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Interventions for treating melioidosis.

BACKGROUND: Melioidosis is an infectious disease caused by a bacterium (Burkholderia pseudomallei) found particularly in some areas in the tropics. It is a serious condition which can be fatal. Beta lactam antibiotics have dramatically reduced the risk of death, but mortality still remains high. OBJECTIVES: To summarise evidence from randomised trials on the effects of treatment regimens on death and relapse. SEARCH STRATEGY: Cochrane Controlled Trials Register, MEDLINE, EMBASE, BIOSIS from 1966 to September 2000 using MeSH terms "pseudomallei", "melioidosis" together with the terms "randomized-controlled-trial", "random allocation"; reference lists in articles on melioidosis; contact with trialists. SELECTION CRITERIA: Randomised and quasi-randomised trials assessing treatments in patients with melioidosis. DATA COLLECTION AND ANALYSIS: Eligibility and trial quality was assessed by two reviewers independently. MAIN RESULTS: For intravenous therapy in the acute phase, we identified five trials with a total of 519 patients. Chloramphenicol, doxycycline, and co-trimoxazole (trimethoprim-sulphamethoxazole) combination regimens were associated with a mortality of 50% or more (two studies). Patients randomised to regimens that included ceftazidime were more likely to survive (relative risk [RR] 0.46, 95% confidence interval [CI] 0.30 to 0.71). When ceftazidime-containing regimens were compared with beta lactam or alternative beta lactamase inhibitor regimens such as co-amoxiclav (amoxycillin-clavulanic acid) and cefoperazone-sulbactam, mortality rates were similar (RR 1.10, 95% CI 0.83 to 1.46), as was the case in one trial of imipenem. For oral therapy in the maintenance phase, we found two trials of 188 participants. Results showed that treatment with the conventional regimen (chloramphenicol, doxycycline, and trimethoprim-sulphamethoxazole) resulted in fewer fatalities in patients compared to a regimen of amoxycillin-clavulanic acid and doxycycline alone. REVIEWER'S CONCLUSIONS: Regimens for the acute phase of illness should contain ceftazidime or imipenem. It is not yet clear if combinations of treatments in the early phase reduce relapse. For oral therapy after the acute phase of treatment, trials suggest that conventional four drug regimens can be used for treatment.

Administration, Oral↗

Changing epidemiology of melioidosis? A case of acute pulmonary melioidosis with fatal outcome imported from Brazil.

Melioidosis is an infectious disease caused by Burkholderia pseudomallei. It is endemic in South East Asia and tropical regions of Northern Australia. Sporadic cases have been described elsewhere. In this article we present a case of acute pulmonary melioidosis with fatal outcome imported from Brazil. The most common pathogen causing severe community-acquired pneumonia in Brazil is Streptococcus pneumoniae. Other possible pathogens include Legionella spp., Mycoplasma pneumonia, Gram-negative rods and viruses. There are few reports of melioidosis in the Americas. This article represents the second known human case of melioidosis from Brazil. Recognition of melioidosis as a possible cause of severe pneumonia, even if a patient has not been travelling in a highly endemic area, is important because of the therapeutic consequences. The epidemiology of melioidosis will be reviewed.

Acute Disease↗

Risk factors for melioidosis and bacteremic melioidosis.

A case-control study was conducted in four hospitals in northeastern Thailand to identify risk factors for melioidosis and bacteremic melioidosis. Cases were patients with culture-proven melioidosis, and there were two types of controls (those with infections, i.e., with community-acquired septicemia caused by other bacteria, and those without infection, i.e., randomly selected patients admitted with noninfectious diseases to the same hospitals). Demographic data, clinical presentations, and suspected risk factors were analyzed. Diabetes mellitus, preexisting renal diseases, thalassemia, and occupational exposure, classified by the soil and water risk assessment, were confirmed to be significant risk factors for melioidosis and bacteremic melioidosis. Only diabetes mellitus was a significant factor associated with bacteremic melioidosis, as compared with nonbacteremia. A significant interaction was found between diabetes mellitus and occupational exposure. Thus, diabetic rice farmers would be the most appropriate population group for targeted control measures such as vaccination in the future.

