Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

Too naïve to lead: When leaders fall for flattery.

Flattery is one of the oldest and most commonly used impression-management tactics in everyday life. Though it often brings benefits to the flatterer, less is known about how it affects the target. In the present research, we explore when and why being flattered can be costly for leaders-common targets of flattery-depending on how they respond to it. We suggest that leaders who are observed rewarding flatterers risk appearing naïve to others. Across seven studies and six supplementary studies (N = 4,612), we find evidence that leaders who grant favors to flatterers are often perceived to have naively "fallen for flattery," which shapes observers' impressions of the leaders and the organizations they represent. A first set of studies (Studies 1-4) detail the variety of factors that lead observers to conclude their leader has fallen for flattery and the resulting impacts to the leaders' reputation and their organization (e.g., competence, warmth, commitment to the leader, organizational fairness). The second set of studies look at the contextual factors that impact what costs leaders pay for being perceived to have fallen for flattery, including the type of flattery (Study 5), who is harmed by the favor (Study 6), and the leader's apparent awareness of the motives underlying flattery (Study 7). Whereas previous research highlights positive consequences of flattery for the flatterer, we find that flattery comes with costs for leaders and their organizations. We discuss theoretical and practical implications for leaders who are frequently flattered. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Outpatient parenteral antibiotic therapy (OPAT) for the management of bronchiectasis.

Background: Patients with bronchiectasis often require hospitalisation for the administration of intravenous antibiotics for the management of acute exacerbations. Increasingly, Outpatient Parenteral Antibiotic Therapy (OPAT) services have become available as a potential alternative for domiciliary management. Aims: This study assessed outcomes in both cystic fibrosis (CF) and non-CF bronchiectasis patients who received OPAT for the management of an acute exacerbation of bronchiectasis. Methods: A retrospective study of consecutive subjects was done in both CF and non-CF groups in a large metropolitan Health Service in Australia from 2016 to 2022. Results: There were 51 episodes of care in the non-CF group (22 subjects) and 73 episodes in the CF group (13 subjects). The non-CF group were nearly all treated with once daily domiciliary intravenous (IV) ceftriaxone (49/51 episodes) for a duration of 9.1 ± 3.0 days (mean and standard deviation (SD)) via a peripherally inserted venous canula (84% of episodes). In contrast, the CF group generally received dual IV antibiotics (64% of episodes), with an average duration of 16.8 ± 6.3 days via central venous access (100%). In the non-CF group, the admission rate to hospital after 1 month was 9.6% and in the CF group was 0%. At 3 and 6 months the readmission rate for the non-CF group was 15.7% and 19.6% and CF group was 21.9% and 31.5%. There was a low rate of complications for the OPAT admissions (2% for the non-CF group and 7% for CF group). Conclusions: OPAT is a viable alternative for the management of bronchiectasis exacerbations.

Exploring the advancements of Australian OPAT.

Outpatient parenteral antimicrobial therapy (OPAT) in Australia has evolved from modest beginnings to a well-established health service with proven benefits in patient outcomes. This is a comprehensive review of the current state of art Australian OPAT with vignettes of the types of OPAT models of care, antimicrobial prescribing and antimicrobial use. In addition, we highlight the similarities and differences between OPAT to other countries and describe Australian OPAT experiences with COVID-19 and paediatrics. Australian OPAT continues to advance with OPAT antifungals, novel treatment options and upcoming high-impact research.

Non-inferiority trial of a shorter (7 days) compared with a longer (14 days) duration of antimicrobial therapy for the treatment of bacteraemic urinary sepsis, measured by microbiological success after the completion of therapy: a substudy protocol for the Bacteraemia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) multicentre randomised controlled trial.

INTRODUCTION: The BALANCE study is a randomised clinical trial (3626 participants) designed to assess the non-inferiority of 7 days (short-course) antibiotic therapy compared with 14 days of therapy for bacteraemia using the pragmatic endpoint of 90-day survival. Based on pilot study data, approximately 30% of enrolees will have a urinary tract infection (UTI) as the source of bacteraemia. METHODS AND ANALYSIS: We aim to assess the non-inferiority of short-course antibiotic therapy for patients with bacteraemia UTIs.Participating sites in four countries will be invited to join this substudy. All participants of this substudy will be enrolled in the main BALANCE study. The intervention will be assigned and treatment administered as specified in the main protocol.We will include participants in this substudy if the probable source of their infection is a UTI, as judged by the site principal investigator, and they have a urine microscopy and culture indicative of a UTI. Participants will be excluded if they have an ileal loop, vesicoureteric reflux or suspected or confirmed prostatitis.The primary outcome is the absence of a positive culture on a test-of-cure urine sample collected 6-12 days after cessation of antimicrobials, with a non-inferiority margin of 15%. Secondary outcomes include the clinical resolution of infection symptoms at test-of-cure. ETHICS AND DISSEMINATION: The study has been approved in conjunction with the main BALANCE study through the relevant ethics review process at each participating site. We will disseminate the results through the Australasian Society for Infectious Diseases, Canadian Critical Care Trials Group, the Association for Medical Microbiology and Infectious Diseases Canada Clinical Research Network (AMMI Canada CRN) and other collaborators. UNIVERSAL TRIAL NUMBER: U1111-1256-0874. MAIN BALANCE TRIAL REGISTRATION: NCT03005145. TRIAL REGISTRATION NUMBER: Australian Clinical Trial Register: ACTRN12620001108909.

