Antifungal agents

Tolnaftate (Tinactin®)

Antifungal Activity  Trichophyton, Microsporum, M. Epidermophyton. Therapeutic Uses  Effective in tinea pedis, tinea versicolor.  Not effective against onychomycosis

Caspofungin (Cancidas)

ECHINOCANDINS  Common mechanism of action: inhibit the synthesis of B(1-3)-glucan, resulting in disruption of the fungal cell wall and cell death. B(1-3)-glucan is not present in mammalian cell walls.  fungi are unlikely to develop resistance to the echinocandin class  lack of nephrotoxicity and few drug interactions make the echinocandin class attractive as antifungal treatment; remarkably well tolerated.  these drugs may be useful in patients with amphotericin B and azole-resistant fungal strains (Aspergillus and esophageal candidiasis in particular)  IV use only  indicated for the treatment of invasive aspergillosis in refractory patients (to amphotericin B or voriconazole)  effective for esophageal candidiasis  slow intravenous infusion  eliminated by the liver, half-life: 36-48 hours  increased liver enzymes (AST, ALT), histamine release, headache, chills, GI side effects occur  renal excretion

Micafungin (Mycamine)

ECHINOCANDINS  approved for the treatment of esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.  mean half-life ranges from 14—17.2 hours  IV infusion

Anidulafungin (Eraxis)

ECHINOCANDINS  approved for the treatment of esophageal candidiasis and other serious yeast and fungal infections  IV infusion

Amphotericin B (Fungizone®)

Mechanism of Action  Amphotericin B is a polyene antifungal antibiotic, interacts with sterol of fungal membrane, ergosterol, that results in the formation of membrane pores and the loss of intracellular components. Also impairs amino acid uptake - protein synthesis effects.  Resistant isolates have less ergosterol in their cell membrane  It is selective in its fungicidal effect because ergosterol, the cell membrane sterol it binds to, is only found in the cell membranes of fungi Spectrum  Broad antifungal spectrum - the most broad spectrum antifungal agent; thus, Amphoterin B remains useful for nearly all life-threatening, systemic mycotic infections (DOC for most systemic infections - sometimes in combo with other antifungals). Pharmacokinetics  Oral absorption is poor; nearly insoluble in water. Use parenteral administration (I.V.)  Liposomal preparations improve pharmacokinetics and decrease adverse effects.  Excreted slowly by the kidney, concentration of drug results in nephrotoxicity. Amphotericin B is also excreted extrarenally.  Renal/hepatic impairment and hemodialysis have little impact on drug concentration (even with a high degree of binding to plasma proteins), therefore no dose adjustment is required. Toxicities: Infusion related:  Fever (20%), chills (50%), muscle spasm, headache, vomiting - these are lessened by reducing the daily dose or infusion rate Cumulative related:  powerful nephrotoxic agent. Renal damage is dose dependent. Lipid formulations have less adverse effects  Variable azotemia. May necessitate dialysis.  The BUN and serum creatinine levels are elevated in nearly all patients.  Prolonged administration may lead to irreversible kidney damage.  Other potentially nephrotoxic agents such as aminoglycosides should be given with great caution.  Hypersensitivity - anaphylaxis, thrombopenia, flushing, pain, etc.  Acute hepatic failure, jaundice, anorexia, nausea, weight loss, hypokalemia. Therapeutic Uses  All patients requiring amphotericin B should be hospitalized initially.  Therapy is from 6 weeks to 3 or 4 months.  By injection - slow IV infusion for systemic infections

Ketoconazole (Nizoral®)

Mechanism of Action: Azoles  Common mechanism of action: Inhibits the synthesis of ergosterol through inhibition of the fungal cytochrome P450 enzyme (the fungal CYP3A enzyme, lanosine 14-demethylase) system which is required for converting lanosterol to ergosterol. The end result is a depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth (fungistatic).  The depletion of ergosterol reduces the binding sites for amphotericin B.  Good alternative for the treatment Amphotericin B resistant organisms. Spectrum  broad antifungal spectrum and has been tried as a substitute for Amphotericin B; better tolerance than Amphotericin B, but not as effective Pharmacokinetics  well absorbed after oral administration  Hepatic elimination  Widely distributed in the body, largely bound to plasma albumin, CNS penetration is low. Toxicity:  Ketoconazole is generally well tolerated.  GI upsets, pruritus  Transient elevation of serum enzymes  Dizziness, somnolence, headache, arthralgia, myalgia, transient fever and chills, nausea and vomiting, etc.  Inhibits P450 system (CYP3A4), drug interactions - other azoles with fewer drug interactions and toxicities have decreased the use of ketoconazole.  gynecomastia, inhibition of adrenal & testicular function