Adolescent↗

Bichat guidelines for the clinical management of glanders and melioidosis and bioterrorism-related glanders and melioidosis.

Glanders and melioidosis are two infectious diseases that are caused by Burkholderia mallei and Burkholderia pseudomallei respectively. Infection may be acquired through direct skin contact with contaminated soil or water. Ingestion of such contaminated water or dust is another way of contamination. Glanders and melioidosis have both been studied for weaponisation in several countries in the past. They produce similar clinical syndromes. The symptoms depend upon the route of infection but one form of the disease may progress to another, or the disease might run a chronic relapsing course. Four clinical forms are generally described: localised infection, pulmonary infection, septicaemia and chronic suppurative infections of the skin. All treatment recommendations should be adapted according to the susceptibility reports from any isolates obtained. Post-exposure prophylaxis with trimethoprim-sulfamethoxazole is recommended in case of a biological attack. There is no vaccine available for humans.

Bioterrorism↗

HLA-DR and -DQ associations with melioidosis.

Melioidosis is an important infectious disease of southeast Asia caused by an intracellular bacterium, Burkholderia pseudomallei. Cellular immunity is postulated to play important roles in immunity to melioidosis that may influence the severity and clinical outcome of the disease. The present study was undertaken to investigate possible associations of melioidosis with HLA class II alleles. HLA typing of HLA-DRB1, -DQA1, and -DQB1 was performed using polymerase chain reaction and sequence-specific oligonucleotide hybridization (PCR-SSO). Seventy-nine melioidosis patients and 105 healthy, ethnically and geographically matched controls were studied. Among 24 DRB1 alleles, 7 DQA1 alleles, and 13 DQB1 alleles identified in this population, an association with melioidosis was observed with DRB1*1602 which was increased in melioidosis patients (10.1%) compared to normal controls (4.8%), p = 0.047 (odds ratio (OR) = 2.25). In addition, significant increase of DRB1*1602 allele frequency and decrease of DQA1*03 were also observed in septicemic melioidosis patients, the most severe form of the disease (p = 0.01, OR = 3.10; and p = 0.047, respectively). Furthermore, a trend of association of DRB1*0701, DQA1*0201, and DQB1*0201 with relapse cases of melioidosis was also noted. In contrast, no HLA association was observed in localized melioidosis or melioidosis with diabetes mellitus. These findings provide the suggestive evidence of an immunogenetic basis of certain aspects of melioidosis.

Alleles↗

The epidemiology of melioidosis in Australia and Papua New Guinea.

Melioidosis was first described in Australia in an outbreak in sheep in 1949 in north Queensland (22 degrees S). Human melioidosis was first described from Townsville (19 degrees S) in 1950. Melioidosis is hyperendemic in the Top End of the Northern Territory (NT) and as in parts of northeastern Thailand it is the commonest cause of fatal community-acquired septicemic pneumonia. In the 9 years since 1989 the prospective NT melioidosis study at Royal Darwin Hospital (12 degrees S) has documented 206 culture confirmed cases of melioidosis, with an average annual incidence of 16.5/100,000. Melioidosis is also seen in the north of Western Australia and north Queensland, including the Torres Strait Islands, but is uncommon in adjacent Papua New Guinea. Serological studies suggest that infection is rare in the Port Moresby region, but there is emerging evidence of melioidosis from Western Province. The NT study has documented inoculating events in 52 (25%) of cases, with an incubation period of 1-21 days (mean 9 days); 84% of cases had acute disease from presumed recent acquisition and 13% had chronic disease (sick, > 2 months). In 4% there was evidence of possible reactivation from a latent focus; 28 of 153 (18%) males had prostatic abscesses. The overall mortality was 21% (43 cases), with a mortality rate in septicemic cases (95) of 39% and in non-septicemic cases (103) of 4%. Pneumonia was the commonest presentation in both groups and, in addition, eight patients (two deaths) presented with melioidosis encephalomyelitis. Melioidosis clusters in temperate Australia are attributed to animals imported from the north. Molecular typing of Burkholderia pseudomallei isolates from temperate southwest Western Australia showed clonality over 25 years. In this outbreak and in studies from the NT, some soil isolates are molecularly identical to epidemiologically related animal and human isolates. Molecular typing has implicated the water supply in two clonal outbreaks in remote aboriginal communities in northern Australia. Further prospective collaborative studies are required to evaluate whether there are truly regional differences in clinical features of melioidosis and to better understand how B. pseudomallei is acquired from the environment.

