The antifungal pipeline for invasive fungal diseases: what does the future hold?

INTRODUCTION: Over the last two decades, we have experienced pressing needs for new additions to the antifungal armamentarium given the emergence of resistant fungi, the growth of at-risk patient populations for invasive fungal diseases (IFD), the high morbidity and mortality associated with IFD. AREAS COVERED: The current review will discuss the five promising antifungal agents for IFD (i.e. fosmanogepix, ibrexafungerp, olorofim, rezafungin, and opelconazole), now in the late-phase clinical studies, and likely to be available for clinical use in the near future. For each agent, we describe its mechanism of action, pharmacokinetic and pharmacodynamic properties, spectrum of activity as well as the safety and efficacy data, including findings from ongoing clinical trials. The potential roles of these novel antifungals in clinical practice and the key considerations for clinical use will also be discussed. EXPERT OPINION: There are unmet needs of these novel agents that should be addressed in the future studies. These include defining their indications and benefits, how to best target them appropriately, surveillance and stewardship of their use.

The 2018 Aged Care National Antimicrobial Prescribing Survey: results show room for improvement.

The annual Aged Care National Antimicrobial Prescribing Survey aims to identify local and national prescribing issues and guide antimicrobial stewardship goals In the 2018 point prevalence survey, medication charts of over 20,000 residents were reviewed from 407 participating facilities across Australia On the day of the survey, almost 10% of residents were prescribed an antimicrobial Nearly two-thirds of recently prescribed antimicrobials were for residents who had no documented signs or symptoms of infection Over a quarter of antimicrobials had been prescribed for longer than six months Incomplete documentation was a prominent barrier to proper review of antimicrobial therapy, with the indication, review date or stop date not documented for many prescriptions Recommendations include using appropriate microbiological testing to guide prescribing, following national antimicrobial prescribing guidelines, documenting the indication for the antimicrobial, and its start, stop and review dates, and monitoring and re-evaluating long-term antimicrobial use

Meeting the challenge for effective antimicrobial stewardship programs in regional, rural and remote hospitals - what can we learn from the published literature?

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.

Safe disposal of prescribed medicines.

The National Return and Disposal of Unwanted Medicines Program provides a free and safe method for the disposal of unwanted and expired medicines. This stops drugs being dumped in landfill and waterways. An audit showed that over 600 tonnes of medicines are returned through the program. A substantial proportion of these medicines were still within their expiry dates. Salbutamol, insulin and frusemide are the most commonly discarded medicines. More than $2 million of public money is wasted each year. Hoarding and non-adherence to treatment contribute to waste. Health professionals may be able to help minimise waste by informing patients about the importance of completing prescribed courses of treatment, and discouraging them from hoarding medicines after reaching the safety net threshold on the Pharmaceutical Benefits Scheme. Prescribe no more than the required quantity of medicines. When starting a new therapy, prescribe a minimal quantity in case the drug is unsuitable for the patient. Advise patients to return all unwanted medicines to a pharmacy for disposal.

Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR for the diagnosis of invasive aspergillosis in adult hematology patients: a systematic review and meta-analysis.

BACKGROUND: The clinical utility of bronchoalveolar lavage (BAL) fluid galactomannan (GM) for the early diagnosis of invasive aspergillosis (IA) varies widely across studies mainly due to heterogeneity of the studied populations. METHODS: We conducted a systematic review and meta-analysis of 16 studies involving 783 adults with hematological malignancies to derive summary estimates of the overall accuracy of BAL-GM for diagnosing IA. FINDINGS: Summary estimates of BAL-GM using an optical density (OD) index cutoff value of 1.5 for proven and probable IA were: sensitivity 0.92 (95% CI = 0.48-0.99), specificity 0.98 (95% CI = 0.78-1.00), positive likelihood ratio 53.7 (95% CI = 3.7-771.8), and negative likelihood ratio 0.08 (95% CI = 0.01-0.83). Comparing serum GM and Aspergillus PCR testing on BAL fluid, BAL-GM conferred greater sensitivity, but lower specificity than the serum GM test, and similar specificity as the PCR assay. The use of BAL-GM with serum GM or BAL-PCR tests increased the sensitivity moderately when a positive result was defined by either assay. INTERPRETATION: GM quantification in BAL fluid at an OD index cutoff value of 1.5 has excellent sensitivity and specificity to assist clinical decision-making in confirming or excluding a diagnosis of IA when results are interpreted with clinical findings. Additional research investigating the effects of antifungal agents, optimal timing and processing of BAL sampling are needed to improve the diagnostic accuracy of BAL-GM testing.

Pharmacoeconomic evaluation of voriconazole vs. liposomal amphotericin B in empiric treatment of invasive fungal infections in Turkey.

