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BackgroundManagement of Scedosporium/Lomentospora prolificans infections remains challenging. We described predisposing factors, clinical manifestations, and outcomes of these rare mold infections, including predictors of early (1-month) and late (18-month) all-cause mortality and treatment failure.MethodsWe conducted a retrospective Australian-based observational study of proven/probable Scedosporium/L prolificans infections from 2005 to 2021. Data on patient comorbidities, predisposing factors, clinical manifestations, treatment, and outcomes up to 18 months were collected. Treatment responses and death causality were adjudicated. Subgroup analyses, multivariable Cox regression, and logistic regression were performed.ResultsOf 61 infection episodes, 37 (60.7%) were attributable to L prolificans. Forty-five of 61 (73.8%) were proven invasive fungal diseases (IFDs), and 29 of 61 (47.5%) were disseminated. Prolonged neutropenia and receipt of immunosuppressant agents were documented in 27 of 61 (44.3%) and 49 of 61 (80.3%) episodes, respectively. Voriconazole/terbinafine was administered in 30 of 31 (96.8%) L prolificans infections, and voriconazole alone was prescribed for 15 of 24 (62.5%) Scedosporium spp infections. Adjunctive surgery was performed in 27 of 61 (44.3%) episodes. Median time to death post–IFD diagnosis was 9.0 days, and only 22 of 61 (36.1%) attained treatment success at 18 months. Those who survived beyond 28 days of antifungal therapy were less immunosuppressed with fewer disseminated infections (both P < .001). Disseminated infection and hematopoietic stem cell transplant were associated with increased early and late mortality rates. Adjunctive surgery was associated with lower early and late mortality rates by 84.0% and 72.0%, respectively, and decreased odds of 1-month treatment failure by 87.0%.ConclusionsOutcomes associated with Scedosporium/L prolificans infections is poor, particularly with L prolificans infections or in the highly immunosuppressed population.

Arthroplasty is a healthcare priority and represents high volume, high cost surgery. Periprosthetic joint infection (PJI) results in significant mortality, thus it is vital that the risk for PJI is minimized. Vancomycin is recommended for surgical prophylaxis in total joint arthroplasty (TJA) by current clinical practice guidelines endorsed by the Infectious Diseases Society of America. This study aimed to develop a new assay to determine vancomycin concentrations in serum and bone, and a minimal physiologically based population PK (mPBPK) model to evaluate vancomycin bone penetration in noninfected patients. Eleven patients undergoing TJA received 0.5-2.0 g intravenous vancomycin over 12-150 min before surgery. Excised bone specimens and four blood samples were collected per patient. Bone samples were pulverized under liquid nitrogen using a cryogenic mill. Vancomycin concentrations in serum and bone were analyzed by liquid chromatography-tandem mass spectrometry and subjected to mPBPK modeling. Vancomycin serum and bone concentrations ranged from 9.30 to 86.6 mg/L, and 1.94-37.0 mg/L, respectively. Average bone to serum concentration ratio was 0.41 (0.16-1.0) based on the collected samples. The population mean total body clearance was 2.12L/h/kg

Interprofessional collaboration between general practitioners (GPs) and community pharmacists (CPs) is central to implement antimicrobial stewardship (AMS) programs in primary care. This study aimed to design a GP-pharmacist antimicrobial stewardship (GPPAS) model in Australian primary care. A seven-component exploratory study was conducted since 2017 to 2021 to inform a GPPAS model. We generated both secondary and primary evidence through a systematic review, a scoping review, a rapid review, nationwide surveys of Australian GPs and CPs including qualitative components and a pilot study of a GPPAS model. All study evidence was synthesised, reviewed, merged and triangulated to design a prototype GPPAS model using a Systems Engineering Initiative for Patient Safety theoretical framework. Secondary evidence informed effective GPPAS interventions, and primary evidence captured interprofessional issues, challenges and future needs to implement GPPAS interventions by GPs and CPs. A GPPAS model framework involving GP-pharmacist team-based five GPPAS sub-models were successfully designed to foster AMS education, antimicrobial audits, diagnostic stewardship, delayed prescribing, and routine review of antimicrobial prescription by improved GP-CP collaboration. A GPPAS model could be used as a guide to collaboratively optimise antimicrobial use by GPs and CPs. Implementation studies on GPPAS model and sub-models are required to integrate GPPAS model into GP-pharmacist interprofessional care models in Australia.

Infections caused by uncommon or rare mould pathogens often complicate the management of lung transplant (Tx) recipients contributing to high mortality. This review explores the epidemiology, diagnosis, and management of Scedosporium and Lomentospora (S/L) infections in lung Tx recipients as well as highlighting constraints in the current management and areas for future research. The number of reported S/L infections remains low among lung Tx recipients whilst the diagnosis and treatment of S/L infections remains challenging. The very few studies which evaluated clinical characteristics, prognostic factors and treatment outcomes of lung Tx patients with lomentosporiosis and/or scedosporiosis were limited by single-centre and observational study design. The requirement to standardise surveillance and culture procedure for S/L infections in lung Tx remains. Better diagnostic tools and antifungal agents are needed to manage S/L infection in this patient cohort. Prospective clinical registries or online databases for lung Tx recipients with these rare mould infections are essential to refine disease management and to improve clinical outcomes in the future.

Aim: To summarise the evidence on pharmacist-led antifungal stewardship (AFS) programs in the hospital setting and to evaluate their impact on the quality of antifungal prescribing and infection management, antifungal usage and clinical outcomes. Data sources: A systematic review of English-language studies identified in MEDLINE and EMBASE was performed on 27 November 2020 and conducted in accordance with PRISMA. Search terms included ‘antifungal agent’, ‘invasive fungal infection’, ‘antimicrobial stewardship’, ‘patient care bundles’ and ‘pharmacist’. Study selection: Eligible studies describing pharmacist-led quality improvement intervention(s) implemented in the hospital setting targeted at optimising systemic antifungal prescribing. Results: Six hundred and forty-six studies were identified, and seven met inclusion criteria. Five were dedicated to optimising candidaemia management, one at optimising intensive care unit prescribing of caspofungin and one on antifungal prescribing in haematology and oncology units. All studies measured varied metrics relating to quality of prescribing and infection management, reporting improvement in proportion of effective antifungal therapy (n = 1/1), appropriate antifungal selection (n = 1/1), dosing (n = 2/3), management of drug–drug interactions (n = 1/1) and reduced time to antifungal initiation (n = 4/4). Studies that implemented a candidaemia bundle of care reported improvements in composite bundle adherence (n = 2/2), with greatest improvement in ophthalmological consultation (n = 4/4), echocardiography (n = 2/2) and infectious diseases consultation (n = 3/3). There was reduction in antifungal expenditure (n = 4/4) and consumption (n = 2/4). Pharmacist-led AFS programs did not influence clinical outcomes. Conclusion: Available evidence suggests that pharmacist-led AFS interventions can improve the quality and timeliness of antifungal prescribing and reduce antifungal usage. Further research is required to assess the impact on clinical and microbiological outcomes.

