Professor Josh Davis

Background: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation). Objective: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19. Data sources: Scientific databases and clinical trial registry platforms. Study eligibility criteria, interventions, and participants: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19. Methods of data synthesis and risk-of-bias assessment: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120. Results: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I2 = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo. Conclusion: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

Purpose: The aim of this study was to determine whether selective decontamination of the digestive tract (SDD) reduces in-hospital mortality in mechanically ventilated critically ill adults admitted to the intensive care unit (ICU) with acute brain injuries or conditions. Methods: We carried out a post hoc analysis from a crossover, cluster randomized clinical trial. ICUs were randomly assigned to adopt or not to adopt a SDD strategy for two alternating 12-month periods, separated by a 3-month inter-period gap. Patients in the SDD group (n = 2791; 968 admitted to the ICU with an acute brain injury) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191; 1093 admitted to the ICU with an acute brain injury) received standard care. The primary outcome was in-hospital mortality within 90¿days. There were four secondary clinical outcomes: death in ICU, ventilator-, ICU- and hospital-free days to day 90. Results: Of 2061 patients with acute brain injuries (mean age, 55.8¿years; 36.4% women), all completed the trial. In patients with acute brain injuries, there were 313/968 (32.3%) and 415/1093 (38%) in-hospital deaths in the SDD and standard care groups (unadjusted odds ratio [OR], 0.76, 95% confidence interval [CI] 0.63¿0.92; p = 0.004). The use of SDD was associated with statistically significant improvements in the four clinical secondary outcomes compared to standard care. There was no significant¿heterogeneity of treatment effect between patients with and without acute brain injuries (interaction p = 0.22). Conclusions: In this post hoc analysis of a randomized clinical trial in critically ill patients with acute brain injuries receiving mechanical ventilation, the use of SDD significantly reduced in-hospital mortality in patients compared to standard care without SDD. These findings require confirmation.

Background and Purpose: Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem¿cilastatin on kidney injury when combined with vancomycin in our translational rat model. Experimental Approach: Male Sprague¿Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem¿cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. Key Results: Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem¿cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem¿cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. Conclusions and Implications: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem¿cilastatin in a translational rat model. The combination of vancomycin + imipenem¿cilastatin was nephroprotective.

Background: ¿Contact precautions,¿ are recommended for hospitalised patients with known methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) colonisation. Despite increasing observational evidence suggesting that gowns and gloves are of no added benefit over hand hygiene and environmental cleaning, guidelines continue to recommend them. Methods: A cross-sectional online survey of infection prevention professionals, infectious diseases physicians and microbiologists in Australian and New Zealand hospitals was conducted. The purpose was to explore variations in current approaches to known MRSA and VRE colonisation, and determine clinical equipoise for a proposed randomised control trial (RCT) to withdraw the use of gowns and gloves in this setting. Results: 226 responses from 122 hospitals across all Australian jurisdiction and multiple regions of New Zealand were received. While most hospitals implement contact precautions for MRSA (86%) and VRE (92%), variations based on MRSA and VRE subtypes are common. There was strong interest in removing glove and gown use for MRSA (72% and 73%, respectively) and VRE (70% and 68%, respectively). 62% of surveyed hospitals expressed interest in participating in a proposed cluster RCT comparing discontinuation of gown and glove use as part of contact precautions for MRSA and VRE, with their ongoing use. Conclusion: The mandated use of PPE in the context of MRSA and VRE colonisation warrants further examination. An RCT is needed to definitively address this issue and to promote a widespread change in practice, if warranted.

Background: This study aimed to identify the success rate of debridement, antibiotics, and implant retention (DAIR) for prosthetic joint infection (PJI) in a large prospective cohort of patients undergoing total knee arthroplasty (TKA). The ability for different PJI classification systems to predict success was assessed. Methods: Prospective data recorded in the Prosthetic Joint Infection in Australia and New Zealand Observational study were analyzed. One hundred eighty-nine newly diagnosed knee PJIs were managed with DAIR between July 2014 and December 2017. Patients were prospectively followed up for 2 years. A strict definition of success was used, requiring the patient being alive with documented absence of infection, no ongoing antibiotics and the index prosthesis in place. Success was compared against the Coventry (early PJI =1 month), International Consensus Meeting (early =90 days), Auckland (early <1 year), and Tsukayama (early =1 month, hematogenous >1 month with <7 days symptoms, chronic >1 month with >7 days symptoms) classifications. Results: DAIR success was 45% (85/189) and was highest in early PJIs defined according to the Coventry (adjusted odds ratio [aOR] = 3.9, P = .01), the International Consensus Meeting (aOR = 3.1, P = .01), and the Auckland classifications (aOR = 2.6, P = .01). Success was lower in both hematogenous (aOR = 0.4, P = .03) and chronic infections (aOR = 0.1, P = .003). Conclusion: Time since primary TKA is an important predictor of DAIR success. Success was highest in infections occurring <1 month of the primary TKA and progressively decreased as time since the primary TKA increased.

Background: Although differentiating between transient synovitis and septic hip arthritis is challenging, clinical prediction rules such as the Kocher criteria (KC) have been shown to help with the diagnosis of septic hip arthritis in children. Their performance in septic arthritis due to less virulent pathogens such as Kingella Kingae, however is unknown. We aimed to describe the performance of these clinical prediction rules in pre-school children with septic hip arthritis due to different pathogens. We hypothesised that the number of KC or modified KC met would be lower in children with septic hip arthritis caused by K. kingae, compared to those caused by Staphylococcus aureus. Methods: In this retrospective multicentre study conducted in Australia and New Zealand between 2012-2016, we included children with confirmed septic hip arthritis due to S. aureus (n=29), K. kingae (n=20), other pathogens (n=32), and no pathogen identified (n=48). We applied the KC (temperature, weight-bearing, erythrocyte sedimentation rate, white blood cell count) and the modified KC (C-reactive protein added) and assessed their sensitivity for septic hip arthritis, using cut offs of KC = 3 and modified KC = 4. Results: The score of the KC and the modified KC was not lower in K. kingae compared to S. aureus (P=0.27, P=0.21). In addition, both the sensitivity for the KC (S. aureus 18/29 (62.1%); K. kingae 12/20 (60.0%)), and for the modified KC (S. aureus 18/29 (62.1%); K. kingae 12/20 (60.0%)) did not differ between K. kingae and S. aureus. Of all children with septic hip arthritis, the sensitivity of both the KC and modified KC were 56.6% (95%CI 47.6-65.3). Conclusions: The clinical prediction rules had comparable performance in K. kingae infections to those caused by S. aureus. Concerningly, less than 60% of the children with confirmed septic hip arthritis met the cut-off values. These prediction rules lack sensitivity to rule-out septic hip arthritis in the early assessment of pre-school aged children with acute hip pain. Level of Evidence: Level III Diagnostic.

