Intrinsic Antifungal Resistance

1. Scope

The Working Group will focus on fungal pathogens that exhibit intrinsic (innate) antifungal resistance or markedly reduced susceptibility to one or more major antifungal drug classes. While Aspergillus terreus will remain a key model organism, the group will broaden its activities to encompass a wider range of clinically relevant, uncommon or emerging fungal species with intrinsic antifungal resistance profiles, e.g. selected uncommon species of Aspergillus, Candida, Fusarium, Scedosporium, Lomentospora, and other rare yeast and molds).

2. Background and Rationale

Intrinsic antifungal resistance is increasingly recognised as a major challenge in the management of invasive fungal infections. Unlike acquired resistance, innate resistance is a stable, species- or complex-level trait that is present in wild-type isolates and restricts therapeutic options from the outset. This has important consequences for empirical treatment, antifungal stewardship and clinical outcomes.

Recent ecological and climate-driven shifts have led to the global emergence and wider geographic distribution of previously uncommon fungal species, some of which display innate resistance to one or more antifungal classes. These trends underscore the urgent need to systematically map and understand innate resistance beyond traditional model organisms.

In parallel, the development of several novel antifungal agents and classes highlights the need for harmonized susceptibility testing frameworks that include emerging and innately resistant species. Evaluating the activity spectra of new compounds against rare yeasts and moulds with intrinsic resistance will be critical for defining therapeutic potential, guiding clinical breakpoints, and informing antifungal pipeline development.

The current ISHAM A. terreus Working Group has already provided a successful platform for international collaboration, focusing on surveillance, susceptibility testing and basic research on the characteristic reduced susceptibility of A. terreus to amphotericin B. These efforts have highlighted:

• The complex and multifactorial nature of innate resistance mechanisms.
• The limitations of current susceptibility testing and interpretive criteria for innately resistant terreus species.
• The clinical impact of infections caused by species with few effective antifungal options.

Expanding this existing Working Group into a broader ISHAM Working Group on innate antifungal resistance is therefore a logical and strategic progress. It will preserve the expertise and momentum of A. terreus network while establishing a structured forum to address innate resistance across multiple genera, in close alignment with other ISHAM and ECMM initiatives on antifungal resistance, diagnostics and guidelines.

3. Mission and Main Objectives

Mission Statement

The ISHAM Working Group on Innate Antifungal Resistance aims to elucidate the mechanisms, epidemiology and clinical impact of intrinsic antifungal resistance in human and animal pathogenic fungi, and to translate this knowledge into improved diagnostics, treatment strategies and guidelines.

Objectives

3.1. Scientific and mechanistic objectives

• Define and regularly update a catalogue of innately resistant fungal pathogens and their characteristic resistance patterns across antifungal classes.
• Promote and coordinate multicentre omic studies (genomic, transcriptomic, proteomic and metabolomics) to identify conserved and species-specific mechanisms of innate resistance.
• Develop and share standardized in vitro and in vivo models, including host–pathogen interaction and biofilm models, for studying innate resistance and evaluating novel antifungal strategies.

3.2. Clinical, diagnostic and surveillance objectives

• Harmonize antifungal susceptibility testing and reporting innately resistant fungi, and provide practical recommendations for clinical laboratories.
• Conduct multicentre clinical studies to assess incidence, risk factors, treatment approaches and outcomes of infections caused by innately resistant species.
• Integrate innate resistance into existing ISHAM/ECMM surveillance activities to ensure consistent global reporting and interpretation.

3.3. Network, education and guideline-related objectives

• Expand the current terreus network into an international consortium on innate antifungal resistance, facilitating exchange of isolates, protocols and data.
• Organise workshops, webinars and dedicated sessions at ISHAM and affiliated meetings to disseminate knowledge on identification, laboratory handling and clinical management of innately resistant fungi.
• Provide expert input to national and international guideline committees, ensuring that concepts of innate resistance and the specific challenges posed by these pathogens are reflected in diagnostic and therapeutic recommendations.

4. Planned Deliverables (First 3–5 Years)

• A position paper defining innate antifungal resistance and listing key innately resistant pathogens, including terreus as a model species.
• A set of standard operating procedures for susceptibility testing and reporting of selected innately resistant fungi.
• At least one multicentre clinical or epidemiological study on infections due to innately resistant species, building on the existing A. terreus datasets.
• A curated isolate collection or virtual biobank linked to a shared database to support ongoing and future research.

5. Continuity and Organisation
The new Working Group will be built directly on the structure and membership of the existing ISHAM A. terreus Working Group, ensuring continuity of leadership, ongoing projects and collaborations. The coordinating team will include experts in clinical mycology, medical microbiology, basic science and epidemiology, with an open invitation to additional centres interested in the topic of innate antifungal resistance.