Objectives There have been efforts to promote timely antimicrobial administration for patients with sepsis, but the importance for other infections is uncertain. This study analysed whether time to first antimicrobial dose (TFAD) in patients with lower limb cellulitis influenced outcome measures such as acute length of stay (LOS) in hospital and 30-day hospital readmission rates for cellulitis. Methods Medical records of patients admitted with lower limb cellulitis or erysipelas over a 15-month period (1 May 2019 to 30 November 2019 and 1 March 2020 to 31 October 2020) were reviewed. Patients requiring intensive care unit (ICU) admission were excluded. The TFAD was the difference (in minutes) between the emergency department triage time and the time that the antimicrobial was first recorded as administered. Analysis included log-transformed linear regression (for LOS) and logistic regression (for 30-day readmission with cellulitis), controlling for confounders where possible. Results The study included 282 patients with lower limb cellulitis. The median TFAD was 177 min (interquartile range, 98–290 min). Linear regression suggested a weak association between TFAD and LOS (P = 0.05; adjusted R2 = 0.01), which was non-significant after adjusting for confounders (P = 0.18). There were too few patients readmitted within 30 days with cellulitis for meaningful analysis. Conclusion After controlling for confounders, no association between increased TFAD and increased acute LOS was identified for patients with lower limb cellulitis who did not require ICU admission (i.e. without septic shock). Conclusions could not be made for 30-day readmission rates for cellulitis.

Antimicrobial stewardship (AMS) in Australia is supported by a number of factors, including enabling national policies, sectoral clinical governance frameworks and surveillance programmes, clinician-led educational initiatives and health services research. A One Health research programme undertaken by the National Centre for Antimicrobial Stewardship (NCAS) in Australia has combined antimicrobial prescribing surveillance with qualitative research focused on developing antimicrobial use-related situational analyses and scoping AMS implementation options across healthcare settings, including metropolitan hospitals, regional and rural hospitals, aged care homes, general practice clinics and companion animal and agricultural veterinary practices. Qualitative research involving clinicians across these diverse settings in Australia has contributed to improved understanding of contextual factors that influence antimicrobial prescribing, and barriers and facilitators of AMS implementation. This body of research has been underpinned by a commitment to supplementing ‘big data’ on antimicrobial prescribing practices, where available, with knowledge of the sociocultural, technical, environmental and other factors that shape prescribing behaviours. NCAS provided a unique opportunity for exchange and cross-pollination across the human and animal health programme domains. It has facilitated synergistic approaches to AMS research and education, and implementation of resources and stewardship activities. The NCAS programme aimed to synergistically combine quantitative and qualitative approaches to AMS research. In this article, we describe the qualitative findings of the first 5 years.

BACKGROUND: The use of antithymocyte globulin (ATG) in allogeneic hematopoietic cell transplant (HCT) is associated with an increased risk of Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD). The dynamics and outcomes of EBV-DNAemia are not well described in this population. METHODS: We retrospectively assessed the kinetics of EBV-DNAemia after ATG conditioning of HCT recipients. Receiver operating characteristic (ROC) curves were used to assess EBV-DNAemia to predict EBV-PTLD in this group. RESULTS: A total of 174/405 (43%) consecutive HCT recipients from two centers met inclusion criteria of ATG conditioned, non-B-cell lymphoma patients. Of these with EBV-DNA measured using standardized IU/ml, 78.6% (92/117) developed EBV-DNAemia: 62% spontaneously resolved; 19% cleared after preemptive rituximab, and 13% developed EBV-PTLD. ROC curve analysis using maximum pre-EBV-PTLD EBV-DNAemia, demonstrated an AUC of 0.912 with EBV-DNAemia of 9782 IU/ml, associated with 82.6% sensitivity and 94.4% specificity for development of EBV-PTLD. Median time for EBV-DNAemia to increase from initial detection to >1000 IU/ml was 7 days; to >10 000 IU/ml, 12 days; and to >100 000 IU/ml, 18 days. Median EBV-DNAemia level prior to administration of rituximab was significantly lower in patients with successful preemptive treatment, compared with those who developed EBV-PTLD (3.41 log10 IU/ml [3.30-3.67] vs. 4.34 log10 IU/ml [3.85-5.13], p = .002; i.e., 2628 IU/ml vs. 21 965 IU/ml, respectively). CONCLUSIONS: EBV-DNAemia >10 000 IU/ml was the strongest predictor of the development of EBV-PTLD, and progression to this level was rapid in ATG-conditioned HCT recipients. This information may guide EBV-PTLD management strategies in these high-risk patients.

Itraconazole (ITZ) is an effective agent when used as primary invasive fungal disease (IFD) prophylaxis, but is limited by drug tolerability and variability in serum concentrations. A new formulation, SUBA-itraconazole (for "super bioavailability"; S-ITZ), addresses the limitations of conventional ITZ formulations.We conducted a retrospective cohort study at 2 Australian centers to evaluate the safety, tolerability, and effectiveness of S-ITZ as primary antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients without grade II-IV acute graft-vs-host disease, from day 1 until approximately day 100 (cohort A) or day 1 until neutrophil engraftment (cohort B). A total of 204 patients and 1410 trough plasma ITZ concentrations were assessed.The incidence of breakthrough proven/probable IFD at day 180 was 1.0% (95% confidence interval [CI], .2%-3.2%), with 1.6% in cohort A and 0% in cohort B, and overall fungal-free survival of proven/probable IFD was 82.9% (95% CI, 76.8%-87.4%). Preengraftment early permanent S-ITZ discontinuation was 3.4% overall, with no significant difference between cohorts. No patients required cessation due to gastrointestinal intolerance attributed to S-ITZ. The geometric mean trough plasma ITZ concentration was 1130ng/mL (interquartile range, 566-1801ng/mL; coefficient of variation, 56.57%) and the median time to achieve therapeutic levels was 10 days.S-ITZ is a safe and well-tolerated oral formulation and is a novel alternative for primary IFD prophylaxis after HCT.

With the advent of newer antifungals, optimum treatment of mucormycosis remains to be fully elucidated. This study systematically evaluated the contemporary management and outcomes of mucormycosis. Mucormycosis cases in patients aged ≥18 years published between January 2000 and January 2017 were identified through Ovid MEDLINE and Embase. Of the 3619 articles identified, 600 (851 individual patient cases) were included in the review. Of the 851 patient cases, antifungal treatment details were available for 785. Intravenous (i.v.) amphotericin B formulations remained the most commonly prescribed first-line antifungals (760/785; 96.8%): 88.2% (670/760) were initiated as monotherapy and 11.8% (90/760) as combination antifungal therapy. Posaconazole oral suspension monotherapy was prescribed as an initial antifungal in 11 cases. It was also administered as maintenance or salvage therapy in 39 and 25 cases, respectively. Itraconazole capsule monotherapy (n = 10) was prescribed primarily for cutaneous disease in patients not receiving any immunosuppressive therapy. All-cause 90-day mortality was 41.0% (349/851). Initial treatment with combination antifungals did not reduce 90-day mortality compared with i.v. conventional amphotericin B or i.v. liposomal amphotericin B monotherapy [35/90 (38.9%) vs. 146/369 (39.6%) vs. 91/258 (35.3%), respectively; P = 0.541]. Concomitant surgical and antifungal therapy was associated with significantly lower 90-day mortality compared with treatment with antifungals alone (OR = 0.23, 95% CI 0.13-0.41; P < 0.001). The findings suggest that first-line antifungals with good efficacy remain an urgent unmet need. Whilst surgery is fundamental to improving survival, the clinical utility of combination antifungal therapy or posaconazole monotherapy requires further investigation.

