Using Behavior Change Theory to Identify Drivers and Barriers for Antifungal Treatment Decisions: A Case Study in a Large Teaching Hospital in the East of England, UK.

INTRODUCTION: Antifungal stewardship (AFS) programs are recognized to contribute to optimizing antifungal prescribing for treatment and prophylaxis. However, only a small number of such programs are implemented. Consequently, evidence on behavioral drivers and barriers of such programs and learnings from existing successful AFS programs is limited. This study aimed to leverage a large AFS program in the UK and derive learnings from it. The objective was to (a) investigate the impact of the AFS program on prescribing habits, (a) use a Theoretical Domains Framework (TDF) based on the COM-B (Capability, Opportunity, and Motivation for Behavior) to qualitatively identify drivers and barriers for antifungal prescribing behaviors across multiple specialties, and (c) semiquantitatively investigate trends in antifungal prescribing habits over the last 5 years. METHODS: Qualitative interviews and a semiquantitative online survey were conducted across hematology, intensive care, respiratory, and solid organ transplant clinicians at Cambridge University Hospital. The discussion guide and survey used were developed to identify drivers of prescribing behavior, based on the TDF. RESULTS: Responses were received from 21/25 clinicians. Qualitative outcomes demonstrated that the AFS program was effective in supporting optimal antifungal prescribing practices. We found seven TDF domains influencing antifungal prescribing decisions-five drivers and two barriers. The key driver was collective decision-making among the multidisciplinary team (MDT) while key barriers were lack of access to certain therapies and fungal diagnostic capabilities. Furthermore, over the last 5 years and across specialties, we observed an increasing tendency for prescribing to focus on more targeted rather than broad-spectrum antifungals. CONCLUSIONS: Understanding the basis for linked clinicians' prescribing behaviors for identified drivers and barriers may inform interventions on AFS programs and contribute to consistently improving antifungal prescribing. Collective decision-making among the MDT may be leveraged to improve clinicians' antifungal prescribing. These findings may be generalized across specialty care settings.

Epidemiology, Outcomes and Resource Utilisation in Patients with Carbapenem Non-susceptible Gram-Negative Bacteria in the UK: A Retrospective, Observational Study (CARBAR UK).

INTRODUCTION: Antimicrobial resistance is an urgent medical challenge. In this two-part study, we investigated the epidemiology and management of carbapenem non-susceptible (Carb-NS) Gram-negative bacteria (GNB) in the UK. METHODS: We conducted a retrospective review of data from UK hospitals (ten in part 1, nine in part 2). In part 1, epidemiological data were collected from patients hospitalised between April 2017 and March 2018 with any laboratory detection of Carb-NS GNB, encompassing both colonisation and infection. In part 2, diagnosis and management pathways in a randomly selected population of adults from part 1 with confirmed Carb-NS GNB infection were assessed. Data were obtained from a detailed medical chart review for ≥ 3 months from index (collection date of first positive Carb-NS GNB sample). RESULTS: Of 42,340 GNB isolates from 36,098 patients colonised/infected with GNB in part 1, 7% were Carb-NS. In 157 patients included in part 2, 234 GNB index samples were collected, of which 197 (82%) were Carb-NS (median number of Carb-NS pathogens per patient, 1; range 1-3). The most frequent Carb-NS isolates were Pseudomonas aeruginosa (36%), Stenotrophomonas maltophilia (29%) and Klebsiella pneumoniae (10%). Median length of hospitalisation was 34 days. Median time from index to appropriate therapy was 3 days, with empirical therapy initiated a median of 1 day before index. Carb-NS infection was believed to contribute to 21 (28%) of 76 deaths during the study. CONCLUSIONS: This study highlights the high incidence of Carb-NS GNB colonisation and infection in the UK and the need for improved management of patients with Carb-NS GNB infection.

Understanding and managing common drug interactions.

