What is melioidosis

Melioidosis also called Whitmore’s disease, is an infectious disease caused by the aerobic, Gram-negative soil-dwelling bacillus bacteria Burkholderia pseudomallei that are commonly found in the soil and water, that can infect humans or animals through direct contact with soil, water, or air contaminated by the bacteria ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹². Because the Burkholderia pseudomallei bacteria reside in soil and water, weather events such as hurricanes, heavy rain, flooding and typhoons have been implicated in outbreaks of melioidosis. Burkholderia pseudomallei is mostly found in tropical climates, especially in Southeast Asia and northern Australia, where it causes widespread melioidosis. In the United States, Burkholderia pseudomallei is found in Puerto Rico, the U.S. Virgin Islands, and the Gulf Coast area of the state of Mississippi. Melioidosis is a rare disease in the United States with most melioidosis illnesses in the United States occur in people who have traveled to areas where the disease is more common. Some cases have also occurred in people who have had contact with contaminated products from overseas ¹².

People can get melioidosis by ¹²:

• Breathing in contaminated dust or water droplets
• Eating or drinking contaminated food or water
• Having contact with contaminated soil or water, especially through skin breaks (cuts, scrapes, etc.) or getting it in their mouths

It’s very rare for people to get melioidosis from another person.

Burkholderia pseudomallei infection was first recognized in Rangoon a city located in southern Myanmar (formerly Burma) by Whitmore and Krishnaswami in 1911 ¹³. In 2016, a statistical model estimated that there would be 165,000 new cases of melioidosis worldwide and 89,000 deaths, suggesting that melioidosis is significantly underreported ¹⁴. Community-acquired pneumonia is the most frequent clinical presentation of melioidosis and bacteremia the most common microbiological diagnosis ¹⁵, ¹⁶ In Ubon Ratchathani, Thailand, Burkholderia pseudomallei accounts for up to approximately 20% of community-acquired bacteremias ¹⁷. At the Royal Darwin Hospital, Australia, Burkholderia pseudomallei has been the most common cause of fatal community-acquired bacteremic pneumonia ¹⁸, ¹⁹.

Melioidosis usually occurs in individuals with specific comorbidities that include diabetes mellitus, hazardous alcohol consumption, chronic lung disease, chronic kidney disease, and immunosuppression ². Patients with cancer are also more likely to develop melioidosis, a result of the immunosuppressive anti-cancer therapy that they frequently receive, although other factors including medical comorbidities and poor nutritional status also contribute to their greater risk ²⁰. Despite the higher incidence of melioidosis in patients with cancer, the characteristics and clinical course of melioidosis in these patients have rarely been described in detail ²¹, ²².

Many kinds of animals can get melioidosis, including:

• Sheep
• Goats
• Pigs, hogs, boar
• Horses
• Cats
• Dogs
• Cows

In the United States, confirmed cases reported in previous years have ranged from zero to five and have occurred among travelers and immigrants coming from places where melioidosis is widespread. Moreover, it has been found among troops of all nationalities that have served in areas with widespread disease.

The greatest numbers of melioidosis cases are reported in:

• Thailand
• Malaysia
• Singapore
• Northern Australia

Though rarely reported, cases are thought to frequently occur in:

• Papua New Guinea
• Most of the Indian subcontinent
• Southern China
• Hong Kong
• Taiwan
• Vietnam
• Indonesia
• Cambodia
• Laos
• Myanmar (Burma)

Outside of Southeast Asia and Australia, cases have been reported in:

• The South Pacific (New Caledonia)
• Sri Lanka
• Mexico
• El Salvador
• Panama
• Ecuador
• Peru
• Guyana
• Puerto Rico
• Martinique
• Guadeloupe
• Brazil
• Parts of Africa and the Middle East

Melioidosis is spread to humans and animals through direct contact with soil, water, or air contaminated by the Burkholderia pseudomallei bacteria. Humans and animals are believed to acquire melioidosis by inhalation of contaminated dust or water droplets, ingestion of contaminated water, and contact with contaminated soil, especially through skin abrasions (e.g., by means of a penetrating injury or open wound), inhalation (e.g., during severe weather or as a result of deliberate release), or ingestion (e.g., through contaminated food or water) (see Figure 2 above) ²³, ¹⁵, ²⁴, ²⁵. Melioidosis is predominantly seasonal; 75 to 81% of cases occur during the rainy season ⁸, ²⁶. Incidence peaks between 40 and 60 years of age, but melioidosis is also well recognized in children ²⁷. Melioidosis has been transmitted to infants through breast milk from mothers with mastitis ⁸.

Melioidosis signs and symptoms can vary greatly and may mimic those of tuberculosis (TB) or common forms of pneumonia ²⁸. Signs and symptoms may include pain or swelling, fever, abscess, cough, high fever, headache, trouble breathing, and more. Although healthy people can also experience signs and symptoms of the disease, people with certain conditions like diabetes, liver disease, kidney disease, lung disease, thalassemia, cancer, or certain autoimmune diseases are more severely affected.

Symptoms of melioidosis or Burkholderia pseudomallei infection include:

• Fever
• Headache
• Trouble breathing
• Stomach or chest pain
• Muscle pain
• Confusion
• Seizure.

A delay in diagnosis can be fatal, since empirical antibiotic regimens used for suspected bacterial sepsis often do not provide adequate coverage for Burkholderia pseudomallei.

Melioidosis diagnosis is made by collecting blood, sputum, urine, or pus samples and growing the bacteria ²⁹. Current treatment is divided into two stages: an intravenous (IV) antibiotic stage and oral antibiotic maintenance stage to prevent recurrence ²⁹.