Objective To explore the attitudes and beliefs of Australian ED clinicians towards antimicrobial stewardship in the ED. Methods Semi-structured one-to-one interviews were conducted with ED clinicians between March and October 2015. Participants were identified via purposive and snowball sampling. Questionnaires were developed using the literature. Interviews were audio-recorded, transcribed and analysed using thematic analysis via the framework approach. Two researchers coded independently, with one using QSR International's NVivo 10 software and the other manually. Emergent themes were identified and classified. Results Twenty-two clinicians (eight doctors, eight nurses and six pharmacists) from seven institutions participated. Participants were aware and concerned about antimicrobial resistance. Clinicians were divided based on their opinion on whether antimicrobials are prescribed appropriately and judiciously in the ED, with many perceiving prescribing to be inappropriate. Prior knowledge of the term 'Antimicrobial Stewardship' was demonstrated by doctors and pharmacists, with a relative lack of awareness by nurses. Four main themes were identified as both barriers and facilitators to antimicrobial stewardship in the ED: individual healthcare provider, resource, organisational and cultural. Uncertainty of diagnosis, time and resource pressures, reliance on previous experience and lack of access to expert opinion were perceived barriers. To facilitate appropriate prescribing, clinicians emphasised the need for routine education and feedback, adequate staffing, robust guidelines, senior medical clinician advocacy and multidisciplinary support. Conclusions Australian ED clinicians were aware of antimicrobial resistance. Many perceive injudicious antimicrobial use as problematic. Consideration of ED clinicians' perceived barriers and facilitators might enhance implementation of antimicrobial stewardship programmes in EDs.

Highlights • Nurse-initiated polymerase chain reaction testing is feasible in nursing homes. • Viruses are common among nursing home residents. • Nurse-initiated respiratory specimen testing is useful for infection prevention. • Further resources are required to impact antibiotic prescribing., Background Diagnostic testing using polymerase chain reaction (PCR) is infrequently initiated for diagnosis of respiratory tract infections (RTIs) in nursing homes. The objectives of this study were to determine the feasibility of implementing nurse-initiated PCR testing of respiratory specimens in nursing home settings and to compare antibiotic prescribing prior to and during the implementation. Methods This was a pragmatic, historically controlled study in 3 nursing homes (181 total beds) in Melbourne, Australia. Results The number of PCR tests of respiratory specimens (over 12 months) increased from 5 to 67 when nurses could initiate the tests. Residents with RTI symptoms had a virus identified by PCR in 50.7% of tests, including 14 positive for influenza. Six outbreaks were identified. When clustering was taken into consideration, incidence rates of antibiotic days of therapy did not change (incidence rate ratio = 0.94, 95% confidence interval, 0.25-3.35, P = .92) despite identification of more viral pathogens. Conclusions In nursing homes, nurse-initiated PCR testing of respiratory specimens is feasible and useful in terms of identifying the cause of many RTIs and outbreaks, and viruses are common in this context. However, the current study suggests the availability of these test results alone does not impact antibiotic prescribing.

The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored.To examine the contemporary epidemiology, clinical manifestations, diagnosis and causative pathogens of mucormycosis.Ovid MEDLINE and Ovid EMBASE from January 2000 to January 2017.Published case reports/series of proven/probable mucormycosis.Patients ≥18 years old.Patient characteristics, disease manifestations and causative pathogens were summarized descriptively. Categorical variables were assessed by chi-square test or Fischer's exact test, and continuous variables by the Wilcoxon-Mann-Whitney or Kruskal-Wallis test. Risk factors for the different clinical manifestations of mucormycosis were identified using multivariate logistic regression.Initial database searches identified 3619 articles of which 600 (851 individual patient cases) were included in the final analysis. Diabetes mellitus was the commonest underlying condition (340/851, 40%) and was an independent risk for rhino-orbital-cerebral mucormycosis (odds ratio (OR) 2.49; 95% CI 1.77-3.54; p 0.001). Underlying haematological malignancy was associated with disseminated infection (OR 3.86; 95% CI 1.78-8.37; p 0.001), whereas previous solid organ transplantation was associated with pulmonary (OR 3.19; 95% CI 1.50-6.82; p 0.003), gastrointestinal (OR 4.47; 95% CI 1.69-11.80; p 0.003), or disseminated (OR 4.20; 95% CI 1.68-10.46; p 0.002) mucormycosis. Eight genera (24 species) of Mucorales organisms were identified in 447/851 (53%) cases, of which Rhizopus spp. (213/447, 48%) was the most common. Compared with other genera, Rhizopus spp. was predominantly observed in patients with rhino-orbital-cerebral mucormycosis (75/213, 35% versus 34/234, 15%; p 0.001). Death was reported in 389/851 (46%) patients. Mortality associated with Cunninghamella infections was significantly higher than those caused by other Mucorales (23/30, 71% versus 185/417, 44%; p 0.001). However, Cunninghamella spp. were isolated primarily in patients with pulmonary (17/30, 57%) or disseminated disease (10/30, 33%).Findings from the current review have helped ascertain the association between various manifestations of mucormycosis, their respective predisposing factors and causative organisms.

To outline key drivers and components of antifungal stewardship (AFS) programmes, the evidence for specific interventions, and methods to assess performance of programmes.Recent developments in antifungal resistance and breakthrough invasive fungal diseases have increased the urgency for effective AFS. In practice, however, few hospitals have dedicated AFS programmes. To date, AFS programmes have centred around the provision of expert bedside reviews and have reduced costs and consumption of antifungal agents. Incorporating tools such as fungal diagnostics and therapeutic drug monitoring into AFS programme models is recommended. However, the application and impact of these tools in this context have not been adequately assessed. The effectiveness of AFS programmes has been measured in multiple ways but a standardized method of evaluation remains elusive. Few studies have explored the impact of AFS interventions on patient outcomes.The uptake of formal AFS programmes has been slow. New initiatives integrating AFS tools in programmes, and measuring the impacts on patient outcomes are required given such data are not readily available. A comprehensive approach to evaluate AFS programmes by correlating the quantity and quality of antifungal prescribing with impacts on patient outcomes is needed. Consensus definitions for core AFS metrics are required to benchmark performance and are essential to the resourcing and sustainability of these programmes.

