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Fungi cause both superficial and serious systemic infections in children. Eradication of fungal infections typically involves the use of agents that inhibit cell membrane function, leading to cell death. Selection of the appropriate medication for fungal infections depends on the susceptibility of the organism and the adverse effects of the drug. The major classes of systemic antifungal agents are polyenes, azoles, and echinocandins.The most commonly used polyene is amphotericin B. Since 1960, this product of the actinomycete Streptomyces nodosus has been widely used for systemic infections against a broad array of fungal species. Amphotericin B deoxycholate, the conventional formulation of this drug, remains the preferred treatment for newborns with systemic candidiasis because of its better penetration into the central nervous system, urinary tract, and eye. However, potential adverse reactions, particularly renal toxicity, necessitate close monitoring. Lipid-associated and liposomal formulations of amphoterin B are less toxic, but their penetration into some tissues, such as the kidney, does not reach therapeutic concentrations.Amphotericin B is only available parenterally. It must be mixed in a dextrose and water solution because saline causes it to precipitate. Because of infusion reactions such as fever and chills, some patients must be premedicated with acetaminophen and diphenhydramine. Less common reactions include nausea, vomiting, headache, malaise, hypotension, and arrhythmias, which require the addition of hydrocortisone, although these reactions are less common in children than in adults.Amphotericin B may cause nephrotoxicity, hepatoxicity, anemia, and neurotoxicity. Nephrotoxicity may be increased by concurrent administration of aminoglycosides, cyclosporine, tacrolimus, cisplatin, nitrogen mustard compounds, and acetazolamide. Early signs of nephrotoxicity include increasing blood urea nitrogen (BUN) and creatinine values, hypokalemia, and hyponatremia. Permanent nephrotoxicity is related to the cumulative dose that is administered. BUN and creatinine should be assessed every other day while adjusting the amphotericin B dose and followed weekly thereafter along with electrolytes. Hydration and sodium repletion before administration of amphotericin B may decrease the risk of developing nephrotoxicity.Two subclasses of azoles are used to treat fungal infections: imidazoles and the newer triazoles. Imidazoles include clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, and sulconazole. Ketoconazole was the first oral antifungal used to treat systemic infections and has a broad spectrum of coverage. Although newer triazole antifungals are available, oral ketoconazole can be used as a secondline therapy for certain Candida species and invasive histoplasmosis, blastomycosis, and coccidiomycosis.Because absorption of oral ketoconazole depends on gastric pH, antacids and histamine-2 blockers may decrease its activity. Ketoconazole can mount therapeutic AUTHOR DISCLOSURE Dr Smitherman has discl...
Fungi cause both superficial and serious systemic infections in children. Eradication of fungal infections typically involves the use of agents that inhibit cell membrane function, leading to cell death. Selection of the appropriate medication for fungal infections depends on the susceptibility of the organism and the adverse effects of the drug. The major classes of systemic antifungal agents are polyenes, azoles, and echinocandins.The most commonly used polyene is amphotericin B. Since 1960, this product of the actinomycete Streptomyces nodosus has been widely used for systemic infections against a broad array of fungal species. Amphotericin B deoxycholate, the conventional formulation of this drug, remains the preferred treatment for newborns with systemic candidiasis because of its better penetration into the central nervous system, urinary tract, and eye. However, potential adverse reactions, particularly renal toxicity, necessitate close monitoring. Lipid-associated and liposomal formulations of amphoterin B are less toxic, but their penetration into some tissues, such as the kidney, does not reach therapeutic concentrations.Amphotericin B is only available parenterally. It must be mixed in a dextrose and water solution because saline causes it to precipitate. Because of infusion reactions such as fever and chills, some patients must be premedicated with acetaminophen and diphenhydramine. Less common reactions include nausea, vomiting, headache, malaise, hypotension, and arrhythmias, which require the addition of hydrocortisone, although these reactions are less common in children than in adults.Amphotericin B may cause nephrotoxicity, hepatoxicity, anemia, and neurotoxicity. Nephrotoxicity may be increased by concurrent administration of aminoglycosides, cyclosporine, tacrolimus, cisplatin, nitrogen mustard compounds, and acetazolamide. Early signs of nephrotoxicity include increasing blood urea nitrogen (BUN) and creatinine values, hypokalemia, and hyponatremia. Permanent nephrotoxicity is related to the cumulative dose that is administered. BUN and creatinine should be assessed every other day while adjusting the amphotericin B dose and followed weekly thereafter along with electrolytes. Hydration and sodium repletion before administration of amphotericin B may decrease the risk of developing nephrotoxicity.Two subclasses of azoles are used to treat fungal infections: imidazoles and the newer triazoles. Imidazoles include clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, and sulconazole. Ketoconazole was the first oral antifungal used to treat systemic infections and has a broad spectrum of coverage. Although newer triazole antifungals are available, oral ketoconazole can be used as a secondline therapy for certain Candida species and invasive histoplasmosis, blastomycosis, and coccidiomycosis.Because absorption of oral ketoconazole depends on gastric pH, antacids and histamine-2 blockers may decrease its activity. Ketoconazole can mount therapeutic AUTHOR DISCLOSURE Dr Smitherman has discl...
Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since those currently available are limited and do not completely provide safe and secure protection. Since the current knowledge regarding the physiology of fungal cells and the infection mechanisms is greater than ever, we have the opportunity to use this for the development of novel generations of antifungals. In this review, we selected and summarized recent studies describing agents employing different antifungal mechanisms. These mechanisms include interference with fungal resistance, including impact on the efflux pumps and heat shock protein 90. Additionally, interference with virulence factors, such as biofilms and hyphae; the impact on fungal enzymes, metabolism, mitochondria, and cell wall; and antifungal vaccines are explored. The agents investigated belong to different classes of natural or synthetic molecules with significant attention given also to plant extracts. The efficacy of these antifungals has been studied mainly in vitro with some in vivo, and clinical studies are needed. Nevertheless, there is a large quantity of products employing novel antifungal mechanisms that can be further explored for the development of new generation of antifungals.
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