Antifungal stewardship (AFS) is the judicious use of today’s antifungal agents with the aim of improving patient outcomes and preserving their future effectiveness. Antifungal resistance (AFR) is increasing globally, with more patients at risk of Invasive Fungal Disease (IFD), highlighting the urgent need to standardize AFS practices in the UK. The aim of this position paper is to understand the current AFS landscape in the UK.
A virtual panel discussion was held from September to October 2023 on an online platform followed by a virtual meeting with nine healthcare professionals from across the UK selected for their expertise on IFD management and AFS. The discussion was structured across four topics: current AFS landscape, key elements of an AFS programme, diagnostics and diagnostic stewardship, and unmet needs in education and training. A thematic analysis was carried out. The results represent the collated and summarized views from these activities.
Participants reported barriers to implementing AFS and its integration within antimicrobial stewardship (AMS) programmes in the UK. The primary challenge identified was a lack of resources, including funding and staff time. Sub-optimal fungal diagnostics and limited mycology expertise was reported as a barrier to AFS, clinical IFD and AFR surveillance. Approaches to combatting these challenges may include investing in formal mycology networks to serve as centres of clinical expertise and diagnostic hubs.
National standards for AFS services and associated outcome metrics need to be established to set a benchmark for centres to improve AFS.
Invasive fungal diseases (IFD) are increasing globally, with recent estimates suggesting an annual incidence of 6.5 million invasive fungal infections and 3.8 million deaths.
Antimicrobial stewardship (AMS) is a systematic approach to educate and support healthcare professionals to follow evidence-based guidelines for the optimal prescribing and administering antimicrobials with the aim of improving patient outcomes while preserving the future effectiveness of antimicrobial agents.
In 2017, a survey of 47 NHS Trusts in England showed that only 11% had a dedicated AFS programme.
In 2022, the WHO published its first Fungal Priority Pathogen List. This list aims to raise public awareness of fungal disease and AFR and to drive global action. A major driver in determining pathogen priority was the potential for AFR.
A virtual panel discussion was held over an 8-week period between 4 September 2023 and 23 October 2023. See Figure
Participants and methods.
Nine participants were selected in total, one participant did not take part in the text-based discussion but attended the virtual meeting. Three publications were given to each advisor as pre-reads.
Participants unanimously agreed that since 2017, when only 43% of Trusts included AFS as part of their AMS programmes,
When asked to consider whether AFS programmes should be independent of AMS programmes, participants believed that it is important to link AFS with AMS, but that AFS must retain its identity within AMS, rather than be engulfed by it. Participants reported that there are many barriers to both implementing AFS and its integration within AMS programmes. The primary challenge identified by participants was a lack of resources, both financial and staff time, echoing the responses to a 2017 survey of NHS Trusts.
Participants observed that there is a lack of staff expertise in IFD and antifungal management in the UK. Low numbers of specialist mycology laboratory and clinical staff and lack of expertise, even among specialists in infection, makes implementing AFS difficult. Participants also highlighted the importance of having more than one mycology or AFS champion within a Trust to ensure the sustainability of AFS programmes. Participants reported that there is a paucity of on-site or nearby laboratories with sufficient mycological diagnostic and antifungal therapeutic drug monitoring (TDM) capacity at UK Trusts. A lack of joined-up services across the UK, frequently results in samples needing to be sent off-site to larger laboratories or reference centres leading to long turnaround times. It was suggested that the centralization of many laboratories, and a public–private provider divide may be partly responsible for this. This variability in access to fungal diagnostics and mycology expertise across the UK may lead to inequitable access for patients to a diagnosis and appropriate treatment in a reasonable timeframe.
Participants proposed that core activities for AFS teams in the UK should be at a minimum providing clinical support and expertise on IFD management (including starting/stopping and choice of antifungal, advice on drug-drug interactions (DDIs), TDM and appropriate diagnostics) facilitated via virtual or in-person ward rounds on at least a weekly basis. The creation, implementation and regular updating of guidelines, providing training and education on AFS and IFD management, and carrying out clinical audit were also suggested as core activities of any AFS team.