Antimicrobial agents that have been effective against melioidosis include:

Intravenous therapy antibiotics for 2 to 8 weeks that consists of:

• Ceftazidime administered every 6-8 hours
• OR
• Meropenem administered every 8 hours

Followed by oral antimicrobial therapy for 3 to 6 months that consists of:

• Trimethoprim-sulfamethoxazole taken every 12 hours
• OR
• Amoxicillin/clavulanic acid (co-amoxiclav) taken every 8 hours.

Patients with penicillin allergies should notify their doctor, who can prescribe an alternative treatment course. Current melioidosis therapy guidelines recommend an initial intensive phase of at least 10 to 14 days of ceftazidime, meropenem, or imipenem administered intravenously (IV) followed by oral eradication therapy, usually with trimethoprim–sulfamethoxazole (TMP-SMX) for 3 to 6 months (Table 3) ³⁰, ³¹, ³², ³³. Carbapenems, such as meropenem and imipenem, have lower minimum inhibitory concentrations (MIC) and superior results in in vitro time-kill studies than ceftazidime, but a randomized comparative study in Thailand did not show a survival advantage of imipenem over ceftazidime ³⁴. The current recommendation for the oral phase of therapy is trimethoprim–sulfamethoxazole (TMP-SMX), which replaces the previous recommendation to give this medication in conjunction with doxycycline ³².

The 2014 Revised Royal Darwin Hospital guideline recommends an intravenous intensive phase including therapy with either ceftazidime at 50 mg/kg of body weight (up to 2 g) every 6 to 8 hour if the patient is in the general medical ward (a hospital room designed for multiple patients, typically with two or more beds, that provides general medical care for a wide range of conditions) or meropenem at 25 mg/kg (up to 1 g) every 8 hour if in the intensive care unit (ICU) ³¹. The duration of this phase is 10 to 14 days for uncomplicated infection or 4 to 6 weeks for persistent septic shock, deep-seated or organ abscesses, extensive lung disease, septic arthritis, osteomyelitis, or neurological melioidosis. The oral eradication phase includes therapy with trimethoprim–sulfamethoxazole (TMP-SMX), dose depending on weight and age, for a period of 3 to 6 months. For a child of <40 kg, a dosage of 8/40 mg every 12 h is recommended. Dosage recommendations for adults include the following: <40 kg, 160/800 mg every 12 hours; 40 to 60 kg, 240/1,200 mg every 12 hours; and >60 kg, 320/1,600 mg every 12 hours ³⁰, ³¹, ³⁵.

A careful search for internal-organ abscesses is recommended, such as with the use of computed tomography (CT scan) or ultrasonography of the abdomen and pelvis. Adjunctive therapy for abscesses includes drainage of collections and aspiration and washout of septic joints.

Figure 1. Burkholderia pseudomallei

Footnotes: Burkholderia pseudomallei organisms are small Gram-negative bacilli with bipolar staining giving them a “safety pin” appearance due to central accumulation of polyhydroxybutyrate (PHB) granules, which do not retain the staining reagents ³⁶. (Magnification ×100). However, the “safety pin” appearance is not specific to Burkholderia pseudomallei. The Gram stain appearance alone is not sufficient to make a presumptive diagnosis.

[Source ²¹ ]

Figure 2. Burkholderia pseudomallei transmission

Footnotes: Burkholderia pseudomallei is a aerobic, Gram-negative soil-dwelling facultative intracellular bacterium that resides in the rhizosphere of tropical soils. Burkholderia pseudomallei causes melioidosis, which is transmitted by cutaneous entry, ingestion, or inhalation of contaminated soil or water. Infection with Burkholderia pseudomallei can cause a wide array of clinical symptoms such as pneumonia, bone, joint, skin, genitourinary, and central nervous system infections, as well as parotid abscesses in children. Mammalian virulence is linked to the Burkholderia pseudomallei intracellular life cycle, which begins with attachment and internalization by host cells. Burkholderia pseudomallei can infect a wide range of eukaryotic cells, including macrophages, monocytes, and neutrophils, as well as nonphagocytic cells. Once internalized, a type 3 secretion system (T3SSBsa) facilitates Burkholderia pseudomallei escape from the phagosome, and the bacteria replicate in the cytoplasm. Autotransporter protein BimA mediates actin polymerization, enabling Burkholderia pseudomallei to spread, cell to cell, using actin-based motility. This process, coupled with the activity of a type 6 secretion system (T6SS-5), results in host membrane fusion and the formation of multinucleated giant cells. Capsule polysaccharides also contribute to virulence and evasion of host innate immunity. Treatment of Burkholderia pseudomallei infections is complicated by the organism’s intrinsic resistance to multiple classes of antimicrobials, largely due to an abundance of efflux pumps and reduced outer membrane permeability. While Burkholderia pseudomallei is commonly associated with endemic ‘hotspots’ in southeast Asia and northern Australia, there is increasing evidence that it is likely endemic in a large range of tropical and subtropical areas, including regions in Africa, South America, the Middle East, Central America, and the Caribbean. Soil and climate conditions favorable for Burkholderia pseudomallei survival are also found in additional areas worldwide. Consequently, it is important for clinical and public health laboratories located outside of high-endemicity areas to be aware of Burkholderia pseudomallei, as well as for improved diagnostic and reporting methods.

[Source ³⁷ ]

Figure 3. Melioidosis geographic distribution

Footnotes: Areas where melioidosis is highly endemic, endemic, or sporadic and possibly endemic are indicated. This reflects current knowledge that is based on limited evidence and is likely to change over time.

