CBRNE - Glanders and Melioidosis 

Updated: Jan 17, 2019
Author: Paul P Rega, MD, FACEP; Chief Editor: Duane C Caneva, MD, MSc 

Overview

Practice Essentials

Glanders and melioidosis are related diseases produced by bacteria of the Burkholderia species, which are gram-negative rods. The two diseases have similar symptoms and similar pathophysiologic consequences.

Burkholderia mallei (nonmotile, nonsporulating, obligate aerobic, gram-negative bacillus) is the causative agent of glanders, which is primarily a disease of animals such as horses, mules, and donkeys.[1]  Glanders has been only a rare and sporadic disease in humans, and no epidemics have been reported. In China during World War II, 30% of the tested horses were infected with glanders, but human cases were rare. The reason for the low transmission rate is not known. In the human population, Burkholderia mallei typically is found in persons with close and frequent contact with infected animals, such as veterinarians, animal caretakers, abattoir workers, and laboratory personnel.[2]

Melioidosis, also known as Whitmore disease, is caused by the bacterium Burkholderia pseudomallei (a motile, aerobic, non–spore-forming bacillus).[3]  It is clinically similar to glanders, although the epidemiology differs. The bacteria thrive in tropical climates. The disease is endemic in Southeast Asia and Australia, and is also found in the Middle East, India, and China (essentially tropical areas between latitudes 20 degrees north and south).[4, 5] Sporadic melioidosis cases have been reported in the United States (typically 0-5 cases per year, usually among immigrants and travelers). However, the worldwide incidence appears to be rising as a result of increased travel and epidemiological sophistication. Both humans and other susceptible animals may contract the disease.

Both organisms are considered potential biological warfare agents, especially in the aerosolized form.[6]  Because they are highly infectious by inhalation and resistant to routine antibiotics, both bacteria have been classified as category B priority pathogens by the National Institutes of Health and the Centers for Disease Control and Prevention (CDC).[7]

Patient education resources are available at First Aid and Injuries Center. Also, see patient education articles Biological Warfare and Personal Protective Equipment.

Background

Glanders and melioidosis are of interest because of significant study for potential weaponization by the United States and other countries in the past. During World War I, glanders was believed to have been spread to infect large numbers of Russian horses and mules on the Eastern Front. The Japanese infected horses, civilians, and prisoners of war during World War II. The United States studied this agent as a possible biological warfare (BW) weapon in 1943-1944 but did not weaponize it. The former Soviet Union is believed to have been interested in glanders as a potential BW weapon, as well.

Pathophysiology

Glanders is caused by Burkholderia mallei (formerly Pseudomonas mallei). The bacteria exist only in infected susceptible hosts and are not found in water, soil, or plants. In nature, humans typically acquire glanders from equids via direct contact with broken skin or mucous membranes. While transmission through intact skin has been reported, it is not well documented. A secondary mode of transmission can be through inhalation of droplets from an infected equid or patient.

Once in the host, synthesis and release of certain toxins occur. Usually, the amount is insignificant, and no clinical disease process ensues. However, if a large quantity of the organism is incorporated, the amount of toxin is sufficient to cause specific symptoms. Antibiotics are of little use. The toxins include pyocyanin (blue-green pigment that interferes with the terminal electron transfer system), lecithinase (causes cell lysis by degrading lecithin in certain cell membranes), collagenase, lipase, and hemolysin.

Melioidosis is an infectious disease caused by B pseudomallei (formerly P pseudomallei). The organism is distributed widely in the soil and water of the tropics. It is spread to humans through direct contact with a contaminated source, especially during the rainy season. The disease usually occurs in the fourth and fifth decades of life, especially among those who have chronic comorbidities such as diabetes, alcoholism, immunosuppression, and renal failure.[5]

B pseudomallei is considered a good candidate as a bioweapon because it is easily available in the tropics, it is fairly easy to cultivate, it is sturdy, and it has a high potential to become bacteremic, thereby increasing morbidity and mortality. The incubation period in naturally acquired infections can vary from days to months to years. The incubation period after an aerosol attack is expected to be from 10-14 days.

