Azole-Resistant Candida Species

Azole-resistant Candida species are yeasts of the genus Candida that have reduced or absent susceptibility to azole antifungals such as fluconazole. Because azoles are widely used to prevent and treat candidiasis, the spread of resistant species and strains - including intrinsically resistant species and the emerging multidrug-resistant Candida auris - is a central concern in the epidemiology of invasive fungal infection.

Definition

Azole-resistant Candida species are Candida isolates whose minimum inhibitory concentration to azole antifungals exceeds the clinical breakpoint defining susceptibility, whether through intrinsic species-level resistance or acquired resistance in a normally susceptible species.

Scope

This topic covers what makes a Candida isolate azole-resistant, the species in which resistance is most prominent, and why it matters for the burden of invasive candidiasis. It is written as a microbiology and antimicrobial-resistance reference; it describes the organisms and their resistance, not how to treat a particular patient.

Core questions

• Which Candida species are intrinsically or commonly azole-resistant, and which acquire resistance?
• How does azole resistance in Candida relate to prior azole exposure and to species shifts in candidaemia?
• Why has Candida auris become emblematic of multidrug-resistant Candida?

Key concepts

• Fluconazole resistance
• Intrinsic versus acquired resistance
• Clinical breakpoints and MIC
• Species distribution in candidaemia
• Candida auris
• Candida glabrata (Nakaseomyces glabratus)
• Candida krusei (Pichia kudriavzevii)
• Antifungal stewardship

Mechanisms

At the species level, some Candida are intrinsically less susceptible to azoles - Candida krusei is intrinsically fluconazole-resistant and Candida glabrata is often dose-dependently susceptible or resistant - while species such as Candida albicans are usually susceptible but can acquire resistance. Acquired azole resistance in Candida is driven by alterations and overexpression of the azole target ERG11/Cyp51, upregulation of efflux pumps, and regulatory mutations, often selected by prior azole exposure (Perlin 2017). Candida auris frequently displays high-level fluconazole resistance and variable resistance to other classes, making it a notable multidrug-resistant species.

Clinical relevance

Azole resistance influences the empirical and population-level management of invasive candidiasis, because the susceptibility of the likely infecting species shapes which drug classes remain useful (Pappas 2016; Kullberg 2015). This entry characterises the resistant organisms and their epidemiology for reference and education; it is not a treatment guide, and decisions about individual antifungal therapy belong to clinicians using current guidelines and local susceptibility data.

Epidemiology

Candidaemia is a leading cause of healthcare-associated bloodstream infection with substantial mortality, and its species distribution has shifted over time, with non-albicans species - several of them less azole-susceptible - making up a growing share (Pfaller 2007; Kullberg 2015). The global emergence and nosocomial transmission of multidrug-resistant Candida auris has intensified concern about azole-resistant Candida as a public-health threat (Perlin 2017).

History

Fluconazole's introduction made azoles a mainstay of candidiasis prophylaxis and therapy, and resistant isolates and intrinsically resistant species were soon recognised as the species distribution of candidaemia evolved (Pfaller 2007). The 2009 description of Candida auris and its subsequent global spread as a multidrug-resistant organism marked a new phase in the history of azole-resistant Candida (Perlin 2017).

Key figures

• Michael A. Pfaller
• Bart Jan Kullberg
• David S. Perlin
• Peter G. Pappas

Seminal works

• pfaller-2007
• kullberg-2015
• perlin-2017

Frequently asked questions

Are all Candida species equally susceptible to azoles?

No. Candida albicans is usually susceptible to fluconazole, but species such as Candida krusei are intrinsically resistant and Candida glabrata is frequently less susceptible, and the recently emerged Candida auris is often multidrug-resistant.

What drives acquired azole resistance in Candida?

Acquired resistance typically results from changes in the azole target enzyme and increased drug efflux, often selected by prior exposure to azole antifungals; this entry describes those mechanisms but does not advise on therapy.