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GLANDERS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Glanders is a specific and contagious disease of solipeds (horses, donkeys, and mules). Humans may also become infected through contact with diseased animals, laboratory accidents, and intentional aerosol dispersement in terrorist attacks. The causative bacteria, Burkholderia mallei (formerly Pseudomonas mallei) is an aerobic, gram-negative, non-spore forming bacilli. It is classified as a Biosafety Level 3 agent. As a critical biological agent, the Centers for Disease Control (CDC) classifies Burkholderia mallei as Category B (second highest priority agents that are moderately easy to disseminate; cause moderate morbidity and low mortality; and require specific enhancements of CDC's diagnostic capacity and enhanced disease surveillance).

Specific Substances

    1) Bacillus mallei
    2) Burkholderia mallei
    3) Farcy
    4) Malleomyces mallei
    5) Pseudomonas mallei

Available Forms Sources

    A) FORMS
    1) Glanders is an airborne bacterial disease first described by Aristotle in 330 B.C. It is usually spread by flies to solipeds ((Anon, 1998)).
    B) SOURCES
    1) The causative organism of glanders exists in nature only in infected susceptible hosts and is not found in water, soil, or plants (CDC, 1999).
    C) USES
    1) Because aerosol spread is efficient, and there is no available vaccine or dependable drug therapy, glanders has been viewed as a potential biological warfare (BW) or terrorist threat, with aerosol release as the primary means of spreading the organism ((Anon, 2000)). In the absence of animal contact and/or in a human epidemic form, the occurrence of glanders is indicative of a BW attack (CDC, 1999).
    2) Documented use of glanders as a biological warfare agent is reported in both World Wars I and II, with deliberate inoculation of horses and mules to deter troops on the Eastern Front (Wheelis, 1998), and in World War II with deliberate inoculation of human prisoners (CDC, 1999).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: Glanders is a disease caused by the bacterium Burkholderia mallei, an aerobic, gram-negative non-spore forming bacillus. It primarily affects horses, but can also present in mules, donkeys and other mammals including humans, dogs, cats and goats.
    B) TOXICOLOGY: Burkholderia mallei naturally exists only in infected, susceptible hosts and is not found in water, soil or plants. Clinical manifestations of glanders can vary greatly, from an asymptomatic state to pneumonia, cutaneous glanders, or an overwhelming septicemia. Transmission to humans occurs through contact of tissue or body fluids of infected animals.
    C) EPIDEMIOLOGY: Glanders is extremely rare in humans. There have been no cases of glanders in the United States since the 1940s. However, sporadic cases of glanders still occur in much of the world, including Africa, Asia, the Middle East, Central America and South America. Although human epidemics have not been reported, B mallei has been used in isolated outbreaks as a biological weapon.
    D) WITH POISONING/EXPOSURE
    1) ADVERSE EFFECTS: Glanders may occur in the following 3 forms in humans: an acute localized form, as a septicemic rapidly fatal illness, or as an acute pulmonary infection. Combinations of these symptoms commonly occur. In addition, a chronic cutaneous form with lymphangitis and regional adenopathy can occur.
    a) Incubation period: Acute form of disease: 1 to 14 days; chronic form of disease: up to 12 weeks.
    b) Following an incubation period of 10 to 14 days after an inhalational exposure, fever, chills, sweats, myalgia, headache, pleuritic chest pain, cervical adenopathy, splenomegaly and generalized papular/pustular eruptions may occur and is almost always fatal without treatment. The disease often manifests as pneumonia.
    c) Cutaneous inoculation may result in localized infection with nodule formation and lymphadenitis. A localized infection typically occurs 1 to 5 days after exposure and can be characterized by swelling at the site and a weeping discharge.
    d) Mucous membrane infection may result in the production of a mucopurulent discharge from the eyes, nose, or lips, with the subsequent development of granulomatous ulcers.
    e) Chronic suppurative infection may present as multiple subcutaneous and intramuscular abscesses, often involving the extremities. Visceral lesions may be documented in some patients. Recovery may occur, or the disease may erupt into an acute septicemic form.
    f) An acute septicemic glanders may be associated with a diffuse papular or pustular eruption, severe systemic symptoms, and early death. Diarrhea and abdominal pain are commonly reported during the initial onset of septicemic glanders.
    0.2.3) VITAL SIGNS
    A) Increased heart rate and body temperature may be seen.
    0.2.4) HEENT
    A) Lacrimation is an early presenting sign in septicemic forms of the disease. Photophobia has been reported in cases of systemic glanders. Systemic invasion may occur via mucosal lesions.