Glanders and melioidosis produce similar clinical syndromes.

Localized form

Bacteria enter the skin through a laceration or abrasion, and a local infection with ulceration develops. The incubation period is 1-5 days. Swollen lymph glands may develop. Bacteria that enter the host through mucous membranes can cause increased mucus production in the affected areas.

Pulmonary form

When bacteria are aerosolized and enter the respiratory tract via inhalation or hematogenous spread, pulmonary infections may develop. Pneumonia, pulmonary abscesses, and pleural effusions can occur. The incubation period is 10-14 days. With inhalational melioidosis, cutaneous abscesses may develop and take months to appear.

Septicemia

When bacteria is disseminated in the bloodstream in glanders, it is usually fatal within 7-10 days. The septicemia that develops affects multiple systems, and cutaneous, hepatic, and splenic involvement may occur. With melioidosis, bacteremia is observed with chronically ill patients (eg, patients with HIV, patients with diabetes). They develop respiratory distress, headaches, fever, diarrhea, pus-filled lesions on the skin, and abscesses throughout the body. Septicemia may be overwhelming, with a 90% fatality rate and death occurring within 24-48 hours.

Chronic form

The chronic form involves multiple abscesses, which may affect the liver, spleen, skin, or muscles. This form also is known as farcy in glanders disease. Melioidosis, in addition to this chronic form, can become reactive many years after the primary infection.

Epidemiology

Glanders was eliminated from US domesticated animals in the 1940s. One human case of glanders in a laboratory worker occurred in 2000. This is the first human case reported in the United States since 1945.[8]

A few isolated cases of melioidosis have occurred in the United States. Confirmed cases range from 0-5 each year and occur among travelers, immigrants, and intravenous drug users.[9]  From 2008 to 2013, 37 confirmed cases of melioidosis in the United States and Puerto Rico were reported to the CDC's Bacterial Special Pathogens Branch of human infections, including 34 human cases and three animal cases. Among individuals with a documented travel history, 64% of reported cases occurred in those with a travel history to endemic areas. During the study period, two incidents of occupational exposures were reported, and no human infections occurred.[10]

Glanders is endemic in Africa, Asia, the Middle East, Central America, and South America.

Melioidosis is endemic in Southeast Asia and northern Australia. In 2011, melioidosis was diagnosed in six individuals in a desert region of Australia over a 4-month period following unusual heavy rains and flooding.[11] Nevertheless, even in these zones, the diagnosis may be delayed.[12] Melioidosis has also been observed in the South Pacific, Africa, India, the Middle East, Central America, and South America. A case of young boy with laboratory-confirmed melioidosis was reported from Malawi in 2011, and the authors' review of the literature indicates that the number of cases seems to be increasing in Africa.[13]

In India, melioidosis has acquired the status of a newly emerging infectious disease.[14] One study in India involving a series of patients with melioidosis revealed that skin and soft-tissue involvement (16%), liver abscess (16%), and bone and joint involvement (16%) were the most common presentations of this disease in patients with diabetes. Septicemia and major organ failure resulting in death was not uncommon.[15]

Prognosis

The mortality rate in the pulmonary form of glanders is 90-95% if untreated and 40% if treated. The mortality rate in the septicemic form of glanders is greater than 95% if untreated and 50% if treated. The mortality rate in the cutaneous form of glanders is 90-95% if it becomes systemic and if untreated but 50% if properly treated. For the chronic form of glanders, the mortality rate may be 50% despite treatment.

