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Background: The autotransporter protein Burkholderia intracellular motility A (BimA) facilitates the entry of Burkholderia pseudomallei into the central nervous system (CNS) in mouse models of melioidosis. Its role in the pathogenesis of human cases of CNS melioidosis is incompletely defined., Methods: Consecutive culture-confirmed cases of melioidosis at two sites in tropical Australia after 1989 were reviewed. Demographic, clinical and radiological data of the patients with CNS melioidosis were recorded. The bimA allele (bimABm or bimABp) of the B. pseudomallei isolated from each patient was determined., Results: Of the 1587 cases diagnosed at the two sites during the study period, 52 (3.3%) had confirmed CNS melioidosis; 20 (38.5%) had a brain abscess, 18 (34.6%) had encephalomyelitis, 4 (7.7%) had isolated meningitis and 10 (19.2%) had extra-meningeal disease. Among the 52 patients, there were 8 (15.4%) deaths; 17/44 (38.6%) survivors had residual disability. The bimA allele was characterized in 47/52; 17/47 (36.2%) had the bimABm allele and 30 (63.8%) had the bimABp allele. Patients with a bimABm variant were more likely to have a predominantly neurological presentation (odds ratio (OR) (95% confidence interval (CI)): 5.60 (1.52-20.61), p=0.01), to have brainstem involvement (OR (95%CI): 7.33 (1.92-27.95), p=0.004) and to have encephalomyelitis (OR (95%CI): 4.69 (1.30-16.95), p=0.02. Patients with a bimABm variant were more likely to die or have residual disability (odds ratio (95%CI): 4.88 (1.28-18.57), p=0.01)., Conclusions: The bimA allele of B. pseudomallei has a significant impact on the clinical presentation and outcome of patients with CNS melioidosis., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Infection with the gram-negative bacterium Burkholderia pseudomallei can result in melioidosis, a life-threatening disease that can be difficult to diagnose. Culture remains the gold standard for diagnosis but requires laboratory resources not available in many endemic regions. A lateral flow immunoassay has shown promise for POC diagnostics but suffers from low sensitivity when used on blood samples. PCR also has low sensitivity on blood, attributed to the low bacterial numbers in blood observed in melioidosis patients, even when bacteraemic., Methods: A prototype i-STAT cartridge was developed to utilize the monoclonal antibody specific for the capsule of pathogenic Burkholderia species employed on the LFI. The resulting POC assay was evaluated on 414 clinical specimens from Darwin, Australia and Cambodia., Results: The i-STAT assay accurately distinguished Australian blood culture positive melioidosis patients from Australian patients hospitalized with other infections (AUC = 0.91, 95% CI 0.817 - 1.0). We derived an assay cutoff with 76% sensitivity and 94% specificity that correctly classified 88% (n = 74) of the Australian patients. Interestingly, only 46% (6/13) of the culture-positive melioidosis patients in Cambodia were classified correctly. Of great importance however, the assay detected capsule from blood samples for 32% of blood culture negative melioidosis patients in both cohorts and previously undiagnosed melioidosis patients in Cambodia. In addition the assay showed high sensitivity and specificity for urine, pus and sputum., Conclusions: Diagnostic tools that are not dependent upon the growth kinetics or the levels of bacteremia of B. pseudomallei represent the next-generation of diagnostics and must be pursued further., (Published by Oxford University Press for the Infectious Diseases Society of America 2018.)

Background: Burkholderia pseudomallei, the causative agent of the high-mortality disease melioidosis, is a gram-negative bacterium that is naturally resistant to many antibiotics. There is no vaccine for melioidosis, and effective eradication is reliant on biphasic and prolonged antibiotic administration. The carbapenem drug meropenem is the current gold standard option for treating severe melioidosis. Intrinsic B. pseudomallei resistance toward meropenem has not yet been documented; however, resistance could conceivably develop over the course of infection, leading to prolonged sepsis and treatment failure., Methods: We examined our 30-year clinical collection of melioidosis cases to identify B. pseudomallei isolates with reduced meropenem susceptibility. Isolates were subjected to minimum inhibitory concentration (MIC) testing toward meropenem. Paired isolates from patients who had evolved decreased susceptibility were subjected to whole-genome sequencing. Select agent-compliant genetic manipulation was carried out to confirm the molecular mechanisms conferring resistance., Results: We identified 11 melioidosis cases where B. pseudomallei isolates developed decreased susceptibility toward meropenem during treatment, including 2 cases not treated with this antibiotic. Meropenem MICs increased from 0.5-0.75 µg/mL to 3-8 µg/mL. Comparative genomics identified multiple mutations affecting multidrug resistance-nodulation-division (RND) efflux pump regulators, with concomitant overexpression of their corresponding pumps. All cases were refractory to treatment despite aggressive, targeted therapy, and 2 were associated with a fatal outcome., Conclusions: This study confirms the role of RND efflux pumps in decreased meropenem susceptibility in B. pseudomallei. These findings have important ramifications for the diagnosis, treatment, and management of life-threatening melioidosis cases.

Background: The scabies mite, Sarcoptes scabiei, is a parasitic arachnid and cause of the infectious skin disease scabies in humans and mange in other animal species. Scabies infections are a major health problem, particularly in remote Indigenous communities in Australia, where secondary group A streptococcal and Staphylococcus aureus infections of scabies sores are thought to drive the high rate of rheumatic heart disease and chronic kidney disease., Results: We sequenced the genome of two samples of Sarcoptes scabiei var. hominis obtained from unrelated patients with crusted scabies located in different parts of northern Australia using the Illumina HiSeq. We also sequenced samples of Sarcoptes scabiei var. suis from a pig model. Because of the small size of the scabies mite, these data are derived from pools of thousands of mites and are metagenomic, including host and microbiome DNA. We performed cleaning and de novo assembly and present Sarcoptes scabiei var. hominis and var. suis draft reference genomes. We have constructed a preliminary annotation of this reference comprising 13,226 putative coding sequences based on sequence similarity to known proteins., Conclusions: We have developed extensive genomic resources for the scabies mite, including reference genomes and a preliminary annotation.

