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Letter to the Editor

Background: Hospital in the Home (HITH) provides home-based care by hospital staff, which reduces inpatient length of stay and promotes a better quality of life. The frequency and precipitants for readmission from HITH back to the acute inpatient service are currently poorly defined. Aim(s): To determine the incidence of hospital readmissions and risk factors for readmissions in a HITH programme of a large hospital network. Method(s): We conducted a retrospective cohort study of adult patients admitted to a large HITH service within a hospital network in Victoria, Australia, from 1 July to 30 September 2017. We used logistic regression to determine if patient characteristics or specific clinical factors were associated with hospital readmission. Result(s): In a cohort of 605 patients under HITH, 72 were readmitted (incidence 11.9%). The median duration under HITH prior to readmission was 7 days (interquartile range, 3-23 days). Most readmissions were due to treatment failure, an associated complication or new clinical problem. In the univariable analysis, older age, direct admission from the emergency department (ED), recent intensive care admission, high Charlson comorbidity index, advanced chronic kidney disease, negative pressure wound therapy and use of antihypertensives were factors associated with readmission. In the multivariable analysis, the variables independently associated with readmissions were the Charlson comorbidity index (odds ratio, OR 1.17, 95% CI: 1.08-1.25) and referrals from the ED (OR 0.18, 95% CI: 0.06-0.58). Conclusion(s): Older age and greater comorbidity increased the odds of readmission, but patients from the ED were low risk compared to inpatient referrals.Copyright © 2021 Royal Australasian College of Physicians

BACKGROUND: Hospital in the Home (HITH) provides home-based care by hospital staff which reduces inpatient length of stay and promotes a better quality of life. The frequency and precipitants for readmission from HITH back to the acute inpatient service are currently poorly defined. AIMS: To determine the incidence of hospital readmissions and risk factors for readmissions in a HITH program of a large hospital network. METHOD(S): We conducted a retrospective cohort study of adult patients admitted to a large HITH service within a hospital network in Victoria, Australia from 1 July to 30 September 2017. We used logistic regression to determine if patient characteristics or specific clinical factors were associated with hospital readmission. RESULT(S): In a cohort of 605 patients under HITH, 72 were readmitted (incidence 11.9%). The median duration under HITH prior to readmission was 7days (interquartile range, 3 to 23days). Most readmissions were due to treatment failure, an associated complication or new clinical problem. In the univariable analysis, older age, direct admission from the Emergency Department, recent intensive care admission, high Charlson comorbidity index, advanced chronic kidney disease, negative pressure wound therapy and use of antihypertensives were factors associated with readmission. In the multivariable analysis, the variables independently associated with readmissions were the Charlson comorbidity index (OR 1.17, 95% CI: 1.08-1.25) and referrals from the Emergency Department (OR 0.18, 95% CI: 0.06-0.58). CONCLUSION(S): Older age and greater comorbidity increased the odds of readmission, but patients from the Emergency Department were low risk compared to inpatient referrals.Copyright This article is protected by copyright. All rights reserved.

Introduction: Escherichia coli is the most commonly identified bacteraemia, and causes a broad spectrum of diseases. The range of clinical conditions associated with E. coli bacteraemia mean that antimicrobial therapy is highly variable. This study aimed to determine the workload, efficiency and potential impact of an antimicrobial stewardship (AMS) bundle approach to E. coli bacteraemia. Method(s): An observational cohort study of patients with E. coli bacteraemia was performed, and a review of each case's entire medical record was undertaken. A number of AMS interventions were modelled on this cohort to assess their impact on overall days of antimicrobial therapy and time to optimized antimicrobial therapy. Result(s): In total, 566 episodes of E. coli bacteraemia were identified. A number of AMS interventions were modelled to assess their impact. The strict implementation of guideline-based therapy was found to increase the number of patients receiving ineffective empirical therapy to 38/266 (14.3%) compared with 27/266 (10.2%) patients when w hen non-guideline-adherent therapy was allowed. A scheduled review by an AMS team on day 3 of empirical therapy could lead to a narrower-spectrum intravenous antibiotic in 237/515 (46%) cases, and 386 cases (68.2% of cohort) could have their duration of therapy reduced by a median of 7 days. Conclusion(s): This study provides detailed description of a large cohort of patients with E. coli bacteraemia. There remains significant variability in empirical treatment, choice of step-down therapy and antimicrobial duration. A significant opportunity exists for AMS programmes to impact the management of E. coli bacteraemia through a bundled approach.Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy

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

© 2020 Elsevier Ltd Of 1033 Escherichia coli urinary tract infection isolates collected from females >12 years of age in Australia in 2019, only 2 isolates were resistant to fosfomycin with a minimum inhibitory concentration (MIC) of >256 mg/L. Despite having different multilocus sequence types, the two isolates harboured an identical plasmid-encoded fosA4 gene. The fosA4 gene has previously been identified in a single clinical E. coli isolate cultured in Japan in 2014. Each fosfomycin-resistant isolate harboured two conjugative plasmids that possessed an array of genes conferring resistance to aminoglycosides, β-lactams, macrolides, quinolones, sulfonamides and/or trimethoprim.

