Melioidosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has melioidosis? What should you expect to find?

Melioidosis is endemic in northern Australia and South East Asia, but cases are also reported in returned travellers. Sporadic cases are recognized in many other regions but appear to be rare.
Melioidosis usually presents with a febrile illness, and in around half of cases there is clinical evidence of pneumonia. Any acute symptom should be regarded as a potentially localizing symptom indicative of a focus of infection. Multiple foci are not uncommon.
Uncommonly, melioidosis may present with chronic symptoms (>2 months) and may have a similar presentation to tuberculosis.

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A physical examination should first be directed towards establishing the severity of illness (general appearance, respiratory distress, shock, vital signs), then the potential sites of involvement (acute symptoms; cough, abdominal pain, dysuria).
Definitive diagnosis requires a positive culture of Burkholderia pseudomallei from a clinical specimen such as blood, urine, sputum or pus.

How did the patient develop melioidosis? What was the primary source from which the infection spread?

Melioidosis is acquired from contact with contaminated mud and pooled surface water in endemic areas (mainly south-east Asia and northern Australia). Reactivation from a latent focus is possible, with the longest latent period described as 62 years following travel to an endemic area.
Most disease is thought to result from percutaneous inoculation (via small cuts and abrasions in the skin).
It is thought that inhalation is also a possible route of acquisition, particularly during severe weather events with heavy rains and wind, and ingestion can also occur from unchlorinated water supplies in endemic regions.

Which individuals are of greater risk of developing melioidosis?

Serological studies suggest that the majority of exposures to B. pseudomallei do not result in clinical disease.
Melioidosis can affect patients of any age who are exposed.
The most common risk factors for exposure are occupational exposure (e.g. rice farmers, outdoor workers) or recreational exposure to mud or pooled surface water in the endemic area.
Around 80% of patients have one or more of diabetes mellitus, chronic renal disease, hazardous alcohol intake, chronic lung disease, malignancy and/or immunosuppression.
Less common risk factors include bronchiectasis and cystic fibrosis (where disease may be similar to that with Burkholderia cepacia) and chronic granulomatous disease.
Severe disease is uncommon in patients without comorbid risk factors.

Beware: there are other diseases that can mimic melioidosis:

There is a wide spectrum of disease, ranging from asymptomatic disease, to chronic disease to acute fulminant sepsis. Pneumonia is present in around half of cases, and primary sepsis without a clinical focus is also common.
Acute sepsis may present similar to any other cause of acute infection, including invasive pneumococcal disease, Staphylococcal sepsis, leptospirosis and scrub typhus.
Chronic disease may present similar to tuberculosis.
Asymptomatic lung disease should be differentiated from fungal nodules and lung carcinoma.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Changes consistent with acute sepsis – leukocytosis, high C-reactive protein
Changes consistent with organ dysfunction – elevated lactate, abnormal liver function tests, low platelets, hypoxia, elevated creatinine and urea

Results that confirm the diagnosis

Isolation of Burkholderia pseudomallei from any body site is diagnostic of melioidosis, as it is never a colonising pathogen
Specimens should be taken routinely from blood, sputum, throat and urine, and from other sites where clinically indicated (including wounds, aspirates, cerebrospinal fluid [CSF])

What imaging studies will be helpful in making or excluding the diagnosis of melioidosis?

Patients with suspected or confirmed melioidosis should be screened for deep organ involvement with a CT abdomen and pelvis ($$$)
If not available and in children, an ultrasound ($$) may be useful, but commonly does not image the pelvis well
Other routine imaging should include a chest radiograph ($)
Other investigations should be performed as clinically indicated (e.g. plain radiograph for osteomyelitis)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?Infectious Diseases should be consulted

If you decide the patient has melioidosis, what therapies should you initiate immediately?

