the IFN production. These immune molecules drive the recruitment of other immune cells such as neutrophils, dendritic cells, B cells, and T cells to the site of infection.[1] T cells seem to be particularly important for controlling B. pseudomallei; T cell numbers are increased in survivors, and low T cell numbers is associated with a high risk of death from melioidosis.[1] Despite this, HIV infection is not a risk factor for melioidosis. Although macrophages show deregulated cytokine responses in individuals with HIV infection, bacterial internalization and intracellular killing are still effective.[1] People infected with B. pseudomallei do develop antibodies against the bacteria, and people that live in endemic areas tend to have antibodies in their blood that recognize B. pseudomallei. However, the effectiveness of these antibodies at preventing melioidosis is unclear.[1]

B. pseudomallei can remain latent in the human body from 19 to 29 years until it is reactivated during human immunosuppression or stress response.[1] However, the site of bacteria during latent infection and the mechanism by which they avoid immune recognition for years are both unclear.[1] Amongst mechanisms suggested are: residing in the nucleus of the cell to prevent being digested, entering a stage of slower growth, antibiotic resistance, and genetic adaption to the host environment.[1] Granulomas (containing neutrophils, macrophages, lymphocytes, and multinucleated giant cells) formed at the infection site in melioidosis have been associated with latent infection in humans.[1]

Diagnosis

Bacterial culture is the definitive diagnosis of melioidosis. B. pseudomallei is never part of human flora. Therefore, any growth of the bacteria is diagnostic of melioidosis. Blood cultures are the most common samples for diagnosis, as bacteria can be detected in the blood in 50 to 60% of melioidosis cases. Other samples such as throat, rectal swabs, pus from abscesses, and sputum can also be used for culture. When bacteria do not grow from people strongly suspected of having melioidosis, repeated cultures should be taken as subsequent cultures can become positive.[1] B. pseudomallei can be grown on sheep blood agar, MacConkey agar, Ashdown's medium (containing gentamicin),[1] or Ashdown's broth (containing colistin).[3] Agar plates for melioidosis should be incubated at 37 °C (98.6 °F) in air [2] and inspected daily for four days. On the agar plates, B. pseudomallei forms creamy, non-haemolytic, colonies after 2 days of incubation. After 4 days of incubation, colonies appear dry and wrinkled.[1] Colonies of B. pseudomallei that are grown on Francis medium (a modification of Ashdown medium with gentamicin concentration increased to 8 mg/L) are yellow. For laboratories located outside endemic areas, Burkholderia cepacia selective agar or Pseudomonas selective agar can be used if Ashdown's medium is not available.[2] It is important not misinterpret the bacterial growth as Pseudomonas or Bacillus spp. Other biochemical screening tools can also be used for detecting B. pseudomallei, including the API 20NE or 20E biochemical kit combined with Gram stain, oxidase test, typical growth characteristics, and resistance to certain antibiotics of the bacteria.[3] Molecular methods such as 16S rDNA probes and polymerase chain reaction (PCR) can also be used to detect B. pseudomallei in culture, but they are only available in research and reference laboratories.[1]

General blood tests in people with melioidosis show low white blood cell counts (indicates infection), raised liver enzymes, increased bilirubin levels (indicates liver dysfunction), and raised urea and creatinine levels (indicates kidney dysfunction).[6] Low blood glucose and acidosis predicts a poorer prognosis in those with melioidosis.[6] However, other tests such as C-reactive protein and procalcitonin levels are not reliable in predicting the severity of melioidosis infection.[6]

By microscopy, B. pseudomallei is seen as gram-negative and rod-shaped, with a bipolar staining similar in appearance to a safety pin. Bacteria can sometimes be seen directly in clinical samples from infected people; however, identification by light microscopy is neither specific nor sensitive. Immunofluorescence microscopy is highly specific for detecting bacteria directly from clinical specimens, but has less than 50% sensitivity.[1][3] A lateral flow immunoassay has been developed but not extensively evaluated.[1][3] An increasing number of laboratories use Matrix-assisted laser desorption/ionization (MALDI-TOF) mass spectrometry to identify the bacteria accurately.[1][3]