Animals↗

Pediatric melioidosis in Pahang, Malaysia.

Melioidosis is much less common in children than in adults. This study investigated the incidence, demographic characteristics, presenting symptoms and outcome of pediatric melioidosis in Pahang, Malaysia. This retrospective study included patients < or =18 years old with positive body fluid cultures for Burkholderia pseudomallei from January 2000 to June 2003. Data on culture results were obtained from 2 referral hospitals. The incidence of pediatric melioidosis was 0.68/100,000 population per year. Of the 13 patients identified during the study period, 10 were male; 9 were Malays, 2 were Indians and 2 were aborigines. The mean age of these patients was 9.5 +/- 5.4 years. None of the patients had a previous history of confirmed melioidosis or predisposing factors for infection. Localized melioidosis was the most common presentation (46.2%) followed by melioidosis with septic shock (38.4%). Among patients with localized melioidosis, head and neck involvement (83.3%) was the most common presentation (2 patients with cervical abscesses, 1 with submandibular abscesses and 2 with acute suppurative parotitis) and another patient had right axillary abscess. All of the patients with septic shock had pneumonia and 2 of them had multi-organ involvement. The mortality among patients with septic shock was 80% and death occurred within 24 h of admission in all cases. In contrast, no complications or death occurred among patients with localized melioidosis. Melioidosis with septic shock is less common than localized melioidosis in pediatric patients, but is associated with very high mortality.

Abscess↗

The epidemiology of melioidosis in Ubon Ratchatani, northeast Thailand.

BACKGROUND: Melioidosis, or infection with Pseudomonas pseudomallei is an important cause of morbidity and mortality in South East Asia and Northern Australia. The epidemiology of melioidosis in Ubon Ratchatani, Northeast Thailand was studied over a 5-year period from 1987 to 1991. METHODS: Rates and, when possible, the risks of developing melioidosis were calculated. The numerator was the number of culture-proven cases of melioidosis seen in the 1000-bed referral hospital of the province. The denominators were obtained from the population census, a survey of Health, Welfare and Use of Traditional Medicine, and the North Eastern Meterological Centre, Thailand. RESULTS: The average incidence of human melioidosis was 4.4 (95% confidence interval [CI]: 3.8-5.0) per 100,000. The disease affected all ages with the highest incidence in 40-60 years olds. Melioidosis was 1.4 (95% CI: 0.4-5.3) times more common in males than females. The disease showed a significant seasonal variation in incidence, and a strong linear correlation with rainfall (r = 0.7, 95% CI: 0.5-0.9) Adults exposed to soil and water in their work (most were rice farmers) had an increased risk of melioidosis (in the 40-59 year age group, relative risk = 4.1, 95% CI: 2.4-6.9). Most adult patients had an underlying disease (mainly diabetes mellitus) predisposing them to this infection. CONCLUSION: Melioidosis may result from either acute exposure to the organism in the soil and water, or 're-activation' of an asymptomatic childhood infection (by an unidentified possibly infective seasonal cofactor). The results from this analysis are consistent with both hypotheses. Further epidemiological studies are needed to identify risk factors so that optimal strategies for control of melioidosis may be developed.

Adolescent↗

Diagnostic value of an antibody enzyme-linked immunosorbent assay using affinity-purified antigen in an area endemic for melioidosis.

