Capacity building to address antimicrobial resistance in remote Australia: The inaugural HOT NORTH Antimicrobial Academy.

BACKGROUND: Rates of antimicrobial resistance (AMR) for some pathogens in Australia are considerably higher in rural and remote compared to urban regions. The inaugural Hot North Antimicrobial Academy was a 9-month educational programme aimed to build workforce knowledge and capacity in antimicrobial use, audit, stewardship, surveillance and drug resistance in remote primary health care. METHODS: The Academy was advertised to Aboriginal and Torres Strait Islander, regional and remote healthcare workers. Participants were Aboriginal health practitioners, nurses, pharmacists and doctors from Queensland, Northern Territory, South Australia and Western Australia working in remote primary health care with a focus on Indigenous health. Due to COVID-19 restrictions, the Academy ran virtually from February-November 2021 using Microsoft Teams. The Academy was evaluated using surveys and yarning circles to assess impact and knowledge gain. RESULTS: Participants and faculty from across Australia attended 19 lectures and mentorship sessions. Eleven participants commenced and eight (73%) completed the Academy. The Academy raised participants awareness of AMR guidelines, governance and generating change; built confidence in advocacy; grew knowledge about drug resistant infections; and created a community of AMR champions in Indigenous health. CONCLUSION: The evaluation confirmed the Academy met the needs of participants, provided opportunities to move stewardship from tertiary hospitals into Indigenous and remote clinics and developed skills in research, audit, stewardship and advocacy for all involved. All sessions were recorded for future use, with facilitation by the National Aboriginal Community Controlled Health Organisation (NACCHO) in future years.

Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial.

BACKGROUND: Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs). OBJECTIVES: This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections. METHODS: We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days. RESULTS: Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome-number of days alive and free of systemic inflammatory response syndrome ≤14 days-was similar between groups: clindamycin (3 days [IQR 1-6]) versus standard therapy (4 days [IQR 0-8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes-microbiological relapse, treatment failure or diarrhoea-were similar between groups. CONCLUSIONS: As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.

Geospatial epidemiology of Staphylococcus aureus in a tropical setting: an enabling digital surveillance platform.

Delivery of information to clinicians on evolving antimicrobial susceptibility needs to be accurate for the local needs, up-to-date and readily available at point of care. In northern Australia, bacterial infection rates are high but resistance to first- and second-line antibiotics is poorly described and currently-available datasets exclude primary healthcare data. We aimed to develop an online geospatial and interactive platform for aggregating, analysing and disseminating data on regional bacterial pathogen susceptibility. We report the epidemiology of Staphylococcus aureus as an example of the power of digital platforms to tackle the growing spread of antimicrobial resistance in a high-burden, geographically-sparse region and beyond. We developed an online geospatial platform called HOTspots that visualises antimicrobial susceptibility patterns and temporal trends. Data on clinically-important bacteria and their antibiotic susceptibility profiles were sought from retrospectively identified clinical specimens submitted to three participating pathology providers (96 unique tertiary and primary healthcare centres, n = 1,006,238 tests) between January 2008 and December 2017. Here we present data on S. aureus only. Data were available on specimen type, date and location of collection. Regions from the Australian Bureau of Statistics were used to provide spatial localisation. The online platform provides an engaging visual representation of spatial heterogeneity, demonstrating striking geographical variation in S. aureus susceptibility across northern Australia. Methicillin resistance rates vary from 46% in the west to 26% in the east. Plots generated by the platform show temporal trends in proportions of S. aureus resistant to methicillin and other antimicrobials across the three jurisdictions of northern Australia. A quarter of all, and up to 35% of methicillin-resistant S. aureus (MRSA) blood isolates in parts of the northern Australia were resistant to inducible-clindamycin. Clindamycin resistance rates in MRSA are worryingly high in regions of northern Australia and are a local impediment to empirical use of this agent for community MRSA. Visualising routinely collected laboratory data with digital platforms, allows clinicians, public health physicians and guideline developers to monitor and respond to antimicrobial resistance in a timely manner. Deployment of this platform into clinical practice supports national and global efforts to innovate traditional disease surveillance systems with the use of digital technology and to provide practical solutions to reducing the threat of antimicrobial resistance.

Challenging immunodominance of influenza-specific CD8+ T cell responses restricted by the risk-associated HLA-A*68:01 allomorph.

Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8+ T cells to mount robust responses. We elucidate the HLA-A*68:01+CD8+ T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP145+CD8+ T cell responses. Dissecting A68/NP145+CD8+ T cells in low vs. medium/high responders reveals that high responding donors have A68/NP145+CD8+ memory T cells with clonally expanded TCRαßs, while low-responders display A68/NP145+CD8+ T cells with predominantly naïve phenotypes and non-expanded TCRαßs. Single-cell index sorting and TCRαß analyses link expansion of A68/NP145+CD8+ T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8+ T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8+ T cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T cell pools.

Benzylpenicillin versus flucloxacillin for penicillin-susceptible Staphylococcus aureus bloodstream infections from a large retrospective cohort study.

In clinical practice, differing opinions exists regarding the optimal management of patients with penicillin-susceptible Staphylococcus aureus (PSSA) bloodstream infection (BSI). The aim of this study was to compare the 30-day mortality of patients treated with benzylpenicillin or flucloxacillin for PSSA BSI from a large prospectively collected data set from Australia and New Zealand. A logistic regression model and propensity score treatment analysis using inverse probability of treatment weighting were used. A total of 915 patients were included in the study, with an overall mortality rate of 12.9% (118/915) [benzylpenicillin 10.5% (33/315) and flucloxacillin 14.2% (85/600)]. Endocarditis was associated with benzylpenicillin treatment choice, whereas skin and soft-tissue infection was associated with flucloxacillin treatment choice. In the multivariate analysis, increased 30-day mortality was associated with flucloxacillin compared with benzylpenicillin [odds ratio (OR) = 1.6, 95% confidence interval (CI) 1.0-2.5; P = 0.05). When adjusted for treatment choice in the propensity score analysis, flucloxacillin was again associated with increased 30-day mortality (OR = 1.06, 95% CI 1.01-1.1; P = 0.03). An increase in 30-day mortality associated with flucloxacillin use suggests a potential benefit for benzylpenicillin therapy in patients with PSSA BSI.

Adjunctive protein synthesis inhibitor antibiotics for toxin suppression in Staphylococcus aureus infections: a systematic appraisal.

Protein synthesis inhibitor antibiotics inhibit synthesis of new proteins, including exotoxins and other important virulence determinants in Staphylococcus aureus. A summary of the literature regarding the use of adjunctive protein synthesis inhibitors for toxin suppression in the setting of S. aureus infections is presented.

A biological model of scabies infection dynamics and treatment informs mass drug administration strategies to increase the likelihood of elimination.

Infections with Sarcoptes scabiei, or scabies, remain common in many disadvantaged populations. Mass drug administration (MDA) has been used in such settings to achieve a rapid reduction in infection and transmission, with the goal of eliminating the public health burden of scabies. While prevalence has been observed to fall substantially following such an intervention, in some instances resurgence of infection to baseline levels has occurred over several years. To explore the biology underpinning this phenomenon, we have developed a theoretical model of scabies life-cycle and transmission dynamics in a homogeneously mixing population, and simulate the impact of mass drug treatment strategies acting on egg and mite life cycle stages (ovicidal) or mites alone (non-ovicidal). In order to investigate the dynamics of the system, we first define and calculate the optimal interval between treatment doses. We calculate the probability of eradication as a function of the number of optimally-timed successive treatment doses and the number of years over which a program is run. For the non-ovicidal intervention, we first show that at least two optimally-timed doses are required to achieve eradication. We then demonstrate that while more doses over a small number of years provides the highest chance of eradication, a similar outcome can be achieved with fewer doses delivered annually over a longer period of time. For the ovicidal intervention, we find that doses should be delivered as close together as possible. This work provides a platform for further research into optimal treatment strategies which may incorporate heterogeneity of transmission, and the interplay between MDA and enhancement of continuing scabies surveillance and treatment strategies.

Calculation of the age of the first infection for skin sores and scabies in five remote communities in northern Australia.