Drug interactions are common in clinical practice and have a direct effect on patients' morbidity and mortality. However, with the appropriate knowledge they can be avoided. The administration of drugs is an essential nursing task and an increasing number of specialist nurses are also independent prescribers. This article details some of the common patterns of drug-drug interactions and aims to support nurses in optimising patients' medicines use.

Real-World Financial and Clinical Impact of Diagnostic-Driven and Empirical-Treatment Strategies in High-Risk Immunocompromised Patients with Suspected Aspergillus Infection in the United Kingdom.

A diagnostic-driven (DD) treatment strategy has proven successful for treating invasive fungal infections (IFIs) caused by Aspergillus. However, uptake of this treatment strategy is not fully embraced. This study compares the economic and clinical impact of DD and empirical-treatment (ET) strategies used within hospitals. Methods: a decision-analytic model was developed to compare costs and clinical outcomes associated with ET or a DD strategy of identifying infections caused by Aspergillus via galactomannan-antigen testing or Aspergillus polymerase chain reaction (PCR) in neutropenic patients with unexplained fever. Patients were treated prophylactically with antifungal treatments as seen in United Kingdom (UK) hospitals. The IFI incidence, response, mortality, resource use, and adverse events were obtained from meta-analyses and other clinical studies. Analyses were performed from the U.K. hospital perspective, and costs were obtained from standard costing sources. Although diagnostic-testing costs increased, total cost and length of stay were reduced by £1,121 and 1.54 days when treating via a DD strategy. Intensive care and general ward days accounted for > 40% of total costs and > 58% of the cost reduction came from reduced antifungal costs. Treating with a DD strategy reduced the number of patients being treated with antifungal agents while survival was increased. Thus, a DD strategy was cost savings (-£136,787 cost per death avoided) compared with an ET strategy. Conclusion: this study suggests that incorporating a DD strategy as the preferred treatment protocol may be a cost-saving and clinically improved treatment strategy for managing neutropenic patients with unexplained fever. IMPORTANCE Patients at risk of invasive fungal infections (IFIs), such as Aspergillus spp., tend to be immunocompromised and usually take several medications which may generate many side effects. Prescribing is further complicated by comorbidities, drug interactions and challenges accessing diagnostics. Therefore, adding another agent may be neither straightforward nor the best option for these types of patients. A diagnostic-driven (DD) treatment strategy has proven successful for treating IFIs. However, uptake of this treatment strategy is not fully embraced in clinical practice perhaps because this strategy is thought to be more costly and/or to result in higher mortality relative to treating empirically. We developed a decision-analytic model to examine the impact of these 2 strategies on costs and health outcomes. This study indicates that incorporating a DD strategy as the preferred treatment protocol may be a cost-saving and clinically improved treatment strategy for managing neutropenic patients with unexplained fever.

Reimbursement of innovative pharmaceuticals in English and Spanish hospitals-The example of isavuconazole.

BACKGROUND: Kron et al (Mycoses, 64, 2021, 86) found cost savings for the use of the innovative pharmaceutical isavuconazole in the inpatient setting in Germany (Bismarck-based healthcare system). Little is known about the reimbursement of innovative pharmaceuticals in the inpatient setting of Beveridge-based healthcare systems. OBJECTIVES: The aim of this study was to evaluate the market access process and reimbursement of isavuconazole, exemplary for innovative pharmaceuticals, in England and Spain. PATIENTS/METHODS: Market access processes of both countries were described. Focussing on typical patient clusters for isavuconazole treatment, reimbursement data regarding inpatients with (i) allogeneic haematopoietic stem cell transplantation or (ii) acute myeloid leukaemia was considered. Data were publicly available and of high topicality (England 2020/2021, Spain 2018). Discounting and a currency conversion to Euro were applied. RESULTS: This study showed that market access processes of both countries are broadly similar. Further, full reimbursement of isavuconazole as an innovative pharmaceutical may lead to reduction in resource utilisation. Without medication costs, isavuconazole can thus result in cost savings for both patient clusters due to a reduction in length of stay. CONCLUSIONS: Expenses for innovative pharmaceuticals may be balanced or even lead to cost savings due to a reduction in length of stay. The latter contributes to a greater patient benefit. For both healthcare system, the analyses highlighted drugs' cost-effectiveness and assessing its added value into reimbursement decisions is highly relevant.