BACKGROUND: Invasive fungal infections (IFI) are associated with considerable expense and mortality on healthcare systems. There is a need to provide evidence of both clinical efficacy and value for money with any health technology. The current pharmacoeconomic evaluation investigated the use of liposomal amphotericin B (LAmB) and voriconazole for the empiric treatment of IFI in the Turkish setting. METHODS: Decision analytic modelling was used to create a pathway for patient treatment with a 5-point composite outcome measure. The data was obtained from a major non-inferiority multicentre randomised controlled study, with an expert panel of clinicians in Turkey providing transition probabilities and cost not available in the literature. Sensitivity analyses were performed on the inputs from the clinical trial and the expert panel. RESULTS: As per the base case analysis, voriconazole was preferred by Turkish Lira (TL) 2,523 per patient treated and TL2,520 per surviving patient. LAmB was the preferred alternative by TL5,362 per successfully treated patient. Removing fever resolution as part of the composite outcome measure resulted in voriconazole being the preferred alternative per successfully treated patient. Univariate sensitivity analysis highlighted that increasing the duration of voriconazole by >1.2 days or decreasing LAmB by >1.0 days changes the result. Monte Carlo Simulation resulted in 69.4% of simulations favouring voriconazole per patient treated. CONCLUSION: There is a strong likelihood that voriconazole is economically more favourable than LAmB in the empiric treatment of IFI in Turkey.

Drug-related problems detected in Australian Community Pharmacies: The PROMISe Trial.

BACKGROUND: Drug-related problems (DRPs) are a major burden on health care systems. Community pharmacists are ideally placed to detect, prevent, and resolve these DRPs. OBJECTIVE: To determine the number and nature of DRPs detected and clinical interventions performed by Australian community pharmacists, using an electronic system. METHODS: An electronic documentation system was designed and integrated into the existing dispensing software of 186 pharmacies to allow pharmacists to record details about the clinical interventions they performed to prevent or resolve DRPs. Participating pharmacies were randomly allocated to 3 groups: group 1 had documentation software, group 2 had documentation software plus a timed reminder to document interventions, and group 3 had documentation software, a timed reminder, and an electronic decision support prompt. Pharmacists classified DRPs, entered recommendations they made, and estimated the clinical significance of the intervention. An observational substudy that included pharmacies without any documentation software was completed to verify intervention rates. RESULTS: Over 12 weeks, 531 participating pharmacists recorded 6230 clinical interventions from 2,013,923 prescriptions, with a median intervention rate of 0.23% of prescriptions. No significant differences were seen between the 3 groups that used documentation software; as expected, however, the pharmacies that used this software had a significantly higher documentation rate compared to the pharmacies without documentation software. The most common interventions were related to drug selection problems (30.8%) and educational issues (24.4%). Recommendations were often related to a change in therapy (40.0%), and 41.6% of interventions were self-rated as highly significant. Drug groups most commonly subject to an intervention included antibiotics, glucocorticoids, nonsteroidal antiinflammatory drugs, and opioids. CONCLUSIONS: The documentation system allowed for the determination of the frequency and types of DRPs, as well as the recommendations made to resolve them in community pharmacy practice. Use of the software, including its electronic prompts, significantly increased the documentation of interventions by pharmacists.

Identification by observation of clinical pharmacists' activities in a hospital inpatient setting

The aim of the study was to quantify clinical pharmacists’ workload in Australia. Specific objectives were to perform a direct observation of the pattern of clinical activities in two acute hospitals and compare that with previously documented self reported patterns. We were also interested in identifying what records kept by pharmacists would capture all the activities they perform. Methods: An observer recorded the activities of clinical pharmacists on six separate days in the medical and surgical wards of two Melbourne metropolitan hospitals. We examined resultant datato determine suitable records by which clinical pharmacists could capture all the activities they perform. To compare the observed pattern of clinical activities with those earlier self-reported by pharmacists, we categorised our data using the Pharmacy Activity Codes present in the penultimate version of the ICD-10-AM classification system. Results: The observer recorded the performance of 807 workload ‘events’, representing 28 separate types of activities. When compressed into the Pharmacy Activity Codes formerly used in the ICD-10-AM classification system, the pattern of activities identified by direct observation matched that which had previously been self-reported by pharmacists. The majority of the activities performed could be captured by completion of a Pharmaceutical Care Plan and by recording pharmacists’ interventions toa database. The remaining activities may be recorded for departmental workload purposes in a simple template format. Conclusion: The pattern of clinical pharmacist activity at the two hospitals was confirmed by direct observation as similar to that previously reported in other Australian hospitals. A Pharmaceutical Care Plan, a database for intervention recording and a simple workload template provide the means to record all activities that clinical pharmacists perform (AU)

