Educational aims
The reader will come to appreciate that:
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Infection occurs through percutaneous inoculation or inhalation with contaminated soil and water.
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Diagnosis of melioidosis can be difficult because of its diverse presentation.
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Melioidosis is increasingly being diagnosed around the world.
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Greater consideration for melioidosis in protracted or atypical pneumonia is warranted regardless of location.
Summary
Melioidosis is a tropical infectious disease caused by the saprophytic gram-negative bacterium Burkholderia pseudomallei . Despite the infection being endemic in southeast Asia and northern Australia, the broad clinical presentations and diagnostic difficulties limit its early detection, particularly in children. Melioidosis more commonly affects the immunocompromised and adults. Melioidosis is increasingly being diagnosed around the world and whole-genome sequencing indicates that these cases are not linked with travel to endemic areas. Research has concentrated on the adult population with limited experience reported in the care of this uncommon, but potentially fatal condition in children presenting with bacteraemia and pneumonia.
Introduction
Melioidosis, an infection caused by the gram-negative bacillus Burkholderia pseudomallei , is an under-recognised disease, particularly in children. Melioidosis is endemic in many southeast Asian countries such as Northern Thailand and Sri Lanka, and in Northern Australia. Adults are infected at higher rates than children. Diagnosis can be difficult due to its diverse clinical presentation, which can range from skin infections to meningoencephalitis. In the paediatric population, the most common presenting symptoms differ from that of the adult population, further delaying its diagnosis. In the paediatric population, melioidosis most commonly presents as parotitis or cutaneous infection (approximately four times more likely in children than adults), whereas in adults melioidosis most commonly presents as pneumonia (approximately three times more likely in adults than in children), which may be unilobar, multilobar or bilateral .
Burkholderia pseudomallei survives in soil and water. Transmission to an animal or human host occurs through percutaneous inoculation with or inhalation of contaminated soil and water . Studies in mice have supported the hypothesis that B. pseudomallei can also directly invade the brain via movement along the olfactory and/or trigeminal nerve root pathways following colonization of the nasal mucosa . Human-to-human transmission is rare. However, there have been cases of transmission via mastitis-infected breastmilk .
Epidemiology
Southeast Asia and tropical northern Australia are the major endemic regions, with a higher incidence during wet season . In endemic areas, annual incidence rates range from 4 to 41.7 cases per 100,000 population . However, modelling of the global burden suggests that melioidosis is massively underdiagnosed, attributed to limited access to laboratory diagnostics and lack of clinical awareness in some endemic areas . Melioidosis is increasingly being diagnosed in new locations around the world, such as in non-tropical areas of Australia, and whole-genome sequencing indicates that these cases are not linked with travel to endemic areas . As melioidosis is caused by a saprophytic organism, which feeds on dead or decaying organic matter, climate change will likely impact geographic spread and incidence . Greater consideration for melioidosis is now warranted regardless of location or patient demographic, particularly in protracted or atypical pneumonia.
The median age at diagnosis is 36 years in the American region, compared to 50, 47, 49 and 60 years for the southeast Asian region, Western-Pacific region, African region, and Eastern Mediterranean region respectively . Below the age of 14 years, the age-sex distribution of melioidosis incidence was similar across regions, whereas for 14 years and older the male to female incidence and mortality of melioidosis was 2:1 . This gender discrepancy is thought to reflect occupational exposure to B. pseudomallei as well as inequality in access to health care , leading to under-diagnosis of cases in females in lower socio-economic endemic areas . Low socioeconomic status is an independent risk factor for death due to melioidosis . Skin infections are the most common presentation seen in children in Australia , while parotid abscesses are the most common presentation in children in some Southeast Asian countries .
Of those who survive acute melioidosis, 5–28 % will develop recurrent infection which could be due to recrudescence of the original strain [estimated < 5 %], or reinfection with a different strain following re-exposure . In the 24-year study (from 1989) of melioidosis in children in the Northern Territory of Australia by McLeod et al., only one of the forty-five children presented with relapsing disease after effective antibiotic treatment .
Diagnosis
Isolation of B. pseudomallei by culture is currently the diagnostic gold standard, but takes up to 7 days . Culture has only an estimated sensitivity of around 60 % . In the endemic area of northern Australia, cultures from multiple sites are recommended for diagnosis, including blood, urine, sputum, throat, rectum and wound . However, unless clinically suspected and communicated to laboratory staff, wrinkled B. pseudomallei colonies are frequently thought to be aerobic spore-bearing bacteria. An aerobic, gram-negative bacillus is likely to be considered as a Pseudomonad , which is unlikely to be identified further to the species level . A throat or sputum culture positive for B. pseudomallei is considered indicative of pulmonary involvement, even in the presence of a normal chest radiograph . Nucleic acid detection methods are not sufficiently specific or sensitive for routine clinical use or to replace culture assays . A range of serological assays have been developed for the diagnosis of melioidosis , which may soon allow transition to culture-independent techniques for diagnosis . The indirect haemagglutination assay (IHA) remains the most widely used diagnostic test . In endemic areas, IHA has limited clinical use because of high background antibody positivity and false negative results in early disease . Serial IHA testing may assist with melioidosis diagnosis in returning travellers to non-endemic areas . Access to laboratory, particularly for rapid diagnostics, are not available or are extremely limited in many melioidosis-endemic regions, which limits diagnosis, delays effective treatment, and contributes to the incomplete understanding of the global burden of disease .