Laboratory Monitoring

    A) No specific studies are needed for most patients - tests should be directed towards a patient's symptoms.
    B) A CBC may reveal a mild leukocytosis with a left shift or a leukopenia.
    C) A chest radiograph may reveal miliary lesions, small multiple lung abscesses, or bronchopneumonia. Radiography can also identify abscesses in the liver and spleen but are not diagnostic.
    D) Diagnostic procedures for glanders may include methylene blue stain or exudates which may reveal secant small bacilli. Burkholderia mallei organisms can be cultured from infected secretions using meat nutrients, although cultures are usually negative until the patient is moribund.
    E) Laboratory workers should use biosafety level 3 containment practices when working with this organism.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUPPORT
    1) Although glanders has been rarely reported in carnivores that have fed on infected horse carcasses, NO human cases of glanders from ingestions have been reported.
    2) In the unlikely event of glanders developing via ingestion in humans, treatment recommendations in the INHALATION EXPOSURE section should be followed.
    0.4.3) INHALATION EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care and appropriate antibiotic therapy are the mainstay of treatment. Strict contact precautions should be maintained. Post-exposure prophylaxis may be considered with antibiotics such as trimethoprim-sulfamethoxazole. For localized disease with mild toxicity, treatment for 60 to 150 days with amoxicillin-clavulanate, tetracyclines, and/or trimethoprim-sulfamethoxazole is reasonable. For extrapulmonary suppurative disease, administer antibiotics as above for 6 to 12 months. Surgical drainage of abscesses is also indicated.
    2) ANTIBIOTIC THERAPY: Antibiotic therapy is the mainstay of treatment. Localized glanders has been reported to be sensitive to amoxicillin/clavulanate, tetracyclines, or cotrimoxazole. Bacteremia secondary to glanders are usually susceptible to tetracyclines, ciprofloxacin, streptomycin, novobiocin, gentamicin, imipenem, ceftazidime, and sulfonamides. In addition, sulfadiazine has been found to be effective in experimental animals and humans. Antibiotics are given for at least 30 days in uncomplicated infections and up to 6 months in complicated cases. Other treatment is symptomatic and supportive. No vaccine against B. mallei infection is available.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care and appropriate antibiotic therapy are the mainstay of treatment. Strict contact precaution should be maintained. Mortality may be high even with antibiotic treatment. For severe toxicity or patients with sepsis, treat with IV ceftazidime combined with IV trimethoprim-sulfamethoxazole for 2 weeks, followed by oral therapy for 6 months. Alternative regimens include streptomycin plus a tetracycline or streptomycin plus chloramphenicol.
    C) DECONTAMINATION
    1) PREHOSPITAL: There is no evidence for the use of activated charcoal. Standard decontamination measures should be used for dermal and eye exposures with irrigation of exposed surfaces with water.
    2) HOSPITAL: There is no evidence for the use of activated charcoal, gastric lavage or whole bowel irrigation.
    D) ANTIDOTE
    1) There is no specific antidote for glanders but many different antibiotics can be used for treatment.
    E) AIRWAY MANAGEMENT
    1) In cases of airway compromise, supportive measures including endotracheal intubation and mechanical ventilation may be necessary.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Home care is not recommended in suspected cases of glanders.
    2) ADMISSION CRITERIA: All patients with suspected glanders should be admitted to the hospital for further observation, treatment, and isolation to prevent further spread. Standard precautions should be applied in the management of patients and contacts. Glanders may present with diffuse pustular rashes; strict isolation and quarantine is indicated until smallpox can be excluded. Use contact precautions while caring for patients with skin involvement.
    3) CONSULT CRITERIA: Infectious disease consultants should be involved in any cases. State health departments should be notified as well as the Centers for Disease Control. Critically ill patients may require the services of a hospital intensivist.
    G) PITFALLS
    1) Since glanders is so rare, the diagnosis can be easily missed as many other infectious diseases can mimic the clinical manifestations of glanders. It has been considered as a potential bioweapon.
    H) PREDISPOSING CONDITIONS
    1) Occupations that are more likely to be exposed to glanders include veterinarians, horse caretakers, equine butchers, and lab workers.
    I) DIFFERENTIAL DIAGNOSIS
    1) Clinical manifestations of glanders can be caused by many other infectious diseases that can cause cutaneous manifestations (eg, smallpox), pneumonias, or septicemia.
    0.4.4) EYE EXPOSURE
    A) SUPPORT
    1) Mucocutaneous exposures to blood, body fluids, secretions, or excretions from patients with suspected glanders infections should be immediately rinsed with copious amounts of water or eyewash solution.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) SUPPORT
    a) Cutaneous inoculation may result in localized infection with nodule formation and lymphadenitis, and possible bacteremia and splenic and hepatic abscesses. Follow treatment recommendations in the INHALATION EXPOSURE section as appropriate.

