Melioidosis

David Dance, MB, CHB, FRCPath

Melioidosis is the name given to any infection caused by Burkholderia (formerly Pseudomonas) pseudomallei. The organism is closely related to B. mallei (the causative agent of glanders) and B. cepacia. It has a wide host range including mammals (especially sheep, goats and pigs), birds and occasionally reptiles.

Epidemiology

The bacterium is an environmental saprophyte found in mud and water (e.g. rice paddy). It is endemic in south and south east Asia (especially Thailand and Singapore) and northern Australia. It is occasionally reported elsewhere in the tropics and is probably greatly underdiagnosed. The disease is highly seasonal, some 80% of cases presenting during the rainy season. Infection is usually acquired through inoculation, occasionally aspiration or inhalation of contaminated water, and hence is associated with soil contact (e.g. rice farmers). The role of ingestion is unclear, and person-to person spread is very rare. Iatrogenic infections have occasionally been reported. In endemic areas, exposure is widespread (80% children in northeast Thailand have antibodies by 4 years of age), but disease is rare, and usually opportunistic (approximately 75% of individuals with severe infections are immunocompromised, especially by diabetes mellitus, chronic renal failure, thalassaemia, steroids, alcoholism and liver disease). Disease is commonest in males aged 40-60 years. The incubation period is variable - it may be as short as 2-3 days, but the organism may remain latent for up to 30 years before infection becomes apparent, usually at times of intercurrent stress.

Pathogenesis

The likelihood of disease developing depends on a balance between the host immune system (in which cell-mediated immunity and, particularly, interferon-gamma production appears to play a key role), the inoculum and, presumably, the intrinsic virulence of the infecting strain. Important virulence factors include lipopolysaccharide, an extracellular capsule, and numerous enzymes. There is some evidence that intracellular persistence contributes to the recalcitrant nature of the infection.

Clinical

Melioidosis has a broad spectrum of manifestations. Overall, 60% of cases are bacteremic. Most of them have a community-acquired sepsis syndrome with a high mortality, although some have a more sub-acute `typhoidal' presentation. Half have an obvious primary focus, usually in the lungs, sometimes in skin or soft tissue. Metastatic abscesses are common in any site, especially the lung, liver, spleen, kidney, prostate, and skin or soft tissue. The remaining 40% have localized infections, again in any organ, but particularly the lung, liver and spleen in adults, and these sites plus the parotid in children. Chronic foci often become granulomatous.

Diagnosis

Consider melioidosis in anyone who has ever lived in endemic area who presents with sepsis and/or abscesses, especially if they are diabetic. However, most imported infections will present within a few weeks of travel to an endemic area. The organism is easy to culture from sterile sites (e.g. blood, pus, urine), but selective media increase the isolation rate from sputum, swabs etc. Identification of B. pseudomallei requires a degree of suspicion, since it is often thought initially to be a contaminant, although most commercial kits should identify it correctly. B. pseudomallei is also a containment level 3 pathogen (UK classification), so warn the laboratory if melioidosis is suspected. PCR and antigen detection systems are under development, but are not yet in widespread use. Numerous serological tests (e.g. indirect hemagglutination, ELISA, immunofluorescence) for both IgG and IgM antibodies are available, but these have poor specificity and sensitivity in endemic areas, although they may be more useful in visitors from non-endemic countries. The high background seropositivity rates in endemic areas may partly result from exposure to a recently described, avirulent environmental organism, B. thailandensis.

Management

Supportive treatment, including drainage of abscesses, is important. B. pseudomallei is intrinsically resistant to many antibiotics, including penicillin and aminoglycosides. Newer beta-lactams substantially reduce mortality rates, but their cost limits their use in endemic areas. There is a lifelong risk of relapse, which may be reduced (but not abolished) by long antibiotic courses. Antibiotic resistance may develop during treatment.

Antibiotic treatment can be divided into the acute phase of treatment (usually about two weeks) and the maintenance phase (to complete 20 weeks of total treatment). Various antibiotic regimens are available for both phases of treatment. Ceftazidime, imipenem or meropenem are currently the treatments of choice during the acute phase. Medications for the maintenance phase include appropriate doses of chloramphenicol, but co-amoxiclav is preferable for children and pregnant women. A recent study found 12 weeks of ciprofloxacin plus azithromycin to be associated with an unacceptably high relapse rate (22%).

References and Further Reading

1. Acta Tropica. Volume 74, issue 2-3, February 2000.

This whole issue is devoted to melioidosis and contains a number of reviews of the subject, as presented at an international meeting that took place in 1998. Proceedings of a follow-up meeting in September 2001 should be published in due course.

2. Dance DAB. Melioidosis and glanders. In: Topley and Wilson's Microbiology and Microbial Infections. Ninth edition. Volume 3. Bacterial Infections. Hausler WJ Jr. and Sussman M, eds. Arnold, London, 1998. Chapter 46, pp. 919-29.

This is a fairly comprehensive, extensively referenced review of the subject up to 1996, when it was written, and is a good starting point for further reading. Some more recent key references are given below.

3. Bart J. Currie et al. Endemic Melioidosis in Tropical Northern Australia: A 10 Year Prospective Study and Review of the Literature. Clin Infect Dis 2000; 31: 981-6.

An excellent and comprehensive review of the disease from an Australian perspective

4. Simpson AJH et al. Comparison of imipenem and ceftazidime as therapy for severe melioidosis. Clin Infect Dis 1999; 29: 381-7.

5. Chetchotisakd P et al. Randomized, double-blind, controlled study of cefoperazone-sulbactam plus cotrimoxazole versus ceftazidime plus cotrimoxazole for the treatment of severe melioidosis. Clin Infect Dis 2001; 33: 29-34.

The two most recent published studies of acute phase treatment.

6. Chaowagul W et al. A comparison of chloramphenicol; trimethoprimsulfamethoxazole, and doxycycline with doxycycline alone as maintenance therapy for melioidosis. Clin Infect Dis 1999; 29: 375-80.

7. Chetchotisakd P et al. Maintenance therapy of melioidosis with ciprofloxacin plus azithromycin compared with cotrimoxazole plus doxycycline. Am J Trop Med Hyg 2001; 64: 24-27.

The two most recent published studies of maintenance treatment.

8. Suputtamongkol Y et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis 1999; 29: 408-13.

The only case-control study of risk factors for melioidosis

9. Woods DE et al. Current studies on the pathogenesis of melioidosis. Microb Infect 1999; 2: 157-62.

A good summary of current work on virulence of B. pseudomallei, a rapidly developing field, using molecular techniques to study pathogenesis.

David is a physicians and a medical microbiologist and presently the Director of the Public Health Laboratory in Plymouth, UK. He has studied more than 1500 patients with melioidosis in Thailand.