Background: Melioidosis is a common community-acquired infectious disease in northeast Thailand associated with overall mortality of approximately 40% in hospitalized patients, and over 70% in severe cases. Ceftazidime is recommended for parenteral treatment in patients with suspected melioidosis. Meropenem is increasingly used but evidence to support this is lacking., Methods: A decision tree was used to estimate the cost-effectiveness of treating non-severe and severe suspected acute melioidosis cases with either ceftazidime or meropenem., Results: Empirical treatment with meropenem is likely to be cost-effective providing meropenem reduces mortality in severe cases by at least 9% and the proportion with subsequent culture-confirmed melioidosis is over 20%., Conclusions: In this context, treatment of severe cases with meropenem is likely to be cost-effective, while the evidence to support the use of meropenem in non-severe suspected melioidosis is not yet available., (© The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Melioidosis is less common in children than adults. The clinical spectrum of disease varies greatly between the 2 groups. Treatment guidelines are currently based on adult studies, and revision of existing guidelines is necessary to instruct specific pediatric management., Methods: Culture-confirmed cases of melioidosis in the Northern Territory between 1989 and 2013 were identified from the Prospective Melioidosis Study. The epidemiology and clinical spectrum of disease for children aged ≤ 16 years were analyzed and compared with the adult data., Results: Forty-five pediatric patients were identified, representing 5% of the total 820 melioidosis cases over 24 years. Most children (84%) had no recognized risk factors for melioidosis, and 80% presented during the wet season. Primary cutaneous melioidosis was the commonest presentation in children (60% vs 13%; P < .001), whereas pneumonia predominated in adults (54% vs 20%; P < .001). Bacteremia was less common in children than in adults (16% vs 59%; P < .001). Brainstem encephalitis occurred in 3 children without risk factors. Children were more likely to report an inoculating event (42%; P < .001). There was no difference in mortality between the groups (P = .178), with 3 children dying (7%); all had identifiable risk factors. Four children with cutaneous melioidosis were successfully treated with oral therapy alone, while 2 had skin lesions that resolved spontaneously., Conclusions: Pediatric melioidosis commonly manifests as localized cutaneous disease in immunocompetent hosts. The disease can be fatal, especially in individuals with risk factors for disease. Melioidosis with encephalomyelitis can result in severe residual disability. Prompt diagnosis requires a high index of clinical suspicion in endemic areas., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months., Methods: Patient data from culture-confirmed cases (2000-2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined., Results: Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine [5-FC] for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2-12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema., Conclusions: Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations.

Background: Melioidosis is an important cause of community-acquired sepsis in Southeast Asia and northern Australia, and pneumonia is the most common presentation. Clinical manifestations range from acute fulminant sepsis to chronic infection mimicking tuberculosis. Pneumonia may be the primary presenting feature, or it can develop secondary to initial disease at a distant focus., Methods: A prospective database of all melioidosis patients at Royal Darwin Hospital (Australia) between 1989 and 2010 was reviewed., Results: Of 624 patients with culture-confirmed melioidosis, 319 (51%) presented with pneumonia as the primary diagnosis. Acute/subacute presentations accounted for the majority of primary pneumonia cases (91%); chronic disease was seen less commonly (9%). Secondary pneumonia developed in 20% of patients with other primary melioidosis presentations and was particularly common in those with positive blood cultures. Risk factors for presentation with primary pneumonia (compared with other primary presentations) were rheumatic heart disease or congestive cardiac failure, chronic obstructive pulmonary disease, smoking, and diabetes mellitus, with P < .05 for these conditions in a multivariate logistic regression model. Patients presenting with pneumonia more frequently developed septic shock (33% vs 10%; P < .001) and died (20% vs 8%; P <.001) compared with patients with other primary presentations. Multilobar disease occurred in 28% of primary pneumonia patients and was associated with greater mortality (32%) than in those with single-lobe disease (14%; P < .001)., Conclusions: Melioidosis pneumonia is often a rapidly progressive illness with high mortality, particularly among those with multilobar disease. Risk factors have been identified, and early diagnosis and treatment should be priorities.

Here we discuss the evolution of the northern Australian Staphylococcus aureus isolate MSHR1132 genome. MSHR1132 belongs to the divergent clonal complex 75 lineage. The average nucleotide divergence between orthologous genes in MSHR1132 and typical S. aureus is approximately sevenfold greater than the maximum divergence observed in this species to date. MSHR1132 has a small accessory genome, which includes the well-characterized genomic islands, νSAα and νSaβ, suggesting that these elements were acquired well before the expansion of the typical S. aureus population. Other mobile elements show mosaic structure (the prophage ϕSa3) or evidence of recent acquisition from a typical S. aureus lineage (SCCmec, ICE6013 and plasmid pMSHR1132). There are two differences in gene repertoire compared with typical S. aureus that may be significant clues as to the genetic basis underlying the successful emergence of S. aureus as a pathogen. First, MSHR1132 lacks the genes for production of staphyloxanthin, the carotenoid pigment that confers upon S. aureus its characteristic golden color and protects against oxidative stress. The lack of pigment was demonstrated in 126 of 126 CC75 isolates. Second, a mobile clustered regularly interspaced short palindromic repeat (CRISPR) element is inserted into orfX of MSHR1132. Although common in other staphylococcal species, these elements are very rare within S. aureus and may impact accessory genome acquisition. The CRISPR spacer sequences reveal a history of attempted invasion by known S. aureus mobile elements. There is a case for the creation of a new taxon to accommodate this and related isolates.