Range Of Toxicity

    A) TOXICITY: As few as 1 to 10 organisms administered via aerosol transmission to hamsters is lethal. There is no specific information describing a toxic dose in humans.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Glanders is a disease caused by the bacterium Burkholderia mallei, an aerobic, gram-negative non-spore forming bacillus. It primarily affects horses, but can also present in mules, donkeys and other mammals including humans, dogs, cats and goats.
    B) TOXICOLOGY: Burkholderia mallei naturally exists only in infected, susceptible hosts and is not found in water, soil or plants. Clinical manifestations of glanders can vary greatly, from an asymptomatic state to pneumonia, cutaneous glanders, or an overwhelming septicemia. Transmission to humans occurs through contact of tissue or body fluids of infected animals.
    C) EPIDEMIOLOGY: Glanders is extremely rare in humans. There have been no cases of glanders in the United States since the 1940s. However, sporadic cases of glanders still occur in much of the world, including Africa, Asia, the Middle East, Central America and South America. Although human epidemics have not been reported, B mallei has been used in isolated outbreaks as a biological weapon.
    D) WITH POISONING/EXPOSURE
    1) ADVERSE EFFECTS: Glanders may occur in the following 3 forms in humans: an acute localized form, as a septicemic rapidly fatal illness, or as an acute pulmonary infection. Combinations of these symptoms commonly occur. In addition, a chronic cutaneous form with lymphangitis and regional adenopathy can occur.
    a) Incubation period: Acute form of disease: 1 to 14 days; chronic form of disease: up to 12 weeks.
    b) Following an incubation period of 10 to 14 days after an inhalational exposure, fever, chills, sweats, myalgia, headache, pleuritic chest pain, cervical adenopathy, splenomegaly and generalized papular/pustular eruptions may occur and is almost always fatal without treatment. The disease often manifests as pneumonia.
    c) Cutaneous inoculation may result in localized infection with nodule formation and lymphadenitis. A localized infection typically occurs 1 to 5 days after exposure and can be characterized by swelling at the site and a weeping discharge.
    d) Mucous membrane infection may result in the production of a mucopurulent discharge from the eyes, nose, or lips, with the subsequent development of granulomatous ulcers.
    e) Chronic suppurative infection may present as multiple subcutaneous and intramuscular abscesses, often involving the extremities. Visceral lesions may be documented in some patients. Recovery may occur, or the disease may erupt into an acute septicemic form.
    f) An acute septicemic glanders may be associated with a diffuse papular or pustular eruption, severe systemic symptoms, and early death. Diarrhea and abdominal pain are commonly reported during the initial onset of septicemic glanders.

Vital Signs

    3.3.1) SUMMARY
    A) Increased heart rate and body temperature may be seen.
    3.3.3) TEMPERATURE
    A) Fever and rigors are common. Sudden onset of fever is an initial sign in the septicemic form of glanders (CDC, 1999; (Anon, 2000); Gaiger, 1913; Stewart, 1904; Howe & Miller, 1947).
    3.3.5) PULSE
    A) Elevated pulse rate may occur in early stages of septicemic glanders (CDC, 1999).