National mycology laboratory diagnostic capacity for invasive fungal diseases in 2017: Evidence of sub-optimal practice.

A survey of laboratory testing capabilities for systemic fungal pathogens was undertaken in the UK, to identify where improved compliance with published standards and guidelines is required and to inform antifungal stewardship (AFS). The survey captured information from laboratories in the UK on diagnostic capacity for invasive fungal diseases (IFD), including identification, serology, molecular diagnostics and susceptibility testing. The survey was circulated in March 2017 through key networks. Of 154 laboratories providing diagnostic mycology services in the UK, 80 (52%) responded to the survey. Results indicated that 85% of respondents identified fungal isolates from high risk patients to species level, and that many laboratories (78%) could access local susceptibility testing for yeasts, whereas 17% could for Aspergillus species. However, direct microscopy was only used in 49% as a first line investigation on samples where it would be appropriate. A low number of respondents identified yeasts cultured from intravascular line tips to species level (63%) and even fewer fully identified urine isolates from critically ill patients (42%) or the immunocompromised (39%). Less than half of respondents advised therapeutic drug monitoring (TDM) for flucytosine. Few laboratories had access to local ß-glucan (4%) or galactomannan (20%) testing. The survey highlights that the current level of fungal diagnostics in the UK is below accepted best practice with an urgent need to improve across many diagnostic areas including the timely accessibility of fungal biomarkers, susceptibility testing and provision of TDM testing. Improvements are important to facilitate the delivery of diagnostic driven AFS strategies as well as appropriate management of IFD.

A whole-health-economy approach to antimicrobial stewardship: Analysis of current models and future direction.

In a Policy Forum, Alison Holmes and colleagues discuss coordinated approaches to antimicrobial stewardship.

Micafungin use in a UK tertiary referral hospital.

OBJECTIVES: Here we sought to describe the real-life usage of micafungin in a UK tertiary referral hospital. METHODS: A prospective, non-interventional, observational surveillance study was performed. RESULTS: Micafungin was commenced in 174 courses involving 148 patients to treat invasive candidiasis and candidaemia (132 courses) and aspergillosis in situations where alternatives such as voriconazole or liposomal amphotericin B could not be used (42 courses). Fungal infection was defined as proven as per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) guidelines in 84 courses (48.3%). Micafungin was well tolerated; 10 patients (6.8%) developed a rise in alanine aminotransferase (ALT) and only 1 patient stopped therapy due to this. Therapy was rationalised to fluconazole in 77 courses (44.3%). There were no differences in intensive care unit admission or deaths when comparing all 174 courses where patients received micafungin for Aspergillus and Candida infection, respectively [49% vs. 42% (P=0.82) and 24% vs. 15% (P=0.186)]. One patient developed disseminated mucormycosis and four patients had recurrent candidaemia (attributed to poor source control) while receiving micafungin. CONCLUSIONS: Micafungin was clinically effective for the treatment of invasive Candida and Aspergillus infections, and usage did not increase the risk of liver dysfunction even in patients with abnormal ALT at baseline.

Fatal breakthrough mucormycosis in a multivisceral transplant patient receiving micafungin: Case report and literature review.