Objective This study evaluated whether a consumer codesigned leaflet about the common skin infection cellulitis would improve patient satisfaction. Methods A patient information leaflet was codesigned with consumers incorporating health literacy principles and attached to a new adult lower limb cellulitis management plan launched in three regional Victorian health services. Health service staff were educated to provide the leaflet during hospital care. Patients discharged with a diagnosis of cellulitis in an 8-month period were followed-up via telephone between 31 and 60 days after their discharge. Each patient was asked to provide feedback on the utility of the leaflet (if received) and their overall satisfaction with the information provided to them using a five-point scale (with scores of 4 or 5 considered to indicate satisfaction). Results In all, 81 of 127 (64%) patients (or carers) were contactable, consented to the study and answered the questions. Of these, 27% (n = 22) reported receiving, accepting and reading the leaflet. The proportion of patients who were satisfied with the information provided to them about cellulitis was 100% for those who received the leaflet, compared with 78% for those who did not receive the leaflet (95% confidence interval 4.8–34%; P = 0.02). Conclusion The provision of a consumer codesigned leaflet increased patient satisfaction with the information received about cellulitis. Real-world strategies to embed the delivery of such resources are required to ensure that more patients receive the benefit. What is known about the topic? There are known deficiencies in the information provided to patients about the common skin condition cellulitis. There is little published evaluation of strategies to address these knowledge deficiencies. What does this paper add? This study evaluated a simple strategy to address patient knowledge deficiencies on cellulitis. It highlights that pertinent information delivered in an accessible way can significantly increase patient satisfaction with the information provided to them. What are the implications for practitioners? These findings are a timely reminder for practitioners that even a simple intervention, such a providing a hard copy information leaflet, can improve patient satisfaction. A national repository of similar consumer codesigned materials would be valuable and could minimise existing duplication of effort in resource development across health sectors. Real-world strategies to embed the delivery of such resources is required to ensure that more patients receive the benefit.

Background: Rising antimicrobial resistance (AMR) in primary care is a growing concern and a threat to community health. The rise of AMR can be slowed down if general practitioners (GPs) and community pharmacists (CPs) could work as a team to implement antimicrobial stewardship (AMS) programs for optimal use of antimicrobial(s). However, the evidence supporting a GP pharmacist collaborative AMS implementation model (GPPAS) in primary care remains limited. Aim: With an aim to design a GPPAS model in Australia, this paper outlines how this model will be developed. Methods: This exploratory study undertakes a systematic review, a scoping review, nationwide surveys, and qualitative interviews to design the model. Medical Research Council (MRC) framework and Normalization Process Theory are utilized as guides. Reviews will identify the list of effective GPPAS interventions. Two AMS surveys and paired interviews of GPs and CPs across Australia will explore their convergent and divergent views about the GPPAS interventions, attitudes towards collaboration in AMS and the perceived challenges of implementing GPPAS interventions. Systems Engineering Initiative for Patient Safety (SEIPS 2.0) model and factor analyses will guide the structure of GPPAS model through identifying the determinants of GPPAS uptake. The implementable GPPAS strategies will be selected based on empirical feasibility assessment by AMS stakeholders using the APEASE (Affordability, Practicability, Effectiveness and cost-effectiveness, Acceptability, Side-effects and safety, Equity) criteria. Discussion: The GPPAS model might have potential implications to inform how to better involve GPs and CPs in AMS, and, to improve collaborative services to optimize antimicrobial use and reduce AMR in primary care.

International audience; The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.

BACKGROUND: Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplant (alloHCT). METHOD: We analyzed 159 alloHCT recipients with 4409 quantitative CMV viral loads to determine pre-transplant predictors of CMV reactivation, clinically significant CMV infection (cs-CMVi, defined as CMV viral load >1000 IU/mL), CMV disease, kinetics of spontaneous clearance of CMV, and survival using a standardized pre-emptive therapy approach to identify at-risk groups to target prevention strategies. RESULTS: Cs-CMVi was most common in D-/R+ unrelated donor transplants (URD). Spontaneous CMV clearance occurred in 26% of patients who reached a viral load of 56-137 IU/mL, 6% at 138-250 IU/mL and in one patient >250 IU/mL. Median time between the first CMV reactivation (>56 IU/mL) and a viral load >250 IU/mL was 13 days, whereas the time from the first viral load >250 IU/mL to reach a vial load >1000 IU/mL was 4 days. Cs-CMVi was associated with a significant increase in non-relapse mortality (NRM) on multivariate analysis. CONCLUSIONS: Overall, this study indicates that D-/R+ URD recipients are at high-risk for cs-CMVi- and CMV-related mortality, and are potential candidates for targeted CMV prophylaxis. Spontaneous clearance of CMV beyond a viral load of 250 IU/mL is uncommon, suggesting that this could be used as an appropriate threshold to initiate pre-emptive therapy.

Background The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. Methods A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18–75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). Findings Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group. Interpretation Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. Funding Research Grants Council, Hong Kong.

Cardiovascular disease is a major burden on the health of Australians, and cardiac health disparities exist for those who live outside of metropolitan areas. Poor patient medication literacy was identified by cardiologists at a regional Victorian health service as a barrier to medication optimisation and a factor in inefficiency in their service. Studies in Australia and overseas have shown pharmacists involved in multi-disciplinary and pre-admission models result in more accurate medication histories, increased patient medication knowledge and lower medication related adverse events. This study introduced a telehealth cardiology pharmacist clinic, with the primary aim of reducing cardiologist time gathering medication information and secondary aims of investigating the patient and cardiologist experience.A cardiology pharmacist clinic was introduced where a pharmacist undertook a consultation with a patient in the days preceding their appointment with their cardiologist. The primary outcome of this study was to determine whether a cardiology pharmacist consultation undertaken prior to a cardiologist consultation reduces the time spent by the cardiologist gathering medication information. This was measured via direct observation of cardiologist consultations with and without a prior cardiology pharmacist clinic consultation. Descriptive and inferential statistics were performed to assess differences in time spent gathering the patient's medication information by the cardiologist. The secondary outcomes included differences between: the total length of cardiologist consultations, the number of cardiologist appointments with a medication uncertainty, and attendance rates for cardiologist consultations with and without a prior cardiology pharmacist clinic consultation. Other secondary outcomes included a quantitative survey assessing patient satisfaction with the pharmacist consultation, satisfaction with telehealth, confidence in medication management. Finally, clinician perceptions of the value of the pharmacist consultation were explored via semi-structured interviews.The time spent gathering medication information immediately before, and during, the cardiologist appointment reduced from 4.66 minutes without a prior cardiology pharmacist clinic consultation to 0.66 minutes with a prior cardiology pharmacist clinic consultation (difference 4 min, 95% CI: 3.27-4.77 p≤001). There was a 4.1-minute reduction in the mean consultation length of the cardiologist appointment if a cardiology pharmacist clinic consultation occurred prior (95% CI: 1.9-6.3, p0.001). There were zero medication uncertainties (0/44) in the cardiologist appointment when the patient had a cardiology pharmacist clinic consultation compared to 51% (22/43) when no cardiology pharmacist clinic consultation had occurred. Patients with a cardiology pharmacist clinic consultation had a 5% (17/340) 'did not attend' (DNA) rate for their next cardiologist appointment. Patients who did not have a cardiology pharmacist clinic consultation had a 24% (202/855) DNA rate to their next cardiologist appointment. There was 100% patient satisfaction with the consultation provided by the cardiology pharmacist (100/100) and telehealth was considered an acceptable mode of delivery by 99% (95/96) of patients. Patients expressed an increase in their confidence to discuss their medications with their cardiologist (84% [81/96]). Benefits described by the clinicians whose patients received the service were greater confidence and ability to make treatment decisions within consultations, as well as improved patient health literacy.A cardiology pharmacist consultation undertaken prior to a cardiologist consultation reduced the time spent by the cardiologist gathering medication information. Importantly, it reduced medication uncertainty in cardiologist consultations which clinicians indicated provided them with greater confidence and ability to make treatment decisions within consultations. Patients who undertook a cardiology pharmacist clinic consultation were more likely to attend their cardiologist consultation, reducing wasted appointments. Patients were highly satisfied with the cardiology pharmacist consultation and considered telehealth an acceptable mode of delivery.