El objetivo del estudio fue cuantificar la carga de trabajo de los farmacéuticos clínicos en Australia. Los objetivos específicos fueron realizar una observación directa de los modelos de actividades clínicas en dos hospitales de agudos y compararlas con los modelos que habían sido previamente autoreportados. También estábamos interesados en identificar que registros llevados los farmacéuticos podrían capturar todas sus actividades. Métodos: Un observador registraba las actividades de los farmacéuticos clínicos en seis días separados en los servicios de médicos y quirúrgicos de dos hospitales metropolitanos de Melbourne. Examinamos los datos resultantes para determinar registros adecuados con los que los farmacéuticos clínicos podrían registrar todas las actividades que realizaban. Para comparar los modelos de actividades clínicas con las auto-reportadas anteriormente, categorizamos los datos utilizando los Códigos de Actividad Farmacéutica (CAF) presentes en la penúltima versión del sistema de clasificación CDI-10-AM. Resultados: El observador registró las actividades de 807 eventos de trabajo, que representaron 28 tipos diferentes de actividades. Al comprimirlos en los CAF anteriormente usados en el sistema CDI-10-AM, los modelos de actividad identificados por observación directa se ajustaban a los que habían sido previamente auto-comunicados por los farmacéuticos. La mayoría de las actividades realizadas podía ser capturada en la cumplimentación de un plan de atención farmacéutica y en registrar las intervenciones del farmacéutico en una base de datos. El resto de las actividades puede registrarse para análisis de carga de trabajo del departamento en un modelo de formato simple. Conclusión: El modelo de la actividad de un farmacéutico clínico se confirmó por observación directa como similar a los previamente comunicado en otros hospitales australianos. Un plan de atención farmacéutica, una base de datos para registro de intervenciones y una simple hoja de registro de carga de trabajo proporcionan los medios de registro de todas las actividades que realizan los farmacéuticos clínicos (AU)

Identification by observation of clinical pharmacists' activities in a hospital inpatient setting.

UNLABELLED: The aim of the study was to quantify clinical pharmacists' workload in Australia. Specific objectives were to perform a direct observation of the pattern of clinical activities in two acute hospitals and compare that with previously documented self-reported patterns. We were also interested in identifying what records kept by pharmacists would capture all the activities they perform. METHODS: An observer recorded the activities of clinical pharmacists on six separate days in the medical and surgical wards of two Melbourne metropolitan hospitals. We examined resultant data to determine suitable records by which clinical pharmacists could capture all the activities they perform. To compare the observed pattern of clinical activities with those earlier self-reported by pharmacists, we categorised our data using the Pharmacy Activity Codes present in the penultimate version of the ICD-10-AM classification system. RESULTS: The observer recorded the performance of 807 workload 'events', representing 28 separate types of activities. When compressed into the Pharmacy Activity Codes formerly used in the ICD-10-AM classification system, the pattern of activities identified by direct observation matched that which had previously been self-reported by pharmacists. The majority of the activities performed could be captured by completion of a Pharmaceutical Care Plan and by recording pharmacists' interventions to a database. The remaining activities may be recorded for departmental workload purposes in a simple template format. CONCLUSION: The pattern of clinical pharmacist activity at the two hospitals was confirmed by direct observation as similar to that previously reported in other Australian hospitals. A Pharmaceutical Care Plan, a database for intervention recording and a simple workload template provide the means to record all activities that clinical pharmacists perform.

Development and validation of the medication-based disease burden index.

BACKGROUND: Medication lists offer an alternative source of data on comorbidities and disease burden. OBJECTIVE: To develop and validate the Medication-Based Disease Burden Index (MDBI). METHODS: A list of medications corresponding to the leading causes of global death was pilot tested and finalized by an expert panel. The resulting index was tested on drug regimens of patients at risk of medication misadventure. Criterion validity of the index was established against Charlson's index and Chronic Disease Score (CDS). Sensitivity, specificity, predictive validity, convergent and discriminant validity, and interrater and test-retest reliabilities of the index were also assessed. RESULTS: The MDBI consisting of specific medications for 20 chronic medical conditions and corresponding disability weightings was developed. The MDBI was tested on 317 patients with mean +/- SD Charlson's index scores of 2.8 +/- 2.2 and CDS scores of 7.3 +/- 2.8. Mean MDBI scores (0.33 +/- 0.28) demonstrated significant correlations with Charlson's index scores (r = 0.31; p < 0.001) and CDS (r = 0.53; p < 0.001). MDBI had satisfactory sensitivity and high specificity. Age of the patients and number of medications had significant correlation with the MDBI scores, but the MDBI scores were not significantly different in males and females. MDBI scores could successfully predict death and planned or unplanned readmissions (OR = 4.7, 95% CI 1.4 to 15.5; p = 0.01). MDBI demonstrated high inter-rater (intraclass correlation coefficient [ICC] = 0.99) and test-retest reliabilities (ICC = 0.98). CONCLUSIONS: Initial testing suggests that MDBI could offer an alternative low-cost and convenient method for quantifying disease burden and predicting health outcomes.