Background: Regional differences in the prevalence of Panton-Valentine leukocidin (PVL) and PVL isoform-harboring strains as well as in the local population structure of Staphylococcus aureus may influence the clinical spectrum of S. aureus infections., Methods: Using a prospective collection of S. aureus isolates from northern Australia, we determined differences between infections caused by (1) PVL(+) and PVL(-) isolates, (2) PVL histidine (H) isoform- and PVL arginine (R) isoform-harboring isolates, and (3) different lineages, including the genetically divergent clonal complex (CC) 75 and the PVL(+) CC93., Results: PVL(+) isolates comprised 54% (128/239) of community-associated methicillin-resistant isolates and 40% (95/239) of methicillin-susceptible S. aureus (MSSA) isolates. There were 113 H isoform- and 110 R isoform-harboring isolates. PVL was associated with truly community-acquired disease, younger age, and presentation with sepsis. We found no differences in infections due to H isoform-harboring isolates, compared with R isoform-harboring isolates. CC93 was the most prevalent lineage. The genetically divergent CC75 caused clinical disease similar to that of other S. aureus clones., Conclusions: PVL(+) and PVL(-) infections are clearly distinct. MSSA contributes a large but underrecognized burden of PVL(+) disease. Compared with elsewhere in the world, there is a relative abundance of the clade that contains CC93 and CC121 in both northern Australia and Asia.

Background: Some strains of non-multidrug-resistant, methicillin-resistant Staphylococcus aureus (nmMRSA) in Australia are likely to have emerged from strains of methicillin-susceptible S. aureus (MSSA) in remote Aboriginal communities., Objective: To describe the clinical epidemiology of infection due to community-associated MRSA strains in an Australian tropical hospital setting with a significant Aboriginal population and to compare infections caused by community-associated strains of MRSA, health-care-associated strains of MRSA, and MSSA strains with respect to demographic risk factors and clinical outcomes. Methods. We queried the microbiology database for the Top End of the Northern Territory, Australia, to determine population incidences for S. aureus infection and conducted a prospective matched case-control study to compare infection due to nmMRSA, MSSA, or multidrug-resistant MRSA at the Royal Darwin Hospital., Results: The annual incidence of S. aureus bacteremia was 65 cases per 100,000 population, but in the Aboriginal population the incidence was 172 cases per 100,000 population (odds ratio [OR] compared with non-Aboriginal population, 5.8 [95% confidence interval {CI}, 3.8-8.9). Female sex (adjusted OR [aOR], 1.5 [95% CI, 1.1-2.0) and remote residence (aOR, 1.8 [95% CI, 1.2-2.5]) were associated with the isolation of nmMRSA rather than MSSA, but disease spectrum and outcomes were similar. Among those from whom nmMRSA was isolated, Aboriginal patients were younger (aOR for each additional year, 0.94 [95% CI, 0.92-0.96]), more likely to be female (aOR, 3.8 [95% CI, 1.7-8.5]), and more likely to reside in a remote community (aOR, 29 [95% CI, 8.9-94]) than non-Aboriginal patients. The presence of Panton-Valentine leukocidin in nmMRSA was associated with double the odds of sepsis (aOR, 2.2 [95% CI, 1.1-4.6])., Conclusions: The association of nmMRSA infection with female sex and remote residence supports the hypothesis that nmMRSA arose from MSSA strains in remote Aboriginal communities where staphylococcal disease is highly prevalent. The similar clinical spectrum and outcomes for nmMRSA infection and MSSA infection suggest that virulence is not correlated with resistance phenotype.

Burkholderia pseudomallei is the aetiological agent of melioidosis. Therapy for this disease is lengthy and limited to only a few antibiotics because of this bacterium's intrinsic antibiotic resistance to many clinically useful antibiotics. These properties of B. pseudomallei may partially be due to expression of efflux pumps of the resistance-nodulation-cell-division (RND) family. The patterns and magnitude of RND efflux pump expression in commonly used strains and clinical isolates of B. pseudomallei from the Royal Darwin Hospital, Darwin, Australia, were assessed in cells grown to late exponential phase using quantitative real-time PCR (qRT-PCR). Expression of the three previously identified RND efflux pumps AmrAB-OprA, BpeAB-OprB and BpeEF-OprC, as well as four other yet uncharacterized pumps, was found to be widespread in the clinical isolates. In 45 of 50 isolates (90%), mRNA was detected for at least one of the seven RND pumps. Of these 45 isolates, 41 (82%) expressed multiple pumps with nine strains expressing all seven pumps tested. While these studies revealed no striking correlation between RND efflux pump expression and clinically significant antibiotic resistance, the data support the notion that RND pumps probably play important roles in this bacterium's physiology, defence against toxic compounds, and perhaps virulence.

Melioidosis, an infection due to the environmental bacterium Burkholderia pseudomallei, is endemic to Southeast Asia and northern Australia, with cases strongly correlated with the monsoonal wet season. We hypothesized that seasonal variation in the mode of acquisition, informed by traditional knowledge, would result in variations in disease characteristics as well as disease incidence. We explored the seasonal variation in acute, culture-confirmed melioidosis using local Aboriginal definitions of seasons in presentations to the Royal Darwin Hospital, the referral centre for the Top End of the Northern Territory, Australia. In 387 patients, we observed an increased proportion of patients with pneumonia (60%) and severe sepsis (25%) associated with presentations in the wet seasons Gunumeleng (October-December) and Gudjewg (January-March) compared with the drier seasons Wurrgeng (June August) and Gurrung (August-October) (pneumonia 26%, severe sepsis 13%). This observation supports the hypothesis that in the wet seasons there may be changes in the mode and/or magnitude of exposure to B. pseudomallei, with a shift from percutaneous inoculation to aerosol inhalation, for instance.

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.

