Effects of Lipid Formulations of Amphotericin B on Activity of Human Monocytes against Aspergillus fumigatus

Abstract

Invasive aspergillosis is the most frequent opportunistic filamentous fungal infection causing excessive morbidity and mortality in immunocompromised patients (9, 12). Mononuclear phagocytes constitute a prominent component of the host defense against Aspergillus spp. (24). In particular, NADP (NADPH)-dependent production of antifungal compounds, such as superoxide anion (O 2 Ϫ ), hydrogen peroxide (H 2 O 2 ), and H 2 O 2 -dependent intracellular intermediates (DIIs), contributes to phagocyte-induced damage of microorganisms including fungi (2,8,16). While O 2 Ϫ production is an early event of oxidative burst, H 2 O 2 and DIIs consisting of compounds such as hydroxyl radical and HOCl are produced at late steps and are even more powerful oxidizing species.For decades, deoxycholate amphotericin B (DAMB) has been considered to be the cornerstone of antifungal therapy for fungal infections including invasive aspergillosis (1, 21). However, due to frequent infusion-related reactions and doselimiting nephrotoxicity, less-toxic lipid-associated formulations, such as liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD), have been developed (5,7,15). These compounds appear to offer a better therapeutic index than DAMB, circumscribing excessive toxicity (5, 7). Although newer azoles and echinocandins have been added to the antifungal armamentarium, amphotericin B formulations remain important agents against invasive aspergillosis.While lipid formulations of amphotericin B differ in their degree of induction of infusion-related reactions, little is known about their immunomodulatory effects when each of them is combined with phagocytes against Aspergillus fumigatus. Specifically, DAMB and ABLC were found to additively augment the fungicidal activity of pulmonary alveolar macrophages against conidia of A. fumigatus (17). However, the studies of the effects of DAMB on oxidative burst of phagocytes as evidenced by O 2 Ϫ production have shown contradictory results (18,22,25,26). To date, there are no reports published on the comparative effects of the four formulations on the antifungal activity of monocytes (MNCs) against A. fumigatus. We therefore investigated whether DAMB, LAMB, ABLC, and ABCD enhance the antifungal activities of monocytes against hyphae of A. fumigatus, as evidenced by monocyte-mediated hyphal damage, production of O 2 Ϫ , and production of H 2 O 2 as well as secondary DIIs, both in response to A. fumigatus.

Innate Immunity toAspergillusSpecies

“…Upon interaction with Aspergillus conidia, human peripheral blood monocytes undergo profound changes in their expression of hundreds of genes (46,137). Human monocytes are capable of ingesting and killing conidia and of inducing damage to Aspergillus hyphae (50,140,156), and this killing can be enhanced in the presence of granulocyte-macrophage colony-stimulating factor, IFN-␥, and fungicidal drugs (41,52,139,166). In the context of neutropenic mice with invasive aspergillosis, these inflammatory mononuclear cells appear in the lungs within hours of the onset of infection (125), but their in vivo role in the defense against invasive aspergillosis has not been directly examined to date.…”

Interaction of Platelets and Anidulafungin against Aspergillus fumigatus

“…The exact mechanism of hyphal damage due to platelets is still unknown. However, a possible enhanced effect of immune effector cells combined with antifungal drugs against virulent fungi has been found in several studies (19)(20)(21)(22).…”

Differential Activities of Newer Antifungal Agents against Candida albicans and Candida parapsilosis Biofilms

“…Biofilm MICs were determined as the minimum antifungal drug concentrations that caused Ն50% reduction in the metabolic activity of the biofilms compared to controls (10). Biofilm formation and antifungal activities were assessed by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]2H-tetrazolium-5-carboxanilide (XTT; 0.25 mg/ml) and coenzyme Q (40 g/ ml) assay spectrophotometrically at 450 nm with a reference wavelength of 690 nm (7). Antifungal activities were expressed as a percentage of metabolic activity of drug-treated biofilms compared to drug-free biofilms (controls, considered to be 100%).…”