[Source ⁸ ]

Figure 4. Melioidosis signs and symptoms

Footnotes: Melioidosis have a wide range of clinical signs and symptoms, and severity varies from an acute fulminant septic illness to a chronic infection. Shown are the routes of infection (blue boxes: percutaneous inoculation, inhalation, and ingestion), the natural history of infection (red boxes: asymptomatic infection, bacteremia, or reactivation of latent focus), and the diverse disease manifestations (white text). Panel A shows cutaneous melioidosis in a healthy host. Panel B shows lung abscesses on the chest radiograph of a patient with acute melioidosis pneumonia, and Panel C shows the corresponding computed tomographic (CT) scan. Panel D shows the skin manifestations in a fatal case of disseminated melioidosis. Panel E shows splenic abscesses on an abdominal CT scan. Panel F shows aspirated pus in a patient with prostatic and periprostatic abscesses, and Panel G shows the abscesses on a CT scan from the patient.

[Source ³⁵ ]

Table 1. Melioidosis treatment

[Source ³⁵ ]

Melioidosis transmission

Melioidosis is an infectious disease caused by the aerobic, Gram-negative soil-dwelling facultative intracellular bacteria Burkholderia pseudomallei that are commonly found in the soil and water, that can infect humans or animals through direct contact with soil, water, or air contaminated by the bacteria. While melioidosis infection has taken place all over the world, Southeast Asia and northern Australia are the areas in which it is primarily found. People can get Melioidosis through direct contact with contaminated soil and surface waters.

Humans and animals are believed to acquire melioidosis by inhalation of contaminated dust or water droplets, ingestion of contaminated water, and contact with contaminated soil, especially through skin abrasions (e.g., by means of a penetrating injury or open wound), inhalation (e.g., during severe weather or as a result of deliberate release), or ingestion (e.g., through contaminated food or water) (see Figure 2 above) ²³, ¹⁵, ²⁴, ²⁵. Melioidosis is predominantly seasonal; 75 to 81% of cases occur during the rainy season ⁸, ²⁶. Incidence peaks between 40 and 60 years of age, but melioidosis is also well recognized in children ²⁷. Melioidosis has been transmitted to infants through breast milk from mothers with mastitis ⁸.

It is very rare for people to get melioidosis from another person. While a few cases have been documented, contaminated soil and surface water remain the primary way in which people become infected.

The incubation period for melioidosis has been evaluated in a single published study, in which 25% of patients who recalled a specific event such as an injury had clinical signs and symptoms 1 to 21 days (mean, 9 days) later ³⁸. The inoculating dose, strain virulence, mode of infection, and risk factors in the host are all likely contributors to the incubation period, clinical presentation, and outcome ³⁵. An incubation period of a day or less was documented after aspiration of Burkholderia pseudomallei in a near-drowning event ³⁹, whereas the longest recorded apparent incubation period was 62 years ⁴⁰.

Besides humans, many animal species are susceptible to melioidosis, including:

• Sheep
• Goats
• Swine
• Horses
• Cats
• Dogs
• Cattle.

Burkholderia pseudomallei

Burkholderia pseudomallei belongs to the Burkholderia genus, which contains over 80 species ⁴¹. Only Burkholderia pseudomallei, Burkholderia mallei, Burkholderia cepacia complex, and Burkholderia gladioli are generally recognized as human pathogens ⁴². These organisms are aerobic, non-spore-forming, nonfermenting Gram-negative bacilli. All are environmental organisms, with the exception of the host-adapted pathogen Burkholderia mallei ⁴².

Burkholderia mallei causes glanders in horses and other solipeds and is highly virulent in humans. Burkholderia cenocepacia is an important cause of opportunistic infection in patients with cystic fibrosis. Burkholderia thailandensis coexists with Burkholderia pseudomallei in the soil in Thailand and Australia. Burkholderia oklahomensis is sporadically found in the midwestern United States. Burkholderia thailandensis and Burkholderia oklahomensis rarely, if ever, cause disease and are much less virulent (by a factor of >100,000) than Burkholderia pseudomallei in hamsters and mice ⁴³, ⁴⁴.

Risk factor for melioidosis

Although healthy people may get melioidosis, having the following medical conditions may increase your risk ², ²¹:

• Diabetes
• Liver disease
• Heavy alcohol use
• Kidney disease
• Thalassemia (a group of inherited genetic blood disorders where the body produces insufficient amounts of healthy hemoglobin, a protein in red blood cells essential for carrying oxygen)
• Cancer, or another condition that weakens the immune system
• Chronic heart disease
• HIV
• Kava
• Smoking
• Chronic lung disease, like cystic fibrosis, chronic obstructive pulmonary disease (COPD), or bronchiectasis.
• Australian Aboriginal and/or Torres Strait Islander race.

Certain activities also may increase your risk of being exposed to the Burkholderia pseudomallei bacteria that causes melioidosis, including:

• Travel to areas where the disease is common.
• Breathing in contaminated water droplets or soil dust that get into the air after severe weather like hurricanes or heavy rainfall.
• Hobbies or jobs that could put you in contact with contaminated soil or water.
• Drinking unchlorinated or untreated drinking water.

Since up to 80% of patients with melioidosis have one or more risk factors for the infection, it has been suggested that melioidosis should be considered an opportunistic infection that is unlikely to have a fatal outcome in a previously healthy person, provided that the infection is diagnosed early and appropriate antibiotic agents and intensive care resources are available ⁴⁵. Risk factors for melioidosis include diabetes (present in 23 to 60% of patients), heavy alcohol use (in 12 to 39%), chronic lung disease (in 12 to 27%), chronic kidney disease (in 10 to 27%), thalassemia (in 7%), glucocorticoid therapy (in <5%), and cancer (in <5%) ⁴⁵, ⁴⁶.

Melioidosis prevention

In areas where the melioidosis disease is widespread, contact with contaminated soil or water can put people at risk for melioidosis.

However, in these areas, there are things that certain groups of people can do to help minimize the risk of exposure:

• If you have open skin wounds, or if you have chronic conditions like diabetes or kidney disease, avoid contact with soil and standing water.
• If you perform agricultural work or have hobbies or jobs that raise your risk of exposure, wear boots, which can prevent infection through your feet and lower legs.
• Healthcare workers can use standard precautions when treating patients with melioidosis to help prevent infection. They should also label samples appropriately if they suspect melioidosis to protect lab personnel.
• Laboratory personnel should follow good laboratory practices, including using appropriate personal protective equipment (PPE) and respiratory protection.

