OBJECTIVES: To determine the prevalence and trends of human hookworm infection (HWI) in the Northern Territory over the past 10 years, and to assess the influence of the community children's deworming program (CCDP). DESIGN, PATIENTS AND SETTING: A retrospective observational analysis of consecutive microbiologically confirmed cases of HWI in patients diagnosed at NT government health care facilities and the main private laboratory servicing the NT between January 2002 and July 2012. MAIN OUTCOME MEASURES: Annual prevalence of HWI (2002-2011); age, sex, Indigenous status, residence, haemoglobin level and eosinophil count of patients with HWI; and proportion of patients within the CCDP target population (children aged 6 months to 16 years, who should receive 6-monthly albendazole). RESULTS: From 64 691 faecal samples examined during the study period, hookworm was detected in 112 patients. There was a downward trend in the annual prevalence of HWI, falling from 14.0 cases per 100 000 population (95% CI, 8.8-19.2) in 2002 to 2.2 per 100 000 population (95% CI, 0.3-4.1) in 2011. Only 16 patients (14.3%) fell within the CCDP target population. Seventy-one patients (63.4%) were living in remote communities, and 94 (84.7%) were recorded as Indigenous Australians. CONCLUSIONS: The prevalence of HWI in the NT reduced over the 10-2013 period. HWI predominantly occurs in individuals outside the CCDP target population. Our data support continuation of the CCDP in conjunction with improvements in housing, health hardware and health promotion. Continued use of albendazole in individuals beyond the CCDP may facilitate the eventual eradication of HWI from the NT.

BACKGROUND: Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%). OBJECTIVE: The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial. METHODS: Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output). RESULTS: Of the 266 participants included, age (p = 0.04), randomisation to combination therapy (p = 0.002), vancomycin area under the concentration-time curve (p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam (p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration-time curve with acute kidney injury also persisted in the multivariable model. CONCLUSIONS: For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration-time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.

In Australia's Northern Territory, the hepatitis B virus (HBV) subgenotype A2 (subtype adw2) vaccine was introduced in 1988 for Indigenous infants. Subsequently, the circulating viral genotype has been identified as subgenotype C4 (subtype ayw3). We assessed HBV vaccine effectiveness (VE) in light of this subtype mismatch. Participants of the Aboriginal Birth Cohort (ABC) study were recruited at birth (1987-1990), with HBV serology obtained at follow-up waves 3 (2005-2007) and 4 (2013-2015). Participants were immune if HBV surface antibody levels exceeded 10 IU/L. We determined the VE against any HBV infection (anti-HBc+) and against chronic infection (HBsAg+ or HBV DNA+), comparing non-vaccinated participants with those fulfilling United States Centers for Disease Control and Prevention (CDC) criteria for full HBV immunisation. Of 686 participants in the ABC study, we obtained HBV serology from 388 at wave 4. 181 participants were immune to HBV and 97 had evidence of any infection. Seven participants were chronically infected, of whom five had received three vaccine doses, and anti-HBc seroconversion had occurred subsequent to the three vaccine doses for two of these seven participants. Comparing the 107 participants who had been vaccinated in accordance with CDC recommendations and 127 who had not been vaccinated, VE against any infection was 67% (95%CI, 43-104%). The odds of being anti-HBc+ was 87% lower in participants raised in urban settings compared to those born into families from remote areas (OR, 0.1; 95%CI, 0.03-0.4). In a setting where there exists a subtype mismatch between vaccine and circulating genotype, the vaccine was largely effective in preventing chronic infection but sub-optimal against any infection. The implications of a high prevalence of anti-HBc seropositivity in this population are unclear and require further study. The fact that anti-HBc seropositivity was strongly associated with remote dwelling suggests ongoing viral exposure in remote settings.

Surgical site skin infections (SSIs) are a preventable complication of delivery via caesarean section (c-section). After observing a high rate of SSIs following c-section, we reviewed SSIs following c-section over a 14-month period. In addition, we assessed all women undergoing c-section during the final 6 months of the study period to determine the risk factors for SSIs in our population. During the review period, 6.9%(40 of 583) of women developed a SSI following c-section. The rate of SSIs was five times higher in Indigenous women compared with non-Indigenous women (16.6% v. 3.3%, P = 0.001). Diabetes mellitus, high ASA score and the use of staples to close the wound were also associated with SSIs (6 of 18 v. 24 of 199, P = 0.02; 2 v. 1, P = 0.003; 10 of 18 v. 49 of 199, P = 0.002). Length of stay was increased by 4 days in women who had the SSI diagnosed during their initial admission (P = 0.001), and a quarter of women with a SSI required readmission. Sixty-four percent (18 of 28) of isolates were Staphylococcus aureus, of which 44% were community-associated methicillin-resistant S. aureus (8 of 18). Twenty-nine percent of isolates were not susceptible to cephazolin, the standard antimicrobial prophylaxis used. After changing surgical skin preparation to alcoholic 2% chlorhexidine, adding gentamicin to cephazolin for preincisional antibiotic prophylaxis and educating staff, the rate of SSIs halved to 3.3%. Many of the SSIs that occurred after the new measures were introduced were in women who had not received gentamicin prophylaxis, highlighting the importance of ongoing staff education.

