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Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20–40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research.

We characterized two bacteriophages, ΦFG02 and ΦCO01, against clinical isolates of Acinetobacter baumannii and established that the bacterial capsule is the receptor for these phages. Phage-resistant mutants harboured loss-of-function mutations in genes responsible for capsule biosynthesis, resulting in capsule loss and disruption of phage adsorption. The phage-resistant strains were resensitized to human complement, beta-lactam antibiotics and alternative phages and exhibited diminished fitness in vivo. Using a mouse model of A. baumannii infection, we showed that phage therapy was effective.

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.

Organ transplant guidelines in many settings recommend that people with potential hepatitis C virus (HCV) exposure or infection are deemed ineligible to donate. The recent availability of highly-effective treatments for HCV means that this may no longer be necessary. We used a mathematical model to estimate the expected difference in healthcare costs, difference in disability-adjusted life years (DALYs) and cost-effectiveness of removing HCV restrictions for lung and kidney donations in Australia. Our model suggests that allowing organ donations from people who inject drugs, people with a history of incarceration and people who are HCV antibody-positive could lead to an estimated 10% increase in organ supply, population-level improvements in health (reduction in DALYs), and on average save AU$2,399 (95%CI AU$1,155-3,352) and AU$2,611 (95%CI AU$1,835-3,869) per person requiring a lung and kidney transplant respectively. These findings are likely to hold for international settings, since this policy change remained cost saving with positive health gains regardless of HCV prevalence, HCV treatment cost and waiting list survival probabilities. This study suggests that guidelines on organ donation should be revisited in light of recent changes to clinical outcomes for people with HCV.

Carbapenem-resistant Enterobacteriaceae (CRE) have emerged as a worldwide problem. Given their degree of immunosuppression and the level of contact with the healthcare system, solid organ transplant (SOT) recipients are at a disproportionately higher risk of acquisition, colonization, and infection with CRE, and outcomes from infection tend to be worse compared to non-transplant patients. Therapeutic options are limited for CRE infections although several newer agents have recently been approved for use. How well these agents perform in the setting of immunosuppression and SOT is unclear. We sought to review the epidemiology of CRE in SOT and the management principles. CRE infections are becoming an increasing problem in SOT, and donor-derived infections present a challenge in the peri-transplant period. Newer treatments for CRE are emerging that are less toxic and potentially more effective than prior CRE-active agents, but supportive clinical data are limited. Newer beta-lactamase inhibitors have good activity against KPC carbapenemases, but they lack activity against metallo-beta-lactamases (e.g., NDM). Promising data is emerging with newer agents that have activity against most carbapenemases, but, again, clinical data is needed. Combination therapy in addition to optimal pharmacokinetic and pharmacodynamics may go some way to improve outcomes against these difficult-to-treat organisms. Other novel therapies that prevent the emergence of resistance (oral beta-lactamase inhibitors) and eradication of resistant Gram-negative colonization (fecal microbiota transplant) may eventually become part of a bundle approach to reduce CRE infections in the future. As in non-transplant patients, CRE infections in the transplant setting are challenging to treat and prevent. Infection prevention and control remains crucial to prevent widespread dissemination, and unique challenges exist with donor-derived CRE and how best to manage recipients in the peri-transplant period. Newer treatments are now in early-phase clinical studies, and in vitro activity data are supportive for several agents providing hope for improved outcomes with these typically difficult-to-treat and highly morbid infections in transplant recipients.

Background Little is known about the morbidity and mortality of invasive fungal disease (IFD) at a population level. The aim of this study was to determine the incidence, trends and outcomes of IFD in all haematology-oncology patients by linking Victorian hospital data to state-based registries. Methods Episodes of IFD complicating adult haematological malignancy (HM) and haematopoietic stem cell transplantation (HSCT) patients admitted to Victorian hospitals from 1st July 2005 to 30th June 2016 were extracted from the Victorian Admitted Episodes Dataset and linked to the date of HM diagnosis from the Victorian Cancer Registry and mortality from the Victorian Death Index. Descriptive analyses and regression modelling were used. Results There were 619,702 inpatient-episodes among 32,815 HM and 1,765 HSCT-patients. IFD occurring twelve-months from HM-diagnosis was detected in 669 (2.04%) HM-patients and 111 (6.29%) HSCT-recipients, respectively. Median time to IFD-diagnosis was 3, 5, 15 and 22 months in acute myeloid leukaemia, acute lymphoblastic leukaemia, Hodgkin lymphoma and multiple myeloma, respectively. Median survival from IFD-diagnosis was 7, 7 and 3 months for invasive aspergillosis, invasive candidiasis and mucormycosis, respectively. From 2005-2016, IFD incidence decreased 0.28% per 1,000 bed-days. Fungal incidence coincided with spring peaks on time-series analysis. Conclusions Data linkage is an efficient means of evaluating the epidemiology of a rare disease, however the burden of IFD is likely underestimated, arguing for better quality hospital level surveillance data to improve management strategies. Electronic supplementary material The online version of this article (10.1186/s12879-019-3901-y) contains supplementary material, which is available to authorized users.

