Trade & Generic Names & General Features Voriconazole (UK-109,496) is a triazole that is structurally related to fluconazole. It is developed by Pfizer Pharmaceuticals ((E):http://www.pfizer.com(E):) and its clinical use was approved by FDA in May 2002. The trade name of voriconazole is Vfend™. Mechanism(s) of Action As with all azole antifungal agents, voriconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol [1674, 1735]. Compared to fluconazole, voriconazole inhibits P45014DM to a greater extend. This inhibition is dose-dependent [2016]. Susceptibility Patterns Voriconazole has favorable in vitro […]

There are a number of topical agents used in treatment of superficial cutaneous mycoses, oropharyngeal candidiasis, and vulvovaginal candidiasis. The superficial cutaneous mycoses that respond to topical therapy include the localized infections of hair, nails, and epidermis due to the dermatophytes and Candida. While some of these topical agents are polyenes, azoles (imidazoles) or allylamines, others are of distinct chemical classes. In addition to those used for treatment of cutaneous, oropharyngeal, and vulvovaginal fungal infections, an ophthalmic topical antifungal agent, pimaricin (natamycin) is also available. Pimaricin is a polyene used in treatment of keratomycosis. Its commercial formulation is an ophthalmic […]

Background Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids (typically serum) and applying well-described pharmacokinetic and pharmacodynamic principles of the drug to optimize a treatment regimen for an individual patient [2197]. Typically, four criteria must be fulfilled to justify the use of serum drug concentrations to guide drug dosing: First, an assay with appropriate sensitivity, specificity and “turnaround time” from the clinical laboratory must be available for analysis of the drug in question. Second, the clinical efficacy or toxicity of the drug must be delayed or difficult to directly measure. Third, the drug must exhibit […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Terbinafine is an allylamine structurally related to naftifine. It is a synthetic antifungal agent. It is highly lipophilic in nature and tends to accumulate in skin, nails, and fatty tissues [656, 1934]. Terbinafine has oral and topical (cream) formulations. Oral preparation has been first introduced in 1991 in United Kingdom and approved for clinical use in 1996 in USA [950, 1014]. It is being manufactured by Novartis Pharmaceuticals. Its trade name is Lamisil. Mechanism(s) of Action As with the other allylamines, terbinafine inhibits ergosterol biosynthesis via inhibition of squalene epoxidase. […]

All drugs have two costs. In addition to their acquisition costs, cost of monitoring and treatment of side effects must also be considered. These secondary costs are especially important with antifungal agents. Invasive fungal infections are often difficult to diagnose, resistant to treatment, and associated with high rates of morbidity and mortality [1980]. It is not surprising, then, that invasive fungal infections are also one of the most expensive complications that can be encountered in hospitalized patients. Until recently, studies examining the pharmacoeconomics of antifungal therapy were a low priority, as few antifungal therapies were available and costs related to […]

Trade & Generic Names Ravuconazole (formerly BMS-207147 and ER-30346) is a triazole structurally related to fluconazole and voriconazole. It is being developed by Bristol-Myers Squibb for oral use. Its trade name has not been announced. Mechanism(s) of Action As with all azole antifungal agents, ravuconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol [2092]. The potency of ravuconazole to inhibit sterol C14 demethylation is similar to that of itraconazole [995]. Susceptibility Patterns Ravuconazole is active against Candida spp., Cryptococcus neoformans, Aspergillus fumigatus, dermatophytes and dematiaceous […]

Posaconazole (Noxafil) Mechanism(s) of Action As with all azole antifungal agents, posaconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Compared to Itraconazole, posaconazole is a significantly more potent inhibitor of sterol C14 demethylation, particularly in Aspergillus [1597]. Susceptibility Patterns The in vitro activity of posaconazole has been tested against more than 18,000 clinical strains of yeasts and moulds. The MIC50 and MIC90 values for posaconazole were 0.063 and 1 mg/mL, respectively. The MIC90 value for posaconazole against all yeasts (18,351 MICs) and moulds (4499 […]