Introduction: Antifungal agents are routinely used in the post-transplant setting for both prophylaxis and treatment of presumed and proven fungal infections. Micafungin is an echinocandin-class antifungal with broad antifungal cover and favorable side effect profile but, notably, it has no activity against molds of the order Mucorales. Presentation of case: A 47-year-old woman underwent multivisceral transplantation for intestinal failure-associated liver disease. She had a prolonged post-operative recovery complicated by invasive candidiasis and developed an intolerance to liposomal amphotericin B. In view of her immunosuppression, she was commenced on micafungin as prophylaxis to prevent invasive fungal infection. However, she developed acute graft versus host disease with bone marrow failure complicated by disseminated mucormycosis which was only diagnosed post mortem. Discussion: Non-Aspergillus breakthrough mold infections with micafungin therapy are rare with only eight other cases having been described in the literature. Breakthrough infections have occurred within one week of starting micafungin. Diagnosis is problematic and requires a high degree of clinical suspicion and microscopic/histological examination of an involved site. The management of these aggressive infections involves extensive debridement and appropriate antifungal cover. Conclusion: A high level of suspicion of invasive fungal infection is required at all times in immunosuppressed patients, even those receiving antifungal prophylaxis. Early biopsy is required. Even with early recognition and aggressive treatment of these infections, prognosis is poor.

An investigation of antifungal stewardship programmes in England.

PURPOSE: We sought to explore the current status of antifungal stewardship (AFS) initiatives across National Health Service (NHS) Trusts within England, the challenges and barriers, as well as ways to improve current AFS programmes. METHODOLOGY: An electronic survey was sent to all 155 acute NHS Trusts in England. A total of 47 Trusts, corresponding to 30 % of English acute Trusts, responded to the the survey; 46 Trusts (98 %) had an antimicrobial stewardship (AMS) programme but only 5 (11 %) had a dedicated AFS programme. Overall, 20 (43 %) Trusts said they included AFS as part of their AMS programmes. From those conducting AFS programmes, 7 (28 %) have an AFS/management team, 16 (64 %) monitor and report on antifungal usage, 5 (20 %) have dedicated AFS ward rounds and 12 (48 %) are directly involved in the management of invasive fungal infections.Results/Key findings. Altogether, 13 acute Trusts (52 %) started their AFS programme to manage costs, whilst 12 (48 %) commenced the programme due to clinical need; 27 (73 %) declared that they would increase their AFS initiatives if they could. Of those without an AFS programme, 14 (67 %) responded that this was due to lack of resources/staff time. Overall, 12 Trusts (57 %) responded that the availability of rapid diagnostics and clinical support would enable them to conduct AFS activities. CONCLUSION: Although a minority of Trusts conduct dedicated AFS programmes, nearly half include AFS as part of routine AMS activities. Cost issues are the main driver for AFS, followed by clinical need. The availability of rapid diagnostics and clinical support could help increase AFS initiatives.

Secondary use of data from hospital electronic prescribing and pharmacy systems to support the quality and safety of antimicrobial use: a systematic review.

Background: Electronic prescribing (EP) and electronic hospital pharmacy (EHP) systems are increasingly common. A potential benefit is the extensive data in these systems that could be used to support antimicrobial stewardship, but there is little information on how such data are currently used to support the quality and safety of antimicrobial use. Objectives: To summarize the literature on secondary use of data (SuD) from EP and EHP systems to support quality and safety of antimicrobial use, to describe any barriers to secondary use and to make recommendations for future work in this field. Methods: We conducted a systematic search within four databases; we included original research studies that were (1) based on SuD from hospital EP or EHP systems and (2) reported outcomes relating to quality and/or safety of antimicrobial use and/or qualitative findings relating to SuD in this context. Results: Ninety-four full-text articles were obtained; 14 met our inclusion criteria. Only two described interventions based on SuD; seven described SuD to evaluate other antimicrobial stewardship interventions and five described descriptive or exploratory studies of potential applications of SuD. Types of data used were quantitative antibiotic usage data ( n = 9 studies), dose administration data ( n = 4) and user log data from an electronic dashboard ( n = 1). Barriers included data access, data accuracy and completeness, and complexity when using data from multiple systems or hospital sites. Conclusions: The literature suggests that SuD from EP and EHP systems is potentially useful to support or evaluate antimicrobial stewardship activities; greater system functionality would help to realize these benefits.

Overexpression of antibiotic resistance genes in hospital effluents over time.

