Definition, Etiology, PathogenesisTop
1. Etiologic agent: Aerobic nonfermenting gram-negative rod-shaped bacteria Burkholderia pseudomallei; a widespread saprophyte dwelling in soil (in rhizosphere) and surface waters in endemic regions. The bacterium is resistant to a number of environmental factors, including pH, salinity, temperature differences, and detergents. It can infect humans and animals and in vivo is a facultatively intracellular microorganism. The vast genetic diversity of B pseudomallei probably has an effect on the pathogen’s varying virulence observed in different regions of the world.
2. Pathogenesis: B pseudomallei resides intracellularly in the human body (it primarily attacks epithelial cells and macrophages). Adhesion to respiratory epithelial cells is facilitated by the polysaccharide capsule that binds to the asialoganglioside aGM1-aGM2 receptor complex. This is one of the initial stages of colonization and subsequent respiratory tract infection via inhalation. Following cell entry the bacteria colonize vacuoles and the cytoplasm. B pseudomallei infects both phagocytes and nonphagocytic cells. T3SS and T6SS systems are essential for the intracellular invasion and bacterial survival. The role of the T3SS system (with needle-like structure) is to introduce various bacterial effector proteins to a target eukaryotic cell; the proteins can alter the cell function and weaken the immune response (eg, by inhibiting the expression of nitric oxide synthase in macrophages). Probably B pseudomallei also delays apoptosis of the infected cells, thus facilitating bacterial survival and propagation of infection. The bacteria can transfer directly from cell to cell by fusion (the T6SS system plays an important role in the process). Stimulation of the host cell fusion may lead to formation of multinucleated giant cells, which are observed in infected tissues. The infection can develop at the portal of entry of the bacteria and/or spread by blood to various organs and systems.
3. Reservoir and transmission: The reservoir is soil and surface waters; the infection is most often spread through transdermal inoculation, by inhalation, or by the oral route (swallowing of contaminated water, eg, when drowning). Inhalation of aerosols containing the bacteria may occur during tropical storms. Transmission between humans, zoonotic infections, hospital infections, and occupational infections in laboratory workers have been reported, but they are very rare. Vertical transmission of the bacteria when breastfeeding with contaminated milk is possible in women with mastitis.
4. Risk factors for infection: Contact with contaminated soil and water, staying in endemic regions, especially during the rainy season, consumption of kava (Piper methysticum infusion drunk in the Pacific area). Risk factors for severe disease: chronic diseases, especially diabetes, chronic kidney disease, nephrolithiasis, chronic lung diseases (including cystic fibrosis, a risk factor for respiratory system colonization, similar as in the case of Burkholderia cepacia), immunosuppressive treatment, alcoholism.
5. Incubation and contagious period: One to 21 days (9 days on average); depending on the infective dose (incubation period is short in patients who received a high infective dose, eg, when drowning), risk factors for a severe course, strain virulence. Latent course is possible, with presenting symptoms appearing after years (median 26 years). Relapses are present in ~6% of patients, with a median relapse time of 9.4 months.
To date, endemic occurrence of melioidosis (also known as Whitmore disease) cases has been described in 46 countries, but the actual data on its prevalence seem to be underestimated (endemic infections are probably present in ≥79 countries). Regions at risk of melioidosis are mainly South and East Asia countries (including the Indian subcontinent), Oceania, and northern Australia. Melioidosis cases have also been reported in countries of both Americas, Africa, and the Middle East. The greatest numbers of cases have been reported in Australia and Thailand, but the actual figures are unknown. The estimated incidence of melioidosis is ~165,000 persons per year, with 89,000 patients dying annually. Between 2000 and 2018, 77 cases of melioidosis were reported in Europe in travelers, mainly those returning from holidays in Thailand. In endemic regions the majority of cases are seen in the rainy season and after extreme weather phenomena, such as tropical storms or tsunami.
Clinical Features and Natural HistoryTop
The course of melioidosis can be acute (symptoms lasting <2 months), chronic (symptoms lasting >2 months), or recurrent (new symptoms and confirmed infection in an individual with a history of melioidosis). The majority of cases are asymptomatic. The dominant clinical manifestations differ depending on the patient's age and geographic region. The most common finding in patients returning from endemic regions is pneumonia. Relapses most often result from suboptimal treatment.
1. Skin lesions: Ulceration or abscesses, rarely cellulitis; lesions appear at the sites of transdermal inoculation.
2. Respiratory system infection:
1) Colonization: In individuals with chronic lung disease (especially with cystic fibrosis) receiving suboptimal treatment; respiratory tract colonization may be the starting point for pneumonia, systemic infection, or different organ involvements during infection reactivation.
2) Pneumonia: Clinically similar to tuberculosis; characteristic features include high-grade fever, night sweats, weight loss, productive cough, hemoptysis; infection occurs by inhalation or by blood (for transdermal transmission).
3. Bacteremia and sepsis: Involvement of various organs is possible via blood-borne dissemination, including the formation of organ abscesses.
4. Gastrointestinal (GI) infection: GI ulceration can be detected in infections acquired via the oral route.
5. Suppurative parotitis with cervical lymph node enlargement is a frequent symptom of melioidosis in children in Thailand and Cambodia, probably associated with consumption of contaminated water.
6. Neuromelioidosis occurs mainly in Australia; the most typical features are brainstem encephalitis with cranial nerve paralysis, polyneuropathy with dominating damage to the motor fibers, and flaccid paralysis of the lower limbs.