Patients with melioidosis should be managed as follows:

acute management of sepsis (recognition of organ dysfunction, fluid resuscitation, timely antibiotics/source control, optimization of oxygen delivery)
Intensive phase antibiotics (ceftazidime or meropenem) for at least 10-14 days
Investigation to define extent of organ involvement, particularly clinically occult deep infection (e.g. splenic, liver, prostate, renal abscesses)
Eradication phase antibiotics (TMP-SMX) for 3 months

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

For patients with severe sepsis where melioidosis is suspected, meropenem is recommended. For patients with a febrile illness (i.e. sepsis without organ dysfunction) where melioidosis is suspected, treatment should broadly cover common bacterial pathogens (e.g. ceftriaxone) until the results of cultures are available. Table I is a list of recommended antibiotics used in the treatment of melioidosis.

Table I.

Phase	Antibiotic	Dose	Alternative
Intensive	Ceftazidime	50mg/kg up to 2g, every 6 hours	Meropenem (severe sepsis; 25mg/kg up to 1g, every 8 hours)Amoxicillin-clavulanate (20/5mg/kg IV every 4 hours)
Eradication	TMP-SMX	8/40mg up to 320/1200mg twice daily for at least 3 months	Doxycycline (2mg up to 100mg PO twice dailyAmoxicillin-clavulanate (20/5mg/kg PO three times daily)

Note ratio of amoxicillin/clavulanate precludes use of “Duo Forte” formulations.

For patients with confirmed melioidosis, ceftazidime (or meropenem for severe sepsis) is recommended. In the intensive phase, TMP-SMX is added for disease involving the central nervous system, bone/joint and prostatic disease.
Patients that present with severe sepsis who are started on meropenem can be switched to ceftazidime once stable.
The intensive phase of treatment can be completed in an outpatient antibiotic programme.

For eradication therapy, oral TMP-SMX is recommended for at least 3 months.
Adherence to treatment is vital to prevent relapse of disease.
Other regimens have been associated with higher rates of relapse, in part due to gastrointestinal intolerance.

2. Next list other key therapeutic modalities.

Adjunctive therapies used for the treatment of severe sepsis generally should be used for severe melioidosis. These include optimization of homeostasis in intensive care, including blood glucose control, limiting of peak airways pressure, renal replacement therapy, prophylaxis against stress ulcers and deep venous thrombosis.
G-CSF is used in some regions for fulminant disease. Although a clinical trial did not demonstrate a mortality benefit, the generalizability of this trial to developed countries is uncertain.

What complications could arise as a consequence of melioidosis?

What should you tell the family about the patient's prognosis?

If patients survive acute infection and complete eradication therapy, then full recovery and no subsequent relapse is expected
However immunity from reinfection is not conferred so new infection can occur in re-exposed individuals
Overall case fatality is around 10-20% in Australia and 40-50% in Thailand
In Australia, fatalities are uncommon in patients with no underlying comorbidities.
Mortality otherwise is related to the severity of sepsis.

What-if scenarios

Deep infection may require prolonged intravenous therapy. This includes osteomyelitis and deep tissue abscesses.
Prostatic abscesses should be sought in all males and if present usually require drainage.

How do you contract melioidosis and how frequent is this disease?

Burkholderia pseudomallei is found in pooled mud and surface water in northern Australia and South East Asia
Smaller numbers of cases have also been described in China (including Hong Kong and Taiwan), India and Bangladesh
Sporadic cases have been described in the Americas, Africa and the Middle East
Most cases (85%) are associated with exposure to the environment during the tropical monsoonal season

The incidence of disease in endemic regions ranges from 5-50 cases per 100,000 annually.
Risk factors are well described and include diabetes, chronic renal disease, hazardous alcohol use, chronic lung disease, immunosuppression, malignancy. Notably HIV infection does not appear to be a risk factor for infection
Most cases present with acute sepsis, either associated with pneumonia, or where no clinical focus is identified.
Infection can also involve skin/soft tissue, bone/joint, intra-abdominal organs (particularly liver and spleen) and the urinary tract.
In Australia, prostatic abscesses (in men) and encephalomyelitis are described
In Thailand, parotid abcesses are a common and characteristic presentation, especially in children
Around half of patients are bacteraemic
Neonatal disease and transmission from breast milk have been described