Background: Burkholderia pseudomallei is endemic in northern Australia, and melioidosis is a common cause of sepsis in the region., Methods: We summarized the cutaneous manifestations of melioidosis from a prospective cohort of 486 patients with culture-confirmed melioidosis in northern Australia, and we compared those who had primary skin melioidosis with those who had other forms of melioidosis., Results: Primary skin melioidosis occurred in 58 patients (12%). Secondary skin melioidosis--multiple pustules from hematogenous spread--was present in 10 patients (2%). Patients with primary skin melioidosis were more likely to have chronic presentations (duration, >or=2 months). On multivariate analysis, patients with primary cutaneous melioidosis were more likely to be children aged

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in Australia may have been facilitated by conditions in socially disadvantaged populations--particularly, remote Australian Aboriginal communities. The appearance of community-associated MRSA was first noticed in Australia during the early 1980s; subsequently, several genetically diverse strains have independently emerged from geographically distinct regions. Molecular and epidemiological studies support the role of genetic transfer of resistance determinants (SCCmecIV) in this process. Conditions in Aboriginal communities--namely, domestic crowding, poor hygiene, and high rates of scabies, pyoderma, and antibiotic use--have facilitated both the clonal expansion and de novo emergence of strains of community-associated MRSA. Combating the worldwide emergence and spread of community-associated MRSA may require novel community-level control strategies targeted at specific groups, such as remote Indigenous populations.

Background: Crusted scabies is a rare and severely debilitating disease characterized by infestation of the skin with up to millions of Sarcoptes scabiei mites, high total IgG levels, extremely high total IgE levels, and the development of hyperkeratotic skin crusts that may be loose, scaly and flaky or thick and adherent., Objectives: To describe crusted scabies skin pathogenesis and identify markers associated with an inappropriate immune response leading to disease progression., Patients/methods: Serial sections from skin biopsies obtained from two patients with severe crusted scabies were examined by immunohistochemistry for cell surface markers and inflammatory and regulatory cytokines. Concurrent levels of total B- and T-cell subsets and IgE, IgA, IgM, IgG and IgG subclasses were analysed in the blood. In addition antibody levels were recorded in a further 33 patients with crusted scabies and 14 patients with ordinary scabies., Results: A predomination of infiltrating CD8+ T lymphocytes in the dermis was observed compared with minimal helper T lymphocytes (CD4+) and the absence of any B cells. The proportion of T and B lymphocytes and T-cell subsets in the blood of these patients were within normal ranges, indicating a selective movement of CD8+ T cells into the dermis. Furthermore, strong staining for the inflammatory cytokine interleukin-1 beta and anti-inflammatory cytokine transforming growth factor-beta1 was observed. Elevated levels of IgE, IgG, IgG1, IgG3 and IgG4 were recorded., Conclusions: Skin-homing cytotoxic T cells contribute to an imbalanced inflammatory response in the dermis of crusted scabies lesional skin. This, in combination with the lack of B cells, is contributing to the failure of the skin immune system to mount an effective response resulting in uncontrolled growth of the parasite.

Major advances have been made in molecular studies of Burkholderia pseudomallei and the immunology of melioidosis. However, there remain large gaps in understanding of the epidemiology of this enigmatic disease. Identified global distribution boundaries of melioidosis continue to expand. Recent data suggest Australian strains of B. pseudomallei may be ancestral to those from Southeast Asia, but the ecology of this environmental bacterium remains elusive. Despite the potential for rapidly progressive septicaemia, the critical virulence factors in B. pseudomallei remain to be clarified. Inhalation following aerosolization of B. pseudomallei may account for the high mortality when melioidosis occurs after severe weather events.

A prospective study was conducted to determine the significance of melioidosis in the Balimo district of Western Province, Papua New Guinea. During 1998, after the establishment of laboratory procedures and increasing local clinical awareness, the disease was found in 1.8% (95% CI 0.37-5.1%) of individuals presenting with fever refractory to standard treatment. The clinical incidence was 20.0 per 100,000 population (95% CI 12.2-30.9). The median age of culture-confirmed cases was 9.5 years (interquartile range 8.3-14.8 years). The seroprevalence of 747 community children in the region tested was 8.2% (95% CI 6.2-10.4%). Most individuals presented during the rainy season with a febrile disease refractory to standard treatment, sometimes mimicking tuberculosis. Some family clustering was apparent. All patients with bacteraemic melioidosis died, but treatment with the available conventional therapies of chloramphenicol, co-trimoxazole or doxycycline resulted in survival and cure in six patients with subacute/localised melioidosis. Further studies are needed to ascertain the local epidemiology and why children appear particularly at risk, as well as to establish the true extent of melioidosis in Papua New Guinea.

Background: Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis., Methods: In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 mu g per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand., Results: Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61-1.06; P=.2), including among patients with confirmed melioidosis (83% vs. 96%; P=.3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31-1.00; P=.05)., Conclusions: Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may "buy time" for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.

Murray Valley encephalitis (MVE) virus, a mosquito-borne flavivirus, is the most common cause of viral encephalitis in the tropical 'Top End' of northern Australia. Clinical encephalitis due to MVE virus has a mortality rate of approximately 30%, with a similar proportion of patients being left with significant neurological deficits. We report the case of a 25-year-old man from the UK who acquired MVE while travelling through northern Australia. He required prolonged admission to the Intensive Care Unit and several years later remains partly ventilator-dependent, with flaccid quadriparesis. To our knowledge, this is the first reported case of MVE virus-induced flaccid paralysis in an adult in northern Australia, although it is well described in children. Paralysis was thought to be due to anterior horn cell involvement in the spinal cord and extensive bilateral thalamic destruction, both of which are well recognised complications of infection with MVE virus. Cases of flaccid paralysis with similar pathology have been described following infection with the related flavivirus Japanese encephalitis virus as well as more recently with West Nile virus. Our case highlights the potential severity of flavivirus-induced encephalitis and the importance of avoiding mosquito bites while travelling through endemic areas.