Prosthetic joint infections (PJI) present a major management challenge for practicing orthopedic surgeons and infectious disease physicians. There are few high-quality data to inform treatment guidelines. The aim of this systematic review was to report the design characteristics and recruitment rates for randomized controlled trials (RCTs) of PJI management. Trials were considered eligible for inclusion if human participants were randomized to any management intervention for PJI. We searched Medline, PubMed, Embase, Web of Science, Cochrane Database, ANZ Clinical Trials Registry, ClinicalTrials.gov, and the EU Clinical Trials Register until the end of May 2023. The systematic review was registered with PROSPERO (CRD42018112646). We identified 15 published RCTs with a total of 1743 participants with PJI. The median (interquartile range [IQR]) number of successfully recruited participants was 63 (38¿140), with 0.28 (0.13¿0.96) enrolments per site per month. Only four trials (36.4%) achieved the target recruitment. All RCTs applied different primary endpoints and varying definitions of a ¿good¿ outcome. Despite recent improvements, PJI RCTs are characterized by slow recruitment and heterogeneous endpoint assessments, which preclude synthesis in a standard meta-analytic framework. To inform international guidelines, future PJI trials should be run as multi-country trials at high-recruiting sites.

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas. Trial registration NCT05137119 . Registered on 30 November 2021.

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.

Background: The Aboriginal health workforce provide responsive, culturally safe health care. We aimed to co-design a culturally safe course with and for the Aboriginal health workforce. We describe the factors which led to the successful co-design, delivery, and evaluation of the ¿Managing hepatitis B¿ course for the Aboriginal health workforce. Methods: A Participatory Action Research approach was used, involving ongoing consultation to iteratively co-design and then develop course content, materials, and evaluation tools. An Aboriginal and Torres Strait Islander research and teaching team received education in chronic hepatitis B and teaching methodologies. Pilot courses were held, in remote communities of the Northern Territory, using two-way learning and teach-back methods to further develop the course and assess acceptability and learnings. Data collection involved focus group discussions, in-class observations, reflective analysis, and use of co-designed and assessed evaluation tools. Results: Twenty-six participants attended the pilot courses. Aboriginal and Torres Strait Islander facilitators delivered a high proportion of the course. Evaluations demonstrated high course acceptability, cultural safety, and learnings. Key elements contributing to success and acceptability were acknowledging, respecting, and integrating cultural differences into education, delivering messaging and key concepts through an Aboriginal and Torres Strait Islander lens, using culturally appropriate approaches to learning including storytelling and visual teaching methodologies. Evaluation of culturally safe frameworks and findings from the co-design process led to the creation of a conceptual framework, underpinned by meeting people¿s basic needs, and offering a safe and comfortable environment to enable productive learning with attention to the following: sustenance, financial security, cultural obligations, and gender and kinship relationships. Conclusions: Co-designed education for the Aboriginal health workforce must embed principles of cultural safety and meaningful community consultation to enable an increase in knowledge and empowerment. The findings of this research can be used to guide the design of future health education for First Nations health professionals and to other non-dominant cultures. The course model has been successfully transferred to other health issues in the Northern Territory.

Importance: Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence. Objective: To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools. Evidence Review: This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group's charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available. Findings: Sixty-three participants with diverse expertise from 8 countries developed the group's charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy. Conclusions and Relevance: The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data..

Background: For decades, the research community has called for participant information sheets/consent forms (PICFs) to be improved. Recommendations include simplifying content, reducing length, presenting information in layers and using multimedia. However, there are relatively few studies that have evaluated health consumers¿ (patients/carers) perspectives on the type and organisation of information, and the level of detail to be included in a PICF to optimise an informed decision to enter a trial. We aimed to elicit consumers¿ views on a layered approach to consent that provides the key information for decision-making in a short PICF (layer 1) with additional optional information that is accessed separately (layer 2). We also elicited consumers¿ views on the optimal content and layout of the layered consent materials for a large and complex Bayesian adaptive platform trial (the SNAP trial). Methods: We conducted a qualitative multicentre study (4 focus groups and 2 semi-structured interviews) involving adolescent and adult survivors of Staphylococcus aureus bloodstream infection (22) and their carers (2). Interview transcripts were examined using inductive thematic analysis. Results: Consumers supported a layered approach to consent. The primary theme that emerged was the value of agency; the ability to exert some control over the amount of information read before the consent form is signed. Three other themes emerged; the need to prioritise participants¿ information needs; the importance of health literacy; the importance of information about a trial¿s benefits (over its risks) for decision-making and the interplay between the two. Conclusions: Our findings suggest that consumers may challenge the one-size-fits-all approach currently applied to the development of PICFs in countries like Australia. Consumers supported a layered approach to consent that offers choice in the amount of information to be read before deciding whether to enter a trial. A 3-page PICF was considered sufficient for decision-making for the SNAP trial, provided that further information was available and accessible.

Background: Treatment outcomes in studies on prosthetic joint infection are generally assessed using a dichotomous outcome relating to treatment success or failure. These outcome measures neither include patient-centred outcome measures including joint function and quality of life, nor do they account for adverse effects of treatment. A desirability of outcome ranking (DOOR) measure can include these factors and has previously been proposed and validated for other serious infections. We aimed to develop a novel DOOR for prosthetic joint infections (PJIs). Methods: The Delphi method was used to develop a DOOR for PJI research. An international working group of 18 clinicians (orthopaedic surgeons and infectious disease specialists) completed the Delphi process. The final DOOR comprised the dimensions established to be most important by consensus with >75 % of participant agreement. Results: The consensus DOOR comprised four main dimensions. The primary dimension was patient-reported joint function. The secondary dimensions were infection cure and mortality. The final dimension of quality of life was selected as a tie-breaker. Discussion: A desirability of outcome ranking for periprosthetic joint infection has been proposed. It focuses on patient-centric outcome measures of joint function, cure and quality of life. This DOOR provides a multidimensional assessment to comprehensively rank outcomes when comparing treatments for prosthetic joint infection.

