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Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%–30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.

Importance Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective To determine whether combining an antistaphylococcal β-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 β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days. 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

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a beta-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective(s): To determine whether combining an antistaphylococcal beta-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participant(s): 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. Intervention(s): Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal beta-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 beta-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. Result(s): 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 signi

Background Early identification of MRSA by diagnostic medical microbiology laboratories enables improved antimicrobial choice and outcomes. The Cepheid Xpert® MRSA/SA BC test rapidly identifies Staphylococcus aureus bloodstream infections through spa gene detection and methicillin resistance via mecA gene detection. Recent emergence of S. aureus with deletions in the spa gene has resulted in false-negative results for this test, leading to misidentification of infections with this organism, particularly MRSA ST45. Objectives To investigate the emergence and prevalence of ST45 MRSA in New South Wales (NSW), Australia. Methods WGS read data from six NSW hospitals were collected for 131 ST45 MRSA isolates and analysed. Results Of the 131 ST45 MRSA investigated, 88.5% (116/131) contained a deletion in the spa gene that appeared to have arisen once in approximately 2010 followed by clonal expansion. Given the successful establishment of this ‘spa-deletion’ MRSA clone, the Cepheid Xpert® MRSA/SA BC test became unreliable for confirming S. aureus bacteraemia in NSW. Subsequently, the algorithm used by this test has been updated and evaluated to take into account the presence of S. aureus with either a spa deletion or SCCmec target variations. Conclusions This study highlighted the applied use of WGS for assessing diagnostic assays and informing necessary changes to ensure the viability of the Cepheid Xpert® MRSA/SA BC test in the context of the new ‘spa-deletion’ MRSA clone. It demonstrated how continued surveillance through WGS can reveal evolutionary events that may impact diagnostic assays, allowing corrective modifications to be made in real time.

Background: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. Methods: Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi-centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12-months. Data were available for 222 patients recruited from February 2011 to December 2012. Results: Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score ≥ 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. Conclusions: This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications.

Background: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. Method(s): Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi-centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12-months. Data were available for 222 patients recruited from February 2011 to December 2012. Result(s): Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score >= 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. Conclusion(s): This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications.Copyright © 2018 The Author(s).

Background: In Australia, community-associated methicillin-resistant Staphylococcus aureus (MRSA) lineage sequence type (ST) 93 has rapidly risen to dominance since being described in the early 1990s. We examined 459 ST93 genome sequences from Australia, New Zealand, Samoa, and Europe to investigate the evolutionary history of ST93, its emergence in Australia and subsequent spread overseas. Results: Comparisons with other S. aureus genomes indicate that ST93 is an early diverging and recombinant lineage, comprising of segments from the ST59/ST121 lineage and from a divergent but currently unsampled Staphylococcal population. However, within extant ST93 strains limited genetic diversity was apparent with the most recent common ancestor dated to 1977 (95% highest posterior density 1973-1981). An epidemic ST93 population arose from a methicillin-susceptible progenitor in remote Northern Australia, which has a proportionally large Indigenous population, with documented overcrowded housing and a high burden of skin infection. Methicillin-resistance was acquired three times in these regions, with a clade harboring a staphylococcal cassette chromosome mec (SCCmec) IVa expanding and spreading to Australia's east coast by 2000. We observed sporadic and non-sustained introductions of ST93-MRSA-IVa to the United Kingdom. In contrast, in New Zealand, ST93-MRSA-IVa was sustainably transmitted with clonal expansion within the Pacific Islander population, who experience similar disadvantages as Australian Indigenous populations. Conclusion: ST93 has a highly recombinant genome including portions derived from an early diverging S. aureus population. Our findings highlight the need to understand host population factors in the emergence and spread of antimicrobial resistant community pathogens.

Objectives: To investigate the genetic context associated with the emergence of vanA VRE in Australia. Methods: The whole genomes of 18 randomly selected vanA-positive Enterococcus faecium patient isolates, collected between 2011 and 2013 from hospitals in four Australian capitals, were sequenced and analysed. Results: In silico typing and transposon/plasmid assembly revealed that the sequenced isolates represented (in most cases) different hospital-adapted STs and were associated with a variety of different Tn1546 variants and plasmid backbone structures. Conclusions: The recent emergence of vanA VRE in Australia was polyclonal and not associatedwith the dissemination of a single 'dominant' ST or vanA-encoding plasmid. Interestingly, the factors contributing to this epidemiological change are not known and future studies may need to consider investigation of potential community sources.

Objectives: To investigate the genetic context associated with the emergence of vanA VRE in Australia. Method(s): The whole genomes of 18 randomly selected vanA-positive Enterococcus faecium patient isolates, collected between 2011 and 2013 from hospitals in four Australian capitals, were sequenced and analysed. Result(s): In silico typing and transposon/plasmid assembly revealed that the sequenced isolates represented (in most cases) different hospital-adapted STs and were associated with a variety of different Tn1546 variants and plasmid backbone structures. Conclusion(s): The recent emergence of vanA VRE in Australia was polyclonal and not associatedwith the dissemination of a single 'dominant' ST or vanA-encoding plasmid. Interestingly, the factors contributing to this epidemiological change are not known and future studies may need to consider investigation of potential community sources.Copyright © The Author 2016.

Mucormycosis is the second most common cause of invasive mould infection and causes disease in diverse hosts, including those who are immuno-competent. We conducted a multicentre retrospective study of proven and probable cases of mucormycosis diagnosed between 2004–2012 to determine the epidemiology and outcome determinants in Australia. Seventy-four cases were identified (63 proven, 11 probable). The majority (54.1%) were caused by Rhizopus spp. Patients who sustained trauma were more likely to have non-Rhizopus infections relative to patients without trauma (OR 9.0, p 0.001, 95% CI 2.1–42.8). Haematological malignancy (48.6%), chemotherapy (42.9%), corticosteroids (52.7%), diabetes mellitus (27%) and trauma (22.9%) were the most common co-morbidities or risk factors. Rheumatological/autoimmune disorders occurred in nine (12.1%) instances. Eight (10.8%) cases had no underlying co-morbidity and were more likely to have associated trauma (7/8; 87.5% versus 10/66; 15.2%; p <0.001). Disseminated infection was common (39.2%). Apophysomyces spp. and Saksenaea spp. caused infection in immuno-competent hosts, most frequently associated with trauma and affected sites other than lung and sinuses. The 180-day mortality was 56.7%. The strongest predictors of mortality were rheumatological/autoimmune disorder (OR = 24.0, p 0.038 95% CI 1.2–481.4), haematological malignancy (OR = 7.7, p 0.001, 95% CI 2.3–25.2) and admission to intensive care unit (OR = 4.2, p 0.02, 95% CI 1.3–13.8). Most deaths occurred within one month. Thereafter we observed divergence in survival between the haematological and non-haematological populations (p 0.006). The mortality of mucormycosis remains particularly high in the immuno-compromised host. Underlying rheumatological/autoimmune disorders are a previously under-appreciated risk for infection and poor outcome.

Background. In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal β-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 β-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.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.