In humans the superior safety profile of lipid

In humans, the superior safety profile of lipid-associated formulations is characterized by decreased acute infusion-related reactions and dose-related nephrotoxicity, allowing the administration of larger doses and therefore similar efficacy with fewer administrations. In vitro studies and human clinical data suggest that amphotericin B lipid complex and liposomal amphotericin B induce a Toll-like receptor 4 reaction instead of a Toll-like receptor 2 reaction, as observed with amphotericin deoxycholate, causing attenuation of the characteristic proinflammatory response. Unlike the other lipid-associated amphotericin B preparations, the amphotericin B colloidal dispersion is associated with a higher frequency of infusion-related reactions associated with an inflammatory gene upregulation similar as amphotericin B deoxycholate. The pathophysiology of amphotericin B–induced nephrotoxicity is associated with a vasoconstrictive effect on the afferent renal arterioles, decreasing the glomerular filtration rate and inducing tubular dysfunction. Complexation with lipids seems to stabilize amphotericin B in a self-associated state so that it is not available to interact with cholesterol in mammalian or avian cellular membranes, which is the presumed major site of toxicity. Moreover, amphotericin B alone binds preferentially to low-density lipoproteins and can be internalized into renal cells that express low-density lipoprotein receptors, resulting in toxicity. Amphotericin B from lipid-associated formulations binds preferentially to high-density lipoproteins, which reduces nephrotoxicity by decreasing the uptake of amphotericin B by renal cells because of their low level of high-density lipoprotein receptors. Recently, Phillips and colleagues demonstrated that a single dose (3 mg/kg BW) of liposomal amphotericin B delivered by aerosol to healthy mallard ducks resulted in minimal systemic distribution of the drug after administration, characterized by low plasma and kidney amphotericin B concentrations and no signs of drug-associated damage on histopathologic examination of renal, hepatic, or cardiac tissue samples. Similarly, based on clinical examination and plasma uric methysergide receptor levels, no signs of nephrotoxicity were observed in a goliath heron (Ardea goliath) with a deep infection with Aspergillus species of its pectoral muscle topically treated with liposomal amphotericin B (1.35 mg/kg, once a day) mixed with sterile, water-soluble, gelatin lubricant for more than 1 month. Studies in mouse and rabbit models of fungal infection and human metaanalyses have shown the liposomal formulation of amphotericin B to be at least as effective as amphotericin B deoxycholate in improving survival and resolving the infection. After intratracheal aerosol administration of liposomal amphotericin B to healthy mallard ducks, drug concentrations in pulmonary parenchyma reached above the targeted MIC for avian isolates of Aspergillus species of 1 μg/mL. Although these lipid formulations are reported to have excellent safety and efficacy, the high price of these drugs may currently preclude their use in veterinary medicine compared with the conventional form. Among many new antifungal drug delivery systems currently under investigation, nanoparticles (NPs) have emerged as an innovative and promising platform able to enhance drug stability, reduce off-target side effects, prolong residence time in the blood, and improve drug efficacy. NPs are characterized by their small particle size ranging from 1 to 1000 nm. Liposomal amphotericin is the first and most successful commercial NP of antifungal drugs in humans. NPs used in drug delivery can be classified into phospholipid vesicles (eg, liposomes), nonphospholipid vesicles, polymeric NPs, polymeric micelles, solid lipid NPs, nanostructured lipid carriers, nanoemulsions, and dendrimers. For example, liposomal nystatin allowed the IV administration of nystatin, increased the maximum tolerated dose in mice from 4 to 16 mg/kg BW, and increased the survival rate of mice infected with Candida albicans. Itraconazole incorporated into poly(lactide-co-glycolide) (PLGA) resulted in a sustained-release formulation for IV administration with plasma itraconazole levels for more than 3 times longer than the commercial formulation. PLGA containing voriconazole was detectable in lungs until 5 to 7 days after pulmonary disposition in mice via an inhalation chamber. Recently, Pardeike and colleagues demonstrated that nebulized itraconazole-loaded nanostructured lipid carriers penetrate deeply into the lungs and air sacs of a falcon, being a prerequisite for pulmonary treatment of aspergillosis.