The risk for glanders infection is increased in veterinarians, horse handlers, equine butchers, slaughterhouse workers and laboratory workers exposed to infected animals or infected specimens.[16] ​ 

Melioidosis has had a reported mortality rate up to 90% if disseminated septicemia is present. In Australia, the mortality rate is 19%, whereas in Thailand it is 50%. It is most widespread in Thailand, where in one hospital, it was responsible for 19% of community-acquired sepsis and 40% of deaths from community-acquired septicemia.[17]  

Although healthy people may get melioidosis, the major risk factors are[18] :

  • Diabetes
  • Liver disease
  • Renal disease
  • Thalassemia
  • Cancer or another immune-suppressing condition not related to HIV
  • Chronic lung disease (such as cystic fibrosis, chronic obstructive pulmonary disease, and bronchiectasis)

Possible complications of these diseases include the following:

  • Septicemia
  • Osteomyelitis
  • Meningitis
  • Brain, lung, liver, or splenic abscess
 

Presentation

History

There is nothing specific about the presentation of these diseases and a strong clinical suspicion is required to assist in making a diagnosis in endemic regions. This is particularly true for patients with predisposing comorbidities, such as diabetes mellitus, chronic renal failure, alcoholism or malignancy; those who are immunosuppressed as the result of either diseases or drug treatment; and those living in or with a history of travel to endemic areas. [19]

Glanders

Glanders is primarily zoonotic. It is transmitted to humans through direct skin or mucous membrane contact with infected animal tissues. It may also be inhaled via infected aerosols or dust contaminated by infected animals. No cases of human-to-human transmission have been reported in the United States.[16]

General symptoms of glanders include fever with chills and sweating, muscle aches, chest pain, muscle tightness, headache, nasal discharge and light sensitivity. If there is a cut or scratch in the skin, a localized infection with ulceration may develop within 1 to 5 days at the site where the bacteria entered the body. Swollen lymph nodes may also be present.

Infections involving the mucous membranes in the eyes, nose, and respiratory tract will cause increased mucus production from the affected sites. Dissemination to other locations in the body may occur 1-4 weeks after infection. Glanders often manifests as pulmonary infection with pneumonia, pulmonary abscesses, and pleural effusion. [2]

The chronic form of glanders involves multiple abscesses within the muscles and skin of the arms and legs or in the lungs, spleen, or liver.

Melioidosis

Melioidosis is transmitted to humans through direct skin contact with contaminated soil or water. Ingestion of contaminated water and inhalation of dust contaminated with the organism are other mechanisms of transmission. Cases of human-to-human transmission are rare but have been documented. The time between an exposure to the bacteria and the emergence of symptoms is not clearly defined, but may range from one day to many years; generally symptoms appear two to four weeks after exposure.[18]

There are several types of melioidosis infection, each with their own set of symptoms. Melioidosis can be categorized as an acute or localized infection, acute pulmonary infection, acute bloodstream infection, or disseminated infection. Sub-clinical infections are also possible. The localized form generally presents as an ulcer, nodule, or skin abscess that may result from inoculation through a break in the skin and cause fever and general muscle aches. The infection may remain localized, or may progress rapidly through the bloodstream.

The onset of pulmonary melioidosis is marked by a high fever, headache, anorexia, general muscle soreness and chest pain. The hallmark of pulmonary melioidosis.is a cough with normal sputum.

Disseminated melioidosis presents with abscess formation in various organs of the body, and may be associated with sepsis. Organs involved  include the liver, lung, spleen, and prostate; involvement of joints, bones, viscera, lymph nodes, skin, or brain may also occur. Disseminated infection is seen in acute or chronic melioidosis. Signs and symptoms, in addition to fever, include weight loss, stomach or chest pain, muscle or joint pain, and headache or seizure.

Patients with diabetes and renal insufficiency are more likely to develop a bloodstream infection leading to septic shock. The symptoms include fever, headache, respiratory distress, abdominal discomfort, joint pain, muscle tenderness, and disorientation. This is typically an infection with rapid onset, and abscesses may be found throughout the body, most notably in the liver, spleen, or prostate.[4, 5]

Physical

Physical findings may include fever, cervical adenopathy, hepatomegaly, or splenomegaly, and skin lesions including the following:.

