Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

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Systemic antifungal therapy
Joseph Taboada and Amy M Grooters
INTRODUCTION
Fungal pathogens have assumed an increasingly important
role in human disease in the past three decades as
immunocompromise associated with bone marrow
transplantation, organ transplantation and human
immunodeficiency virus infection has become more
prevalent. The need for more effective and less toxic
options for the treatment of systemic mycoses in human
patients has prompted a search for new agents that
selectively target the fungal cell wall and for new ways
to increase the efficacy and safety of traditional antifungal
agents, such as amphotericin B and the azoles. As a
result, veterinarians now have access to a rapidly
expanding armamentarium of compounds with high
efficacy and low toxicity for the treatment of mycotic
infections in small animal patients.
Targets for antifungal drug therapy
Historically, progress in the development of antifungal
drugs has been slow in comparison to antibacterial
agents. One important reason for this delay is that, as
eukaryotic organisms, fungi contain few drug targets
that are not also present in mammalian cells, making
the search for agents with selective fungal toxicity difficult.
The vast majority of traditional antifungal drugs
target ergosterol, an essential component of the fungal
cell membrane. The selectivity of these drugs is based
on their greater affinity for ergosterol in the fungal cell
membrane than for cholesterol in the mammalian cell
membrane and limits, but does not eliminate, their
potential for toxicity to mammalian cells. The ideal
antifungal agent would be one that targets structures
present in fungal pathogens that are absent in other
eukaryotic cells. The fungal cell wall, a structure that is
both unique and essential to fungi, would seem to be
such a target. For this reason, compounds that interfere
with the synthesis of important fungal cell wall components
such as glucan, chitin and mannoproteins have
become a focus in the development of new antifungal
agents.
AMPHOTERICIN B
Amphotericin B, a polyene antibiotic, acts by binding
to ergosterol in the fungal cell membrane, disrupting
membrane stability and quickly causing cell death.
Because of its efficacy against a broad spectrum of yeast
and filamentous fungal pathogens, amphotericin B has
traditionally been the treatment of choice for invasive
fungal infections in human and small animal patients.
However, its application has been hindered by
nephrotoxicity, which limits the total dose that can be
administered and prevents its use in patients with
underlying renal dysfunction. However, the use of
novel delivery systems has been effective in reducing
nephrotoxicity and improving organ-specific delivery of
amphotericin B.
Clinical applications
● Initial treatment of choice for rapidly progressive
systemic mycoses in which oral triazoles are unlikely
to act quickly enough.
● Initial therapy for dogs with cryptococcal meningitis
in which case it may be combined with flucytosine
as well as fluconazole.
● Treatment of systemic mycoses that fail to respond
to azole therapy.
● Treatment of animals with mycotic gastrointestinal
disease such as pythiosis or zygomycosis in which
persistent vomiting precludes the administration of
oral medications.
● Treatment of blastomycosis, histoplasmosis, cryptococcosis,
coccidioidomycosis, candidiasis, sporotrichosis
and pythiosis.
Mechanism of action
Amphotericin B binds to ergosterol in the fungal cell
membrane, causing depolarization and increased membrane
permeability, leakage of cell contents and cell
death. The clinical usefulness of this drug is based on
its greater affinity for ergosterol in the fungal cell
membrane than for cholesterol in the mammalian cell
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