No vaccines are currently available for glanders or melioidosis ¹.

Currently there is limited evidence to demonstrate effective prevention of infection in humans ⁴⁷, ⁴⁸. Amoxicillin-clavulanic acid, doxycycline, and trimethoprim–sulfamethoxazole (TMP-SMX) have been assessed in a 10-day postexposure prophylaxis mouse model. Trimethoprim–sulfamethoxazole (TMP-SMX) was the only agent to achieve 100% survival at 21 days in this study; however, additional murine research demonstrated 44% and 83% survival following a 14- or 21-day course ⁴⁹, ⁵⁰. Current international consensus guidelines recommend a 21-day course of trimethoprim–sulfamethoxazole (TMP-SMX). Alternative prophylactic therapy includes doxycycline or amoxicillin-clavulanic acid ⁴⁷, ³⁰. Prophylaxis for specific at-risk populations may be considered. One study reported that trimethoprim–sulfamethoxazole (TMP-SMX) prophylaxis for hemodialysis patients during the wet season in a region of endemicity is likely to be effective in reducing incidence of infection and that an oral dose of 160/800 mg daily appears to be well tolerated and safe in this patient cohort ⁵¹. Notably, compared to that in a neighboring region, the study appears to have included a higher proportion of indigenous hemodialysis patients in rural dialysis centers. This region had a lower incidence of melioidosis among their hemodialysis cohort, and therefore, rates of adverse effects, and cost-effectiveness modelling, would not support universal prophylaxis of their population ⁵².

Melioidosis symptoms

There are several types of melioidosis infection, each with their own set of signs and symptoms. However, it is important to note that melioidosis has a wide range of signs and symptoms and severity varies from an acute fulminant septic illness to a chronic infection (the presence of symptoms for >2 months, accounting for 11% of all cases) that can be mistaken for other diseases such as tuberculosis (TB) or more common forms of pneumonia or cancer ⁹, ²⁶.

You usually develop symptoms of melioidosis within 1 to 3 weeks after you’ve been infected with the Burkholderia pseudomallei bacteria. Some cases have developed symptoms months or years after exposure. Melioidosis can affect one body system or affect the entire body. Because of these factors, melioidosis is hard to diagnose and may be mistaken for other diseases.

Sometimes melioidosis is just in one area (localized), and it may look like an ulcer or skin sore. You might have a fever, swelling, and muscle aches.

Most often, melioidosis shows up as a lung infection. You might have a cough, chest pain, high fever, headache, and you might not feel like eating.

Whether you’ve just come down with melioidosis or you’ve had it for a long time, it can affect different organ systems throughout the body (disseminated infection). It can cause problems with the liver, spleen, prostate, joints, bones, lymph nodes, skin, or brain. Melioidosis can lead to a dangerous bloodstream infection (sepsis).

Localized Infection:

• Localized pain or swelling
• Fever
• Ulceration
• Abscess

Pulmonary Infection:

• Cough
• Chest pain
• High fever
• Headache
• Anorexia

Bloodstream Infection:

• Fever
• Headache
• Respiratory distress
• Abdominal discomfort
• Joint pain
• Disorientation

Disseminated Infection:

• Fever
• Weight loss
• Stomach or chest pain
• Muscle or joint pain
• Headache
• Seizures

The time between an exposure to the Burkholderia pseudomallei bacteria that causes melioidosis disease and the emergence of symptoms is not clearly defined, but may range from one day to many years; generally symptoms appear two to four weeks after exposure.

In a descriptive study involving 540 patients in tropical Australia over a 20-year period, the primary presenting feature was pneumonia (in 51% of patients), followed by genitourinary infection (in 14%), skin infection (in 13%), bacteremia without evident focus (in 11%), septic arthritis or osteomyelitis (in 4%), and neurologic involvement (in 3%) ⁴⁵. The remaining 4% of patients had no evident focus of infection. Over half of patients have bacteremia on presentation, and septic shock develops in approximately one fifth ⁴⁵. Internal-organ abscesses and secondary foci in the lungs, joints, or both are common.

A notable difference in presentation between patients in tropical Australia and those in Southeast Asia is suppurative parotitis, which accounts for up to 40% of cases of melioidosis in children in Thailand and Cambodia but is extremely rare in Australia ²⁷. In Australia, prostatic melioidosis is present in approximately 20% of male patients, and neurologic melioidosis is manifested as brain-stem encephalitis, often with cranial-nerve palsies (especially cranial nerve VII [7th cranial nerve or facial nerve]), or as myelitis with peripheral motor weakness ⁴⁵. Recurrent melioidosis occurs in approximately 1 in 16 patients, often in the first year after the initial presentation ⁴⁵, ⁵³. Roughly a quarter of recurrences are due to reinfection, with the remainder due to relapse from a persistent focus of infection ⁵³. Mortality rates for melioidosis are approximately 40% in northeast Thailand (35% in children) ⁴⁶ and 14% in Australia ⁴⁵.