Heent

    3.4.1) SUMMARY
    A) Lacrimation is an early presenting sign in septicemic forms of the disease. Photophobia has been reported in cases of systemic glanders. Systemic invasion may occur via mucosal lesions.
    3.4.3) EYES
    A) Lacrimation is an early presenting sign in septicemic forms of the disease (CDC, 1999; Howe & Miller, 1947).
    B) Photophobia has been reported in cases of systemic glanders (CDC, 1999; Howe & Miller, 1947).
    C) Acute infection of the conjunctival mucosa may result in mucopurulent discharge. Systemic invasion may occur via mucosal lesions (CDC, 1999).
    3.4.5) NOSE
    A) Acute infection of the nasal mucosa may be characterized by inflammation and swelling of the nose and can be followed by mucopurulent, blood streaked discharge from the nose. Infection may be associated with septal and turbinate nodules and granulomatous ulcerations (Van Zandt et al, 2013; CDC, 1999; Pollack, 1994).
    B) Chronic infection may exhibit nasal discharge and ulceration in approximately 50% of cases (CDC, 1999).
    3.4.6) THROAT
    A) Acute oral infection may result in ulcerations of the mouth and throat as well as cutaneous lesions which may become papular and/or pustular. Mucopurulent discharge may occur from the lips (CDC, 1999; Pollack, 1994).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Physical examination may commonly reveal tachycardia, particularly in early stages of the septicemic form of glanders (CDC, 1999; Howe & Miller, 1947).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension could occur in severe, progressive cases of septicemic glanders.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE OF LUNG
    1) WITH POISONING/EXPOSURE
    a) A pulmonary infection secondary to glanders exposure can result in pneumonia, pulmonary abscess, pleuritis, and pleural effusion. Symptoms can include cough, dyspnea, chest pain and mucopurulent sputum. Nonspecific symptoms can include: fatigue, fever, chills, headache, myalgias, lymphangitis, sore throat, pleuritic chest pain, and gastrointestinal symptoms. It may take up to 2 to 3 weeks for symptoms to occur following exposure (Van Zandt et al, 2013). A chest x-ray will show localized infection in the lobe of the lung (Centers for Diseas Control and Prevention, 2011)
    B) PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) The pulmonary form of glanders may occur following inhalation of organisms or by hematogenous spread. Chest x-ray often shows miliary nodules (0.5 to 1.0 cm) and/or a bilateral bronchopneumonia, segmental, or lobar pneumonia and necrotizing nodular lesions. Pneumonia may be present with or without bacteremia (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999; Howe & Miller, 1947). Lung abscesses appear in the early stages, before cavitation and necrosis (Howe & Miller, 1947).
    C) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Respiratory distress, often requiring mechanical ventilatory support, may occur, particularly when bacteremia or the pulmonary form is present (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999).
    b) CASE REPORT/LABORATORY EXPOSURE: Progressive respiratory failure requiring mechanical ventilation was reported in a laboratory worker exposed to B. mallei. Illness was likely due to percutaneous exposure through microabrasions of the skin (the individual admitted to not wearing latex protective gloves at all times). The patient recovered following antibiotic therapy (included: imipenem, doxycycline and azithromycin) (Srinivasan et al, 2001).
    D) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Pleuritic chest pain is a common symptom of the septicemic or pulmonary form of glanders (CDC, 1999; Gaiger, 1913; Stewart, 1904; Howe & Miller, 1947).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Following inhalation and a 10- to 14-day incubation period, headache, sometimes severe, and fatigue are common presenting symptoms (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999; Stewart, 1904; Howe & Miller, 1947).
    B) MENINGITIS
    1) WITH POISONING/EXPOSURE
    a) Rarely, chronic cases of glanders may evolve into osteomyelitis, brain abscess, and meningitis (CDC, 1999).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea and abdominal pain are commonly reported during the initial onset of septicemic glanders (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999).
    B) SPLENOMEGALY
    1) WITH POISONING/EXPOSURE
    a) Physical examination often reveals a mild splenomegaly (CDC, 1999; Pollack, 1994; Howe & Miller, 1947).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABSCESS
    1) WITH POISONING/EXPOSURE
    a) Hepatic and splenic involvement may occur following exposure to B. mallei. Splenomegaly may be common. Abdominal CT has shown multiple hepatic and splenic lesions consistent with abscesses. Cultures of the abscess fluid should reveal B. mallei (MMWR, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Mild leukocytosis with a shift to the left may be seen on CBC (CDC, 1999; Howe & Miller, 1947).
    B) LEUKOPENIA
    1) WITH POISONING/EXPOSURE
    a) Persistent leukopenia may be present in many cases (CDC, 1999; Howe & Miller, 1947).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ABSCESS
    1) WITH POISONING/EXPOSURE
    a) Cutaneous and intramuscular abscesses on the legs and arms are characteristic of the chronic form of glanders. Enlargement and induration of the regional lymph channels and nodes are generally associated with the cutaneous and intramuscular lesions (CDC, 1999; Pollack, 1994; Gaiger, 1913). Abscesses can also occur in the lungs, spleen and/or liver (Centers for Diseas Control and Prevention, 2011).
    B) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Following systemic invasion from mucosal or cutaneous lesions, a papular and/or pustular rash may occur. The rash may be mistaken for smallpox lesions (CDC, 1999; Pollack, 1994).
    C) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Fever, rigors and profuse sweating may be common following the sudden onset of septicemic glanders (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999; Stewart, 1904; Howe & Miller, 1947).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Sudden onset of myalgia may occur following development of septicemic glanders (CDC, 1999; Howe & Miller, 1947).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) LYMPHANGITIS
    1) WITH POISONING/EXPOSURE
    a) Chronic cutaneous glanders (localized infection) often presents with lymphangitis and regional adenopathy. Cutaneous and intramuscular lesions of chronic cutaneous glanders are generally associated with enlargement and induration of the regional lymph channels and nodes. Cervical adenopathy is a common presentation in early septicemic forms of the disease (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999; Pollack, 1994; Stewart, 1904; Howe & Miller, 1947).
    1) Routine laboratory handling of the organism, without observing precautions, has resulted in initial presentation of unilateral lymphadenopathy, suggesting a cutaneous inoculation (Srinivasan et al, 2001; MMWR, 2000; Pollack, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific studies are needed for most patients - tests should be directed towards a patient's symptoms.
    B) A CBC may reveal a mild leukocytosis with a left shift or a leukopenia.
    C) A chest radiograph may reveal miliary lesions, small multiple lung abscesses, or bronchopneumonia. Radiography can also identify abscesses in the liver and spleen but are not diagnostic.
    D) Diagnostic procedures for glanders may include methylene blue stain or exudates which may reveal secant small bacilli. Burkholderia mallei organisms can be cultured from infected secretions using meat nutrients, although cultures are usually negative until the patient is moribund.
    E) Laboratory workers should use biosafety level 3 containment practices when working with this organism.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Complete blood counts should be obtained in all suspected cases of glanders. Patients may exhibit a mild leukocytosis with a shift to the left or leukopenia (CDC, 1999).
    B) BLOOD/SERUM CHEMISTRY
    1) Hepatic and splenic involvement may occur, thus liver function tests should be obtained in all patients.
    4.1.4) OTHER
    A) OTHER
    1) CULTURES
    a) Diagnostic procedures include a gram stain of exudates which may reveal scant small gram negative rods, which stain irregularly with methylene blue (CDC, 1999). This agent has been demonstrated in blood, sputum, and abscess materials.
    b) On ordinary nutrient agar B. mallei grows slowly. Growth is accelerated with the addition of 1% to 5% glucose or 5% glycerol or use of a meat infusion nutrient media. At 37.5 degrees C, primary isolation requires 48 hours. The establishment of B. mallei can be made with cultures of autopsy nodules in septicemic cases (CDC, 1999). Pulmonary forms of glanders may present with or without bacteremia. Blood cultures are generally negative until the patient becomes moribund (Srinivasan et al, 2001; MMWR, 2000; CDC, 1999).
    1) When working with this organism, biosafety level 3 standards are recommended for laboratory personnel.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray in all suspected cases of glanders. Miliary nodules (0.5 to 1 cm), small multiple lung abscesses, and/or bilateral bronchopneumonia, segmental or lobular pneumonia and necrotizing nodular lesions as viewed on chest x-ray may be seen in the pulmonary form of glanders (CDC, 1999; Pollack, 1994).
    B) RADIOGRAPHS
    1) Radiography can also identify abscesses in the liver and spleen but are not diagnostic (Van Zandt et al, 2013).
    C) CT RADIOGRAPH
    1) Abdominal computerized tomography scan may be indicated in more severe cases. Multiple hepatic and splenic lesions consistent with abscesses may be found, which is common in advanced cases (MMWR, 2000).