Serological tests such as indirect haemagglutination have been used to detect the presence of antibodies against B. pseudomallei. However, different groups of people have widely different levels of antibodies, so interpretation of these tests depends on location. In Australia, less than 5% of people have B. pseudomallei antibodies, so the presence of even relatively low amounts of antibody is unusual and could suggest melioidosis. In Thailand, many people have antibodies against B. pseudomallei so only a relatively high amount of antibody in the blood suggests melioidosis.[1][3] 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 a false-positive reaction if someone is previously exposed to non-pathogenic B. thailandensis.[2] Latex agglutination is useful in screening for suspected B. pseudomallei colonies.[1] A commercial ELISA kit for melioidosis appears to perform well.[31] but no ELISA test has yet been clinically validated as a diagnostic tool.[32]

It is not possible to diagnose melioidosis on imaging studies alone[33] (such as X-rays, ultrasound, and CT scans),[2][33] but imaging is routinely performed to assess the extent of disease spread.[34] 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.[33][34]

Prevention

Person-to-person transmission is exceedingly unusual;[16][17][18] and patients with melioidosis are not considered contagious. In the United States, lab workers can handle clinical specimens of B. pseudomallei under BSL-2 conditions, while mass production of such organisms requires BSL-3 precautions.[35] There are also several cases of hospital-acquired infection of melioidosis. Therefore, healthcare providers are recommended to practice hand hygiene and universal precautions.[1]

Large-scale water chlorination has been successful at reducing B. pseudomallei in the water 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 at high risk of contact with the bacteria should wear protective gear (such as boots and gloves) during work. Those 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.[1]

Postexposure prophylaxis

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 are intolerant to co-trimoxazole. Since co-trimoxazole can cause severe side effects, only high-risk individuals tend to receive such treatments. Low-risk individuals would receive frequent monitoring instead.[1]

Vaccination

Several vaccine candidates are being researched; but as of 2018, there is no vaccine approved for public use.[1] 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.[36]

Treatment

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 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 are resistant to penicillin, ampicillin, 1st and 2nd generation cephalosporin, gentamicin, streptomycin, tobramycin, macrolides, and polymyxins.[1] On the other hand, B. pseudomallei isolates from the region of Sarawak, Malaysia are susceptible to gentamicin.[1] Optimal therapy for melioidosis have been determined as a result from clinical trials in Thailand.[6]

Intensive phase

Intravenous ceftazidime is the current drug of choice for treatment of acute melioidosis and should be administered for at least 10 to 14 days.[1][37][38] Meropenem,[1][39] imipenem[1] and the cefoperazone-sulbactam combination (Sulperazone)[1][40] are also effective.[41] Intravenous amoxicillin-clavulanate (co-amoxiclav) may be used if none of the above four drugs is available;[1] co-amoxiclav prevents death from melioidosis as well as ceftazidime.[5] Intravenous antibiotics are given for a minimum of 10 to 14 days. The median fever clearance time in melioidosis is 9 days.[1]

Meropenem is the preferred antibiotic therapy for neurological melioidosis and those with septic shock admitted into intensive care units. Co-trimoxazole is recommended for neurological melidosis, osteomyelitis, septic arthritis, skin and gastrointestinal infection, and deeply seated abscess.[1] 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.[1] 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).[1] Resistance to ceftazidime, carbapenems, and co-amoxiclav are rare in the intensive phase but are more prominent during eradication therapy. There are no differences between using cefoperazone/sulbactam or ceftazidime to treat melioidosis as both show similar death rates and disease progression following treatment.[2] For those with kidney impairment, the dosage of ceftazidime, meropenem, and co-trimoxazole should be lowered.[3] Once the clinical condition improved, meropenem can be switched back to ceftazidime.[1]

Eradication phase

Following the treatment of the acute disease, eradication (or maintenance) treatment with co-trimoxazole is the drug of choice and should be used for at least 3 months. For those with neurological melioidosis and osteomyelitis, drugs should be given for 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 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.[1] Chloramphenicol is no longer routinely recommended for this purpose. Co-amoxiclav is an alternative for patients unable to take co-trimoxazole and doxycycline (e.g. pregnant women and children under the age of 12),[1][42][43] but is not as effective and has higher relapse rate.[1] Single agent treatment with a fluoroquinolone (e.g., ciprofloxacin)[1][44][45] or doxycycline[1][46] for the oral maintenance phase is ineffective.[1][47]

