Burkholderia

Burkholderia species are gram-negative bacilli with 2 clinically relevant pathogens: B. pseudomallei (causing melioidosis) and B. cepacia complex (causing opportunistic infections). Melioidosis is commonly seen in Asia and Australia. Infection is transmitted by contact with contaminated soil or water (via skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin wounds). The disease affects multiple systems, and can present with pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, encephalomyelitis, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin abscesses. Diagnosis is by culture of specimen (depending on the organ involved). Treatment requires an initial intensive antibiotic therapy followed by prolonged eradication therapy. Burkholderia cepacia complex (BCC) generally affects immunocompromised individuals such as those with cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis (CF). It can be transmitted from person to person or through contaminated devices. While BCC is a rare infection, it is important to diagnose, as BCC is multi-drug resistant and infection is a relative contraindication to lung transplantation.

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Classification

Gram negative bacteria classification flowchart

Gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview:
Most bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thin layer of peptidoglycan do not retain the crystal violet stain utilized in Gram staining. These bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview do, however, retain the safranin counterstain and thus appear as pinkish-red on the stain, making them gram negative. These bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview can be further classified according to morphology (diplococci, curved rods, bacilli, and coccobacilli) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview can be more narrowly identified by growing them on specific media (triple sugar iron (TSI) agar) where their enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes can be identified (urease, oxidase) and their ability to ferment lactose can be tested.
* Stains poorly on Gram stain
** Pleomorphic rod/coccobacillus
*** Require special transport media

Image by Lecturio.

Characteristics

Basic features

Burkholderia:

  • Gram-negative bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus
  • Obligately aerobic
  • Motile (with polar flagella)
  • Non-lactose fermenting
  • Oxidase positive
  • Culture: grows in standard bacteriologic media

Clinically significant species:

  • Burkholderia pseudomallei:
    • Widely distributed in soil and fresh surface water in endemic regions 
    • Cause of melioidosis
  • Burkholderia cepacia complex (BCC): group of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview that grows in water, soil, plants, animals, and decaying vegetable materials
Image: “” by. License:

Burkholderia pseudomallei colonies on a blood agar plate

Image: “Burkholderia pseudomallei 01” by CDC. License: Public Domain

Burkholderia pseudomallei

Etiology and epidemiology

  • Associated with melioidosis (also known as Whitmore disease)
  • Endemic areas:
    • Southeast Asia
    • Northern Australia
    • South Asia (including India)
    • China
  • Rare in the United States
  • Seasonal peak in wet (rainy) seasons

Pathophysiology

Transmission:

  • Contact with contaminated water or soil, especially through skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin wounds (predominant mode)
  • Inhalation of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in dust and aerosols
  • Ingestion of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in contaminated foods or water
  • Animal-to-human and human-to-human transmissions are rare.

Host risk factors include:

  • Diabetes
  • Alcohol abuse
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
  • Renal disease
  • Thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia
  • Kava consumption
  • Immunosuppressive condition (e.g., cancer)
  • Chronic lung disease including cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis (CF), bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis, and chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD))

Clinical presentation

  • Incubation period: 
    • 1–21 days
    • Influenced by a dose of inoculation, host risk factors, mode of transmission
  • Most patients are asymptomatic.
  • Presentation can be:
    •  Acute:
      • Majority of cases
      • Symptoms for < 2 months
    • Chronic: symptoms for > 2 months

Symptoms can present in various systems:

  • Bacteremia or sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Focal abscess in organs (i.e., liver, kidney, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen)
  • Respiratory:
    • Fever
    • Cough
    • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
    • Respiratory distress
    • Chronic symptoms: productive cough, hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis, night sweats (similar to tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis)
  • Dermatologic:
    • Skin changes (ulceration, abscess) that fail to resolve with antibiotic treatment
    • Rarely develops cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
  • Genitourinary:
    • Fever with dysuria
    • Urinary retention
    • Tender prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands
  • Joints:
    • Septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis
    • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
  • Neurologic (encephalomyelitis):
    • Cerebellar signs
    • Cranial nerve palsies
    • Upper motor neuron weakness

Diagnosis

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:

  • Culture of specimens that can include:
    • Blood
    • Sputum 
    • Urine
    • Swabs from rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin wound/ulcer/abscess, throat
  • Gram stain of specimen(s):
    • Gram-negative bacilli
    • Bipolar staining with a “safety pin” appearance
  • Serology: limited use
  • Antigen and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure detection: Most are not yet commercially available.