Flucytosine (Ancobon®)

Mechanism of action  Metabolic antagonism of fungal DNA and RNA. Flucytosine is converted to 5-fluorouracil which interferes with fungal DNA and RNA synthesis (and ultimately protein synthesis). Spectrum  Antifungal activity: DOC for Cryptococcus neoformans Pharmacokinetics  Well absorbed orally  Enters CSF and aqueous humor  Renal elimination Toxicity  Depression of bone marrow - anemia, leukopenia, thrombocytopenia  GI disturbances  May elevate AST, ALT - Indicates liver impairment. Effect is reversible upon discontinuation of the drug.

Miconazole (Monistat®, Micatin®)

Mechanism of action: similar to other azoles Antifungal Activity  Trichophyton, Epidermophyton, Microsporum, Candida, Cryptococcus, Aspergillus. Therapeutic Uses  Tinea pedis - 4 weeks  Vulvovaginal Candidiasis - Monistat Cream - 2 weeks.  Monistat 7R vaginal tablets - 7 days  Miconazole is claimed to be superior to Nystatin for Vulvovaginal candidosis.

Voriconazole (Vfend)

Spectrum • DOC for Aspergillus (with Amphotericin B) - unlike fluconazole, voriconazole exhibits activity against molds • approved for: -primary treatment of invasive aspergillosis -salvage therapy for infections due to Scedosporium sp. (Scedosporium apiospermum) or Fusarium sp. in patients refractory to or intolerant of other antifungal therapy -esophageal candidiasis Pharmacokinetics  IV and oral; hepatic elimination  drug interactions are numerous for voriconazole -dose reduction required for drugs metabolized by cytochrome P450 enzymes  extensively metabolized by, and is an inhibitor of cytochrome P450 enzymes 2C19, 2C9 and 3A4  enzyme CYP2C19 exhibits genetic polymorphism resulting in an approximately 4-fold higher voriconazole exposure in poor metabolizers vs. extensive metabolizers Toxicity  most frequent adverse effect has been visual impairment or photopsia characterized as transient alterations in the perception of light; reversible after discontinuation of the drug (within 14 days) or may disappear during continued dosing  headache, nausea/vomiting, fever, chills, peripheral edema, chest pain were other common adverse events in voriconazole studies.

Itraconazole (Sporanox®)

Spectrum  Itraconazole is an oral triazole antifungal agent that is closely related to ketoconazole but appears to have fewer adverse effects.  active against many of the same fungi as ketoconazole and fluconazole but has greater activity against Aspergillus (but voriconazole is the DOC for Asp).  approved for the treatment of Blastomyces dermatitidis, Histoplasma capsulatum,onychomycosis, esophageal candidiasis, and oropharyngeal candidiasis  Itraconazole is also under investigation for the treatment of dermatophyte skin infections Pharmacokinetics  oral - bioavailability: -from capsules s 40—55% if administered on an empty stomach; 90—100% if administered with a meal or cola beverage. -from the oral solution is about 55% under fed conditions and increases to about 72% under fasting conditions. -pharmacokinetic differences between the capsules and oral solution - two dosage forms should not be used interchangeably -To ensure maximal absorption, itraconazole oral solution should be administered without food, unlike the capsules or tablets which should be administered with a full meal.  Itraconazole is hepatically metabolized to at least 30 metabolites, one of which, hydroxy- itraconazole, is active.  Both the parent drug and its major metabolite are highly bound to plasma protein; protein binding for itraconazole is 99.8% and for hydroxy itraconazole is 99.5%. Adverse reactions:  GI effects - nausea/vomiting, diarrhea, and abdominal pain.  Adverse dermatological effects reported during therapy with itraconazole include rash, which appears more frequently in immunocompromised patients, and pruritus.  inhibits CYP3A4, numerous interactions (similar to ketoconazole)

TERBINAFINE (Lamisil®)

Topical  oral or topical  Oral terbinafine is highly effective for treating onychomycosis due to its fungicidal activity and ability to concentrate within the nail and has been found to be superior to griseofulvin and to itraconazole for the treatment of onychomycosis.  exerts its antifungal effect through interfering with fungal ergosterol biosynthesis by inhibiting the enzyme squalene monooxygenase.  fungicidal activity against dermatophytes. It is much less active, however, against Candida. widely distributed, including the CNS and nail beds.  there does not appear to be a need for dosage adjustments in patients with hepatic or renal impairment. Adverse reactions  GI disturbances  Rare cases of hepatic failure in patients with underlying hepatic diseases