Prevalence of skin sores and scabies in remote Australian Aboriginal communities remains unacceptably high, with Group A Streptococcus (GAS) the dominant pathogen. We aim to better understand the drivers of GAS transmission using mathematical models. To estimate the force of infection, we quantified the age of first skin sores and scabies infection by pooling historical data from three studies conducted across five remote Aboriginal communities for children born between 2001 and 2005. We estimated the age of the first infection using the Kaplan-Meier estimator; parametric exponential mixture model; and Cox proportional hazards. For skin sores, the mean age of the first infection was approximately 10 months and the median was 7 months, with some heterogeneity in median observed by the community. For scabies, the mean age of the first infection was approximately 9 months and the median was 8 months, with significant heterogeneity by the community and an enhanced risk for children born between October and December. The young age of the first infection with skin sores and scabies reflects the high disease burden in these communities.

What risk of endocarditis is low enough to justify the omission of transoesophageal echocardiography in Staphylococcus aureus bacteraemia? A narrative review.

BACKGROUND: Recent criteria which can identify patients with Staphylococcus aureus bacteraemia (SAB) who are at very low risk of endocarditis raise the question of whether transoesophageal echocardiography (TOE) is appropriate for these patients. AIMS: To estimate the probability of occult endocarditis complicating SAB below which a TOE-guided treatment strategy no longer offers the best 180-day survival, and to examine the key uncertainties affecting this result. SOURCES: Estimates of the parameters required to calculate the Pauker-Kassirer testing threshold were identified from studies published prior to 1 June 2017 using a composite search strategy that involved a systematic search for relevant controlled trials and guidelines, followed by a non-systematic iterative search of the observational literature. CONTENT: Estimates of the necessary parameters were generally consistent across the literature with the exception of the procedural mortality of TOE. In our base-case scenario (TOE mortality 0.1%), the testing threshold for TOE in apparently uncomplicated SAB was a 1.1% probability of occult endocarditis. Sensitivity analyses revealed that the procedural mortality of TOE was a key uncertainty affecting estimates of the testing threshold. IMPLICATIONS: None of the available clinical tools can place patients with SAB below this probability of endocarditis with 95% confidence. Future work in this area should concentrate on improving the precision of these tools and on exploring the value of alternative echocardiography strategies. In addition, a better understanding of the harms of TOE is required to ensure that recommendations regarding the role of this investigation in the management of patients with SAB are appropriate.

The prediction of a family group of two-dimensional node-line semimetals.

Using first-principles calculations, we predict a family group of two-dimensional semimetals MX (M = Pd, Pt; X = S, Se, Te), which has a zig-zag type mono-layer structure in the Pmma (no. 41) layer group. Band structure analysis reveals that node-line features are caused by band inversion and the inversion exists even in the absence of spin-orbital-coupling. First-principles calculations show the robust lattice stability of these predicted materials. This work provides the possibility of making a group of novel two-dimensional materials with semimetal features.

A double-blind randomized controlled trial of ibuprofen compared to placebo for uncomplicated cellulitis of the upper or lower limb.

OBJECTIVES: Cellulitis is a common skin infection resulting in inflammation that may take weeks to resolve despite appropriate antibiotics. It is unclear whether the adjunctive use of nonsteroidal anti-inflammatory drugs hastens the resolution of inflammation in patients with cellulitis. METHODS: We conducted a double-blind, randomized controlled trial comparing ibuprofen 400 mg three times daily for 5 days with identical placebo in adults with uncomplicated cellulitis of the upper or lower limb who were treated with intravenous cefazolin via an outpatient parenteral antibiotic treatment service at one of two Australian hospitals. Participants were assessed twice daily by a study nurse. The primary outcome measure was the proportion of patients with regression of inflammation 48 hours after the first effective dose of parenteral antibiotics (trial registration ANZCTR 12611000515998). RESULTS: Fifty-one patients were enrolled; 48 had sufficient data available to be included in the modified intention-to-treat analysis. Inflammation had begun to regress at 48 hours in 20 participants (80%) in the ibuprofen group compared to 15 (65%) in the placebo group (absolute risk difference +15%; 95% confidence interval -10 to +40; p >0.05). There was no significant difference in any secondary outcome. Ibuprofen appeared safe, with no patients developing renal impairment or necrotizing fasciitis. CONCLUSIONS: This trial demonstrated no significant benefit of adjunctive ibuprofen in adults with uncomplicated cellulitis. The trial was powered to detect a large effect, and hence it is unclear whether the 15% absolute increase in the primary end point in the ibuprofen group was attributable to chance.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Quasi-One-Dimensional Metal-Insulator Transitions in Compound Semiconductor Surfaces.