Implementing antimicrobial stewardship (AMS) programs is central to optimise antimicrobial use in primary care. This study aims to assess general practitioners&rsquo, (GPs&rsquo, ) awareness of AMS, uptake of AMS strategies, attitudes towards GP&ndash, pharmacist collaboration in AMS and future AMS improvement strategies. A paper-based survey of nationally representative GPs across Australia was conducted in 2019. Of 386 respondent GPs, 68.9% were familiar with AMS. Respondents most frequently used the Therapeutic Guidelines (TG) (83.2%, 321/385) and delayed antimicrobial prescribing (72.2%, 278/385) strategies, whereas few utilised point-of-care tests (18.4%, 71/382), patient information leaflets (20.2%, 78/384), peer prescribing reports (15.5%, 60/384) and audit and feedback (9.8%, 38/384). GPs were receptive to pharmacists&rsquo, recommendations on the choice (50.5%, 192/381) and dose (63%, 241/382) of antimicrobials, and more than 60% (235/381) supported a policy fostering increased GP&ndash, pharmacist collaboration. Most GPs agreed to have AMS training (72%, 278/386), integration of electronic TG (eTG) with prescribing software (88.3%, 341/386) and policies limiting the prescribing of selected antimicrobials (74.4%, 287/386) in the future. Conclusively, GPs are aware of the importance of judicious antimicrobial prescribing but inadequately uptake evidence-based AMS strategies. The majority of GPs support GP&ndash, pharmacist collaborative AMS approaches to optimise antimicrobial use. Developing a feasible GP&ndash, pharmacist collaborative AMS implementation model and facilitating stewardship resources and training could foster AMS activities in primary care.

BackgroundGuidance on assessment of the quantity and appropriateness of antifungal prescribing is required to assist hospitals to interpret data effectively and structure quality improvement programmes.ObjectivesTo achieve expert consensus on a core set of antifungal stewardship (AFS) metrics and to determine their feasibility for implementation.MethodsA literature review was undertaken to develop a list of candidate metrics. International experts were invited to participate in sequential web-based surveys to evaluate the importance and feasibility of metrics in the area of AFS using Delphi methodology. Three surveys were completed. Consensus was predefined as ≥80% agreement on the importance of each metric.ResultsEighty-two experts consented to participate from 17 different countries. Response rate for each survey was >80%. The panel included adult and paediatric physicians, microbiologists and pharmacists with diverse content expertise. Consensus was achieved for 38 metrics considered important to routinely include in AFS programmes, and related to antifungal consumption (n = 5), quality of antifungal prescribing and management of invasive fungal infection (IFI) (n = 24), and clinical outcomes (n = 9). Twenty-one consensus metrics were considered to have moderate to high feasibility for routine collection.ConclusionsThe identified core AFS metrics will provide a framework to comprehensively assess the quantity and quality of antifungal prescribing within hospitals to develop quality improvement programmes aimed at improving IFI prevention, management and patient-centred outcomes. A standardized approach will support collaboration and benchmarking to monitor the efficacy of current prophylaxis and treatment guidelines, and will provide important feedback to guideline developers.

Epstein-Barr virus associated post-transplant lymphoproliferative disorders (EBV PTLD) are recognized as a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). The number of patients at risk of developing EBV PTLD is increasing, partly as a result of highly immunosuppressive regimens, including the use of anti-thymocyte globulin (ATG). Importantly, there is heterogeneity in PTLD management strategies between alloHSCT centers worldwide. This review summarizes the different EBV PTLD prevention strategies being utilized including the alloHSCT and T-cell depletion regimes and the risk they confer; monitoring programs, including the timing and analytes used for EBV virus detection, as well as pre-emptive thresholds and therapy with rituximab. In the absence of an institution-specific policy, it is suggested that the optimal pre-emptive strategy in HSCT recipients with T-cell depleting treatments, acute graft vs host disease (GVHD) and a mismatched donor for PTLD prevention is (a) monitoring of EBV DNA post-transplant weekly using plasma or WB as analyte and (b) pre-emptively reducing immune suppression (if possible) at an EBV DNA threshold of >1000 copies/mL (plasma or WB), and treating with rituximab at a threshold of >1000 copies/mL (plasma) or >5000 copies/mL (WB). There is emerging evidence for prophylactic rituximab as a feasible and safe strategy for PTLD, particularly if pre-emptive monitoring is problematic. Future management strategies such as prophylactic EBV specific CTLs have shown promising results and as this procedure becomes less expensive and more accessible, it may become the strategy of choice for EBV PTLD prevention.

The aim of this study was to systematically evaluate whether non-weight-based dosing (non-WBD) or weight-based dosing (WBD) of vancomycin leads to a higher proportion of patients achieving the pharmacokinetic/pharmacodynamic target. Studies from January 1985 to February 2017 were identified through Cochrane, MEDLINE and Embase databases. Those conducted in adults with end-stage renal disease receiving high-flux haemodialysis (HD) and intravenous vancomycin were included. The primary outcome was the proportion of patients with a pre-HD vancomycin concentration of 15-20 mg/L and/or an area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) ratio ≥400. Of the 3948 studies screened, 5 met the inclusion criteria. The proportion of patients with pre-HD concentrations between 15-20 mg/L were 35% (non-WBD) and 13% (WBD) post-loading dose. During maintenance dosing, the proportion of patients with pre-HD concentrations between 15-20 mg/L were 37% (non-WBD) and 50-67% (WBD). The proportion of pre-HD concentrations

Objectives: This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin). Methods: A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016. Results: Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97-2.13) mg/L versus 0.81 (0.48-1.15) mg/L, P

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (a,notsign2693) incurred a lower total cost than micafungin (a,notsign4422), with a net cost saving of a,notsign1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of +/- 100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Despite the availability of evidence-based guidelines, antibiotics for cellulitis remain inappropriately prescribed. This evidence–practice gap is more evident in low-resource settings, such as rural hospitals. This implementation study developed and introduced a cellulitis management plan to improve antibiotic prescribing for cellulitis in three health services in regional Australia. Appropriateness of antibiotic prescribing for cellulitis at Day 1 was the primary outcome measure. Adults with ICD-10-AM codes for lower-limb cellulitis admitted as inpatients of the three health services between May and November 2019 (baseline, n = 165) and March and October 2020 (post-implementation, n = 127) were included in the assessment. The uptake of the cellulitis management plan was 29.1% (37/127). The appropriateness of antibiotic prescribing for cellulitis at Day 1 was similar at baseline (78.7%, 144/183) and in the intention-to-treat post-implementation group (81.8%, 126/154) [95% CI −5.6% to 11.3%, p = 0.50]. Commencement of the cellulitis management plan resulted in a non-statistically significant increase in antibiotic appropriateness at Day 1 compared to when a cellulitis management plan was not commenced (88.1% vs. 79.5%, 95% CI −5.6% to 19.8%, p = 0.20) Evaluation of more real-world strategies to address evidence–practice gaps, such as the appropriateness of antibiotic prescribing for cellulitis, is required.

