David A. B. Dance

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.

The global distribution of Burkholderia pseudomallei and melioidosis: an update

While Southeast Asia and northern Australia are well recognized as the major endemic regions for melioidosis, recent reports have expanded the endemic zone. Severe weather events and environmental disasters such as the 2004 Asian tsunami have unmasked locations of sporadic cases and have reconfirmed endemicity in Indonesia. The endemic region now includes the majority of the Indian subcontinent, southern China, Hong Kong and Taiwan. Sporadic cases have occurred in Brazil and elsewhere in the Americas and in island communities such as New Caledonia, in the Pacific Ocean, and Mauritius in the Indian Ocean. Some of the factors that are critical to further elucidating the global distribution of Burkholderia pseudomallei and melioidosis include improved access to diagnostic laboratory facilities and formal confirmation of the identity of bacterial isolates from suspected cases.

Rapid Diagnosis of Bacteremic Pneumococcal Infections in Adults by Using the Binax NOW Streptococcus pneumoniae Urinary Antigen Test: a Prospective, Controlled Clinical Evaluation

ABSTRACT The diagnosis of severe pneumococcal infections is inadequate, relying heavily on culture of Streptococcus pneumoniae from blood or other normally sterile fluids, and is severely limited by prior administration of antibiotics. We evaluated prospectively the Binax NOW S. pneumoniae urinary antigen test, a rapid immunochromatographic assay, for the diagnosis of bacteremic pneumococcal infections in hospitalized adult patients. Antigen was detected in 88 of 107 cases overall, resulting in a test sensitivity of 82% (95% confidence interval [95% CI], 74 to 89%). Antigen detection was greater in those with pneumonia (67 of 77 [87%]) than in those without pneumonia (21 of 30 [70%]) (P = 0.04). Urinary antigen was also detected in 3 of 106 adult patients with community-acquired septicemic infections caused by other organisms, giving a test specificity of 97% (95% CI, 92 to 99%). For 45 pneumococcal bacteremia patients with a positive test on treatment day 1, urinary antigen excretion was monitored for the first week of antibiotic treatment. Antigen was still detectable in 83% (29 of 35 tested; 95% CI, 66 to 93%) on treatment day 3. Detection of urinary antigen is a valuable, sensitive, and rapid test for the early diagnosis of bacteremic pneumococcal infections in adult patients, even after antibiotic treatment has commenced.

Melioidosis as an emerging global problem.

There is remarkably little known about the incidence of melioidosis outside a few countries (Thailand, Australia, Singapore and Malaysia). Presumably it is widespread in tropical south east Asia. Elsewhere there are tantalising glimpses of the tip of what may be a large iceberg. Since a specific diagnosis of melioidosis requires awareness on the part of clinicians, and the existence of a laboratory capable of isolating and identifying Burkholderia pseudomallei, a luxury not available in most rural tropical areas, the size of this iceberg is likely to remain unknown for the foreseeable future. There is mounting evidence that the disease is endemic in the Indian sub-continent and the Caribbean, and there have been unsubstantiated reports of recent cases in South Africa and the Middle East. It is unclear whether melioidosis has really spread to such areas relatively recently, or has been there but unrecognised for a long time. Almost all cases diagnosed in temperate climates have been imported from the tropics, with the exception of a unique outbreak which occurred in France in the mid-1970s. With increasing world wide travel of both humans and other animals, the potential exists for melioidosis to spread to new and fertile pastures.

Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis

Burkholderia pseudomallei, a highly pathogenic bacterium that causes melioidosis, is commonly found in soil in Southeast Asia and Northern Australia1,2. Melioidosis can be difficult to diagnose due to its diverse clinical manifestations and the inadequacy of conventional bacterial identification methods3. The bacterium is intrinsically resistant to a wide range of antimicrobials, and treatment with ineffective antimicrobials may result in case fatality rates (CFRs) exceeding 70%4,5. The importation of infected animals has, in the past, spread melioidosis to non-endemic areas6,7. The global distribution of B. pseudomallei and the burden of melioidosis, however, remain poorly understood. Here, we map documented human and animal cases and the presence of environmental B. pseudomallei and combine this in a formal modelling framework8–10 to estimate the global burden of melioidosis. We estimate there to be 165,000 (95% credible interval 68,000–412,000) human melioidosis cases per year worldwide, from which 89,000 (36,000–227,000) people die. Our estimates suggest that melioidosis is severely underreported in the 45 countries in which it is known to be endemic and that melioidosis is probably endemic in a further 34 countries that have never reported the disease. The large numbers of estimated cases and fatalities emphasize that the disease warrants renewed attention from public health officials and policy makers.