Serology studies support that most infections with B. pseudomallei are asymptomatic, and the proportion of exposed individuals that develop latent infection is not known . In the Darwin prospective study, only 29 (3 %) of patients were considered to have possible activation from latency . The potential to develop melioidosis following activation of latent infection is well recognised in reported historical cases , particularly in returning war veterans from the Vietnam War . However, such historical cases likely reflect unrecognised chronic and/or recrudescent melioidosis, which would today be diagnosed earlier with appropriate sampling and current laboratory protocols .
Current treatment protocols
Current treatment guidelines are largely based on adult studies. In the endemic countries of Southeast Asia and of Australia there are no national guidelines, however there are regional guidelines. The 24-year Darwin Prospective Melioidosis Study from 1989 has undertaken long-term studies and developed the current treatment guidelines that are used globally. The 2015 Darwin melioidosis guideline, which was revised in 2020 recommends a prolonged antibiotic regimen with an initial intravenous course of ceftazidime, followed by an oral antibiotic eradication phase with trimethoprim-sulfamethoxazole. A minimum two weeks of intravenous antibiotics is recommended, extended to a minimum of three weeks for increased severity such as bacteraemia or bilateral or multilobe pneumonia, and the presence of complications such as osteomyelitis. A minimum 12-week oral antibiotic course is recommended. The United States Centers for Disease Control and Prevention [CDC] however, recommends an initial intravenous regimen of ceftazidime or meropenem, for a duration of two to eight weeks (to be guided by severity), followed by an oral eradication regimen of trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid for a minimum 12 weeks . These recommendations are based on a randomized controlled trial in Thailand that compared ceftazidime with the prior conventional therapy for severe melioidosis. The trial demonstrated that ceftazidime resulted in a 50 % reduction in overall mortality . There is limited clinical trial evidence to support the durations and dosages recommended in melioidosis treatment guidelines .
Prognosis
The infection carries a significant mortality rate (10–50 %) even when appropriately treated ; this rate may be underestimated due to misdiagnosis . The estimated annual global disease burden of melioidosis is approximately 165,000 cases, including 89,000 deaths . Melioidosis is mainly considered an opportunistic disease as adult patients are typically immunocompromised or with morbidities such as diabetes mellitus, chronic renal failure, and lung disease . However, in children it is increasingly being recognised in the otherwise healthy population . In the Northern Territory of Australia study by McLeod et al., the paediatric mortality rate was 7 % (N = 3/45) and there was no statistical difference in mortality between children and adults (7 % vs 14 %, p =.178) . However, in Far North Queensland, the rates of bacteraemia and mortality in children are much higher, 60 % and 50 % respectively . The cause of this is uncertain, though is thought to be partly explained by delayed diagnosis .
In a study of paediatric cases of melioidosis over a nine-year period to 2018 in Cambodia, Chandna et al. had an in-hospital mortality rate of 11.5 % (N = 41) and found that significant independent risk factors for mortality were pneumonia and B. pseudomallei bacteraemia . In the neonatal population, the mortality rate was 72.5 % in one study .
Illustrative Case
In June 2023, a previously healthy three-year-old Cambodian boy presented to a Paediatric hospital in Phnom Penh with fevers and a productive cough for five days. He had recently completed a five-day course of oral medication (unclear if antibiotic or other medication) and two doses of cefaclor antibiotic without improvement in symptoms.
Biochemistry investigations revealed a leucocytosis with neutrophilia, an elevated C-reactive protein (CRP) and a mild transaminitis ( Table 1 ). A chest Xray identified a right middle zone opacification ( Fig. 1 ). A computed tomography (CT) chest was not performed in this admission. An abdominal ultrasound identified homogenous hepatomegaly. He was admitted and received antibiotics ceftriaxone (third-generation cephalosporin) and gentamicin (aminoglycoside) intravenously for five days. A blood culture collected on day 6 of admission grew Burkholderia pseudomallei ( Table 2 ) and his antibiotics were changed to ceftazidime (third generation cephalosporin) and ciprofloxacin (fluroquinolone) for seven days. His biochemistry abnormalities showed improvement though did not normalise. The patient had defervesced, and he was discharged home on amoxicillin/clavulanic acid.
| Day of admission | White Blood Cell × 10 9 /L (RR 5.0–15) | Neutrophils × 10 9 /L (RR 1.5–8.0) | Haemoglobin g/dL (RR 11–14) | Platelets × 10 9 /L (RR 200–490) | C-Reactive Protein mg/L (RR < 6) | ALT U/L (RR < 32) | AST U/L (RR < 31) | Blood culture | Urine culture |
|---|---|---|---|---|---|---|---|---|---|
| Day 1 | 34.6 | 29.7 | 11 | 571 | – | – | – | – | – |
| Day 6 | 25.1 | 18.5 | 9.7 | 406 | 50.7 | 78 | 120 | – | – |
| Day 7 | 26.1 | 20.8 | 10.1 | 276 | 60.7 | – | – | B. pseudomallei | No growth |
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