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

Objectives: Primary Objective: To determine the efficacy of a candidate antiviral on time to virological cure compared to standard of care within 14 days of randomisation Secondary objectives: * To determine the safety of the antiviral * To determine the clinical benefit of the antiviral over placebo according to the WHO 7-point ordinal scale * To determine the clinical benefit of the antiviral over placebo on time to resolution of clinical symptoms * To determine the effect of the antiviral over placebo on biomarkers of inflammation and immune activation Trial design: This is a multi-centre, triple-blind, randomised placebo controlled phase II, 2-arm trial with parallel-group design with allocation ratio 1:1. Participant(s): Inclusion Criteria: * Provision of informed consent by the participant * Age >=18 years * Confirmed SARS-CoV-2 by nucleic acid testing in the past 5 days * COVID-19 related symptom initiation within 5 days * Female patients of childbearing potential must have a negative pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. Exclusion criteria: * Known allergy to the study medication * Is on another clinical trial investigating an antiviral treatment for COVID-19 * Pregnancy * Patients with severe hepatic dysfunction equivalent to Grade C in the Child-Pugh classification * Patients with renal impairment requiring dialysis * Is deemed by the Investigator to be ineligible for any reason Participants will be recruited from, and the study visits will take place at Alfred Hospital, Monash Health, Austin Health in Victoria, Australia for hospitalised participants as well as recruitment in the community in participants homes for eligible people not requiring hospitalisation. Intervention and comparator: The first candid

Background: The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards. Method(s): We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients. Result(s): A total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1-4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the I

Objectives: Objective: To undertake a pilot, feasibility RCT of umbilical cord blood derived cell therapy for treatment of adult patients infected with SARS-CoV-2 virus related moderate-to-severe pneumonia to prevent progression to severe ARDS. Hypothesis: Expanded cord blood derived cell therapy will be feasible, well tolerated and show potential efficacy in the treatment of acute COVID-19 related moderate to severe pneumonia in adult patients because of their powerful anti-inflammatory and immunomodulatory properties. Trial design: Pilot, parallel design randomised controlled trial. Participant(s): The trial will recruit 24 hospitalised patients with confirmed SARS-CoV-2 infection and pneumonia from July to December 2020 at Monash Medical Centre in Melbourne, Australia. Intervention and comparator: Intervention: Intravenous injection of expanded umbilical cord blood cells at a dose of 5 million cells/kg (maximum dose - 500 million cells). Cell infusion will occur over 30-60 minutes through a peripheral intravenous cannula. Standard supportive care will continue as needed. Comparator: Standard supportive care. Main outcomes: Safety and tolerability of cell administration within first 24 hours of administration; clinical improvement on a seven-category clinical improvement ordinal scale. Randomisation: Randomisation will be done using computer generated allocation to intervention/ control groups in a 1:1 ratio (in blocks of 6) using sealed opaque envelopes. Blinding (masking): This will be an unblinded study, given that it is the first study using expanded cord blood cells in COVID-19 patients. There will be no placebo infusion. Numbers to be randomised (sample size): Twelve participants in each group. Total n=24. Trial Status: CBC-19 protocol v2, dated 23rd April 2020. Recruitment has not started yet. Estimated recruitment timeline is between 1st July - 31st December 2020. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12620000478910, reg

Of 1033 Escherichia coli urinary tract infection isolates collected from females >12 years of age in Australia in 2019, only 2 isolates were resistant to fosfomycin with a minimum inhibitory concentration (MIC) of >256 mg/L. Despite having different multilocus sequence types, the two isolates harboured an identical plasmid-encoded fosA4 gene. The fosA4 gene has previously been identified in a single clinical E. coli isolate cultured in Japan in 2014. Each fosfomycin-resistant isolate harboured two conjugative plasmids that possessed an array of genes conferring resistance to aminoglycosides, beta-lactams, macrolides, quinolones, sulfonamides and/or trimethoprim.Copyright © 2020 Elsevier Ltd

During a pandemic when hospitals are stretched and patients need isolation, the role of hospital-in-the-home (HITH) providing acute medical care at home has never been more relevant. We aimed to define and address the challenges to acute home care services posed by the COVID-19 pandemic. Planning for service operation involves staffing, equipment availability and cleaning, upskilling in telehealth and communication. Planning for clinical care involves maximising cohorts of patients without COVID-19 and new clinical pathways for patients with COVID-19. The risk of SARS-CoV-2 transmission, specific COVID-19 clinical pathways and the well-being of patients and staff should be addressed in advance.Copyright © 2020 Royal Australasian College of Physicians

Rapid detection and isolation of COVID-19 patients is the only means of reducing hospital transmission. We describe the impact of implementation of on-site SARS-CoV-2 RT-PCR testing on reduction in result turnaround time, isolation duration, pathology test ordering and antibiotic use in patients who do not have COVID-19. Copyright © 2020 by The Society for Healthcare Epidemiology of America. All rights reserved.