The treatment of infections caused by methicillin-resistant Staphylococcus aureus is complicated by the emergence of strains with intermediate-level resistance to vancomycin (termed VISA). We have characterised a molecular pathway involved in the in vivo evolution of VISA mediated by the regulatory proteins YycH and YycI. In contrast to their function in other bacterial species, we report a positive role for these auxiliary proteins in regulation of the two-component regulator WalRK. Transcriptional profiling of yycH and yycI deletion mutants revealed downregulation of the ‘WalRK regulon’ including cell wall hydrolase genes atlA and sle1, with functional autolysis assays supporting these data by showing an impaired autolytic phenotype for each deletion strain. Using bacterial-two hybrid assays, we showed that YycH and YycI interact and that YycHI also interacts with the sensor kinase WalK, forming a ternary protein complex. Mutation to YycH or YycI associated with clinical VISA strains had a deleterious impact on the YycHI/WalK complex, suggesting that the interaction is important for the regulation of WalRK. Taken together, we have described a novel antibiotic resistance strategy for the human pathogen S. aureus, whereby YycHI mutations are selected for in vivo leading to reduced WalRK activation, impaired cell wall turnover and ultimately reduced vancomycin efficacy.

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 clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection. Trial registration The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014). Electronic supplementary material The online version of this article (doi:10.1186/s13063-014-0541-9) contains supplementary material, which is available to authorized users.

Eight patients with invasive bacteremic community-acquired methicillin-resistant Staphylococcus aureus infection in southeast Queensland, Australia, are reported. One patient died of septic shock. Haematogenous seeding to lungs, bone, and other sites was common. All isolates carried the virulence factor Panton-Valentine leukocidin and were either the southwest Pacific clone or the newly described Queensland clone. Clinicians should consider community-acquired methicillin-resistant Staphylococcus aureus infection in any patient presenting to hospital with severe staphylococcal sepsis or pneumonia.

Background Information about the feasibility, barriers and facilitators of antimicrobial stewardship (AMS) in residential aged care facilities (RACFs) has been scant. Exploring the prevailing perceptions and attitudes of key healthcare providers towards antibiotic prescribing behaviour, antibiotic resistance and AMS in the RACF setting is imperative to guide AMS interventions. Methods Semi-structured interviews and focus groups were conducted with key RACF healthcare providers until saturation of themes occurred. Participants were recruited using purposive and snowball sampling. The framework approach was applied for data analysis. Results A total of 40 nurses, 15 general practitioners (GPs) and 6 pharmacists from 12 RACFs were recruited. Five major themes emerged; perceptions of current antibiotic prescribing behaviour, perceptions of antibiotic resistance, attitude towards and understanding of AMS, perceived barriers to and facilitators of AMS implementation, and feasible AMS interventions. A higher proportion of GPs and pharmacists compared with nurses felt there was over-prescribing of antibiotics in the RACF setting. Antibiotic resistance was generally perceived as an issue for infection control rather than impacting clinical decisions. All key stakeholders were supportive of AMS implementation in RACFs; however, they recognized barriers related to workload and logistical issues. A range of practical AMS interventions were identified, with nursing-based education, aged-care specific antibiotic guidelines and regular antibiotic surveillance deemed most useful and feasible. Conclusions Areas of antibiotic over-prescribing have been identified from different healthcare providers’ perspectives. However, concern about the clinical impact of antibiotic resistance was generally lacking. Importantly, information gathered about feasibility, barriers and facilitators of various AMS interventions will provide important insights to guide development of AMS programs in the RACF setting. Electronic supplementary material The online version of this article (doi:10.1186/1471-2334-14-410) contains supplementary material, which is available to authorized users.