Table 2. Melioidosis clinical presentation by region

Clinical presentation	No./total (%)
	Australia	Malaysia	Singapore	India	Thailand
Fever	a —	119/128 (93)	293/372 (79)	21/32 (66)	95/134 (71)
Pulmonary infection	412/763 (54)	225/537 (42)	203/614 (33)	53/226 (23)	121/247 (49)
Skin/soft tissue infection	123/761 (16)	99/402 (25)	65/372 (17)	23/180 (13)	35/247 (14)
Bone and joint infection	22/597 (4)	35/402 (9)	2/372 (1)	36/226 (16)	35/247 (14)
Genitourinary infection b	—	10/360 (3)	—	5/180 (3)	8/134 (6)
Neurological infection	22/751 (3)	21/370 (6)	2/372 (1)	19/180 (11)	2/30 (7)
Liver abscess	17/597 (3)	46/537 (9)	—	20/180 (11)	93/247 (38)
Splenic abscess	30/597 (5)	45/537 (8)	—	20/226 (9)	68/247 (28)
Prostate abscess	83/408 (20)	5/225 (2)	—	8/226 (4)	13/155 (8)
Parotid abscess	2/794 (0)		—	77/226 (3)	5/134 (4)
Mycotic pseudoaneurysm	3/597 (1)	4/67 (6)	—	—	—
Pericardial effusion/pericarditis	4/540 (1)	1/67 (1)	1/372 (0)	3/180 (2)	—
No clinical focus	66/597 (11)	69/392 (18)	—	9/95 (9)	—
Septic shock	174/715 (24)	93/225 (41)	—	32/180 (18)	26/134 (19)
Bacteremia	477/794 (60)	391/537 (73)	592/986 (60)	87/226 (38)	491/874 (56)
Mortality	118/794 (15)	212/527 (40)	260/614 (42)	32/180 (18)	1,205/2,913 (41)

Footnotes:

^{a —}, no data reported.
^b Excluding prostate.

[Source ²¹ ]

Melioidosis diagnosis

Microbiological culture of Burkholderia pseudomallei from any specimen in a patient with suspected melioidosis remains the diagnostic “gold standard” ²¹. But culture of Burkholderia pseudomallei is not optimal because the sensitivity may be as low as 60% ⁵⁴. Culture specimens include blood, throat, urine, respiratory secretions, and, when available, cerebrospinal fluid (CSF), pus, and swabs from wounds or surface lesions as appropriate, for all patients with suspected Burkholderia pseudomallei cases. Burkholderia pseudomallei grows well on most routine laboratory media ²¹. Improved isolation of the organism from nonsterile sites can be achieved by the use of selective media such as Ashdown’s media and selective enrichment broth ⁵⁵. Any positive culture is considered diagnostic for melioidosis because Burkholderia pseudomallei is not considered to be a member of the colonizing microbiota.

Bacteremia has been found to occur in 38 to 73% of cases ²¹. In one study isolating Burkholderia pseudomallei from blood using the BacT/Alert (bioMérieux, Marcy l’Etoile, France) automated blood culture system, 62.5% of isolates were detected in 24 hour and 93% were detected within 48 hour of incubation. The time for the system to signal positive (mean ± standard error) was 23.9 ± 14.9 hour ⁵⁶. When comparing the BacT/Alert system with conventional culture, which utilized in-house brain heart infusion media and visual detection, the automated system was found to have a sensitivity of 73.5%, compared to 90.3% for conventional culture ⁵⁷. The major benefit of the automated system was a shorter time to positivity, approximately 1 day ⁵⁷. Additionally, a study evaluating the sensitivity of the BacT/Alert FA aerobic bottle and BacT/Alert MB bottle with those of Middlebrook 7H9 broth, glycerol, and sodium polyanethol sulfonate demonstrated improved organism recovery with the MB bottle for patients with prior antimicrobial exposure ⁵⁸. The Bactec (Becton Dickinson, Sparks, MD) automated blood culture system has also been used in laboratories for the isolation of Burkholderia pseudomallei from blood and sterile fluid. There are, however, limited data regarding the comparative sensitivity and time to positivity ⁵⁹, ⁶⁰. The urine culture of patients with melioidosis is estimated to be positive for 28% of cases in Thailand ⁶¹. Centrifugation of the sample and culture of the pellet improve sensitivity. Additionally, a quantitative urine culture revealed a comparatively higher mortality rate with increasing counts, with in-hospital mortality of 39% in culture-negative patients, 58% with a quantification of <10³ CFU/ml, and up to 71% with a quantification of >10⁵ CFU/ml ⁶¹. Throat swabs are an effective method of organism recovery, and routine screening of suspected melioidosis patients is performed in certain centers ⁶², ⁶³.

Laboratory procedures for maximizing the culture and identification of Burkholderia pseudomallei have been developed, but a delay in the identification of Burkholderia pseudomallei or a misidentification as another species is not uncommon in laboratories that are unfamiliar with this organism ³³. A direct polymerase-chain-reaction assay of a clinical sample to detect Burkholderia pseudomallei and Burkholderia mallei may provide a more rapid test result than culture, but the assay is less sensitive than culture , especially when performed on blood ⁶⁴, ⁶⁵, ⁶⁶. Serologic testing alone is inadequate for confirming the diagnosis, especially in endemic regions where the background seropositivity rate can be more than 50% ⁶⁷. If empirical therapy for melioidosis is begun and Burkholderia pseudomallei is not subsequently detected in adequate cultures of specimens obtained before therapy, completion of a full course of antimicrobial therapy is generally not recommended.

Gram staining and examination under light microscopy of clinical specimens or bacterial colonies can identify gram-negative bacilli with a granular or safety pin appearance, but this appearance is not specific for Burkholderia pseudomallei. Gram-negative organisms that are oxidase positive, gentamicin- and colistin-resistant, and susceptible to amoxicillin/clavulanic acid, also known as co-amoxiclav, should be strongly suspected to be Burkholderia pseudomallei. During a public health emergency, or where Burkholderia pseudomallei may be of high prevalence in the community, a selective medium such as Ashdown agar ⁶⁸ that will suppress overgrowth of normal microbiota in nonsterile specimens (e.g., throat swabs) should be used for suspected cases. However, rare gentamicin-susceptible Burkholderia pseudomallei isolates exist (1 in 1,000), which will not grow on Ashdown agar ⁶⁹.

