Scedosporiosis and lomentosporiosis: modern perspectives on these difficult-to-treat rare mold infections.

SUMMARYAlthough Scedosporium species and Lomentospora prolificans are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different Scedosporium species. L. prolificans is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.

Costs associated with invasive Scedosporium and Lomentospora prolificans infections: a case-control study.

BACKGROUND: Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. METHODS: A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. RESULTS: Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. CONCLUSIONS: The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial.

Penetration of Vancomycin into Noninfected Bone in Patients Undergoing Total Joint Arthroplasty Evaluated by a Minimal Physiologically Based Population Pharmacokinetic Modeling Approach.

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/kg0.75. Inclusion of total body weight as a covariate substantially decreased interindividual variability in clearance. The bone/blood partition coefficient (Kpbone) was estimated at 0.635, reflecting the average bone/blood concentration ratio at steady-state. The model predicted median ratio of vancomycin area under the curve (AUC) for bone/AUC for serum was 44%. Observed vancomycin concentrations in bone were overall consistent with perfusion-limited distribution from blood to bone. An mPBPK model overall well described vancomycin concentrations in serum and bone.

Epstein-Barr virus related post-transplant lymphoproliferative disorder prevention strategies in allogeneic hematopoietic stem cell transplantation.

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.

Cytomegalovirus (CMV) management in allogeneic hematopoietic cell transplantation: Pre-transplant predictors of survival, reactivation, and spontaneous clearance.

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.

Dynamics of Epstein-Barr virus on post-transplant lymphoproliferative disorders after antithymocyte globulin-conditioned allogeneic hematopoietic cell transplant.

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.

Consensus guidelines for improving patients' understanding of invasive fungal disease and related risk prevention in the haematology/oncology setting, 2021.

Patients with invasive fungal disease (IFD) are at significant risk of morbidity and mortality. A productive partnership between patients, their carers/families, and the multidisciplinary team managing the infection and any underlying conditions, is essential. Sharing information and addressing knowledge gaps are required to ensure those at risk of IFD avoid infection, while those with suspected or confirmed infection optimise their therapy and avoid toxicities. This new addition to the Australian and New Zealand consensus guidelines for the management of IFD and antifungal use in the haematology/oncology setting outlines the key information needs of patients and their carers/families. It specifically addresses risk factor reduction, antifungal agents and adherence, and the risks and benefits of complementary and alternative therapies. Knowledge gaps are also identified to help inform the future research agenda.

Antimicrobial stewardship by Australian community pharmacists: Uptake, collaboration, challenges, and needs.

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.

Towards OPtimising Care of Regionally-Based Cardiac Patients With a Telehealth Cardiology Pharmacist Clinic (TOPCare Cardiology).

INTRODUCTION: 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. METHODS: 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. RESULTS: 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, p<0.001). 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. CONCLUSION: 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.

Optimizing vancomycin dosage regimens in relation to high-flux haemodialysis.

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.

Antifungal stewardship: developments in the field.

PURPOSE OF REVIEW: To outline key drivers and components of antifungal stewardship (AFS) programmes, the evidence for specific interventions, and methods to assess performance of programmes. RECENT FINDINGS: 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. SUMMARY: 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.

Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma 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 < 0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose-response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L. Conclusions: The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets.

Economic evaluation of micafungin versus liposomal amphotericin B (LAmB) for treating patients with candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome.

Mathematical modelling of vancomycin-resistant enterococci transmission during passive surveillance and active surveillance with contact isolation highlights the need to identify and address the source of acquisition.

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.

Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: The Alfred's experience.

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.

Interdisciplinary pharmacometrics linking oseltamivir pharmacology, influenza epidemiology and health economics to inform antiviral use in pandemics.

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.

Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial.