Background: Peri-prosthetic joint infection (PJI) is a devastating complication of joint replacement surgery. Determining the optimal duration of intravenous (IV) antibiotics for PJI managed with debridement and implant retention (DAIR) is a research priority. Methods: Patients undergoing DAIR for early and late-acute PJI of the hip or knee were randomised to receive 2 (short-course) or 6 (standard-course) weeks of IV antibiotics, with both groups completing 12 weeks of antibiotics in total. The primary endpoint of this pilot, open-label, randomised trial was a 7-point ordinal desirability of outcome ranking (DOOR) score, which accounted for mortality, clinical cure and treatment adverse events at 12 months. Duration of IV treatment was used as a tiebreaker, with shorter courses ranked higher. Outcome adjudication was performed by expert clinicians blinded to the allocated intervention (Australia and New Zealand Clinical Trials Registry ACTRN12617000127303). Results: 60 patients were recruited; 31 and 29 were allocated to short- and standard-course treatment, respectively. All had an evaluable outcome at 12 months and were analysed by intention-to-treat. Clinical cure was demonstrated in 44 (73%) overall; 22 (71%) in the short-course group and 22 (76%) in the standard-care group (P=0.77). Using the DOOR approach, the probability that short- was better than standard-course treatment was 59.7% (95% confidence interval 45.1-74.3). Conclusions: In selected patients with early and late-acute PJI managed with DAIR, shorter courses of IV antibiotics may be appropriate. Due to small sample size, these data accord with, but do not confirm, results from other international trials of early transition to oral antibiotics.

Aims National joint registries under-report revisions for periprosthetic joint infection (PJI). We aimed to validate PJI reporting to the Australian Orthopaedic Association National Joint Arthroplasty Registry (AOANJRR) and the factors associated with its accuracy. We then applied these data to refine estimates of the total national burden of PJI. Methods A total of 561 Australian cases of confirmed PJI were captured by a large, prospective observational study, and matched to data available for the same patients through the AOANJRR. Results In all, 501 (89.3%) cases of PJI recruited to the prospective observational study were successfully matched with the AOANJRR database. Of these, 376 (75.0%) were captured by the registry, while 125 (25.0%) did not have a revision or reoperation for PJI recorded. In a multivariate logistic regression analysis, early (within 30 days of implantation) PJIs were less likely to be reported (adjusted odds ratio (OR) 0.56; 95% confidence interval (CI) 0.34 to 0.93; p = 0.020), while two-stage revision procedures were more likely to be reported as a PJI to the registry (OR 5.3 (95% CI 2.37 to 14.0); p = 0.001) than debridement and implant retention or other surgical procedures. Based on this data, the true estimate of the incidence of PJI in Australia is up to 3,900 cases per year. Conclusion In Australia, infection was not recorded as the indication for revision or reoperation in one-quarter of those with confirmed PJI. This is better than in other registries, but suggests that registry-captured estimates of the total national burden of PJI are underestimated by at least one-third. Inconsistent PJI reporting is multifactorial but could be improved by developing a nested PJI registry embedded within the national arthroplasty registry.

Background: Hepatitis B virus (HBV) vaccination in the Northern Territory (NT) was funded for all Aboriginal and Torres Strait Islander newborns in 1988 and for all newborns in 1990. The prevalence of HBV in the Northern Territory was found to be higher in Aboriginal and Torres Strait Islander women than in non-Indigenous women across 2005-2010. We examined more recent data to assess whether the gap remains. Methods: We linked data from two routinely collected registries, the NT Perinatal Register and the NT Notifiable Diseases System, to investigate the prevalence of HBV infection, according to eligibility for infant HBV vaccination, in women giving birth during 2005-2015. Results: There were 22,781 women recorded as giving birth in public hospitals in the Northern Territory during 2005-2015. Hepatitis B virus prevalence was highest in Aboriginal and Torres Strait Islander (1.8%) and overseas-born women (1.8%). Among Aboriginal and Torres Strait Islander women, estimated hepatitis B virus prevalence was significantly higher in those born before the implementation of the vaccination program than in those born afterwards (2.4% versus 0.3%). Prevalence was highest amongst those living in very remote areas, both overall (2.2%) and within the birth cohort eligible for HBV vaccination. Conclusions: Hepatitis B virus prevalence in Northern Territory Aboriginal and Torres Strait Islander women appears to be declining as more individuals vaccinated as part of infant vaccination programs reach adulthood. Prevalence remains highest in remote areas, highlighting the importance of ongoing monitoring and of promoting vaccination in these regions.

Background Antibiotic resistance is a key global health threat, and antibiotic overuse is a significant contributing factor. Antibiotic stewardship is a vital issue for general practice. Objective The aim of this article is to discuss evidence-based strategies for general practitioners (GPs) and general practices to contribute to antibiotic stewardship and, thus, reduce the overall burden of antibiotic prescribing in the community. Discussion For individual GPs, and for practices, there is good evidence for the effectiveness of several strategies. As well as having a firm grasp of the clinical evidence in the area, important strategies for GPs include: eliciting and exploring patient understanding and expectations, and incorporating these in communication and management; offering delayed prescribing; using appropriate non-antibiotic symptomatic management; and, when prescribing antibiotics, doing so only for genuine clinical indications, with the appropriate antibiotic, at the appropriate dose, for the shortest appropriate duration. Practices can adopt a practice culture and practicewide prescribing policies that promote antibiotic stewardship.

Introduction: Culture-negative (CN) prosthetic joint infections (PJIs) account for approximately 10% of all PJIs and present significant challenges for clinicians.We aimed to explore the significance of CN PJIs within a large prospective cohort study, comparing their characteristics and outcomes with culture-positive (CP) cases. Methods: The Prosthetic joint Infection in Australia and New Zealand Observational (PIANO) study is a prospective, multicentre observational cohort study that was conducted at 27 hospitals between 2014 and 2017. We compared baseline characteristics and outcomes of all patients with CN PJI from the PIANO cohort with those of CP cases. We report on PJI diagnostic criteria in the CN cohort and apply internationally recognized PJI diagnostic guidelines to determine optimal CN PJI detection methods. Results: Of the 650 patients with 24-month outcome data available, 55 (8.5 %) were CN and 595 were CP. Compared with the CP cohort, CN patients were more likely to be female (32 (58.2 %) vs. 245 (41.2 %); p D0.016), involve the shoulder joint (5 (9.1 %) vs. 16 (2.7 %); p =0.026), and have a lower mean C-reactive protein (142 mg L-1 vs. 187 mg L-1; p =0.016). Overall, outcomes were superior in CN patients, with culture negativity an independent predictor of treatment success at 24 months (adjusted odds ratio, aOR, of 3.78 and 95%CI of 1.65-8.67). Suboptimal diagnostic sampling was common in both cohorts, with CN PJI case detection enhanced using the Infectious Diseases Society of America PJI diagnostic guidelines. Conclusions: Current PJI diagnostic guidelines vary substantially in their ability to detect CN PJI, with comprehensive diagnostic sampling necessary to achieve diagnostic certainty. Definitive surgical management strategies should be determined by careful assessment of infection type, rather than by culture status alone.

