Antifungal drug resistance: evolution, mechanisms and impact

Abstract

Microorganisms have a remarkable capacity to evolve resistance to antimicrobial agents, threatening the efficacy of the limited arsenal of antimicrobials and becoming a dire public health crisis. This is of particular concern for fungal pathogens, which cause devastating invasive infections with treatment options limited to only three major classes of antifungal drugs. The paucity of antifungals with clinical utility is in part due to close evolutionary relationships between these eukaryotic pathogens and their human hosts, which limits the unique targets to be exploited therapeutically. This review highlights the mechanisms by which fungal pathogens of humans evolve resistance to antifungal drugs, which provide crucial insights to enable development of novel therapeutic strategies to thwart drug resistance and combat fungal infectious disease.

Blocking β‐1,6‐glucan synthesis by deleting KRE6 and SKN1 attenuates the virulence of Candida albicans

“…Candidemia has an incidence of between 1.1 and 24 cases per 100,000 individuals and associated high mortality rates often above 30% (Grubb et al ., ; Sanguinetti et al ., ). The worldwide emergence and spread of antifungal‐resistant strains and the availability of only a few classes of antifungal drugs further increase the difficulty of treating invasive fungal infections (Morace et al ., ; Perlin, ; Revie et al ., ).…”

Prospective CYP2C19‐Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations

“…Epidemiology studies have shown that drug‐resistant Aspergillus and non‐ Aspergillus molds are commonly observed among those with breakthrough infections . Prolonged exposure to suboptimal voriconazole concentrations may mechanistically promote acquired resistance and selection of subpopulations with primary resistance . The CYP2C19*17 allele is a risk factor for low voriconazole concentrations and can affect ~ 25% of patients.…”

“…21,22 Prolonged exposure to suboptimal voriconazole concentrations may mechanistically promote acquired resistance and selection of subpopulations with primary resistance. [23][24][25] The CYP2C19*17 allele is a risk factor for low voriconazole concentrations and can affect ~ 25% of patients. There is limited clinical guidance for utilization of prophylactic voriconazole in CYP2C19 rapid metabolizers, but Clinical Pharmacogenetic Implementation Consortium guidelines have recommended avoidance of voriconazole for CYP2C19 rapid metabolizers with an invasive fungal infection.…”

Pathogenic Budding Yeasts Isolated outside of Clinical Settings

“…Understanding the ecology of pathogenic yeasts is critical to human health for multiple reasons. First, mortality from infections by these yeasts remains high, and candidiasis is the fourth most common hospital-associated bloodstream infection (4, 14, 15). Second, Candida auris recently emerged as a multi-drug resistant opportunistic pathogen, with additional strains exhibiting resistance to many anti-fungal drugs (14, 16).…”

“…First, mortality from infections by these yeasts remains high, and candidiasis is the fourth most common hospital-associated bloodstream infection (4, 14, 15). Second, Candida auris recently emerged as a multi-drug resistant opportunistic pathogen, with additional strains exhibiting resistance to many anti-fungal drugs (14, 16). Finally, it is unclear whether there might be environmental reservoirs that could act as contact points for their primary hosts, or whether the niches of pathogenic yeasts are indeed exclusively endothermic animals and clinical environments (17).…”