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Resistance to antifungal treatment is growing

3D image of Mucorales

Resistance to antifungals is growing1-3

Resistance to azoles and echinocandins is increasing worldwide,4,5 and antifungal prophylaxis has led to a variety of rare and resistant breakthrough infections.3,6 With these life-threatening and difficult-to-treat fungal infections on the rise, could resistance levels soon become a global health emergency?

Microscopic image of pink and blue fungal pathogens in a Petri dish setting

WHAT IS INTRINSIC RESISTANCE VS. ACQUIRED RESISTANCE?

Fungi may be primarily resistant to the action of antifungal drugs (intrinsic resistance), or they may be initially susceptible but develop secondary mechanisms of resistance after exposure to antifungals and the selection of resistant clones (acquired resistance).7

Examples of fungal species that demonstrate acquired resistance:

  • Candida glabrata to fluconazole
  • Aspergillus fumigatus to azoles

Examples of fungal species that demonstrate intrinsic resistance:

  • Candida krusei and Aspergillus species to fluconazole
  • Cryptococcus species to echinocandins
Image of fungal pathogens in a Petri dish

WHY ARE RESISTANT FUNGAL INFECTIONS ON THE RISE?

Many antifungals are no longer effective in treating invasive fungal infections (IFIs) due to the:8

  • Widespread and long-term use of antifungal prophylaxis
  • Sub-optimal drug delivery to the host
  • Use of medically related antifungals in agriculture

MULTIDRUG RESISTANCE CAN ELIMINATE ALL AVAILABLE TREATMENT OPTIONS8

Azole resistance among Candida and Aspergillus species is one of the greatest challenges to clinical success, followed by echinocandin and multidrug resistance among some Candida species, particularly Candida glabrata.8 The spread of agriculturally derived azole-resistant Aspergillus fumigatus and emerging threats such as multidrug resistant Candida auris are also a cause for concern.8

As much as 30%–50% of antifungal prescriptions could be optimised or are inappropriate.9 Overprescribing of antifungal agents puts patients at great risk for drug toxicities and drug interactions, and has the potential to select for resistant fungi.9

Photo of four doctors discussing in hallway

MINIMISING RESISTANCE: RECOMMENDATIONS FOR ANTIFUNGAL STEWARDSHIP

The current variability in antifungal use, inappropriate dosing, and delays in initiating appropriate therapy indicate a need for antifungal stewardship to improve the prevention, diagnosis, and management of IFIs.10 Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve successful clinical outcomes, while minimising selective pressure and adverse events.10

Robust antifungal stewardship programmes that integrate rapid diagnostics, therapeutic drug monitoring, and clinical intervention teams are required to help overcome drug resistance in clinics.8

Example performance measures for antifungal stewardship evaluations include:9

Mortality or prophylaxis, fungal-free survival
Length of stay and clinical response (treatment success, stable disease, failure)
Appropriate choice of antifungal agent, dose, route, duration and time to (targeted or optimal) therapy
Adherence with practice guidelines
Persistent culture positivity or time to culture resolution
Recurrent or breakthrough infection
Performance of quality measures (ophthalmologic examination, galactomannan testing or follow-up cultures performed)
Therapeutic drug monitoring performed or achievement of therapeutic levels
Photo of nurse with blood samples

HOW IS RESISTANCE IMPACTING PATIENTS IN HAEMATOLOGY SETTINGS?

The number of rare and difficult-to-treat breakthrough infections is rising, including azole-resistant strains and emergent pathogens such as non-albicans Candida, non-fumigatus Aspergillus and the zygomycetes influenced by numerous factors, including extensive antifungal prophylaxis.1–3,11–14 In one study across three continents, Candida auris was found to be resistant in 93% of patients treated with fluconazole.15

Approximately half of all invasive aspergillosis cases occur in patients with haematological malignancies such as acute myeloid leukaemia, acute lymphoblastic leukaemia, and recipients of allogenic haemopoietic stem cell transplantation (HSCT).3

NOW, THE LANDSCAPE OF BREAKTHROUGH IFIs IS SHIFTING AWAY FROM ASPERGILLUS SPECIES:3,16

Mucormycosis has emerged as the second most common invasive mould breakthrough infection in patients with haematological malignancies and patients who underwent HSCTs.17

Prognosis is poor and mortality rates can be as high as 80% in these patients.17

In haematalogical patients living in Brazil, Fusarium species are a leading cause of breakthrough infection.3

A higher level of antifungal resistance has been observed in Fusarium vs. Aspergillus species and mortality rates exceed 75% in patients with disseminated fusariosis.3

With the increasing number of patients in haematology settings at risk of IFIs,11 a variety of fungal pathogens should be considered when selecting an appropriate antifungal.

Man in ICU bed with masked nurses giving him oxygen

HOW IS RESISTANCE IMPACTING PATIENTS IN INTENSIVE CARE UNITS?

The most commonly experienced IFI in intensive care units (ICUs) is candidaemia,18 however 20-30% of candidaemia cases involve intrinsic resistance to fluconazole or echinocandins.4 Prolonged drug exposure to Candida isolates may have led to reduced echinocandin susceptibility.1

The emergence of drug-resistant isolates of Candida species increases the risk for IFIs and could be associated with poor outcomes for patients.1

3D image of Candida

RESISTANT NON-ALBICANS INFECTIONS NOW ACCOUNT FOR ~50% OF ALL INVASIVE CANDIDIASIS CASES19

Resistant Candida species include C. parapsilosis, C. albicans, C. glabrata, C. tropicalis and C. auris.1,20 Other infections that have been observed in the ICU include azole-resistant aspergillosis,21 and mucormycosis, which can occur as breakthrough infections following azole prophylaxis.22-25 Azole resistance was reported in 3.2% of A. fumigatus isolates in Europe.6

Photo of two doctors talking whilst walking down corridor

Be ready for IFIs.

With a broad-spectrum, fungicidal treatment that demonstrates low resistance risk.

References

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Date of preparation: April 2022. Job code: IHQ-AMB-0427.