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Whitmore disease

Overview

Also known as Meliodosis, is an infectious disease caused by the gram negative bacterium, Burkholderia pseudomallei, found in soil and water. 

It is closely related to Burkholderia mallei which causes glanders. 

The disease is endemic in parts of southeast asia, taiwan, and northern australia. Northeast Thailand has the highest incidence of meliodosis recorded in the world (21.3 cases per 100,000 people per year). 

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Symptoms - Whitmore disease

  • pain in chest
  • pain in bones or joints
  • cough
  • skin infections
  • lung nodules
  • pneumonia 

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Causes - Whitmore disease

Burkholderia pseudomallei is normally found in soil and surface water; a history of contact with soil or surface water is therefore almost invariable in patients with melioidosis; that said, the majority of patients who do have contact with infected soil suffer no ill effects. Even within an area, the distribution of B. pseudomallei within the soil can be extremely patchy,and competition with other Burkholderia species has been suggested as a possible reason. Contaminated ground water was implicated in one outbreak in northern Australia. Also implicated are severe weather events such as flooding tsunamis and typhoons.

The single most important risk factor for developing severe melioidosis is diabetes mellitus. Other risk factors include thalassaemia, kidney disease, occupation (rice paddy farmers), and cystic fibrosis. The mode of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei. Person-to-person spread has been described but is extremely unusual.HIV infection does not predispose to melioidosis.

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Prevention - Whitmore disease

Person-to-person transmission is exceedingly unusual; and patients with melioidosis should not be considered contagious. Lab workers should handle Burkholderia pseudomallei under BSL-3 isolation conditions, as laboratory acquired melioidosis has been described.

In endemic areas, people (rice-paddy farmers in particular) are warned to avoid contact with soil, mud and surface water where possible.[citation needed] 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.

Post exposure prophylaxis 

After exposure to B. pseudomallei (particularly following a laboratory accident) combined treatment with co-trimoxazole and doxycycline is recommended. Trovafloxacin and grepafloxacin have been shown to be effective in animal models.

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Diagnosis - Whitmore disease

A definitive diagnosis is made by culturing the organism from any clinical sample, because the organism is never part of the normal human flora.

A definite history of contact with soil may not be elicited as melioidosis can be dormant for many years before manifesting.Attention should be paid to a history of travel to endemic areas in returned travellers. Some authors recommend considering possibility of melioidosis in every febrile patient with a history of traveling to and/or staying at endemic areas.

A complete screen (blood culture, sputum culture, urine culture, throat swab and culture of any aspirated pus) should be performed on all patients with suspected melioidosis (culture on blood agar as well as Ashdown's medium). A definitive diagnosis is made by growing B. pseudomallei from any site. A throat swab is not sensitive but is 100% specific if positive, and compares favourably with sputum culture. The sensitivity of urine culture is increased if a centrifuged specimen is cultured, and any bacterial growth should be reported (not just growth above 104 organisms/ml which is the usual cut off). Very occasionally, bone marrow culture may be positive in patients who have negative blood cultures for B. pseudomallei, but these are not usually recommended. A common error made by clinicians unfamiliar with melioidosis is to only send a specimen from the affected site (which is the usual procedure for most other infections) instead of sending a full screen.

Ashdown's medium, a selective medium containing gentamicin, may be required for cultures taken from non-sterile sites.Burkholderia cepacia medium may be a useful alternative selective medium in non-endemic areas, where Ashdown's is not available. A new medium derived from Ashdown known as Francis medium may help differentiate B. pseudomallei from B. cepacia and may help in the early diagnosis of melioidosis, but has not yet been extensively clinically validated.

Many commercial kits for identifying bacteria may misidentify B. pseudomallei (see Burkholderia pseudomallei for a more detailed discussion of these issues).

There is also a serological test for melioidosis (indirect haemagglutination), but this is not commercially available in most countries. A high background titre may reduce the positive predictive value of serological tests in endemic countries. A specific direct immunofluorescent test and latex agglutination, based on monoclonal antibodies, are used widely in Thailand but are not available elsewhere. There is almost complete cross-reactivity with B. thailandensis.There exists a commercial ELISA kit for melioidosis which appears to perform well. but no ELISA test has yet been clinically validated as a diagnostic tool.