  • Severe urticaria has been reported during primary melioidosis

  • During septicemia, flushing, cyanosis, and a disseminated pustular eruption can be seen. Pustules often are associated with regional lymphadenitis, cellulitis, or lymphangitis

  • Rarely, ecthyma gangrenosum–like lesions and cutaneous abscesses (that sometimes ulcerate) may develop

Specifically, in melioidosis septicemia, high fevers and rigor are present. These findings may be accompanied by confusion, dyspnea, abdominal pain, muscle tenderness, pharyngitis, diarrhea, and jaundice. While the typical foci in these severe cases begin from the skin or the lungs, metastasis (liver, spleen, kidney, brainstem, parotid gland) will occur, leading to acidosis, shock, and death within 48 hours of presentation.[4, 5]

Causes

Glanders is primarily zoonotic. It is rare in humans, and no epidemics have been reported. Human cases of glanders have occurred primarily in occupational settings and include laboratorians, veterinarians, and animal caretakers.

Human cases of melioidosis have been transmitted via sexual contact and intravenous drug use. The disease has been observed in immigrants, military personnel, and travelers.  Diabetes is considered as an important risk factor.[4]

Physical Examination

A recent review of melioidosis in Malaysia revealed the major findings on clinical exam:

Pneumonia and soft tissue abscesses were the most prominent findings.  [4]  

Complications

For melioidosis:  Septic shock, abscesses of the liver, spleen, and prostate, and death

 

DDx

Diagnostic Considerations

Melioidosis has a wide range of signs and symptoms that can be mistaken for other forms of pneumonia.[18]  Melioidosis can cause granulomatous legions which can make differentiating it from tuberculosis.[6]

Differential Diagnoses

 

Workup

Approach Considerations

The laboratory should be alerted when a diagnosis of glanders or melioidosis is suspected. Some automated culture systems may misidentify B pseudomallei as Psuedomonas spp.[6] Although clinical diagnostic laboratories functioning at Biosafety Level 2 (BSL-2) may isolate B. pseudomallei and B. mallei from patient specimens, once B. pseudomallei or B. mallei is suspected, work should be transfered to a BSL-3 facility.[18, 16]

Regarding human glanders, imaging may reveal abscesses in the lungs, liver and spleen.  Studies into the validation of serologic tests for glanders is largely experimental.[2]

 

Laboratory Studies

Basic laboratory tests include complete blood cell count (CBC) and liver function studies. The CBC may reveal a mild leukocytosis with a left shift or leukopenia. With glanders, the white blood cell count (WBC) is often normal or minimally elevated. Elevated liver enzyme levels in glanders may signify hepatic abscess formation. In melioidosis specifically, laboratory studies may demonstrate anemia, leukocytosis, hepatic impairment, renal insufficiency, and coagulopathy.

Microbiology

Gram stain may reveal small, gram-negative bacilli, which stain irregularly with methylene blue or Wright stain, and they may demonstrate a safety pin bipolar appearance. The organisms can be cultured from abscesses, secretions, sputum, blood and urine with standard media. Primary isolation requires 48 to 72 hours. Another useful culture medium for isolation of B pseudomallei  from non-sterile sites (sputum, pharynx swabs) is Ashdown's selective medium.[6]

Blood culture results for B mallei are often negative, while blood cultures for B pseudomallei often positive and positive urine cultures can indicate prostatitis or renal abscesses.  In septicemic melioidosis, blood culture results may be negative until just before death. Meat nutrient agar or the addition of 1-5% glucose may accelerate growth of bacteria. 

Polymerase chain reaction (PCR) assays are rapid and spedific but may be less sensitive than cultures. 

