Human Melioidosis

Gassiep, Ian; Armstrong, Mark; Norton, Robert

doi:10.1128/cmr.00006-19

Cited by 153 publications

(249 citation statements)

References 585 publications

(1,029 reference statements)

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“…The overwhelming majority of patients with cardiac involvement were males (95.1%). Although this is consistent with the male predominance worldwide, this is a higher percentage when compared to figures of 58.5% in Thailand to 84% in Singapore [ 53 ]. This study identified that the majority of patients were farmers, military personnel, agriculturists, construction or shipyard workers, so this may be due to males receiving disproportionately more occupational exposure to contaminated soil and water.…”

Section: Discussionsupporting

confidence: 84%

“…There were 49 patients with pericardial involvement reported in the literature [ 3 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 50 , 51 , 52 , 53 ], with sufficient information for study inclusion obtained to include 32 patients (78.0%) [ 10 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 50 , 51 , 52 , 53 …”

Section: Resultsmentioning

confidence: 99%

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Melioidosis and the Heart: A Systematic Review

Velusamy

Muhi

2020

TropicalMed

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Melioidosis is caused by Gram-negative bacterium Burkholderia pseudomallei. Clinical presentation can vary from pneumonia, sepsis and multi-focal abscess formation. The aim of this study was to systemically review the cardiac manifestations of melioidosis in the literature and describe their epidemiology, microbiological diagnosis and outcomes. A systematic review of the peer-reviewed literature was carried out in PubMed and Google Scholar for human melioidosis cases with cardiac involvement. Quantitative data for cases of melioidosis were obtained, including age, sex, microbiological diagnosis, treatment, and outcome. 980 articles were screened, of which 31 articles were eligible. The most common cardiac site of infection was pericarditis, followed by endocarditis and myocarditis. Over 95% of cardiac involvement occurred in males, and mortality was the lowest in pericarditis and highest in myocarditis. Valvular vegetations were all small, left-sided, and did not require surgery. Antibiotic treatment included a bactericidal induction therapy with ceftazidime or a carbapenem ± TMP-SMX, followed by eradication therapy with TMP–SMX in most patients as previously established. In conclusion, melioidosis varies in clinical presentation and is also known as a great imitator. Although cardiac involvement is rare, this is the first systematic review to summarise all cases reported in the literature to date.

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Melioidosis and the Heart: A Systematic Review

Velusamy

Muhi

2020

TropicalMed

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“…While chronic melioidosis is also a clinically relevant form of the disease, the work described here focused exclusively on developing an acute model. In context of human disease, acute melioiodis is the majority of reported cases (estimated to be greater than 80% of human cases) and results from recent exposure to bacteria [ 2 , 43 ]. Characteristics associated with acute melioidosis include bacteremic pneumonia (depending on the route of infection may be primary or secondary pneumonia) and systemic inflammatory and immune responses observed in multiple organ systems.…”

Section: Discussionmentioning

confidence: 99%

“…Characteristics associated with acute melioidosis include bacteremic pneumonia (depending on the route of infection may be primary or secondary pneumonia) and systemic inflammatory and immune responses observed in multiple organ systems. The formation of large granulomas in various organs is also considered a hallmark of melioidosis disease [ 2 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model

