Responding to the emergence of antifungal drug resistance: perspectives from the bench and the bedside

Abstract

The incidence of serious fungal infections is increasing rapidly, and yet the rate of new drugs becoming available to treat them is slow. The limited therapeutic armamentarium is a challenge for clinicians, because the available drugs are often toxic, expensive, difficult to administer, ineffective or a combination of all four. Given this setting, the emergence of resistance is especially concerning, and a review of the topic is timely. Here we discuss antifungal drug resistance in Candida spp. and Aspergillus spp. with reference to the most commonly used first-line antifungal agents - azoles and echinocandins. We review the resistance mechanisms of the leading pathogens, how resistance can be identified in the diagnostic lab and the clinical implications of resistance once detected.

Figure 1.. Illustration of the three broad pathways via which patients can acquire resistant fungal infections.

White crosses indicate susceptible organisms; red crosses indicate resistant organisms. Pills indicate antifungals, used either in human health or agriculture.

Figure 2.. Overview of the major resistance mechanisms in Candida sp.

(A) Shows normal binding of azoles (red) to lanosterol 14α-demethylase (Erg11); and normal binding of echinocandins (peach) to β-(1,3)-D-glucan synthase (Fks, including the three functional subunits Fks1, Fks2 and Fks3, and the regulatory subunit Rho1). (B) Shows reduced azole binding due to conformational changes in lanosterol 14α-demethylase. (C) Shows reduced azole efficacy due to increased production of lanosterol 14α-demethylase (+/- conformational changes). (D) Reduced azole efficacy secondary to bypassing metabolic toxicities. (E & F) Show reduced azole efficacy due to increased efflux pump activity. (G) Illustrates reduced azole efficacy due to uptake of replacement sterols. (H) Shows conformational changes to either Fks1 or Fks2 subunit of β-(1,3)-D-glucan synthase leading to reduced echinocandin binding.

Figure 3.. Overview of the major resistance mechanisms in Aspergillus sp.

(A) Shows normal binding of azoles (red) to 14-α-sterol demethylase (Cyp-51A); and normal binding of echinocandins (peach) to β-(1,3)-D-glucan synthase (Fks, including the three functional subunits Fks1, Fks2, and Fks3, and the regulatory subunit Rho1). (B) Shows reduced azole binding due to conformational changes in 14-α-sterol demethylase. (C) Shows reduced azole efficacy due to increased production of 14-α-sterol demethylase (+/- conformational changes). (D) Shows reduced azole efficacy due to increased efflux pump activity. (E) Shows conformational changes in the Fks1 subunit of β-(1,3)-D-glucan synthase leading to reduced echinocandin binding.