In Australia, co-trimoxazole is used in children and pregnant mothers after the first 12 weeks of pregnancy. Meanwhile, in Thailand, co-amoxiclav is the drug of choice for children and pregnant women. However, B. pseudomallei often acquires resistance when this drug is used.[1] 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 5 mg 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.[1] Resistance to cotrimoxazole is rare in Australia.[2]

Surgical treatment

Surgical drainage is indicated for single, large abscesses 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 the majority of them can resolve with antibiotic treatment.[1] In Australia, prostate abscess may require routine imaging and drainage.[6]

Others

Immunomodulating therapies such as granulocyte colony-stimulating factor, Interleukin 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.[1]

Prognosis

In well-resourced settings, where the disease can be detected and treated early, the risk of death is 10%. In resource-poor settings, the risk of death from the disease is more than 40%.[1]

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 who have 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.[1] 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.[1][47][48]

Underlying medical conditions such as diabetes mellitus, chronic kidney disease, and cancer can worsen the long-term survival and disability of those who recover from infection. The most severe complication of melioidosis is encephalomyelitis. It can cause quadriparesis (muscle weakness in all the limbs), partial flaccid paraparesis (muscle weakness of both legs) or foot drop. For those with previous melioidosis-associated bone and joint infections, complications such as sinus infection, bone and joint deformities with limited range of motion can occur.[1] Acute parotitis in children may be complicated with facial nerve paralysis. It is relatively common in Thailand, but has been reported only once in Australia.[6]

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 as a category B,[49] Tier 1 select agent.[1] Another similar bacterium, Burkholderia mallei was used by the Germans in World War I to infect livestock shipped to Allied countries.[50] Deliberate infection of human prisoners of war and animals using B. mallei were carried out in China's Pingfang District by the Japanese during World War II.[6] The Soviet Union reportedly used B. mallei during the Soviet–Afghan War in 1982 and 1984.[50] B. pseudomallei, like B. mallei, was studied by both the US[51] and Soviet Union as a potential biological warfare agent, but never weaponized.[50] Other countries such as Iran, Iraq, North Korea, and Syria may have investigated the properties of B. pseudomallei 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 B. pseudomallei has never been used in biological warfare.[2]

Epidemiology

Melioidosis is an understudied disease which remains endemic in developing countries. In 2015, the International Melioidosis Society was formed to raise awareness of the disease. As of 2018, melioidosis is not included in the WHO list of neglected tropical diseases.[1] Melioidosis is endemic in parts of southeast Asia (including Thailand,[52] Laos,[53][54][55] Singapore,[56] Brunei,[57] Malaysia, Burma and Vietnam), China,[58] Taiwan[59][60] and northern Australia.[21][61] Flooding can increase its extent, including flooding in central Australia.[62] Multiple cases have also been described in Hong Kong,[63] India,[64][65][66][67] and sporadic cases in Central and South America,[68][69][70] the Middle East, the Pacific and several African countries.[71][72] The disease is clearly associated with increased rainfall, with the number (and severity) of cases rising following increased precipitation.[1][56][73][74][75][76][77]

Melioidosis is found in all age groups.[1] For Australia and Thailand, the median age of infection is at 50 years; 5 to 10% of the patients are less than 15 years.[1] The single most important risk factor for developing melioidosis is diabetes mellitus, followed by hazardous alcohol use, chronic kidney disease, and chronic lung disease.[78] Greater than 50% of people with melioidosis have diabetes; diabetics have a 12-fold 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 and Interleukin 12 by mononuclear cells causes greater risk of septic shock. The diabetes drug glibenclamide can also blunt monocyte's inflammatory responses.[1] Other risk factors include thalassaemia, occupation (e.g. rice paddy farmers),[78][79] cystic fibrosis,[16][69] recreational exposure to soil, water, being male, age > 45 years, and prolonged steroid use/immunosuppression.[1] However, 8% of children and 20% of adults with melioidosis have no risk factors.[1] HIV infection does not predispose to melioidosis.[80][81][82] Infant cases have been reported possibly due to mother-to-child transmission, community acquired infection, or healthcare-associated infection.[1] Those who are well may also be infected with B. pseudomallei. For example, 25% of children staying in endemic areas started producing antibodies against B. pseudomallei in between 6 months and 4 years, suggesting they were exposed to it over this time. This means that many people without symptoms will test positive in serology tests in endemic areas.[2] In Thailand, the seropositivity rate exceeds 50%, while in Australia the seropositivity rate is only 5%.[3]

