Dermatology

Glanders (Farcy, Burkholderia mallei infection, equinia, malleus)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Burkholderia malleli is able to cause two forms of human infection. Farcy is a subcutaneous form of the bacterial infection that presents with small papules and pustules at the site of skin inoculation. These quickly become subcutaneous nodules and fistulae with draining sinuses to the surface of the skin. Ulcerations form with a thick, sticky purulent surface. Localized tender lymphadenopathy is present.

Farcy typically occurs within the first week of exposure. Episodes of farcy can occur for weeks with associated constitutional symptoms. Farcy has been shown to spread via the lymphatics, and areas of ulcerations will erode through the overlying skin. These ulcerations have been termed farcy buds, which appear as nodules along a cord following the lymphatic drainage.

This form of the disease (farcy) will eventually disseminate hematagenously and cause glanders. Glanders is a life-threatening infection of the pulmonary system.

Veterinarians and animal handlers, especially those that work with the equine family of animals, including horses, mules, and donkeys, are at the highest risk of exposure and developing the disease. Horses, donkeys and mules can have cutaneous, mucosal, and respiratory disease.

Characteristic findings on physical examination

An increase in the production of mucous secretions is often the first sinopulmonary finding. It can rapidly cause necrosis of the bronchi and alveoli, leading to respiratory arrest.

Respiratory symptoms include dyspnea, shortness of breath, hemoptysis, and eventually an inability for the infected individual to ventilate properly. This causes a decrease in blood oxygenation level, which leads to death. On average, death occurs in 10 days. Glanders can also be caused by direct inhalation of the bacteria from nasal or mucosal secretions of an infected animal.

Inhalation of the organism can cause severe pneumonia and septicemia in a matter of days. The organism is highly infective and infection of the host only requires a a small number of bacteria.

Expected results of diagnostic studies

Culture results from skin lesions, abscesses, and respiratory aspirates will grow the gram-negative rod Burkholderia mallei. Computed tomography (CT) scans are nonspecific, but may show abscess formation in the liver, spleen, lung, or other tissues. This bacterium does not stain with acid fast stains and is a non-spore-forming rod. The organism is a nonmotile, slow-growing bacterium that does not produce pigment when cultured. There is no commercially available serological test.

Who is at Risk for Developing this Disease?

Glanders is an exceedingly rare condition, with only one documented case occuring in a human since 1967. in a laboratory worker). The last case of naturally acquired glanders in the United States was in the early 1950s.

The most recent case of glanders (in 2000) was diagnosed in a laboratory worker that was working with the Burkholderia mallei bacterium. If an outbreak of glanders were to occur, immediate consultation with the Centers for Disease Control (CDC) and the local Federal Bureau of Investigation (FBI) should be performed. The potential use of glanders as a biological weapon of mass destruction is a small possibility in today’s world.

Glanders is almost exclusively a disease of horses, donkeys, and mules, but it has been reported in lions and other carnivores that eat infected meat. Those individuals who directly come in contact with horses are most at risk for developing the disease. Horse handlers, breeders, veterinarians, jockeys, and other stable personal are at the highest risk.

Breaks in the cutaneous skin barrier, such as an abrasion or cut, may increase the risk of bacterial infection. The disease is still seen in horses in the Middle East, Central and South America, parts of Asia, and Africa. People living in these areas are at the highest risk.

There is no effective vaccine for glanders, but the disease was essentially wiped off the face of the Earth through veterinary use of the mallein skin test. If an animal tests positive, it is euthanized.

The use of Burkholderia mallei as a biological weapon of mass destruction is a concern. If these bacteria were to be weaponized in a aerosol form, and if the strain were resistant to antibiotics, they would have a devastating effect. It is for this reason that any cases of this disease need to be promptly reported to the CDC and the FBI. It should be noted that the one case diagnosed in 2000 was from a military research laboratory working with this bacterium.

What is the Cause of the Disease?

Glanders is caused by the zoonotic gram-negative nonencapsulated nonmotile aerobic bacterium, Burkholderia mallei. This bacterium has had many changes in its name over time and has been variously referred to as Pseudomonas mallei, Bacillus mallei, Pfeifferella mallei, Loefflerella mallei, Malleomyces mallei, and Actinobacillus mallei.

This organism needs a mammalian host to survive and has not been found to survive long outside a host. It is not a soil organism.

Systemic Implications and Complications

This disease is fatal in 95% of cases if untreated, and in 50% of cases when treated with traditional single-agent antibiotic therapy. The disease kills within 10 days.

Treatment Options

No thoroughly studied therapies exist. Before the use of antibiotics, 95% of cases were fatal; 50% of cases are fatal with traditional antibiotics. The newer antibiotic treatments may or may not be better.

Treatment options are summarized in Table I.

Table I.

