Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 9 SYSTEMIC ANTIFUNGAL THERAPY
● Infusion-related side effects such as pyrexia, tremors,
nausea and vomiting may occur in some animals
during intravenous administration of amphotericin
B. These effects can be diminished by pretreating
patients with an antihistamine (e.g. diphenhydramine,
2 mg/kg IV or PO), aspirin (10 mg/kg PO), or
a physiological dose of a glucocorticoid prior to subsequent
infusions.
● Other potential side effects include thrombophlebitis,
hypomagnesemia, cardiac arrhythmias and nonregenerative
anemia.
Contraindications and precautions
Amphotericin B should be used with caution in animals
that have pre-existing renal disease. In azotemic animals
with systemic mycoses that are not immediately lifethreatening,
the use of triazole antifungal agents should
be considered instead of amphotericin B for initial
treatment.
Known drug interactions
● Because amphotericin B deoxycholate is solubilized
in a phosphate-containing buffer, it should not be
diluted in calcium-containing fluids.
● The use of amphotericin B with other nephrotoxic
drugs (such as aminoglycosides) should be avoided.
Amphotericin b lipid complex
(ABLC; Abelcet®)
The use of novel delivery systems has been effective in
reducing toxicity and improving organ-specific delivery
of many drugs, including amphotericin B. The development
of liposomal-encapsulated and lipid-complexed
preparations of amphotericin B has reduced its nephrotoxicity
and increased its uptake by specific tissue sites.
There are currently three novel formulations of amphotericin
B marketed for clinical use in human patients:
amphotericin B lipid complex (Abelcet®), amphotericin
B colloidal dispersion (Amphotec®) and liposomeencapsulated
amphotericin B (AmBisome®). These formulations
offer an improved therapeutic index, in part
because they increase the drug’s uptake by tissues such
as the liver and lungs, preventing its accumulation in
the kidneys. Of the three formulations, amphotericin B
lipid complex (Abelcet®) has been the most extensively
evaluated in small animals.
Clinical applications
Clinical trials in human patients have documented the
efficacy and improved therapeutic index of lipidcomplexed
amphotericin B for the treatment of many
common fungal pathogens, including Candida, Aspergillus,
Cryptococcus, Histoplasma, Blastomyces and
Coccidioides immitis. In small animal patients, ABLC
has been used successfully for the treatment of blastomycosis,
coccidioidomycosis, histoplasmosis, cryptococcal
meningitis, protothecosis and pythiosis.
Mechanism of action
The improved therapeutic index of ABLC has been demonstrated
in numerous animal studies. In dogs receiving
multiple doses, ABLC was determined to be 8–10 times
less nephrotoxic than conventional amphotericin B.
This decreased nephrotoxicity can be attributed to
several factors.
● Lipid binding results in reduction of amphotericininduced
direct tubular toxicity.
● Lipid binding reduces the amount of free amphotericin
in solution.
● Lipid complexes provide the opportunity for selective
transfer of amphotericin from its lipid carrier to
ergosterol in the fungal cell membrane.
● Binding of lipid-complexed amphotericin to highdensity
lipoproteins results in decreased uptake by
renal cells.
In human studies, lipid-based products significantly
reduced the risk of all-cause mortality by an estimated
28% compared with conventional amphotericin B.
The primary reduction in toxicity was related to
reduced nephrotoxicity. Infusion-related toxicities
were not significantly different from conventional
amphotericin B.
In animal studies the primary reason for increased
efficacy is reduced toxicity, allowing higher cumulative
doses to be obtained. The increased efficacy of ABLC
may also be due to the rapid uptake of lipid complexes
by the reticuloendothelial (RE) system. As a result, the
drug is able to target sites of inflammation and organs
of the RE system, such as the liver, spleen and lungs.
Once at the target site, lipases from either fungal or
inflammatory cells may release the amphotericin B from
its lipid complex, allowing it to bind to and disrupt the
fungal cell membrane.
Formulations and dose rates
ABLC is diluted in 5% dextrose to a concentration of 1 mg/mL
and infused intravenously over 1–2 h. As with traditional amphotericin,
serum creatinine, BUN and potassium should be checked prior to
each administration. Preloading with saline fl uids to protect from
nephrotoxicity does not appear to be necessary when administering
ABLC.
DOGS
• 2–3 mg/kg of ABLC IV 3 days per week for a total of 9–12
treatments, to a cumulative dose of 24–27 mg/kg
CATS
• 1 mg/kg 3 days per week for a total of 12 treatments to a
cumulative dose of 12 mg/kg
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