Background: Aboriginal and Torres Strait Islander people are disproportionately affected by hepatitis B virus (HBV) infection. A proposed mismatch between standard vaccines and the HBV/C4 sub-genotype prevalent in Aboriginal people in the Northern Territory (NT) may reduce vaccine effectiveness. Aims: To determine HBV prevalence in the NT by Indigenous status and to explore patterns of immunity following implementation of universal vaccination, using a large longitudinal diagnostic dataset. Methods: A retrospective analysis of all available HBV serology results in the NT from 1991 to 2011 was conducted, with HBV prevalence and vaccination status analysed according to adigenous status, age and sex using individuals' patterns of HBsAg, anti-HBs and anti-HBc serology over repeated tests. Results: 100 790 individuals were tested (33.4% Indigenous) between 1991 and 2011 (26.1% of the 2011 NT population), with a total of 211 802 tests performed. In 2011, the proportion of HBV positive individuals in the NT was 3.17% (5.22% in Indigenous populations) compared to previous 2011 estimates of 1.70% (3.70% in Indigenous populations). The vaccine failure rate was lower than expected with only one presumed vaccinated person subsequently developing HBsAg positivity (0.02%). Evidence of suboptimal vaccine efficacy by breakthrough anti-HBc positivity in vaccinated individuals was demonstrated in 3.1% of the vaccinated cohort, of which 86.4% identified as Indigenous (HR 1.17). No difference in HBeAg positivity or seroconversion was observed between Indigenous and non-Indigenous individuals living with CHB. Conclusions: The burden of CHB in Indigenous people in the NT has previously been underestimated. A higher HBV prevalence in the NT than described in previous cross-sectional studies was found, including a higher prevalence in Indigenous people. Evidence of suboptimal vaccine efficacy was demonstrated predominantly in Indigenous individuals.

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung¿Knapp¿Sidik¿Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Background: Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative. Methods: We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days. Results: Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI},-12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC ß-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified. Conclusions: Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen. Clinical Trials Registration: NCT02437045.

Objectives: The Pre-school Osteoarticular Infection (POI) study aimed to describe the burden of disease, epidemiology, microbiology and treatment of acute osteoarticular infections (OAI) and the role of Kingella kingae in these infections. Methods: Information about children 3¿60 months of age who were hospitalized with an OAI to 11 different hospitals across Australia and New Zealand between January 2012 and December 2016 was collected retrospectively. Results: A total of 907 cases (73%) were included. Blood cultures grew a likely pathogen in only 18% (140/781). The peak age of presentation was 12 to 24 months (466/907, 51%) and Kingella kingae was the most frequently detected microorganism in this age group (60/466, 13%). In the majority of cases, no microorganism was detected (517/907, 57%). Addition of PCR to culture increased detection rates of K. kingae. However, PCR was performed infrequently (63/907, 7%). Conclusions: This large multi-national study highlights the need for more widespread use of molecular diagnostic techniques for accurate microbiological diagnosis of OAI in pre-school aged children. The data from this study supports the hypothesis that a substantial proportion of pre-school aged children with OAI and no organism identified may in fact have undiagnosed K. kingae infection. Improved detection of Kingella cases is likely to reduce the average length of antimicrobial treatment.

Background: Acutely infected total knee arthroplasty (TKA) is commonly treated with debridement, antibiotics, and implant retention (DAIR). There are no direct comparative studies to determine whether debridement should be performed open or arthroscopically for infected TKA. The aim of this study is to compare the outcomes of open vs arthroscopic debridement of infected TKAs. Methods: All patients at a university teaching hospital with an infected TKA treated with DAIR between 2002 and 2017 were analyzed. The primary outcome was successful treatment defined using international consensus criteria. Secondary outcomes included antibiotic suppression, prosthesis retention, mortality, postoperative range of motion, and length of stay. Clinical, laboratory, surgical, and antibiotic treatment data were collected. Propensity score matching was performed to control for selection bias. Results: DAIR was used in 141 patients. The initial DAIR procedure was open for 96 patients and arthroscopic for 45 patients. The success rate was 29% greater for open DAIR (45% open vs 16% arthroscopic; P < .001). After propensity score matching, this benefit was estimated to be 36% (95% confidence interval, 22%-50%; P < .0001). When those on antibiotic suppression were also considered successfully treated, open DAIR was still superior by 34% (95% confidence interval, 18%-51%; P < .0001). Conclusion: For infected TKA, open DAIR is a more successful index procedure compared with arthroscopic DAIR. Open DAIR remained more successful even when antibiotic suppression is considered successful treatment.

Since coronavirus disease 2019 (COVID-19) emerged in Wuhan, China in December 2019 and spread around the world, over 1100 clinical studies have been registered globally on clinical trials registries, including over 500 randomised controlled trials. Such rapid development and launch of clinical trials is impressive but presents challenges, including the potential for duplication and competition. There is currently no known effective treatment for COVID-19. In order to focus on those studies most likely to influence clinical practice, we summarise the 31 currently registered randomised trials with a target sample size of at least 1000 participants. We have grouped these trials into four categories: prophylaxis; treatment of outpatients with mild COVID-19; treatment of hospitalised patients with moderate COVID-19; and treatment of hospitalised patients with moderate or severe disease. The most common therapeutic agent being trialled currently is hydroxychloroquine (24 trials with potential sample size of over 25¿000 participants), followed by lopinavir¿ritonavir (seven trials) and remdesevir (five trials) There are many candidate drugs in pre-clinical and early phase development, and these form a pipeline for future large clinical trials if current candidate therapies prove ineffective or unsafe.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: 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. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-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 ß-lactam was administered for 7 days. Main Outcomes and Measures: 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. Results: 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%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-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. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

Background: Infectious diseases (ID) physicians perform a pivotal role in directing the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Aim: To assess the impact of SARS-CoV-2 on workload and the perceptions of ID physicians regarding the national response in Australia and New Zealand in the pre-pandemic. Methods: A survey of ID physicians in Australia and New Zealand was undertaken from 3 to 10 March 2020. Respondents were asked to estimate time spent on SARS-CoV-2-related activities in February and report their agreement with statements on a 5-point Likert scale ranging from ¿strongly agree¿ to ¿strongly disagree¿. We also asked about the intended use of investigational agents. Results: There were 214 respondents (36% of 600 eligible participants). The median workload due to SARS-CoV-2-related activities was 34% of one full-time equivalent (interquartile range 18¿68%). Less than a quarter (50, 23%) of respondents had experience managing cases, while 33% (70) had experience preparing during similar pandemics. Nevertheless, 88% (188/213) believed they were well informed when giving testing and management advice, and 45% (95/212) believed their national response was well coordinated. Additionally, 41% (88/214) were worried about becoming infected through occupational exposure. Over half (116, 54%) the respondents intended to use lopinavir/ritonavir in confirmed cases of COVID-19 with severe disease. Conclusions: ID physicians spent a large proportion of time on SARS-CoV-2-related activities. Increased staffing is required to avoid burnout. Importantly, ID physicians feel well informed when giving advice. A national body should be established to co-ordinate response. Treatment efficacy trials are needed to clarify the utility of unproven treatments.