Background: Acute rheumatic fever is a major cause of heart disease in Aboriginal Australians. The epidemiology differs from that observed in regions with temperate climates; streptococcal pharyngitis is reportedly rare, and pyoderma is highly prevalent. A link between pyoderma and acute rheumatic fever has been proposed but is yet to be proven. Group C beta-hemolytic streptococci and group G beta-hemolytic streptococci have also been also implicated in the pathogenesis., Methods: Monthly, prospective surveillance of selected households was conducted in 3 remote Aboriginal communities. People were questioned about sore throat and pyoderma; swab specimens were obtained from all throats and any pyoderma lesions. Household population density was determined., Results: From data collected during 531 household visits, the childhood incidence of sore throat was calculated to be 8 cases per 100 person-years, with no cases of symptomatic group A beta-hemolytic streptococci pharyngitis. The median point prevalence for throat carriage was 3.7% for group A beta-hemolytic streptococci, 0.7% for group C beta-hemolytic streptococci, and 5.1% for group G beta-hemolytic streptococci. Group A beta-hemolytic streptococci were recovered from the throats of 19.5% of children at some time during the study. There was no seasonal trend or correlation with overcrowding. Almost 40% of children had pyoderma at least once, and the prevalence was greatest during the dry season. In community 1, the prevalence of pyoderma correlated with household crowding. Group C and G beta-hemolytic streptococci were rarely recovered from pyoderma lesions., Conclusions: These data are consistent with the hypothesis that recurrent skin infections immunize against throat colonization and infection. High rates of acute rheumatic fever were not driven by symptomatic group A beta-hemolytic streptococci throat infection. Group G and C beta-hemolytic streptococci were found in the throat but rarely in pyoderma lesions.

Endemic histoplasmosis occurs uncommonly in Australia and has not previously been reported in the tropical Northern Territory, nor in Aboriginal Australian patients. We report one suspected and one confirmed case of severe disseminated histoplasmosis in Aboriginal Australians from the Northern Territory. Underlying illness included chronic cardiac disease and Type 1 diabetes mellitus, respectively, and neither patient was infected with HIV. The clinical presentations resembled malignancy. Diagnosis of histoplasmosis was made on the basis of bowel histology in Case 1, demonstrating characteristic yeasts, and lymph node histology and culture in Case 2. Histoplasmosis should be considered in relevant clinical situations, even in HIV-negative patients who have not left Australia.

Background: Melioidosis, the infection due to the environmental organism Burkholderia pseudomallei, is endemic to northern Australia and South East Asia. It is associated with exposure to mud and pooled surface water, but environmental determinants of this disease are poorly understood. We defined case-clusters in northern Australia, determined their contribution to the observed rate of melioidosis, and explored clinical features and associated environmental factors., Methods: Using geographical information systems data, we examined clustering of melioidosis cases in time and geographical space in the Top End of the Northern Territory of Australia between 1990 and 2002 using a scan statistic. DNA macrorestriction analysis, resolved by pulsed field gel electrophoresis, was performed on isolates from patients., Results: We defined five case-clusters involving 27 patients that occurred within 7-28 days and/or a radius of 100-300 km. Clustered cases were associated with extreme weather events or environmental contamination; no difference in the clinical pattern of disease was noted from other patients not involved in clusters. Isolates from patients linked to environmental contamination were caused by isolates with similar DNA macrorestriction patterns, but isolates from patients linked to severe weather events had more diverse DNA macrorestriction patterns., Conclusion: Case-clusters of melioidosis where isolates exhibit diverse DNA macrorestriction patterns in our region are linked to extreme weather events and outbreaks where isolates are predominantly of the same DNA macrorestriction pattern are linked with contamination of an environmental source.

Ivermectin is increasingly being used to treat scabies, especially crusted (Norwegian) scabies. However, treatment failures, recrudescence, and reinfection can occur, even after multiple doses. Ivermectin resistance has been documented for some intestinal helminths in animals with intensive ivermectin exposure. Ivermectin resistance has also been induced in arthropods in laboratory experiments but, to date, has not been documented among arthropods in nature. We report clinical and in vitro evidence of ivermectin resistance in 2 patients with multiple recurrences of crusted scabies who had previously received 30 and 58 doses of ivermectin over 4 and 4.5 years, respectively. As predicted, ivermectin resistance in scabies mites can develop after intensive ivermectin use.

Human scabies, caused by skin infestation with the arthropod mite, Sarcoptes scabiei, typically results in a papular, intensely pruritic eruption involving the interdigital spaces, and flexure creases. Recent research has led to a reassessment of the morbidity attributable to this parasite in endemic communities, particularly resulting from secondary skin sepsis and postinfective complications including glomerulonephritis. This has led to studies of the benefits of community based control programmes, and to concerns regarding the emergence of drug resistance when such strategies are employed. The renewed research interest into the biology of this infection has resulted in the application of molecular tools. This has established that canine and human scabies populations are genetically distinct, a finding with major implications for the formulation of public health control policies. Further research is needed to increase understanding of drug resistance, and to identify new drug targets and potential vaccine candidates.

Group A streptococci (GAS) cause several human diseases that differentially affect distinct host populations. Genotypes were defined by multilocus sequence typing and emm typing for 137 organisms collected from individuals in a remote aboriginal island community in tropical Australia and compared with >200 isolates obtained from sources elsewhere in the world. The majority of aboriginal-derived isolates shared emm types and housekeeping alleles with GAS isolates recovered from outside Australia, but these emm types and alleles were in novel combinations. There were many examples in which isolates from aboriginal and non-Australian subjects shared the same emm type, but for approximately 50% of emm types, the multilocus genotypes of isolates of the same emm type but from different regions were very different. A single emm type may typically define a single clone within the United States and on the remote island that is the focus of this study, but in many cases, these clones will be different, and this finding has implications for attempts to make global associations between emm types and certain disease manifestations.