Existing examples of Peierls-type 1D systems on surfaces involve depositing metallic overlayers on semiconducting substrates, in particular, at step edges. Here we propose a new class of Peierls system on the (101[over ¯]0) surface of metal-anion wurtzite semiconductors. When the anions are bonded to hydrogen or lithium atoms, we obtain rows of threefold coordinated metal atoms that act as one-atom-wide metallic structures. First-principles calculations show that the surface is metallic, and below a certain critical temperature the surface will condense to a semiconducting state. The idea of surface scaffolding is introduced in which the rows are constrained to move along simple up-down and/or sideways displacements, mirroring the paradigm envisioned in Peierls's description. We predict that this type of insulating state should be visible in the partially hydrogenated (101[over ¯]0) surface of many wurtzite compounds.

Whole genome sequencing reveals extensive community-level transmission of group A Streptococcus in remote communities.

Impetigo is common in remote Indigenous children of northern Australia, with the primary driver in this context being Streptococcus pyogenes [or group A Streptococcus (GAS)]. To reduce the high burden of impetigo, the transmission dynamics of GAS must be more clearly elucidated. We performed whole genome sequencing on 31 GAS isolates collected in a single community from children in 11 households with ⩾2 GAS-infected children. We aimed to determine whether transmission was occurring principally within households or across the community. The 31 isolates were represented by nine multilocus sequence types and isolates within each sequence type differed from one another by only 0-3 single nucleotide polymorphisms. There was evidence of extensive transmission both within households and across the community. Our findings suggest that strategies to reduce the burden of impetigo in this setting will need to extend beyond individual households, and incorporate multi-faceted, community-wide approaches.

Differing epidemiology of two major healthcare-associated meticillin-resistant Staphylococcus aureus clones.

BACKGROUND: Two meticillin-resistant Staphylococcus aureus (MRSA) clones, sequence type (ST) 22 and ST239, have successfully spread globally. Across Australia, ST22 has supplanted ST239 as the main healthcare-associated MRSA. To understand the reasons underlying this shift, the epidemiology and clinical features of infections due to ST22 and ST239 MRSA isolates from a tertiary hospital in Melbourne, Australia were compared. METHODS: Over six months, consecutive MRSA isolates with clinical data were collected from specimens referred to Alfred Health Pathology (AHP). Isolates were genotyped by a multi-locus-sequence-typing-based high-resolution melting method. FINDINGS: Three hundred and twenty-eight of 1079 (30%) S. aureus isolated by AHP were MRSA. Of these, 313 were genotyped; 78 (25%) were clonal complex (CC) 22 (representing ST22) and 142 (45%) were CC239 (representing ST239). Common clinical syndromes included skin or soft tissue, respiratory tract and osteo-articular infections. On multi-variate logistic regression, compared with CC239, CC22 was associated with older patients [adjusted odds ratio (aOR) 1.04 for each year increase, 95% confidence interval (CI) 1.02-1.07)], and patients from subacute hospitals (aOR 2.7, 95% CI 1.2-5.8) or long-term care facilities (LTCFs; aOR 5.5, 95% CI 2.0-14.5). Median time from patient admission to MRSA isolation was nine days for CC239 and one day for CC22 (P < 0.01). MRSA strain epidemiology varied according to hospital unit. CONCLUSIONS: CC22 and CC239 MRSA have differing ecological niches. CC22 is associated with elderly patients in LTCFs, and CC239 is associated with nosocomial acquisition. Infection control strategies involving LTCFs and their residents will likely be required to achieve continued MRSA control.

Reduction in Staphylococcus aureus bacteraemia rates in patients receiving haemodialysis following alteration of skin antisepsis procedures.

This study examined all cases of Staphylococcus aureus bacteraemia (SAB) in the haemodialysis cohort at the Royal Darwin Hospital, Australia over a seven-year period. Midway through this period, antisepsis for arteriovenous fistulae (AVF) and central venous catheters (CVC) changed from 0.5% chlorhexidine solution to 2% chlorhexidine solution. Rates of SAB episodes were calculated using registry data. Trends in SAB over time were analysed using an interrupted regression analysis. Following the change to 2% chlorhexidine, average SAB rates decreased by 68%, and it is estimated that 0.111 cases of SAB/patient-year were prevented. CVC-related SAB rates remained low throughout. These results support the use of 2% chlorhexidine in skin antisepsis for patients with AVF.