Where to start? The Irish Emergency Department Antimicrobial Discharge (EDAD) study: a multicentre, prospective cohort analysis.

Objectives: To determine the percentage of patients across Ireland who are discharged from the Emergency Department (ED) with an antimicrobial prescription, the indication, classification of infections, and guideline compliance. To identify potential areas for antimicrobial stewardship (AMS) interventions in the ED. Patients and methods: A multicentre, prospective cohort analysis study in EDs across eight hospitals in Ireland. At each site, patients aged 1 month and older who presented to the ED and were discharged directly from the ED were included. A random selection of records of patients discharged from the ED were reviewed until a minimum of 30 records with an infection diagnosis resulting in an antibiotic prescription were obtained per hospital. The number of patient discharges with no antibiotic prescriptions were included to calculate the denominator. The indication, infection classification and guideline compliance data were collected on the 30 prescriptions in the participating hospitals. Results: A total of 2619 patient records were reviewed. Of these, 249 (9.5%) patients were discharged with antimicrobial prescriptions from the ED. Most (158; 63%) were classified as probable bacterial infection, 21 (8%) as probable viral, and 18 (7%) had no documented evidence of infection. Three indications accounted for 73% of antimicrobial prescriptions: skin/soft tissue infection; ear, nose and throat infection; and urinary tract infection. Overall guideline compliance was 64%. Conclusions: Several areas for AMS interventions to optimize antimicrobial prescribing in the ED were identified, including targeted local and national guideline reviews, delayed prescribing, improved point-of-care testing and prescriber and patient education.

Genomic Epidemiology Identifies Azole Resistance Due to TR34/L98H in European Aspergillus fumigatus Causing COVID-19-Associated Pulmonary Aspergillosis.

Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA, including the prevalence of resistance-associated alleles. We present a population genomic analysis of 21 CAPA isolates from four European countries with these isolates compared against 240 non-CAPA A. fumigatus isolates from a wider population. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically encoded azole-resistant mechanisms. The phylogenetic analysis of the 21 CAPA isolates showed that they were representative of the wider A. fumigatus population with no obvious clustering. The prevalence of phenotypic azole resistance in CAPA was 14.3% (n = 3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. The relatively high prevalence of azole resistance alleles that we document poses a probable threat to treatment success rates, warranting the enhanced surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes when CAPA is suspected.

Predictors for Prolonged Hospital Stay Solely to Complete Intravenous Antifungal Treatment in Patients with Candidemia: Results from the ECMM Candida III Multinational European Observational Cohort Study.

BACKGROUND: To date, azoles represent the only viable option for oral treatment of invasive Candida infections, while rates of azole resistance among non-albicans Candida spp. continue to increase. The objective of this sub-analysis of the European multicenter observational cohort study Candida III was to describe demographical and clinical characteristics of the cohort requiring prolonged hospitalization solely to complete intravenous (iv) antifungal treatment (AF Tx). METHODS: Each participating hospital (number of eligible hospitals per country determined by population size) included the first ~ 10 blood culture proven adult candidemia cases occurring consecutively after July 1st, 2018, and treating physicians answered the question on whether hospital stay was prolonged only for completion of intravenous antifungal therapy. Descriptive analyses as well as binary logistic regression was used to assess for predictors of prolonged hospitalization solely to complete iv AF Tx. FINDINGS: Hospital stay was prolonged solely for the completion of iv AF Tx in 16% (100/621) of candidemia cases by a median of 16 days (IQR 8 - 28). In the multivariable model, initial echinocandin treatment was a positive predictor for prolonged hospitalization to complete iv AF Tx (aOR 2.87, 95% CI 1.55 - 5.32, p < 0.001), while (i) neutropenia, (ii) intensive care unit admission, (iii) catheter related candidemia, (iv) total parenteral nutrition, and (v) C. parapsilosis as causative pathogen were found to be negative predictors (aOR 0.22 - 0.45; p < 0.03). INTERPRETATION: Hospital stays were prolonged due to need of iv AF Tx in 16% of patients with candidemia. Those patients were more likely to receive echinocandins as initial treatment and were less severely ill and less likely infected with C. parapsilosis.

European candidaemia is characterised by notable differential epidemiology and susceptibility pattern: Results from the ECMM Candida III study.