Although only one case of melioidosis has ever been reported in Bangladesh,[83] at least five cases have been imported to the UK from that country. News reports have indicated that B. pseudomallei has been isolated from soil in Bangladesh,[84] but this remains to be verified. This suggests that melioidosis is endemic to Bangladesh and that a problem of underdiagnosis or under-reporting exists there.[85] most likely due to a lack of adequate laboratory facilities in affected rural areas. A high frequency of B. pseudomallei-positive soil samples were 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 CFU/g soil).[86] 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 explanation is that importation of medicinal plant products or exotic reptiles could have resulted in the introduction of melioidosis in the United States.[3]

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.[87] In about half of those cases (54% or 89,000), people will die.[1] 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).[88] In Northeast Thailand, 80% of children are positive for antibodies against B. pseudomallei by the age of 4;[89] the figures are lower in other parts of the world.[90][91][92][93] Under-reporting is a common problem as only 1,300 cases were reported worldwide since 2010, less than 1% of the projected incidence based on modeling.[1] Lack of laboratory diagnositic capabilities and lack of disease awareness amongst health care providers also causes underdiagnosis. Even if bacterial cultures turn positive for B. pesudomallei, they can be discarded as contaminants especially in laboratories in non-endemic areas.[1]

History

Pathologist Alfred Whitmore and his assistant Krishnaswami first reported melioidosis among beggars and morphine addicts at autopsy in Rangoon, present-day Myanmar, in a report published in 1912.[4] 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.[94] In the story of “The Dying Detective”, Holmes received a box designed to inoculate the victim with “Tapanuli fever” upon opening. “Tapanuli fever” was thought by many to represent melioidosis.[6] The term “melioidosis” was first coined in 1921.[1] It was distinguished 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.[95] The first human case of melioidosis was reported in Sri Lanka in 1927.[1] In 1932, 83 cases were reported in South and Southeast Asia with 98% mortality.[1] In 1936, the first animal (sheep) case of melioidosis was reported in Madagascar, South Africa.[1] In 1937, soil and water were identified as the habitats of B. pseudomallei.[1] During the Vietnam War from 1967 to 1973, 343 American soldiers were reported with melioidosis, with about 50 cases transmitted through inhalation.[1] An outbreak of melioidosis at the Paris Zoo in the 1970s (known as L’affaire du jardin des plantes) was thought to have originated from an imported panda or horses from Iran.[6][96] The first evidence of B. pseudomallei (in soil) in Brazil was reported in 1983.[1]

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 used unless no other alternatives are available.[37] 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.[97] Aerosolised B. pseudomallei was first isolated in 1989.[1] In the same year, Ceftazidime had been shown to reduce the risk of death of melioidosis from 74% to 37%.[1] B. pseudomallei was previously classified as part of the genus Pseudomonas; until 1992.[98] In 1992, the pathogen was formally named B. pseudomallei.[1] 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.[98] In 2002, B. pseudomallei was classified as a "Category B agent". A 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 a "Tier 1 select agent" by the U.S. Centers for Disease Control. In 2014, co-trimoxazole was established as the oral eradication therapy. In 2015, B. pseudomallei DNA was detected in filtered air using quantitative PCR.[1] In 2016, a statistical model was developed to predict the occurrence of global melioidosis per year. In 2017, whole genome sequencing suggested Australia as the early reservoir for melioidosis.[1]

Synonyms

  • Pseudoglanders[99]
  • Whitmore's disease (after Captain Alfred Whitmore, who first described the disease)[4]
  • Nightcliff gardener's disease (Nightcliff is a suburb of Darwin, Australia where melioidosis is endemic)[100]
  • Paddy-field disease[101]
  • Morphia injector's septicaemia[102]

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