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Chapter 30 : Antifungal Polyenes

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Abstract:

This chapter discusses the pharmacology of the antifungal polyenes, with an emphasis on their role in the management of invasive infections. Amphotericin B primarily acts by binding to ergosterol, the principal sterol in the cell membrane of most fungi. The interaction with ergosterol results in the formation of transmembrane channels, which leads to an efflux of protons and monovalent cations, depolarization of the membrane, and ultimately, cell death. A second mechanism of action of amphotericin B may involve oxidative damage of the cell through a cascade of oxidative reactions linked to its own oxidation, with formation of free radicals or an increase in membrane permeability. In preclinical single- and multidose distribution studies in rodents spanning the entire dosing interval and using equimolar doses of 1 mg/kg of amphotericin B, lung levels achieved by amphotericin b colloidal dispersion (ABCD) and unilamellar vesicle liposomal formulation (LAMB) were lower and those achieved by amphotericin b lipid complex (ABLC) were similar or slightly higher than those obtained with amphotericin B deoxycholate (DAMB). The published data indicate that ABLC is less nephrotoxic than DAMB and effective against invasive opportunistic mycoses. The experience with ABLC in the treatment of fungal diseases caused by endemic fungi, however, is limited. Compared to DAMB, infusionrelated reactions appear to be similar in frequency and extent. The plasma pharmacokinetics of liposomal nystatin (Nyotran) were investigated in human immunodeficiency virus (HIV)-infected patients at doses ranging from 2 to 7 mg/kg.

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30

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Figures

Image of Figure 1.
Figure 1.

Structural formulas for amphotericin B (top) and nystatin A1 (bottom).

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30
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Image of Figure 2.
Figure 2.

(A) Schematic of a (hypothetical) single-length amphotericin B or nystatin channel. Each polyene molecule is depicted as a plane. The hydrophilic polyhydroxyl polar regions of the molecules face the center of the channel (shaded surface); the exterior is completely nonpolar. The cleft between each of two polyene molecules can accommodate a sterol molecule. The black dots represent the terminal OH group, and the protuberances represent the amino sugar. (B) Diagram of a (hypothetical) double-length (a) and a single-length (b) channel. A normal bilayer is depicted between both channels. Double-length channels are formed from two single-length channels hydrogen bonded in the middle of the membrane through the ring of hydroxyl groups (black dots). Double-length channels only occur when a polyene has access to both sides of the bilayer, i.e., under certain experimental conditions in vitro. (Adapted from .)

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30
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Image of Figure 3.
Figure 3.

Time kill assay of versus in antibiotic medium 3. Whereas demonstrated concentration-dependent fungicidal activity of amphotericin B with an approximately 105-fold reduction in viable CFU by 24 h at drug concentrations of ≥4 μg/ml, there was less than 1 log kill of at all concentrations of amphotericin B tested. (Adapted from .)

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30
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Image of Figure 4.
Figure 4.

Simplified model of the distribution of amphotericin B after intravenous administration. From the central plasma compartment, independent of the formulation, the drug distributes into three hypothetical peripheral tissue compartments which display quantitatively different uptake. There is a slow redistribution from those peripheral compartments back into plasma. Elimination occurs in unchanged form from the plasma pool via the kidney and bile fluid. HC, high-concentration compartment; IC, intermediate-concentration compartment; LC, low-concentration compartment.

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30
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Image of Figure 5.
Figure 5.

Schematic of the molecular composition of amphotericin B formulations. (A) DAMB forms aggregates of mixed micelles containing amphotericin B and deoxycholate. (B) ABCD forms disk-like colloidal structures composed of amphotericin B and cholesterylsulfate. (C) ABLC is composed of DMPC and DMPG in a 7:3 molar ratio complexed with amphotericin B and forms large ribbon-like structures. (D) LAMB consists of small, unilamellar vesicles made up of hydrogenated soy phos-phatidyl choline and disteaoryl phosphatidyl glycerol stabilized by cholesterol and combined with amphotericin B. Liposomal nystatin (not shown) consists of multilamellar liposomes composed of DMPC and DMPG combined with nystatin.

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30
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Image of Figure 6.
Figure 6.

Response of primary pulmonary aspergillosis in rabbits to antifungal therapy with DAMB or LAMB as measured by the residual burden of in lung tissue. Note that at similar doses LAMB was not as effective as DAMB and that similar efficacy was achieved only at higher dosages. (Modified from Francis et al., 1994.)

Citation: Groll A, Walsh T. 2009. Antifungal Polyenes, p 391-415. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch30
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