Serum from seven patients with ordinary scabies and six with crusted scabies were screened by immunoblotting for IgE- and IgG-specific proteins in an extract of the mite, Sarcoptes scabiei variety canis. Sera from atopic individuals without sensitivity to house dust mites were used as controls. Serum from all of the patients with crusted scabies showed strong IgE binding to 11-21 and IgG binding to 1-7 scabies proteins. In contrast, three of the seven patients with ordinary scabies showed IgE binding to one to six scabies proteins, and their antibody binding was much weaker. Patients with crusted scabies had serum antibody that reacted with larger molecular weight proteins compared with patients with ordinary scabies. The results of this study indicate that patients with crusted scabies showed a pronounced IgE response to scabies mites, whereas patients with ordinary scabies did not.

Melioidosis, caused by the intracellular pathogen Burkholderia pseudomallei, is endemic in northern Australia and Southeast Asia. Risk factors for this infection have also been associated with functional neutrophil defects. Because of this, granulocyte colony-stimulating factor (G-CSF) was adopted for use in patients with septic shock due to melioidosis in December 1998. We compared the mortality rates from before and after the introduction of G-CSF therapy at the Royal Darwin Hospital (Darwin, Australia) during the period of 1989-2002. The mortality rate decreased from 95% to 10% after the introduction of G-CSF. Risk factors, the duration of illness before presentation, and the severity of illness were similar in both groups. A smaller decrease in mortality among patients in the intensive care unit who did not have melioidosis was observed, suggesting that other changes in management did not account for the magnitude of the benefit seen. We conclude that G-CSF may have contributed to the reduction in the mortality rate among patients with septic shock due to melioidosis.

Prompted by 2 outbreaks of melioidosis with fatalities linked to culture-positive drinking water, we theorized that there may be a correlation between low drinking water pH or lack of chlorination and the rate of melioidosis in rural communities in tropical Australia. However, following adjustment for rainfall, such associations were not apparent in a multivariate regression model.

Melioidosis, due to infection with the environmental organism Burkholderia pseudomallei, continues to be associated with high mortality despite improvements in antibiotic therapy. Using simple clinical findings and baseline laboratory tests available at the time of admission, we attempted to define those patients with acute melioidosis who were at higher risk of death. Using data, collected prospectively from the period October 1989 to June 2002, from patients with acute culture-confirmed melioidosis presenting at the Royal Darwin Hospital, Darwin, Australia, a number of variables were selected that were easily available at the time of admission and reflected organ dysfunction. Mortality was predicted in univariate logistic and multivariate models by the presence of pneumonia, age at diagnosis, serum urea, serum bilirubin, lymphocyte count, and serum bicarbonate. A score was assigned from 0 to 2, based on the degree of abnormality. A melioidosis score was formed from the sum of these scores, with a maximum score of 11. A score of < or = 3 (n = 140) was associated with a mortality of 8.6%, whereas a score of > or = 4 (n = 112) was associated with a mortality of 44.6%. Although this scoring system requires external validation, it may help identify a suitable target group of patients for intensive intervention such as early admission to an intensive care unit, the early use of meropenem, and goal-directed resuscitation therapies.

We recently managed 4 patients with cystic fibrosis who had acquired Burkholderia pseudomallei infection after exposure in a region of endemicity. Person-to-person transmission between 2 siblings may have occurred; otherwise, the evidence suggests that cystic fibrosis may increase the likelihood of infection with this organism, and patients should be warned of this possibility and cautioned to avoid high-risk activities.

Despite recognition of acute respiratory distress syndrome in both falciparum and vivax malaria, disease-related changes in pulmonary function have not been defined, and underlying mechanisms are not well understood. Respiratory symptoms, pulmonary function, pulmonary phagocytic cell activity, and longitudinal changes were examined in 26 adults with uncomplicated falciparum, vivax, and ovale malaria after treatment. Self-limiting cough occurred in both falciparum (36%) and vivax or ovale (53%) malaria. In infection with each malaria species, admission measures of airflow and gas transfer were lower than predicted, and mean lung (99m)technetium-sulfur-colloid uptake was significantly increased. Changes were most evident in falciparum malaria, with treatment resulting in initial worsening of airflow obstruction and gas transfer. Altered pulmonary function in malaria is common and includes airflow obstruction, impaired ventilation, impaired gas transfer, and increased pulmonary phagocytic activity, and its occurrence in both vivax and falciparum malaria suggests that there may be common underlying inflammatory mechanisms.

In a prospective study of melioidosis in northern Australia, 252 cases were found over 10 years. Of these, 46% were bacteremic, and 49 (19%) patients died. Despite administration of ceftazidime or carbapenems, mortality was 86% (43 of 50 patients) among those with septic shock. Pneumonia accounted for 127 presentations (50%) and genitourinary infections for 37 (15%), with 35 men (18%) having prostatic abscesses. Other presentations included skin abscesses (32 patients; 13%), osteomyelitis and/or septic arthritis (9; 4%), soft tissue abscesses (10; 4%), and encephalomyelitis (10; 4%). Risk factors included diabetes (37%), excessive alcohol intake (39%), chronic lung disease (27%), chronic renal disease (10%), and consumption of kava (8%). Only 1 death occurred among the 51 patients (20%) with no risk factors (relative risk, 0.08; 95% confidence interval, 0.01-0.58). Intensive therapy with ceftazidime or carbapenems, followed by at least 3 months of eradication therapy with trimethoprim-sulfamethoxazole, was associated with decreased mortality. Strategies are needed to decrease the high mortality with melioidosis septic shock. Preliminary data on granulocyte colony-stimulating factor therapy are very encouraging.