Therapeutic ladder for treatment of glanders.
Medical Surgical Physical
Treatment should be based on culture and sensitivities Drain abscess and debride infected necrotic tissue Supportive intensive care, isolation
Doxycycline 100mg orally, twice daily, with imipenem 0.5g-1.0g every 6 hours    
After the patient stabilizes, replace the imipenem with azithromycin 250mg daily, and continue with the doxycycline 100mg, twice daily, for 6 months    
Sulfadiazine 25mg/kg intravenous, four times daily    

Optimal Therapeutic Approach for this Disease

There is no optimal therapeutic approach to this disease, as it is so rare. Animals with the disease are quickly euthanized and the carcasses disposed of properly to prevent the disease’s spread. The treatment regimen using doxycycline and imipenem, and later changing to doxycylcine and azithromycin for 6 months, as outlined in the New England Journal of Medicine article, is a prudent choice. No resistance to these antibiotics was found in the paper by Thibault et al.

Contact information for reporting any cases of glanders is as follows:

CDC

1-770-488-7100. This is the emergency-only line.

All other calls to the CDC should go to: 1-800-CDC-INFO

CDC Division of Bioterrorism: 1-404-639-0385

Website: www.CDC.gov

FBI

1-800 CALLFBI (225-5234)

Patient Management

Patients should be followed up for resolution of their pulmonary symptoms, as well as for resolution of any abscess formation. After the patient is stabilized and well enough to be discharged from the hospital, the combination oral antibiotic therapy should be continued for 6 months. Follow-up should be coordinated with an infectious disease specialist.

Unusual Clinical Scenarios to Consider in Patient Management

As this is such a rare disease, an outbreak of cases should make one suspicious of a Bioterrorism attack.

Individuals that work with horses and related animals are the most likely to be infected, especially if they are from a region of the world where glanders still exists.

This disease should not be confused with melioidosis. Melioidosis is caused by Burkholderia pseudomallei, and is endemic in Northern Australia and South Asia.

What is the Evidence?

Srinivasan, A, Kraus, CN, DeShazer, D. "Glanders in a military research microbiologist". N Eng J Med. vol. 345. 2001. pp. 256-8.

(The most recent and only report of a glanders diagnosis in the United States in almost 40 years. The infected individual was a military laboratory worker that was researching Burkholderia mallei, and was treated with doxycycline and imipenem.)

Larsen, JC, Johnson, NH. "Pathogenesis of Burkholderia pseudomallei and Burkholderia mallei". Mil Med. vol. 174. 2009. pp. 647-51.

(Discusses in detail the military significance of these two organisms. It details the genomics and virulence determinants of these bacteria.)

Sarkar-Tyson, M, Smither, SJ, Harding, SV. "Protective efficacy of heat-inactivated B. thailandensis, B. mallei or B. pesudomallei against experimental melioidosis and glanders". Vaccine. vol. 27. 2009. pp. 4447-51.

(State-of-the-art research on the work being performed to develop a vaccine for these three organisms)

Judy, BM, Whitlock, GC, Torres, AG. "Comparison of the in vitro and in vivo susceptibilities of Burkholderia malleli to ceftazidime and levofloxacin". BMC Microbiol. vol. 9. 2009. pp. 88.

(This paper evaluated the use, in vitro, of ceftazidime and levofloxacin in killing Burkholderia mallei. Both agents worked well in vitro.)

Rosenbloom, M, Leikin, JB, Vogel, SN. "Biological and chemical agents: a brief synopsis". Am J Ther. vol. 9. 2002. pp. 5-14.

(A nice review of all potential biological agents that can be used as weapons of mass destruction. Good charts that go through each organism with diagnosis, pathology, prevention, and treament.)

Dvorak, GD, Spickler, AR. "Glanders". J Am Vet Med Assoc. vol. 233. 2008. pp. 570-7.

(An overall thorough review of the disease. A must-read for those with an interest in this disease.)

Thibault, FM, Hernandez, E, Vidal, DR. "Antibiotic susceptibility of 65 isolates of Burkholderia pseudomallei and Burkholderia mallei to 35 antimicrobial agents". J Antimicrob Chemother. vol. 54. 2004. pp. 1134-8.

(Fifteen isolates of Burkholderia mallei were exposed to thirty-five unique antibiotics in vitro. One hundred percent of the bacteria were resistant to clindamycin, fosfomycin, norfloxacin, and ticarcillin. Many agents showed no resistance and theoretically could be used in clinical practice.)

Whitlock, GC, Estes, DM, Torres, AG. "Glanders: off to the races with Burkholderia mallei". FEMS Microbiol Rev. vol. 277. 2007. pp. 115-22.

(One of the best reviews of glanders. Excellent discussion on the pathogenic determinants and host immune response.)

Whitlock, GC, Lukaszewski, RA, Judy, BM. "Host immunity in the protective response to vaccination with heat-killed Burkholderia mallei". BMC Immunol. vol. 9. 2008. pp. 55.

(This paper detailed the use of a mouse model to begin to develop a vaccine for Burkholderia mallei. It is postulated that IFN-gamma and TNF- alpha are both required to mount a response to the vaccine.)
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