Clinical repercussions of Glanders (Burkholderia mallei infection) in a Brazilian child: a case report

Abstract Glanders is a relatively unknown zoonotic disease caused by Burkholderia mallei. This bacterium affect solipeds and humans, and can be used as a biological warfare. Glanders is characterized as an occupational disease. We report the case of an 11-year-old boy who was presented to an emergency department with chest pain and dyspnea. He evolved into septic shock, pneumonia, and multiple abscesses. B. mallei was found in the exudate culture. Human infection is rare and difficult to confirm. The knowledge on glanders is important for differential diagnosis from other serious illnesses causing pneumonia and multiple abscesses.

Emerging role of biologics for the treatment of melioidosis and glanders.

Introduction: Two important pathogenic species within the genus Burkholderia, namely Burkholderia pseudomallei (Bpm) and Burkholderia mallei (Bm), are the causative agents of the life-threatening diseases melioidosis and glanders, respectively. Due to their high mortality rate and potential for aerosolization, they have gained interest as potential biothreat agents and are classified as Tier 1 Select Agents.Areas covered: The manuscript provides an overview of the literature covering the efforts taken in the last 10 years to develop new therapeutics measures against both Bpm and Bm, with attention on novel therapeutic agents.Expert Opinion: As a result of the complicated antibiotic regimens necessary to treat these infections, development of novel therapeutics is needed to treat both diseases. In recent years, the understanding of the pathogenesis of Burkholderia has improved significantly and so have the efforts to develop novel therapeutic agents with high efficacy, either alone, or in combination with conventional antibiotics.

Innate immune response to Burkholderia mallei.

PURPOSE OF REVIEW: Burkholderia mallei is a facultative intracellular pathogen that causes the highly contagious and often the fatal disease, glanders. With its high rate of infectivity via aerosol and recalcitrance toward antibiotics, this pathogen is considered a potential biological threat agent. This review focuses on the most recent literature highlighting host innate immune response to B. mallei. RECENT FINDINGS: Recent studies focused on elucidating host innate immune responses to the novel mechanisms and virulence factors employed by B. mallei for survival. Studies suggest that pathogen proteins manipulate various cellular processes, including host ubiquitination pathways, phagosomal escape, and actin-cytoskeleton rearrangement. Immune-signaling molecules such as Toll-like receptors, nucleotode-binding oligomerization domain, myeloid differentiation primary response protein 88, and proinflammatory cytokines such as interferon-gamma and tumor necrosis factor-α, play key roles in the induction of innate immune responses. Modifications in B. mallei lipopolysaccharide, in particular, the lipid A acyl groups, stimulate immune responses via Toll-like receptor4 activation that may contribute to persistent infection. SUMMARY: Mortality is high because of septicemia and immune pathogenesis with B. mallei exposure. An effective innate immune response is critical to controlling the acute phase of the infection. Both vaccination and therapeutic approaches are necessary for complete protection against B. mallei.

Efficacy of postexposure therapy against glanders in mice.

Burkholderia mallei, the causative agent of glanders, is a CDC Tier 1 Select Agent for which there is no preventive vaccine and antibiotic therapy is difficult. In this study, we show that a combination of vaccination using killed cellular vaccine and therapy using moxifloxacin, azithromycin, or sulfamethoxazole-trimethoprim can protect BALB/c mice from lethal infection even when given 5 days after infectious challenge. Vaccination only, or antibiotic therapy only, was not efficacious. Although antibiotics evaluated experimentally can protect when given before or 1 day after challenge, this time course is not realistic in the cases of natural infection or biological attack, when the patient seeks treatment after symptoms develop or after a biological attack has been confirmed and the agent has been identified. Antibiotics can be efficacious after a prolonged interval between exposure and treatment, but only if the animals were previously vaccinated.

Immunopotentiation for bacterial biodefense.

Activation of the innate immune system can enhance resistance to a variety of bacterial and viral infections. In situations where the etiological agent of disease is unknown, such as a bioterror attack, stimulation of innate immunity may be particularly useful as induced immune responses are often capable of providing protection against a broad range of pathogens. In particular, the threat of an intentional release of a highly virulent bacterial pathogen that is either intrinsically resistant to antibiotics, or has been weaponized via the introduction of antibiotic resistance, makes immunopotentiation an attractive complementary or alternative strategy to enhance resistance to bacterial biothreat agents. Francisella tularensis, Yersinia pestis, Bacillus anthracis, and Burkholderia mallei or pseudomallei can all be easily disseminated via the respiratory route and infections can result in high mortality rates. Therefore, there has been a marked increase in research on immunotherapeutics against these Tier 1 select agents over the last 10 years that will be covered in this review. In addition, immunopotentiation against non-Tier 1 select agents such as Brucella spp., and Coxiella burnetii has also been studied and will be reviewed here. In particular, we will focus on cellular targets, such as toll-like receptors (TLRs), carbohydrate receptors and cytokine receptors, which have been exploited by immunomodulatory regimens that confer broad-spectrum protection against virulent bacterial pathogens.

In Vitro and In Vivo studies of monoclonal antibodies with prominent bactericidal activity against Burkholderia pseudomallei and Burkholderia mallei.