Commercial Burkholderia cepacia agar is a good alternative if Ashdown agar is not available ⁷⁰. Bacterial colonies are usually visible after 24 hour. Colonies grown on Ashdown agar might have a violet or purple rugose, cornflower-like appearance. Colonies on nonselective media can vary in appearance and can be rugose or smooth. After positive identification is established, isolates should be collected for strain characterization and epidemiologic information as well as to aid forensic data investigations.

Biochemical tests such as the API 20NE (bioMérieux Inc., Durham, NC, USA) and Vitek II (bioMérieux Inc.) might help with confirmation, but misidentifications by both systems have been reported ⁷¹. Bacterial identification methods that use assays with polyclonal or monoclonal antibodies against B. pseudomallei and B. mallei have been described, e.g., a direct immunofluorescence assay that can be applied directly to clinical specimens and has been reported to have a sensitivity of 66% ⁷² and a latex agglutination assay that can be used to identify colonies. Both of these assays use in-house reagents developed in Thailand that are not commercially available but would be useful during a public health emergency for which there is a need to quickly distinguish between melioidosis and other illnesses that produce similar signs and symptoms.

Time to positive culture result (which is correlated with the level of bacteremia) is a prognostic indicator of death. Melioidosis results in a mortality rate of 74% if blood cultures show positive results within 24 h, compared with 41% mortality rate if >24 h pass before blood cultures become positive ⁷³.

Melioidosis treatment

When a melioidosis infection is diagnosed, the disease can be treated with the use of appropriate medication.

The type of infection and the course of treatment will impact long-term outcome. Treatment generally starts with intravenous (within a vein) antimicrobial therapy for 10-14 days, followed by 3-6 months of oral antimicrobial therapy.

Antimicrobial agents that have been effective against melioidosis include:

Intravenous therapy antibiotics for 2 to 8 weeks that consists of:

• Ceftazidime administered every 6-8 hours
• OR
• Meropenem administered every 8 hours

Followed by oral antimicrobial therapy for 3 to 6 months that consists of:

• Trimethoprim–sulfamethoxazole (TMP-SMX) taken every 12 hours
• OR
• Amoxicillin/clavulanic acid (co-amoxiclav) taken every 8 hours.

Patients with penicillin allergies should notify their doctor, who can prescribe an alternative treatment course.

Current melioidosis therapy guidelines recommend an initial intensive phase of at least 10 to 14 days of ceftazidime, meropenem, or imipenem administered intravenously (IV) followed by oral eradication therapy, usually with trimethoprim–sulfamethoxazole (TMP-SMX) for 3 to 6 months (Table 3) ³⁰, ³¹, ³², ³³. Carbapenems, such as meropenem and imipenem, have lower minimum inhibitory concentrations (MIC) and superior results in in vitro time-kill studies than ceftazidime, but a randomized comparative study in Thailand did not show a survival advantage of imipenem over ceftazidime ³⁴. The current recommendation for the oral phase of therapy is trimethoprim–sulfamethoxazole (TMP-SMX), which replaces the previous recommendation to give this medication in conjunction with doxycycline ³².

The 2014 Revised Royal Darwin Hospital guideline recommends an intravenous intensive phase including therapy with either ceftazidime at 50 mg/kg of body weight (up to 2 g) every 6 to 8 hour if the patient is in the general medical ward (a hospital room designed for multiple patients, typically with two or more beds, that provides general medical care for a wide range of conditions) or meropenem at 25 mg/kg (up to 1 g) every 8 hour if in the intensive care unit (ICU) ³¹. The duration of this phase is 10 to 14 days for uncomplicated infection or 4 to 6 weeks for persistent septic shock, deep-seated or organ abscesses, extensive lung disease, septic arthritis, osteomyelitis, or neurological melioidosis. The oral eradication phase includes therapy with trimethoprim–sulfamethoxazole (TMP-SMX), dose depending on weight and age, for a period of 3 to 6 months. For a child of <40 kg, a dosage of 8/40 mg every 12 h is recommended. Dosage recommendations for adults include the following: <40 kg, 160/800 mg every 12 hours; 40 to 60 kg, 240/1,200 mg every 12 hours; and >60 kg, 320/1,600 mg every 12 hours ³⁰, ³¹, ³⁵.

Although trimethoprim–sulfamethoxazole (TMP-SMX) is thought to be a bacteriostatic antimicrobial with time-dependent action, a time-kill study demonstrated that achievable in vivo drug concentrations appear to have a concentration-dependent bactericidal effect ⁷⁴. Second-line oral antimicrobial agents include doxycycline and amoxicillin-clavulanic acid. The recommended amoxicillin-clavulanic acid dosage is 20/5 mg per kilogram of body weight three times per day ⁷⁵, ⁸, ³⁵. Previous Thai recommendations for oral therapy included a four-drug regimen consisting of trimethoprim–sulfamethoxazole (TMP-SMX), chloramphenicol, and doxycycline ⁷⁶. However, one open-label randomized trial demonstrated no difference in efficacy of this regimen and poorer tolerability than with the combination of trimethoprim–sulfamethoxazole (TMP-SMX) and doxycycline. Furthermore, this trial revealed that duration of therapy was critical, with patients receiving less than 12 weeks of therapy incurring a 5.7-fold-increased risk of relapse or death ⁷⁷. More recent evidence has shown noninferiority and improved tolerability when comparing trimethoprim–sulfamethoxazole (TMP-SMX) alone and trimethoprim–sulfamethoxazole (TMP-SMX) with doxycycline ⁷⁸. Therefore, the current Thai recommendation for duration of oral therapy is 12 to 20 weeks, compared to the Australian recommendation of 3 to 6 months ⁸, ⁵³.