Methods

    A) BIOASSAY
    1) Serologic and DNA-based diagnostic assays currently are not standardized, widely available, or approved by the Food and Drug Administration. Biosafety level 3 laboratory precautions should be observed when working with this organism (Srinivasan et al, 2001; MMWR, 2000).
    B) IMMUNOASSAY
    1) Agglutination tests may not become positive for 7 to 10 days. A high background titer in normal sera (1:320 to 1:640) may cause interpretation to become difficult. Complement fixation tests are considered superior to agglutination tests, as they as more specific and are considered positive if the titer is equal to, or exceeds 1:20 (CDC, 1999).
    a) If further testing is required, as in the case of anti-complimentary individuals, an enzyme-linked immunosorbent assay (ELISA) is reported that is sensitive for B. mallei. A competitive ELISA (CELISA) test has been adapted for use in the serodiagnosis of B. mallei (in equine serum) ((Katz, 1998)). A dot ELISA was compared to complement fixation and was considered superior in its rapidity and easiness and in the fact that it was not influenced by anti-complementary activity of the serum ((Anon, 1998)).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Suspected cases of glanders should be admitted to the hospital. Standard precautions should be applied in the management of patients and contacts. Glanders may present with diffuse pustular rashes; strict isolation and quarantine is indicated until smallpox can be excluded. Use contact precautions while caring for patients with skin involvement.
    B) Glanders may present as acute pulmonary disease with purulent sputum. Respiratory isolation pending exclusion of plague is advisable if sputum studies disclose gram-negative bacilli with bipolar "safety pin" appearance when using Wright or methylene blue stains.
    6.3.3.2) HOME CRITERIA/INHALATION
    A) Home care is not recommended in suspected cases of glanders.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) An infectious disease specialist should be consulted.
    B) All suspected cases should be reported to the state health department as well as the CDC. Health department personnel will work with the CDC and the attending physician in the treatment of glanders.
    6.3.4) DISPOSITION/EYE EXPOSURE
    6.3.4.3) CONSULT CRITERIA/EYE
    A) Persons with conjunctiva exposure to blood, body fluids, secretions, or excretions from a patient with suspected glanders infection should receive medical evaluation and follow-up management.