Identification of Pseudomonas pseudomallei in clinical practice: use of simple screening tests and API 20NE.

The API 20NE kit and a simple screening system involving Grams stain, the oxidase reaction, colistin and gentamicin resistance, and colonial characteristics on a differential agar medium, were used to test 400 strains of Pseudomonas pseudomallei. The API kit identified 390 (97.5%) strains correctly on first testing and all but one of the remainder on second testing. Only one strain was initially misidentified (as Ps cepacia). The screening system was 100% accurate in identifying Ps pseudomallei. In non-endemic areas the API 20NE kit may be used to identify sporadic imported strains of Ps pseudomallei. Such kits may also help to delineate the geographical distribution of melioidosis. In endemic areas the screening tests described offer a cheap, simple, and accurate means of presumptively identifying Ps pseudomallei from clinical specimens.

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

Biochemical characteristics of clinical and environmental isolates of Burkholderia pseudomallei

The biochemical characteristics of 213 isolates of Burkholderia pseudomallei from patients with melioidosis and 140 isolates from the soil in central and northeastern Thailand were compared. Whereas the biochemical profiles of all the clinical isolates were similar, all soil isolates from the central area and 25% of isolates from northeastern Thailand comprised a different phenotype. This was characterised by the ability to assimilate L-arabinose (100%), adonitol (100%), 5-keto-gluconate (90%) and D-xylose (84%), but failure to assimilate dulcitol (0%), erythritol (0%) and trehalose (10%). Compared with clinical isolates, these organisms had similar antibiotic susceptibility profiles and were also recognised by a specific polyclonal antibody against B. pseudomallei. As melioidosis is rare in central Thailand, but common in the northeast, this raises the possibility that this biochemical phenotype may be less virulent, or may even represent a different species.

Ecology of Burkholderia pseudomallei and the interactions between environmental Burkholderia spp. and human-animal hosts.

Early workers thought that melioidosis was a zoonosis with a reservoir in rodents, but we now know that Burkholderia pseudomallei is a widely distributed environmental saprophyte. In northeast Thailand, two thirds of paddy fields yield the organism, and 80% of children have antibodies by the time they are 4 years old. However, interpretation of these results has been complicated by the recent recognition of avirulent, antigenically cross-reacting environmental organisms for which the name B. thailandensis has been proposed. We still know very little about the climatic, physical, chemical and biological factors which control the proliferation and survival of Burkholderia spp. in the environment, although epidemiological studies show space-time clustering of melioidosis. It is assumed that most human and animal melioidosis arises through exposure to contaminated soil or muddy water, although only 6% of human cases have a clear history of inoculation, and a further 0.5% of cases follow near-drowning. Laboratory animals have also been infected by ingestion, inhalation and insect bites, but evidence of infection acquired naturally by these routes remains anecdotal. Sporadic cases have resulted from iatrogenic inoculation, laboratory accidents, and person-to-person or animal-to-person spread. Whether exposure to B. pseudomallei will result in disease probably depends on the balance between the virulence of the strain, the immune status of the host (e.g. diabetes mellitus) and the size of the inoculum.

Isolation of Pseudomonas pseudomallei from soil in north-eastern Thailand

In order to optimize the recovery from soil of Pseudomonas pseudomallei, the cause of melioidosis, 3 selective broths were compared. A basal salt solution containing L-threonine (TBSS) performed significantly better than trypticase soy broth containing crystal violet and colistin 50 mg/L (CVC50), both in isolation rate and suppression of overgrowth of other organisms, but the addition of colistin to TBSS gave the best results overall. In a survey in north-eastern Thailand, P. pseudomallei was recovered from 114 (68%) of the 167 sites tested. A detailed study of a single rice farm showed that the isolation rate increased with depth of soil sample, and P. pseudomallei could still be isolated during the dry season, although only from moist soil in areas where other crops were cultivated and around the water source.