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT>MIC) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT>0.1 mg/L) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration–time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20–30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs.

Objectives This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients. Methods This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015. Results Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min. Conclusions Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.

Aims A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. Methods The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration–time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R0), a measure of transmissibility, was linked by reduction of viral shedding duration. The number of infected patients per population of 100 000 susceptible individuals was simulated for a series of pandemic scenarios, varying oseltamivir dose, R0 (1.9 vs. 2.7), and drug uptake (25%, 50%, and 80%). The number of infected patients for each scenario was entered into the health economics module, a decision analytic model populated with branch probabilities, disease utility, costs of hospitalized patients developing complications, and case-fatality rates. Change in quality-adjusted life years was determined relative to base case. Results Oseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios. Conclusion This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework.

Introduction Cytomegalovirus (CMV) is a frequent infectious complication after allogeneic HSCT, with seropositive recipients demonstrating higher mortality in registry studies. Pre-emptive treatment (PET) strategies have widely been implemented universally, however with new prophylactic agents available, at-risk groups need to be identified to ensure CMV prophylaxis is appropriately targeted. Methods Retrospective single centre cohort study of all allogeneic HSCT from 2013-2018 inclusive. Patients were assessed for clinically significant CMV infection (cs-CMVi), visceral disease and survival at a 1-year landmark analysis based on CMV serostatus and donor type (sibling [Sib]/Matched Unrelated Donor [MUD]). CMV PCR was measured by IU/mL, cs-CMVi defined as >1000iu/mL and were treated with PET ganciclovir/valganciclovir, or foscarnet if neutropenic. All MUDs received either "Rutuu" protocol high dose prednisolone (pre 2015) or Thymoglobulin ATG 4.5mg/kg (2015 onwards). Results Of 173 consecutive adult alloHSCTs, cs-CMVi developed in 54% D-/R+ vs 30% D+/R+or- (P Conclusions In alloHSCT recipients without CMV prophylaxis, CMV serostatus and donor type are significant predictors of CMV reactivation and overall survival, with CMV D-/R+ MUDs the highest risk group for cs-CMVi and mortality, therefore potential candidates for CMV prophylaxis.

Background The objective of this study was to understand how aged care home health professionals perceive antimicrobial use near the end of life and how they perceive potential antimicrobial stewardship activities near the end of life in aged care homes. Methods Qualitative semi-structured interviews were undertaken with general practitioners, nurses, and pharmacists who provide routine care in aged care homes in Victoria, Australia. Interviews were coded using frameworks for understanding behavior change. Results Themes were established within 14 interviews, and an additional 6 interviews were undertaken to ensure thematic saturation. Two major themes emerged: (i) Antimicrobial stewardship activities near the end of life in aged care homes need to enable aged care home nurses to make decisions substantiated by evidence-based clinical knowledge. Antimicrobial stewardship should clearly be part of an aged care home nurse's role, and accreditation standards provide powerful motivation for behavior change. (ii) Antimicrobial stewardship activities near the end of life in aged care homes must address family confidence in resident wellbeing. Antimicrobial stewardship activities should be inclusive of family involvement, and messages should highlight the point that antimicrobial stewardship improves care. Conclusions Antimicrobial stewardship activities that reinforce evidence-based clinical decision-making by aged care home nurses and address family confidence in resident wellbeing are required near the end of life in aged care homes. Accreditation standards are important motivators for behavior change in aged care homes.

Background The excessive use of antimicrobials in aged-care homes is a widely recognised phenomenon. This is problematic because it can harm residents, and is detrimental to public health. Residents in the final month of life are increasingly likely to be prescribed an antimicrobial, commonly without having signs and symptoms of infection that support antimicrobial use. Objectives We aimed to describe the perspectives of health professionals on antimicrobial use near the end of life in aged-care homes and investigate the potential opportunities for nurses to undertake antimicrobial stewardship activities near the end of life in aged-care homes. Design One-on-one, semi-structured, qualitative interviews. Settings and participants Twelve nurses, six general practitioners and two pharmacists providing routine care to residents of aged-care homes in Victoria, Australia were interviewed. Diversity in terms of years of experience, aged-care funding type (government, private-for-profits and not-for-profits) and location (metropolitan and regional) were sought. Methods Interviews were transcribed and open coded in a descriptive manner using validated frameworks for understanding behaviour change. The descriptive code was then used to build an interpretive code structure based on questions founded in grounded theory. Results Thematic saturation was reached after fourteen interviews, and an additional six interviews were conducted to ensure emergent themes were consistent and definitive. There are opportunities for aged-care home nurses to undertake antimicrobial stewardship activities near the end of life in the provision of routine care. Aged-care home nurses are influential in antimicrobial decisions near the end of life in routine care because of their leadership in advance care planning, care co-ordination and care provision in an environment with stopgap and visiting medical resources. Nurses also have social influence among residents, families and medical professionals during critical conversations near the end of life. Past negative social interactions within the aged-care home environment between nurses and families can result in ‘fear-based’ social influences on antimicrobial prescribing. Conclusions The work of facilitating advance care planning, care coordination, care delivery, and communicating with families and medical professionals provide important opportunities for aged-care home nurses to lead appropriate antimicrobial stewardship activities near the end of life.

Background Since 2015 the Aged Care National Antimicrobial Prescribing Survey has collected and reported data on antibiotic use in Australian aged care homes (ACHs) as part of the Australian Commission on Safety and Quality in Health Care's Antimicrobial Use and Resistance in Australia project. The objective of this study was to analyze this data source with regards to prescribing for urinary tract infections (UTIs) to improve the use of antibiotics. Methods This cross-sectional study analyzed the 2016 and 2017 survey data. Antibiotic prescribing for urinary tract indications was compared with national guideline recommendations. Results A total of 662 antibiotic prescriptions from 247 ACHs were analyzed. For all prophylactic antibiotics for UTI, 51.8% were prescribed for longer than 6 months, contrary to the guideline recommendation. Most antibiotics prescribed for treatment (71.6%) were for cystitis. Cefalexin was most frequently selected for treatment of cystitis, with 10.4% of these prescriptions being concordant with the recommendations. Prescribing additional daily doses of cefalexin occurred in 63.2% of prescriptions. Conclusions Antimicrobial stewardship activities targeting UTI prophylaxis for durations longer than 6 months, and excessive daily doses of cefalexin to treat cystitis could yield significant reductions in unnecessary antibiotic consumption among Australian residents of ACHs.

