Melioidosis

Melioidosis (also called Whitmore disease or Nightcliff gardener's disease) 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.

The causative organism, Burkholderia pseudomallei, was thought to be a member of the Pseudomonas genus and was previously known as Pseudomonas pseudomallei. This organism is phylogenetically related closely to Burkholderia mallei, the organism that causes glanders.

Epidemiology
Melioidosis is endemic in parts of south east Asia (including Thailand, Singapore, Malaysia, Burma and Vietnam) and northern Australia. Multiple cases have also been described in southern China and Hong Kong, Brunei, Taiwan, India, and Laos, 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 Bangladesh, at least five cases have been imported to the UK from that country, which suggests that that melioidosis is endemic to that country and that there is a serious problem of underdiagnosis or under-reporting in that country, most likely due to a lack of adequate laboratory facilities. An outbreak at the Paris Zoo in the 1970s ("L’affaire du jardin des plantes") was thought that have resulted from an imported panda. .

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. It affects humans as well as other animals such as goats, sheep, horses and cattle. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud. The mode of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei.

The single most important risk factor for developing severe melioidosis is diabetes mellitus. Other risk factors include thalassaemia, kidney disease, and occupation (rice paddy farmers). There is a clear association with increased rainfall: with the number (and seversity) of cases increasing following increased precipitation.

Acute melioidosis
In the subgroup of patients where an inoculating event was noted, the mean incubation period 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 "Vietnamese 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. It has been suggested that B. pseudomallei abscesses have a characteristic honeycomb architecture (hypoechoic, multi-septate, multiloculate). .

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 manifestation include intravascular infection, lymph node 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 tuberculosis, sometimes being called "Vietnamese tuberculosis".

Diagnosis
A definitive diagnosis is made by culturing the organism from any clinical sample.

A definite history of contact with soil may not be elicited as melioidosis can be dormant for many years before becoming acute. 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 the diagnosis of 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.

Imaging of the abdomen using CT scans or ultrasound is recommended routinely, as abscesses may not be clinically apparent and may be coexist with disease elsewhere. Australian authorities suggest imaging of the prostate specificcally 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 differential diagnosis is extensive; melioidosis may mimic many other infections, including tuberculosis.

Current treatment
The treatment of melioidosis is divided into two stages, an intravenous high intensity stage and an oral maintenance stage to prevent recurrence. Surgical drainage is usually indicated for prostatic abscesses and septic arthritis, may be indicated for parotid abscesses and not usually indicated for hepatosplenic abscesses.


 * Intravenous intensive phase.
 * Intravenous ceftazidime is the current drug of choice for treatment of acute melioidosis. Meropenem, imipenem and cefoperazone-sulbactam (Sulperazone&reg;) are also active. Intravenous amoxicillin-clavulanate (co-amoxiclav) may be used if none of the above four drugs are available, but it produces inferior outcomes. Intravenous antibiotics 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: it is not uncommon for patients to require parenteral treatment continuously for more than a month.


 * Intravenous meropenem is routinely used in Australia and outcomes appear to be good, and meropenem is currently being tested with ceftazidime in a Thai clinical trial (ATOM).

Adjunctive treatment with GCSF or co-trimoxazole 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-trimoxazole and doxycycline be used for 12 to 20 weeks to reduce the rate of recurrence. 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.  Single agent treatment with a fluoroquinolone 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.

Historical treatment
Prior to 1989, the standard treatment for acute melioidosis was a four-drug combination of chloramphenicol, 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.

Prognosis
Without access to appropriate antibiotics (principally ceftazidime 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.

Relapse 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 higer 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
There are only few unusual cases documented for person-to-person transmission; no isolation is required for patients with melioidosis. Lab workers should handle Burkholderia pseudomallei under BSL-3 isolation conditions, as laboratory acquired melioidosis has been described. Following laboratory exposure, post exposure prophylaxis with cotrimoxazole has been suggested but has not been evaluated by clinical trials.

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.

Biological warfare potential
There has been interest in melioidosis because it has the potential to be developed as a biological weapon. 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 BW agent.

Synonyms
The majority of these synonyms are obsolete eponyms.
 * pseudoglanders
 * Whitmore's disease (after Captain Alfred Whitmore, who first discovered the disease)
 * Nightcliff gardener's disease (Nightcliff is a suburb of Darwin, Australia where melioidosis is endemic)
 * Paddy-field disease