Melioidosis: Clinical impact and public health threat in the tropics

Abstract

This review briefly summarizes the geographical distribution and clinical impact of melioidosis, especially in the tropics. Burkholderia pseudomallei (a gram-negative bacterium) is the major causative agent for melioidosis, which is prevalent in Singapore, Malaysia, Thailand, Vietnam, and Northern Australia. Melioidosis patients are increasingly being recognized in other parts of the world. The bacteria are intrinsically resistant to many antimicrobial agents, but prolonged treatment, especially with combinations of antibiotics, may be effective. Despite therapy, the overall case fatality rate of septicemia in melioidosis remains significantly high. Intracellular survival of the bacteria within macrophages may progress to chronic infections, and about 10% of patients suffer relapses. In the coming decades, melioidosis will increasingly afflict travelers throughout many global regions. Clinicians managing travelers returning from the subtropics or tropics with severe pneumonia or septicemia should consider acute melioidosis as a differential diagnosis. Patients with open skin wounds, diabetes, or chronic renal disease are at higher risk for melioidosis and should avoid direct contact with soil and standing water in endemic regions. Furthermore, there are fears that B. pseudomallei may be used as a biological weapon. Technological advancements in molecular diagnostics and antibiotic therapy are improving the disease outcomes in endemic areas throughout Asia. Research and development efforts on vaccine candidates against melioidosis are ongoing.

Fig 1. Global geographical distribution of melioidosis.

The areas of high endemicity in Southeast Asia (Thailand, Vietnam, Cambodia, Malaysia, and Singapore)/Northern Australia. Possible endemic, sporadic areas, environmental isolates only, and unconfirmed travel history/only serology evidence are indicated. However, sporadic cases have been reported throughout the world in Pakistan, India, Bangladesh, Indonesia, Philippines, Sri Lanka, Papua New Guinea, Madagascar, France, Mexico, Brazil, Colombia, Venezuela, Ecuador, the Middle East (Iran), and the Caribbean.

Fig 2. Schematic representation showing the virulence and pathogenesis of melioidosis infection.

B. pseudomallei is transmitted from its environmental reservoir to lung epithelial cells, where it initially attaches, possibly through bacterial components such as the capsule and type IV pili. Following invasion of epithelial cells, the T3SS-3 effectors assist in vacuolar escape and intracellular motility due to BimA-mediated actin polymerization. The activation of TLR-2, TLR-4, and TLR-5 by bacterial LPS and flagella results in recruitment of innate immune cells, such as neutrophils, macrophages, and natural killer cells. IRAK-M, interleukin-1-associated kinase 3; TLR, toll-like receptor; LPS, lipopolysaccharide; CD14, cluster of differentiation; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; TNF-α, tumor necrosis factor alpha; NLRC-4, NRL family CARD domain-containing protein 4; NLRP3, NACHT, LRR, and PYD domain-containing protein 3; ACS, acetyl-CoA synthetases; PCR, polymerase chain reaction.

Fig 3. Ultrastructural examination of B. pseudomallei used for infection.

(A) Scanning electron microscopy (SEM) image showing Bp before the infection with U-937 cells. (B) Bp-infected cells were examined by a transmission electron microscopy (TEM) with large number of bacilli (Bp) presented in the cytoplasm. Light micrograph showing B. pseudomallei infection of mouse spleen; section stained by Haematoxylin and Eosin (H&E) imaged with different magnification. (C–D) Large abscesses (Abs) with focal areas of necrosis, surrounded by a rim of meshed fibrous tissue (f) are evident after 2 weeks IP challenge with 1.7x105 CFU/ml. The bacterial invasion is more in spleen and liver than kidney. Bp, B. pseudomallei; abs, abscess; f, fibrous tissue; rs, rough surface; s, septa; sb, single bacilli; n, nucleus; ph, phagocytosis.

Fig 4. Schematic diagram for melioidosis diagnosis and list of sensitive and resistance antibiotics.

There are several factors, such as inactivation of enzyme, target deletion, and drug efflux pumps from the cells mediated by chromosomally encoded genes. Furthermore, the overproduction and point mutations in class A PenA β-lactamase affect some of the important drugs (i.e., ceftazidime and amoxicillin-clavulanic acid) that are responsible for the development of resistance mechanisms. However, the deletion of penicillin binding protein-3 (PBP-3) leads to ceftazidime resistance, and BpeEF-OprC efflux pump overexpression causes doxycycline, trimethoprim, and trimethoprim (TMP)-sulfamethoxazole (SFZ) resistance.