There was agreement among participants that the minimum core members of the AFS team are a microbiology/infectious disease consultant and a specialist AMS pharmacist. The core members of the AFS MDT would ideally also include a healthcare scientist with fungal diagnostic expertise, a radiologist, a data analyst and a member of the specialist clinical team looking after the patient, who are essential for providing clinical context and without whose buy-in meaningful decisions would not be possible. See Figure
Proposed members of the core AFS team and AFS MDT. ID, infectious disease.
The role of the infection prevention and control team in AFS was considered to be primarily related to outbreak management (e.g.
One participant highlighted that a potential limitation of AFS programmes is that they tend to focus on those already being treated with an antifungal, missing high risk patients where IFI is not being considered due to lack of expertise. This highlights the need for clinical teams to be educated on the risk factors for fungal disease in their patient cohort.
Participants unanimously agreed that in their experience there were barriers to implementing local antifungal guidelines. The primary barriers reported by participants were again a lack of resources, particularly time available for guideline creation and implementation, as well as lack of staff with sufficient expertise. From a clinical perspective, antifungals are often started empirically and therefore it is challenging to make recommendations for when to cease antifungal treatment in the absence of timely diagnostics. Multiple participants highlighted the need for frequent users of the guideline (e.g. haematology and ICU) to be involved in guideline creation to ensure applicability and future adherence. It was reported that implementing guidelines for empiric therapy can be more challenging than for proven infection (a rarity for most IFD), particularly in settings where on-site diagnostics are unavailable, meaning patients can remain on empiric therapy for prolonged periods until results are available. As with AMS, behavioural change was reported as a challenge to implementing AFS guidelines.
Participants were also asked to give their opinion on whether there is a need for national antifungal guidelines in the UK. All agreed that international guidelines are useful, and some believed these are sufficient to negate the need for national guidelines. However, others proposed that a national action plan or executive summary may be beneficial to raise awareness of IFDs among UK healthcare professionals, collating key points from across international guidelines into a single source for fungal pathogens most relevant to the UK. It was also suggested that guidelines with minimum recommendations for fungal diagnostic and TDM capabilities and minimum staffing for AFS roles for specific healthcare settings with at-risk groups would be of value. Participants highlighted that the British Society of Medical Mycology is currently updating its best practice guidelines for diagnostics and TDM which will help to fill this gap.
The true burden of fungal disease needs to be demonstrated to incentivize investment in AFS. Participants were asked about barriers to carrying out surveillance on fungal infections, resistance and antifungal consumption. Carrying out clinical surveillance of fungal infections is challenging primarily due to sub-optimal diagnostics with limited proven definitive diagnoses, meaning often only a possible or probable diagnosis can be achieved. The use of biomarkers is increasingly critical to the diagnosis of IFD, and local availability of these tests is highly variable.
The lack of widespread laboratories with capacity to identify and speciate fungi, perform antifungal susceptibility testing (AST) and in the case of moulds lack of a cultured pathogen, and subsequent challenges with result reporting- were all barriers reported to IFD surveillance. To address this, it was suggested that certain priority fungal pathogens (e.g.
Resistance surveillance challenges reported overlapped with those affecting disease surveillance. The variability in access to AST in the UK was highlighted in a 2017 survey of mycology laboratory diagnostic capacity that showed only 55% of survey respondents performed susceptibility testing of yeasts on-site or at their centralized hub.
Antifungal consumption data was considered the most achievable metric to report on for AFS programmes, however, its usefulness is limited by the fact that it is not linked to clinical data to indicate whether the antifungals are being used for empiric, targeted or prophylactic treatment. There is also a lack of a clear meaningful denominator to compare across centres and assess trends over time.
AMS metrics are usually reported to senior management in NHS Trusts, however, the most important outcomes to measure for AFS are unclear. Participants unanimously agreed that patient outcomes should be measured in any AFS programmes with metrics such as length of hospital stay, adverse drug reactions and in-hospital mortality suggested. Other outcomes suggested were guideline adherence, trends in fungal epidemiology including resistance data (e.g. for invasive candidiasis), antifungal consumption per occupied bed days, number of DDIs identified and indication for antifungal use. Cost-effectiveness outcomes were also highlighted as being very important at Trust level. Participants suggested outcome data at a national level could be reported to the UK Health Security Agency (UKHSA) and at a Trust level AFS data should be integrated into the annual AMS report. Ultimately, for Trusts to benchmark their AFS activities, national standards need to be set out.