Background: Cryptococcus neoformans and Cryptococcus gattii are yeasts responsible for invasive infection, primarily pulmonary and neurological. Their clinical epidemiology has been previously described in an Australian national study, but this included no data from the Hunter region, where we anecdotally noted a high incidence of infection. We aimed to describe the epidemiology, management and outcomes of cryptococcal disease in the Hunter region and to compare this with previous Australian data. Methods: We searched our laboratory database for positive cryptococcal antigen and culture results from January 2003¿December 2016. We extracted demographic factors, risk factors, clinical presentation, treatment and outcomes from medical records. We used the 2010 census-derived estimated resident population to calculate population-based incidences. Results: Over a 13-year period, 107 patients had either a positive culture or a positive cryptococcal antigen with a compatible clinical syndrome. Of these, 46 (42.2%) were C. neoformans, 28 (25.7%) C. gattii, and 33 (30.3%) antigen only. The crude incidence (per million with 95% CI) for all disease was 9.5, and for culture proven disease was 2.5 for C. gattii and 4.1 for C. neoformans. Geospatial mapping by species revealed no evident cluster. Of the 63 patients where detailed information was available, around half were immunocompromised (3 [15%] for C. gattii and 25 [81%] for C. neoformans, p < 0.001). Complications were common, including visual loss (11 cases, 17.7%) and hearing loss (5 cases, 8%). Adverse outcomes at one year (death or neurological sequelae) occurred in 42%, and was significantly more likely (OR = 5.2, 95% CI 1.4¿18.8) in those with raised intracranial pressure at baseline. Adverse outcomes were no more common in those treated with lower doses of liposomal amphotericin (=150 mg/day, 5/10) than those treated with the recommended dose of 3¿5 mg/kg (=150 mg; 13/27). Conclusion: Although a rare disease, cryptococcosis is more common in the Hunter region than in other parts of Australia, and long-term sequelae are serious and common.

Background Chronic hepatitis B (CHB) is endemic in the Aboriginal population of Australia's Northern Territory (NT). However, many people's hepatitis B virus (HBV) status remains unknown. Objective 1. To maximise the utility of existing HBV test and vaccination data in the NT by creating a linked dataset and computerised algorithmic coding. 2. To undertake rigorous quality assurance processes to establish feasibility of using the linked dataset and computerised algorithmic coding for individual care for people living with CHB. Methods Step 1: We used deterministic data linkage to merge information from three separate patient databases. HBV testing and vaccination data from 2008-2016 was linked and extracted for 19,314 people from 21 remote Aboriginal communities in the Top End of the NT. Step 2: A computerised algorithm was developed to allocate one of ten HBV codes to each individual. Step 3: A quality assurance process was undertaken by a clinician, using standardised processes, manually reviewing all three databases, for a subset of 5,293 Aboriginal people from five communities to check the accuracy of each allocated code. Results The process of data linking individuals was highly accurate at 99.9%. The quality assurance process detected an overall error rate of 17.7% on the HBV code generated by the computerised algorithm. Errors occurred in source documentation, primarily from the historical upload of paper-based records to electronic health records. An overall HBV prevalence of 2.6% in five communities was found, which included ten cases of CHB who were previously unaware of infection and not engaged in care. Conclusions Data linkage of individuals was highly accurate. Data quality issues and poor sensitivity in the codes produced by the computerised algorithm were uncovered in the quality assurance process. By systematically, manually reviewing all available data we were able to allocate a HBV status to 91% of the study population.

The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.

Staphylococcus aureus is a Gram-positive bacteriumthat is among the most common pathogens in humans causing a broad spectrum of clinical manifestations.1 Its ability to express multiple extracellular toxins, including haemolysins, leukotoxins, exfoliative toxins, enterotoxins and toxic shock syndrome toxin-1 (TSST-1), which destroy host cells and circumvent host immune defence mechanisms, contribute to its success as a pathogen.2 Treatment of S. aureus infection routinely relies on cell-wall-active antibiotics, including b-lactams and glycopeptides, which do not attenuate toxin production. Indeed, in vitro and animal studies have demonstrated that b-lactams (at subinhibitory concentrations) can increase S. aureus toxin production3-5 and vancomycin has minimal effect (Figure 1).3,4 The principal protein synthesis inhibitor (PSI) antibiotics that are active against S. aureus and reduce bacterial toxin production are clindamycin and linezolid. Other PSI antibiotics with antistaphylococcal activity include macrolides, chloramphenicol, fusidic acid and streptogramins (quinupristin/dalfopristin, pristinamycin), which all bind to the 50S ribosomal subunit, interfering with its functions of controlling guanosine triphosphate hydrolysis, the formation of peptide bonds and channelling the peptide through the subunit tunnel. Tetracyclines, tigecycline and aminoglycosides are PSI antibiotics that all bind to the 30S subunit and interfere with the principal function of decoding mRNA to peptides (Figure 1).3,6 Whilst the antibiotic mechanism of action has been established, evidence is conflicting regarding the mechanism of action (transcription, translation or both) PSIs have on toxin production.3,7 The resulting impact that antibiotic resistance has on S. aureus toxin production in laboratory in vitro studies is also inconsistent.8,9 The addition of a PSI antibiotic to standard therapy (cell-wallactive antibiotic) may be used in the treatment of S. aureus infections to: broaden coverage during empirical therapy; achieve synergy; enhance tissue biofilm penetration; or limit toxin production.10 This review summarizes the current, available evidence on combination antibiotic therapy for suppression of toxin synthesis in the treatment of S. aureus infections, with a focus on the PSI antistaphylococcal antibiotics for which there is the most evidence, namely clindamycin, linezolid and gentamicin.

