Melioidosis

Melioidosis, i.e. Burkholderia pseudomallei pneumonia, is a Level 1 topic from Section 2.1.3 in the first edition of the CICM Syllabus for the Second Part Examination. It appears among the "rarer infections with specific ICU considerations" alongside tropical and nontropical infectious diseases that appear to have been selected according to some kind of hidden design parameters that likely have nothing to do with their incidence. The same weird list contains common things like meningitis and infective endocarditis alongside tetanus and botulism. Burkholderia appeared in Question 6 from the first paper of 2024 as the subject of an "assessment and management" question, 40% list regurgitation and 60% generic sepsis management boilerplate, which made it theoretically possible to pass even for those who simply did not have the melioidosis details memorised. Still, "several candidates failed to answer at all or wrote very little", the examiners remarked with some hint of sadness, reminding us that the surest way to score zero marks is to leave the page blank.

In summary:

It was certainly not going to be possible to reason through this answer from basic principles. One would have had to either have some ID background, or had taken the syllabus document seriously and picked apart the learning objectives. For future instances, the exam candidates are referred to Sridharan et al, 2021 or Chakravorty & Heath (2019). There is also the CDC entry on melioidosis and the 2024 Revised Darwin Melioidosis Guideline.

Aetiology

Burkholderia pseudomallei is a mostly aerobic gram-negative rod, and is often said to be related to Pseudomonas, as in fact it went by Pseudomonas pseudomallei  until 1992 when Yabuuchi et al (1992) decided to reclassify them because of some genetic and metabolic distinctions (for example, Burkholderia species were capable of oxidize and assimilate disaccharides and polyalcohols which no Pseudomonas could handle). The other Burkholderia worth noting is B.cepacia, an opportunistic pathogen that generally grows in the ectatic bronchi of cystic fibrosis patients and other immunocompromised hosts.

Walter Hagemeyer Burkholder (1891-1983) was unfortunately no longer around to see this thing renamed after him. These bugs are not "true" mallei, they are pseudomallei, because the disease they cause was  described as "false glanders" by Whitmore in 1913, whereas "true glanders", caused by B.mallei, is a disease of horses and mules which is largely unknown in the developed world. Mallei the disease  in this case has nothing to do with malleus the hammer, a piece of Latin which tabletop gaming nerds will instantly recognise; it is in fact bastardised from Greek into Latin, and the original word "melis" was, in Aristotle's time, used to refer to the contagious"distemper of asses", a turn of phrase that begs to be repurposed for acrimonious faculty meetings. 

It lives in soil and stagnant water, and usually grows in aerobic bottles but is in fact a facultative anaerobe, as it can use NO₃^- as final electron acceptor in the absence of oxygen, and is rather at home deep in anoxic soil and at the bottom of ponds. Infections are is generally associated with a history of disturbing such water and such soil, eg. in the context of swimming, farming, construction or exposure to wild weather. In general contact with moist surface soil in endemic regions seems to be enough. "The highest prevalence of melioidosis is observed in rice farmers, servicemen, miners, adventure travelers, and indigenous peoples in the main endemicity zone of northern Australia and Southeast Asia", report Inglis & Sagripanti (2006). It is often associated with paddy farming.  When in the host, it behaves just like any other gram negative in the blood, growing readily on standard blood cultures. 

Superpowers

The secret agent trick of Burkholderia species is an intrinsic resistance to colistin, with which each Burkholderia is born. It is in fact resistant to all kinds of antibiotics, often to a hilarious extent. Loutet & Valvano (2011) describe experiments where Burkholderia would reproduce happily on agar where penicillin was the sole source of carbon, and thrive in solutions which contained enough chlorhexidine to act as disinfectants. Some of this is owed to a unique outer membrane structure, where the sugar 4-amino-4- deoxy-l-arabinose (Ara4N) is integrated into the lipid A component of LPS. 

Clinical course of melioidosis

Incubation period is about 4-9 days, thought he range is 1-21, i.e. it is plausible to catch this during a two-week holiday, not have the holiday ruined by sepsis, and then develop it conveniently just as one returns to work. The majority of patients end up with pneumonia, about 509% are bacteraemic at presentation, and 20% are in septic shock. A chronic version lasting for longer than two months is also possible, which looks more like tuberculosis, with cavitating lesions and retractive fibrosis.

Assessment of melioidosis

In answering an "outline your assessment" sort of question for the CICM exam, one would need to do more than merely list the questions one would pose to the patient and their family. Some rationale for why the questions are being asked is probably necessary. The main objectives are to assess the risk of melioidosis (as opposed to another similar condition) and to build the case for hitting the patient  empoirically with the expensive and potentially restricted antibiotics while waiting for culture results.

History that builds a suspicion of melioidosis

This bug is endemic to the following regions:

• Southeast Asia, especially North-eastern Thailand
• Northern Australia
• South India
• Sri Lanka
• Southern China
• Papua New Guinea
• Also reported in Central and South America, Africa, the Middle East, the Caribbean, New Caledonia and Mauritius.

Risk factors for acquiring the disease during one's travel in a susceptible area include:

• Demographic factors
  • Aboriginal and Torres Strait Islander peoples
  • Agricultural workers
  • Construction workers
  • Ecotourists
• High risk activities:
  • Alcohol excess (binging)
  • Swimming and near drowning
  • Drinking unchlorinated potable water
  • Travelling during the season of heavy rainfall (October to April)
  • Routes of transmission are exposure through broken skin, inhalation, and ingestion, so basically anything you do on holiday could theoretically be a risk
• Predisposing comorbidities:
  • Diabetes
  • Renal disease
  • Chronic lung disease
  • Thalassemia
  • Malignancy
  • Immunosuppressive therapy
• Presenting history is often nonspecific: fevers, weight loss and productive cough, often unresponsive to multiple courses of antibiotics in the community
• The rate of progression is reasonably quick, i.e. this is not usually a slowly developing indolent disease.

