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Background Periprosthetic joint infection (PJI) is a devastating condition and there is a lack of evidence to guide its management. We hypothesized that treatment success is independently associated with modifiable variables in surgical and antibiotic management. Methods The is a prospective, observational study at 27 hospitals across Australia and New Zealand. Newly diagnosed large joint PJIs were eligible. Data were collected at baseline and at 3, 12, and 24 months. The main outcome measures at 24 months were clinical cure (defined as all of the following: alive, absence of clinical or microbiological evidence of infection, and not requiring ongoing antibiotic therapy) and treatment success (clinical cure plus index prosthesis still in place). Results Twenty-four-month outcome data were available for 653 patients. Overall, 449 patients (69%) experienced clinical cure and 350 (54%) had treatment success. The most common treatment strategy was debridement and implant retention (DAIR), with success rates highest in early postimplant infections (119 of 160, 74%) and lower in late acute (132 of 267, 49%) and chronic (63 of 142, 44%) infections. Selected comorbidities, knee joint, and Staphylococcus aureus infections were independently associated with treatment failure, but antibiotic choice and duration (including rifampicin use) and extent of debridement were not. Conclusions Treatment success in PJI is associated with (1) selecting the appropriate treatment strategy and (2) nonmodifiable patient and infection factors. Interdisciplinary decision making that matches an individual patient to an appropriate management strategy is a critical step for PJI management. Randomized controlled trials are needed to determine the role of rifampicin in patients managed with DAIR and the optimal surgical strategy for late-acute PJI.

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 = 0.016), 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.

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.

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.

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). Method(s): 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. Result(s): 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

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

Contains fulltext : 229191.pdf (Publisher’s version ) (Open Access), There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.

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

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHOD(S): Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULT(S): 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam non-susceptible breakpoint (MIC > 16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% CI 2.8 - 87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3% - 15%) and 8% (95% CI 2% - 15%) for the original PA population and the post-hoc MA populations, which reduced to 5% (95% CI -1% - 10%) after excluding strains with piperacillin/tazobactam MIC values > 16 mg/L. Isolates co-harboring ESBL and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-mortality of 14% (95% CI 2% - 28%). CONCLUSION(S): After excluding non-susceptible strains, the 30-day mortality difference was from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA co-harboring ESBLs suggests meropenem remains the preferred choice for definitive treatment of ceftriaxone non-susceptible E. coli and Klebsiella.Copyright © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permission

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.

Nocardia infection of the central nervous system (CNS) is an uncommon but clinically important disease, often occurring in immunocompromised individuals and carrying a high mortality rate. We present 20 cases of microbiologically proven CNS nocardiosis diagnosed in Queensland from 1997 to 2015 and review the literature from 1997 to 2016. Over 50% of cases occurred in immunocompromised individuals, with corticosteroid use posing a particularly significant risk factor. Nine (45%) patients were immunocompetent and 3 had no comorbidities at time of diagnosis. Nocardia farcinica was the most frequently isolated species (8/20) and resistance to trimethoprim-sulfamethoxazole (TMP-SMX) was found in 2 isolates. Overall, 35% of our patients died within 1 year, with the majority of deaths occurring in the first month following diagnosis. Interestingly, of the 7 deaths occurring at 1 year, 6 were attributed to N farcinica with the seventh isolate being unspeciated, suggesting the virulence of the N farcinica strain.Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.

Background Healthcare-associated infections (HAIs) remain a significant patient safety issue, with point prevalence estimates being ~5% in high-income countries. In 2016–2017, the Researching Effective Approaches to Cleaning in Hospitals (REACH) study implemented an environmental cleaning bundle targeting communication, staff training, improved cleaning technique, product use, and audit of frequent touch-point cleaning. This study evaluates the cost-effectiveness of the environmental cleaning bundle for reducing the incidence of HAIs. Methods A stepped-wedge, cluster-randomized trial was conducted in 11 hospitals recruited from 6 Australian states and territories. Bundle effectiveness was measured by the numbers of Staphylococcus aureus bacteremia, Clostridium difficile infection, and vancomycin-resistant enterococci infections prevented in the intervention phase based on estimated reductions in the relative risk of infection. Changes to costs were defined as the cost of implementing the bundle minus cost savings from fewer infections. Health benefits gained from fewer infections were measured in quality-adjusted life-years (QALYs). Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefit of adopting the cleaning bundle over existing hospital cleaning practices. Results Implementing the cleaning bundle cost $349 000 Australian dollars (AUD) and generated AUD$147 500 in cost savings. Infections prevented under the cleaning bundle returned a net monetary benefit of AUD$1.02 million and an incremental cost-effectiveness ratio of $4684 per QALY gained. There was an 86% chance that the bundle was cost-effective compared with existing hospital cleaning practices. Conclusions A bundled, evidence-based approach to improving hospital cleaning is a cost-effective intervention for reducing the incidence of HAIs.

