Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities.

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

Broad spectrum SARS-CoV-2-specific immunity in hospitalized First Nations peoples recovering from COVID-19.

Indigenous peoples globally are at increased risk of COVID-19-associated morbidity and mortality. However, data that describe immune responses to SARS-CoV-2 infection in Indigenous populations are lacking. We evaluated immune responses in Australian First Nations peoples hospitalized with COVID-19. Our work comprehensively mapped out inflammatory, humoral and adaptive immune responses following SARS-CoV-2 infection. Patients were recruited early following the lifting of strict public health measures in the Northern Territory, Australia, between November 2021 and May 2022. Australian First Nations peoples recovering from COVID-19 showed increased levels of MCP-1 and IL-8 cytokines, IgG-antibodies against Delta-RBD and memory SARS-CoV-2-specific T cell responses prior to hospital discharge in comparison with hospital admission, with resolution of hyperactivated HLA-DR+ CD38+ T cells. SARS-CoV-2 infection elicited coordinated ASC, Tfh and CD8+ T cell responses in concert with CD4+ T cell responses. Delta and Omicron RBD-IgG, as well as Ancestral N-IgG antibodies, strongly correlated with Ancestral RBD-IgG antibodies and Spike-specific memory B cells. We provide evidence of broad and robust immune responses following SARS-CoV-2 infection in Indigenous peoples, resembling those of non-Indigenous COVID-19 hospitalized patients.

Risk factors for mortality in patients with diabetic foot infections: a prospective cohort study.

BACKGROUND: An increasing prevalence of diabetes mellitus has led to a high risk of diabetic foot infections (DFI) and associated morbidity. However, little is known about the relationship between DFI and mortality. AIM: To investigate the risk of mortality and associated factors in patients with DFI in an Australian context. METHODS: A prospective cohort study of inpatients with DFI between May 2012 and October 2016 was done at Royal Darwin Hospital, a tertiary referral hospital for the Top End of the Northern Territory. Primary outcome was 1-year mortality with Cox regression analysis undertaken to assess risk factors for mortality. RESULTS: Four hundred and thirteen consecutive adult diabetic patients with 737 admissions were referred to the High-Risk Foot Service for DFI. Cumulative risk of mortality at 1 year was 8.9% (95% confidence interval (CI) 6.4-12.2). On univariable analysis, mortality was associated with older age (hazard ratio (HR) per year increase 1.08, 95% CI 1.06-1.11, P = 0.001), haemodialysis (HR 3.64, 1.74-7.62, P < 0.001), isolation of Pseudomonas aeruginosa (HR 2.32, 1.05-5.12, P = 0.04) and ischaemic heart disease (HR 2.05, 1.04-4.07, P = 0.04), while indigenous status (HR 0.48, 0.25-0.95, P = 0.04) and HbA1c > 7% (HR 0.45, 0.20-0.99, P < 0.05) were protective. After adjusting for confounders, independent risk factors for mortality were haemodialysis (adjusted HR 5.76, 95% CI 2.28-14.59, P < 0.001) and older age (adjusted HR 1.09, 1.06-1.13, P < 0.001). Patients on haemodialysis had a cumulative risk of mortality of 24.5% (95% CI 14.0-40.8) at 1 year. CONCLUSION: There is a high risk of mortality associated with DFI, substantially increased in patients undergoing haemodialysis, highlighting the importance of early and dedicated interventions targeted at this high-risk group.

Antimicrobial prescribing in referral hospitals in Timor-Leste: results of the first two national point prevalence surveys, 2020-21.