Objectives: Effluents contain a diverse abundance of antibiotic resistance genes that augment the resistome of receiving aquatic environments. However, uncertainty remains regarding their temporal persistence, transcription and response to anthropogenic factors, such as antibiotic usage. We present a spatiotemporal study within a river catchment (River Cam, UK) that aims to determine the contribution of antibiotic resistance gene-containing effluents originating from sites of varying antibiotic usage to the receiving environment. Methods: Gene abundance in effluents (municipal hospital and dairy farm) was compared against background samples of the receiving aquatic environment (i.e. the catchment source) to determine the resistome contribution of effluents. We used metagenomics and metatranscriptomics to correlate DNA and RNA abundance and identified differentially regulated gene transcripts. Results: We found that mean antibiotic resistance gene and transcript abundances were correlated for both hospital ( ρ = 0.9, two-tailed P <0.0001) and farm ( ρ = 0.5, two-tailed P <0.0001) effluents and that two ß-lactam resistance genes ( bla GES and bla OXA ) were overexpressed in all hospital effluent samples. High ß-lactam resistance gene transcript abundance was related to hospital antibiotic usage over time and hospital effluents contained antibiotic residues. Conclusions: We conclude that effluents contribute high levels of antibiotic resistance genes to the aquatic environment; these genes are expressed at significant levels and are possibly related to the level of antibiotic usage at the effluent source.

The Changing Epidemiology of Invasive Fungal Infections.

Invasive fungal infections (IFI) are an emerging problem worldwide with invasive candidiasis and candidemia responsible for the majority of cases. This is predominantly driven by the widespread adoption of aggressive immunosuppressive therapy among certain patient populations (e.g., chemotherapy, transplants) and the increasing use of invasive devices such as central venous catheters (CVCs). The use of new immune modifying drugs has also opened up an entirely new spectrum of patients at risk of IFIs. While the epidemiology of candida infections has changed in the last decade, with a gradual shift from C. albicans to non-albicans candida (NAC) strains which may be less susceptible to azoles, these changes vary between hospitals and regions depending on the type of population risk factors and antifungal use. In certain parts of the world, the incidence of IFI is strongly linked to the prevalence of other disease conditions and the ecological niche for the organism; for instance cryptococcal and pneumocystis infections are particularly common in areas with a high prevalence of HIV disease. Poorly controlled diabetes is a major risk factor for invasive mould infections. Environmental factors and trauma also play a unique role in the epidemiology of mould infections, with well-described hospital outbreaks linked to the use of contaminated instruments and devices. Blastomycosis is associated with occupational exposure (e.g., forest rangers) and recreational activities (e.g., camping and fishing).The true burden of IFI is probably an underestimate because of the absence of reliable diagnostics and lack of universal application. For example, the sensitivity of most blood culture systems for detecting candida is typically 50 %. The advent of new technology including molecular techniques such as 18S ribosomal RNA PCR and genome sequencing is leading to an improved understanding of the epidemiology of the less common mould and dimorphic fungal infections. Molecular techniques are also providing a platform for improved diagnosis and management of IFI.Many factors affect mortality in IFI, not least the underlying medical condition, choice of therapy, and the ability to achieve early source control. For instance, mortality due to pneumocystis pneumonia in HIV-seronegative individuals is now higher than in seropositive patients. Of significant concern is the progressive increase in resistance to azoles and echinocandins among candida isolates, which appears to worsen the already significant mortality associated with invasive candidiasis. Mortality with mould infections approaches 50 % in most studies and varies depending on the site, underlying disease and the use of antifungal agents such as echinocandins and voriconazole. Nevertheless, mortality for most IFIs has generally fallen with advances in medical technology, improved care of CVCs, improved diagnostics, and more effective preemptive therapy and prophylaxis.

Patient and public understanding and knowledge of antimicrobial resistance and stewardship in a UK hospital: should public campaigns change focus?