Background The hospital environment is a reservoir for the transmission of microorganisms. The effect of improved cleaning on patient-centred outcomes remains unclear. We aimed to evaluate the effectiveness of an environmental cleaning bundle to reduce health care-associated infections in hospitals. Methods The REACH study was a pragmatic, multicentre, randomised trial done in 11 acute care hospitals in Australia. Eligible hospitals had an intensive care unit, were classified by the National Health Performance Authority as a major hospital (public hospitals) or having more than 200 inpatient beds (private hospitals), and had a health-care-associated infection surveillance programme. The stepped-wedge design meant intervention periods varied from 20 weeks to 50 weeks. We introduced the REACH cleaning bundle, a multimodal intervention, focusing on optimising product use, technique, staff training, auditing with feedback, and communication, for routine cleaning. The primary outcomes were incidences of health-care-associated Staphylococcus aureus bacteraemia, Clostridium difficile infection, and vancomycin-resistant enterococci infection. The secondary outcome was the thoroughness of cleaning of frequent touch points, assessed by a fluorescent marking gel. This study is registered with the Australian and New Zealand Clinical Trial Registry, number ACTRN12615000325505. Findings Between May 9, 2016, and July 30, 2017, we implemented the cleaning bundle in 11 hospitals. In the pre-intervention phase, there were 230 cases of vancomycin-resistant enterococci infection, 362 of S aureus bacteraemia, and 968 C difficile infections, for 3 534 439 occupied bed-days. During intervention, there were 50 cases of vancomycin-resistant enterococci infection, 109 of S aureus bacteraemia, and 278 C difficile infections, for 1 267 134 occupied bed-days. After the intervention, vancomycin-resistant enterococci infections reduced from 0·35 to 0·22 per 10 000 occupied bed-days (relative risk

Importance: Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6

Objectives: To characterize MDR Escherichia coli from bloodstream infections (BSIs) in Australia, New Zealand and Singapore. Method(s): We collected third-generation cephalosporin-resistant (3GC-R) E. coli from blood cultures in patients enrolled in a randomized controlled trial fromFebruary 2014 to August 2015. WGS was used to characterize antibiotic resistance genes, MLST, plasmids and phylogenetic relationships. Antibiotic susceptibility was determined using disc diffusion and Etest. Result(s): A total of 70 3GC-R E. coli were included, of which the majority were ST131 (61.4%). BSI was most frequently from a urinary source (69.6%), community associated (62.9%) and in older patients (median age 71 years). The median Pitt score was 1 and ICU admission was infrequent (3.1%). ST131 possessed more acquired resistance genes than non-ST131 (P=0.003). Clade C1/C2 ST131 predominated (30.2% and 53.5% of ST131, respectively) and these were all ciprofloxacin resistant. All clade A ST131 (n"6) were community associated. The predominant ESBL types were blaCTX-M (80.0%) and were strongly associated with ST131 (95% carried blaCTX-M), with the majority blaCTX-M-15. Clade C1 was associated with blaCTX-M-14 and blaCTX-M-27, whereas blaCTX-M-15 predominated in clade C2. Plasmid-mediated AmpC genes (mainly blaCMY-2) were frequent (17.1%) but were more common in non-ST131 (P<0.001) isolates from Singapore and Brisbane. Two strains carried both blaCMY-2 and blaCTX-M. The majority of plasmid replicon types were IncF. Conclusion(s): In a prospective collection of 3GC-R E. coli causing BSI, community-associated Clade C1/C2 ST131 predominate in associationwith blaCTX-M ESBLs, although a significant proportion of non-ST131 strains carried blaCMY-2.Copyright © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

IMPORTANCE Extended-spectrum beta-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum beta-lactamase producers. OBJECTIVES To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. DESIGN, SETTING, AND PARTICIPANTS Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. INTERVENTIONS Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. RESULTS Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6

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

Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20–50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. Methods/Design We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a powe