Seeing your life story as a Hero's Journey increases meaning in life.

Meaning in life is tied to the stories people tell about their lives. We explore whether one timeless story-the Hero's Journey-might make people's lives feel more meaningful. This enduring story appears across history and cultures and provides a template for ancient myths (e.g., Beowulf) and blockbuster books and movies (e.g., Harry Potter). Eight studies reveal that the Hero's Journey predicts and can causally increase people's experience of meaning in life. We first distill the Hero's Journey into seven key elements-protagonist, shift, quest, allies, challenge, transformation, legacy-and then develop a new measure that assesses the perceived presence of the Hero's Journey narrative in people's life stories: the Hero's Journey Scale. Using this scale, we find a positive relationship between the Hero's Journey and meaning in life with both online participants (Studies 1-2) and older adults in a community sample (Study 3). We then develop a restorying intervention that leads people to see the events of their life as a Hero's Journey (Study 4). This intervention causally increases meaning in life (Study 5) by prompting people to reflect on important elements of their lives and connecting them into a coherent and compelling narrative (Study 6). This Hero's Journey restorying intervention also increases the extent to which people perceive meaning in an ambiguous grammar task (Study 7) and increases their resilience to life's challenges (Study 8). These results provide initial evidence that enduring cultural narratives like the Hero's Journey both reflect meaningful lives and can help to create them. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A systematic review of optimal pharmacokinetic/pharmacodynamic parameters for beta-lactam therapy in infective endocarditis.

BACKGROUND: Beta-lactam antibiotics are the mainstay of therapy for most bacterial causes of infective endocarditis (IE). Traditionally considered as agents with a broad therapeutic index, there is increasing recognition that standard doses may be subtherapeutic or toxic in critically ill patients. Optimizing therapy for efficacy requires a defined pharmacokinetic (PK)/pharmacodynamic (PD) target associated with clinical and microbiological cure. OBJECTIVES: To elucidate the factors that influence beta-lactam PK and PD variability in IE and to examine optimal PK/PD target parameters for therapy. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and laboratory in vivo animal or human studies examining PK and/or PD of beta-lactam antibiotics in IE were eligible. Ovid MEDLINE, Embase and Cochrane Central Registry were searched using defined terms. The Office of Health Assessment and Translation (OHAT) tool was used for assessing risk of bias. RESULTS: From 2677 abstracts, 62 articles were selected for review and synthesis, comprising: 45 animal studies investigating the broad categories of beta-lactam diffusion into vegetations, PK/PD determinants of outcome, mode of antibiotic delivery and synergistic impact of agents; and 17 human studies totalling 347 participants. Findings supported the importance of time-dependent killing for beta-lactams but heterogeneous data limited the determination of an optimal PK/PD target for IE treatment. CONCLUSION: Beta-lactam PK and PD in endocarditis are variable and specific to the particular antibiotic-organism combination. Time-dependent killing is important, consistent with non-endocarditis studies, but there is little agreement on optimal drug exposure. Clinical studies examining PK/PD targets in endocarditis are required to further inform drug selection and dosing.

Current and Emerging Treatment Options for Multidrug Resistant Escherichia coli Urosepsis: A Review.

Escherichia coli is a versatile commensal and pathogenic member of the human microflora. As the primary causative pathogen in urosepsis, E. coli places an immense burden on healthcare systems worldwide. To further exacerbate the issue, multi drug resistance (MDR) has spread rapidly through E. coli populations, making infections more troublesome and costlier to treat. This paper aimed to review the literature concerning the development of MDR in uropathogenic E. coli (UPEC) and explore the existing evidence of current and emerging treatment strategies. While some MDR strains maybe treated with ß-lactam-ß-lactamase inhibitor combinations as well as cephalosporins, cephamycin, temocillin and fosfomycin, current treatment strategies for many MDR UPEC strains are reliant on carbapenems. Carbapenem overreliance may contribute to the alarming dissemination of carbapenem-resistance amongst some UPEC communities, which has ushered in a new age of difficult to treat infections. Alternative treatment options for carbapenem resistant UPEC may include novel ß-lactam-ß-lactamase or carbapenemase inhibitor combinations, cefiderocol, polymyxins, tigecycline, aminoglycosides or fosfomycin. For metallo-ß-lactamase producing strains (e.g., NDM, IMP-4), combinations of cefazidime-avibacam with aztreonam have been used. Additionally, the emergence of new antimicrobials brings new hope to the treatment of such infections. However, continued research is required to successfully bring these into the clinic for the treatment of MDR E. coli urosepsis.

Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

Background: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes. Methods: People with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety. Findings: Between 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms. Interpretation: Favipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection. Funding: The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

Prospective study of policies and use of therapies for COVID-19 among Australian health services during 2020.

BACKGROUND: The COVID-19 pandemic has generated significant debate about how emerging infections can be treated in the absence of evidence-based therapies to combat disease. In particular, the use of off-label therapies outside of a clinical trial setting has been controversial. AIM: To longitudinally study policies and prescribing practices pertaining to therapies for COVID-19 in Australian health services during 2020. METHODS: Prospective data were collected from participating Australian health services who may care for patients with COVID-19 via an electronic portal. A single informant from each health service was emailed a survey link at regular intervals. Information was sought regarding changes to COVID-19 policy at their service and use of therapies for COVID-19. RESULTS: Overall, 78 hospitals were represented from 39 respondents with longitudinal data collection from May to December 2020. All Australian states/territories were represented with the majority (34/39; 87%) of respondents located in a major city. Just over half (20/39) of respondents had a written policy for COVID-19 therapy use at their health service at survey enrolment and policies changed frequently throughout the pandemic. Therapy use outside of a clinical trial was reported in 54% of health services, most frequently in Victoria, correlating with higher numbers of COVID-19 cases. At study commencement, hydroxychloroquine was most frequently used, with corticosteroids and remdesivir use increasingly throughout the study period. CONCLUSION: Our results reflect the reactive nature of prescribing of therapies for COVID-19 and highlight the importance of evidence-based guidelines to assist prescribers.

Potential interventions for an antimicrobial stewardship bundle for Escherichia coli bacteraemia.

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. METHODS: 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. RESULTS: 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: 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.

Observational study of the incidence and factors associated with patient readmission from home-based care under the Hospital in the Home programme.

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 programme of a large hospital network. METHODS: 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. RESULTS: 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). CONCLUSIONS: Older age and greater comorbidity increased the odds of readmission, but patients from the ED were low risk compared to inpatient referrals.

Impact of on-site compared to off-site testing for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) on duration of isolation and resource utilization.

Rapid detection and isolation of coronavirus disease 2019 (COVID-19) patients is the only means of reducing hospital transmission. We describe the impact of implementation of on-site severe acute respiratory coronavirus virus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction (RT-PCR) testing on reducing turnaround time, isolation duration, pathology test ordering, and antibiotic use in patients who do not have COVID-19.

An adaptive randomised placebo controlled phase II trial of antivirals for COVID-19 infection (VIRCO): A structured summary of a study protocol for a randomised controlled trial.

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. PARTICIPANTS: 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 candidate antiviral is favipiravir Arm 1: Favipiravir 1800 mg favipiravir BD on Day 1 followed by 800 mg BD favipiravir for the next 13 days. Arm 2: Placebo MAIN OUTCOMES: Primary outcome: Time to virological cure as defined by 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by nucleic acid testing during the 14 days after enrolment. RANDOMISATION: Randomisation performed at the Alfred Hospital Clinical Trials Pharmacy using computer generated block-randomisation lists with 6 participants per block. Within each block half of the participants will be randomised to the candidate antiviral and the other half to placebo. Randomisation is stratified by study site, with participants enrolled in the community considered as a study site. BLINDING (MASKING): Study participants, study investigators and the study statistician will be blinded to treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study aims to recruit 190 people (95/arm) with the first candidate antiviral favipiravir TRIAL STATUS: Protocol version 2.0 Dated 31-Jul-2020. Recruitment will take place between July 2020 and December 2020. TRIAL REGISTRATION: clinicaltrials.gov NCT04445467 First posted 24-Jun-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Planning and clinical role of acute medical home care services for COVID-19: consensus position statement by the Hospital-in-the-Home Society Australasia.

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.

Identification and characterisation of fosfomycin resistance in Escherichia coli urinary tract infection isolates from Australia.

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, ß-lactams, macrolides, quinolones, sulfonamides and/or trimethoprim.

Umbilical cord blood therapy to prevent progression of COVID-19 related pneumonia: a structured summary of a study protocol for a pilot randomised controlled trial.

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. PARTICIPANTS: 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, registered 16th April 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Incidental mucocutaneous cytomegalovirus detection and its predictive value for systemic disease.

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.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

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.