Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 9 SYSTEMIC ANTIFUNGAL THERAPY
ANTIFUNGAL AGENTS THAT TARGET
THE FUNGAL CELL WALL
Because of their potential for greater selective toxicity,
compounds that interfere with the synthesis of important
fungal cell wall components (glucan, chitin and
mannoproteins) have recently become a focus in the
development of new antifungal agents.
b-glucan synthase inhibitors
Echinocandins and pneumocandins represent a class of
antifungal agents (the lipopeptides) that hold perhaps
the greatest promise for changing the way in which
systemic mycoses are treated in the next decade. These
fungicidal compounds act by inhibiting β-glucan synthase,
blocking the synthesis of 1,3-β-D-glucan, a structural
fungal cell wall component that is not present in
mammalian cells. Recently, a new generation of echinocandins
with improved water solubility, enhanced
potency and an expanded spectrum of antifungal activity
has been developed. Because of their poor oral bioavailability,
these drugs can only be administered
intravenously. The primary limitation of this class of
antifungals is their ineffectiveness against Cryptococcus
neoformans, which contains very little glucan synthase.
In general, the echinocandins are well tolerated and
are associated with relatively few adverse effects in
humans.
Caspofungin (Cancidas®, Merck), the first of the β-
glucan synthase inhibitors to gain FDA approval, is a
broad-spectrum parenteral formulation that has potent
activity against Aspergillus and Candida species. In
addition, it is highly effective for the treatment of Pneumocystis
carinii (jiroveci) pneumonia because of its
ability to prevent development of the cyst form, in
which glucans are a major structural wall component.
In human patients, caspofungin is indicated for the
treatment of invasive aspergillosis and candidiasis. Its
clinical niche is similar to that of the newer formulations
of amphotericin B, but with fewer side effects, and with
fewer drug interactions than the azoles. In veterinary
patients, caspofungin is indicated for the treatment of
systemic aspergillosis, pythiosis, lagenidiosis and refractory
endemic mycoses other than crytococcosis. Unfortunately,
its expense renders it unavailable to the vast
majority of small animal patients.
Micafungin (Mycamine®, Astellas Pharma) is a
similar echinocandin that has been approved by the
FDA for the treatment of oroesophageal candidiasis and
the prevention of candidal infections in neutropenic
patients.
Anidulafungin (Pfizer) is an echinocandin with a spectrum
of activity similar to that of caspofungin. It has
been evaluated in clinical trials for the treatment of
oroesophageal candidiasis, candidemia and invasive
candidiasis and is currently under FDA review.
Chitin synthase inhibitors
Nikkomycins are competitive inhibitors of chitin synthase
that have been most extensively evaluated for their
activity against Coccidioides immitis, a fungal pathogen
with high chitin content. One member of this group,
Nikkomycin Z, was found to be highly effective for the
treatment of coccidioidomycosis in animal models.
Unfortunately, the spectrum of activity of nikkomycins
for other systemic mycoses is limited and as a result, this
class of antifungals is no longer being developed.
Lufenuron (Program®) is a chitin synthase inhibitor
of the benzoylphenyl urea class. It has been evaluated
for the treatment of pulmonary coccidioidomycosis in
17 dogs treated with 5–10 mg/kg once daily for 16
weeks. Clinical and radiographic improvement was
noted in most of these dogs. However, because spontaneous
remission may occur in infected dogs without
treatment, it is unclear whether or not the clinical
improvement was attributable to lufenuron administration.
Dogs with disseminated coccidioidomycosis have
not responded well to lufenuron therapy. A recent in
vitro study showed that lufenuron had no antifungal
activity against isolates of Coccidioides immitis and
Aspergillus fumigatus. Lufenuron is not recommended
for the treatment of systemic mycoses in veterinary
patients.
FURTHER READING
Barrett JP, Vardulaki KA, Conlon C et al 2003 A systematic review of
the antifungal effectiveness and tolerability of amphotericin B
formulations. Clin Ther 25: 1295-1320
Boothe DM, Herring I, Calvin J et al 1997 Itraconazole disposition after
single oral and intravenous and multiple oral dosing in healthy cats.
Am J Vet Res 58: 872-877
Chen A, Sobel JD 2005 Emerging azole antifungals. Expert Opin
Emerg Drugs 10: 21-33
Clode AB, Davis JL, Salmon J et al 2006 Evaluation of concentration of
voriconazole in aqueous humor after topical and oral administration
in horses. Am J Vet Res 67: 296-301
Davidson AP 2005 Coccidioidomycosis and aspergillus. In: Ettinger SJ,
Feldman EC (eds) Textbook of veterinary internal medicine, 6th edn.
Elsevier, Philadelphia, PA: 690-699
De Marie S 1996 Liposomal and lipid-based formulations of
amphotericin B. Leukemia 10(suppl 2): S93-S96
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