BACKGROUND: The rising global tide of antimicrobial resistance is a well-described phenomenon. Employing effective and innovative antimicrobial stewardship strategies is an essential approach to combat this public health threat. Education of the public and patients is paramount to enable the success of such strategies. METHODS: A panel of hospital multidisciplinary healthcare professionals was set up and a short quiz containing true/false statements around antimicrobial stewardship and resistance was designed and piloted. An educational leaflet with the correct replies and supporting information was also produced and disseminated. Participants were recruited on a single day (18 November 2015) from the hospital outpatient clinics and the hospital outpatient pharmacy waiting room. RESULTS: One hundred and forty-five completed quizzes were returned, providing a total of 1450 answers. Overall, 934 of 1450 (64%) statements were scored correctly whilst 481 (33%) were scored incorrectly; 35 (3%) statements were left unscored. We speculate that these results may demonstrate that respondents understood the statements, as only a small proportion of statements were left unanswered. The question dealing with the definition of antimicrobial resistance and the question dealing with the definition of antimicrobial stewardship obtained the most incorrect replies (85% and 72%, respectively). However, a specific factual recall question regarding only one microorganism (MRSA) received the most correct responses (99%). CONCLUSIONS: We describe a simple, innovative method of engagement with patients and the general public to help educate and disseminate important public health messages around antimicrobial resistance and stewardship. We also identified the need for public health campaigns to address the knowledge gaps found around this topic.

An Evidence-Based Antimicrobial Stewardship Smartphone App for Hospital Outpatients: Survey-based Needs Assessment Among Patients.

BACKGROUND: Current advances in modern technology have enabled the development and utilization of electronic medical software apps for both mobile and desktop computing devices. A range of apps on a large variety of clinical conditions for patients and the public are available, but very few target antimicrobials or infections. OBJECTIVE: We sought to explore the use of different antimicrobial information resources with a focus on electronic platforms, including apps for portable devices, by outpatients at two large, geographically distinct National Health Service (NHS) teaching hospital trusts in England. We wanted to determine whether there is demand for an evidence-based app for patients, to garner their perceptions around infections/antimicrobial prescribing, and to describe patients' experiences of their interactions with health care professionals in relation to this topic. METHODS: A cross-sectional survey design was used to investigate aspects of antimicrobial prescribing and electronic devices experienced by patients at four hospitals in London and a teaching hospital in the East of England. RESULTS: A total of 99 surveys were completed and analyzed. A total of 82% (80/98) of respondents had recently been prescribed antimicrobials; 87% (85/98) of respondents were prescribed an antimicrobial by a hospital doctor or through their general practitioner (GP) in primary care. Respondents wanted information on the etiology (42/65, 65%) and prevention and/or management (32/65, 49%) of their infections, with the infections reported being upper and lower respiratory tract, urinary tract, oral, and skin and soft tissue infections. All patients (92/92, 100%) desired specific information on the antimicrobial prescribed. Approximately half (52/95, 55%) stated it was "fine" for doctors to use a mobile phone/tablet computer during the consultation while 13% (12/95) did not support the idea of doctors accessing health care information in this way. Although only 30% (27/89) of respondents reported on the use of health care apps, 95% (81/85) offered information regarding aspects of antimicrobials or infections that could be provided through a tailored app for patients. Analysis of the comments revealed the following main global themes: knowledge, technology, and patient experience. CONCLUSIONS: The majority of respondents in our study wanted to have specific etiological and/or infection management advice. All required antimicrobial-related information. Also, most supported the use of electronic resources of information, including apps, by their doctors. While a minority of people currently use health apps, many feel that apps could be used to provide additional support/information related to infections and appropriate use of antimicrobials. In addition, we found that there is a need for health care professionals to engage with patients and help address common misconceptions around the generation of antimicrobial resistance.

Antimicrobial stewardship: the role of the nurse.

Infections caused by organisms resistant to multiple drugs are associated with morbidity and mortality, prolonged hospital stay and increased costs. Since antibiotic use is the main factor in the development of resistance, it is hoped that the judicious use of antibiotics will reduce the emergence of antimicrobial resistance. This article addresses antibiotic misuse in the inpatient setting and outlines the role of the nurse in optimising antibiotic therapy through antimicrobial stewardship.