These very potent agents act by binding to the fungal cell membrane and causing the fungus to leak electrolytes. Amphotericin B Amphotericin B Lipid Complex (ABLC) Amphotericin B Colloidal Dispersion (ABCD) Liposomal Amphotericin B (L-AMB) Liposomal Nystatin

Griseofulvin

Background Nephrotoxicity is one of the more problematic adverse effects of antifungal therapy, specifically with amphotericin B. Although generally reversible, up to 10{64e6c1a1710838655cc965f0e1ea13052e867597ac43370498029d1bc5831201} of patients with significant kidney dysfunction on amphotericin B will require persistent dialysis after discontinuation of the antifungal [Groll, Piscitelli et al. 1998]. A patient’s risk of developing severe kidney damage during amphotericin B therapy depends on the dose and duration of amphotericin B, underlying health and fluid status of the patient, previous or underlying kidney disease, and the receipt of other potentially nephrotoxic drugs (e.g., aminoglycoside antibiotics, radiocontrast dye, cyclosporine, etc.). For these reasons, the incidence […]

Micafungin (Mycamine®) Trade & Generic Names & General Features Micafungin is a glucan synthesis inhibitor of the echinocandin structural class. It is currently approved for the prevention of Candida infections in patients undergoing hematopoetic stem cell transplantation or the treatment of esophageal candidiasis. Mechanism(s) of Action As with other echinocandins, micafungin blocks the synthesis of a major fungal cell wall component, 1-3-beta D-glucan [1267]. Susceptibility Patterns Micafungin appears to be similar to caspofungin and anidulafungin in terms of susceptibility profile. It has a broad spectrum of activity against Candida spp., including azole-resistant C. albicans. [1418]. As with other agents of […]

Shown are the agents that have been licensed or are under development for use as therapy of the fungal infections of man. Picking the most appropriate agent for a given disease is sometimes complex. To aid in this process, see our discussion of agents of choice and the discussions of the individual mycoses themselves. Mixed into the list are also the many topical agents in use for cutaneous mycoses. Please also see our discussion on antifungal pharmacology, nephrotoxicity, drug dosing in renal and liver dysfunction, drug interactions, therapeutic drug monitoring, cost analysis, and pharmacoeconomic analysis of antifungal therapy. Group Drugs […]

Trade & Generic Names & General Features Liposomal nystatin is a lipid-based polyene antifungal agent. It is composed of nystatin incorporated into liposomes containing dimyristoyl phosphotidyl choline and dimyristoyl phosphotidyl glycerol. Aiming to reduce the systemic toxicity of nystatin, liposomal nystatin was first developed in 1987 by Lopez-Berestein et al. [1505, 2382]. It is being manufactured by Aronex Pharmaceuticals under the generic name liposomal nystatin and the trade name Nyotran™. It is in late Phase III clinical trials. Mechanism(s) of Action Similar to other polyene antifungal agents, nystatin binds to ergosterol in the fungal membrane. This binding disrupts osmotic integrity […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Liposomal amphotericin B (L-AMB) is a lipid formulation of amphotericin B. As with the other lipid formulations, the major goal of developing L-AMB has been to attain a compound with lower toxicity and with at least similar efficacy compared to the parent compound, amphotericin B deoxycholate. L-AMB is composed of amphotericin B complexed with hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol. Unlike the other lipid formulations of amphotericin B, it is a true liposome composed of unilamellar lipid vesicles [14, 1044]. L-AMB is being manufactured by Nexstar Pharmaceuticals (San Dimas, CA, […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Ketoconazole is an imidazole antifungal agent. As with other imidazoles, it has five-membered ring structures containing two nitrogen atoms. It is marketed as Nizoral™ by Janssen Pharmaceutica ((E):http://us.janssen.com/(E):). Ketoconazole has oral tablet, cream and dandruff shampoo formulations. The oral formulation is available in USA since 1981. Ketoconazole is the only member of the imidazole class that is currently used for treatment of systemic infections. Ketoconazole is a highly lipophilic compound. This property leads to high concentrations of ketoconazole in fatty tissues and purulent exudates. Expectedly, the distribution of ketoconazole into […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Itraconazole is triazole antifungal agent. As with other triazoles, it has five-membered ring structures containing three nitrogen atoms [2092]. It is available in oral capsule form (since 1992), oral solution in cyclodextrin (since 1997) and intravenous formulation in hydroxy-propyl-beta-cyclodextrin (since 1999). In its capsule and oral solution form, itraconazole is marketed as Sporanox™ by Janssen Pharmaceuticals ((E):http://us.janssen.com/(E):). The intravenous formulation is marketed by Ortho Biotech. Itraconazole is a highly lipophilic compound. While it achieves high concentrations in fatty tissues and purulent exudates, its penetration into aqueous fluids remains very limited. […]

