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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↗

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↗

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↗

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: 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↗

Application of indirect hemagglutination test and indirect fluorescent antibody test for IgM antibody for diagnosis of melioidosis in Thailand.

In hyperendemic areas such as Thailand, rapid diagnosis of melioidosis depends upon both bacteriological culture and serological methods. However, interpretation of indirect hemagglutination (IHA) for melioidosis which is the only test available, is seriously hampered by increased IHA titers present in one-third to one-half of the population. In order to get the best results from the available tests, IHA and indirect fluorescent antibody for IgM (IFA-IgM) were evaluated in controls and patients in Thailand. IHA titers of greater than or equal to 1:40 were considered remote or recent exposure to P. pseudomallei. IHA titers of this level were found in 47.1% of 227 blood donors and 29.5% of 210 sera submitted for other tests, while IFA-IgM was positive in only one donor who had an IHA titer of 1:1,280. IHA was positive in eight out of nine patients with melioidosis with IHA titers of less than 1:20 to 1:2,560. IFA-IgM was positive in six out of seven melioidosis patients whose sera were available for this test including a serum with IHA titer of less than 1:20. Six patients were predisposed by diabetes mellitus. Among sera serologically tested for melioidosis, 33 had IHA titers of 1:80-1:1,280, 10 of which were positive for IFA-IgM. This study demonstrates high background IHA titers among IHA titers among Thai people which greatly limits its use for serodiagnosis of melioidosis. In sharp contrast, serodiagnosis by IFA-IgM was more successful. Positive IFA-IgM among healthy Thais did exist indicating that serologic tests for melioidosis at best are only supplementary to bacteriological culture and clinical awareness.

Animals↗

Childhood melioidosis in northeastern Thailand.

Eighteen cases of childhood melioidosis in Northeastern Thailand were reviewed. The mean age was 6.8 years with a range from eight months to 15 years. Twelve cases (66.7%) had localized melioidosis, six of which had pneumonia. Three patients were diagnosed as pharyngocervical melioidosis, the newly recognized syndrome. Nine cases (50.0%) had associated diseases including dengue hemorrhagic fever (DHF) in five cases. In all five cases, melioidosis was diagnosed during the convalescent stage as a cause of pyrexia with or without pneumonia. Pseudomonas pseudomallei strains isolated from 12 patients were all sensitive to chloramphenicol, cotrimoxazole and kanamycin. Ceftazidime, cefotaxime and ceftriaxone were also active against all six isolates tested. Three cases died, all were diagnosed as disseminated septicaemic melioidosis at postmortem. The overall mortality rate was 16.7%. The septicaemic form of melioidosis can resemble many diseases such as septicaemia due to Staphylococcus aureus or gram-negative organisms other than P. pseudomallei while the localized from may mimic pulmonary tuberculosis. A high index of clinical suspicion is required in making a diagnosis of melioidosis, particularly in areas where the disease is endemic.

Child↗

Musculoskeletal melioidosis: clinical and imaging features.

OBJECTIVE: Melioidosis is a tropical infection caused by a gram-negative bacillus, Pseudomonas pseudomallei. The disease manifests initially as localized suppurative lesions and can progress to acute disseminated septicemia with 65-90% mortality if inadequately treated. Musculoskeletal involvement is common. The purpose of this study was to describe the clinical features and imaging appearances of musculoskeletal melioidosis. DESIGN: We retrospectively analyzed the clinical profiles and images of 26 patients diagnosed over a 6-year period as suffering from melioidosis. PATIENTS: The study group comprised 11 patients with musculoskeletal melioidosis and 15 patients with nonmusculoskeletal melioidosis. RESULTS AND CONCLUSIONS: We found that musculoskeletal melioidosis mimicks other infections both clinically and radiologically. Clinical awareness is therefore crucial, as diagnosis can only be established by bacteriological and immunological studies. Prompt treatment with long-term combination antibiotics in high dosages and surgical drainage of abscesses improves survival.

Adult↗

The use of bone marrow culture for the diagnosis of melioidosis.

We have evaluated prospectively the contribution of bone marrow culture to the diagnosis of melioidosis. Bone marrow (BMC) and blood cultures (BC) were collected concurrently from 105 patients with suspected acute, severe melioidosis. 67 patients were subsequently proved to have the disease whilst other significant organisms were isolated from these specimens in 5 cases. Overall, 67.2% of BC and 64.2% of BMC from melioidosis patients grew Pseudomonas pseudomallei. Time to positivity did not differ significantly in paired BC and BMC specimens. These results do not support the routine use of BMC in the diagnosis of acute, severe melioidosis. In one patient with pulmonary melioidosis, however, blood cultures were repeatedly negative, whilst bone marrow grew P. pseudomallei, and this preceded the development of a distant focus of infection. This suggests that culture of bone-marrow may be of value in certain blood culture-negative patients with melioidosis.

Acute Disease↗