The entry point and timing of ancient human migration into continental Sahul (the combined landmass of Australia, New Guinea, and Tasmania) are subject to debate. Unique strains of hepatitis B virus (HBV) are endemic among modernday Australian Aboriginals (HBV/C4) and Indigenous Melanesians (HBV/C3). We postulated that HBV genomes could be used to infer human population movements because the main HBV transmission route in endemic populations is via mother-to-child for genotypes B and C infections. Phylogenetic and phylogeographic analyses of HBV genomes inferred the origin of HBV/C4 to be >59 thousand years ago (ka) (95% HPD: 34-85 ka), and most likely to have occurred on the Sunda Shelf (southeast extension of the continental shelf of Southeast Asia). Our analysis further suggested an age of >51 ka (95% Highest Posterior Density (HPD): 36-67 ka) for the most recent common ancestor of HBV/C4 in Australia, correlating with the arrival time of anatomically modern humans into Australia, with the entry point suggested along a southern route via Timor. While we also inferred the origin of HBC/C3 to be on the Sunda Shelf, our analyses suggested that it was carried into Melanesia by Indigenous Melanesians who migrated through New Guinea north of the highlands. These findings reveal that HBV genomes can be used to infer ancient human population movements.

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.

Background: To better understand the molecular epidemiology of MRSA and to assess the utility of 19-target binary typing we undertook large-scale epidemiological surveillance of MRSA from invasive and non-invasive clinical specimens, and screening swabs. Methods: Binary typing was performed on clinical MRSA isolates collected in New South Wales (NSW), Australia between 01/01/2012 - 31/12/2017. Binary type (BT) predicted multilocus sequence type (ST) and spa types based on results from isolates which had been characterised by both methods. Results: 7624 MRSA isolates were analysed of which 3581 (47%) were wounds or skin & softtissue isolates (W/SSTI), 2436 (32%) screening swabs, 469 (6%) blood cultures (BC), 780 (10%) others, and 358 (5%) unknown. We identified 731 BTs, 54 spa types, and 31 STs. ST239 was the commonest MRSA clone in 2012 (30%), but it decreased to 7% in 2017 (p <0.001). In contrast, <0.5% of MRSA were ST45 in 2012 compared to 14% in 2017 (p<0.001). An emergence of PVL-positive ST22 was also noted. Of all isolates, 28% (2122/7624) were lukS/PVL positive; the proportion, among prospectively collected isolates increased from 24% (1406/5858) to 33% (1933/5858) between 2012 and 2017 (p <0.0001). 43% (1534/3581) W/SSTI, 20% (95/469) BC and 10% (239/2436) screening swabs were PVL-positive. Conclusions: A major change in the epidemiology of MRSA was noted with a decline of ST239, an emergence of ST45 and PVL-positive ST22, and a significant increase in PVL-positive isolates. Binary typing can be a useful routine laboratory test for prospective molecular surveillance of MRSA colonisation and infection.

Gram-negative bacilli are the causative organisms in a significant proportion of patients with severe community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU). Clinical guidelines recommend broad-spectrum antimicrobials for empirical treatment despite alarming global trends in antimicrobial resistance. In this study, we aimed to assess the safety and efficacy of gentamicin, an aminoglycoside with potent bactericidal activity, for empirical Gram-negative coverage of severe CAP in patients admitted to the ICU. A retrospective cohort study was performed at a university teaching hospital where the severe CAP guideline recommends penicillin, azithromycin and gentamicin as empirical cover. Ceftriaxone plus azithromycin is used as an alternative. Adults with radiologically-confirmed severe CAP were included, comparing those who received gentamicin in the first 72 h of admission with those who did not. Participants were identified using ICD-10 codes for bacterial pneumonia and data manually extracted from electronic medical records. Of 148 patients admitted with severe pneumonia, 117 were given at least one dose of gentamicin whereas the remaining 31 were not. The two groups were well matched in terms of demographics, co-morbidities and disease severity. There were no significant differences between the gentamicin and no-gentamicin groups in the incidence of acute kidney injury [60/117 (51%) vs. 16/31 (52%), respectively], hospital mortality [20/117 (17%) vs. 7/31 (23%)] and secondary outcomes including relapse and length of hospital stay. In conclusion, gentamicin is safe and has similar outcomes to alternative Gram-negative antimicrobial regimens for empirical coverage in severe CAP patients admitted to the ICU.

Background: Epidemiological data suggest that chronic HCV infection (CHC) is associated with increased cardiovascular risk, but it is unknown if it is associated with endothelial dysfunction. We aimed to assess the effect of antiviral treatment on endothelial function in non-cirrhotic adults with CHC. Methods: Self-controlled before and after study. All patients had genotype-1 CHC and were treated with 12 weeks of paritaprevir/ritonavir, ombitasvir and dasabuvir (PrOD), with ribavirin added for those with genotype-1a infection. Endothelial function was assessed at three time points before antiviral treatment, at treatment weeks 1, 4, 8 and 12, and 12 weeks after the end of treatment. The main assessment tools were reactive hyperaemia peripheral arterial tonometry (RHPAT) and serum concentrations of angiopoietin-2 (Ang-2) and E-selectin. Results: A total of 16 patients were enrolled. Mean (SD) age was 51.4 (6.9) years and 11 participants (69%) were male. All 16 patients achieved a sustained virological response. The mean (SD) baseline RHPAT index was 2.05 (0.48), and there was no significant change during treatment (mean within-patient change from baseline to end of treatment =-0.23 [0.45]; P= not significant). There was a significant improvement in both mean Ang-2 (baseline 2.44 [0.79] ng/ml, within-patient change -0.60 [0.44]; P<0.001) and E-selectin (baseline 48.7 [21.5] ng/ml, within-patient change -14.4 [13.0]; P<0.001). Conclusions: Removing HCV viraemia is associated with a significant improvement in endothelial function as measured by serum markers, but not in bedside microvascular reactivity. Chronic HCV viraemia may be associated with endothelial cell dysfunction and therefore long-term cardiovascular risk.

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.

Background. Antibiotic resistance is a public health concern, and is linked to over-prescribing. In self-limiting infections such as acute otitis media (AOM) and acute sinusitis, prescribing remains high despite strong guideline recommendations against the routine use of antibiotics. Early career General Practitioners may find evidence-based prescribing challenging. Aim. To establish the prevalence and associations of antibiotic prescribing for AOM and acute sinusitis by Australian vocational trainees in General Practice. Method. A cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study. This ongoing, multicentre prospective cohort study documents trainees' consultation-based clinical experiences. Univariate and logistic regression analyses were conducted on data recorded in consultations for AOM or acute sinusitis in nine collection periods during 2010-2014. Results. Data from 856 individual trainees (response rate 95.2%) were analysed. AOM was managed in 0.9% of encounters. Antibiotics were prescribed in 78.8% of cases. Prescribing was significantly associated with longer consultation time and first presentation for this problem. There was no significant association with patient age group. Acute sinusitis was managed in 0.9% of encounters. Antibiotics were prescribed in 71.2% of cases. Later-stage trainees and trainees who did not receive their primary medical qualification in Australia were more likely to prescribe an antibiotic for acute sinusitis. Conclusion. Early career GPs are not prescribing in an evidence-based manner. The complexity of guidelines for AOM and acute sinusitis may be confusing for prescribers, especially early career doctors struggling with inexperience and diagnostic uncertainty. Educational interventions are necessary to bring prescribing rates closer to quality benchmarks.