Trade & Generic Names & General Features Griseofulvin is an antifungal agent first isolated from a Penicillium spp. in 1939. The compound is insoluble in water. It is effective after oral ingestion and reaches the skin and hair. It is deposited primarily in keratin precursor cells. Ingestion with a heavy meal and reduction in particle size enhances the absorption of griseofulvin [1347]. Griseofulvin is currently produced by different companies. The microcystalline form is marketed as Grifulvin V™ (Ortho Dermatological). (Fulvicin U/F™ (Schering) and Grisactin™ (Wyeth-Ayerst), the other two microcrystalline products are no longer marketed.) Ultramicrocrystalline form is marketed as Gris-PEG™ […]

The glucan synthesis inhibitors are, collectively, agents which are presumed to block fungal cell wall synthesis by inhibiting the enzyme 1,3-beta glucan synthase. As technical issues in the laboratory have made formal proof of the assertion that this enzyme is actual target of these compounds, it is most correct to speak of them at present as being glucan synthesis inhibitors rather than glucan synthase inhibitors. There are three such agents at present, with all three belonging to the chemical family also known as the echinocandins. Caspofungin Micafungin Anidulafungin

Trade & Generic Names Flucytosine (5-fluorocytosine; 5-FC; 4-amino-5-fluoro-2-pyrimidone) is an antimetabolite type of antifungal drug. It is chemically a pyrimidine. It is activated by deamination within the fungal cells to 5-fluorouracil. Flucytosine is marketed as AncobonTM by Roche Laboratories. It is available as oral capsules since 1972 in USA. Its intravenous formulation is no longer available. Mechanism(s) of Action Flucytosine is the the only available antimetabolite drug having antifungal activity. It inhibits fungal protein synthesis by replacing uracil with 5-flurouracil in fungal RNA. Flucytosine also inhibits thymidylate synthetase via 5-fluorodeoxy-uridine monophosphate and thus interferes with fungal DNA synthesis [219, 2055]. […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Fluconazole is a widely used bis-triazole antifungal agent. As with other triazoles, it has five-membered ring structures containing three nitrogen atoms. It is marketed as Diflucan® by Pfizer Pharmaceuticals ((E):http://www.pfizer.com(E):). Both oral and intravenous formulations of fluconazole are available. Mechanism(s) of Action As with all azole antifungal agents, fluconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol [1394, 1445, 1674]. Susceptibility Patterns Fluconazole is generally considered to be a fungistatic agent. It is principally active […]

This page summarizes primary and alternative drugs for the treatment of specific fungal infections. This page focuses on medical therapeutic approaches and it must be remembered that other therapeutic measures (most commonly, surgical excision and debridement) are required in combination with antifungal therapy for some fungal infections. Please refer to the related page about each fungal infection for additional data. Please also see our discussion on cost analysis and pharmacoeconomic analysis of antifungal therapy. The tables are presented in two sections. The first table shows drugs of choice and the second table shows suitable dosages. These abbreviations are used throughout […]