The diagnosis of IFD is challenging with often only a probable or possible diagnosis achieved based on a combination of host, mycological and clinical criteria.
Participants acknowledged that requirements around diagnostic capability vary according to population. Participants were asked what the minimum fungal diagnostic capabilities should be in the UK, based on a hospital setting, and their suggestions are outlined in Table
Suggested mycology laboratory diagnostic capabilities and turnaround times by hospital settings for fungal disease, excluding dermatophyte infections
| District general hospital (DGH) | Teaching hospital (TH) | Specialist centres (e.g. sizeable haematology-oncology population) | |||
|---|---|---|---|---|---|
| Diagnostics | Turnaround times | Diagnostics | Turnaround times | Diagnostics | Turnaround times |
|
Microscopy Culture/ID of very common fungi Histology optimized for fungal recovery/ID Access to ID and susceptibility testing and TDM via a referred service |
Culture and Histology: in line with guidelines (with allowance for extended incubation) Microscopy: 24 h in line with guidelines (with allowance for extended incubation) |
As per DGH but also to include; CrAg LFA Simplified BDG testing (e.g. STAT) Ability to ID common fungi Access to further ID and susceptibility testing and TDMb |
CrAg LFA: 24 h
Simplified BDG testing (e.g. STAT):72 h |
As per DGH and TH but also to include; GM-EIA BDG testing Pneumocystis PCR Candida PCRb with support of reference laboratory Local access to susceptibility for yeasts and moulds with support of reference laboratory Access to TDM Ability to locally ID some uncommon yeasts and common moulds with support of reference laboratory |
GM-EIA: 48 h BDG: 48 h
Pneumocystis PCR: 48–72 h Candida PCR: 48–72 h |
ID, identification; CrAg, cryptococcal antigen; LFA, lateral flow assay; BDG, (1,3)-β-D-glucan; GM-EIA, Galactomannan enzyme immunoassay; PCR, polymerase chain reaction.
aVery common fungi such as
bSend away service is minimal requirement.
cCommon fungi may include very common fungi as before plus additional
dTo include common ID of fungi as above and additionally differentiate
Challenges were also highlighted in relation to AST and TDM. As discussed, AST is rarely set up in local laboratories and often considered too specialist, with staff generally lacking the appropriate mycology expertise and training with generic healthcare scientists only having a theoretical basic knowledge of the field. Participants suggested that susceptibility testing may only be performed when there is a lack of treatment response, leading to potential data bias. A significant barrier to TDM is the infrastructure required to set up a local service and subsequent time delays when samples must be sent away. This is compounded by limited awareness of when TDM is required. The establishment of regional fungal diagnostic hubs may address these delays. Additionally, embedding TDM guidance within an electronic prescribing system with prompts to support appropriate and timely requests was suggested to mitigate this.
Participants discussed the implementation of a diagnostic-driven or pre-emptive approach to antifungal management in the UK. A diagnostic-driven strategy has already been implemented at some centres both in the UK and globally whereby fungal biomarkers or computed tomography imaging are used to direct treatment, rather than commencing antifungals empirically. Participants acknowledged that there is sufficient evidence to support this approach in certain patient cohorts such as haemato-oncology patients.
Education for clinicians is critical to improving AFS. Participants agreed that education on IFDs at an undergraduate level in medicine and pharmacy would introduce an awareness of mycology and AFS at an early stage. To increase the level of expertise within AMS teams, peer-to-peer training for clinicians and healthcare scientists with a specialist interest in infection such as AMS pharmacists and infectious disease trainees would be beneficial. This may include experts presenting and leading teaching rounds in established centres. The priority education topics for AFS suggested were fungal pathogens, monitoring parameters including TDM and diagnostic approaches and criteria.