Melioidosis, an infection caused by Burkholderia pseudomallei, is endemic in southeast Asia. The septicemic form of melioidosis is the leading cause of death from nonhospital-acquired septicemia in the northeastern part of Thailand. A major factor that contributes to the high mortality is the delay in isolation and identification of the causative organism. The present study was undertaken to evaluate the use of enzyme-linked immunosorbent assays based on an immunoaffinity-purified antigen for detecting specific IgG and IgM antibodies to this organism as a rapid serodiagnostic method for melioidosis. The diagnostic value of these tests was evaluated in an actual clinical situation in an area endemic for melioidosis. The specificity of specific IgG test (82.5%) and the specific IgM test (81.8%) were significantly better than that of the indirect hemagglutination (IHA) test (74.7%). The sensitivity of the specific IgG assay (85.7%) was higher than that of the IHA test (71.0%) and the specific IgM test (63.5%). Specific IgG antibody was detected in a majority of septicemic melioidosis (87.8%), as well as in localized forms (82.6%). The specific IgG test was also better than the specific IgM test and the IHA test in identifying acute melioidosis cases in the first five days after admission. In addition, the IgG antibody level to this antigen remained high over a period of more than five years in those who had recovered from melioidosis and remained clinically free of the disease. These results indicate that the detection of specific IgG antibody is clinically useful for the diagnosis of acute melioidosis in an endemic area.

Acute Disease↗

Burkholderia pseudomallei-specific recombinant protein and its potential in the diagnosis of melioidosis.

Melioidosis is an important public health problem in Southeast Asia and Northern Australia. This disease is caused by the gram-negative bacilli, Burkholderia pseudomallei. Wide spectra of clinical manifestations are observed in melioidosis ranging from asymptomatic to septicemic infection. Although serodiagnostic methods of melioidosis have been improved significantly in recent years, a highly specific diagnostic test that can differentiate asymptomatic seropositive individuals and melioidosis patients remains to be the subject of current investigations. In this study, a B. pseudomallei-specific gene, pBps-1, expressing a novel 18.7 kDa recombinant protein was selected from genomic libraries of two B. pseudomallei virulent isolates by using pooled sera from septicemic melioidosis patients. Nucleotide sequence analysis demonstrated that this gene is unique and does not show substantial similarity with any known genes in the Genbank database. The Bps-1 recombinant protein was evaluated for its potential in serodiagnosis of melioidosis by Western blot analysis. A high degree of specificity was demonstrated using sera from healthy individuals in the endemic (98.5%) and non-endemic areas (100%), with moderate sensitivity (69.7%) in melioidosis patients. The study demonstrated that this approach can be used to obtain highly specific recombinant antigens such as that described in the present report. A combination of such antigens should provide materials for successful serodiagnosis of melioidosis in the endemic areas.

Antibodies, Bacterial↗

Neurological melioidosis.

Neurological abnormalities have long been recognised in animals with melioidosis, including laboratory rodents and sheep in the first Australian outbreak in 1949. Autopsies in animals have shown microabscesses and lymphocytic infiltration to be present on occasion in the same animal, but Burkholderia pseudomallei is usually able to be grown from central nervous system (CNS) tissue. In humans CNS melioidosis is unusual, but both macroscopic brain abscesses and encephalitis occur. There has been a recently recognised syndrome of meningoencephalitis with varying involvement of brainstem, cerebellum and spinal cord. The prospective melioidosis study at Royal Darwin Hospital has documented 12 cases of CNS melioidosis over 9 years out of a total of 232 cases of melioidosis (5%). Prominent features on presentation were unilateral limb weakness (6), predominant cerebellar signs (2), mixed cerebellar and brainstem features with peripheral weakness (2) and flaccid paraparesis (2). Eight patients had unilateral VIIth nerve palsy and six bulbar palsy, with five requiring prolonged ventilation. Brain CT scans are usually normal initially, but MRI shows dramatic changes. Three patients died and only three made a full recovery. In two patients with predominant mononuclear CSF pleocytosis, B. pseudomallei was cultured from CSF and autopsy in one of these showed necrotising encephalitis with microabscesses. Although it has been postulated that a neurotropic exotoxin may account for melioidosis encephalomyelitis, the recent findings and comparison with the animal data suggest that direct organism spread within the CNS may be primarily responsible. Preliminary molecular typing of isolates shows no evidence of a specific strain of B. pseudomallei responsible for CNS melioidosis end further studies are required to determine if the apparent higher rate of CNS disease in Australia is due to true regional differences or is from increased ascertainment.

Adult↗

Melioidosis epidemiology and risk factors from a prospective whole-population study in northern Australia.