Additional tests:

  • Chest X-ray findings vary:
    • Infiltrates
    • Pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion
    • Lobar consolidation
    • Cavitation and abscesses with fluid level
    • Chronic findings: fibrosis with nodular, cavitating, or streaky infiltrates
  • CT scan or MRI:
    • Evaluate abdominal multifocal infections
    • Check prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands

Management

Resistant to: 

  • Penicillin/ampicillin
  • 1st- and 2nd-generation cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." Cephalosporins
  • Gentamicin
  • Tobramycin
  • Streptomycin 

Initial regimen(s) depends on severity of illness and system(s) affected: 

  • Stable (non-critical) without CNS infection: ceftazidime
  • Critically ill: 
    • Imipenem
    • Meropenem
  • CNS infection: meropenem (higher dose)
  • Adjunctive antibiotic: trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim-sulfamethoxazole (TMP-SMX)
  • Additional management:
    • Abscess drainage
    • Supportive care (e.g., fluid management)
    • Recombinant human granulocyte-colony stimulating factor (G-CSF) for those in septic shock Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and Septic Shock

Eradication treatment:

  • After the initial phase of intensive treatment, additional antibiotic intake is recommended to reduce relapse.
  • In general, duration is at least 3–6 months (depending on type of infection).
  • Some require > 6 months (i.e., arterial infection, often a mycotic aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms).
  • Options:
    • Oral TMP-SMX with folic acid
    • Oral doxycycline (alternative)

Prevention:

  • Avoid skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin exposure to soil and water, especially in the wet season.
  • High-risk individuals (e.g., patients with CF) should avoid travel in endemic areas during the wet season.
  • In a bioterrorism event or accidental laboratory exposure, post-exposure prophylaxis (PEP) with TMP-SMX is recommended.

Burkholderia cepacia Complex

Etiology and epidemiology

BCC:

  • A group of different species that make up the complex
  • Opportunistic human pathogen
  • Species commonly isolated in the sputum of patients with CF:
    • B. multivorans
    • B. cenocepacia 

Epidemiology:

  • Rare infection and not commonly found in an ambulatory setting
  • In the United States, reports of infection and contamination include: 
    • In 2004: nosocomial infections from B. cepacia due to contaminated sublingual probes
    • In 2004: recall of over-the-counter nasal spray due to contamination
    • In 2005: pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia from contaminated mouthwash

Pathophysiology

Transmission:

  • Device and/or medicine contamination
  • Contamination of water and environmental sources
  • Contact with contaminated surfaces
  • Person-to-person contact

Medical devices that can be contaminated and produce infection:

  • Pressure monitoring devices 
  • Indwelling Foley catheters, urometers, irrigation fluids
  • IVs, central catheters, IV fluids
  • Respiratory equipment (respirator tubing condensate, ultrasonic nebulizers, inhalation medications)

Host risk factors:

  • Generally with low virulence and presents minimal risk for healthy people
  • Those at risk:
    • Individuals with weakened immune systems 
    • Individuals with CF or chronic lung disease ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis, chronic granulomatous disease Chronic Granulomatous Disease Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. Chronic Granulomatous Disease)

Clinical presentation

Most infected people have no symptoms. Those with symptoms can have:

  • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Pneumonia
  • Chronic lung infection in CF:
    • Decreases survival
    • Related to recurrent, severe infections
  • Other manifestations depend on organ system involved.

Diagnosis

  • Culture of body fluids (in organ affected)
    • Selective media containing colistin (e.g., B. cepacia selective agar): recommended for sputum of patients with CF
    • Growth is slow, and may take 3 days.
  • Additional testing (e.g., imaging) done depending on system involved
B. Cepacia complex infection

B. cepacia complex infection:
Chest X-ray of a patient showing right-sided pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia. Tracheal aspirate and blood cultures grew B. cepacia.

Image: “Cepacia Syndrome in a Non-Cystic Fibrosis Patient” by Hauser N, Orsini J. License: CC BY 3.0

Management

  • Known for being multi-drug resistant
  • Antibiotic options (multiple agents used):
    • Co-trimoxazole
    • Ceftazidime
    • Minocycline
    • Carbapenems
  •  Screen all patients with CF for B. cenocepacia prior to transplantation, as colonization is a relative contraindication for lung transplantation.

References

  1. Currie, B., Anstey, N. (2021). Melioidosis: Epidemiology, clinical manifestations and diagnosis. UpToDate. Retrieved May 28, 2021, from https://www.uptodate.com/contents/melioidosis-epidemiology-clinical-manifestations-and-diagnosis
  2. Currie, B., Anstey, N. (2021). Melioidosis: Treatment and prevention. UpToDate. Retrieved May 28, 2021, from https://www.uptodate.com/contents/melioidosis-treatment-and-prevention
  3. Currie, B., Ward, L., Cheng, A. (2010). The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study. PLoS Negl Trop Dis. 4:e900.
  4. Mahmood, S., Ahmed, S. (2018). Burkholderia cepacia. Medscape. Retrieved May 29, 2021, from https://emedicine.medscape.com/article/237122-overview
  5. Riedel, S., et al. (Eds.). (2019). Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas, acinetobacter, burkholderia, and stenotrophomonas. In Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed.) https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217771138 
  6. Torok, E., Moran, E., Cooke, F. (2009). Oxford Handbook of Infectious Diseases and Microbiology. Oxford University Press. 
  7. Zaas, A., Palmer, S., Messina, J. (2021). Bacterial infections following lung transplantation. UpToDate. Retrieved May 28, 2021, from https://www.uptodate.com/contents/bacterial-infections-following-lung-transplantation

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