Disease caused by group A streptococci (GAS) in tropical regions often takes the form of impetigo, whereas pharyngitis tends to predominate in temperate zones. GAS derived from asymptomatic throat infections and pyoderma lesions of rural Aboriginal Australians were evaluated for phylogenetic distant emm genes, which represent ecological markers for tissue site preference. On the basis of the percentage of total isolates from a given tissue, emm pattern A-C organisms exhibited a stronger predilection for the throat, whereas pattern D organisms preferred the skin. Only 16% of isolates collected by active surveillance displayed pattern A-C, which reflects the low incidence of oropharyngeal infection. Importantly, most (70%) pattern A-C organisms were isolated from skin sores, despite their innate tendency to infect the throat. Combined with findings from nontropical populations, analysis of the data supports the hypothesis that GAS tissue preferences are genetically predetermined and that host risk factors for infection strongly influence the differential reproduction of individual clones.

We performed a retrospective/prospective review of all cases of disease due to nontuberculous mycobacteria (NTM) reported in the Northern Territory, Australia, during the period 1989-1997. Fifty-eight cases were reported, with an average yearly incidence of 3.9 cases per 100,000 persons. The number increased significantly for the second half of the study period (39 vs. 19 cases; P<.02). The yearly incidence of pulmonary Mycobacterium avium/Mycobacterium intracellulare complex (MAC) disease not associated with human immunodeficiency virus (HIV) infection was 2.1 cases per 100,000 population. MAC was the most common isolate (78%) and pulmonary disease the most frequent clinical presentation (62%). Disease due to NTM or MAC was not found more commonly in rural areas. Significant risks for non-HIV-associated pulmonary MAC disease included male sex (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0-4.5) and age >50 years (OR, 26.5; 95% CI, 10.9-67.3), but aboriginal people appeared underrepresented (OR, 0.77; 95% CI, 0.30-1.87). Mycobacterium tuberculosis was almost 5 times more likely than NTM to be the cause of non-HIV-associated mycobacterial pulmonary disease (153 vs. 32 cases; OR, 4.79; 95% CI, 3.22-7.14). Mycobacterial lymphadenitis in aboriginal children was more likely to be tuberculous than nontuberculous (OR, 6.5; 95% CI, 1.4-41.7), but not in nonaboriginal children (OR, 1.0). With treatment, 66% of the cases of non-HIV-associated pulmonary MAC disease had favorable outcomes, and 7% of patients had progressive fatal disease. Outcomes of therapy for lymphadenitis and skin/soft-tissue disease were excellent, but those of HIV-associated disseminated MAC disease were poor.

In melioidosis-endemic regions the importance of re-activation of Burkholderia pseudomallei from latent foci remains unclear. This topic was assessed in a 10-year prospective study (1989-99) of melioidosis in the tropical north of the Northern Territory of Australia, together with other aspects of the nature of melioidosis. Incubation period from defined inoculating events was previously ascertained as 1-21 (mean 9) days. Of 252 total cases 244 (97%) were considered to be from recent acquisition of B. pseudomallei infection and 8 (3%) were considered to be re-activation from a latent focus. Acute illness occurred in 222 (88%) cases; 30 (12%) cases had chronic illness (symptomatic for > 2 months). Of the 207 patients surviving the initial illness, 27 (13%) had a confirmed relapse (mean time from initial diagnosis of 8 months), with 5 relapsing twice. Of these 32 relapses, 15 (3 fatal) were associated with poor adherence to the eradication therapy antibiotics and 10 (none fatal) were failures of eradication with doxycycline monotherapy. Following initial intensive therapy with ceftazidime or meropenem for at least 14 days, eradication therapy with trimethoprim-sulphamethoxazole monotherapy for at least 3 months had been more successful.

Resistance of Sarcoptes scabiei to various topical therapies has been described, but clinical assessment of treatment failure is problematic and in-vitro assays are generally not available. We describe a simple in-vitro analysis used to evaluate the relative efficacy of a range of topical, oral, and herbal treatments available in Australia for the treatment of scabies. S. scabiei var. hominis mites were collected from skin scrapings obtained from 7 crusted scabies patients over a period of 2 years (1997 and 1998). Larvae, nymphal instars, and adult mites were tested within 3 h of collection and continuously exposed to selected commercially available treatment products until death, with the elapsed time recorded. Neem was the only product to show little acaricidal activity. Survival curves indicated that, of the other agents, 5% permethrin (Lyclear) had the slowest killing time, with 35% of mites still alive after 3 h, and 4% still alive after 18-22 h of constant exposure. In contrast, no mites were alive after 3 h exposure to 25% benzyl benzoate (Ascabiol), 1% lindane (Quellada), 5% tea tree oil and 100-8000 ng/g of ivermectin (Equimec). Despite the slower killing time with 5% permethrin, there was no evidence of any mite tolerance in vivo or treatment failure in any patients or contact cases.

Crusted scabies is a severe debilitating disease due to hyperinfestation with the ectoparasite Sarcoptes scabiei. Treatment protocols include oral ivermectin and topical scabicides. After single-dose ivermectin, there may be early recrudescence, whereas after 3 doses at 14-day intervals, there is an apparent cure. However, such patients often present again after 6-12 months. To clarify the biology of recurrence, we studied genetic markers in sequential populations of S. scabiei mites from treated patients with multiple episodes of crusted scabies. Individual mites were genotyped at hypervariable microsatellite loci by a fluorescence-based polymerase chain reaction. Results indicated that sequential populations of mites were genetically more similar to each other than to mites from other patients. Although the majority of recurrent scabies is probably due to reinfestation from inadequately treated contacts, there was evidence that in very severe crusted scabies, treatment with even 3 doses of ivermectin 14 days apart may be inadequate and relapse may occur.

Infections of the upper respiratory tract and skin due to group A Streptococcus are common, and the organism is highly transmissible. In industrialized countries and to some extent in developing countries, control efforts continue to emphasize that group A streptococcal pharyngitis should be properly diagnosed and appropriately treated. In developing countries and in indigenous populations where the burden of group A streptococcal diseases appears greatest, the epidemiology is less completely defined and may differ from that in industrialized countries. There is a need for accurately collected epidemiological data from developing countries, which may also further clarify the pathogenesis of group A streptococcal infections and their sequelae. While proper treatment of group A streptococcal pharyngitis continues to be essential in all populations, it may be appropriate in developing countries to consider additional strategies to reduce rates of pyoderma.

