The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review

Abstract

Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success. Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis. Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.

Monoclonal Antibodies Opsonize Burkholderia spp. and Reduce Intracellular Actin Tail Formation in a Macrophage Infection Assay

“…It is known that neutrophils ( 34 , 35 ) and NK and CD8 cells ( 36 ) are likely to contribute to removal of bacteria. As an antibody therapy, the anti-CPS MAb 3VIE5 could be particularly useful as a combination therapy with antibiotics, and potentially with other host-directed compounds, such as autophagy inducers ( 37 ). This could involve utilizing the MAb to prevent bacterial motility within the intracellular environment, while the secondary component, such as the autophagy inducer or antibiotic, promotes bacterial clearance.…”

A call to action: time to recognise melioidosis as a neglected tropical disease

“…One of the most important reasons for its neglect is the fact that melioidosis does not spread readily from person to person. 1,45 This means that explosive outbreaks of infection, such as those seen with COVID-19 or Ebola, do not occur, although the disease continues to kill many thousands of people in endemic areas every year. The limited risks of inhabitants of high-income, non-endemic countries acquiring this potentially fatal disease naturally has also contributed to the low priority accorded to melioidosis.…”

“…The limited risks of inhabitants of high-income, non-endemic countries acquiring this potentially fatal disease naturally has also contributed to the low priority accorded to melioidosis. 45,46…”

Burkholderia pseudomalleiclinical isolates are highly susceptiblein vitroto cefiderocol, a novel siderophore cephalosporin

“…The mortality rate for patients presenting with melioidosis ranges from 10-30% in Burma, Singapore, Thailand and Vietnam 20 , while in Australia it remains approximately 10% 24 . Recent research has focused on new or repurposed compounds in order to provide improved treatment options for such infections, particularly given the potential of B. pseudomallei to be genetically manipulated or used as an agent of biologic warfare 25,26 . Therefore, with the need for new treatment options for B. pseudomallei and other GNB, and promising efficacy of cefiderocol as a treatment option, the aim of this study was to assess the in vitro activity of cefiderocol against a large sample size of clinical B. pseudomallei isolates from endemic regions of Australia.…”