Antifungal drug resistance mechanisms

Antifungal resistance is a prominent feature in the management of invasive mycoses, with important implications for morbidity and mortality. Microbiological resistance, the most common cause of refractory infection, is associated with a fungal pathogen for which an antifungal MIC is higher than average or within the range designated as the resistant breakpoint. Four major mechanisms of resistance to azoles have been described in Candida spp.: decreased intracellular drug concentration by activation of efflux systems or reduction of drug penetration, modification of the target site, upregulation of the target enzyme and development of bypass pathways. Conversely, echinocandins are a poor substrate for multidrug efflux transporters, and their mechanisms of resistance are associated with point mutations and/or overexpression of FKS1 and FKS2 genes. Acquired resistance to flucytosine results from defects in its metabolism through enzymatic mutations, whereas resistance to amphotericin B may be mediated by increased catalase activity or defects in ergosterol biosynthesis.