It is not possible to make the diagnosis on imaging studies alone (X-rays and scans), but imaging is routinely performed to assess the full extent of disease. Imaging of the abdomen using CT scans or ultrasound is recommended routinely, as abscesses may not be clinically apparent and may coexist with disease elsewhere. Australian authorities suggest imaging of theprostate specifically due to the high incidence of prostatic abscesses in northern Australian patients. A chest x-ray is also considered routine, with other investigations as clinically indicated. The presence of honeycomb abscesses in the liver are considered characteristic, but are not diagnostic.

The differential diagnosis is extensive; melioidosis may mimic many other infections, including tuberculosis.

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Prognosis - Whitmore disease

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.

Recurrence occurs in 10 to 20% of patients. While molecular studies have established that the majority of recurrences are due to the original infecting strain, a significant proportion of recurrences (perhaps up to a quarter) in endemic areas may be due to reinfection, particularly after 2 years. Risk factors include severity of disease (patients with positive blood cultures or multifocal disease have a higher risk of relapse), choice of antibiotic for eradication therapy (doxycycline monotherapy and fluoroquinolone therapy are not as effective), poor compliance with eradication therapy and duration of eradication therapy less than 8 weeks.

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Treatment - Whitmore disease

The treatment of melioidosis is divided into two stages, an intravenous high intensity phase and an eradication phase to prevent recurrence.

Intravenous ceftazidime is the current drug of choice for treatment of acute melioidosis.Meropenem, imipenem and the cefoperazone-sulbactam combination (Sulperazone)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. Even with appropriate antibiotic therapy, fevers often persist for weeks or months, and patients may continue to develop new lesions even while on appropriate treatment. The median fever clearance time in melioidosis is 10 days: and failure of the fever to clear is not a reason to alter treatment. It is not uncommon for patients to require parenteral treatment continuously for a month or more.
Intravenous meropenem is routinely used in Australia: outcomes appear to be good and meropenem is currently being tested with ceftazidime in a Thai clinical trial (ATOM).
There are theoretical reasons for believing that mortality might be lower in patients treated with imipenem: first, there is lessendotoxin released by dying bacteria during imimipenem treatment, and the minimum inhibitory concentration for imipenem is lower than for ceftazidime. However, no clinically relevant difference was found in mortality between imipenem and ceftazidime treatment. The MIC of meropenem is higher for B. pseudomallei than for many other organisms, and patients being haemofiltered will need more frequent or higher doses.
Moxifloxacin, cefepime, tigecycline and ertapenem do not appear to be effective in vitro. Piperacillin-sulbactam,doripenem and biapenem appear to be effective in vitro, but there is no clinical experience on which to recommend their use.
Adjunctive treatment with GCSF or co-trimoxazole were not associated with decreased fatality rates in trials in Thailand.
Following the treatment of the acute disease, it is recommended that eradication (or maintenance) treatment with co-trimoxazoleand 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 anddoxycycline (e.g., pregnant women and children under the age of 12), but is not as effective. Single agent treatment with afluoroquinolone (e.g., ciprofloxacin) or doxycycline for the oral maintenance phase is ineffective.
In Australia, co-trimoxazole is used on its own for eradication therapy, with relapse rates that are lower than those seen in Thailand; there is also in vitro evidence to suggest that co-trimoxazole and doxycycline are antagonistic, and that co-trimoxazole on its own may be preferable. A randomised controlled trial (MERTH) to compare this with the current standard of co-trimoxazole and doxycycline started in 2006 and is due for completion in 2008. Studies reinforce the need for adequate follow up and good adherence to the eradication phase of therapy. Dosing for co-trimoxazole is based on weight: (<40 kg: 160/800 mg every 12 hours; 40–60kg: 240/1200 mg every 12 hours, >60 kg: 320/1600 mg every 12 hours).
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