What does it cost? The cost of antifungal therapy is institution-, treatment setting-, and patient-specific.   The information presented below serves as a general reference to cost issues associated with antifungal therapy. On this page, three tables are provided comparing the U.S. average wholesale price (AWP) for antifungals: Used to treat invasive infections, Used to treat onychomycosis, and Used as topical therapy. All AWP pricing data were extracted from the 2006 Drug Topics Redbook (Published by Medical Economics, Inc. (E):http://www.medec.com). Please note, the AWP does not necessarily reflect contract prices paid by individual institutions, which can vary widely based on […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Formerly L-743,872 and MK-0991, caspofungin is a polypeptide antifungal related to pneumocandin B0. It is a glucan synthesis inhibitor of the echinocandin structural class. It is manufactured by Merck Research Laboratories and its trade name is Cancidas™. Mechanism(s) of Action Caspofungin blocks the synthesis of a major fungal cell wall component, 1-3-beta-D-glucan. Although some authorities suggest that the inhibition of glucan synthesis occurs via inhibition of 1,3-beta-glucan synthase [1267], there is yet no evidence to prove this theory. The lack of glucan synthesis enzymes in mammalian tissue makes this an […]

Manufacturer’s Prescribing Information Trade & Generic Names & General Features Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphthalenemethyl-amine hydrochloride) is a benzylamine derivative and a new generation topical antifungal compound. It has favorable activity against various dermatophytes, as well as Candida albicans. Butenafine achieves high concentrations in skin and remains in skin tissue for prolonged periods (24 hours in guinea pigs). It is mostly distributed in epidermis. A small amount is detectable also in dermis, probably due to its transport via sebaceous glands and hair follicles. Importantly, butenafine exerts anti-inflammatory as well as antifungal activity in vivo. This property is particularly beneficial in dermatophytic infections that […]

The azole antifungal agents inhibit the synthesis of ergosterol by blocking the action of 14-alpha-demethylase. Fluconazole Itraconazole Ketoconazole Ravuconazole Posaconazole Voriconazole

This class has only example, flucytosine. This small molecule is a DNA substrate analog that leads to incorrect DNA synthesis. Flucytosine

Fungal Cell Structure and Targets Knowledge of fungal cell structure and function is essential for understanding the pharmacology of antifungal agents. Like mammalian cells, fungi are eukaryotes with DNA organized into chromosomes within the cell nucleus and have distinct cytoplasmic organelles including endoplasmic reticulum, Golgi apparatus, mitochondria, and storage vacuoles. This homology to mammalian cells also extends to biosynthetic pathways, where fungi share similar mechanisms for DNA replication and protein synthesis. The similarity of fungal and mammalian cells creates a number of problems for designing drugs that are selectively toxic to fungal cells but not the human host. Antifungal agents […]

Background Drug interactions can arise with virtually any antifungal therapy and occur primarily in the gastrointestinal tract, liver and kidneys by several distinct mechanisms. The majority of drug interactions are pharmacokinetic in nature, resulting in changes in the absorption or elimination of the interacting drug as well as the antifungal agent [922]. In the GI tract, changes in pH, complexation with ions, or interference with transport and enzymatic processes in the intestinal lumen can interfere with drug absorbance. Induction or inhibition of metabolism in the liver can inhibit or accelerate, respectively, drug clearance from the body. In the kidney, decreases […]

Antifungal Dosage Adjustment in Hepatic Failure A number of antifungals require biotransformation into more water-soluble metabolites by the liver before excretion from the body. Antifungals are also known to have, like many other drugs, potentially toxic effects in the liver that may be enhanced with pre-existing liver disease. Therefore, antifungal therapy must be used in caution in patients with hepatic insufficiency. In terms of drug dosing, patients with moderate to severe hepatic dysfunction often exhibit a decreased capacity to metabolize certain antifungal agents, leading to decreased overall drug clearance, an increase in the plasma/serum area under the concentration curve (AUC), […]