The objectives of this study were to assess Candida spp. distribution and antifungal resistance of candidaemia across Europe. Isolates were collected as part of the third ECMM Candida European multicentre observational study, conducted from 01 to 07-07-2018 to 31-03-2022. Each centre (maximum number/country determined by population size) included ∼10 consecutive cases. Isolates were referred to central laboratories and identified by morphology and MALDI-TOF, supplemented by ITS-sequencing when needed. EUCAST MICs were determined for five antifungals. fks sequencing was performed for echinocandin resistant isolates. The 399 isolates from 41 centres in 17 countries included C. albicans (47.1%), C. glabrata (22.3%), C. parapsilosis (15.0%), C. tropicalis (6.3%), C. dubliniensis and C. krusei (2.3% each) and other species (4.8%). Austria had the highest C. albicans proportion (77%), Czech Republic, France and UK the highest C. glabrata proportions (25-33%) while Italy and Turkey had the highest C. parapsilosis proportions (24-26%). All isolates were amphotericin B susceptible. Fluconazole resistance was found in 4% C. tropicalis, 12% C. glabrata (from six countries across Europe), 17% C. parapsilosis (from Greece, Italy, and Turkey) and 20% other Candida spp. Four isolates were anidulafungin and micafungin resistant/non-wild-type and five resistant to micafungin only. Three/3 and 2/5 of these were sequenced and harboured fks-alterations including a novel L657W in C. parapsilosis. The epidemiology varied among centres and countries. Acquired echinocandin resistance was rare but included differential susceptibility to anidulafungin and micafungin, and resistant C. parapsilosis. Fluconazole and voriconazole cross-resistance was common in C. glabrata and C. parapsilosis but with different geographical prevalence.

Beyond consumption: a qualitative investigation of hospital clinician attitudes to receiving feedback on antimicrobial prescribing quality.

Background: Feedback on optimal antimicrobial prescribing to clinicians is an important strategy to ensure antimicrobial stewardship (AMS) in the hospital setting. Objective: To explore the perceptions of antimicrobial prescribing feedback among clinicians in acute care. Study design: Prospective qualitative design. Setting: A large inner-city tertiary referral center in Dublin, Ireland. Participants: Clinicians were recruited from the hospital clinician population. Methods: A qualitative study was conducted with a purposive sample of multidisciplinary clinicians. Focus groups and semistructured interviews were used to collect data that were analyzed inductively to identify themes. Results: In total, 30 clinicians from medical, surgical, nursing and pharmacy professions participated in the study. We identified 5 themes: (1) antimicrobial consumption perceived as a proxy measure for prescribing quality; (2) lack of connection between antimicrobial prescribing and patient outcomes; (3) relevance and impact of antimicrobial prescribing feedback associated with professional role; (4) attitudes regarding feedback as an AMS strategy; and (5) knowledge regarding AMS, including antimicrobial prescribing quality measures. Conclusions: Focused feedback on antimicrobial prescribing, with clear goals for improvement, could serve as a useful AMS strategy among clinicians in the acute-care setting. The need for further education and training in AMS was also identified.

The use of complexity theory to inform antimicrobial stewardship: a scoping review.

BACKGROUND: Complexity theory has previously been used as a conceptual lens in human healthcare research. Antimicrobial stewardship (AMS) is an inherently complex healthcare intervention; however, the extent to which complexity has been operationalized in AMS is currently unclear. AIM: To investigate if, and how, complexity theory has been used to inform AMS in human healthcare. METHODS: Scoping review methodology. Empirical research or policy specifically referencing complexity in relation to AMS were considered in any human healthcare setting and geographical location. Databases searched were: Cinahl, Cochrane Library, Embase, Medline, National Institute for Health and Care Excellence, PsycInfo, Scopus and Web of Science from inception to June 2020. Grey literature and other databases searched: EVIPNet, Google, Mednar, Proquest Theses, and the World Health Organization library of national antimicrobial resistance action plans. Non-English language articles were excluded. RESULTS: Of 612 records retrieved, 8 articles were included. Heterogeneity in study design and geographical location were noted. Three interventional studies evaluated AMS in hospital (n = 2) and long-term care (n = 1) settings. Remaining studies were non-interventional and proposed AMS strategies conceptualized through complexity theory. The importance of close engagement between researchers or policy administrators and the target population was emphasized in all studies, as a means of ensuring AMS relevance and success. CONCLUSIONS: There is a paucity of AMS research informed by complexity theory, and no policy documents could be located using complexity as a guiding theory. Mixed methods, informed by complexity theory, is a potentially suitable strategy to develop, implement and evaluate AMS as a complex intervention.

Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment.

Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

Lessons from an Educational Invasive Fungal Disease Conference on Hospital Antifungal Stewardship Practices across the UK and Ireland.

Invasive fungal disease (IFD) is a growing health burden. High mortality rates, increasing numbers of at-risk hosts, and a limited availability of rapid diagnostics and therapeutic options mean that patients are increasingly exposed to unnecessary antifungals. High rates of prescriptions promote patient exposure to undue toxicity and drive the emergence of resistance. Antifungal stewardship (AFS) aims to guide antifungal usage and reduce unnecessary exposure and antifungal consumption whilst maintaining or improving outcomes. Here, we examine several AFS approaches from hospitals across the UK and Ireland to demonstrate the benefits of AFS practices and support the broader implementation of AFS as both a necessary and achievable strategy. Since the accuracy and turnaround times (TATs) of diagnostic tools can impact treatment decisions, several AFS strategies have included the development and implementation of diagnostic-driven care pathways. AFS informed treatment strategies can help stratify patients on a risk basis ensuring the right patients receive antifungals at the optimal time. Using a multidisciplinary approach is also key due to the complexity of managing and treating patients at risk of IFD. Through knowledge sharing, such as The Gilead Antifungal Information Network (GAIN), we hope to drive practices that improve patient management and support the preservation of antifungals for future use.

Multi-triazole-resistant Aspergillus fumigatus and SARS-CoV-2 co-infection: A lethal combination.

We report a case of severe COVID-19 pneumonia complicated by fatal co-infection with a multi-triazole resistant Aspergillus fumigatus and highlight the importance of recognising the significance of Aspergillus sp. isolation from respiratory samples. Early diagnosis and detection of triazole resistance are essential for appropriate antifungal therapy to improve outcome in patients with coronavirus associated invasive aspergillosis.

Fungal Infections Complicating COVID-19: With the Rain Comes the Spores.

Within the last 12 months, coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spread globally to pandemic proportions [...].

Prospective observational study of respiratory Aspergillus colonization or disease in patients with various stages of chronic obstructive pulmonary disease utilizing culture versus nonculture techniques.

Chronic obstructive pulmonary disease (COPD) patients have been recognized to be at increased risk of Aspergillus spp. colonization, which may progress to invasive pulmonary aspergillosis (IPA). The objective of this study was to determine the frequency of Aspergillus colonization, or disease, in a cohort of COPD patients. A prospective observational study was undertaken to determine Aspergillus colonization, or disease, in consecutive COPD patients undergoing bronchoscopy. Fungal culture as well as galactomannan antigen (GM) and Aspergillus nucleic acid detection (PCR) were performed on bronchoalveolar lavage fluid (BAL) samples. One hundred and fifty patients were recruited. One hundred and twelve (74.7%) were outpatients, 38 (25.33%) were inpatients, of whom 6 (4%) were in the intensive care unit. Most patients (N = 122, 81.3%) were either COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages 1 or 2. Nine (6%) patients were on systemic steroids, 64 (42.7%) on inhaled steroids, and 9 (6%) on both. Seventeen patients (11.3%) had at least one positive test for Aspergillus detection (culture ± galactomannan ± polymerase chain reaction [PCR]), 13 (76.4%) of whom were COPD GOLD stages 1 or 2.  Five patients had probable or putative IPA. Aspergillus sp. was detected in five patients (3.3%) by culture, but detection increased to 17 (11.3%) by the additional testing for GM or Aspergillus DNA. The frequency of Aspergillus detection in this cohort of COPD patients may reflect the predominance of early GOLD stages among the study population but deserves further investigation to determine its relevance as a predictive risk factor for IPA. LAY SUMMARY: COPD is a risk factor for Aspergillus spp. colonization. Bronchoalveolar lavage samples of 150 COPD patients were tested for presence of Aspergillus fumigatus, which was detected in five patients (3.3%) by culture, but detection of Aspergillus increased to 17 (11.3%) by additional GM and PCR testing.

The prevalence of positive urine dipstick testing and urine culture in the asymptomatic pregnant woman: A cross-sectional study.