7. Other: Septic arthritis, osteomyelitis, mediastinitis, pericarditis.
1. Identification of the etiologic agent:
1) Bacterial culture is the basic test performed in the diagnostic workup of melioidosis; biologic material: blood, urine, throat swabs, respiratory secretions, ulcerative swabs, pus; in the case of central nervous system (CNS) infection, cerebrospinal fluid (CSF) culture is rarely positive, therefore melioidosis is confirmed based on the results of other biologic material cultures or serologic studies.
2) Serologic studies:
a) Detection of bacterial antigens: Latex tests, lateral flow assays (LFAs); currently unavailable in routine clinical practice.
b) Detection of specific antibodies (enzyme-linked immunosorbent assay [ELISA], indirect hemagglutination assay [IHA]); currently the tests have limited utility in clinical practice (lack of standardization, high rate of false-negative results in patients with acute melioidosis and false-positive results in healthy individuals from endemic regions) and are of use mainly in the diagnostic workup of chronic melioidosis, when bacterial culture results are negative, and in neuromelioidosis.
3) Molecular tests: Detection of bacterial genetic material using reverse transcription polymerase chain reaction (RT-PCR); tested material: blood, urine. Clinical utility is limited due to, among others, lack of standardization.
2. Other methods: In pulmonary melioidosis chest radiography visualizes infiltrations in the upper lung fields (especially in chronic disease), sometimes with cavities. The image may resemble tuberculosis. In the case of blood-borne spread, pulmonary abscesses can be observed. If other organs are involved (particularly in CNS infection and other organ abscesses), computed tomography (CT) and magnetic resonance imaging (MRI) are helpful.
Diagnosis is based on positive results of biologic material culture.
1. Cutaneous melioidosis: Skin infections of other bacterial etiologies, anthrax, cutaneous leishmaniasis, erythema nodosum.
2. Pulmonary melioidosis: Tuberculosis, pneumonias of other etiologies.
3. Parotitis: Suppurative parotitis of other etiologies, mumps, sialolithiasis.
4. Septic melioidosis: Sepsis of other etiology, plague, typhoid fever, malaria, dengue fever.
5. Organ abscesses: Abscesses of other etiologies.
B pseudomallei is naturally resistant to penicillin, ampicillin, first- and second- generation cephalosporins, aminoglycosides, and polymyxins. Therapy includes an initial phase of intensive treatment and an eradication phase.
1. Intensive IV antibiotic therapy:
1) Patients not requiring treatment at the intensive care unit (ICU): IV ceftazidime 2 g every 6 hours.
2) Patients requiring ICU treatment: IV meropenem 1 g (2 g for CNS infection) every 8 hours.
Treatment duration: ≥14 days until clinical improvement. Severe disease: ≥4-8 weeks; pneumonia: 2 to 4 weeks; bacteremia without focal infection: 2 weeks; skin and soft tissue infection: 2 weeks; abscesses and organ involvement: 4 weeks; arthritis: 4 weeks; osteomyelitis: 6 weeks; neuromelioidosis: 8 weeks; aneurysm caused by vascular wall infection: 8 weeks.
2. Eradication phase: Oral cotrimoxazole at a dose depending on body weight: <40 kg: 160/800 mg every 12 hours; 40 to 60 kg: 240/1200 mg every 12 hours; >60 kg: 320/1600 mg every 12 hours. Treatment duration: pneumonia: 3 months; bacteremia (without focal infection): 3 months; skin and soft tissue infection: 3 months; abscesses and organ involvement: 3 months; arthritis: 3 months; osteomyelitis: 6 months; neuromelioidosis, 6 months; intravascular infection, 6 months. Oral folic acid supplementation at 5 mg/d should be taken during treatment.
If cotrimoxazole is contraindicated, continuation of treatment with doxycycline or amoxicillin with clavulanic acid (20/5 mg/kg of body weight every 8 h) is recommended.
In patients with septic shock, IV granulocyte colony-stimulating factor (G-CSF) 300 microg is used once daily for 10 days or during stay at the ICU. Contraindications: acute coronary event, total leukocyte count >50×109/L.
Relapses are more frequent in patients with multifocal lesions and positive blood culture results and in those who finished the treatment prematurely.
B pseudomallei can be used as biologic weapon.
If antibiotic therapy is initiated early, the prognosis is usually good (mortality <10%). The prognosis is poor in patients from risk groups, in disseminated disease, and in the case of nervous system involvement. In septic disease the mortality rates are high. Approximately 14% of patients hospitalized because of melioidosis die in Australia, and ~35%, in Thailand.
1. Immunoprophylaxis: None available.
2. Pharmacoprophylaxis: Antibiotic prophylaxis after high-risk exposure is to be considered in people at risk for severe disease: oral doxycycline 100 mg every 12 hours for 3 weeks or oral amoxicillin with clavulanic acid for 3 weeks, at a dose depending on body weight: ≤60 kg, 1 g/250 mg every 8 hours; >60 kg, 1.5 g/375 mg every 8 hours.
1. Individuals with risk factors for severe melioidosis staying in endemic regions should avoid skin exposure to soil and surface waters during the rainy season and stay indoors in weather favoring B pseudomallei aerosol formation.
2. Patients with cystic fibrosis should avoid traveling to endemic regions during the rainy season.
3. Patient isolation: Only individuals with productive cough.
4. Personal protective equipment (PPE): Protective masks.