Methods for detecting and differentiating the B. pseudomallei complex has been under investigation due to phenotypic and genotypic similarities of these species. Although B. thailandensis and B. oklahomensis are generally avirulent, both display similar phenotypic characteristics to that of B. pseudomallei.  Real-time PCR assays have been developed but require multiple real-time PCR reactions in order to correctly identify B. pseudomallei, B. mallei, and B. thailandensis.  A multiplex PCR assay is under development that can specifically detect and differentiate between B. mallei, B. pseudomallei, and B. thailandensis in a single-tube format.1722 [4, 5]

Serologic tests

Serologic tests are of limited value, particularly in endemic areas where seroprevalence is high. Indirect hemagglutination tests are the most frequently used serologic assay in endemic regions but are poorly standardized. 

For B. mallei, agglutination test results may be positive after 7-10 days, but a high background titer found in normal sera makes interpretation difficult. Complement fixation (CF) tests are more specific, but less sensitive, and may require 40 days for conversion. CF is considered positive if the titer is 1:20 or greater. A 4-fold increase in the titer supports diagnosis of B. pseudomallei.[6]

 

Imaging Studies

Chest radiography may demonstrate bilateral bronchopneumonia, miliary nodules, segmental or lobar infiltrates, and cavitating lesions. With melioidosis, an abnormal chest radiography finding is present in up to 80% of patients (usually diffuse nodular shadowing).[4]

Abdominal and pelvic ultrasound, CT or MRI may reveal abscesses in the spleen, liver and/or prostate.{ref323-INVALID REFERENCE}

Bone and soft tissue musculoskeletal involvement may be seen with plain radiographs and magnetic resonance imaging. These findings are consistent with disseminated melioidosis.[19]

 

Treatment

Approach Considerations

Use standard precautions (ie, use of disposable surgical masks, face shields, and gowns when appropriate) to prevent human-to-human transmission of glanders and melioidosis.

Emergency Department Care

Implement barrier protection with secretion precautions. While person-to-person transmission is unlikely, isolation rooms for these patients are advisable. Patients should be masked to prevent droplet dissemination. Current practices to disinfect and sterilize patient-care equipment and environmental surfaces are sufficient for managing areas where glanders and melioidosis patients are evaluated, admitted, and treated.[18, 16]

Obtain radiography, and collect blood, urine, sputum, and skin lesion fluid.

Initiate rapid administration of supportive care and intravenous antibiotic therapy for severe disease. Ventilatory support may be needed for patients with severe pneumonia.  Septicemia requires agressive care including fluid resuscitation, vasopressors and management of coagulopathy.[6]

Consultations

Glanders and melioidosis are reportable diseases; notify local health authorities of suspected cases. The occurrence of glanders in the absence of animal attack, occupational exposure, and/or in an epidemic is presumptive evidence of a biological warfare attack. Consultation with an infectious disease specialist, the Centers for Disease Control and Prevention, and the Federal Bureau of Investigation may be warranted.

Medical Care

Limited information exists about antibiotic therapy for glanders and melioidosis in humans because clinical studies examining antibiotic effectiveness in vivo are rare. All patients, regardless of severity, will need an antibiotic treatment regimen. Treatment consists of an intravenous (IV) therapy for a minimum of 10 to 14 days until there is clinical improvement. This phase of treatment may last up to 4 to 8 weeks for critical illness, severe pulmonary disease, deep abscesses, bone, joint or CNS involvement. Oral eradication therapy follows and lasts 3 to 6 months.[18, 6] {ref13222324-INVALID REFERENCE}

Intravenous therapy consists of ceftazidime administered every 6-8 hours or meropenem administered every 8 hours.[18, 6, 16]  Meropenem is advised for patients with CNS involvement. A switch to meropenem is also indicated if there are positive blood cultures after 7 days of treatment or clinical deterioration at any time with ceftazidime therapy. Fever may persist and does not indicate treatment failure.[6]  

Oral eradication therapy consists of trimethoprim-sulfamethoxazole (TMP-SMX) or doxycycline taken every 12 hours.[18, 6, 16]

 

The prevention of relapse in melioidosis is critical since it has been reported to occur in 23% of cases. Hence, the rationale behind the prolonged therapy. Other antibiotics with activity against Burkholderia pseudomallei include ceftriaxone, ticarcillin-sulbactam, and aztreonam.