Objectives: To describe antimicrobial use (AMU) in patients admitted to hospitals in Timor-Leste. Methods: In 2020 and 2021, we undertook antimicrobial prescribing point prevalence surveys across all six hospitals in Timor-Leste (one national and five municipal) to describe AMU and appropriateness in admitted patients. Results: In 2020, 291/394 (73.9%) surveyed patients had been prescribed antimicrobials, compared with 260/403 (64.5%) in 2021 (P = 0.004). Most (309/551; 56.1%) were prescribed one antimicrobial, and 179/551 (32.5%) were prescribed two. The most commonly prescribed antibiotics were ceftriaxone (38.5% in 2020, 41.5% in 2021) and ampicillin (35.7% in 2020, 32.3% in 2021), followed by gentamicin, metronidazole and cloxacillin. Reserve antibiotics like meropenem and vancomycin were minimally used. Of all antimicrobial prescriptions, 70.8% were deemed appropriate in 2020 and 69.1% in 2021. Antimicrobial prescriptions for surgical and post-partum prophylaxis were frequently deemed inappropriate [37/50 (74.0%) and 39/44 (88.6%) prescriptions, respectively]. Conclusions: Most patients admitted to hospital in Timor-Leste are prescribed antimicrobials, and approximately one-third of these prescriptions are inappropriate. However, this was in the context of limited local guideline availability at the time of surveys and limited microbiological culture capacity outside of the capital, Dili. Improved microbiological guidance, iterative guideline revisions based on local antimicrobial resistance (AMR) surveillance data, and enhanced stewardship activities including further point prevalence studies, could improve antimicrobial use, optimize patient outcomes and reduce AMR in Timor-Leste.

Australian guideline on management of diabetes-related foot infection: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease.

BACKGROUND: Diabetes-related foot infections cause substantial morbidity and mortality, both globally and in Australia. There is a need for up-to-date evidence-based guidelines to ensure optimal management of patients with diabetes-related foot infections. We aimed to identify and adapt high quality international guidelines to the Australian context to become the new Australian evidence-based guideline for people with a diabetes-related foot infection. METHODS: Following Australian National Health and Medical Research Council (NHMRC) procedures we identified the 2019 International Working Group on the Diabetic Foot (IWGDF) guidelines as suitable for adaptation to the Australian context. Guidelines were screened, assessed and judged by an expert panel for the Australian context using the guideline adaptation frameworks ADAPTE and Grading of Recommendations Assessment, Development and Evaluation (GRADE). Judgements led to recommendations being adopted, adapted or excluded, with additional consideration regarding their implementation, monitoring and future research for the Australian context. Clinical pathways were then developed to assist implementation. RESULTS: Of 36 original diabetes-related foot infection IWGDF sub-recommendations, 31 were adopted, four were adapted and one was excluded. Adaption was primarily undertaken due to differences or clarification of the sub-recommendations' intended population. One sub-recommendation was excluded due to substantial differences in judgements between the panel and IWGDF and unacceptable heterogeneity of the target population. Therefore, we developed 35 evidence-based sub-recommendations for the Australian context that should guide best practice diagnosis and management of people with diabetes-related foot infection in Australia. Additionally, we incorporated these sub-recommendations into two clinical pathways to assist Australian health professionals to implement these evidence-based sub-recommendations into clinical practice. The six guidelines and the full protocol can be found at: https://www.diabetesfeetaustralia.org/new-guidelines/ . CONCLUSIONS: A new national guideline for the diagnosis and management of people with diabetes-related foot infections were successfully developed for the Australian context. In combination with simplified clinical pathway tools they provide an evidence-based framework to ensure best management of individuals with diabetes-related foot infections across Australia and highlight considerations for implementation and monitoring.

Gastrointestinal Carriage of Antimicrobial Resistance in School-Aged Children in Three Municipalities of Timor-Leste.

Invasive bacterial infections are a leading cause of death in children, primarily in low- and middle-income countries (LMIC). Links between carriage of antimicrobial-resistant organisms and more resistant infections have been established; however, little has been reported regarding community carriage of antibiotic-resistant organisms such as extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales in LMIC. The aim of this study was to determine colonic carriage of ESBL-producing fluoroquinolone- and aminoglycoside-resistant Enterobacterales in healthy children in three municipalities of Timor-Leste. In November 2020, 621 stool samples were collected from school-aged children and underwent screening for the presence of Enterobacterales species and antimicrobial resistance (AMR). Ciprofloxacin-resistant Gram-negative organisms were cultured from 16.5% (95% CI 6.2−26.9), and gentamicin resistance was identified in 6.8% (95% CI 2.8−10.7). Compared to the prevalence of ciprofloxacin resistance in Dili (36.1%), there was significantly lower prevalence in the rural municipalities of Ermera (12.9%; AOR 0.38, 95% CI 0.24−0.60, p < 0.001) and Manufahi (4.5%; AOR 0.07, 95% CI 0.01−0.51, p = 0.009). The overall cluster-adjusted prevalence of ESBL-producing bacteria was 8.3%, with no significant differences between municipalities. This study demonstrates high rates of carriage of AMR among school-aged children in Timor-Leste, with higher rates observed in Dili compared to rural municipalities. Empiric antibiotic guidelines should include recommendations for treating community-acquired infections that account for the possibility of antimicrobial resistance.