OBJECTIVE: Pregnancy induces unique physiological changes to the urinary tract, leaving pregnant women more susceptible to pyelonephritis. Urinary tract infections are generally diagnosed using urine sampling and testing with reagent sticks (dipstick) or laboratory culture. This study aimed to establish the prevalence of positive urine reagent strip and urine culture in asymptomatic pregnant women. STUDY DESIGN: This was a cross-sectional study of 300 women attending routine antenatal clinics. Samples were analysed using an automated urine dipstick analyser for the presence of glucose, protein, leucocyte esterase, blood, and nitrites. All samples were cultured. Multinomial logistic regression was performed to investigate risk factors for urine contamination and infection. Sensitivities and specificities were calculated for common dipstick findings for positive and mixed urine culture. RESULTS: One-in-three (37.0 % [111/300], 95 % CI 31.6-42.8 %) women had at least one positive finding on reagent strip testing. Ten per cent ([29/300], 95 % CI 6.7-13.7 %) of samples had a positive culture for a single organism, whereas 46.7 % ([140/300], 95 % CI 40.9-52.5 %) of samples were positive for multiple organisms (mixed culture). 43.7 % ([131/300], 95 % CI 38.0-49.5 %) of samples had a negative culture. Organisms cultured were similar to previous reports from high-income countries. BMI was identified on regression analysis as a risk factor for contamination. CONCLUSIONS: There is a high prevalence of positive urine dipstick and contaminated culture in asymptomatic pregnant women. BMI is a risk factor for urine culture contamination and further research into this topic is essential given trends in obesity worldwide.

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges.

Aspergillus co-infection in patients with severe coronavirus disease 2019 (COVID-19) pneumonia, leading to acute respiratory distress syndrome, has recently been reported. To date, 38 cases have been reported, with other cases most likely undiagnosed mainly due to a lack of clinical awareness and diagnostic screening. Importantly, there is currently no agreed case definition of COVID-19 associated invasive pulmonary aspergillosis (CAPA) that could aid in the early detection of this co-infection. Additionally, with the global emergence of triazole resistance, we emphasize the importance of antifungal susceptibility testing in order to ensure appropriate antifungal therapy. Herein is a review of 38 published CAPA cases, which highlights the diagnostic and therapeutic challenges posed by this novel fungal co-infection.

Evaluating patient attitudes to increased patient engagement with antimicrobial stewardship: a quantitative survey.

BACKGROUND: Antimicrobial stewardship (AMS) describes interventions designed to optimize antimicrobial therapy, minimize adverse treatment consequences and reduce the spread of antimicrobial resistance (AMR). Previous research has investigated the patient's role in healthcare infection prevention but the patient's role in AMS has not been extensively explored. OBJECTIVES: To investigate the willingness of hospital inpatients to question staff about prudent antimicrobial use in an Irish hospital and evaluate the impact of patient and public involvement in research (PPI) on this study. METHODS: A survey was co-designed with the hospital Patient Representative Group (PRG) to evaluate patient willingness to engage with prudent antimicrobial treatment. A random sample of 200 inpatients was selected to self-complete the survey using pen and paper. PRG members provided feedback on their involvement. RESULTS: Of the 200 inpatients randomly selected to participate, 120 did not fulfil the inclusion criteria. Of the remaining 80, 67 participated (response 84%). Median respondent age was 58 years, 30% were employed and 30% had a third-level education degree. Over 90% had not heard of AMS while just over 50% had not heard of AMR. Patients preferred asking factual questions rather than challenging ones but did not have a preference in asking questions of doctors compared with nurses. Older patients were less likely to ask questions. PRG members reported an overall positive experience as research collaborators. CONCLUSIONS: Future patient-centred AMS interventions should empower patients to ask about antimicrobial treatment, in particular the older patient cohort. PPI is a valuable component of patient-centred research.

ECMM CandiReg-A ready to use platform for outbreaks and epidemiological studies.