OBJECTIVES: The aims of this study were to describe the epidemiology of melioidosis in tropical northern Australia and to assess the importance of defined risk factors. METHODS: The data were taken from a 14-year prospective study of 364 cases of melioidosis in the 'Top End' of the Northern Territory. A whole-population logistic regression model was used to estimate the crude and adjusted relative risk (RR) for the defined risk factors. RESULTS: The mean age of the study population was 46.8 years, 264 (72.5%) were male, 178 (49%) were aboriginal Australians and 59 (16.2%) died from melioidosis. Average annual incidence was 19.6 cases per 100 000 population, with an estimated rate of 260 cases per 100,000 diabetics per year. Using a whole-population logistic regression model, the estimated crude and adjusted RR [95% confidence intervals (CI)] for melioidosis were 6.3 (5.1-7.8) and 4.0 (3.2-5.1) for those aged > or = 45 years, 2.3 (1.8-2.9) and 2.4 (1.9-3.0) for males, 2.9 (2.3-3.5) and 3.0 (2.3-4.0) for aboriginal Australians, 21.2 (17.1-26.3) and 13.1 (9.4-18.1) for diabetics, 2.7 (2.2-3.4) and 2.1 (1.6-2.6) for those with excess alcohol consumption, 6.8 (5.4-8.6) and 4.3 (3.4-5.5) for chronic lung disease and 6.7 (4.7-9.6) and 3.2 (2.2-4.8) for chronic renal disease, respectively. CONCLUSIONS: Diabetes, excess alcohol intake, chronic renal disease and chronic lung disease are each independent risk factors for melioidosis. In tropical northern Australia, male sex, aboriginal ethnicity and age of > or = 45 years are also independent predictors for melioidosis. Impaired polymorph function may be critical in the predisposition to melioidosis.

Adolescent↗

Melioidosis: the tip of the iceberg?

For nearly 80 years clinical melioidosis has been considered a rare disease. This bacterial infection is caused by Pseudomonas pseudomallei, a saprophyte found in soil and surface water of endemic areas. Consequently, those who have most contact with soil, the rural poor, are likely to be at greatest risk of infection. Since the diversity of clinical manifestations necessitates the isolation and identification of the causative organism for a definitive diagnosis of melioidosis and the population at greatest risk within endemic areas rarely have access to an appropriate level of health care, the disease has probably been underrecognized. Melioidosis is now known to be an important cause of human morbidity and mortality in Thailand, and this may be true throughout Southeast Asia, which is usually regarded as the main endemic area for the disease. In Australia, melioidosis causes a smaller number of human infections, while disease among livestock has important economic and possible public health implications. Sporadic reports of the infection indicate its presence in several other tropical regions: in the Indian subcontinent, Africa, and Central and South America. Clinical melioidosis may be highly prevalent in these areas, but underdiagnosed as a result of a lack of awareness of the clinical and microbiological features of the disease, or simply because of a lack of health care facilities. Furthermore, during the last two decades the importation and transmission of melioidosis within nontropical zones have been documented. The causative organism is not difficult to grow, and modern antibiotics have improved disease prognosis. Further studies are needed to determine the true worldwide distribution and prevalence of melioidosis so that improved therapeutic and preventive measures can be developed and applied.

Global Health↗

Pulmonary melioidosis.

Melioidosis is the name given to all diseases caused by the bacterium Pseudomonas pseudomallei. Melioidosis is a tropical disease and prevails in parts of Southeast Asia, northern Australia, and Central and South America. However, in recent years, cases of melioidosis have been reported in the United States and other areas. The organism can infect any organ system, although the lung is the most common organ affected. Pulmonary melioidosis presents either as an acute fulminant pneumonia or as an indolent cavitary disease. In northeastern Thailand, the incidence of P pseudomallei infection is extremely high with significant mortality. One of the key problems with treating melioidosis is its recalcitrance to therapy and high relapse rate. In addition, this Gram-negative rod is resistant to aminoglycosides. In nonendemic regions, patients with melioidosis more typically present with reactivation disease occurring months to years after initial exposure to the organism. The pulmonary disease is mainly in the apices and resembles tuberculosis. With the increasing mobility of people throughout the world and the influx of immigrants from endemic to nonendemic areas, it is important that clinicians be aware of this disease. This article will review the epidemiology, clinical presentations, diagnosis, and treatment of pulmonary melioidosis.

Burkholderia pseudomallei↗