Background: The Researching Effective Approaches to Cleaning in Hospitals (REACH) study will generate evidence about the effectiveness and cost-effectiveness of a novel cleaning initiative that aims to improve the environmental cleanliness of hospitals. The initiative is an environmental cleaning bundle, with five interdependent, evidence-based components (training, technique, product, audit and communication) implemented with environmental services staff to enhance hospital cleaning practices. Methods/design: The REACH study will use a stepped-wedge randomised controlled design to test the study intervention, an environmental cleaning bundle, in 11 Australian hospitals. All trial hospitals will receive the intervention and act as their own control, with analysis undertaken of the change within each hospital based on data collected in the control and intervention periods. Each site will be randomised to one of the 11 intervention timings with staggered commencement dates in 2016 and an intervention period between 20 and 50 weeks. All sites complete the trial at the same time in 2017. The inclusion criteria allow for a purposive sample of both public and private hospitals that have higher-risk patient populations for healthcare-associated infections (HAIs). The primary outcome (objective one) is the monthly number of Staphylococcus aureus bacteraemias (SABs), Clostridium difficile infections (CDIs) and vancomycin resistant enterococci (VRE) infections, per 10,000 bed days. Secondary outcomes for objective one include the thoroughness of hospital cleaning assessed using fluorescent marker technology, the bio-burden of frequent touch surfaces post cleaning and changes in staff knowledge and attitudes about environmental cleaning. A cost-effectiveness analysis will determine the second key outcome (objective two): the incremental cost-effectiveness ratio from implementation of the cleaning bundle. The study uses the integrated Promoting Action on Research Implementation

Clostridium difficile rose in prominence in the early 2000s with large-scale outbreaks of a particular binary toxin-positive strain, ribotype 027, in North America and Europe. In Australia outbreaks of the same scale had not and have not been seen. A survey of C. difficile across Australia was performed for 1 month in 2010. A collection of 330 C. difficile isolates from all States and Territories except Victoria and the Northern Territory was amassed. PCR ribotyping revealed a diverse array of strains. Ribotypes 014/020 (30.0%) and 002 (11.8%) were most common, followed by 054 (4.2%), 056 (3.9%), 070 (3.6%) and 005 (3.3%). The collection also contained few binary toxin positive strains, namely 027 (0.9%), 078 (0.3%), 244 (0.3%), 251 (0.3%) and 127 (0.3%). The survey highlights the need for vigilance for emerging strains in Australia, and gives an overview of the molecular epidemiology of C. difficile in Australia prior to an increase in incidence noted from mid-2011.

BACKGROUND: Antibiotic allergies are frequently reported and have significant impacts upon appropriate prescribing and clinical outcomes. We surveyed infectious diseases physicians, allergists, clinical immunologists and hospital pharmacists to evaluate antibiotic allergy knowledge and service delivery in Australia and New Zealand. METHODS: An online multi-choice questionnaire was developed and endorsed by representatives of the Australasian Society of Clinical Immunology and Allergy (ASCIA), Australasian Society of Infectious Diseases (ASID) and Society of Hospital Pharmacists Australia (SHPA). The 37-item survey was distributed in April 2015 to members of ASCIA, ASID, SHPA and Royal Australasian College of Physicians. RESULTS: Of 277 respondents, 94% currently use or would utilise antibiotic allergy testing (AAT) and reported seeing up to 10 patients/week labelled as antibiotic-allergic. Forty-two per cent were not aware of or did not have AAT available. Most felt that AAT would aid antibiotic selection, antibiotic appropriateness and antimicrobial stewardship (79%, 69% and 61%, respectively). Patients with histories of immediate hypersensitivity were more likely to be referred than those with delayed hypersensitivities (76% vs. 41%, p=0.0001). Lack of specialist physicians (20%) and personal experience (17%) were barriers to service delivery. A multidisciplinary approach was the preferred AAT model (53%). Knowledge gaps were identified, with the majority over-estimating rates of penicillin/cephalosporin (78%), penicillin/carbapenem (57%) and penicillin/monobactam (39%) cross-reactivity. CONCLUSIONS: A high burden of antibiotic allergy labelling and demand for AAT is complicated by a relative lack availability or awareness of AAT services in Australia and New Zealand. Antibiotic allergy education and deployment of AAT, accessible to community and hospital-based clinicians, may improve clinical decisions and reduce antibiotic allergy impacts. A collaborative approa