Monitoring

    A) No specific studies are needed for most patients - tests should be directed towards a patient's symptoms.
    B) A CBC may reveal a mild leukocytosis with a left shift or a leukopenia.
    C) A chest radiograph may reveal miliary lesions, small multiple lung abscesses, or bronchopneumonia. Radiography can also identify abscesses in the liver and spleen but are not diagnostic.
    D) Diagnostic procedures for glanders may include methylene blue stain or exudates which may reveal secant small bacilli. Burkholderia mallei organisms can be cultured from infected secretions using meat nutrients, although cultures are usually negative until the patient is moribund.
    E) Laboratory workers should use biosafety level 3 containment practices when working with this organism.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) INGESTION: Although glanders has been rarely reported in carnivores that have fed on infected horse carcasses, no human cases of glanders from ingestions have been reported. There is no evidence for the use of activated charcoal.
    2) INHALATION: Treatment is symptomatic and supportive. Antibiotic therapy is the mainstay of treatment.
    3) OCULAR: Exposed eyes should be irrigated with copious amounts of room temperature water for at least 15 minutes.
    4) DERMAL: Wash exposed skin extremely thoroughly with soap and water.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) There is no evidence for the use of activated charcoal, gastric lavage or whole bowel irrigation.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Supportive care and appropriate antibiotic therapy are the mainstay of treatment. Strict contact precautions should be maintained. Post-exposure prophylaxis may be considered with antibiotics such as trimethoprim-sulfamethoxazole. For localized disease with mild toxicity, treatment for 60 to 150 days with amoxicillin-clavulanate, tetracyclines, and/or trimethoprim-sulfamethoxazole is reasonable. For extrapulmonary suppurative disease, administer antibiotics as above for 6 to 12 months. Surgical drainage of abscesses is also indicated.
    b) ANTIBIOTIC THERAPY: Antibiotic therapy is the mainstay of treatment. Localized glanders has been reported to be sensitive to amoxicillin/clavulanate, tetracyclines, or cotrimoxazole. Bacteremia secondary to glanders are usually susceptible to tetracyclines, ciprofloxacin, streptomycin, novobiocin, gentamicin, imipenem, ceftazidime, and sulfonamides. In addition, sulfadiazine has been found to be effective in experimental animals and humans. Antibiotics are given for at least 30 days in uncomplicated infections and up to 6 months in complicated cases. Other treatment is symptomatic and supportive. No vaccine against B. mallei infection is available.
    c) Mortality can still be high despite antibiotic use. Currently, no pre-exposure prophylaxis is available; however, based on animal sensitivities, postexposure prophylaxis may be tried with TMP-SMX (CDC, 1999).
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Supportive care and appropriate antibiotic therapy are the mainstay of treatment. Strict contact precaution should be maintained. Mortality may be high even with antibiotic treatment. For severe toxicity or patients with sepsis, treat with IV ceftazidime combined with IV trimethoprim-sulfamethoxazole for 2 weeks, followed by oral therapy for 6 months. Alternative regimens include streptomycin plus a tetracycline or streptomycin plus chloramphenicol.
    B) MONITORING OF PATIENT
    1) No specific studies are needed for most patients - tests should be directed towards a patient's symptoms.
    2) A CBC may reveal a mild leukocytosis with a left shift or a leukopenia.
    3) A chest radiograph may reveal miliary lesions, small multiple lung abscesses, or bronchopneumonia. Radiography can also identify abscesses in the liver and spleen but are not diagnostic.
    4) Diagnostic procedures for glanders may include methylene blue stain or exudates which may reveal secant small bacilli. Burkholderia mallei organisms can be cultured from infected secretions using meat nutrients, although cultures are usually negative until the patient is moribund.
    5) Laboratory workers should use biosafety level 3 containment practices when working with this organism.
    C) DETERMINATION OF PROGNOSIS
    1) The extent and severity of infection will vary with size of the inoculum, the patient's underlying state of health, availability of protective mask or other respiratory protective devices, and other factors. Late activation or recrudescence has been reported to result years or decades later in isolated cases ((Anon, 2000)).
    D) AIRWAY MANAGEMENT
    1) In cases of airway compromise, supportive measures including endotracheal intubation and mechanical ventilation may be necessary.
    E) ANTIBIOTIC
    1) SUMMARY: Mortality may be high despite antibiotic use. Due to the limited number of infections in humans, therapeutic evaluation of most of the antibiotic agents is limited. Most antibiotic sensitivities are based on in vitro animal data (Van Zandt et al, 2013; CDC, 1999; (Anon, 2000)). In general, sulfadiazine has been found to be effective in both experimental animals and humans. In addition, the bacterium that causes glanders is usually susceptible to the following antibiotics: tetracyclines, ciprofloxacin, streptomycin, novobiocin, gentamicin, imipenem, ceftazidime and sulfonamides (Centers for Diseas Control and Prevention, 2011).
    2) LOCALIZED DISEASE: Administer one of the following for a duration of 60 to 150 days:
    a) Amoxicillin/clavulanate: 60 mg/kg/day in 3 divided oral doses.
    b) Tetracycline: 40 mg/kg/day in 3 divided oral doses. Tetracyclines are not generally recommended for pregnant women or children less than 8-years-old.
    1) Doxycycline was used in experimentally infected hamsters and was found effective; however, relapse occurred in treated animals approximately 4 to 5 weeks after challenge (Russell et al, 2000).
    c) Trimethoprim/sulfa (TMP, 4 mg per kg per day/sulfa, 20 mg per kg per day) in 4 divided oral doses.
    3) LOCALIZED DISEASE WITH MILD TOXICITY: Combine 2 of the above oral regimens for a duration of 30 days, followed by monotherapy with either amoxicillin/clavulanate or TMP/sulfa for 60 to 150 days.
    4) EXTRAPULMONARY SUPPURATIVE DISEASE: Administer antibiotic therapy as above for a total of 6 to 12 months. Perform surgical drainage of abscesses as necessary.
