Melioidosis

Prof Paul Turner

Cambodia-Oxford Medical Research Unit
University of Oxford
Outline
• The aetiologic agent: Burkholderia pseudomallei

• Melioidosis: global epidemiology

• Melioidosis in Cambodia

• Research data from Angkor Hospital for Children

www.tropmedres.ac/comru-cambodia |
 Burkholderia pseudomallei
• Environmental Gram negative bacillus
• Genus Burkholderia contains >40 species
• Pathogens: B. mallei, B. cenocepacia
• Non-pathogens: B. thailandensis, B. oklahomensis

Gram stain: bipolar / “safety pin” Growth on Ashdown agar

Gram stain photo credit: Wuthiekanun V, et al. Clin Diagn Lab Immunol. 2005
A complex genome (for bacteria)

Schematic circular diagrams of the large and small chromosomes of the B. pseudomallei genome

Holden MTG, et al. PNAS 2004;101:14240-14245

 “We also identified geographically distinct
genes/variants in Australasian or Southeast Asian
isolates alone, with virulence-associated genes being
among those over-represented. This provides a
potential explanation for clinical manifestations of
melioidosis that are geographically restricted”

Origin in Origin in
Africa Australia
Found in soil: wide distribution

Predicted environmental suitability for B. pseudomallei persistence at 5 × 5 km2 spatial resolution

Limmathurotsakul D, et al. Nat Microbiol. 2016;1(1): 15008

Human disease data

Global evidence consensus and geographic locations of occurrence data from 1910 to 2014

Estimated to be 5 cases per 100,000 people at risk (2015)

Limmathurotsakul D, et al. Nat Microbiol. 2016;1(1): 15008

 Risk factors
Age
• Peaks in 40-60y olds
• 5-15% of cases are in children
Diabetes mellitus
Heavy alcohol consumption
Chronic pulmonary disease
Chronic renal disease
Thalassemia
Steroid therapy
Cancer

Wiersinga WJ et al. N Engl J Med 2012;367:1035-1044

Clinical Events after Infection with
B. pseudomallei

Incubation period: 1 – 21 days (mean 9 days)

Longest recorded was 62 years
Wiersinga WJ et al. N Engl J Med 2012;367:1035-1044
Parotitis
A common presentation in (SE Asian) children

White NJ. Melioidosis. Lancet. 2003;361(9370):1715-22 Dance DA, et al. J Infect Dis. 1989;159(4):654-60
Diagnosis
Culture
• Blood, pus, throat swab, sputum, rectal swab, urine

Radiology
• CXR, abdominal USS*, head/neck USS

Other assays
• PCR: sub-optimal sensitivity from blood
• RDTs are being developed and evaluated
• Serology (IHA) is not used for diagnostic purposes

*Should be done in all culture confirmed cases

Dance D. Int J Antimicrob Agents. 2014;43(4):310-8
Antibiotic treatment
Parenteral Intensive phase
• Ceftazidime (50mg/kg 8-hrly)
OR
• Meropenem (25mg/kg 8-hrly)
• Duration: at least 10 days but often should be longer (e.g. 4 weeks if pneumonia + ICU)

Oral eradication phase

• Co-trimoxazole (8/40mg/kg 12-hrly)
OR
• Co-amoxiclav (20/5mg/kg 8-hrly)
• Duration: at least 12 weeks

Some unanswered questions

• Do all patients need the intensive phase IV treatment?
• Is meropenem better than ceftazidime?
Dance D. Int J Antimicrob Agents. 2014;43(4):310-8
An answer to a common
question…
If empirical therapy for melioidosis is begun
and B. pseudomallei is not subsequently
detected in adequate cultures of
specimens obtained before therapy,
completion of a full course of antimicrobial
therapy is generally not recommended

Wiersinga WJ et al. N Engl J Med 2012;367:1035-1044

Melioidosis in Cambodia

ID Cases. 2015;2(1):16-8
Annual confirmed cases
October 2005 – September 2017
Estimates of disease in 2015

Limmathurotsakul D, et al. Nat Microbiol. 2016;1(1): 15008

Am J Trop Med Hyg, 2010. 82(6): p. 1106-12

Emerg Infect Dis, 2008. 14(2): p. 301-3

Pediatr Infect Dis J, 2012. 31(8): p. 865-8

AHC
Data

Pediatr Infect Dis J, 2013. 32(7): p. e272-6

Indirect hemagglutination assay (IHA)
titre for 968 children living in Siem Reap

Wuthiekanun V, et al. Emerg Infect Dis. 2008;14(2):301-3

“AMR” is not a big problem, but intrinsic
resistance limits treatment choices

AHC blood culture isolates 2013-15: no AHC isolates

acquired AMR

Dance DA, et al. Int J Antimicrob Agents. 2014;44(4):368-9

Patient characteristics
173 cases

Median age was 5.7 years

3 neonatal cases

Comorbidities
2 thalassemia,1 chronic renal failure, 1 probable ALL, 1 SLE
No diabetics
48% of <10 year olds had a weight-for-age z-score of <2

19 cases in 2009 and 35-44 cases in later years

>80% of cases occurred during the rainy season
Disease incidence
Commune-level incidence for Siem Reap province
• 2008 national census data
• Children <15y

Median annual incidence

28 to 35 cases per 100,000 children
Presentation, clinical syndromes, outcomes
Median duration of symptoms was 7 days

Six children had chronic presentations Principal focus of infection N %

Bacteraemic 39 22.5
Pneumonia 29 16.8
24% had disseminated infection No focus found 6 3.4
Parotitis 2 1.2
Skin / soft tissue infection 2 1.2
Outcomes Non-bacteraemic / Blood culture 134 77.5
not done
• Overall mortality was 17% Skin / soft tissue infection 60 34.6
Parotitis 51 29.4
• Mortality in bacteraemic patients was 72% Lymph node abscess* 15 8.6
Pneumonia 4 2.3
Vaginal discharge 2 1.2
Learning points Otitis / mastoiditis 1 0.6
• Investigation often incomplete Periorbital cellulitis 1 0.6
Secondary foci of infection (in addition to a primary
• Follow-up data capture can be challenging focus)
Skin / soft tissue infection 4
Otitis / mastoiditis 2
Lymph node abscess 5
Melioidosis cases in Cambodia were associated with
• Humidity
• Rainy days
• Maximum wind speed

Children have a higher odds of infection, compared to adults, in the

highly humid months (OR 2.79, 95% CI 1.83 – 4.26)

Lung and disseminated infections were more common in the windy

months
PLOS NTD. 2019;13(7):e0007598
Summary
Melioidosis is a significant public health problem in Cambodia
• Unusually, we currently have more data about paediatric infections
• These are the tip of the iceberg
• Need more surveillance data, especially in adult patients

Investigation and treatment can be challenging

• It should be considered in all infection work-ups: the disease is endemic and common
• Standard diagnostic and treatment algorithms are available
• Diagnosis and treatment is highly cost effective using standard health economic analyses

Further work is needed to define country-specific risk factors and prevention strategies

All of the research published through AHC – COMRU is available to all at no cost
Thank you.

Cambodia Oxford Medical Research Unit

Angkor Hospital for Children | Siem Reap | Cambodia