Substance abuse through the deliberate inhalation of petrol (petrol sniffing or gasoline sniffing) is prevalent in inner-urban and remote rural communities. Although acute toxic encephalopathy is a well-documented consequence of petrol sniffing, the neurological and cognitive effects of chronic petrol sniffing are unknown. A structured neurological examination and the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess neurological and cognitive function in 33 current-sniffers (individuals who had sniffed petrol for >6 months), 30 ex-sniffers (individuals who had sniffed petrol in the past but had abstained for 6 months) and 34 matched non-sniffers (individuals who had never sniffed petrol). No subject was, or had been, encephalopathic from petrol sniffing and all were residing in their community. Blood lead and hydrocarbon levels and information about petrol sniffing behaviour were obtained from each subject. When compared with non-sniffers, current-sniffers showed higher rates of abnormal tandem gait, rapid alternating hand movements, finger to nose movements, postural tremor, bilateral palmomental reflexes and brisk deep reflexes. Cognitive deficits occurred in the areas of visual attention, visual recognition memory and visual paired associate learning. Ex-petrol sniffers showed higher rates of abnormal tandem gait and bilateral palmomental reflexes and cognitive deficits in the areas of visual recognition memory and pattern-location paired associate learning. Blood lead levels and length of time of petrol sniffing correlated significantly with the magnitude of neurological and cognitive deficits. Blood hydrocarbon levels were not related to neurocognitive deficits, although this may have been due to methodological difficulties in obtaining hydrocarbon levels. These results suggest that subtle neurological and cognitive abnormalities do occur in individuals who abuse petrol but who do not have acute toxic encephalopathy and that the severity of these abnormalities is reduced with abstinence.

The 2 known host trees of Cryptococcus neoformans var. gattii, Eucalyptus camaldulensis and E. tereticornis, do not occur naturally in the 'Top End' of the Northern Territory (NT) of Australia. Nine clinical isolates of C. neoformans var. gattii from the NT were analysed by random amplification of polymorphic deoxyribonucleic acid (RAPD) and polymerase chain reaction 'fingerprinting'. Two isolates were assigned to RAPD profile VGI, previously established as the common RAPD profile. The remaining 7 were assigned to profile VGII; 6 of these isolates were recovered from individuals living in the 'Top End'. The results strongly support the existence of an alternative environmental niche for C. neoformans var. gattii, as all isolates from Eucalyptus spp. in Australia to date have been of RAPD profile VGI.

In February 1995, single-dose azithromycin was given to children with trachoma and their household contacts who were children. For children with trachoma, rates of carriage of pneumococci immediately before treatment with azithromycin and 2-3 weeks, 2 months, and 6 months after treatment were 68% (54 of 79), 29% (11 of 38), 78% (29 of 37), and 87% (34 of 39), respectively. The proportion of carriage-positive children with azithromycin-resistant Streptococcus pneumoniae strains was 1 of 54 (1.9%) before treatment and then 6 of 11 (54.5%), 10 of 29 (34.5%), and 2 of 34 (5.9%) at follow-up visits. The profile of pneumococcal serotypes changed after azithromycin treatment. Azithromycin-resistant strains (serotypes 10F, 23A, and 45) were isolated from 1 (1.3%) of 79 pretreatment swab specimens, from 16 (21.3%) of 75 swab specimens collected up to 2 months after treatment, and from 2 (6%) of 32 obtained 6 months after treatment. Mathematical modeling showed a more rapid appearance of azithromycin-resistant pneumococcal strains in previously colonized children than in previously noncolonized children. Thus, it appears that the selective effect of azithromycin allowed the growth and transmission of preexisting azithromycin-resistant strains. More research is needed to clarify the clinical relevance and implications of azithromycin use.

Pseudomonas pseudomallei, which causes melioidosis, is most commonly associated with pulmonary infection. We describe seven patients who developed a neurological syndrome as the predominant manifestation of melioidosis: this syndrome was characterized by peripheral motor weakness (mimicking Guillain-Barré syndrome), brain-stem encephalitis, aseptic meningitis, and respiratory failure. Neurological melioidosis occurred in the absence of demonstrable foci of infection in the central nervous system (CNS) in five of six patients whose cerebrospinal fluid was available for culture. Computed tomography and magnetic resonance imaging of the brain and spinal cord of these patients were not suggestive of pyogenic infection, although the latter procedure detected brain-stem encephalitis. Autopsy findings in one case confirmed brain-stem encephalitis without evidence of direct bacterial infection. The clinical presentation of neurological melioidosis includes features of an exotoxin-induced neurological syndrome, with profound neurological disease occurring in the absence of apparent direct infection of the CNS. This syndrome appears to be a newly recognized clinical presentation of melioidosis.

Eleven cases of blood culture-positive, community-acquired pneumonia due to the human commensal Acinetobacter baumannii were studied in Darwin in the Northern Territory of Australia during the 10-year period from March 1981 through February 1991. Demographic risk factors included male gender, age of greater than 45 years, and Aboriginal ethnic background. Multiple clinical risk factors, including cigarette smoking, alcoholism, chronic obstructive airway disease, and diabetes mellitus, were noted in all cases and contributed to the high mortality (64%). In all cases pneumonia was clinically fulminant. A fatal outcome was strongly associated with inappropriate initial antibiotic therapy. All tested isolates of Acinetobacter were sensitive to gentamicin and resistant to cefotaxime. The 34 previously reported cases of community-acquired acinetobacter pneumonia are reviewed, and appropriate therapeutic regimens are identified.