Aim: Our aim was threefold: first, to determine the incidence of active TB in our cohort, second to investigate the risk factors for active TB and third, to understand current screening practices. The ultimate goal was to use our findings to inform development of local and national guidelines. Method(s): The records of all adult patients who underwent renal transplantation at our centre from 2005 to 2014 were retrospectively reviewed to assess current screening practices, the risks for and burden of active TB. Result(s): A total of 660 individuals underwent renal transplantation during this period, totalling 3647 person years of follow up. Two patients were diagnosed with active TB after renal transplant, resulting in an incidence of 55 per 100 000 person-years. Of 656 transplant recipients, 102 (15.5%) were born in high TB incidence countries and 89 (13.5%) had an interferon gamma release assay (IGRA) at any point. Individuals born in high TB risk countries had a much higher incidence of active TB (353 per 100 000 person-years). Ten individuals had positive IGRA tests, of whom two were treated for active TB, two received chemoprophylaxis and six were not treated. Conclusion(s): In the absence of formal guidelines, IGRA-based screening for LTBI was infrequently performed. Our data suggest that screening and treatment of renal transplant recipients born in high incidence countries is an important preventive measure.Copyright © 2018 Asian Pacific Society of Nephrology

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

Multiplex polymerase chain reaction (PCR) testing has revolutionised microbiological practice but also increased the number of positive results of uncertain significance. This phenomenon has been seen in the increasing detection of cytomegalovirus (CMV) in mucocutaneous swabs for herpesviruses, the microbiological significance of which is a priori unclear. The aim of our study was to determine if an incidental finding of a positive CMV result represented CMV disease, if it facilitated a timely diagnosis of CMV disease or whether there were any deleterious outcomes. We performed a retrospective review of patients with an incidentally positive PCR result for CMV on external and mucosal swabs, including medical comorbidities and presence of immunosuppression, subsequent investigations, whether a diagnosis of CMV disease was made, and treatment. CMV detection was infrequent, detected in 158 (3.4%) of 4626 herpes multiplex PCR tests performed. The majority (60.4%) of patients were immunocompromised, and amongst these patients a positive swab represented a new diagnosis or already known CMV disease in 14%. In seven patients (5%), all of whom were immunocompromised, the positive CMV PCR on a swab led to further investigation and subsequent diagnosis and treatment of CMV disease. Whilst not recommended for diagnosis of CMV disease, if CMV is detected on a mucocutaneous swab in an immunocompromised patient, further assessment and investigation for CMV disease should be undertaken.Copyright © 2020 Royal College of Pathologists of Australasia

The optimisation of antibiotic dosing therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacokinetic/pharmacodynamic parameters, maximising efficacy and minimising toxicity. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy compared to linear regression analysis and population methods. This article summarises various methods for dose optimisation of antibiotics with a focus on Bayesian programs.Copyright © 2019, Springer Nature Switzerland AG.

We report a case of reactivation of cutaneous leishmaniasis caused by Leishmania major in a 40-year-old man from Afghanistan, in the context of immune suppression. His last potential exposure was 7 years before the clinical presentation. To our knowledge, this is the most temporally distant reactivation of cutaneous leishmaniasis reported in a non-endemic country.Copyright © 2019 by The American Society of Tropical Medicine and Hygiene.

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

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: Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections. Methods/Design: The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia c

To find out whether food-producing animals (FPAs) are a source of extraintestinal expanded-spectrum cephalosporin-resistant Escherichia coli (ESCR-EC) infections in humans, Medline, Embase, and the Cochrane Database of Systematic Reviews were systematically reviewed. Thirty-four original, peer-reviewed publications were identified for inclusion. Six molecular epidemiology studies supported the transfer of resistance via whole bacterium transmission (WBT), which was best characterized among poultry in the Netherlands. Thirteen molecular epidemiology studies supported transmission of resistance via mobile genetic elements, which demonstrated greater diversity of geography and host FPA. Seventeen molecular epidemiology studies did not support WBT and two did not support mobile genetic element-mediated transmission. Four observational epidemiology studies were consistent with zoonotic transmission. Overall, there is evidence that a proportion of human extraintestinal ESCR-EC infections originate from FPAs. Poultry, in particular, is probably a source, but the quantitative and geographical extent of the problem is unclear and requires further investigation.Copyright © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.