    5) SEVERE AND/OR SEPTIC DISEASE: Give ceftazidime 120 mg/kg/day in 3 divided doses, combined with TMP/sulfa (TMP, 8 mg/kg/day/sulfa, 40 mg/kg/day in 4 divided doses). Initially give as parenteral therapy for 2 weeks, followed by oral therapy for 6 months.
    a) Alternatively, streptomycin plus a tetracycline (doxycycline) or streptomycin plus chloramphenicol may be used.
    6) CASE REPORT: A likely laboratory cutaneous inoculation of B. mallei in a microbiologist resulted in unilateral lymphadenopathy and bacteremia with hepatic and splenic abscesses. The laboratory acquired B. mallei was sensitive to imipenem and doxycycline. Following IV imipenem and doxycycline for 2 weeks the patient was switched to oral doxycycline and azithromycin. The patient's liver and spleen abscesses continued to resolve while on oral antibiotics (Srinivasan et al, 2001; MMWR, 2000).
    7) SULFADIAZINE in doses of 25 mg/kg administered intravenously 4 times daily for 3 weeks has been reported to be efficacious in some cases (MMWR, 2000) (CDC, 1999).
    8) MANAGEMENT GUIDELINES FOR LABORATORY EXPOSURES
    a) POSTEXPOSURE ANTIBIOTIC PROPHYLAXIS REGIMENS
    1) Burkholderia mallei and B. pseudomallei are often one of several organism associated with occupational laboratory exposures. Based on work conducted by the Special Immunizations Program at the United States Army Medical Research Institute of Infectious Diseases, the following recommendations were suggested for postexposure prophylaxis in laboratory workers exposed to bioterrorism agents. The guidelines are based on the risk of exposure, the virulence of the organism, and vaccination status of the individual (Rusnak et al, 2004)
    1) ASSESSMENT OF POSTEXPOSURE:
    a) MODERATE/HIGH RISK
    1) INHALATION: Defined as not wearing a respirator with direct splash of an infectious agent or aerosolized dried agent outside of BSC; or exposure from centrifuge accident with viable organism; or break in respiratory protection in an environment with an infectious agent or animal with potential to be aerosolized.
    2) PERCUTANEOUS/CUTANEOUS: Percutaneous exposure to any of the following: needle or blade with prior contact with a solution containing the agent; or contact with blood/fluids of an infected animal that is ill or likely to have the organism in the blood/fluids. Cuts from any source that might contain the infectious agent or contact with intact skin, but a delay in cleaning the area.
    b) MINIMAL-RISK EXPOSURE:
    1) INHALATION: Defined as an exposure to an organism that is unlikely to be aerosolized or spill that is contained within the BSC or an exposure to an infectious agent that is unlikely to be aerosolized.
    2) PERCUTANEOUS/CUTANEOUS: Percutaneous exposure to any of the following: from needle or blade with prior blood/fluids of an animal infected with an agent, but the animal not likely to be bacteremic or shedding organisms; or scratch or bite from an animal infected with an agent, but not likely to be ill. Direct contact with infectious agent to skin, but cleaned immediately.
    c) NEGLIGIBLE OR NO RISK-EXPOSURE:
    1) INHALATION or PERCUTANEOUS: No discernible contact with either an aerosolized or percutaneous/cutaneous (eg, needle stick, abrasion or cuts to skin) infectious agent or an infected animal. Injury or break in laboratory technique, but not in the presence of an infected animal or organism.
    b) PROPHYLACTIC ANTIBIOTIC THERAPY
    1) Currently, the guidelines recommend prophylactic antibiotic therapy for all moderate or high-risk exposures regardless of vaccination status. Prophylaxis was also recommended for unvaccinated individuals with minimal risk exposures. Lastly, clinical judgement should guide prophylactic antibiotic therapy on a case-by-case basis (Rusnak et al, 2004).
    2) PROPHYLACTIC REGIMEN: B. mallei OR B. pseudomallei: Doxycycline or ciprofloxacin for 10 days; however, no data currently supports this recommendation (Rusnak et al, 2004).
    3) Although trimethoprim-sulfamethoxazole and quinolones have also been found to have antimicrobial activity against B. mallei, there is no human data to support their use for postexposure prophylaxis for glanders (Rusnak et al, 2004a).
    c) SYMPTOMATIC LABORATORY EXPOSURES
    1) Although there is no FDA approved treatment for glanders, the following regimen has been suggested to manage symptomatic laboratory worker exposures. The protocol is based on a 2-pronged approach that consists of intravenous therapy followed by oral eradication therapy (Van Zandt et al, 2013).
    a) INTENSIVE INTRAVENOUS THERAPY: IV medications can include imipenem, meropenem, or ceftazidime with or without trimethoprim-sulfamethoxazole. The dosing schedule is for a minimum of 10 days and can be longer depending on the severity of illness (Van Zandt et al, 2013):
    1) Imipenem: 25 mg/kg up to 1 g every 6 hours
    2) Meropenem: 25 mg/kg up to 1 g every 8 hours
    3) Ceftazidime: 50 mg/kg up to 2 g every 6 hours
    b) ORAL ERADICATION THERAPY: The duration of oral therapy is dependent on the severity of illness (up to 12 weeks and as long as 12 months in some cases). The treatment of choice is trimethoprim/sulfamethoxazole with or without doxycycline (Van Zandt et al, 2013):
    1) TMP-SMX: 8/40 mg/kg up to 320 mg/1600 mg every 12 hours
    2) Doxycycline: 2.5 mg/kg up to 100 mg every 12 hours
    3) Alternatively, Amoxicillin-clavulanate: 500 mg every 8 hours or 875 mg every 12 hours for adults
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    G) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    6.8.2) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION
    1) INTACT SKIN should be washed with soap and water under running water.
    2) CUTS should be encouraged to bleed, then placed under running water.
    6.9.2) TREATMENT
    A) DRAINAGE OF ABSCESS
    1) Drainage of abscesses may be necessary. Barrier precautions should be used since drainage material is potentially highly infectious.
    B) SUPPORT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ADULT
    1) CASE REPORT: A likely laboratory cutaneous inoculation of B. mallei in a microbiologist resulted in unilateral lymphadenopathy and bacteremia with hepatic and splenic abscesses. The patient also developed progressive respiratory failure which required mechanical ventilation. The laboratory acquired B. mallei was sensitive to imipenem and doxycycline. Following intravenous imipenem and doxycycline for 2 weeks the patient was switched to oral doxycycline and azithromycin. The patient's liver and spleen abscesses continued to resolve while on oral antibiotics (Srinivasan et al, 2001; MMWR, 2000).