BACKGROUND: Recent outbreaks of Candida auris further exemplify that invasive Candida infections are a substantial threat to patients and healthcare systems. Even short treatment delays are associated with higher mortality rates. Epidemiological shifts towards more resistant Candida spp. require careful surveillance. OBJECTIVES: Triggered by the emergence of C auris and by increasing antifungal resistance rates the European Confederation of Medical Mycology developed an international Candida Registry (FungiScope™ CandiReg) to allow contemporary multinational surveillance. METHODS: CandiReg serves as platform for international cooperation to enhance research regarding invasive Candida infections. CandiReg uses the General Data Protection Regulation compliant data platform ClinicalSurveys.net that holds the electronic case report forms (eCRF). Data entry is supported via an interactive macro created by the software that can be accessed via any Internet browser. RESULTS: CandiReg provides an eCRF for invasive Candida infections that can be used for a variety of studies from cohort studies on attributable mortality to evaluations of guideline adherence, offering to the investigators of the 28 ECMM member countries the opportunity to document their cases of invasive Candida infection. CandiReg allows the monitoring of epidemiology of invasive Candida infections, including monitoring of multinational outbreaks. Here, we describe the structure and management of the CandiReg platform. CONCLUSION: CandiReg supports the collection of clinical information and isolates to improve the knowledge on epidemiology and eventually to improve management of invasive Candida infections. CandiReg promotes international collaboration, improving the availability and quality of evidence on invasive Candida infection and contributes to improved patient management.

Post-influenzal triazole-resistant aspergillosis following allogeneic stem cell transplantation.

Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis (IPA). Delays in diagnosis contribute to delayed commencement of antifungal therapy. In addition, the emergence of resistance to first-line triazole antifungal agents puts emphasis on early detection to prevent adverse outcomes. We present 2 allogeneic stem cell transplant patients who developed IPA due to triazole-resistant Aspergillus fumigatus following influenza infection. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.

A prospective study of fungal biomarkers to improve management of invasive fungal diseases in a mixed specialty critical care unit.

PURPOSE: The diagnosis of invasive fungal diseases (IFD) in critical care patients (CrCP) is difficult. The study investigated the performance of a set of biomarkers for diagnosis of IFD in a mixed specialty critical care unit (CrCU). METHODS: A prospective observational study in patients receiving critical care for ≥7days was performed. Serum samples were tested for the presence of: (1-3) - ß-d-glucan (BDG), galactomannan (GM), and Aspergillus fumigatus DNA. GM antigen detection was also performed on bronchoalveolar lavage (BAL) samples. The patients were classified using published definitions for IFD and a diagnostic algorithm for invasive pulmonary aspergillosis. Performance parameters of the assays were determined. RESULTS: In patients with proven and probable IFD, the sensitivity, specificity, PPV and NPV of a single positive BDG were 63%, 83%, 65% and 83% respectively. Specificity increased to 86% with 2 consecutive positive results. The mean BDG value of patients with proven and probable IFD was significantly higher compared to those with fungal colonization and no IFD (p value<0.0001). CONCLUSION: New diagnostic criteria which incorporate these biomarkers, in particular BDG, and host factors unique to critical care patients should enhance diagnosis of IFD and positively impact antifungal stewardship programs.

Determining the analytical specificity of PCR-based assays for the diagnosis of IA: What is Aspergillus?

A wide array of PCR tests has been developed to aid the diagnosis of invasive aspergillosis (IA), providing technical diversity but limiting standardisation and acceptance. Methodological recommendations for testing blood samples using PCR exist, based on achieving optimal assay sensitivity to help exclude IA. Conversely, when testing more invasive samples (BAL, biopsy, CSF) emphasis is placed on confirming disease, so analytical specificity is paramount. This multicenter study examined the analytical specificity of PCR methods for detecting IA by blind testing a panel of DNA extracted from a various fungal species to explore the range of Aspergillus species that could be detected, but also potential cross reactivity with other fungal species. Positivity rates were calculated and regression analysis was performed to determine any associations between technical specifications and performance. The accuracy of Aspergillus genus specific assays was 71.8%, significantly greater (P < .0001) than assays specific for individual Aspergillus species (47.2%). For genus specific assays the most often missed species were A. lentulus (25.0%), A. versicolor (24.1%), A. terreus (16.1%), A. flavus (15.2%), A. niger (13.4%), and A. fumigatus (6.2%). There was a significant positive association between accuracy and using an Aspergillus genus PCR assay targeting the rRNA genes (P = .0011). Conversely, there was a significant association between rRNA PCR targets and false positivity (P = .0032). To conclude current Aspergillus PCR assays are better suited for detecting A. fumigatus, with inferior detection of most other Aspergillus species. The use of an Aspergillus genus specific PCR assay targeting the rRNA genes is preferential.