Update on Antifungal Drug Resistance

Abstract

Invasive fungal infections remain a major source of global morbidity and mortality, especially among patients with underlying immune suppression. Successful patient management requires antifungal therapy. Yet, treatment choices are restricted due to limited classes of antifungal agents and the emergence of antifungal drug resistance. In some settings, the evolution of multidrug-resistant strains insensitive to several classes of antifungal agents is a major concern. The resistance mechanisms responsible for acquired resistance are well characterized and include changes in drug target affinity and abundance, and reduction in the intracellular level of drug by biofilms and efflux pumps. The development of high-level and multidrug resistance occurs through a stepwise evolution of diverse mechanisms. The genetic factors that influence these mechanisms are emerging and they form a complex symphony of cellular interactions that enable the cell to adapt and/or overcome drug-induced stress. Drivers of resistance involve a complex blend of host and microbial factors. Understanding these mechanisms will facilitate development of better diagnostics and therapeutic strategies to overcome and prevent antifungal resistance.

Keywords: Acquired resistance; Antifungal resistance; Aspergillus fumigatus; Azoles; Candida albicans; Candida glabrata; Echinocandins; Polyenes.

Fig. 1

Echinocandin resistance in C. glabrata in Europe and America. Resistance rate varies among different studies. The rate reported from institutional studies is higher than that from population-based surveys, where only the initial blood isolate is included to avoid biasing the data set. Adapted from Arendrup et al. [14]

Fig. 2

Exposure to azole drugs triggers fungal stress responses that promote fungal adaptation and drug tolerance and, ultimately, emergence of stable genetic alterations that confer drug resistance. The HSP90 protein chaperone and its client, protein phosphatase calcineurin, are key stress signal transduction molecules that both upregulate pathways leading to drug tolerance and promote genome instability, increasing the likelihood of generating drug-resistant strains. Fungal biofilms, which readily form in vivo, are intrinsically resistant to azoles due to drug sequestration within the extracellular matrix and expression of drug efflux transporters

Fig. 3

Binding of lanosterol and itraconazole within active site heme region Erg11 from S. cerevisiae. a Lanosterol binding and coordination with heme shown with electron density profile. b Itraconazole binding to same region shown with electron density. c Bound itraconazole and amino acids commonly mutations to confer resistance. Adapted from Monk et al. [64••]