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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: 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.

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: 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.

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.

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.

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.

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.

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.

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.

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.

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.