The Darwin Prospective Melioidosis Study: a 30-year prospective, observational investigation.

BACKGROUND: The global distribution of melioidosis is under considerable scrutiny, with both unmasking of endemic disease in African and Pacific nations and evidence of more recent dispersal in the Americas. Because of the high incidence of disease in tropical northern Australia, The Darwin Prospective Melioidosis Study commenced in October, 1989. We present epidemiology, clinical features, outcomes, and bacterial genomics from this 30-year study, highlighting changes in the past decade. METHODS: The present study was a prospective analysis of epidemiological, clinical, and laboratory data for all culture-confirmed melioidosis cases from the tropical Northern Territory of Australia from Oct 1, 1989, until Sept 30, 2019. Cases were identified on the basis of culture-confirmed melioidosis, a laboratory-notifiable disease in the Northern Territory of Australia. Patients who were culture-positive were included in the study. Multivariable analysis determined predictors of clinical presentations and outcome. Incidence, survival, and cluster analyses were facilitated by population and rainfall data and genotyping of Burkholderia pseudomallei, including multilocus sequence typing and whole-genome sequencing. FINDINGS: There were 1148 individuals with culture-confirmed melioidosis, of whom 133 (12%) died. Median age was 50 years (IQR 38-60), 48 (4%) study participants were children younger than 15 years of age, 721 (63%) were male individuals, and 600 (52%) Indigenous Australians. All but 186 (16%) had clinical risk factors, 513 (45%) had diabetes, and 455 (40%) hazardous alcohol use. Only three (2%) of 133 fatalities had no identified risk. Pneumonia was the most common presentation occurring in 595 (52%) patients. Bacteraemia occurred in 633 (56%) of 1135 patients, septic shock in 240 (21%) patients, and 180 (16%) patients required mechanical ventilation. Cases correlated with rainfall, with 80% of infections occurring during the wet season (November to April). Median annual incidence was 20·5 cases per 100 000 people; the highest annual incidence in Indigenous Australians was 103·6 per 100 000 in 2011-12. Over the 30 years, annual incidences increased, as did the proportion of patients with diabetes, although mortality decreased to 17 (6%) of 278 patients over the past 5 years. Genotyping of B pseudomallei confirmed case clusters linked to environmental sources and defined evolving and new sequence types. INTERPRETATION: Melioidosis is an opportunistic infection with a diverse spectrum of clinical presentations and severity. With early diagnosis, specific antimicrobial therapy, and state-of-the-art intensive care, mortality can be reduced to less than 10%. However, mortality remains much higher in the many endemic regions where health resources remain scarce. Genotyping of B pseudomallei informs evolving local and global epidemiology. FUNDING: The Australian National Health and Medical Research Council.

Skin and soft tissue infection caused by Basidiobolus spp. in Australia.

Fungi from the order Entomophthorales are rare but well recognized cause of tropical fungal infection, typically causing subcutaneous truncal or limb lesions in immunocompetent hosts. They may also mimic malignancy by causing intrabdominal mass, sometimes resulting in obstructive gastrointestinal or renal presentations. A 4-year-old female presented with a progressively growing abdominal wall lesion over several months, developing into acute inflammation of the abdominal wall with systemic symptoms. She underwent surgical debridement and fungal culture of subcutaneous tissue was positive for Basidiobolus spp with characteristic histopathological findings. Treatment with voriconazole followed by itraconazole over a total duration of 6 weeks led to complete resolution. Basidiobolus spp is an unusual cause of infection with characteristic mycological and histopathological findings. Infection can present in a number of ways ranging from a slow-growing mass in the subcutaneous soft tissue to an invasive mass in the gastrointestinal tract. Identification of its unique beak-like zygospore and Splendore-Hoeppli phenomenon on histopathological specimens can be pathognomonic and could provide the key to early diagnosis. Review of the literature found that timely diagnosis and commencement of antifungal therapy can be curative with or without surgical treatment. Considering the rarity of this tropical infection, this case provides the opportunity for revision of the typical presentations and diagnostic findings of Basidiobolus spp. With early recognition and suitable treatment, outcomes are generally favorable.