Participants agreed that virtual educational materials are the most useful to educate HCPs on IFD and AFS. Both apps and online resources were highlighted as valuable formats to deliver these materials. There are currently several online resources available to support healthcare professionals with implementing AFS programmes
Pooling expertise was considered important for supporting the management of complex patients. Useful methods reported included the setting up of regional networks, creating useful contact lists for clinical queries and virtual ward rounds led by expert personnel. Participants agreed that MDT-led approaches for complex patients provide great benefit, where they are currently in place, and the set-up of more, well organized and sufficiently funded regional networks would be of value. Pooling expertise by spotlighting centres where the AFS model is working effectively across teams was proposed as an approach to benchmark AFS activities within the NHS. Currently, no national education standards exist for AMS, including AFS: implementing accreditation that individuals or Trusts could work towards may support improved AFS practices in the UK.
Patient education was also highlighted as a gap. Across the UK there is a paucity of information for patients receiving antifungals either for treatment or prophylaxis. Participants advised they are not aware of any safety-netting materials for immunosuppressed patients at risk of developing an IFD when they are discharged home, e.g. advice to avoid building work or composting/gardening. Addressing this gap may improve patient and physician awareness of IFDs, encourage health advocacy and optimize AFS. It was suggested that counselling patients on their antifungal treatment plan, when it will be reviewed and potential switches available to them, would be an effective approach.
The findings from this panel discussion suggest that progress in the AFS landscape since 2017 in the UK has been limited. Lack of financial and staffing resources were reported as the main barriers to implementing AFS activities. Moreover, there is inadequate access to fungal diagnostic results within an acceptable timeframe. Mycology expertise is lacking even among laboratory and clinical infection specialists. Approaches to combatting these challenges may include setting up formal mycology networks across the country and linking them to regional diagnostic hubs to ensure all sites have access to mycology expertise and timely diagnostic results. The establishment of maximum acceptable turnaround times may support better practice. Making certain fungal pathogens notifiable would support AFR surveillance and outbreak management. Progress is being made, however, the ESPAUR fungal subgroup has recently been re-established in England and new BSMM guidelines on best practice for diagnosis and TDM are being revised. Additionally, UK Research and Innovation has recently awarded funding to eight new research networks tackling AMR, of which one is focussed on fungal disease. Globally the Joint Programming Initiative on AMR (JPIAMR) is supporting an international Fungal Network for antifungal resistance surveillance as well as funding for other initiatives to detect and mitigate of AFR. Antifungal research and development, as well as data on surveillance and real-world usage to inform stewardship of new to market antifungal agents is imperative to combatting AFR. To this end, inclusion of antifungals within the UK Antimicrobial Registry (UKAR)
This panel discussion and paper was funded by Pfizer Ltd. The text-based platform services were provided by medCrowd (part of medDigital Ltd).
External authors were not reimbursed for their authorship of this paper.
T.F. is supported by the Manchester NIHR Biomedical Research Centre. C.M. has received an educational grant and consultancy fees from Pfizer. S.S. has received honorarium from Gilead Sciences and Pfizer for educational activities. N.T. has received consultancy fees and speaker fees for NAPP, consultancy fees from Pfizer Ltd and received a travel grant from Gilead Sciences. P.L.W. has performed diagnostic evaluations and received meeting sponsorship from Associates of Cape Cod, Bruker, Dynamiker and Launch Diagnostics; speaker fees, expert advice fees and meeting sponsorship from Gilead; and speaker and expert advice fees from F2G. T.B. has received speaker fees from Gilead Sciences, Pfizer and Mundipharma, research grants from Pfizer, Gilead and MSD and Advisory Board fees from Mundipharma and Pfizer. S.A. has received consultancy, advisory board and speaker fees and received grant funding from Pfizer, Gilead, NAPP-Mundi Pharma, Shionogi and Hikma. A.B. has received financial sponsorship in support of educational events from Shionogi, Tillotts Pharma, MSD and Pfizer, received grants for clinical/academic projects from Pfizer and consultancy fees from NAPP and Pfizer. G.K., Z.R. and E.H. are employees of Pfizer Ltd. G.K. and Z.R. hold shares in Pfizer Inc.