Background: Acute sore throat is a common condition presenting to family practitioners. It is usually self-limiting, with antibiotic treatment recommended only for high-risk presentations. Overprescribing of antibiotics contributes to individual and community resistance. Learning to prescribe in the context of diagnostic uncertainty and patient pressures is a challenge for early-career doctors. Prescribing habits develop early and tend not to change with time. Objective: To establish the prevalence and associations of antibiotic prescribing for acute sore throat by Australian vocational trainees in family practice. Method: A cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study. This ongoing, multicentre prospective cohort study documents the nature of trainees' consultation-based clinical experiences. Univariate and logistic regression analyses were conducted on data recorded in consultations for sore throat in nine collection periods during 2010-14. Results: Data from 856 individual trainees (response rate 95.2%) were analysed. Sore throat was managed in 2.3% encounters. Antibiotics were prescribed for 71.5% of sore throat diagnoses. The variables associated with prescribing were inner-regional location and higher socio-economic area. There was no significant association with younger age of patient or greater trainee experience. If an antibiotic was prescribed, the trainee was more likely to seek information from guidelines or a supervisor. Conclusions: The high frequency of antibiotic prescribing and the lack of attenuation in prescribing with increased experience suggest current educational interventions and the apprenticeship model of training is not fostering appropriate practice in this important clinical area. Targeted educational interventions, for supervisors as well as trainees, are indicated.

Background. Inappropriate antibiotic prescription and subsequent antibacterial resistance are major threats to health worldwide. Objectives. We aimed to establish whether early-career 'apprenticeship-model' experience in family practice influences antibiotic prescribing for respiratory tract infections and to also establish other associations of antibiotic prescribing changes during this early-career experience. Methods. A longitudinal analysis (2010-2014) of a cohort study of Australian GP registrars' (vocational trainees') consultations. Registrars from five regional training programs recorded data from 60 consecutive consultations, once each 6-month training Term, including the diagnoses managed and medications prescribed. The outcomes were whether an antibiotic was prescribed for the diagnoses 'upper respiratory tract infection (URTI)' and 'acute bronchitis/bronchiolitis'. Generalized linear mixed modelling was used to account for repeated measures on registrars and to include the time component: 'Term'. Results. A total of 856 registrars recorded 108759 consultations, including 8715 'URTI' diagnoses (5.15% of diagnoses) and 2110 'acute bronchitis/bronchiolitis' diagnoses (1.25%). Antibiotics were prescribed in 16.3% [95% confidence interval (CI) 14.9-17.8] of URTI and 72.2% (95% CI 69.6-74.6) of acute bronchitis/bronchiolitis diagnoses. Moving from an earlier to later term did not significantly influence registrars' antibiotic prescribing for URTI [adjusted odds ratio (OR) 0.95; 95% CI 0.87, 1.04, P = 0.27] or acute bronchitis/bronchiolitis [OR 1.01 (95% CI 0.90-1.14), P = 0.86]. Significant associations of antibiotic prescribing for URTIs were the registrar being non-Australian educated, greater patient age, practices not privately billing patients, pathology being ordered, longer consultation duration and the registrar seeking in-consultation information or advice (including from their supervisor). Conclusions. Early-career experience/training failed to produce rational antibiotic prescribing for URTI and acute bronchitis/bronchiolitis. Our findings suggest that prescribing interventions could target the registrar-supervisor dyad.

Over-prescription of antibiotics for non-pneumonia respiratory tract infections (RTIs) is a major concern in general practice. Australian general practice registrars (trainees) have inappropriately high rates of prescription of antibiotics for RTIs. The 'apprenticeship' educational model and the trainee- trainer relationship are drivers of this inappropriate prescribing. We aimed to reduce registrars' non-pneumonia RTI antibiotic prescribing via an educational intervention (a 90-min face-To-face workshop supported by online modules), complemented by delivery of the same intervention, separately, to their trainers. We conducted a pre-and post-intervention comparison of the registrars' intention to prescribe antibiotics for common RTIs using McNemar's test. We similarly tested changes in supervisors' intended prescribing. Prescribing intentions were elicited by responses to six written clinical vignettes (upper respiratory tract infection, otitis media, sore throat and three acute bronchitis vignettes). We found that, for registrars, there were statistically significant reductions in antibiotic prescribing for the sore throat (24.0% absolute reduction), otitis media (17.5% absolute reduction) and two of the three acute bronchitis (12.0% and 18.0% absolute reduction) vignettes. There were significant reductions in supervisors' antibiotic prescribing intentions for the same four vignettes. We conclude that our intervention produced a significant change in registrars' intention to prescribe antibiotics for non-pneumonia RTIs.

Rationale: Optimization of ß-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of ß-lactam antibiotics. Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of ß-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent ß-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous ß-lactam administration was not independently associated with clinical cure. Conclusions: Compared with intermittent dosing, administration of ß-lactamantibioticsby continuous infusionincritically ill patientswith severe sepsis is associated with decreased hospital mortality.

Background. In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal ß-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. Methods. In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. Results. We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P =. 06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. Conclusions. Combining an antistaphylococcal ß-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).

The objective of this paper is to describe paediatric infectious diseases consultations across Australia and New Zealand. We surveyed infectious diseases physicians at 51 hospitals over a period of 2 weeks in 2012. Compared with adult consults, paediatric consults were more frequently received from general paediatricians/physicians and intensive care, yet less frequently from surgeons and emergency. Respiratory, skin/soft tissue and bone/joint infections were the most frequent consultations in children. These data demonstrate the breadth of formal infectious diseases consults in children. Differences between paediatric and infectious diseases consultations need to be considered when planning both paediatric and adult physician training and future curriculum development.