Objective To assess community pharmacists’ (CPs’) awareness and uptake of evidence-based antimicrobial stewardship (AMS) strategies, attitudes toward collaboration with general practitioners (GPs), and needs to improve AMS practices. Methods A nationwide survey of randomly sampled community pharmacies across Australia was conducted in April-October 2019. Results The response rate of CPs was 30.7% (613 of 2000) and 592 participating CPs (96.5%) described the key barriers to and facilitators of improving AMS. CPs (447 of 613, 72.9%) were familiar with AMS but felt that they would require training (468 of 612, 76.5%) and access to AMS practice guidelines (566 of 605, 93.6%). Respondents perceived that AMS programs could reduce the inappropriate use of antimicrobials (409 of 612, 66.8%) and the costs of treating infection (508 of 612, 83.0%). CPs often counseled patients (591 of 609, 97.0%) and reviewed drug interactions or allergies (569 of 607, 93.8%) before dispensing antimicrobials. Respondents less often used the national Therapeutic Guidelines: Antibiotic (274 of 602, 45.5%) or assessed guideline-compliance of prescribed antimicrobials (231 of 609, 37.9%). CPs were less likely to communicate with GPs (254 of 609, 41.8%) when an antimicrobial prescription was believed to be suboptimal and perceived that GPs are not receptive to their intervention regarding the antimicrobial choice (500 of 606, 82.6%) and dosage (416 of 606, 68.6%). Point-of-care tests (114 of 596, 19.1%) and patient information leaflets (149 of 608, 24.5%) were used uncommonly. Most respondents supported policies that could foster GP-pharmacist collaboration (560 of 606, 92.4%), limit accessibility of selected antimicrobials (420 of 604, 74.4%), and reduce repeat-dispensing of antimicrobial prescriptions (448 of 604, 74.2%). CPs faced interpersonal, interactional, structural, and resource-level barriers to collaborate with GPs for practicing AMS. Conclusions CPs are aware of the importance of sensible use of antimicrobials but have had limited training and resources to conduct AMS activities. Improving GPs’ receptiveness and system structures for increased GP-CP collaboration seem to be a priority to accelerate CP-led AMS implementation. Further study is required to understand the views of stakeholders about the feasibility of implementing evidence-based GP-CP collaborative AMS approaches.

Objectives This study describes the safety, clinical effectiveness and trough plasma concentration (Cmin) of intravenous (iv) posaconazole, provided as part of Merck Sharp and Dohme Australia's Named Patient Programme (NPP) in non-clinical trial settings. Methods A multicentre, retrospective study on the NPP use of iv posaconazole between July 2014 and March 2015 across seven Australian hospitals. Results Seventy courses of iv posaconazole were prescribed and evaluated in 61 patients receiving treatment for haematological malignancy. Sixty-one courses were prescribed for prophylaxis against invasive fungal disease (IFD), the majority of which (59) were initiated in patients with gastrointestinal disturbances and/or intolerance to previous antifungals. The median (IQR) duration for prophylaxis was 10 (6-15) days. No breakthrough IFD was observed during or at cessation of iv posaconazole. Nine courses of iv posaconazole were prescribed for treatment of IFD with a median (IQR) duration of 19 (7-30) days. Improvement in signs and symptoms of IFD was observed in five cases at cessation of, and six cases at 30 days post-iv posaconazole. Cmin was measured in 39 courses of iv posaconazole, with the initial level taken [median (IQR)] 4 (3-7) days after commencing iv posaconazole. The median (IQR) of initial Cmin was 1.16 (0.69-2.06) mg/L. No severe adverse events specifically attributed to iv posaconazole were documented, although six courses were curtailed due to potential toxicity. Conclusions This non-clinical trial experience suggests that iv posaconazole appeared to be safe and clinically effective for prophylaxis or treatment of IFD in patients receiving treatment for haematological malignancies.

Background Little is known about the use of sedation drugs for the management of acute agitation in Hong Kong's Accident and Emergency Departments (AEDs) and how it compares with Australasian practice. Objective The aim of this study was to determine drug preferences, clinicians' perceived confidence in management, barriers/gaps in training and perceived usefulness of existing clinical practice guidelines (CPGs) in Hong Kong. Method A validated questionnaire was used, with case vignettes typical of patients presenting to AEDs with acute agitation. The questionnaire was distributed by hand to all trainees and fellows of the Hong Kong College of Emergency Medicine (HKCEM). Two reminders were sent. Results Of 483 HKCEM members, 280 (58.0% [95% CI 53.5–62.3]) responded. For monotherapy, 46.8% (95% CI 41.0–52.6) of respondents chose haloperidol to manage the undifferentiated patient, followed by midazolam (33.9%, 95% CI 28.6–39.7) and diazepam (13.9%, 95% CI 10.4–18.5). Most respondents (83.6%, 95% CI 78.8–87.5) would not administer combination therapy. Respondents were confident in managing agitation overall. The lack of local/institutional CPGs (55.7%, 95% CI 49.9–61.4) was perceived as an important barrier. Institutional guidelines were considered the most useful CPGs (66.4%, 95% CI 60.7–71.7). Most respondents (72.9%, 95% CI 67.4–77.7) perceived a HKCEM endorsed CPG would be useful. Conclusion Haloperidol and benzodiazepines are frequently used as monotherapy for the management of acute agitation in Hong Kong's AEDs. Management in Hong Kong differs from Australasian practice in that combination therapy is less common and clinicians' choice of sedation drugs are less variable overall. Results suggest that future work on CPG development and training regarding the safe use of combination therapy would be well received.

ObjectiveThe aim of this study was to explore the features of sustainable antimicrobial stewardship (AMS) programs in Australian rural hospitals and develop recommendations on incorporating these features into rural hospitals’ AMS programs. MethodsLead AMS clinicians with knowledge of at least one AMS program sustained for >2 years in a health service in rural Australia were recruited to the study. A series of interviews was conducted and the transcripts analysed thematically using a framework method. ResultsFifteen participants from various professional disciplines were interviewed. Key features that positively affected the sustainability of AMS programs in rural hospitals included a hospital executive who provided strong governance and accountability, dedicated resources, passionate local champions, area-wide arrangements and adaptability to engage in new partnerships. Challenges to building AMS programs with these features were identified, particularly in engaging hospital executive to allocate AMS resources, managing the burn out of passionate champions and formalising network arrangements. ConclusionsStrategies to increase the sustainability of AMS programs in rural hospitals include using accreditation as a mechanism to drive direct resource allocation, explicit staffing recommendations for rural hospitals, greater support to develop formal network arrangements and a framework for integrated AMS programs across primary, aged and acute care. What is known about the topic?AMS programs facilitate the responsible use of antimicrobials. Implementation challenges have been identified for rural hospitals, but the sustainability of AMS programs has not been explored. What does this paper add?Factors that positively affected the sustainability of AMS programs in rural hospitals were a hospital executive that provided strong governance and accountability, dedicated resources, network or area-wide arrangements and adaptability. Challenges to building AMS programs with these features were identified. What are the implications for practitioners?Recommended actions to boost the sustainability of AMS programs in rural hospitals are required. These include using accreditation as a mechanism to drive direct resource allocation, explicit staffing recommendations for rural hospitals, greater support to develop network arrangements and support to create integrated AMS programs across acute, aged and primary care.

