Antifungal resistance: current trends and future strategies to combat

Abstract

Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically available antifungal agents. In addition current drugs may be limited by drug-drug interactions and serious adverse effects/toxicities that prevent their prolonged use or dosage escalation. Fluconazole resistance is of particular concern in non-Candida albicans species due to the increased incidence of infections caused by these species in different geographic locations worldwide and the elevated prevalence of resistance to this commonly used azole in many institutions. C. glabrata resistance to the echinocandins has also been documented to be rising in several US institutions, and a higher percentage of these isolates may also be azole resistant. Azole resistance in Aspergillus fumigatus due to clinical and environmental exposure to this class of agents has also been found worldwide, and these isolates can cause invasive infections with high mortality rates. In addition, several species of Aspergillus, and other molds, including Scedosporium and Fusarium species, have reduced susceptibility or pan-resistance to clinically available antifungals. Various investigational antifungals are currently in preclinical or clinical development, including several of them that have the potential to overcome resistance observed against the azoles and the echinocandins. These include agents that also target ergosterol and b-glucan biosynthesis, as well as compounds with novel mechanisms of action that may also overcome the limitations of currently available antifungal classes, including both resistance and adverse effects/toxicity.

Keywords: Aspergillus; Candida albicans; Candida auris; acquired resistance; azoles; echinocandins; intrinsic resistance; investigational antifungals; non-albicans Candida species.

Figure 1

Fluconazole resistance overall and in non-Candida albicans isolates as per the World Health Organization. Note: Reprinted from World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. Available from: http://www.who.int/drugresistance/documents/surveillancereport/en/. Copyright 2014.

Figure 2

Investigational antifungal agents with mechanisms of action similar to that of the azoles via inhibition of ergosterol biosynthesis (VT-1129, VT-1161, VT-1598), or echinocandins via inhibition of 1,3-β-D-glucan synthesis (CD101, SCY-078).

Figure 3

Investigational antifungal agents with novel mechanisms of action, including prevention of fungal pyrimidine via inhibition of dihydroorotate dehydrogenase (F901318), prevention of GPI-anchored protein maturation via inhibition of fungal inositol aceyltransferase (AX001), collapse of fungal mitochondrial membrane potential (T-2307), and an unknown mechanism of action following transport into fungal cells by the Sit1 (VL-2397). Abbreviations: GPI, glycosylphosphatidylinositol; Sit1, siderophore iron transporter 1.