et al. 2021

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Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a major cause of sepsis and mortality in endemic regions of Southeast Asia and Northern Australia. B. pseudomallei is a potential bioterrorism agent due to its high infectivity, especially via inhalation, and its inherent resistance to antimicrobials. There is currently no vaccine for melioidosis and antibiotic treatment can fail due to innate drug resistance, delayed diagnosis and treatment, or insufficient duration of treatment. A well-characterized animal model that mimics human melioidosis is needed for the development of new medical countermeasures. This study first characterized the disease progression of melioidosis in the African green monkey (AGM) and rhesus macaque (RM) for non-human primate model down-selection. All AGMs developed acute lethal disease similar to that described in human acute infection following exposure to aerosolized B. pseudomallei strain HBPUB10134a. Only 20% of RMs succumbed to acute disease. Disease progression, immune response and pathology of two other strains of B. pseudomallei, K96243 and MSHR5855, were also compared using AGMs. These three B. pseudomallei strains represent a highly virulent strain from Thailand (HBPUB101034a), a highly virulent strains from Australia (MSHR5855), and a commonly used laboratory strains originating from Thailand (K96243). Animals were observed for clinical signs of infection and blood samples were analyzed for cytokine responses, blood chemistry and leukocyte changes in order to characterize bacterial infection. AGMs experienced fever with aerosolized B. pseudomallei at the onset of acute disease. Inflammation, abscesses and/or pyogranulomas were observed in lung with all three strains of B. pseudomallei. Inflammation, abscesses and/or pyogranulomas were observed in lymph nodes, spleen, liver and/or kidney with B. pseudomallei, HBPUB10134a and K96243. Additionally, the Australian strain MSHR5855 induced brain lesions in one AGM similar to clinical cases of melioidosis seen in Australia. Elevated serum levels of IL-1β, IL-1 receptor antagonist, IL-6, MCP-1, G-CSF, HGF, IFNγ, MIG, I-TAC, and MIP-1β at terminal end points can be significantly correlated with non-survivors with B. pseudomallei infection in AGM. The AGM model represents an acute model of B. pseudomallei infection for all three strains from two geographical locations and will be useful for efficacy testing of vaccines and therapeutics against melioidosis. In summary, a dysregulated immune response leading to excessive persistent inflammation and inflammatory cell death is the key driver of acute melioidosis. Early intervention in these pathways will be necessary to counter B. pseudomallei and mitigate the pathological consequences of melioidosis.

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“…Chloroxine is soluble to 644 μM in water, and the peak ceftazidime concentration in serum is 130 μM [55]. Furthermore, B. pseudomallei invades and multiplies in phagocytic cells [56], so modification for penetration of these cells would be necessary. A wider range of starting lead scaffolds would likely be necessary for such optimization.…”

Section: Plos Onementioning

confidence: 99%

Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

et al. 2021

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Burkholderia pseudomallei is a soil-dwelling organism present throughout the tropics. It is the causative agent of melioidosis, a disease that is believed to kill 89,000 people per year. It is naturally resistant to many antibiotics, requiring at least two weeks of intravenous treatment with ceftazidime, imipenem or meropenem followed by 6 months of orally delivered co-trimoxazole. This places a large treatment burden on the predominantly middle-income nations where the majority of disease occurs. We have established a high-throughput assay for compounds that could be used as a co-therapy to potentiate the effect of ceftazidime, using the related non-pathogenic bacterium Burkholderia thailandensis as a surrogate. Optimization of the assay gave a Z’ factor of 0.68. We screened a library of 61,250 compounds and identified 29 compounds with a pIC50 (-log10(IC50)) greater than five. Detailed investigation allowed us to down select to six “best in class” compounds, which included the licensed drug chloroxine. Co-treatment of B. thailandensis with ceftazidime and chloroxine reduced culturable cell numbers by two orders of magnitude over 48 hours, compared to treatment with ceftazidime alone. Hit expansion around chloroxine was performed using commercially available compounds. Minor modifications to the structure abolished activity, suggesting that chloroxine likely acts against a specific target. Finally, an initial study demonstrates the utility of chloroxine to act as a co-therapy to potentiate the effect of ceftazidime against B. pseudomallei. This approach successfully identified potential co-therapies for a recalcitrant Gram-negative bacterial species. Our assay could be used more widely to aid in chemotherapy to treat infections caused by these bacteria.

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Human Melioidosis

Cited by 153 publications

References 585 publications

Melioidosis and the Heart: A Systematic Review

Melioidosis and the Heart: A Systematic Review

Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model

Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

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