Background Clinical studies and mathematical simulation suggest that active surveillance with contact isolation is associated with reduced vancomycin-resistant enterococci (VRE) prevalence compared to passive surveillance. Models using pre- and post-intervention data that account for the imperfect observation and serial dependence of VRE transmission events can better estimate the effectiveness of active surveillance and subsequent contact isolation; however, such analyses have not been performed. Methods A mathematical model was fitted to surveillance data collected pre- and post-implementation of active surveillance with contact isolation in the haematology-oncology ward. We developed a Hidden Markov Model to describe undetected and observed VRE colonisation/infection status based on the detection activities in the ward. Bayesian inference was used to estimate transmission rates. The effectiveness of active surveillance was assumed to be via increased detection and subsequent contact isolation of VRE positive patients. Results We estimated that 31% (95% credible interval: 0.33–85%) of the VRE transmissions were due to cross-transmission between patients. The ratio of transmission rates from patients with contact isolation versus those without contact isolation was 0.33 (95% credible interval: 0.050–1.22). Conclusions The majority of the VRE acquisitions in the haematology-oncology ward was estimated to be due to background rates of VRE, rather than within ward patient to patient acquisition. The credible interval for cross-transmission was wide which results in a large degree of uncertainty in the estimates. Factors that could account for background VRE acquisition include endogenous acquisition from antibiotic selection pressure and VRE in the environment. Contact isolation was not significantly associated with reduced VRE transmission in settings where the majority of VRE acquisition was due to background acquisition, emphasising the need to identify and address the source of acquisition. As the credible interval for the ratio of VRE transmission in contact isolated versus non-contact isolated patients crossed 1, there is a probability that the transmission rate in contact isolation was not lower. Our finding highlights the need to optimise infection control measures other than active surveillance for VRE and subsequent contact isolation to reduce VRE transmission. Such measures could include antimicrobial stewardship, environmental cleaning, and hand hygiene. Electronic supplementary material The online version of this article (10.1186/s12879-018-3388-y) contains supplementary material, which is available to authorized users.

Summary Background Many regional and remote (‘regional’) hospitals are without the specialist services that support antimicrobial stewardship (AMS) programmes in hospitals in major cities. This can impact their ability to implement AMS activities. Aim To identify factors that impact on the delivery of AMS programmes in regional hospitals. Methods Healthcare clinicians who have primary AMS responsibilities or provide AMS support to a health service or across health services with an Australian Statistical Geography Standard Remoteness classification of inner regional, outer regional, remote or very remote were recruited purposively and via snowballing. A series of focus groups and interviews were held, and the discussions were audiotaped and transcribed verbatim. The transcripts were coded by two researchers, and thematic analysis was undertaken using a framework method. Findings Four focus groups and one interview were conducted (22 participants). Six main themes that impacted on AMS programme delivery were identified: culture of independence and self-reliance by local clinicians, personal relationships, geographical location of the hospital influencing antimicrobial choice, local context, inability to meaningfully benchmark performance, and lack of resources. Possible strategies to support the delivery of AMS programmes in regional hospitals proposed by participants were categorized into two main themes: those that may be best developed or managed centrally, and those that should be a local responsibility. Conclusion AMS programme delivery in regional hospitals is influenced by factors that are not present in hospitals in major cities. These findings provide a strong basis for the development of strategies to support regional hospitals to implement sustainable AMS programmes.

INTRODUCTION: Antimicrobial resistance (AMR) has been recognised as an urgent health priority, both nationally and internationally. Australian hospitals are required to have an antimicrobial stewardship (AMS) program, yet the necessary resources may not be available in regional, rural or remote hospitals. This review will describe models for AMS programs that have been introduced in regional, rural or remote hospitals internationally and showcase achievements and key considerations that may guide Australian hospitals in establishing or sustaining AMS programs in the regional, rural or remote hospital setting. METHODS: A narrative review was undertaken based on literature retrieved from searches in Ovid Medline, Scopus, Web of Science and the grey literature. 'Cited' and 'cited by' searches were undertaken to identify additional articles. Articles were included if they described an AMS program in the regional, rural or remote hospital setting (defined as a bed size less than 300 and located in a non-metropolitan setting). RESULTS: Eighteen articles were selected for inclusion. The AMS initiatives described were categorised into models designed to address two different challenges relating to AMS program delivery in regional, rural and remote hospitals. This included models to enable regional, rural and remote hospital staff to manage AMS programs in the absence of on-site infectious diseases (ID) trained experts. Non-ID doctor-led, pharmacist-led and externally led initiatives were identified. Lack of pharmacist resources was recognised as a core barrier to the further development of a pharmacist-led model. The second challenge was access to timely off-site expert ID clinical advice when required. Examples where this had been overcome included models utilising visiting ID specialists, telehealth and hospital network structures. Formalisation of such arrangements is important to clarify the accountabilities of all parties and enhance the quality of the service. Information technology was identified as a facilitator to a number of these models. The variance in availability of information technology between hospitals and cost limits the adoption of uniform programs to support AMS. CONCLUSION: Despite known barriers, regional, rural and remote hospitals have implemented AMS programs. The examples highlighted show that difficulty recruiting ID specialists should not inhibit AMS programs in regional, rural and remote hospitals, as much of the day-to-day work of AMS can be done by non-experts. Capacity building and the strengthening of networks are core features of these programs. Descriptions of how Australian regional, rural and remote hospitals have structured and supported their AMS programs would add to the existing body of knowledge sourced from international examples. Research into AMS programs predominantly led by GPs and nursing staff will provide further possible models for regional, rural and remote hospitals.

Objectives: To develop a population pharmacokinetic (PK) model for vancomycin in adults receiving high-flux haemodialysis (HFHD) in an effort to optimize vancomycin dosing in this population. Methods: A population PK model using NONMEM was developed using retrospective data collected from 48 vancomycin courses administered to patients (n = 37) receiving HFHD. Fixed-dose [1.5 g loading dose (LD), 1 g maintenance dose (MD)], literature-adapted weight-based (WBL; 20 mg/kg LD, 10 mg/kg MD) and hospital-adapted weight-based (WBH; 25-30 mg/kg LD, 20-25 mg/kg MD) dosage regimens were then simulated using the Monte Carlo method. The PTA was an AUC24/MIC ≥400 with success being a PTA ≥90%. Results: The data were best described using a two-compartment model. It was observed that fixed-dose and WBL dosage regimens resulted in a PTA ≤90% for most days. The WBH dosing achieved a PTA ≥90% on most days, but there were supratherapeutic concentrations with repeated dosing of vancomycin. If HFHD was delayed by 48-72 h after the LD, the PTA would fall below 90%. A dose-optimized regimen was developed: 30 mg/kg LD and 10 mg/kg MD given on HFHD days. An additional dose of 500 mg or 1 g was administered 24 h after the LD if HFHD occurred 48-72 h post-LD. This dose-optimized regimen afforded a PTA ≥90% on all days of therapy and achieved clinically acceptable pre-haemodialysis concentrations. Conclusions: Current vancomycin dosage regimens used clinically do not achieve a PTA ≥90% for most days of therapy for people receiving HFHD. A dose-optimized regimen was developed, which could be implemented in clinical practice.