Our laboratory has developed more than a hundred mouse monoclonal antibodies (MAbs) against Burkholderia pseudomallei and Burkholderia mallei. These antibodies have been categorized into different groups based on their specificities and the biochemical natures of their target antigens. The current study first examined the bactericidal activities of a number of these MAbs by an in vitro opsonic assay. Then, the in vivo protective efficacy of selected MAbs was evaluated using BALB/c mice challenged intranasally with a lethal dose of the bacteria. The opsonic assay using dimethyl sulfoxide-treated human HL-60 cells as phagocytes revealed that 19 out of 47 tested MAbs (40%) have prominent bactericidal activities against B. pseudomallei and/or B. mallei. Interestingly, all MAbs with strong opsonic activities are those with specificity against either the capsular polysaccharides (PS) or the lipopolysaccharides (LPS) of the bacteria. On the other hand, none of the MAbs reacting to bacterial proteins or glycoproteins showed prominent bactericidal activity. Further study revealed that the antigenic epitopes on either the capsular PS or LPS molecules were readily available for binding in intact bacteria, while the epitopes on proteins/glycoproteins were less accessible to the MAbs. Our in vivo study showed that four MAbs reactive to either the capsular PS or LPS were highly effective in protecting mice against lethal bacterial challenge. The result is compatible with that of our in vitro study. The MAbs with the highest protective efficacy are those reactive to either the capsular PS or LPS of the Burkholderia bacteria.

Protection from pneumonic infection with burkholderia species by inhalational immunotherapy.

Burkholderia mallei and B. pseudomallei are important human pathogens and cause the diseases glanders and melioidosis, respectively. Both organisms are highly infectious when inhaled and are inherently resistant to many antimicrobials, thus making it difficult to treat pneumonic Burkholderia infections. We investigated whether it was possible to achieve rapid protection against inhaled Burkholderia infection by using inhaled immunotherapy. For this purpose, cationic liposome DNA complexes (CLDC), which are potent activators of innate immunity, were used to elicit the activation of pulmonary innate immune responses. We found that mucosal CLDC administration before or shortly after bacterial challenge could generate complete or nearly complete protection from inhalational challenge with 100% lethal doses of B. mallei and B. pseudomallei. Protection was found to be dependent on the CLDC-mediated induction of gamma interferon responses in lung tissues and was partially dependent on the activation of NK cells. However, CLDC-mediated protection was not dependent on the induction of inducible nitric oxide synthase, as assessed by depletion studies. We concluded that the potent local activation of innate immune responses in the lung could be used to elicit rapid and nonspecific protection from aerosol exposure to both B. mallei and B. pseudomallei.

Bichat guidelines for the clinical management of glanders and melioidosis and bioterrorism-related glanders and melioidosis.

Glanders and melioidosis are two infectious diseases that are caused by Burkholderia mallei and Burkholderia pseudomallei respectively. Infection may be acquired through direct skin contact with contaminated soil or water. Ingestion of such contaminated water or dust is another way of contamination. Glanders and melioidosis have both been studied for weaponisation in several countries in the past. They produce similar clinical syndromes. The symptoms depend upon the route of infection but one form of the disease may progress to another, or the disease might run a chronic relapsing course. Four clinical forms are generally described: localised infection, pulmonary infection, septicaemia and chronic suppurative infections of the skin. All treatment recommendations should be adapted according to the susceptibility reports from any isolates obtained. Post-exposure prophylaxis with trimethoprim-sulfamethoxazole is recommended in case of a biological attack. There is no vaccine available for humans.

Biological and chemical agents: a brief synopsis.

The objective of this article is to provide a concise overview of the most likely biological and chemical agents that could be used as biochemical weapons. The diagnosis, pathology, prevention, decontamination, treatment, and disposition of these biological and chemical agents are presented in a tabular format for quick reference purposes. The information provided outlines the bare essentials needed to deal with any emergency or catastrophic event involving these agents.

[Glanders--an eradicable disease--or a threat?]. / Vozhrivka--eradikovaná nemoc--nebo hrozba?

Glanders (malleus), attacking equids and transmissible to humans, does not occur in our geographical area any more, but world-wide eradication has not yet been achieved. Cases of glanders have been reported from India, Iraq, Mongolia and China and in 2001 also from South America. The disease is caused by Burkholderia mallei (earlied known as Bacillus, Pfeiferella, Loefflerella, Malleomyces, Actinobacillus, or Pseudomonas mallei). The continual interest of microbiologists in the causative agents indicates that glanders cannot be regarded as a closed historic episode. Occupational infections of laboratory personnel occurred during World War II and the years thereafter and the last accident was reported in May 2000. Topical problems of glanders include the development of a vaccine and antibiotic therapy tested in experimentally infected subjects.

[The principles of the therapy of glanders in monkeys]. / Printsipy terapii sapa u obez'ian.

The effect of pathogenetic therapy in the normalization of homeostasis disturbances in monkeys has been shown under experimental conditions. Data on the possibility of using hemosorption in the treatment of severe forms of glanders are presented. The conclusion on the necessity of using complex treatment for the effective therapy of glanders in humans has been made.