loaded NEs using Capmul PG8 and lipid-based surfactants, which demonstrated zones of inhibition with an average measurement of 19.1±1.4 when tested against A. niger. Through ex vitro investigations, it was shown that this nanosystem demon­strated enhanced AmB release and exhibited the most efcient penetration through the stratum corneum barrier, surpassing both the AmB drug solution and Fungisome® (a commercially available liposomal AmB medication) (Hussain etal. 2016). In an alternative framework, NE has presented an enhanced nanosystem that aims to enhance the localized antifungal efcacy of AmB while minimizing the potential for systemic absorption (Sosa etal. 2017). While drug-loaded NEs have demon­strated effectiveness in the treatment of topical fungal infections, further research is needed to assess their efcacy in combating invasive fungal infections.

cell, such as drugs, toxins, or metabolites. Some fungi have efux pumps that can recognize and expel azole antifungals from the cell, reducing their intracellular con­centration and effectiveness. Efux pumps fall into two primary families: ATP­binding cassette transporters and major facilitator superfamily transporters. These pumps use a proton electrochemical gradient across the plasma membrane to extrude substrates (Cannon etal. 2009). Fungi can develop resistance to azoles by increasing the expression or activity of these efux pumps, either by mutations or by induction. The target enzyme of azoles is sterol 14α-demethylase (Cyp51A), which is involved in the synthesis of ergosterol. Azoles bind to the heme group of Cyp51A and inhibit its function, leading to reduced ergosterol production and impaired membrane integrity. Fungi can develop resistance to azoles by altering the structure or function of Cyp51A, either by point mutations or by recombination with other Cyp51 genes (Xie etal. 2014). Aspergillus spp. have two genes that code for 14-α-demethylase: CYP51A and CYP51B.However, most of the azole resis­tance in Aspergillus spp. is due to mutations in CYP51A (Gonçalves etal. 2016). There are different types of mutations in CYP51A, such as point mutations (changes in a single nucleotide) or non-synonymous mutations (changes in an amino acid). These mutations can confer different levels of resistance to different azoles. For instance, some non-synonymous mutations in amino acids 98, 138, 220, 431, 434, and 448 can make Aspergillus spp. resistant to all azoles (Howard etal. 2009). These changes can reduce the afnity or increase the turnover of Cyp51A for azoles, resulting in decreased inhibition. ERG11 is the gene that encodes Cyp51A in fungi. Fungi can develop resistance to azoles by increasing the expression of ERG11, either by gene amplication, duplication, or upregulation. This can result in increased production of Cyp51A, which can overcome the inhibitory effect of azoles by saturating their binding sites or by increasing the residual activity of the enzyme (Berman and Krysan 2020). It is not easy to manage patients with azole­resistant infection. Mostly, lipid AmB products and combination therapy with an azole or echinocandin are the potential treatment options (Berman and Krysan 2020).