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Antifungal Therapy
Daniel S. Foy, MS, DVM, DACVIM (SAIM), DACVECC

College of Veterinary Medicine, Midwestern University, Glendale, AZ, USA

Until relatively recently, treatment of systemic mycoses The cause of nephrotoxicity remains incompletely
was limited to intravenous amphotericin B and oral keto­ understood, but is potentially related to both direct tox­
conazole. However, in the last two decades, significant icity to epithelial cell membranes and renal vasoconstric­
progress has been made in the development of first‐ tion. In people, serum creatinine is monitored during
generation triazole drugs, newer second‐generation treatment; a clinically significant increase is considered a
triazole drugs, and echinocandins. new elevation above the normal range, or an increase of
New antifungal therapies are often constrained by the greater than 20% from the baseline value.
fact that fungal organisms are eukaryotic, and therefore The inherent nephrotoxicity of the original ampho­
greater potential exists for host toxicity. For example, tericin B formulation led to the development of three
traditional antifungal medications that target ergosterol, new formulations: liposomal preparation, lipid complex,
or its production, can cause toxicity in mammalian cells and colloidal dispersion with cholesterol sulfate.
via inhibition of cholesterol production or damage to cell Liposomal amphotericin B (lip‐amB) achieves higher
membranes. Newer therapies are being directed at com­ plasma concentrations than the original formulation; this
ponents unique to fungal organisms, thereby sparing is thought to be due to decreased uptake by the reticu­
mammalian cells. Although in vitro testing frequently loendothelial system (RES). Liposomes containing
finds antifungal drugs to be fungicidal, most appear to be amphotericin B fuse with the fungal cell membrane, lead­
fungistatic in vivo, thus the host immune system must ing to fungal cell death. Lip‐amB has been evaluated for
eliminate the organisms. safety in healthy beagle dogs, and when dosed at 1 mg/kg/
day for 29 days, no azotemia was noted, and minimal
renal tubular necrosis was seen on histopathology.
Amphotericin B Amphotericin B lipid complex (ABLC) is composed of a
suspension of amphotericin B complexed with two phos­
Since its discovery in 1956 and increased availability in pholipids: dimyristoylphosphatidylcholine and dimyris­
the early 1960s, amphotericin B has become, and remains, toylphosphatidylglycerol. ABLC is taken up by the cells of
the reference treatment for invasive fungal infections. the RES, and subsequently concentrates in the liver, lungs,
Amphotericin B is a macrocyclic polyene antibiotic origi­ and spleen. The lipid complexes are likely disrupted by
nally extracted from Streptomyces nodosus. This drug phospholipases at sites of inflammation or infection, lead­
forms micelles with fungal ergosterol, which creates ing to the release of amphotericin B. Repeated dosing of
channels in the fungal membrane, alters cell permeability, up to 5 mg/kg/day in research dogs found ABLC to be
and allows leakage of ions and cellular components from 8–10‐fold less nephrotoxic, on the basis of renal values
the fungal organism. The effectiveness of amphotericin B and histology, than conventional amphotericin B.
is due to its greater affinity for ergosterol, the major sterol Importantly, although mean glomerular filtration rate
of fungal cell membranes, relative to cholesterol. (GFR) decreased over the course of treatment, only one of
Effective amphotericin B treatment requires intrave­ 10 dogs that received 8–12 mg/kg ABLC showed a
nous (IV) administration, with the major limiting factor decrease in GFR below the reference range.
in its use being cumulative nephrotoxicity; however, The third lipid‐incorporated preparation to be devel­
the only absolute contraindication to use is anaphylaxis. oped was amphotericin B colloidal dispersion (ABCD).

Clinical Small Animal Internal Medicine Volume II, First Edition. Edited by David S. Bruyette.
© 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/bruyette/clinical