Range Of Toxicity

Summary

    A) TOXICITY: As few as 1 to 10 organisms administered via aerosol transmission to hamsters is lethal. There is no specific information describing a toxic dose in humans.

Minimum Lethal Exposure

    A) SUMMARY
    1) ANIMAL DATA: As few as 1 to 10 organisms administered via aerosol transmission to hamsters is lethal. Albino mice, which are "resistant species", can be infected with higher inhalation doses (CDC, 1999).
    2) In humans, mortality can be high even following antibiotic use (CDC, 1999).

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) INHALATION: The extent and severity of infection in humans will vary with size of the inoculum, the person's underlying state of health, availability of protective mask or other respiratory protective devices. Late activation or recrudescence has been reported to result years or decades later in isolated cases ((Anon, 2000)).
    a) INCUBATION: The incubation period is 10 to 14 days following inoculation (CDC, 1999; (Anon, 2000); Howe & Miller, 1947).

Pharmacology Toxicology

Toxicologic Mechanism

    A) The causative agent of glanders is Burkholderia mallei (formerly Pseudomonas mallei), which is an aerobic, gram-negative, non-spore forming bacillus ((Anon, 2000); CDC, 1999). Disease occurs primarily in solipeds (horses, donkeys, and mules). The organism exists in nature only in infected susceptible hosts and is not found in water, soil, or plants (CDC, 1999). Clinical manifestations of B. mallei infection, or glanders, varies greatly from an asymptomatic state, to pneumonia, to cutaneous glanders, to overwhelming septicemia. Relapse of the disease may occur.
    B) Burkholderia pseudomallei, which causes melioidosis (a glanders-like disease), may encapsulate and persist intracellularly. Both B. pseudomallei and B. mallei are similar in their antigenicity, biochemistry and, most likely, in their pathogenicity, especially with respect to intracellular survival. It is thus presumed that B. mallei reacts similarly to B. pseudomallei, thus necessitating correct selection of antimicrobial agent and long duration of therapy (at least 30 days in uncomplicated infections and up to 6 months in complicated cases) (Koch et al, 1997; Russell et al, 2000).
    1) Intracellular survival of organisms renders melioidosis (and glanders) quiescent in infected persons for potentially years and may contribute to abscess formation in the spleen and liver following reactivation from dormancy (Leelarasamee & Bovornkitti, 1989).
    C) Burkholderia pseudomallei (similar to B. mallei) has been reported to contain a heat-stable principle with classic endotoxin activity. A thermolabile lethal exotoxin and a proteolytic enzyme have been recorded in culture filtrates of B. pseudomallei. The toxins are thought to contribute to lethality of disease in humans (Leelarasamee & Bovornkitti, 1989).

References

General Bibliography

    1) Anon: Field Manual: Treatment of Biological Warfare Agent Casualties. Army FM 8-284; Navy Navmed P-5042; Air Force Afman (1) 44-156; Marine Corps MCRP 4-11.1C. Office of The Surgeon General Department of the Army at TMM Publications. Washington, DC, USA. 2000. Available from URL: http:\\www.nbc-med.org/SiteContent/MedRef/OnlineRef/fieldManuals/FM8_284/fm8_284.pdf. As accessed Accessed July 11, 2000.
    2) Anon: Glanders. International Association of Equine Professional. Wildomar, CA, USA. 1998. Available from URL: http:\\iaep.com/pages/edwatch/glanders.html. As accessed Accessed September 27, 1999.
    3) Blancou J: Early methods for the surveillance and control of glanders in Europe. Rev Sci Tech Off Int Epiz 1994; 13:545-557.
    4) CDC: Biological warfare and terrorism. The military and public health response. Student Material, Untied States Army Medical research Institute of Infectious Disease, Ft. Frederick, MD, 1999.
    5) Centers for Diseas Control and Prevention: Glanders. Centers for Disease Control and Prevention (CDC). Atlanta, GA. 2011. Available from URL: http://www.cdc.gov/glanders/. As accessed 2015-10-07.
    6) Gaiger SH: Glanders in man. J Comp Path Ther 1913; 26:223-226.
    7) Howe C & Miller WR: Human glanders: report of six cases. Ann Intern Med 1947; 260:93-115.
    8) JB Katz: Immunoblotting and competitive ELISA for the confirmatory serodiagnoses of equine piroplasmosis, dourine and glanders. United States Animal Health Association. Richmond, VA, USA. 1998. Available from URL: http:\\www.usaha.org/speeches/speech98/s98katz.html. As accessed Accessed July 11, 2000.
    9) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    10) Koch FW, Zoller M, & Pankow W: Acute septic course of melioidosis (Pseud. Pseudomallei infection) after a visit to Thailand. Deut Med Wochenschr 1997; 122:122-126.
    11) Leelarasamee A & Bovornkitti S: Melioidosis: review and update. Rev Infect Dis 1989; 2:413-425.
    12) MMWR: Laboratory-acquired human glanders - - Maryland. MMWR, 49(24):532-535 (May), 2000.
    13) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    14) Pollack ML: Pseudomonas infections. In: Harrison's Principles of Internal Medicine, 13'th ed, McGraw-Hill, New York, NY, 1994.
    15) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    16) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    17) Rusnak JM, Kortepeter MG, Aldis J, et al: Experience in the medical management of potential laboratory exposures to agents of bioterrorism on the basis of risk assessment at the United States army medical research institute of infectious diseases (USAMRIID) . JOEM 2004a; 46(8):801-811.
    18) Rusnak JM, Kortepeter MG, Hawley RJ, et al: Management guidelines for laboratory exposures to agents of bioterrorism. JOEM 2004; 46(8):791-800.
    19) Russell P, Eley SM, & Ellis J: Comparison of efficacy of ciprofloxacin and doxycycline against experimental melioidosis and glanders. J Antimicrob Chemother 2000; 45:813-818.
    20) Srinivasan A, Kraus CN, DeShazer D, et al: Glanders in a military research microbiologist. N Engl J Med 2001; 345(4):256-258.
    21) Stewart JC: Pyaemic glanders in the human subject. Report of a recent case of laboratory origin terminating in recovery. Ann Surgery 1904; 40:109-113.
    22) Van Zandt KE, Greer MT, & Gelhaus HC: Glanders: an overview of infection in humans. Orphanet J Rare Dis 2013; 8:131.