Travel-associated melioidosis: a narrative review.

BACKGROUND: Melioidosis, caused by Burkholderia pseudomallei, may be considered a neglected tropical disease that remains underdiagnosed in many geographical areas. Travellers can act as the sentinels of disease activity, and data from imported cases may help complete the global map of melioidosis. METHODS: A literature search for imported melioidosis for the period 2016-22 was performed in PubMed and Google Scholar. RESULTS: In total, 137 reports of melioidosis associated with travel were identified. The majority were males (71%) and associated with exposure in Asia (77%) (mainly Thailand, 41%, and India, 9%). A minority acquired the infection in the Americas-Caribbean area (6%), Africa (5%) and Oceania (2%). The most frequent comorbidity was diabetes mellitus (25%) followed by underlying pulmonary, liver or renal disease (8, 5 and 3%, respectively). Alcohol/tobacco use were noted for seven and six patients, respectively (5%). Five patients (4%) had associated non-human immunodeficiency virus (HIV)-related immunosuppression, and three patients (2%) had HIV infection. One patient (0.8%) had concomitant coronavirus disease 19. A proportion (27%) had no underlying diseases. The most frequent clinical presentations included pneumonia (35%), sepsis (30%) and skin/soft tissue infections (14%). Most developed symptoms <1 week after return (55%), and 29% developed symptoms >12 weeks after. Ceftazidime and meropenem were the main treatments used during the intensive intravenous phase (52 and 41% of patients, respectively) and the majority (82%) received co-trimoxazole alone/combination, for the eradication phase. Most patients had a favourable outcome/survived (87%). The search also retrieved cases in imported animals or cases secondary to imported commercial products. CONCLUSIONS: As post-pandemic travel soars, health professionals should be aware of the possibility of imported melioidosis with its diverse presentations. Currently, no licensed vaccine is available, so prevention in travellers should focus on protective measures (avoiding contact with soil/stagnant water in endemic areas). Biological samples from suspected cases require processing in biosafety level 3 facilities.

Vitamin D (1α,25(OH)2D3) supplementation minimized multinucleated giant cells formation and inflammatory response during Burkholderia pseudomallei infection in human lung epithelial cells.

Melioidosis is an infectious disease with high mortality rates in human, caused by the bacterium Burkholderia pseudomallei. As an intracellular pathogen, B. pseudomallei can escape from the phagosome and induce multinucleated giant cells (MNGCs) formation resulting in antibiotic resistance and immune evasion. A novel strategy to modulate host response against B. pseudomallei pathogenesis is required. In this study, an active metabolite of vitamin D3 (1α,25-dihydroxyvitamin D3 or 1α,25(OH)2D3) was selected to interrupt pathogenesis of B. pseudomallei in a human lung epithelium cell line, A549. The results demonstrated that pretreatment with 10-6 M 1α,25(OH)2D3 could reduce B. pseudomallei internalization to A549 cells at 4 h post infection (P < 0.05). Interestingly, the presence of 1α,25(OH)2D3 gradually reduced MNGC formation at 8, 10 and 12 h compared to that of the untreated cells (P < 0.05). Furthermore, pretreatment with 10-6 M 1α,25(OH)2D3 considerably increased hCAP-18/LL-37 mRNA expression (P < 0.001). Additionally, pro-inflammatory cytokines, including MIF, PAI-1, IL-18, CXCL1, CXCL12 and IL-8, were statistically decreased (P < 0.05) in 10-6 M 1α,25(OH)2D3-pretreated A549 cells by 12 h post-infection. Taken together, this study indicates that pretreatment with 10-6 M 1α,25(OH)2D3 has the potential to reduce the internalization of B. pseudomallei into host cells, decrease MNGC formation and modulate host response during B. pseudomallei infection by minimizing the excessive inflammatory response. Therefore, 1α,25(OH)2D3 supplement may provide an effective supportive treatment for melioidosis patients to combat B. pseudomallei infection and reduce inflammation in these patients.

A macrophage-targeted platform for extending drug dosing with polymer prodrugs for pulmonary infection prophylaxis.

Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the pathogen's intrinsic antibiotic resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in under-resourced settings. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with an aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria's relative resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.

Is GSK3ß a molecular target of chloroquine treatment against COVID-19?

The recent clinical trial reports pertaining to the efficacy of chloroquine and hydroxychloroquine against COVID-19 albeit yet to be validated with larger clinical trials, have sparked much interest globally to evaluate whether this anti-malarial drug can be repurposed for the treatment of COVID-19. In addition to its anti-viral activity, the anti-inflammatory activity of chloroquine may also contribute to its efficacy. Based on our data obtained from an animal infection model of melioidosis (a disease caused by the bacteria Burkholderia pseudomallei), treatment with chloroquine can result in the phosphorylation and consequent inhibition of glycogen synthase kinase-3ß (GSK3ß). This serine/threonine protein kinase is now recognised as a point of convergence for host inflammatory response. In view of this, it is plausible that the mechanism for the anti-inflammatory effect of chloroquine against COVID-19 involves inhibition of host GSK3ß.