Clinical examination findings classical in melioidosis

• Respiratory findings are not very specific: productive cough, shortness of breath and fever.
• Features of severity need to be mentioned in exam answers, even though in the bedside setting they would jump out at you. These are mostly mentioned because they would trigger an escalation to a higher level of care (eg. transfer to a hospital where there is an ICU)
  • Severity of respiratory distress 
  • Features of shock
  • Signs of CNS involvement
• Features of systemic involvement
  • Abdominal examination for solid organ abscesses
  • For some reason this bacterium loves the Australian prostate;  prostatic abscesses are seen in 18% of males with acute melioidosis, but for some reason only in the NT. A PR exam could therefore be appropriate, even for visiting Queenslanders.

Laboratory investigations

The following seem like some kind of minimum:

• FBC, EUC, CMP, LFT to observe the organ system effects
• Blood cultures and inflammatory markers
• Sputum
• Swabs from lesions and sputum samples should be placed into Ashdown’s selective medium, a ruddy glorp which is selective for B.pseudomallei by being lethally toxic to all other bugs (as it is full of crystal violet and gentamicin).
• It grows readily on this stuff, and basically nothing else does, which makes it easy to identify this organism via culture (making serology and PCR less meaningful).

Imaging in melioidosis

To find something unique about the radiology of this disease, which is occasionally referred to as "the great masquerader" for its protean appearance, was difficult. Dhiensiri et al (1988) present a series of chest Xrays from their experience of 183 patients in rural Thailand, and concluded that the findings are almost TB-like:

• Nodular appearance, but also with fluffy alveolar ground glass
• Bilateral
• Usually basal rather than apical (unlike TB)
• Occasionally cavitating (especially if chronic), but the cavities are thin-walled and rarely filled with enough fluid to form a level (unlike S.aureus)
• Also unlike TB, there is usually no pleural effusion, and minimal mediastinal lymphadenopathy
• Also unlike TB the areas of ground glass can transform into confluent consolidation, whereas TB would never do a "proper" pneumonia like that.

Extrapulmonary clues are probably more useful:

• Liver and splenic abscesses: multiloculated lesions, "honeycomb" or "string of pearls" sign
• Prostatic abscesses
• Splenic vein thrombosis

But again, many of these can be associated with other disseminated infections, i.e. one cannot look at a hepatic/splenic abscess and say confidently "Yerp, that there is swarming with Burkholderia pseudomallei, I don'ty even need a positive culture." 

So, do you aspirate these? Generally, the rule seems to be "yes"; but to discuss this here would interrupt the flow of logical chapter structure. Fortunately, the next section is:

Management of melioidosis

Many of these patients will present with respiratory failure and septic shock, which is where the intensivist really earns their keep. It is easy to make the diagnosis because of the readiness of the organism to grow on standard media, the incidence of bacetraemia, and the barndoor-obvious risk history ("so, you've been ecoutouristing in rain season Thailand, barefoot and living off the land while drinking cheap local alcohol and neglecting your diabetes?"). Resuscitation of sepsis is therefore an essential element of the management approach, and was weighed heavily in the marking of Question 6 from the first paper of 2024, where apparently it was possible to almost pass even when one did not have any specific information about B.pseudomallei.

The antibiotic choices are also easy:

• Ceftazidime 2 g q6h
• OR meropenem 1g tds
• AND/OR trimethoprim – sulfamethoxazole which is added early for severe illness, or continued late for eradication therapy 

Antibiuotics continue for at least 14 days, and then eradication therapy follows.

Unusual features of management which may be memorable include:

• Eradication therapy with oral Bactrim for  3-6 months
• Folate supplementation to prevent the bone marrow sequelae
• GM-CSF is given to these patients routinely, as Cheng et al (2004) reported that functional neutrophil defects were often associated with this condition, and those are not usually something you might test for. The evidence for this is based on retrospective data from one centre (the Royal Darwin Hospital), where the mortality decreased from 95% to 10% after the introduction of routine G-CSF in 1998. Sure, the WCC may be raised, but they still do it until it gets up to 50,000×10⁶/L.

Abscesses need to be drained or debrided. 

• Where B.pseudomallei presents with a soft tissue infection primarily, the debridement and drainage seems to be a good method of preventing  progression to systemic and pulmonary infection
• Where the systemic disease is already being treated with antibiotics, big abscess cavities usually need to be drained surgically anyway ( Sasmal & Kumar, 2023) to help an earlier resolution and prevent recurrence.

Complications and known sequelae

Without going on an extensive tangent, leaving the reader to explore Maluda et al (2020) at their pleasure, this condition could be expected to also offer:

• Solid organ abscesses (liver, kidney,m adrenal, prostate)
• Neurological involvement, including brain abscess
• Septic arthritis
• Osteomyelitis
• Pericarditis, "pyopericardium"
• Reactivation (in 4%, even following apparently effective treatment)

Maluda et al (2020) reported a mortality of only ~4.3%, which seems to be lower than many cases of "usual" community-acquired pneumonia, but one must recall that often this condition is observed in relatively well healthy travellers farmers and construction workers (mean age of 46 years).

Relevant guidelines and evidence

The 2024 Revised Darwin Melioidosis Guideline is probably the only one to mention here, and the management steps listed therein are already reproduced above. The CDC guideline does not expand much on these, beyond adding some recommendations for post-exposure prophylaxis (21 days of oral TMP-SMX)