Research in the Northern Territory of Australia has revealed decreased rates of relapse or recrudescence depending on duration of intensive-phase therapy ⁷⁹. With a median intensive phase of 26 days, the relapse or recrudescence rate decreased from 5.2% to 0.5% irrespective of compliance to eradication/oral phase ⁷⁹. Current Darwin Northern Territory of Australia guidelines recommend a minimum intensive phase of 2 weeks for skin abscess, bacteremia without focus, and pneumonia without lymphadenopathy or ICU admission ⁷⁹. Four weeks is required for pneumonia with lymphadenopathy or ICU admission or deep-seated collection (abscess anywhere other than skin), 6 weeks for osteomyelitis, and 8 weeks for CNS or arterial infection ⁷⁹. This study alters traditional thinking that choice and duration of eradication therapy are the most important predictors of relapse ⁷⁹. Further analysis of septic arthritis and osteomyelitis management suggests that 5 weeks of intravenous therapy or 4 weeks for an isolated single joint without osteomyelitis will suffice. Three months of oral eradication-phase therapy appears to demonstrate a similar rate of relapse or complications. However, there is insufficient evidence to recommend a shorter course of therapy for osteomyelitis ⁸⁰. A relapse rate of approximately 9.7% between 1986 and 2004 was reported from Thailand ⁸¹. This has improved to approximately 6% with an unspecified intravenous phase of at least 10 days ⁸¹, ⁸². There is a role for 3 months of oral-only therapy for uncomplicated soft tissue infection, provided that investigations for deep-seated collections are negative ⁸³, ⁸⁴.

Adjunctive therapy may include the addition of granulocyte colony-stimulating factor (G-CSF), which has been studied in multiple locations with various results ⁸⁵, ⁸⁶, ⁸⁷. Initial observational data suggested that decreased in-hospital mortality from 95 to 10% was attributable to the use of granulocyte colony-stimulating factor (G-CSF) ⁸⁷. However, it was subsequently argued that concomitant improvement in other management factors confounded these results ⁸⁸. A randomized controlled trial of G-CSF use in severe melioidosis sepsis demonstrated a longer duration of survival when measured in hours, but no overall mortality benefit ⁸⁶. The current Darwin in the Northern Territory of Australia guidelines recommend 300 μg of intravenous G-CSF daily for patients with septic shock, initiated as soon as a probable microbiological diagnosis of melioidosis is made and continuing for either 10 days or the duration of intensive care unit stay contingent on clinical progress. Contraindications to commencement or continuation include an acute coronary event or total blood white cell count of >50,000 ×106/liter ³¹.

Source control is an important feature in overall management ⁴⁸. Abscesses in most organ systems of patients with melioidosis often resolve after antibiotic therapy; however, prostatic abscesses greater than 1 cm usually require surgical debridement and drainage ⁸⁹, ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ⁹⁵.

Fever clearance may be slow, with a median of 9 days in one study, and therefore, this may not necessarily stand as an indication for surgical intervention ⁹⁶. While ideal, source control may not be achieved in every circumstance, particularly in resource-limited settings. It is important to note that treatment success has been achieved with prolonged therapy in the setting of undrained abscesses ²³, ⁹⁴.

Table 3. Melioidosis treatment and prophylaxis

Phase or adjustment	Drug and dose	Clinical manifestation(s) (duration of treatment)
Intensive	Ceftazidime, 2 g i.v. (child, 50 mg/kg up to 2 g), every 6 hours, OR Meropenem, 1 g i.v. (child, 25 mg/kg up to 1 g), every 8 hours (2 g for central nervous system (CNS) infection)	Pneumonia (2–4 wks); Bacteremia, no focus (2 wks); Skin and soft tissue (2 wks); Abscess, deep tissue (4 wks); Septic arthritis, single joint (4 wks); Osteomyelitis (6 wks); Neurological (8 wks); Mycotic aneurysm (8 wks)
Renal dose adjustment
Ceftazidime
Creatinine clearance of (ml/min):
31–50 ml/min	≤60 kg, 1 g q8h; >60 kg, 2 g q8h
15–30 ml/min	≤60 kg, 1 g q12h; >60 kg, 2 g q12h
<15 ml/min	≤60 kg, 1 g q24h
Dialysis
Hemodialysis	As for creatinine clearance of <15 ml/min, dose post-hemodialysis
Continuous ambulatory peritoneal dialysis	As for creatinine clearance of <15 ml/min, dose post-hemodialysis, may administer intraperitoneally with dwell time of >6 h and 25% extra dose for convenience
Continuous renal replacement therapy	2 g q12h
Meropenem
Creatinine clearance of (ml/min):
31–50 ml/min	1 g q12h
15–30 ml/min	1 g q12h
<15 ml/min	1 g q24h
Dialysis
Hemodialysis	As for creatinine clearance of <15 ml/min, dose post-hemodialysis
Continuous ambulatory peritoneal dialysis	As for creatinine clearance of <15 ml/min
Continuous renal replacement therapy	1 g q12h
Trimethoprim-sulfamethoxazole (TMP-SMX)
Creatinine clearance of (ml/min):
31–50 ml/min	≤60 kg, 240/1,200 mg every 12 hours; >60 kg, 320/1,600 mg every 12 hours
15–30 ml/min	≤60 kg, 240/1,200 mg every 24 hours; >60 kg, 320/1,600 mg every 24 hours
<15 ml/min	≤60 kg, 240/1,200 mg every 24 hours; >60 kg, 320/1,600 mg every 24 hours
Dialysis
Hemodialysis	As for creatiine clearance of <15 ml/min, dose post-hemodialysis
Continuous ambulatory peritoneal dialysis	As for creatiine clearance of <15 ml/min
Continuous renal replacement therapy	As for creatiine clearance of 15–30 ml/min
Eradication	Trimethoprim-sulfamethoxazole (child, 6/30 mg/kg up to 240/1,200 mg; adult 40–60 kg, 240/1,200 mg; >60 kg, 320/1,600 mg orally, every 12 hours) and folic acid, 5 mg (child, 0.1 mg/kg up to 5 mg) orally, daily	Pneumonia (3 mo); bacteremia, no focus (3 mo); skin and soft tissue (3 mo); abscess, deep tissue (3 mo); septic arthritis, single joint (3 mo); osteomyelitis (6 mo); neurological (6 mo); endovascular (6 mo)
Prophylaxis	Trimethoprim-sulfamethoxazole (<40kg, 160/800 mg; 40–60 kg, 240/1,200 mg; >60 kg, 320/1,600 mg orally, every 12 hours) and folic acid, 5 mg (child, 0.1 mg/kg up to 5 mg) orally, daily OR Doxycycline (2.5 mg/kg/dose up to 100 mg orally, every 12 hours) OR Amoxicillin-clavulanate (≤60 kg, 1,000/250 mg; >60 kg, 1,500/375 mg, every 8 hours)	High probability postexposure (3 wks)
	Trimethoprim-sulfamethoxazole (160/800 mg orally, daily) and folic acid (5 mg orally, daily)	Hemodialysis patients, wet season, high-incidence region (26 wks)