STUDY OBJECTIVE: We aim to determine the most efficacious of 3 common medication regimens for the sedation of acutely agitated emergency department (ED) patients. METHODS: We undertook a randomized, controlled, double-blind, triple-dummy, clinical trial in 2 metropolitan EDs between October 2014 and August 2015. Patients aged 18 to 65 years and requiring intravenous medication sedation for acute agitation were enrolled and randomized to an intravenous bolus of midazolam 5 mg-droperidol 5 mg, droperidol 10 mg, or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg, or olanzapine 5 mg. The primary outcome was the proportion of patients adequately sedated at 10 minutes. RESULTS: Three hundred forty-nine patients were randomized to the 3 groups. Baseline characteristics were similar across the groups. Ten minutes after the first dose, significantly more patients in the midazolam-droperidol group were adequately sedated compared with the droperidol and olanzapine groups: differences in proportions 25.0% (95% confidence interval [CI] 12.0% to 38.1%) and 25.4% (95% CI 12.7% to 38.3%), respectively. For times to sedation, the differences in medians between the midazolam-droperidol group and the droperidol and olanzapine groups were 6 (95% CI 3 to 8) and 6 (95% CI 3 to 7) minutes, respectively. Patients in the midazolam-droperidol group required fewer additional doses or alternative drugs to achieve adequate sedation. The 3 groups' adverse event rates and lengths of stay did not differ. CONCLUSION: Midazolam-droperidol combination therapy is superior, in the doses studied, to either droperidol or olanzapine monotherapy for intravenous sedation of the acutely agitated ED patient.

Cost-effectiveness analysis of anidulafungin vs fluconazole for the treatment of invasive candidiasis (IC) in Turkey.

Anidulafungin has been shown to be non-inferior to, and possibly more efficacious, than fluconazole in treating patients with invasive candidiasis (IC). This study aimed to determine the cost-effectiveness of anidulafungin vs fluconazole for treatment of IC in the Turkish setting. A decision analytic model was constructed to depict downstream economic consequences of using anidulafungin or fluconazole for treatment of IC in the Turkish hospitals. Transition probabilities (ie treatment success, observed or indeterminate treatment failures) were obtained from a published randomised clinical trial. Cost inputs were from the latest Turkish resources. Data not available in the literature were estimated by expert panels. Sensitivity analyses were performed to assess the robustness of the model outcome. While anidulafungin [TL 17 171 (USD 4589)] incurred a higher total cost than fluconazole [TL 8233 (USD 2200) per treated patient, treatment with anidulafungin was estimated to save an additional 0.58 life-years, with an incremental cost-effectiveness ratio of TL 15 410 (USD 4118) per life-years saved. Drug acquisition cost and hospitalisation were the main cost drivers for anidulafungin and fluconazole arms respectively. The model findings were robust over a wide range of input variables except for anidulafungin drug cost. Anidulafungin appears to be a cost-effective therapy in treating IC from the Turkish hospital perspective.

Patterns of use and appropriateness of antibiotics prescribed to patients receiving haemodialysis: an observational study.

BACKGROUND: There are limited published data on the types and appropriateness of oral and intravenous (IV) antibiotics prescribed to patients receiving haemodialysis. This information is critical to optimise antibiotic prescribing. Therefore this study aims to describe the patterns of use and the appropriateness of oral and IV antibiotics prescribed to patients receiving haemodialysis. METHODS: This was a prospective, observational study across four community and two hospital inpatient haemodialysis units in Melbourne, Australia. Data were collected from July 2014 to January 2015 from participants. Antibiotic regimens prescribed were compared with nationally available antibiotic guidelines and then classified as being either appropriate, inappropriate or not assessable by an expert multidisciplinary team using the National Antimicrobial Prescribing Survey tool. RESULTS: Overall, 114 participants consented to this study where 55.3% (63/114) received antibiotics and 235 antibiotic regimens were prescribed at a rate of 69.1 antibiotic regimens/100 patient-months. The most common oral antibiotics prescribed were amoxycillin/clavulanic acid and cephalexin. The most common IV antibiotics prescribed were vancomycin, piperacillin/tazobactam, cephazolin and ceftriaxone. The percentage of inappropriate antibiotic regimens prescribed were 34.9% (15/43) in the community setting and 22.1% (40/181) in the hospital setting. Furthermore, 29.4% (30/102) of oral and 20.5% (25/122) of IV antibiotic regimens were inappropriate with incorrect dosing as the primary reason. CONCLUSION: Although this study is limited by the sample size, it describes the high antibiotic exposure that patients receiving haemodialysis experience. Of concern is inappropriate dose and frequency being a major issue. This requires interventions focused on the quality use of medicines and antimicrobial stewardship aspects of prescribing in this population.

Open-Label Study of Absorption and Clearance of 1% Voriconazole Eye Drops.

Twenty participants undergoing elective cataract surgery received 1% voriconazole eye drops (1 drop per eye) either 20, 40, 60, or 80 min before surgery. Median voriconazole concentrations of 1.9 to 3.2 mg/liter in aqueous humor samples were attained over the first 80 min, which were higher than in vitro MIC90 values for typical fungi that cause keratitis.