Selective toxicity antifungal drugs

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

What is it about fungal cells that is different to human cells and allows selective toxicity of antifungal drugs such as amphotericin, ketoconazole and terbinafine ... 

It is not surprising that the membranes of prokaryotic cells such as bacteria and fungi have characteristics differing considerably from eukaryotic cells. Compounds that will disrupt the functions of these membranes, but not similarly affect mammalian cells, may be useful as selectively toxic antimicrobials. In fact, there now exist a number of important antifungal and antibacterial drugs that do just that—they disrupt the membranes of these pathogens. 

Figure 48-2. Sites of action of some antifungal drugs. The cell cytoplasmic membrane shown is that of a typical fungus. Because ergosterol is not a component of mammalian membranes, significant selective toxicity is achieved with the azole drugs.

To evaluate whether incorporation of AmB into lipid formulations reduces nephrotoxicity, any comparison of conventional AmB with a new formulation of the drug should address the following questions 1) do the different formulations have the same or different actions 2) if they have the same action, what is the dose ratio between antifungal and toxic effects, especially nephrotoxicity and 3) is there a selective advantage in the dose ratios indicating a wider therapeutic margin, i.e., is the dose ratio of lipid formulation of AmB/ AmB lower for the antifungal effect compared to the nephrotoxic effect ... 

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