Background: Optimal antibacterial dosing is imperative for maximising clinical outcome. Many factors can contribute to changes in the pharmacokinetics of antibacterials to the extent where dose adjustment may be needed. In acute illness, substantial changes in important pharmacokinetic parameters such as volume of distribution and clearance can occur for certain antibacterials. The possibility of interethnic pharmacokinetic differences can further complicate attempts to design an appropriate dosing regimen. Factors of ethnicity, such as genetics, body size and fat distribution, contribute to differences in absorption, distribution, metabolism and elimination of drugs. Despite extensive previous work on the altered pharmacokinetics of antibacterials in some patient groups such as the critically ill, knowledge of interethnic pharmacokinetic differences for antibacterials is limited. Objectives: This systematic review aims to describe any pharmacokinetic differences in antibacterials between different ethnic groups, and discuss their probable mechanisms as well as any clinical implications. Methods: We performed a structured literature review to identify and describe available data of the interethnic differences in the pharmacokinetics of antibacterials. Results: We found 50 articles that met our inclusion criteria and only six of these compared antibacterial pharmacokinetics between different ethnicities within the same study. Overall, there was limited evidence available. We found that interethnic pharmacokinetic differences are negligible for carbapenems, most ß-lactams, aminoglycosides, glycopeptides, most fluoroquinolones, linezolid and daptomycin, whereas significant difference is likely for ciprofloxacin, macrolides, clindamycin, tinidazole and some cephalosporins. In general, subjects of Asian ethnicity achieve drug exposures up to two to threefold greater than Caucasian counterparts for these antibacterials. This difference is caused by a comparatively lower volume of distribution and/or drug clearance. Conclusion: Interethnic pharmacokinetic differences of antibacterials are likely; however, the clinical relevance of these differences is unknown and warrants further research.

Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to ß-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.

Background. Despite a high burden of staphylococcal skin disease in children and high incidence of Staphylococcus aureus bacteremia in adult Indigenous populations in northern Australia, there are few studies describing incidence or clinical information of invasive S aureus (ISA) infections in children. Methods. We conducted a retrospective review for all cases of S aureus bacteremia and sterile site infections, for children under 15 years, in northern Australia over a 4-year period (2007-2010). Cases were categorized as neonatal (<28 days) and pediatric (=28 days). Results. Forty-four cases (9 neonatal, 35 pediatric)were identified.The annual incidence of ISAwas 27.9 cases per 100 000 population. Among pediatric cases, the annual incidencewas significantly higher in the Indigenous (46.6) compared with the non-Indigenous (4.4) population (IRR: 10.6 [95%confidence interval, 3.8-41.4]). Pediatric infectionswere predominantly community-associated (86%).Clinical infection sites included osteoarticular (66%), pleuropulmonary (29%), and endocarditis (9%), and multifocal diseasewas common (20%). Eighty-three percent of pediatric cases presented with sepsis; 34%resulted in intensive care admission. Neonatal cases were all born prematurely; 89%were late-onset infections. Overall, 27%of infections were due to methicillin-resistant S aureus (MRSA).Comparedwithmethicillin-sensitive S aureus(MSSA), therewasnodifference in severityorpresentation in pediatricMRSA cases, but a higher proportion ofMRSA cases were readmitted. Conclusions. The annual incidence of ISA infection in this study is among the highest described, largely due to a disproportionate burden in Indigenous children. Infections are frequently severe and infection with MRSA is common. Children presenting with suspected ISA in this region should be treated empirically for MRSA.

Indigenous Australians experience a significant health burden from chronic hepatitis B infection; however, the strain of hepatitis B virus (HBV) found among Indigenous Australians has not been well characterized. Blood samples were collected from 65 Indigenous Australians with chronic HBV infection from across the Top End of Australia's Northern Territory. Phylogenetic analysis of HBV from these samples revealed that 100% of the isolates were genotype C, sub-genotype C4, expressing the serotype ayw3. This strain is a divergent group within the HBV/C genotype, and has only been described in Indigenous Australians. Evidence of recombination was suggested by discordant phylogenetic clustering of the C4 sequences when comparing the full genome to the surface region and confirmed by recombination analysis which showed the surface gene region to be most closely related to genotype J, while the remaining regions of the genome were most similar to genotype C sequences. Mutational analysis revealed the presence of multiple mutations that have been linked with more rapid liver disease progression and an increased risk of hepatocellular carcinoma. These mutations were detected in the majority of sequences examined. Variants associated with vaccine failure were detected as the predominant viral quasi-species in 3/35 samples. In summary, the HBV C4 variant found in this population has a high potential to cause advanced liver disease and to escape vaccination programs. Further in vitro functional and natural history studies are warranted in order to determine the clinical and public health consequences of infection with the HBV C4 variant in these communities. © 2014 Wiley Periodicals, Inc.

We retrospectively audited hospital occupational exposure events over a 10-year period, in a human T-cell lymphotropic virus type 1 (HTLV-1)-endemic area of Central Australia, and report on 53 individuals exposed to HTLV-1 with no transmissions documented (95% confidence interval, 0%-1.5%). This has important implications for the management of exposures including the role of postexposure prophylaxis. © The Author 2014.

Background: Hepatitis B is endemic in the Indigenous communities of the Northern Territory of Australia and significantly contributes to liver-related morbidity and mortality. It is recognised that low health literacy levels, different worldviews and English as a second language all contribute to the difficulties health workers often have in explaining biomedical health concepts, relevant to hepatitis B infection, to patients. The aim of this research project was to explore the knowledge, perceptions and experiences of remote dwelling Indigenous adults and their health care providers relating to hepatitis B infection with a view to using this as the evidence base to develop a culturally appropriate educational tool. Methods: The impetus for this project came from health clinic staff at a remote community in Arnhem Land in the Northern Territory, in partnership with a visiting specialist liver clinic from the Royal Darwin Hospital. Participants were clinic patients with hepatitis B (n = 12), community members (n = 9) and key informants (n = 13); 25 were Indigenous individuals. A participatory action research project design was used with purposive sampling to identify participants. Semi-structured interviews were undertaken to explore: current understanding of hepatitis B, desire for knowledge, and perspectives on how people could acquire the information needed. All individuals were offered the use of an interpreter. The data were examined using deductive and inductive thematic analysis. Results: Low levels of biomedical knowledge about Hepatitis B, negative perceptions of Hepatitis B, communication (particularly language) and culture were the major themes that emerged from the data. Accurate concepts grounded in Indigenous culture such as "only your blood can tell the story" were present but accompanied by a feeling of disempowerment due to perceived lack of "medical" understanding, and informed partnerships between caregiver and patient. Culturally appropriate discussions in a patient's first language using visual aids were identified as vital to improving communication. Conclusions: Having an educational tool in Indigenous patient's first language is crucial in developing treatment partnerships for Indigenous patients with hepatitis B. Using a culturally appropriate worldview as the foundation for development should help to reduce disempowerment and improve health literacy.