ANTIFUNGAL THERAPY: PAST, PRESENT, AND FUTURE
ANDREW HANZLICEK, DVM, MS, DACVIM MiraVista Diagnostics, Indianapolis, Indiana
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Skin lesions, due to vasculitis, have also been reported which are most common with itraconazole. 1 Adverse effects of itraconazole can be mostly avoided with therapeutic drug monitoring of itraconazole blood levels (see below). The antifungal activity of azoles is determined by the area-under-the- curve, when blood concentrations are plotted against minimum inhibitory concentrations (AUC/MIC). This means that the daily dose (mg/kg/day), not the frequency, is most important. As such, fluconazole and itraconazole can be administered once or twice daily to dogs and cats. 3 FLUCONAZOLE Fluconazole is a relatively small molecule with low protein binding, which leads to better penetration of immunoprotected sites such as the CNS and eye. It can be given with food or on an empty stomach and can be given concurrently with antacids. FDA generic tablets of several sizes (50, 100, 200 mg) and solution make fluconazole an affordable option. Fluconazole is highly bioavailable, although a recent population based pharmacokinetic study found high variability in blood concentrations. 2 This suggests that therapeutic drug monitoring might be useful clinically. Dimorphic fungi such as Histoplasma, Blastomyces , and Coccidioides are significantly more sensitive to itraconazole as compared with fluconazole. In addition to inherent resistance, acquired resistance to fluconazole has been reported.
Fluconazole is excreted mostly unchanged in the urine making it ideal for fungal infections of the urinary tract. Doses might need to be decreased with kidney disease. Fluconazole is the drug of choice for cryptococcosis and is the most commonly used drug for coccidioidomycosis (valley fever). It can also be used to treat histoplasmosis and blastomycosis when itraconazole is not tolerated. Fluconazole is not effective against molds such as Aspergillus . 4 ITRACONAZOLE Itraconazole, as compared with fluconazole, is a larger molecule with higher protein binding leading to relatively lower concentrations in immunoprotected sites. Due to high lipid solubility, absorption of the capsule is increased with a fatty meal. In contrast, the solution can be given with food or on an empty stomach. Absorption is dependent on the acidic gastric environment and is decreased by the concurrent administration of antacids. To facilitate oral bioavailability, itraconazole solution contains a solubilizing agent (cyclodextrin) and capsules contain drug coated spheres. Compounded itraconazole lacks these important inactive ingredients, and due to very low GI absorption, compounded drug consistently provides sub-therapeutic blood concentrations. Even when FDA approved drug is used, there is considerable variability in the GI absorption between animals. 3 This, along with dose-dependent adverse effects and known therapeutic blood concentrations, supports the use
Photo courtesy of Dr. Andrew Hanzlicek, MS, DACVIM
of itraconazole therapeutic drug monitoring. Itraconazole blood levels can be measured by chromatography- mass spectrometry or by bioassay. The bioassay measures the antifungal activity of the blood by measuring the inhibition of the growth of a fungus in the lab. It has the advantages of measuring itraconazole and active metabolites (hydroxy-itraconazole) and is significantly less expensive. Chromatography-spectrometry has the advantage of not being affected by concurrent administration of other antifungal drugs but is considerably more expensive and does not measure all active metabolites. For smaller animals, if the itraconazole solution is undesirable, FDA approved capsules can be opened and put over soft food or placed into smaller capsules. Moreover, every other day administration of 100 mg capsules has been shown to achieve therapeutic blood concentrations in cats. 4 (continued)
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