GRISEOFULVIN (Fulvicin U/F®)

Topical  produced from a fungus called Penicillium griseofulvum, is one of the oldest antifungal agent mostly used to treat ringworm infections of skin, hair, and nails. Antifungal Spectrum  Epidermophyton, Microsporum, and Trichophyton Mechanism of Action  Binds to the microtubules of certain fungi and destroys the mitotic spindle structure thereby prevent cell division and multiplication of susceptible fungi.  fungistatic Pharmacokinetics  Oral  Poor solubility results in poor absorption from GI tract.  Microcrystalline form of griseofulvin is claimed to provide slightly better absorption. Its absorption is also better when given with fatty food.  It binds specially to keratin. High concentrations of griseofulvin are found in the Stratum corneum and outer most layer of the epidermis. It also binds to keratin precursor cells and makes them resistant to fungal infection.  Most of the drug is excreted unchanged in the feces. Toxicity  GI disturbance, GI upset, headache, and other CNS effects.  Hematological disturbances, skin rashes, photosensitivity, angioedema, albuminuria, hepatotoxicity, leukopenia, etc.  Estrogen-like effects in some children  Disulfiram-like effects  Contraindication: acute intermittent porphyria, hepatocellular failure, pregnancy Drug Interactions  Reduces the activity of warfarin like anticoagulants  Barbiturates decrease the absorption of griseofulvin from the GI Therapeutic Uses  Systemic treatment of dermatophytosis (Mycotic infection of the skin, hair, nails (athlete's foot, onychomycosis)).  mostly used to treat ringworm infections of skin, hair, and nails.  Binds to the microtubules of certain fungi and destroys the mitotic spindle structure  fungistatic  It binds specially to keratin

Naftifine (Naftin®)

 Naftifine is a broad-spectrum antifungal agent believed to interfere with sterol biosynthesis, similarly to terbinafine.  It is used topically primarily for tinea pedis, tinea cruris, and tinea corporis. Contraindications/Precautions: Not for ophthalmic use. Drug Interactions: No significant interactions. Adverse Reactions: Burning, stinging, dryness, erythema, pruritus, local irritation, rash.

NYSTATIN (Mycostatin®)

 Nystatin is another polyene antibiotic (similar to amphotericin B), primarily used for candidal and also other fungal infections.  It binds to sterol moiety in fungal membrane, altering permeability thereby, allowing leakage of small molecules from the cell & causing cell death.  oral or topical  Not absorbed appreciably from GI tract.  Not absorbed from skin or mucous membrane.  Mild to transitory nausea, vomiting, and diarrhea may occur after oral use. Antifungal Activity  Candida, Cryptococcus, Histoplasma, Blastomyces, Trichophyton, Epidermophyton, and Microsporum audouinii Therapeutic Uses Administered orally or topically for Candida infections of:  Skin - creams, powders, ointments.  Intestinal tract  Mucous membrane (vaginal tablets)

Fluconazole (Diflucan)

 appears to be less toxic than amphotericin B or flucytosine and better tolerated than ketoconazole.  Fluconazole appears to have a lower binding affinity for mammalian cytochrome P-450 enzymes than ketoconazole, but it may still increase serum concentrations of phenytoin (Dilantin; and others), cyclosporine, and oral hypoglycemic drugs, and potentiate the effect of warfarin, etc. Spectrum  cryptococcal meningitis  various forms of candidiasis.  in vivo against many systemic fungal pathogens, including Aspergillus, Blastomyces dermatitides, Candida albicans, Cryptococcus neoformans, Coccidioides immitis, and Histoplasma capsulatum. Pharmacokinetics  In comparison to ketoconazole, fluconazole is more water soluble, more reliably absorbed orally; only weakly protein bound.  Excellent oral bioavailability - better than itraconazole or ketoconazole; IV administration as well (more water soluble)  penetrates well into other body fluids, particularly cerebrospinal fluid (CSF)  Renal elimination Toxicity  Nausea, vomiting, diarrhea, abdominal pain, headache, rash, and modest elevations of aminotransferase activity.  fluconazole should be discontinued in patients with progressive hepatic dysfunction.  unlike with high dose of ketoconazole, the inhibition of testicular and adrenal steroidogenesis has not been a problem with fluconazole.  much fewer drug interactions than the other azoles - least effect of all azoles on hepatic microsomal enzymes.

Clotrimazole (Lotrimin®, Mycelex®, Gyne-Lotrimin®)

 like other azoles  Use - Candidiasis  May cause burning, local erythema.