BACKGROUND AND AIM: The hepatitis B surface antigen was first described in the blood of an Indigenous Australian man, yet little is known about its molecular epidemiology in this population, in which it is endemic. The study aimed to determine the clinical and molecular epidemiology of hepatitis B virus (HBV) in Indigenous people from northern Australia. METHODS: Following ethics approval and informed consent, blood specimens and clinical details from Indigenous adults known to be infected with HBV and who were born and raised in Indigenous communities in northern Australia were obtained. HBV genotypes were determined in isolates with sufficient HBV DNA by polymerase chain reaction by sequencing of the polymerase/surface gene. RESULTS: Between June 2010 and June 2012, 65 patients were recruited from six different regions of northern Australia. Thirty-two patients (49%) were hepatitis B e-antigen-positive, and 48% were hepatitis B e-antibody-positive. No patients were found to be coinfected with hepatitis C virus or human immunodeficiency virus. Of the 49 samples with sufficient viral load for genotyping, 100% were infected with genotype C4, previously only reported from two Indigenous Australians. All isolates had wild-type polymerase gene sequences despite 14 currently or previously receiving antiviral treatment. The canonical sG145R vaccine-escape variant was detected in the surface antigen of virus from two patients. CONCLUSIONS: The exclusive HBV genotype in this ancient population is genotype C4. Whole genome sequencing and clinical follow-up of this cohort are in progress, with the aim of exploring the clinical significance of these findings.

BACKGROUND: Chronic hepatitis B (CHB) is endemic in the Aboriginal and Torres Strait Islander population of Australia's Northern Territory. Progression to liver disease can be prevented if holistic care is provided. Low health literacy amongst health professionals is a known barrier to caring for people living with CHB. We co-designed and delivered a culturally safe "Managing hepatitis B" training course for the Aboriginal health workforce. Here, we present an evaluation of the course. OBJECTIVES: 1. To improve course participants CHB-related knowledge, attitudes, and clinical practice. 2. To evaluate the "Managing hepatitis B" training course. 3. To enable participants to have the skills and confidence to be part of the care team. METHODS: We used participatory action research and culturally safe principles. We used purpose-built quantitative and qualitative evaluation tools to evaluate our "Managing hepatitis B" training course. We integrated the two forms of data, deductively analysing codes, grouped into categories, and assessed pedagogical outcomes against Kirkpatrick's training evaluation framework. RESULTS: Eight courses were delivered between 2019 and 2023, with 130 participants from 32 communities. Pre- and post-course questionnaires demonstrated statistically significant improvements in all domains, p<0.001 on 93 matched pairs. Thematic network analysis demonstrated high levels of course acceptability and significant knowledge acquisition. Other themes identified include cultural safety, shame, previous misinformation, and misconceptions about transmission. Observations demonstrate improvements in post-course engagement, a deep understanding of CHB as well as increased participation in clinical care teams. CONCLUSIONS: The "Managing hepatitis B" training course led to a sustained improvement in the knowledge and attitudes of the Aboriginal health workforce, resulting in improved care and treatment uptake for people living with CHB. Important non-clinical outcomes included strengthening teaching and leadership skills, and empowerment.

Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported.We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome.Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir.In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

Accurate detection of acute kidney injury (AKI) in clinical trials is important. Using a 'baseline' creatinine from trial enrolment may not be ideal for understanding a participant's true baseline kidney function. We aimed to determine if a 'pre-trial baseline creatinine' resulted in comparable creatinine concentrations to a 'trial baseline creatinine', and how the timing of baseline creatinine affected the incidence of AKI in the Combination Antibiotic therapy for MEthicillin Resistant Staphylococcus aureus (CAMERA2) randomised trial. Study sites retrospectively collected a pre-trial baseline creatinine from up to 1 year before CAMERA2 trial enrolment ideally when the patient was medically stable. Baseline creatinine from CAMERA2 (the 'trial baseline creatinine'), was the highest creatinine measurement in the 24 h preceding trial randomisation. We used Wilcoxon sign rank test to compare pre-trial and trial baseline creatinine concentrations. We included 217 patients. The median pre-trial baseline creatinine was significantly lower than the median trial baseline creatinine (82 μmol/L [IQR 65-104 μmol/L] versus 86 μmol/L [IQR 66-152 μmol/L] p = <0.001). Using pre-trial baseline creatinine, 48 of 217 patients (22%) met criteria for an AKI at CAMERA2 enrolment and only 5 of these patients met criteria for an AKI using the CAMERA2 study protocol (using baseline creatinine from trial entry). Using a baseline creatinine from the time of trial enrolment failed to detect many patients with AKI. Trial protocols should consider the optimal timing of baseline creatinine and the limitations of using a baseline creatinine during an acute illness.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days. The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. ClinicalTrials.gov Identifier: NCT02365493.

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.