Currently, no proven preexposure or postexposure prophylaxis is available. Postexposure prophylaxis with TMP/SMX may be attempted. No vaccine is available for human glanders or melioidosis.

Investigational therapy

BAL 30072, an investigational intravenously administered monosulfactam antibiotic, shows excellent activity against B pseudomallei.[20] Antibiotics represent only one aspect of research into therapy for glanders and melioidosis, however, since these disease entities have demonstrated resistance to the more traditional antimicrobial regimens. Another promising avenue of therapy is inhalational immunotherapy with cationic liposome DNA complexes (CLDC). These complexes are potent activators of innate immunity within the pulmonary system, which makes this modality an attractive approach to inhalational exposure to these bacteria.[21]

Surgical Care

Large abscesses and empyemas should be drained. Prostatic and parotid abscesses in melioidosis may require surgical intervention. Small absesses in the spleen or liver usually respond to prolonged antibiotic therapy.[6]  

Prevention

Biosafety level 3 containment practices are required for laboratory staff when working with cases of glanders and melioidosis.

In countries where glanders is endemic in animals, identification and elimination of the disease in the animal population prevents disease in humans.[16]

In areas where melioidosis is endemic, persons who have chronic illnesses that lead to an immunocompromised state should avoid contact with soil and standing water. Wearing boots and gloves during agricultural work is advised.[18]

No vaccine is available for glanders or melioidosis. Because of the disease's resistance to multiple antibiotics (ie, beta-lactams, aminoglycosides, macrolides, polymixins) and the frequency of relapses (13-26%), the research for a viable vaccine continues and a wide range of proteins and polysaccharides have been identified which protective immunity in mice. Several live attenuated and subunit vaccine formulations have been evaluated in animal studies but development of effective vaccines against these bacteria remain in preclinical stages.[22, 23]

 

Medication

Medication Summary

Limited information exists about antibiotic therapy for glanders and melioidosis because clinical studies examining antibiotic effectiveness in humans are rare. In general, these diseases show poor responsiveness to traditional antimicrobial regimens and require prolonged therapy.[2, 4, 5]

Because human glanders is so infrequent, efficacious antibiotic therapy is largely limited.  No treatment regimen is FDA-approved, but anecdotal regimens have included imipenem, meropenem, ceftazidime with or without TMX/SMX. [2]

Antibiotics

Class Summary

Base choice of antibiotic and route of administration on the clinical setting.

Meropenem (Merrem IV)

Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gram-negative bacteria.

Has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem.

Imipenem and cilastatin (Primaxin)

For treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to potential for toxicity.

Ceftazidime (Fortaz)

Bactericidal, exerting effect by inhibition of enzymes responsible for cell wall synthesis.

Tetracycline (Minocin)

Primarily bacteriostatic and believed to exert antimicrobial effect by inhibition of protein synthesis.

Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS, Septra, Septra DS)

SMX inhibits bacterial synthesis of dihydrofolic acid by competing with PABA. TMP blocks production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase; thus, it blocks 2 consecutive steps in biosynthesis of nucleic acids and proteins essential to many bacteria.

Amoxicillin and clavulanate (Augmentin)

Semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Susceptible to degradation by beta-lactamases, and, thus, spectrum of activity does not include organisms that produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to penicillins, which possesses ability to inactivate a wide range of beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. Formulation of amoxicillin and clavulanic acid protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other beta-lactam antibiotics. Possesses properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor.

Streptomycin

Aminoglycoside antibiotic recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.