The mode of acquisition is not well defined, but in 25% of patients a history of an inoculating event is described (mean 9 days, range 1-21 days)
Inoculation with subsequent local and haematogenous dissemination is thought to be the dominant mode of spread
Acquisition via ingestion is thought to be possible but is better described in animals (with involvement of the gastrointestinal tract)
The contribution of inhalation is unknown, but is suggested by animal studies and some epidemiological data (higher seroprevalance in helicopter crews in Vietnam War, increase in pneumonia during monsoon season).

Case clusters of disease have been associated with flooding associated with tropical cyclones and other extreme events (e.g. tsunami), and less commonly with contaminated environmental foci (drinking water supplies, contaminated detergent).Transmission is not known to occur from animals to humans, and only rare cases of human to human transmission have been described.

What pathogens are responsible for this disease?

Burkholderia pseudomallei

How do these pathogens cause melioidosis?

Little is known about the pathogensis of disease. Neither humoral or cell-mediated immunity have been shown to be protective, and it is thought that host responses are primary based on innate immunity (supported by the susceptibility of patients with chronic granulomatous disease). Impairment of polymorph and macrophage function may explain the susceptibility of diabetics. Typically for bacteria found in the envrionment, Burkholderia pseudomallei possesses a wide range of endotoxins and exotoxins that have been implicated in pathogenesis, with intracellular survival and cell-to-cell migration playing an important role in disease.

What other clinical manifestations may help me to diagnose and manage melioidosis?

There are few characteristic presentations of melioidosis, which may affect almost any organ in the body, so a high index of suspicion is required in patients at risk.
Although the majority of patients present soon after exposure, incubation periods of many years of decades are described so a full travel history is required.
In patients with melioidosis, deep sites of infection should be actively sought, even if one focus is clinically evident. This includes routine imaging of abdominal and pelvic organs, and other sites as clinically indicated.

After commencing treatment, patients may not respond immediately – the median duration of fever after commencing appropriate therapy is around 9 days.
Blood cultures are commonly negative after starting treatment; persistently positive cultures should prompt a search for deep infection.
Sputum cultures may remain positive for some weeks (or even longer in patients with structural lung disease)

After completion of intensive phase antibiotics, attention is required to ensure that patients are adherent to eradication phase antibiotics. This includes counselling and education about the importance of adherence and active management of potential adverse reactions to treatment.

What other additional laboratory findings may be ordered?

Serology (using indirect hemagglutination) is available in some laboratories but is poorly standardized. In patients from endemic areas, background seropositivity is common and is regarded as evidence of prior exposure. In acute infection, seroconversion may occur after presentation.
Nucleic acid detection using PCR has been studied but is not widely used outside of research settings.
Direct immunofluorescence (IF) is used in some endemic countries but is not commercially available.
In the United States, suspected B. pseudomallei isolates should be confirmed by the Laboratory Response Network (LRN) of the CDC.

How can melioidosis be prevented?

No vaccines are available
Post-exposure prophylaxis is recommended for laboratory workers involved in accidental exposure to pure culture.
Routine advice for travellers includes avoidance of exposure to mud and pooled surface water in endemic regions, particularly for patients with risk factors.
Patients should also be aware that disease may present up to many years after exposure.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Wiersinga, WJ, Currie, BJ, Peacock, SJ. “Melioidosis”. N Engl J Med. vol. 367. 2012 Sep 13. pp. 1035-44. (Excellent overview of the current status of this disease)

Cheng, AC, Currie, BJ. “Melioidosis: epidemiology, pathophysiology, and management”. Clin Microbiol Rev.. vol. 18. 2005 Apr. pp. 383-416. (Extensive review of melioidosis)

DRG CODES and expected length of stay

Melioidosis (ICD-10: A24.1-4). Expected hospital length of stay 14-42 days (outpatient antibiotics possible).

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