[Source ²¹ ]

Melioidosis prognosis

Melioidosis overall survival is affected by multiple factors, including premorbid host determinants. Diabetes, Australian Aboriginal and/or Torres Strait Islander race, chronic renal disease, and older age negatively impact mortality ²³, ¹⁶, ⁹⁷, ⁹⁸. In southern Thailand, septic shock on admission has a reported in-hospital mortality odds ratio of 29.14 to 68.20 ⁹⁹. An odds ratio (OR) is a measure of association between an exposure and an outcome. The odds ratio (OR) represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure ¹⁰⁰.

• Odds ratio (OR) =1 Exposure does not affect odds of outcome
• Odds ratio (OR) >1 Exposure associated with higher odds of outcome
• Odds ratio (OR) <1 Exposure associated with lower odds of outcome

It has been shown that 73.7% of patients with a positive blood culture occurring within 24 hour of incubation died during their admission. This compared with a 40.9% in-hospital mortality rate for patients whose blood cultures signaled positive more than 24 hour from incubation ⁵⁶. A bacteremia quantification of ≤1 CFU/ml has been associated with a 42% mortality rate, while a positive blood culture with >100 CFU/ml resulted in a fatal outcome in 96% of patients ¹⁰¹.

Although mortality remains high in developing nations such as Thailand, two centers in Australia have demonstrated a remarkable decrease in overall mortality over the preceding two decades ²³, ¹⁶, ¹⁰². The initial peak mortality of 30% in one facility has decreased to 9% in all patients monitored throughout treatment ²³. When comparing presentation with septic shock and death over time, the improvement has been found to be dramatic, improving from 100% mortality to 27% ²³. Patients over 50 years of age have an increased mortality, with an odds ratio of 2.0, compared with the rate for those under 50. The presence of any risk factor has a reported mortality odds ratio of 9.4 ²³. With regard to bacteremia, repeated positive blood culture after the first or second week of therapy is a strong predictor of mortality, with an odds ratio of 4.2 after adjustment for age, sex, diabetes, blood pressure, pneumonia, and duration of intravenous antibiotics. Importantly, repeated culture of Burkholderia pseudomallei from nonsterile sites did not confer increased risk of death ¹⁰³. The mortality of chronic melioidosis is low and is estimated at 2% in Australia ²³.

In children, the mortality rates range from 7% overall in a prospective Australian study to 16.8% in-hospital mortality from a retrospective Cambodian study ¹⁰⁴, ⁸³. This Cambodian study revealed a 71.8% in-hospital mortality rate in bacteremic children, and another study revealed a similarly high in-hospital mortality rate (73%) in a Thai neonatal population who presented with either neonatal meningitis or bacteremia ¹⁰⁴, ¹⁰⁵. Additional prospective data from Cambodia reveal an overall mortality rate of 62% ¹⁰⁶. Specifically in Cambodia, potential reasons for a high mortality rate may be a combination of inadequate microbiology diagnostic services coupled with empirical therapy without adequate Burkholderia pseudomallei activity ¹⁰⁷. Combined Malaysian data report an overall in-hospital mortality rate of 33 to 54% ¹⁰⁸, ¹⁰⁹, ⁹⁷, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³. Bacteremic patients have a mortality rate of of 48 to 65%, and nonbacteremic patients had a substantially lower case-fatality rate, 19%. Additionally, the mortality rate was 100% among those patients, while patients without septic shock had a mortality rate of 30% ¹⁰⁸, ¹¹³.

Genetic risk factors for melioidosis-associated mortality have recently been described ¹¹⁴. In a study of melioidosis patients in northeast Thailand, HLA-B*46 and HLA-C*01 were associated with an increased risk of death ¹¹⁴. A recent evaluation of the TLR1 variants common in East Asian populations demonstrated an association with a severe bacteremic phenotype and potentially worse outcome (580). Conversely, genetic polymorphisms for two flagellin-sensing receptors, TLR5 and NLRC4, have demonstrated survival benefit in patients with melioidosis ¹¹⁵, ¹¹⁶, ¹¹⁷. A review of 600 Thai patients with melioidosis infection reported a protective effect with regard to in-hospital death and organ failure in patients with a TLR5 genetic variant resulting in decreased function ¹¹⁵. A specific NLRC4 region polymorphism was also associated with survival in patients with pulmonary involvement. Furthermore, coinheritance of both TLR5 and NLRC4 polymorphisms has a cumulative effect on survival ¹¹⁶. It is interesting that while these receptors are required for functional immunity, in the setting of Burkholderia pseudomallei infection they appear to have a potentially detrimental immunomodulatory effect resulting in inflammation-associated organ failure ¹¹⁵.

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